POLICIES AND PROCEDURES MANUAL 2005 by nxx13296

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POLICIES AND PROCEDURES
         MANUAL
           2005




SPRINGFIELD COMMITTEE FOR
         RESEARCH
INVOLVING HUMAN SUBJECTS




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 POLICIES AND PROCEDURES OF THE SPRINGFIELD COMMITTEE FOR
        RESEARCH INVOLVING HUMAN SUBJECTS (SCRIHS)

This manual contains the policies and procedures that guide the Institutional Review
Board (IRB), or SCRIHS, and SIU School of Medicine (SOM) in carrying out their duties
and obligations for the protection of human subjects. It was written based on federal
guidelines and regulatory requirements of the Department of Health and Human Services
(DHHS), the Food and Drug Administration (FDA), and the Office of Human Research
Protections (OHRP), the HIPAA Privacy Rule, ethical codes such as the Belmont Report,
and the existing policies and procedures of the IRB.

This manual provides a description of the regulations, procedures, forms, and guidelines
for investigators, research staff, and IRB members. The manual is updated on a regular
basis.

                                TABLE OF CONTENTS

Section I: Ethical Principles that Govern the IRB – P.13

A. Belmont Report

B. Other Codes that Provide Ethical and Regulatory Guidance and Principles

C. The Common Rule

Section II: What is Human Subjects Research? – P. 15

Section III: Federal Regulations – P. 16

A. Federal Regulations

B. Federal Wide Assurance

Section IV: Responsibilities of Investigators and Subjects Rights – P. 17

A. Investigators’ Responsibilities

B. Research Subjects’ Rights

Section V: IRB Regulatory Authority and Governing Principles – P. 20

A. Mission of the IRB: To Protect Human Subjects Involved as Participants in Research

B. Authority of the IRB

C. What Research Should be Submitted to the IRB?

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D. IRB Relationship to Others

       1.   The Authorized Institutional Official
       2.   The Department Chairperson as an Affirmation of Study Submissions
       3.   Departmental Nominations for Service on the IRB
       4.   Support for the IRB Processes
       5.   Principal Investigators and Authorized Study Personnel
       6.   Sponsors and Contract Research Organizations (CROs)
       7.   SCRIHS Contact with Research Subjects
       8.   Regulatory Agencies

Section VI: Management, Operations, and Processes of the IRB – P. 24

A. The Management of the IRB

       1. IRB Membership - Overview
       2. Minimum and Maximum Number of Members
       3. Legal Counsel
       4. Appointment of IRB members
       5. Appointment and Use of Alternate Members
       6. Process and Notification of Appointment
       7. Removal from the IRB
       8. Affiliate Representatives
       9. Internal Consultants
       10. External Consultants
       11. New Member Orientation and Training
       12. Compensation of IRB Chairs
       13. IRB Member Liability Coverage
       14. Indemnification of Members

B. IRB Membership

       1. Leadership Responsibilities and Duties of the IRB Chair
       2. Responsibilities of the Vice Chair
       3. Attendance
       4. Continuing Education
       5. Review and Meeting Preparation
       6. Participation During the Meeting
       7. Reviews Outside the Meeting
       8. Conflict of Interest
       9. Voting
       10. Confidentiality of Reviews




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C. Other Participants and Roles at the IRB Meeting

       1. Role of SCRIHS Staff at Meetings
       2. Investigators/Visitors

D. The Operations of the IRB

       1.   Scheduling IRB Meetings
       2.   Agenda Deadline
       3.   Contents of the Box of Materials for Each Meeting
       4.   Time Frame/Delivery/Pickup

E. IRB Records and Retention Requirements

       1.   List of IRB Members and Qualifications
       2.   IRB Members and SCRIHS Staff Conflict of Interest Statements
       3.   Compliance Assurance
       4.   Written Procedures and Guideline
       5.   SCRIHS Website
       6.   Minutes of Meetings
       7.   Handwritten Notes and Meeting Documentation
       8.   IRB Retention of Documentation Other than Protocols
       9.   Study Files

F. The Functions of the IRB

       1. Continuing Review: Which Studies Should Be Reviewed More Frequently
          than Yearly?
       2. Determining that no Material Changes Have Occurred Since Previous IRB
          Review
       3. Insuring that Changes in Approved Research are not Initiated without IRB
          Review and Approval
       4. Insuring Prompt Reporting to the IRB of Unanticipated Problems or Scientific
          Misconduct Involving Risks to Subjects and Others

G. How is Discussion Handled about General Topics Not Related to a Specific Study?

H. Criteria for IRB Approval

I. Voting Requirements

       1.   Types of Votes
       2.   Quorum
       3.   Rescheduling IRB Meetings Because of a Loss of Quorum
       4.   Voting Rights of Alternate Members
       5.   Conference Calls

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      6. Conflict of Interest-Board Members Voting on Their Own Study

Section VII: Educational Requirements for Investigators and Staff Involved in
Human Subjects Research – P. 37

Section VIII: IRB Review, Approval, and Communication – P.38

A. Requirements for IRB Submissions

      1. Submission Overview
      2. Departmental Sign-off
      3. Site Management

B. The Review Process

      1.   Pre-review by Staff
      2.   Primary and Secondary Reviewer System
      3.   Conduct of the IRB Meeting
      4.   Discussion during IRB Meeting
      5.   Categories of Action Taken by the Board

C. Types of Submissions: Guidelines and Review Process

      1. New Protocol Submissions
         a. Full Board Review
         b. Expedited Review (Expedited Categories)
      2. Exempt Review (Exempt Categories)
         a. Regulations
         b. Categories of Exemption and Guidance on Each Category
         c. Types of Research Excluded from Exempt Review
         d. Review Process
         e. Duration of Exemption Certification
         f. Recruitment and Exempt Research
         g. Informed Consent and Exempt Research
      3. Amendments
         a. What is an Amendment?
         b. Federal Regulations
         c. What Do Investigators Need to Do to Submit an Amendment?
         d. What is Reviewed Administratively?
         e. What is Reviewed by the Committee?
      4. Adverse Events
         a. Overview and Regulations
         b. Definitions
         c. Categories and Requirements for Submission
         d. Observational or Outcome Studies
         e. Adverse Event Reporting Schedule

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         f. Review of Adverse Event Reports
         g. Reporting to the FDA and/or Sponsor
         h. Consequences of Not Reporting in the Required Timeframe or Incomplete
            Reporting
      5. Protocol Deviations/Violations
         a. What is the Protocol?
         b. Why is it Important that the Protocol be Followed?
         c. Examples of Protocol Deviations
         d. How to Report Protocol Deviations, Violations or Suspected Deviations
         e. Who Reports Protocol Violations?
         f. How the IRB Processes Protocol Deviations
         g. What Investigators and Stuff Can Do to Avoid Protocol Deviations
      6. Terminations
      7. Continuing Reviews
         a. Regulations
         b. When is a Continuing Review Required?
         c. What is Expected
         d. What to Report
         e. Collating Instructions for Continuing Review Submissions
         f. Letter of Justification for Continuing Review Submissions
         g. Turnaround Time After Review
         h. What are the Consequences of Not Responding?
         i. The Review Process

D. Administrative Review

E. Communication from the IRB

      1. How Does the IRB Communicate Various Actions to Investigators?
      2. What Do IRB Stamps Mean?

F. General Guidance for Investigators Working with the IRB and with SCRIHS Staff

      1.   General Guidance
      2.   Who Can Help Me?
      3.   Who Handles My Study Once it Has Been Submitted?
      4.   Deadlines
      5.   Guidance on IRB Submission Packet
      6.   Where Are the Forms I Need for Submission?
      7.   Can I Submit Forms Via the Web?
      8.   Turnaround Time
      9.   Responses to Pending Letters

G. IRB Decisions and the Appeal Process

      1. Investigators Attending the IRB meeting

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       2. What Does Disapproval of a Study or of an Amendment Mean? Can It Come
          Back as a New Study?
       3. Criteria for Appeal
       4. How the Appeal is Resolved

Section IX: Consent – P.72

A. Overview
   1. Participation in Research is Voluntary
   2. Disclosure of Benefits and Risks
   3. Federal Regulations and Guidelines

B. Constructing the Consent Form
   1. Elements of Consent
   2. General Guidance for Developing an Informed Consent Form
   3. Consent Forms for Studies Involving Children or Others Unable to Give Informed
      Consent
   4. Glossaries and Lay Language

C. The Consent Process
   1. Who Should Obtain Consent—Authorized Study Personnel
   2. PIs Role in Consent
   3. Training to Obtain Consent
   4. Taking the Consent Form Home Prior to Signing
   5. Debriefing
   6. Regulations about which Consent Form to Use
   7. Reconsenting Subjects when the Consent From has Changed
   8. Regulations about Signing and Storing Consent Forms
   9. Witnesses
   10. Consent by Someone Other than the Patient

D. Special Types of Consent and Additional Consent Templates
   1. Blood Withdrawal Qualifying for Expedited Review
   2. General Requirements for Blood Withdrawal
   3. Specific Requirements for Minimal Risk Blood Collection Qualifying for
      Expedited Review
   4. Specific Requirements for Minimal Risk Blood Collection Qualifying for
      Expedited Review Involving Children
   5. Conversion of Teaspoons, Tablespoons, Ounces, Milliliters (mls), Cups, Pints
   6. Oral Consent
   7. Children and Assent
   8. Pharmacokinetic Studies as Part of a Clinical Trial

E. Waiver of Consent
   1. Regulations and Overview



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     2. Examples of Situations Where a Request for Waiver of Consent Would Not Be
        Approved by the IRB

     3. Waiver of Written Informed Consent
           a. Verbal Consent and Script Still Required
           b. Passive Consent
     4. Waiver or Alteration of all Elements of Consent (no verbal and no written
        consent)
     5. Definition of Minimal Risk

Section X: HIPAA – P. 89

A. Summary of the HIPAA Privacy Rule
B. Policy Regarding the Use or Disclosure of Patient Data for Research
C. Written Authorization
D. De-identification
E. Waiver of Individual Authorization
F. Limited Data Set
G. Reviews that are Preparatory to Research
H. Research on Decedents
I. Research Recruitment under HIPAA
J. Accounting for Research Disclosures
K. Research Subjects’ Access to Research Records
L. Record Retention

Section XI: Subject Recruitment – P. 97

A.   What are Subject Recruitment Materials?
B.   Advertising Guidelines for Human Subject Recruitment Materials
C.   What Subject Recruitment Materials must be Reviewed by the IRB
D.   Procedures for Investigators
E.   Tone and Style of Recruitment Materials
F.   Recruiting Strategies and Methods
G.   FDA Rules on Recruitment and Payment for Study Subjects
H.   Inclusion of Women, Minorities and Children
I.   Use of Vulnerable Populations as Potential Research Subjects
J.   What is Coercion and Undue Influence?
K.   Competing Studies by the Same Investigator
L.   Recruitment Registries
M.   Disease Registries
N.   Contacting SIU Employees about Participation in Research Studies
O.   Accessing Student Information and Records
P.   Privacy and Confidentiality
Q.   Screening Patient Data
R.   Payment for Participation
S.   Compensation for Injury


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T. Incentives for Participation Other Than Payment
U. Lotteries
V. Reimbursement of Expenses
W. Extra Costs for Subject because of Study Participation
X. Finder’s Fees/KickBacks
Y. Guidelines on Press Releases and Recruitment: Media Relations Departments

Section XII: Special Issues – P. 108

A.  Cognitively Impaired Policy
B.  Children
C.  Fetuses, Dead Fetuses, Placenta
D.  Genetics and Consent
E.  International Research and Consent
F.  Research Involving Medical Students
G.  Non-English Speaking and Illiterate Subjects: Enrollment in Research Studies
    1. Regulations and Overview
    2. Obtaining a Certified Translation of the Consent Form for a Study
    3. Who Can Conduct the Consent Interview if the Subject is Non-English Speaking?
    4. How Does an Investigator Enroll a Subject who Unexpectedly Shows Up and
        Does Not Speak English?
    5. What About Illiterate Persons who Understand English but do Not Read or Do
        Not Read Well Enough to Understand the Consent Form Documentation?
    6. Are illiterate persons considered a vulnerable population?
H. Patient Information Sheets and Booklets
I. Photography and Recording
J. Secondary Data
K. Sensitive Information
L. Tissue and Blood Collection
    1. Surgical Waste and Extra Materials
    2. Storage for Future Use
M. Vulnerable Populations
N. Case Reports
O. International Research

Section XIII: IND’s, IDE’s, Treatment IND’s, Single Patient IND’s, Parallel Track,
General Transfer – P. 127

A. Investigational New Drug Applications (INDs)

     1.   What is an Investigational New Drug Application?
     2.   Overview
     3.   Types of INDs
     4.   How do I know if I do not need to submit an IND?
     5.   How does an investigator apply for an IND?
     6.   IRB Responsibilities


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B. Investigational Device Exemption (IDE) Application

   1.   What is a Medical Device?
   2.   What is an Investigational Device?
   3.   Significant Risk Devices
   4.   Non-Significant Risk Devices
   5.   FDA Guidance on How to Submit an IDE
   6.   What does the IRB do?

C. Off-Label (Unapproved Use of FDA-Regulated Products in Medical Practice versus
   research

D. Treatment INDs, Single-Patient INDs (also called Compassionate Use) and Parallel
   Track

   1. Treatment INDs
   2. Single Patient Use
   3. Parallel Track

E. Gene Transfer Research

Section XIV: Emergency Use and Humanitarian Use Devices – P. 134

A. Emergency Use Exemption for Drugs, Biologics, and Devices

   1.  Definitions and Regulations
   2.  How often can an Emergency Use Exemption be Used?
   3.  What If The Test Article Is Already Being Used In A Research Study?
   4.  How Is The Sponsor Involved?
   5.  What If The Sponsor Of The Drug/Device Will Not Grant The SIU Investigator
       Status As A Clinical Investigator?
   6. How is the FDA Involved? Obtaining an Emergency IND or IDE
   7. How is Emergency Use Used During Business Hours?
   8. How Is Emergency Use Used After Business Hours Or When There Is Not Time
       To Notify The IRB?
   9. Informed Consent and Emergency Use
   10. What If The Patient Cannot Give Prior Consent?
   11. Follow-up and After-use Procedures

B. Guidelines for Humanitarian Use Devices (HUD’s)

   1. What is a Humanitarian Use Device (HUD)?
   2. What is a Humanitarian Device Exemption (HDE)?
   3. Who Is Responsible For Ensuring That A HUD Is Not Administered To Or
      Implanted In A Patient Prior To Obtaining IRB Approval At A Health Care
      Facility?

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   4. What Types Of Reviews Are Irbs Responsible For With Respect To Huds?
   5. Does An IRB Have To Review And Approve Each Individual Use Of The HUD?
   6. What do I Submit to the IRB?
   7. Is Consent Required?
   8. Do I have to Submit a Continuing Review?
   9. Submitting Data Safety Monitoring Reports
   10. May The Device Be Used More Than Once Without Notifying The IRB Each
       Time?
   11. Other Resources

Section XV: Compliance and Quality Control – P.143

A. Compliance Policy

B. Procedures for Handling Noncompliance

C. Investigator Requirements for Organizing Regulatory and Research Documentation
   (Quality Control)

   1. Overview
   2. Basic Procedures for Maintaining Regulatory Documents
   3. Calendar Reminder
   4. Research Staff for Maintaining Regulatory Documents
   5. Regulatory Binders: Suggested Organization
   6. Consent Forms
   7. Subject Files
   8. Source Documents
   9. Case Report Forms
   10. Sponsor Documents
   11. Monitor Visits
   12. Getting Ready for an Audit – SCRIHS, FDA, Outside Mentor, OHRP, Other
   13. Conclusion
   14. Resources

Section XVI: Conflict of Interest Policy – P. 153

Section XVII: Social Science – P. 153

Section XVIII: Research in Foreign Countries – P. 155

Section XIX: Resources – P. 155

A. Ethical Codes

B. General IRB and Human Subjects Information



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C. Federal Agencies and Guidance

   1. DHHS Federal Regulations Governing Human Subjects
   2. Health Insurance Portability and Accountability Act (HIPAA)
   3. Guidance from Federal Agencies and Other Organizations

        a.   Center for Disease Control
        b.   Food and Drug Administration (FDA)
        c.   International Conference on Harmonization
        d.   Office of Research Integrity (ORI)
        e.   Veterans Health Administration (VHA)

D. Of Interest to Researchers and Human Subject Protections Protections Staff and
   Board Members

   1. Ethics Organizations
   2. Ethical Codes of Professional Organizations
   3. Listserv E-Mail Group

E. Special Topics

   1.   Mandated Reporting-State of Illinois
   2.   Minors/Emancipation-State of Illinois
   3.   Human Experimentation Resources on the Web
   4.   National Clearinghouse on Child Abuse and Neglect
   5.   Human Genome Study
   6.   AIDS Confidentiality Act-State of Illinois




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Section I: Ethical Principles that Govern the IRB

A. Belmont Report

The basic foundation for the ethical conduct of human subjects research at Southern
Illinois University School of Medicine, Memorial Medical Center, and St. John’s
Hospital is based on the principles described in the Belmont Report. The complete report
can be found at: (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/belmont.htm).

The three basic principles governing the ethical conduct of research involving human
subjects are outlined below and excerpted from the Belmont Report. The principles of
respect for persons, beneficence and justice are accepted as absolutely essential
requirements for the ethical conduct of human subjects research. These principles govern
the review and conduct of research at Southern Illinois University School of Medicine,
Memorial Medical Center, and St. John’s Hospital.

Respect for persons incorporates at least two ethical convictions: first, that individuals
should be treated as autonomous agents (that they have the right to make decisions for
themselves) and second, that persons with diminished autonomy (e.g., minors, prisoners,
and persons with cognitive impairment) are entitled to protection. This principle reflects
the need for proper informed consent, which must include all the essential elements of
consent and the additional elements (if applicable) as outlined in the federal regulations
(see Section IX.B1). Three elements crucial to the informed consent process are
information, comprehension, and voluntariness.

Beneficence, implies an obligation to protect human subjects from harm by assessing the
risks and benefits of the research. The anticipated benefits must be greater than the
anticipated risks in order to comply with this principle.

Justice requires that the research subjects be fairly selected through a process that
involves consideration of the purpose and expected outcome of the research. Selection
should include consideration of the subject as an individual and as a member of society
without regard to race, sex and ethnic group. The population of research subjects should
be similar to the population expected to benefit from the outcome of the research.

IRB policies are based on the following general ethical principles:

   1. The rights and welfare of all subjects must be adequately protected to safeguard
      the physical and psychological well being of a subject and the subject's rights of
      privacy and self-determination must be preserved.
   2. Risks must be minimized by using procedures that are consistent with sound
      research design and which do not unnecessarily expose subjects to risk.
   3. Risks must be reasonable in relation to anticipated benefits to subjects or to the
      importance of the knowledge that may be gained.




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   4. Recruitment and selection of subjects must be equitable within the context of the
       purposes and design of the study. Subjects must not be arbitrarily excluded on the
       basis of gender, age, race, national origin, religion, creed, education or
       socioeconomic status.
   5. If informed consent is required, it must be obtained from the subject or the
       subject's legally authorized representative prior to the subject's participation in
       any activity performed solely for research purposes.
   6. The informed consent process must be documented by a consent form signed by
       the subject and the investigator or other authorized study personnel, a copy of
       which must be given to the subject.
   7. The subject's consent must be based upon an understanding of the research
       including the risks and possible discomfort of the research, and alternative
       procedures that are available.
   8. The informed consent document must provide the subject with the ability to
       refuse participation or to discontinue participation at any time without prejudice.
   9. Provisions must be made to monitor data to ensure the safety of subjects.
   10. Adequate provisions must be made to protect the privacy of subjects and the
       confidentiality of data.
   11. Additional safeguards must be included in the study to protect the rights and
       welfare of subjects who are likely to be vulnerable to coercion or undue influence.
   12. Some professional organizations and societies have formulated their own
       guidelines for research involving human subjects. Such guidelines can supplement
       but do not supersede or diminish the protections and requirements outlined above.
   13. Local and state laws and regulations can supplement the protections and
       guidelines outlined above.

B. Other Codes that Provide Ethical and Regulatory Guidance and Principles

In addition, there are various other statements and declarations that support the ethical
principles and standards that are stated above. These statements include: the Declaration
of Geneva, the Nuremberg Code, the Helsinki Declaration and other documents which
guide the IRB and the researcher in conducting ethical research that protects human
subjects.

The list below will help investigators and IRB members with guidance on the ethical and
regulatory principles discussed above.

   •   World Medical Association Declaration of Helsinki: Ethical Principles for
       Medical Research Involving Human Subjects (amended October 2000)
       (www.wma.net/e/policy/17-c_e.html)
   •   DHHS Office for Protection from Research Risks ("OPRR") Institutional Review
       Board Guidebook (1993) (http://ohrp.osophs.dhhs.gov/irb/irb_guidebook.htm)
   •   DHHS Office for Human Research Protection ("OHRP"), Compliance Activities:
       Common Findings and Guidance
       (http://ohrp.osophs.dhhs.gov/references/findings.pdf)
   •   OHRP, "Dear Colleague Letters" (http://ohrp.osophs.dhhs.gov/dearcoll.htm)


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   •   FDA Information Sheets; Guidance for Institutional Review Boards and Clinical
       Investigators (www.fda.gov/oc/ohrt/irbs/default.htm)
   •   Good Clinical Practice in FDA-Regulated Clinical Trials
       (www.fda.gov/oc/gcp/default.htm)
   •   FDA International Conference on Harmonization, Guidance on General
       Considerations for Clinical Trials, 62 Federal Register 66113 (December 17,
       1997). (www.fda.gov/cder/guidance/1857fnl.pdf)
   •   International Conference on Harmonization, Good Clinical Practice Guidelines
       (www.ich.org)

C. The Common Rule

The Federal Policy for the Protection of Human Subjects is referred to as the Common
Rule. The Common Rule applies to human subject research across departments within the
federal government and is mandated by the Executive Branch of the United States.
Essentially the Common Rule is an agreement that all agencies within the federal
government will use the same federal regulations and definitions in determining the
applicability of human subjects protections. The provisions of the Common Rule are
identical to the DHHS Regulations (45 CFR 46, Subpart A).

Section II: What is Human Subjects Research?

RESEARCH is any systematic activity designed to develop or contribute to generalizable
knowledge.

To develop or contribute to generalizable knowledge requires that the results (or
conclusions) of the activity are intended to be extended beyond a single individual or an
internal program. Normally, research is reported at a professional meeting, or published
and distributed in a journal or through other media. Some systematic investigations may
not be research. For example, quality assurance studies for improving a service, if not
disseminated outside the local institution, usually are not considered research. Classroom
evaluations are also for "internal" purposes only and usually are not considered research.

Determining whether quality assurance, classroom evaluations, or demonstration studies
become research is based partially on the intent at the outset of the study. Does the
investigator intend to disseminate results beyond the local institution or to "generalize"
results to share with populations other than those studied? Will the results benefit others
beyond those in the local study? These questions must be considered when evaluating
whether activities may or may not be considered research.

Medical practice is not designed to contribute to generalizable knowledge; however,
medical treatment may generate information that is usable for research. Medical data
from the treatment of several persons, when used for an investigational purpose is an
activity designed to contribute to generalizable knowledge and therefore is considered
research.



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Social and behavioral science research covers many disciplines and methodologies. The
field employs a variety of methodological approaches including: surveys and
questionnaires, interviews, direct observation, physiological manipulations and recording,
descriptive methods, laboratory and field experiments, standardized tests, economic
analyses, statistical modeling, ethnography, and evaluation.

HUMAN SUBJECTS refers to living individuals about whom an investigator (whether
professional or student) conducting research obtains:

   1. Data through INTERVENTION or INTERACTION with the individual, OR
   2. IDENTIFIABLE PRIVATE INFORMATION.
   3. RETRIEVES RECORDED DATA

Definitions:

INTERVENTION includes both physical procedures by which data are gathered (e.g.,
venipuncture) and manipulations of the subject or the subject's environment that are
performed for research purposes.

INTERACTION includes communication or interpersonal contact between investigator
and subject.

PRIVATE INFORMATION includes information about behavior that occurs in a context
in which an individual can reasonably expect that no observation or recording is taking
place and information, which has been provided for specific purposes by an individual,
which the individual can reasonably expect, will not be made public (e.g., a medical
record). Private information must be individually identifiable, i.e., the identity of the
subject is or may readily be ascertained by the investigator or associated with the
information, in order for obtaining [or using] the information to constitute research
involving human subjects.

To determine is data being collected is IDENTIFIABLE PRIVATE INFORMATION,
ask the question "If I realize that I omitted a data point when I was reviewing a medical
record (or interviewing a subject) for my research data, can I go back to that record (or
that subject) to "fill-in" the omitted data point?" If the answer to that question is "Yes",
then the information collected was IDENTIFIABLE.

[Note: IRB approval is required not only during the period when patients are being
entered into the study, but for the entire time that PRIVATE INFORMATION about
study subjects is being collected/analyzed for investigational purposes.]

Section III: Federal Regulations

A. Federal Regulations

The IRB's authority to exist and act is guided by both ethical principles and Federal law.
The guiding ethical principles are embodied in the Nuremberg Code of 1947, the

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Declaration of Helsinki of 1950 and its subsequent modifications, the Belmont Report:
Ethical Principles and Guidelines for the Protection of Human Subjects of Research of
1979, and other appropriate ethical standards recognized by Federal Departments and
Agencies that have adopted the Federal Policy for the Protection of Human Subjects.

The U.S. Governmental Regulations empowering the IRB's activities are included within
the U.S. Code of Federal Regulations (C.F.R.) Title 45 C.F.R. 46 U.S., the Department of
Health and Human Services (DHHS) / Office for Human Research Protections (OHRP)
Regulations, including the "Common Rule" regulations that have been adopted by
multiple Federal agencies; and the FDA regulations included in Title 21 C.F.R. 50, 56,
312, and 812.

These regulations are summarized in Protecting Human Research Subjects - Institutional
Review Board Guidebook, OHRP, NIH, Bethesda, 1993 ISBN 0-16-041834-8.
(http://ohrp.osophs.dhhs.gov/irb/irb_guidebook.htm)

The application of this authority and these regulations apply to all research studies
conducted at Southern Illinois University School of Medicine regardless of funding
sources.

B. Federal Wide Assurance

SIU School of Medicine has an approved Federal-Wide Assurance with the Department
of Health and Human Service. Our Federal-Wide Assurance number is: FWA00003491.
The Assurance was approved on 10/7/2002 and will expire on 8/11/2008. Compliance
can be verified at the Office for Human Research Protections (OHRP) website at:
http://ohrp.cit.nih.gov/search/fasurdtl.asp?ASURIDENT=FWA00003491&Submit=SEA
RCH. The Federal-Wide Assurance requires that all research approved by SCRIHS meets
the requirements of the federal government for protection of human subjects regardless of
sponsorship and funding.

Section IV: Responsibilities of Investigators and Subjects Rights

A. Investigators’ Responsibilities

All investigators conducting research under the auspices of the Southern Illinois
University School of Medicine Institutional Review Board are responsible for the rules
outlined below.

   1. Study Design: In designing a study, investigators should consider the three
      underlying ethical principles for conducting research with human subjects: respect
      for persons (informed consent); beneficence (risk/benefit ratio); and justice
      (equitable selection of subjects).

   2. Study Conduct: Investigators are responsible for the ethical conduct of their
      research and the conduct of participating faculty, students, or staff. Faculty who
      supervise student research are responsible for ensuring that the students comply

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   with all Federal regulations and Southern Illinois University School of Medicine
   rules and guidelines, and hospital requirements.

3. Subject Protection: Investigators acknowledge and accept their responsibility for
   protecting the rights and welfare of human research subjects and for complying
   with all applicable federal and state regulations and guidelines; and all provisions
   of the Southern Illinois University School of Medicine Federal-Wide Assurance,
   regulations, and guidelines for the conduct of research.

4. Investigator and Research Staff Training: Investigators and research staff must
   participate in training and educational sessions provided by the University in
   order to become certified to conduct research with human subjects.

5. IRB Review: Investigators are responsible for ensuring that all research involving
   human subjects reviewed by SCRIHS prior to initiation of the research.

6. Exemptions: Investigators cannot make the final determination of exemption from
   applicable federal regulation nor provisions of the Assurance. The investigator
   must submit a request for exemption from human subjects review to SCRIHS and
   the validity of the claim for exemption will be reviewed administratively by
   SCRIHS.

7. IRB Decisions: Investigators are responsible for complying with all IRB policies,
   decisions, conditions and requirements. Investigators are responsible for ensuring
   that the research is implemented as specified in the approved IRB protocol.

8. Informed Consent: Unless otherwise authorized by the IRB, investigators are
   responsible for obtaining and documenting informed consent in accordance with
   federal regulations, using the consent form currently approved by the IRB. The
   use of expired or unapproved consent forms does not constitute valid consent.
   Each subject must be provided with a copy of the IRB-approved informed consent
   document at the time of the consent process. All original signed consent
   documents are to be retained by the Principal Investigator.

9. Informed Consent-Minors: Unless otherwise authorized by the IRB, investigators
   are responsible for ensuring that assent is obtained from research subjects who are
   minors and documented in accordance with IRB policies and requirements.

10. Changes in Research: Investigators will promptly report proposed changes in
    previously approved human subject research activities to the IRB. The proposed
    changes will not be initiated without IRB review and approval, except where
    necessary to eliminate apparent immediate hazards to subjects.

11. Continuing Review: Investigators are responsible for reporting progress of
    approved research to the IRB as often as, and in the manner prescribed by the
    approving IRB on the basis of risks to subjects, but no less than once per year.



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   12. Reporting Adverse Events and Protocol Deviations: Investigators will promptly
       report to the IRB any deviations from the protocol or any injuries, adverse events,
       or other unanticipated problems involving risks to subjects and/or others. Reports
       will follow federal guidelines for reporting as well as SCRIHS policies for
       reporting.

   13. Record Retention: Investigators are responsible for retaining and documenting
       research files and informed consent documents as based on University policy.

   14. Multi-center Trials: When other hospitals or institutions are participating in
       research protocols for which a Southern Illinois University School of Medicine
       investigator has primary responsibility, those institutions must possess an
       applicable Federal-Wide assurance prior to involvement of human subjects in
       those research protocols.

   15. Investigators must obtain approval of their clinical practice site(s); including but
       not limited to, Memorial Medical Center and St. John’s Hospital, prior to
       implementing studies approved by the IRB.

   16. Study Closure or Change of PI: The Investigator is responsible for notifying
       SCRIHS immediately of a change of Principal Investigator or of the closure of a
       study.
   17. If the federal government is auditing an investigator, it is the investigator’s
       responsibility to notify the SCRIHS office.

B. Research Subjects’ Rights

The following is a list of the rights of all research subjects involved in studies reviewed
and approved by SCRIHS. The research subjects have the right to:

   1. Be informed of the nature and purpose of the research study including why, when,
      where, and for how long they will be involved.

   2. Be given an explanation of the procedures to be followed in the research study
      and be given information about any drug or device to be used.

   3. Be given a description of risks to be expected from the study, if applicable.

   4. Be told about any frequently occurring side effects or discomforts that they might
      experience as a subject in this research study.

   5. Be given information on what medical treatment is available should complications
      arise as result of their participation in the research study.

   6. Be given a disclosure of any appropriate alternative procedures, drugs, or devices
      that might be advantageous to them, and their relative risks and benefits.


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   7. Be given an explanation of any benefits that they might reasonably be expected to
      receive from their participation in this study.

   8. Be given the opportunity to ask any questions concerning the research study and
      the procedures involved before, during and after the study.

   9. Be given an opportunity to decide to consent or not to consent to participate in a
      research study without the intervention of any element of force, fraud, deceit,
      duress, coercion or undue influence on their decision.

   10. Be instructed that consent to participate in the study may be withdrawn at any
       time and that they may discontinue participation in the study without prejudice to
       future treatment and without undue influence to continue participation.

   11. Be given a copy of a fully signed and dated consent form when one is required for
       the study.
   12. Be provided with information on who to contact if questions or problems should
       occur.

Section V: IRB Regulatory Authority and Governing Principles

A. Mission of the IRB: To Protect Human Subjects Involved as Participants in
   Research

   An Institutional Review Board (IRB) is a specially constituted administrative review
   board established for the purpose of protecting the rights and welfare of human
   subjects recruited as volunteers to participate in research. Southern Illinois
   University’s IRB is the Springfield Committee for Research Involving Human
   Subjects (SCRIHS). SCRIHS is responsible for reviewing all research involving
   human subjects, ensuring the equitable selection of research subjects, and overseeing
   institutional compliance with all federal guidelines and regulations related to research
   with human subjects. All research involving the collection of data from human
   subjects must be submitted to SCRIHS. The role of SCRIHS is to provide a service to
   the University and our affiliated hospitals (Memorial Medical Center and St. John’s
   Hospital) by facilitating ethical treatment of research subjects while at the same time
   supporting the investigator's endeavor to advance knowledge.

B. Authority of the IRB

The jurisdiction of the IRB (SCRIHS) is defined by agreements with the Federal
Government described in the Federal-Wide Assurance (FWA) and regulations formulated
by the institution with which it is affiliated.

SCRIHS has the authority to:

   •   approve, require modifications to secure approval of, defer action on, or
       disapprove research protocols involving human subjects;

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   •   require progress reports from the investigators;

   •   oversee the conduct of research;

   •   suspend or terminate approval of a study;

   •   place restrictions on a study;

   •   conduct reviews and audits regarding research activities as needed to obtain
       information necessary for the fulfillment of their responsibilities under the
       institutional assurances and provide information as needed to the Institution.

No research involving human subjects may be conducted within this Institution or its
affiliates without SCRIHS review and approval of the study prior to involving human
subjects. Federal regulation states: Research covered ... that has been approved by an
IRB may be subject to further appropriate review and approval or disapproval by
officials of the institution. However, those officials may not approve the research if it has
not been approved by an IRB (45 CFR S46.112).

No other office, department, committee or person competes with SCRIHS for its
authority to disapprove or modify research. Thus, SCRIHS is the final authority for
safeguarding human research subjects. Failure to have human research reviewed and
approved by this Institution's IRB is a violation of University policy, federal regulations
the Federal-Wide Assurance (FWA), and hospital policy. Faculty, staff, and students of
the institutions covered by the FWA may be subject to a misconduct inquiry if they
engage in research involving human subjects without prior SCRIHS approval.

C. What Research Should Be Submitted to the IRB?

Prior to implementation, SCRIHS must review and approve any study which involves
human subjects if one or more of the following criteria apply:

   1. The research is sponsored by SIU School of Medicine, or
   2. The research is conducted by or under the direction of any employee or agent of
      SIU School of Medicine in connection with his or her institutional
      responsibilities, or
   3. The research is conducted by or under the direction of any employee or agent of
      SIU School of Medicine, using any property or facility of this institution, or
   4. The research involves the use of SIU School of Medicine’s non-public
      information to identify or contact human research subjects or prospective
      subjects.

Investigators affiliated with Memorial Medical Center or St. John’s Hospital must have
research reviewed and approved by SCRIHS when the research conducted at either
hospital is under the direction of any staff member, is sponsored by, utilizes any property
or facility of, and/or is involved in the use of any non-public information of the SIU
School of Medicine.

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Federal regulations have established very specific guidelines as to how the review
process should be conducted. Based on the criteria defined in the federal regulations, a
submitted research proposal involving human subjects may be reviewed by SCRIHS in
three ways:

               a)     Full Board Review
               b)     Expedited Review
               c)     Exemption Certification

Although some research is exempt from IRB review, only the SCRIHS staff and SCRIHS
Chairman can determine whether a study is exempt.

D. IRB Relationship to Others

   1. The Authorized Institutional Official

   For matters relating to the execution of its duties and responsibilities, SCRIHS has
   direct access to the Authorized Institutional Official (Dean and Provost for the School
   of Medicine), or his/her designee, the Associate Dean for Research and Faculty
   Affairs.

   The Dean and Provost for the School of Medicine is the Authorized Institutional
   Official and, as such, is the signatory on the Federal-Wide Assurance. The
   Authorized Institutional Official delegates signatory authority to the SCRIHS Chairs
   and the Associate Dean for Research and Faculty Affairs.

   2. The Department Chairperson as an Affirmation of Study Submissions

   SCRIHS requires the department chairperson to confirm that the investigators
   (faculty, students or staff) within the department are qualified to perform the roles
   proposed for them in the research protocol, and/or that a qualified investigator will
   supervise them. The signature further confirms that required facilities and services are
   available, and that the researcher meets known Institution and sponsor eligibility
   requirements. It also represents a general acceptance of expressed or implied time
   commitments. When human subjects research is being conducted, chairpersons
   should understand the importance of commitment of adequate time and resources to
   follow IRB-approved procedures, thus ensuring the safety of research subjects.

   Chairs’ signatures must be original and cannot be delegated to departmental
   secretaries or other personnel. Under no circumstances may signature stamps be used
   since it is not possible to prove who reviewed and stamped the document. If a chair is
   out-of-town when a signature is needed, the signature can be submitted later or the
   vice-chair of the department may be designated as the signatory for IRB submissions
   on a short-term basis. Chairs should communicate to SCRIHS who has been
   designated as the signatory for their department for such short-term authority.



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In the event that an investigator does not have a chair, the primary reporting
supervisor should be the person signing the IRB submission. For example, if a person
works for an institute or research center and does not have a departmental
appointment, the Director of the institute or the research center should sign the IRB
submissions. If there are questions about who should sign an IRB submission,
SCRIHS should be consulted. If there is an exception made, all parties should
document the reasons for the designated signatory.

3. Departmental Nominations for Service on the IRB

Chairpersons, Professors, Committee members, and hospital Executives will assist in
the IRB membership process by nominating faculty and staff as prospective IRB
members. The process is discussed later in the section on IRB Committee
appointment.

4. Support for the IRB Processes

The IRB will keep investigators' chairpersons informed of cases of investigator
noncompliance with IRB policies and procedures.

Department Chairpersons are encouraged to request that the SCRIHS staff conduct
educational programs for members of their departments, or encourage members to
attend Institution-wide SCRIHS educational programs. Further, department
Chairpersons will receive reports of non-compliance with institutionally mandated
training programs.

5. Principal Investigators and Authorized Study Personnel

All authorized study personnel (persons with a role in the conduct of the research
study) should be listed on the Application for Approval. Other information required
to be outlined on this form is each person’s department, role in the study, role in the
consent process and expertise to be involved in the capacity stated.

The list of authorized study personnel involved in the research study may be different
(usually longer) than the key personnel list included in a federal grant. The list should
be updated continuously as new personnel are added. Because new personnel must
have completed the required human subjects training before working on a study, it is
important that the addition of staff be reported to SCRIHS promptly. All changes in
authorized study personnel as well as change of PI or Co-Investigators must be
reported as an Amendment Summary and the consent form changed accordingly.

Authorizations to Use and Disclose Protected Health Information (HIPAA form) that
also include co-investigators will have to be updated if there is a change in authorized
study personnel and they were previously listed on the authorization form.




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   6. Sponsors and Contract Research Organizations (CROs)

   All submissions should come directly to the principal investigator from the sponsor
   and then the principal investigator should forward the submission on to SCRIHS.
   When sponsors bypass the investigator and send materials directly to SCRIHS, the
   office is not sure if the investigators also received copies of the materials.
   Investigators should emphasize to sponsors and CROs that materials be sent directly
   the investigator's office first.

   Normally all contact with sponsors or CROs is through the Principal Investigator.
   Occasionally in order to expedite communication on important matters such as an
   emergency use issue or a protracted discussion about the language of a consent form,
   SCRIHS staff or the SCRIHS Chair will talk directly with the sponsor.

   In the event of issues of misconduct and study suspension, SCRIHS reserves the right
   to contact the sponsor regarding the events.

   7. SCRIHS Contact with Research Subjects

   Most contact between SCRIHS and a research subject involves a subject calling to
   file a complaint about their participation in a research study. Occasionally, subjects
   are contacted directly by SCRIHS if there are questions regarding the conduct of a
   research study.

   As part of the quality assurance program, SCRIHS may observe the consent process
   or other procedures involved in a research study.

   8. Regulatory Agencies

   As required by Federal regulations and by the Federal-Wide Assurance, the IRB will
   directly contact the appropriate governmental authority at OHRP and/or FDA
   regarding any questions or to file reports of reportable events, such as serious
   unexpected harm to subjects, serious or continuing investigator noncompliance, or
   termination or suspension of research protocols.

Section VI: Management, Operations, and Processes of the IRB

A. The Management of the IRB

   1. IRB Membership-Overview

   The Springfield Committee for Research Involving Human Subjects (SCRIHS) is
   composed of representatives from appropriate departments, divisions, and hospital
   affiliates which submit materials for IRB review. Members are also recruited for
   specific expertise, such as prisoner advocates, mentally handicapped representatives,
   etc. As required by federal regulations, a non-affiliated person or community member
   must also be assigned to the IRB.

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The provision of review expertise is one of the building blocks of a sound human
subjects protections program. The ability to review research protocols, understand
what "standard of care" is, and understand risks are some of the expectations for
potential board members. Those departments with a strong research component may
have more representation on SCRIHS. SCRIHS must include at least one member
whose primary concerns are in scientific areas and at least one member whose
primary concerns are in nonscientific areas.

SCRIHS must have a sufficient number of community members to assure that a
member is always present to conduct business. As required by federal law, an IRB
may not conduct business if a community member is not present. Community
members have a position on SCRIHS as full members and as such are encouraged to
participate as do University and hospital members. They represent an important voice
in the subject protections process and are encouraged to express their opinion at the
SCRIHS meetings.

2. Minimum and Maximum Number of Members

As required by federal law, the IRB must have a minimum of 5 voting members.
There is no maximum number of voting members. A quorum is represented by one-
half plus one of the total designated membership.

3. Legal Counsel

SIU has appointed a University lawyer to the IRB. The University Legal Counsel is a
voting member of the committee who is consulted any time there is a question
regarding federal and state law or regulations.

4. Appointment of IRB Members

Potential committee members are identified through a variety of sources including:

   a) Self-identification - a person expresses an interest in serving on the IRB.
   b) Nomination by current IRB members.
   c) Nomination by Department Chairs. This is particularly important in that
      departments submitting protocols for IRB review should have adequate
      representation on the IRB so that expertise is available for a thorough review.
   d) Nomination by SCRIHS staff.
   e) Suggestions by others either from the affiliates, the Dean's office, or other
      university departments.

Whenever there are changes to IRB membership, updated rosters are forwarded to
OHRP utilizing the processes provided for in the FWA regulations.




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5. Appointment and Use of Alternate Members

SCRIHS is made up of primary members and their appointed alternates. The
alternate’s area of expertise should be similar to that of their corresponding primary
member. The goal in appointing alternates is to maintain representation from the
primary member’s area of experience when the primary member is not able to attend
the meeting. Alternates also help to ensure quorum when primary members are
absent.

6. Process and Notification of Appointment

After consultation with the Associate Dean for Research and Faculty Affairs, the
SCRIHS Chair, and the supervisor of SCRIHS, notifies candidates who are qualified
and willing to serve on the SCRIHS committee of their appointment. New members
receive an appointment letter from the Dean. New members are also asked to submit
a current C.V. or resume for SCRIHS records, which will be kept with a copy of the
appointment letter.

7. Removal from the IRB

The Dean of SIU School of Medicine, the Associate Dean for Research for Research
and Faculty Affairs or the SCRIHS Chair may remove members from SCRIHS for
reasons such as failure to attend SCRIHS meetings, failure to do reviews in a timely
manner, and lack of efficient review.

However, such action is generally a consequence of repeated failure to maintain
duties and responsibilities despite oral and written notification from the Department
Chair or the SCRIHS Chair.

Members cannot be removed from SCRIHS because of their voting record, their
opinions pertaining to certain types of research, or in an attempt to alter SCRIHS
membership for the purpose of obtaining approval for a certain protocol or class of
protocols that have been disapproved previously.

8. Affiliate Representatives

SIU School of Medicine has affiliation agreements with Memorial Medical Center
and St. John’s Hospital. Due to the amount of research that is conducted at both sites,
each hospital is required to have two hospital representatives on SCRIHS.

9. Internal Consultants

Occasionally, when there is insufficient expertise on the committee to determine
whether a protocol should be approved as submitted, an internal consultant may be
requested. In this case, the committee will motion that an internal consultant be
identified and contacted for review of the protocol. The consultant is asked to write a
review and/or to respond to specific comments or questions from the committee.

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SCRIHS reserves the right to request an internal consultant at any time. Normally, the
principal investigator is not asked to suggest a consultant.

10 . External Consultants

Occasionally, when there is not sufficient expertise on the committee (or within the
SIU community) to determine whether a protocol should be approved as submitted,
an external consultant may be requested. In this case, the committee will motion that
an external consultant be identified and contacted for review of the protocol. The
consultant is asked to write a review and/or to respond to specific comments or
questions from the committee.

External consultants are used when the proposed research study is highly
experimental, presents a high degree of risk to the subjects, or presents questions that
cannot be answered by members of SCRIHS, or internal consultants.

SCRIHS reserves the right to request an external consultant at any time. Normally,
the principal investigator is not asked to suggest a consultant. External consultants
can be identified by experts who can suggest an appropriate reviewer for a particular
protocol. External consultants will not be paid.

11. New Member Orientation and Training

New members must complete a training course on the purposes and functions of the
committee, and conduct a review of their duties prior to reviewing proposals. Persons
who have served on an IRB previously may start reviewing studies sooner, if they
feel comfortable with the process.

New members are given the following materials in a welcome packet: a) The
SCRIHS Policies and Procedures Manual; b) the SCRIHS consent form template and
the NIH consent form template; c) the Code of Federal Regulations; d) the School’s
Assurance of Compliance with HHS Regulations; e) University of Rochester Manual,
“Protecting Study Volunteers in Research”; f) IRB member training packet; g) a copy
of a memo listing the scheduled meeting dates for the next year; and h) A Guide to
HIPAA.

After a person has agreed to serve on the SCRIHS committee, they attend one or two
IRB meetings without receiving items to review. If preferred, the individual can be
paired with experienced IRB members and sit next to them during the meeting. The
experienced member can serve as a mentor during these meetings.

The first several times a new member attends a meeting and is a designated reviewer,
the member will be assigned as a "secondary" reviewer, or be assigned to review
"low-risk" studies. A member of the SCRIHS staff will provide feedback and answer
any questions that the new member may have concerning his/her reviews.


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  12. Compensation of IRB Chairs

  Compensation for IRB chairs is negotiated with the Research Provost in consultation
  with the Dean. Compensation is negotiated annually based on the annual appointment
  renewal.

  13. IRB Member Liability Coverage

  Members are covered under the University's liability insurance program, insofar as
  their acts or omissions related to the IRB are concerned.

  14. Indemnification of Members

  All members of the IRB will soon be indemnified in their service on the IRB. This
  section will be updated as more information is received.

B. IRB Membership

  1. Leadership Responsibilities and Duties of the IRB Chair

  The attributes and responsibilities listed below have been found to promote effective
  leadership for an IRB Chair:

     •   The ability to conduct meetings of the IRB in an efficient and fair manner.

     •   The ability to set a tone of openness that encourages dialogue in IRB
         meetings.

     •   The ability to encourage community members to participate and to make them
         feel welcome, valued, and able to contribute.

     •   The ability to show respect for the diverse backgrounds, perspectives and
         sources of expertise of all IRB members, especially for the contributions of
         the non-scientists, and the ability to foster such respect among the IRB
         members.

     •   Attentiveness to the details and requirements of the Federal regulations and all
         other regulations that govern IRBs and human subject protections, and a
         skillful application of the requirements to foster ethically and scientifically
         sound research that protects human subjects.

     •   The confidence and courage to uphold IRB judgments that may not always be
         popular with principal investigators, department chairs, Deans, and other
         research staff.

     •   Investment of adequate time, interest and commitment to provide guidance
         and expertise to IRB members, scientists and others.

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   •   Participation in regular monthly IRB meetings.

   •   The ability to review problem protocols and to resolve issues when necessary.

   •   A willingness to step in and urge committee members to complete reviews in
       a timely manner or to actually do the review in instances when the reviewer
       has delayed the study.

(The National Institutes of Health requirement for IRB Chairs has provided a
framework for this list of responsibilities.)

2. Responsibilities of the Vice-Chair

Vice-Chairs are chosen from members already serving on the IRB. They are chosen
in consultation with the IRB Chair and the SCRIHS staff. Vice-Chairs convene the
IRB meetings when the Chair is unavailable. They may also be asked to review
problematic or complicated protocols that require additional input outside of the two
reviewers. Vice-Chairs are not necessarily "in training" to become Chairs. The Vice-
Chairs have approval and signatory authority if the Chair is not available or if the
Chair has a conflict of interest with a proposed study.

3. Attendance

Members are expected to attend the monthly SCRIHS meetings. Members who have
repeated difficulties attending monthly meetings will be required to meet with the
SCRIHS Chair to discuss their participation. If attendance continues to be a problem,
members will be asked to leave the committee.

If a SCRIHS member will not be able to attend a meeting, the SCRIHS office requires
at least two weeks notice. If SCRIHS staff does not receive notice, it is assumed that
all members are attending and staff will assign protocols to reviewers accordingly.
Once the agenda is finished and materials are distributed, it is very difficult to
reassign protocols to new reviewers, hence the need for two weeks notice.

Likewise, as a courtesy to the SCRIHS staff, IRB members are encouraged to provide
any advanced notice of scheduled absences (e.g., scheduled vacations, seminars,
symposiums). It is also extremely helpful to inform staff if a member is going to be
late to an IRB meeting, or if they need to leave early. This information helps facilitate
the meeting and assures compliance regarding quorums.

Business at the meeting cannot be conducted without a quorum. A quorum is half of
the membership of the panel plus one person. A quorum may be lost if too many
members leave the meeting early.

It is also important that members respond as soon as possible to the SCRIHS staff if
contacted about attendance.


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4. Continuing Education

Continuing education will consist of reading materials distributed to members, and
attendance at workshops/seminars offered by the SCRIHS office. Notices published
by the FDA and OHRP dealing with changes to policy, regulation, or law will be
distributed to members either via email or at the meetings. All members are expected
to participate in continuing educational opportunities provided to IRB members.

5. Review and Meeting Preparation

Members are expected to complete the review of the materials on the agenda prior to
the meeting. It is not acceptable to conduct reviews during the meeting. Members are
expected to complete the reviewer sheets when they are assigned as the primary or
secondary reviewer. The completed reviewer sheets and any other additional written
comments should be set aside or given to SCRIHS staff directly after the meeting.

6. Participation During the Meeting

Members are expected to:

   •   Participate actively in convened meetings.
   •   Be supportive of the community member's participation and help them
       whenever needed to explain protocols.
   •   Be prepared by having reviewed assigned protocols and other materials that
       are distributed.

7. Reviews Outside the Meeting

Members who request a "return to reviewer" status are expected to complete the
review in a timely manner.

Members who are the primary or secondary reviewer when a study is tabled are
expected to be available for the following IRB meeting to present and discuss the
resubmission. Members may be asked to review the resubmission more than one time.

8. Conflict of Interest

Members should notify the office if they are assigned to review a study which may
contain a conflict of interest. The SCRIHS staff tries to avoid this problem but may
not be aware of a conflict above and beyond being authorized study personnel for that
protocol.

Members should review the agenda prior to the meeting to ascertain if there are any
studies to be considered that include them as PI, Co-investigator, or in another role
that might present a conflict of interest.


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   In the situation where an IRB member has a conflict of interest with the study being
   reviewed, the member will be asked to leave the room, and will not be involved in the
   discussion and voting of that study.

   9. Voting

   Voting records are recorded to assure a quorum is in effect when decisions are made
   in IRB meetings. They are considered to be confidential records of the IRB and will
   not be shared with sponsors and others. The voting record of individual IRB members
   is kept confidential.

   10. Confidentiality of Reviews

   IRB members do not have to reveal that they reviewed a particular study, nor will the
   SCRIHS staff reveal who reviewed a study. If the reviewer wishes to identify
   himself/herself in the process of preparing the review to ask questions of the
   investigator, this can be done. Often problems can be solved ahead of time by
   discussing issues with investigators, yet reviewers are under no obligation to reveal
   their identity to the investigators. When a dialogue needs to occur with an
   investigator, either SCRIHS staff or the Chair of the IRB will handle the discussion if
   the reviewer does not wish to be involved.

   All IRB members are required to sign a Confidentiality Statement at the time they are
   appointed to the committee. The signed Confidentiality Statements are kept on file in
   the SCRIHS office.

C. Other Participants and Roles at the IRB Meeting

   1. Role of SCRIHS Staff at Meetings

   SCRIHS staff provides support for the IRB Chair and the IRB members during the
   meeting. Staff makes sure that reviewer's packets have been picked up and delivered.
   They set up the meeting room, provide dinner, and provide sufficient seating for all
   members and guests. They also manage the timing and flow of the meeting, assist the
   Chair in making sure all items on the agenda are discussed, manage conflict of
   interest, manage those coming and going from the room, ensure there is a quorum at
   all times during the meeting, take notes for minutes, and assist in any way possible to
   facilitate an efficient, effective, and compliant meeting. SCRIHS staff does not vote
   at the IRB meeting.

   2. Investigators/Visitors

   Investigators may ask to attend a meeting to discuss their study with the IRB. This
   generally occurs when a study has already been tabled at a previous meeting. The
   IRB may seek additional information and explanation from an investigator.
   Sometimes, when a large or complicated research program is planned, the IRB


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   benefits from a presentation about the program by the investigator. Investigators do
   not vote during the IRB meeting and are not present when votes are taken.

   Visitors are allowed at IRB meetings. This usually occurs when a person who is
   considering joining the committee wants to observe a meeting. If the Dean has not
   officially appointed the prospective new member, they are considered a visitor.
   Visitors must sign a Certificate of Confidentiality.

D. The Operations of the IRB

   1. Scheduling IRB Meetings

   IRB meetings are scheduled on the second Wednesday of each month. These dates
   are posted on the SCRIHS website at: www.siumed.edu/adraf/scrihs1.html. The
   meetings begin at 5:30 p.m., unless a situation arises where a quorum cannot be met
   or maintained. In that case, the meeting will be re-scheduled at the closest date where
   a quorum can be reached. At times, it is also necessary to re-schedule a meeting due
   to holidays.

   When there is reason to change a meeting date, the SCRIHS staff will send an email
   to all committee members and their secretaries (if that information has been
   provided). Members should respond as soon as possible. If the SCRIHS staff does
   not receive a response within 2-3 days of sending the email, we will attempt to
   contact the member by phone.

   2. Agenda Deadline

   The agenda deadlines are also posted with the meeting dates on the website. The
   deadline is always the last Wednesday of the month (unless the meeting date has been
   changed). Deadlines are firm and investigators must consider this when planning to
   prepare a submission and have it reviewed. No late submissions will be accepted.

   3. Contents of the Box of Materials for Each Meeting.

   All board members will receive copies of the meeting agenda, minutes from the last
   month’s meeting, and any other administrative matters that require full Board
   approval and/or discussion. In addition, members will receive copies of all
   previously tabled protocols, new protocols, amendment summaries, adverse events,
   and continuing reviews, which appear on that meeting’s agenda.

   The primary and secondary reviewers for each new protocol will receive a reviewer’s
   checklist attached to the front of their assigned protocol(s). This checklist should be
   completed and returned to SCRIHS staff by the end of the meeting. Reviewers will
   also receive copies of the Investigator’s Brochure or Tech Manuals for studies they
   are assigned to review that involve an investigational drug or device. When
   applicable, the reviewers will receive copies of additional literature or letters from
   governmental agencies associated with the protocol they are reviewing. In the case of

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   continuing reviews, only one reviewer is assigned and will receive a full copy of the
   protocol for the study; all other members will receive protocol summaries.

   4. Time Frame/Delivery/Pick-up

   The IRB members will receive their materials for review one week prior to the
   scheduled IRB meetings. These materials are delivered by campus mail in most cases.
   When this is not possible, SCRIHS staff will deliver the materials to the member’s
   designated site.

E. IRB Records and Retention Requirements

   1. List of IRB Members and Qualifications

   IRB member lists are maintained by SCRIHS staff. There are two lists: one for public
   presentation and one for office use. The list for public presentation is available on the
   SCRIHS website. This list may be copied and shared with sponsors or others
   requesting IRB membership rosters.

   C.V.s or resumes of IRB members are collected upon appointment to the IRB.

   2. IRB members and SCRIHS Staff Conflict of Interest Statements

   IRB members and SCRIHS staff sign conflict of interest statements on an annual
   basis. Copies of the signed conflict of interest statements are maintained in the
   SCRIHS office.

   3. Compliance Assurance

   The Institutional Review Board at SIU School of Medicine is duly constituted to
   comply with federal laws 45 CRF 46 and 21 CRF 50 and 56. Further, the SCRIHS
   office has reviewed the provided guidance regarding International Conference of
   Harmonization (ICH) Good Clinical Practice (GCP) guidelines for IRBs. The
   Springfield Committee for Research Involving Human Subjects (SCRIHS) operates
   in accordance with the laws, guidelines, and regulations listed above.

   Signed copies of this compliance assurance can be made available to sponsors and
   others requiring such certification by contacting SCRIHS.

   4. Written Procedures and Guidelines

   SCRIHS updates policies on a regular basis. Every attempt will be made to inform
   investigators of new policies.

   The manual is updated on the SCRIHS website. Updates are incorporated into the
   printed manual only once a year, unless warranted by a major change in regulations.


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Investigators will be advised to obtain changes to the manual from the SCRIHS
website.

5. SCRIHS Website

The SCRIHS website (www.siumed.edu/adraf/scrihs1.html) is the official distribution
point for policies, procedures, and forms for the IRB. Investigators and their research
staff are encouraged to check the website on a regular basis. Materials are updated as
new regulations are distributed or policies and procedures change.

The official forms for IRB submissions are on the website. It is expected that
investigators and their staff will use the most up-to-date version of forms and
procedures that are posted.

6. Minutes of Meetings

Minutes are prepared following the IRB meeting and distributed to Board Members in
the following month’s box of materials. After review, any necessary corrections are
made. The final version of the minutes will be kept on file in the SCRIHS office.
Minutes are confidential and are not available to the public for review. They are
available only to IRB members, SCRIHS staff, and Institutional officials unless
otherwise required by law.

7. Handwritten Notes and Meeting Documentation

Handwritten notes, agendas, and copies of the minutes are maintained in files in the
SCRIHS office. These files are considered to be a written record of the meeting.
Meeting files are retained for five years.

8. IRB Retention of Documentation Other than Protocols

The SCRIHS office documents any communication related to research protocols
between the PI or other research staff. This includes documenting phone
conversations, email, correspondence, etc. SCRIHS also documents communication
with IRB members, the IRB chair, Institutional authorities, governmental agencies
regarding protocol-related questions or problems, requests for guidance, issues of
misconduct or non-compliance, and any other information SCRIHS staff feels is
pertinent.

9. Study Files

IRB protocol files are maintained in the SCRIHS office while the study is active.
They are assigned an IRB protocol number. Investigator name and IRB protocol
number are used to organize files. Each additional study receives a new and distinct
number.



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   Investigators and Co-Investigators are able to access their SCRIHS study file with
   prior permission from the SCRIHS staff.

   When studies are terminated, the complete file is removed from active study files and
   placed in the terminated files. Terminated files from the previous year are kept in the
   SCRIHS storage room. After one year, terminated files are sent to microfiche for
   storage.

F. The Functions of the IRB

   1. Continuing Review: Which Studies Should Be Reviewed More Frequently
   than Yearly?

   The designated reviewer and the IRB panel, when reviewing a study on an annual
   basis, will make recommendations as to whether a study should be reviewed more
   than once a year. Factors that are considered include; the number of adverse events,
   the risk level of the study and if there have been protocol violations in the study being
   reviewed. Furthermore, uncertainty regarding the risk and efficacy of the study, or
   protocol violations in multiple studies by a single investigator can indicate that more
   frequent monitoring is required.

    The recommendation of how frequently a study should be reviewed is communicated
   to the investigator in writing.

   2. Determining That No Material Changes Have Occurred Since Previous IRB
   Review

   During the annual review, a complete analysis of the information contained in the
   continuing review form, consent form and protocol help determine if procedures or
   revisions have been implemented without IRB review. Additionally, audits of
   research sites are performed to substantiate information provided in the reports.

   At times, when the IRB reviews materials, they find changes that have occurred since
   the last IRB review. Such changes should be reported to the IRB before they are
   implemented. Investigators must be vigilant in submitting new procedures, new
   questionnaires, new dosages, or any other alterations to their studies prior to their
   continuing review.

   3. Insuring that Changes in Approved Research Are Not Initiated without IRB
   Review and Approval

   To remain in compliance with federal regulations, the IRB reminds investigators that
   study changes should not be initiated prior to IRB review and approval. Reporting
   revisions is a relatively simple process that is covered in training.




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   4. Insuring Prompt Reporting to the IRB of Unanticipated Problems or
   Scientific Misconduct Involving Risks to Subjects and Others

   Adverse events and protocol violation reporting are systems that are in place which
   assist the IRB in monitoring these facets of study activity. Adverse event and
   protocol violation information must be reported in a timely manner. The guidelines
   and forms for reporting can be found on the SCRIHS website. Investigators who have
   questions about what to report should discuss this with the SCRIHS staff.

G. How is Discussion Handled About General Topics Not Related to a Specific
   Study?

When the IRB has topics to discuss that are not related to a specific protocol (e.g.,
specific audit findings, investigator non-compliance, “Hot Topics” in IRB news,
humanitarian use requests, etc.) they generally reserve the early portion of the meeting
for that discussion. Because review of protocols is a priority, a time limit is often set to
review these topics.

H. Criteria for IRB Approval

To assure that a review is complete, the reviewers must carefully weigh the risks and
benefits of the study, whether vulnerable populations are included, and make other
considerations when reviewing proposed research. (Especially with FDA controlled
studies.) They must also be certain that certain elements are present in the informed
consent. These elements are based on federal guidelines. The Reviewers Checklist,
located on the SCRIHS website, will provide you with a list of those elements and
considerations.

I. Voting Requirements

   1. Types of Votes

   The Chair calls for a vote after the consideration of each study. The votes are
   recorded on the minutes/agenda worksheet maintained by the SCRIHS staff during
   the meeting. IRB members can vote yes, no, or abstain. Those who must leave the
   room because of a conflict of interest cannot vote on the study. In order to vote, IRB
   members must be in the meeting room or participating via conference call.

   2. Quorum

   The Board must have a quorum to conduct business. A quorum is half of the
   membership of a panel plus one person.

   If a quorum is not present at the beginning of the IRB meeting, the meeting cannot
   start. If a quorum is lost during a meeting, and it appears that it cannot be
   reconstituted, the meeting must stop and all study reviews must be held over until the
   meeting can be reconvened.

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   During the meeting, SCRIHS staff monitors when board members come and go to
   assure that a quorum is always in place while business is being conducted.


   3. Rescheduling IRB Meetings Because of a Loss of Quorum

   If quorum is not attained, or is lost, the meeting is rescheduled for a later time when a
   sufficient number of members are available to attend. SCRIHS staff will make every
   effort to reschedule the meeting the following week. Review packets are collected
   and redistributed as necessary.

   When the IRB approves some of the studies presented on the agenda while a quorum
   is present, the investigators will be notified of the Board’s decision in writing.

   4. Voting Rights of Alternate Members

   An alternate member may vote only when a regular member is absent.

   5. Conference Calls

   An IRB member who cannot be available in person can attend the meeting by
   conference call. This will be considered the equivalent of attending the meeting in
   person. They must participate in the entire meeting, if their participation is necessary
   for a quorum.

   6. Conflict of Interest — Board Members Voting on Their Own Study

   IRB members who are an investigator or authorized study personnel of a study being
   reviewed cannot participate in the discussion or vote. They will be excused from the
   room during the discussion and voting. However, before they are excused they can
   answer any questions the board may have. IRB members must be vigilant in notifying
   the IRB Chair about their participation or conflict of interest in studies listed on the
   agenda

Section VII: Education Requirement for Investigators and Staff Involved in Human
             Subjects Research

All persons involved in human subjects research that is reviewed by SCRIHS are
required to complete the SCRIHS education requirements prior to implementation of, or
participation in, a research study. Individuals must complete a SCRIHS training session
and test for initial certification. Once an individual has completed the initial education
requirements, they will be required to re-certify every 365 days. Final approval of a
research study will be delayed if any individual listed as an Investigator, Co-Investigator,
or Authorized Study Personnel (ASP) has not completed their SCRIHS education
requirements.


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This section will be updated with more detail once the education program is completed.

Section VIII: IRB Review, Approval and Communication

A. Requirements for IRB Submissions

   1. Submission Overview

   The IRB reviews research studies regardless of funding. Most sponsors and agencies
   will not release funds and some will not review proposals until the IRB has reviewed
   and approved the proposed research. SCRIHS cannot issue approvals until the
   submission has received a complete review and an approval letter is written. It is the
   responsibility of the investigator to allow sufficient time for submission and review.
   IRB deadlines are posted on the SCRIHS website at:
   www.siumed.edu/adraf/scrihs1.html

   2. Departmental Sign-off

   All IRB submissions originating at SIU School of Medicine require a departmental
   endorsement. Normally, the chair of the department is the signatory. Occasionally,
   the department chair may designate another person to sign IRB submissions in his/her
   absence. This must be discussed with the supervisor of SCRIHS and appropriate
   documentation must be in place if the Department Chair is not signing IRB
   submissions on a regular basis. Stamped signatures are not acceptable. Signatures
   must be original.

   3. Site Management

   When an investigator is the site manager for a multi-site study, he/she must submit
   the study as a separate submission (one submission for the site management portion
   of the study and one submission if SIU is a site on the study). The responsibilities of
   site management include ensuring that all sites are IRB compliant. Investigators who
   assume this role should have adequate staff to handle these tasks. Furthermore, they
   will be expected to report, at the time of the first continuing review, that all sites are
   in compliance. Investigators should seek guidance from SCRIHS about what is
   reportable and how to handle a submission of a site management study. Often, this
   means there are two submissions: one for the local site and one for the overall site
   management.

   Investigators must verify that all study sites are in compliance by collecting IRB
   approval letters from the others sites. The approval letters must indicate that the sites
   have approval from their local IRBs. In addition, site managers need to ensure that
   annual renewal takes place in a timely manner for all sites.




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B. The Review Process

   1. Pre-review by Staff

   SCRIHS staff will review all IRB submissions prior to sending them to board
   members. Submissions will be checked for completeness, use of consent templates,
   and other standard forms and language. They will alert investigators ahead of time
   when additional materials are needed to complete the submission. A checklist is used
   to determine that all elements of the consent form are present. Any attachments will
   be reviewed at this time as well.

   2. Primary and Secondary Reviewer System

   SCRIHS uses a primary and secondary reviewer system for all full-board new
   protocols and amendment summaries. All members of the committee will receive a
   copy of the following materials for each new protocol: HIPAA Application,
   Authorized Study Personnel form, protocol, consent form(s) (or waiver request) and
   HIPAA Authorization (or waiver request). The primary and secondary reviewers
   receive a copy of the materials listed above as well as a copy of the Application for
   Approval. When applicable the following may be included with a submission:
   recruitment materials, investigator's brochure or tech manual, questionnaire, patient
   information booklets, and other attachments. Reviewers are to review all the materials
   in a submission packet.

   Primary and secondary reviewers must complete a Reviewers Checklist for each
   protocol or amendment they review. In the meeting, the primary reviewer makes a
   presentation summarizing the study and then shares his/her comments about the
   study. The second reviewer may agree or disagree with the first reviewer and may
   add additional comments.

   3. Conduct of the IRB Meeting

   The SCRIHS staff checks the availability of a quorum. If a quorum is present, the
   IRB Chair convenes the meeting; at this time announcements are presented. The
   minutes from the previous meeting are presented, discussion is called for if necessary,
   then the minutes are voted on. If there are corrections to the minutes they are noted.

   The IRB Chair can order the agenda of the meeting to accommodate those who may
   have to leave early, visitors, investigators attending to discuss studies, and any other
   reason for reordering the agenda.

   The SCRIHS staff ensures all items are discussed and provides additional
   commentary when required. Staff will closely monitor the discussions of protocols.
   Notes taken by staff are used in collaboration with Reviewer Checklists to write the
   minutes and letters, which notify investigators of the Board’s conclusions.



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   Administrative amendments, adverse events, expedited studies and exempt studies
   that are processed by SCRIHS staff each month are reported in the minutes. These are
   presented at the following month’s meeting. Unless there is a question by a board
   member, these items are not usually discussed at the meetings.


   4. Discussion During IRB Meeting

   The key element to a good review is a meaningful discussion before the Board, about
   the study or submission. All IRB members should feel free to express their thoughts.
   Some studies require more discussion than others.

   The chair will assure that all IRB members who wish to speak have an opportunity to
   do so; however, the Chair has the right to limit discussion when redundancy occurs.

   5. Categories of Action Taken by the Board

   The categories of decisions the board can make when considering a submission of
   any type are as follows:

   •   Approved in the form submitted (no changes required)

   •   Approved pending revisions (Once the requested changes are made the Chair will
       sign for final approval. When submissions are approved pending revisions the
       investigator has ninety (90) days to make the required changes and return them to
       the SCRIHS staff. After ninety (90) days, the submission will have to return again
       for full board review.)

   •   Approved pending revisions and re-review by primary and secondary reviewers
       (once requested changes are made, the assigned reviewers will re-review. If
       changes are satisfactory, Chair will sign for final approval)

   •   Tabled (reasons for tabling can be scientific merit concerns, major changes to the
       consent form and/or protocol the committee would like made prior to re-review
       and/or major questions regarding the study that require the investigator to attend
       the next meeting and address the committee’s concerns. Tabled studies are not
       approved or disapproved but are studies that will be re-reviewed by the committee
       once changes are made or further clarification is received.)

   •   Disapproved (Investigator cannot implement the proposed study)

C. Types of Submissions: Guidelines and Review Process

   1. New protocol submissions

   The starting point for studies that require full-board or expedited IRB review is to call

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the SCRIHS office to request a new protocol number. After receiving a number the
investigator then begins filling out the Application for Approval Form.

The Application for Approval has been expanded, and to appropriately complete will
require attention to detail and knowledge about the study. It is usually not reasonable
to have a secretary or non-researcher fill out an Application. If investigators have
sufficient staff dedicated to handling submissions for the IRB, those staff may be
trained by SCRIHS staff on the most efficient ways to fill out these forms.

The Authorized Study Personnel section of the Application must be filled out
completely. This section aids the IRB in understanding who is involved in the
research study and what their roles and responsibilities will be. This section also
allows SCRIHS to verify that all involved persons have completed the required
human subjects research training.

In addition to the Application for Approval, the investigator should submit the
following (when applicable): a protocol, consent form(s), HIPAA Authorization,
questionnaires, advertisements; or other materials for subject recruitment, data
collection forms. For clinical studies an investigator's brochure, technical manual, or
other materials need to be included as well.

** The Application for Approval provides investigators with a list of exactly what
needs to be submitted for full board or expedited study as well as the necessary
number of copies. Investigators should follow the instructions carefully to ensure a
complete submission.

   a. Full Board Review

   Full board review is required for any research study involving greater than
   minimal risk.

   Full board review means that a legally constituted board with a quorum meets to
   consider submissions. The items presented may have one or two reviewers
   depending upon the type of submission. Board members receive copies of
   submissions prior to the meeting. These items are listed on the agenda.

   b. Expedited Review (Expedited Categories)

   If an investigator feels the proposed research study meets the criteria (listed
   below) for expedited review as set forth in 45 CFR 46.110 and the Federal
   Register, the study may be submitted to the SCRIHS office as an expedited study
   submission. The SCRIHS staff and IRB Chair will make a final determination if
   the study may be reviewed via the expedited process. If the SCRIHS staff and/or
   SCRIHS Chair determine that the protocol does not meet the criteria, the PI will
   be informed that the submitted protocol will need to go for full-board review.



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A research study may be reviewed by the expedited process if:

a) The research presents “MINIMAL RISK” to the human subjects. MINIMAL
RISK is defined as “the probability and magnitude of harm or discomfort
anticipated in the research are no greater in and of themselves than those
ordinarily encountered in daily life or during the performance of routine physical
or psychological examination or tests.”

AND

b) The involvement of human subjects meets one or more of the following
criteria specified by Federal Regulations (45 CFR 46.110):

Note that the expedited review process may not be used where identification of
the subjects and/or their responses would reasonably place them at risk of
criminal or civil liability or be damaging to the subjects’ financial standing,
employability, insurability, reputation, or be stigmatizing, unless reasonable and
appropriate protection will be implemented so that risks related to invasion of
privacy and breach of confidentiality are no greater than minimal.

1. Clinical studies of drugs and medical devices only when one of the following
conditions is met:
   • Research on drugs for which an investigational new drug application (21
       CFR Part 312) is not required.
       (Note: Research on marketed drugs that significantly increases the risks or
       decreases the acceptability of the risks associated with the use of the
       product is not eligible for expedited review.)

   •   Research on medical devices for which (i) an investigational device
       exemption application (21 CFR Part 812) is not required; or (ii) the
       medical device is cleared/approved for marketing and the medical device
       is being used in accordance with its cleared/approved labeling.

2. Collection of blood samples by finger stick, heel stick, ear stick, or
venipuncture as follows:

From healthy, nonpregnant adults who weigh at least 110 pounds. For these
subjects, the amounts drawn may not exceed 550 ml in an 8 week period and
collection may not occur more frequently than 2 times per week; OR

From other adults and children, considering the age, weight, and health of the
subjects, the collection procedure, the amount of blood to be collected, the
frequency with which it will be collected. For these subjects, the amount drawn
may not exceed the lesser of 50 ml or 3 ml per kg in an 8 week period and
collection may not occur more frequently than 2 times per week.



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3. Prospective collection of biological specimens for research purposes by
noninvasive means.

Examples: (a) hair and nail clippings in a non-disfiguring manner; (b) deciduous
teeth at time of exfoliation or if routine patient care indicates a need for
extraction; (c) permanent teeth if routine patient care indicates a need for
extraction; (d) excreta and external secretions (including sweat); (e) uncannulated
saliva collected either in an unstimulated fashion or stimulated by chewing
gumbase or wax or by applying a dilute citric solution to the tongue; (f) placenta
removed at delivery; (g) amniotic fluid obtained at the time of rupture of the
membrane prior to or during labor; (h) supra- and subgingival dental plaque and
calculus, provided the collection procedure is not more invasive than routine
prophylactic scaling of the teeth and the process is accomplished in accordance
with accepted prophylactic techniques; (i) mucosal and skin cells collected by
buccal scraping or swab, skin swab, or mouth washings; (j) sputum collected after
saline mist nebulization.

4. Collection of data through noninvasive procedures (not involving general
anesthesia or sedation) routinely employed in clinical practice, excluding
procedures involving x-rays or microwaves. Where medical devices are
employed, they must be cleared/approved for marketing. (Studies intended to
evaluate the safety and effectiveness of the medical device are not generally
eligible for expedited review, including studies of cleared medical devices for
new indications.)

Examples: (a) physical sensors that are applied either to the surface of the body or
at a distance and do not involve input of significant amounts of energy into the
subject or an invasion of the subject’s privacy; (b) weighing or testing sensory
acuity; (c) magnetic resonance imaging; (d) electrocardiography,
electroencephalography, thermography, detection of naturally occurring
radioactivity, electroretinography, ultrasound, diagnostic infrared imaging,
doppler blood flow, and echocardiography; (e) moderate exercise, muscular
strength testing, body composition assessment, and flexibility testing where
appropriate given the age, weight, and health of the individual.

5. Research involving materials (data, documents, records, or specimens) that
have been collected or will be collected solely for non-research purposes (such as
medical treatment or diagnosis).

6. Collection of data from voice, video, digital, or image recordings made for
research purposes.

7. Research on individual or group characteristics or behavior (including, but not
limited to, research on perception, cognition, motivation, identity, language,
communication, cultural beliefs or practices, and social behavior) or research



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   employing survey, interview, oral history, focus group, program evaluation,
   human factors evaluation, or quality assurance methodologies.


   There is no deadline for expedited submissions. Protocols that meet expedited
   criteria are assigned a primary and secondary reviewer from the committee. The
   materials are sent to the reviewers who are given two (2) weeks to review and
   return their comments to the SCRIHS staff. If both reviewers approve the protocol
   as submitted, SCRIHS staff will process the Application for Approval and return
   the original signed application and an approved stamped consent form (or a
   waiver approval if applicable) to the PI. If one or both of the reviewers request
   changes, the PI will receive a revision letter explaining the necessary changes. If
   one or both of the reviewers feel that the study needs to be reviewed by the full
   board, the PI will receive a written explanation of what will be necessary for the
   study to be placed on the next agenda.

   The Application for Approval provides investigators with a list of exactly what
   needs to be submitted for an expedited study as well as the number of copies.
   Investigators should follow the instructions carefully to ensure a complete
   submission.

2. Exempt Review (Exempt Categories)

   a. Regulations

   According to Federal Guidelines (45 CFR 46), research that presents little or no
   risk to human subjects (non-vulnerable subjects) does not require review by a
   convened Institutional Review Board. Although the study does not require full
   board approval, SCRIHS staff, in consultation with the IRB chair, must certify the
   exemption before the research study may commence. If the risks to human
   subjects appear questionable or the study does not fit into the federally defined
   categories for exemption as set forth is 45 CFR 46.101(b), SCRIHS will notify the
   investigator that he/she must submit the study as a new study, for either full board
   or expedited review.

   In some instances, researching sensitive topics or vulnerable populations cannot
   be certified as exempt. SCRIHS can help investigators determine what application
   to complete by discussing plans for the research study.

   b. Categories of Exemption and Guidance on Each Category

   The categories listed below are federally defined and listed in the regulation, 45
   CFR 46.101(b). Guidance on the category is offered in italics.

   1. EVALUATION/COMPARISON OF INSTRUCTIONAL
   STRATEGIES/CURRICULA


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Research conducted in established or commonly accepted educational settings,
involving normal educational practices, such as (i) research on regular and special
education instructional strategies, or (ii) research on the effectiveness of or the
comparison among instructional techniques, curricula, or classroom management
methods.

2. EDUCATIONAL TESTS, SURVEYS, INTERVIEWS, OR OBSERVATIONS
Research involving the use of educational tests (cognitive, diagnostic, aptitude,
achievement), survey procedures, interview procedures or observation of public
behavior, unless: (i) information obtained is recorded in such a manner that
human subjects can be identified, directly or through identifiers linked to the
subjects; and (ii) any disclosure of the human subjects' responses outside the
research could reasonably place the subjects at risk of criminal or civil liability or
be damaging to the subjects' financial standing, employability, or reputation.

Guidance on this category: This means that data must be collected without names
or other identifiers. Identifiers include birth dates, addresses, phone numbers,
medical record numbers, SSN, license numbers, IP addresses (internet protocol),
photographs, unique identification numbers, codes or other identifiers. (i.e., once
you collect your data, you should have no way of linking that data back to the
individual or the original data source.)

Observation of public behavior means that the researcher has no contact with the
subjects. For example, watching children play jump rope on a city playground
and recording their rhymes and songs but without talking with the children or
approaching them.

Exemption for survey and interview research does not apply to research in which
the subjects are children, except for research involving observation of public
behavior if the investigator does not participate in the activities being observed.

3. PUBLIC OFFICIALS OR CANDIDATES FOR PUBLIC OFFICE
Research involving the use of educational tests (cognitive, diagnostic, aptitude,
achievement), survey procedures, interview procedures or observation of public
behavior that is not exempt under the previous paragraph if: (i) the human
subjects are elected or appointed public officials or candidates for public office; or
(ii) Federal statute(s) require(s) without exception that the confidentiality of the
personally identifiable information will be maintained throughout the research
and thereafter.

Guidance on this category: An example of this category would be interviewing
persons running for office about their views on a topic.

4. COLLECTION OR STUDY OF EXISTING DATA
Research involving the collection or study of existing data, documents, records,
pathological specimens, or diagnostic specimens, if these sources are publicly


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available or if the information is recorded by the investigator in such a manner
that subjects cannot be identified, directly or through identifiers linked to the
subjects.

Guidance on this category: One factor to be considered is what access the
researcher may have to the identifiers. Often researchers propose that their
research assistant will de-identify the data for the researcher. This would not be
considered truly de-identified because the researcher could access the links, as
the employer of the research assistant. De-identification must be done by a party
who has no interest or involvement in the study. For example, a tissue bank can
truly provide de-identified samples to a researcher as the bank is set up as the
gatekeeper of the samples.

Publicly available data sets such as Medicare data, and other data for secondary
analysis fall in this category.

Additional guidance on the "Research Use of Stored Samples or Data" is
available at: http://ohsr.od.nih.gov/info/ninfo_14.php3

Additional guidance if your research is in the social science/behavioral area.
http://obssr.od.nih.gov/IRB/areyou.htm

5. RESEARCH & DEMONSTRATION STUDIES
Research and demonstration studies which are conducted by or subject to
approval of federal Departmental or Agency heads (such as the Secretary of
HHS), and which are designed to study, evaluate, or otherwise examine: (i) Public
benefit or service programs; (ii) procedures for obtaining benefits or services
under those programs; (iii) possible changes in or alternatives to those programs
or procedures; (iv) possible changes in methods or levels of payment for benefits
or services under those programs.

Guidance on this category: This is a fairly narrow category. A researcher cannot
declare his/her study a demonstration study unless it is officially classified and
funded in that manner. This means that a research study to find out whether the
local YMCA is delivering useful services to the homeless is not a demonstration
study unless it is funded by HHS or other federal agencies. Though the program
may provide public benefit, it is not funded by the federal programs that define
"public benefit."

6. FOOD QUALITY EVALUATION & CONSUMER ACCEPTANCE
STUDIES
Taste and food quality evaluation and consumer acceptance studies, (i) if
wholesome food, without additives are consumed or (ii) if a food is consumed that
contains a food ingredient at or below the level and for a use found to be safe, or
agricultural chemical or environmental contaminant at or below the level found to
be safe, by the FDA or approved by the EPA or the Food Safety and Inspection


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Service of the U.S. Department of Agriculture.

Guidance on this category: Surveys of college students about the dining hall
experience and taste testing in the college dining hall probably would be exempt
under this category.

c. Types of Research Excluded from Exempt Review

   •   Research involving pregnant women, and/or fetuses or human in
       vitro fertilization or the institutionalized cognitively impaired.
   •   Research involving other vulnerable populations.
   •   Medical Records review when identifiers are collected.
   •   Survey or interview techniques including minors as subjects.
   •   Techniques that expose the subject to discomfort or harassment
       beyond levels encountered in daily life.
   •   Research involving deception.
   •   Surveys about sensitive topics such as sexual activity, illegal drug
       use, or criminal activities or background.
   •   Use of recording devices: In the State of Illinois, data recorded on
       videotape, film, or tape recorder requires that consent for these
       procedures be documented using a consent form. In most cases an
       expedited or full review will be required if you plan to record
       (voice or film) subjects during data collection.

d. Review Process

Though the category of "exemption" means that the convened IRB will
not review the study, the SCRIHS staff and Chair do review the
application to determine if the study can truly be declared exempt under
Federal regulations.

All materials required for review must be submitted with the Exemption
Application. Exemption reviews and approvals are often held up because
of an incomplete submission that require SCRIHS staff to contact the
investigator and request additional materials. All materials submitted
provide clues as to whether a study can be declared exempt.

After the submission is completed, it takes 7 to 10 days to review and
process the application and letter. Often, investigators assume IRB review
is not necessary while the funding agency requires review. Please be sure
of the expectations and deadlines of your funding agency. Be sure to leave
enough time for the process. Research may not start until the approval
letter has been received.

Investigators who complete a study under an exemption should let the IRB
know that the study is no longer active.

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If changes are made to the study that might affect the certified exempt
status, the investigator should send a letter to SCRIHS (addressed to the
Chair) explaining the changes to the study. This letter will be noted by the
Chair and kept in the file. If the changes do affect the exempt status, the
investigator will be notified in writing and the appropriate action will be
taken.

e. Duration of Exemption Certification

An Exemption Certifications is valid for a five-year period. After that
time, if the research is still active, a new application should be submitted
to the SCRIHS office. Investigators are advised to close exempted studies
when the research has been completed.

When investigators submit continuation grants, a new exemption letter is
not generated. SCRIHS does not generate new letters for exempt studies
on an annual basis.

f. Recruitment and Exempt Research

Because of stipulations regarding the collection of identifiers in research
which meets exempt criteria, investigators need to be clear on the
recruitment strategy they wish to employ for collecting subjects for
research. Investigators cannot collect names or call persons back to
schedule interviews; they can't ask people to fill out demographic
questionnaires as a pre-screening mechanism to identify potential subjects;
nor can they review patient medical records to find individuals who
qualify.

g. Informed Consent and Exempt Research

Exempt research does not require informed consent to be obtained from
participants. However, there are times when an investigator will be asked
to give participants a letter or information sheet that explains the research.
Even if obtaining informed consent is not necessary in exempt research,
the participant will be provided with information that will allow them to
make a decision about participation. Information about the research study
can be provided in an informal manner, but should include the standard
elements of consent.

   •   Rationale for the study, brief description of research study.
   •   Explain what each subject will be asked to do and how long it will
       take.
   •   Describe who will be recruited and why they have been chosen.
   •   Emphasize that participation is voluntary.

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     •   Clarify issues regarding anonymous vs. confidential data
         collection.
     •   Describe incentives/compensation offered or costs that may be
         incurred.
     •   Explain any reimbursement for parking or other costs.

  Provide the name of the person conducting the research, the faculty
  advisor (if student researchers), the department, affiliation, and a
  telephone number for inquiries. Advise that subjects may call SCRIHS for
  information about subject's rights.

  Sometimes the information about the study can be delivered verbally and in this
  case, SCRIHS can request that a verbal script be submitted with the exemption
  application.

  Definitions:

  Human samples include blood and other body fluids, tissues, DNA.
  Human data include responses to questionnaires or surveys, medical histories
  and diagnoses.
  Source means the individual who provided the sample or from whom data were
  collected.
  Identified means samples or data that are still attached to a readily available
  subject identifier such as a name, social security number, address, telephone
  number, medical record number, or coded, etc.
  Coded means that collected samples or data are unidentified for research
  purposes by use of a random or arbitrary alphanumeric code but the samples may
  still be linked to their sources through use of a key to the code available to an
  investigator or collaborator.
  Unlinked means human data or samples that were initially collected with
  identifiers but, prior to research use, have been irreversibly stripped of all
  identifiers by use of an arbitrary or random alphanumeric code and the key to the
  code is destroyed, thus making it impossible for anyone to link the samples to the
  sources.
  Unidentified means that the samples or data were collected without identifiers of
  any kind. Samples or data may retain demographic or diagnostic information and
  still be considered unidentified if such information cannot be used to reveal the
  identity of the source.
  Existing means collected prior to the research for a purpose other than the
  proposed research. It includes data or specimens collected in research and non-
  research activities.

3. Amendments

  a. What is an Amendment?


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Amendments can be changes to subject selection methods, changes to a survey
instrument, the addition of more subjects, a major procedural change in the
protocol, increasing or decreasing dosages, leaving out or adding additional tests,
a change in the PI, Co- Investigator; or other Authorized Study Personnel,
amendments or notices from the sponsor, updated investigator's brochures,
changes to patient information booklets, new recruitment procedures, press
releases or media advertisements, changes to the risks, any deletions or additions
to the informed consent document, and more.

If there are any questions as to whether or not an Amendment Summary is
needed, call the SCRIHS office for guidance.

b. Federal Regulations

The Code of Federal Regulations (45 CFR 46.103b(4)(iii)) state that
written procedures are needed "for ensuring prompt reporting to the IRB
of proposed changes in a research activity, and for ensuring that such
changes in approved research, during the period for which IRB approval
has already been given, may not be initiated without IRB review and
approval except when necessary to eliminate apparent immediate hazards
to the subject.

If amendments are made on an emergent basis because of safety concerns,
this must be reported to the IRB immediately.

c. What Do Investigators Need to Do to Submit an Amendment?

All amendments must be submitted on the Amendment Summary form.
This form is available on the SCRIHS website.

The Amendment Summary form is set up to provide adequate information
for the SCRIHS staff so that they can completely understand the requested
change. The proposed change(s) should be clearly described. The current
procedure should be described together with the proposed change and the
reason for the change. In some cases the sponsor will provide a list of
changes, which includes a highlighted copy of the document. In that case,
the changes can be summarized on the Amendment Summary form with a
note such as “see attached changes”. Along with the list of the protocol
and/or consent changes, the PI will still need to submit full copies of the
protocol and/or consent, which reflect the changes.

Keep in mind, if the study is being implemented at one or both of the
hospitals, enough copies of all materials must be submitted for one or both of
the hospitals as well.




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For example, if the study is being implemented at both hospitals, the PI will need
to submit the following materials for an Amendment Summary:

   •   1 copy of the Amendment Summary form (signed by the PI)
   •   3 copies of the protocol and/or consent changes (list of changes or
       highlighted changes) for sponsored studies
   •   1 clean copy of the full protocol incorporating the changes
   •   4 clean copies of the consent incorporating the changes (1 for SCRIHS, 1
       for each hospital and 1 to stamp and send back to PI)
   •   3 copies of any other revised materials (advertisements, revised survey,
       updated Investigator Brochures, HIPAA forms, etc.)

d. What is Reviewed Administratively?

Amendments that do not substantially alter the protocol, the consent form, or
significantly change the risk/benefit ratio may be reviewed administratively.
Revisions of a minor nature, (e.g., minor changes to the protocol or consent,
changes in personnel, new telephone numbers, corrections, small increases in the
study population), are reviewed administratively. Investigator Brochures that do
not include new information on risks may be reviewed administratively. Changing
the PI can be reviewed administratively, provided the submission has a sign-off
by the relinquishing investigator.

Amendments that are reviewed administratively are stamped on the revised form.
An approval letter is not prepared.

e. What is Reviewed by the Committee?

Amendments that go to the IRB Board are those that raise new ethical concerns,
substantially alter the risks, or the consent form, introduce new procedures,
change dosages, substantially increase subject involvement, alter compensation in
some substantial way, and other similar types of changes. The sponsor or
Cooperative Group (in cancer studies) will indicate which amendments require
full board review. Also, the addition of any vulnerable populations (including
children) must be reviewed by the full board.

The SCRIHS staff and the IRB Chair reserve the right to refer any amendment to
the Board that they feel warrants full board review.

Amendments considered by the IRB receive an approval letter and a newly
stamped consent form when applicable. Investigators should note that a newly
stamped consent form does not alter the annual review date. The annual review is
the only time that the expiration date is altered.




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   Amendments may not be implemented until approved by the IRB, unless a
   protocol must be changed immediately to avoid harm to subjects. In this
   case, the amendment must be submitted immediately.

4. Adverse Events

   a. Overview and Regulations

   Federal regulations require investigators to promptly report to the IRB, in writing,
   any unexpected problems involving risks to subjects or others. Examples of
   adverse events include adverse reactions to drugs, medical devices or
   radioisotopes or any unexpected event associated with study procedures. Adverse
   events could have an impact on the risk/benefit ratio and may require the IRB to
   reconsider the approval of the study, require protocol modifications, or to review
   the study more than once a year.

   Reporting of Adverse Events applies to both clinical studies and social
   science studies.

   b. Definitions

   Associated with the drug/device/protocol - there is reasonable possibility that the
   experience may have been caused by the drug/device/protocol.

   Disability - a substantial disruption of a person's ability to conduct normal life
   functions.

   Life-threatening adverse experience - any adverse experience that places the
   patient or subject at immediate risk of death. .

   Serious adverse event - any adverse experience that results in any of the following
   outcomes: death, a life-threatening adverse experience, inpatient hospitalization or
   prolongation of existing hospitalization, a persistent or significant disability/
   incapacity or a congenital anomaly/birth defect or is considered medically
   important.

   Unanticipated adverse event - any adverse experience, the nature, severity, or
   frequency of which is not consistent with the current investigator's brochure, risk
   information described in the investigational plan, or consent form.

   Expected Adverse Event- any adverse experience, the nature, severity or
   frequency of which is consistent with the current investigator's brochure, risk
   information described in the general investigational plan, or consent form




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c. Categories and Requirements for Submission

Expected Serious Adverse Event

An adverse experience referring to any event in which the outcome is fatal or life-
threatening, causes permanent disability, requires in-patient hospitalization,
results in congenital anomaly, is considered medically important consistent with
the current investigator's brochure or risk information described in the general
investigational plan or consent form.

If the serious adverse event is expected as indicated by the applicable product
information, it MUST be listed as a risk in the “Risks” section of the Informed
Consent.

An Expected Serious Adverse Event MUST be submitted to the SCRIHS office.

If an Expected Serious Adverse Event occurs multiple times and is of a serious
nature, a re-evaluation of the overall risk/benefit ratio of the research protocol
may be necessary.

Unexpected Serious Adverse Event

An adverse experience referring to any event in which the outcome is fatal, life-
threatening, causes permanent disability, requires in-patient hospitalization,
results in congenital anomaly, or is considered medically important that is not
consistent with the current investigator's brochure, risk information described in
the general investigational plan, or consent form.

An Unexpected Serious Adverse Event MUST be submitted to the SCRIHS
office.

Expected Non-Serious Adverse Event

An adverse experience that does not refer to any event in which the outcome is
fatal or life-threatening, causes permanent disability, requires in-patient
hospitalization, results in congenital anomaly, or is not considered medically
important that is consistent with the current investigator's brochure, risk
information described in the general investigational plan, or consent form.

If the non-serious adverse event is expected as indicated by the applicable product
information, it MUST be listed as a risk in the “Risks” section of the Informed
Consent.




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An Expected Non-Serious Adverse Event DOES NOT need to be submitted to
the SCRIHS office.

Unexpected Non-Serious Adverse Event

An adverse experience that does not refer to any event in which the outcome is
fatal or life-threatening, causes permanent disability, requires in-patient
hospitalization, results in congenital anomaly, or is not considered medically
important that is not consistent with the current investigator's brochure, risk
information described in the general investigational plan, or consent form.

An Unexpected Non-Serious Adverse Event that is Definitely or Probably
Related MUST be submitted to the SCRIHS office.

Each event must be reviewed to determine if it has a relationship to the research
and whether or not it could be an untoward effect of the drug, device or a research
intervention.

Keep in mind, if the study is being implemented at one or both of the
hospitals, enough copies of all materials must be submitted for one or both of
the hospitals as well.

d. Observational or Outcome Studies

Observational studies include: research that does not involve intervention,
alteration in standard clinical care, or does not employ invasive or non-invasive
procedure in subjects. Studies limited to the recording of data on individuals
receiving standard medical care, the use of existing specimens or data, or the
retrospective review of health information are; for the purposes of this policy are
considered observational studies.

For observational studies, (e.g., studies that do not involve an intervention or
alteration in standard clinical care), adverse events DO NOT need to be reported
to the SCRIHS office. The events will be considered not related to the study itself.
However, if subject complaints arise from an observational study, the IRB should
be notified in writing of the subject's concern and how the concern was addressed.

e. Adverse Event Reporting Schedule

Expected Serious and Unexpected Non-Serious Events MUST be submitted to
the SCRIHS office within five (5) working days if it is a LOCAL event. If it is a
NON-LOCAL event, submit according to this schedule once the information is
received from the sponsor.




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Unexpected Serious Events MUST be submitted to the SCRIHS office within 48
hours if it is a LOCAL event. If it is a NON-LOCAL event, submit according to
this schedule once the information is received from the sponsor.

NOTE: The reporting schedule, as described above, does not relieve the
investigator of his/her sponsor’s requirements for earlier reporting.

Please be sure to specify whether the adverse event being submitted is local
or non-local and whether it is an initial report or a follow-up.

f. Review of Adverse Event Reports

Upon submission of the Adverse Event Form, it will be reviewed for timely
reporting. If the SCRIHS Chair feels the adverse event requires full board
consideration, the investigator will be notified by letter, and the adverse event will
be reviewed and the next convened SCRIHS meeting.

If the adverse event can be reviewed administratively, the SCRIHS staff will
process the report and the Chair will sign for approval. After the document has
been approved, a copy of the signed adverse event report will be mailed to the
principal investigator.

The SCRIHS office tracks all adverse events by protocol number. If SCRIHS
records show that a reported adverse event is being experienced multiple times
and is not listed in the consent form as a risk, the Chair may require that the event
be added to the consent form before new patients can be enrolled. The Chair also
holds the right to request that a risk be moved from a “Less Likely” category to a
“Likely” category if the adverse event has been reported multiple times. In some
cases, these situations may warrant re-consenting of previously enrolled subjects.

When a new risk must be added to the consent, or other changes are made to
current risks listed in the consent form, an Amendment Summary, highlighting
these changes, should accompany the revised consent form.

g. Reporting to the FDA and/or the Sponsor

It is the responsibility of all investigators to report Serious Adverse Events
(SAEs) to the sponsor (as described in the protocol) and/or the FDA. Such reports
must be made in a timely manner. These reports are generally different from the
reports to the IRB.

The IRB at the SIU School of Medicine delegates the investigator as the party
responsible for such reporting. Reporting regulations are described in 21 CFR
56.108(b)(1). For more information on who to contact at the FDA when reporting
a serious adverse event, use "Good Clinical Practice in FDA-regulated Clinical
Trials" at: www.fda.gov/oc/gcp/contactogcp.html.


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   h. Consequences of Not Reporting in the Required Timeframe or
   Incomplete Reporting

   As noted in the "Responsibilities of Investigators", reporting adverse events
   according to the listed time frames is a requirement of Investigators. Investigators
   who routinely report adverse events later than the prescribed time table or without
   sufficient information face possible sanctions.

   In studies with high risk, there are often many serious adverse events; and good
   compliance requires time and staff. Investigators must take this into account when
   starting a study.

5. Protocol Deviations/Violations

   a. What is the Protocol?

   A protocol is "a detailed study plan which specifies how a study will be
   performed." The protocol directs the research efforts of the sponsor and
   investigators by providing information and instruction on the background of the
   drug or device, objectives and rationale of the study, methods for implementing
   the study, and methods for analyzing results."

   b. Why is it Important That the Protocol be Followed?

   "Undetected protocol non-compliance may lead to incorrect decisions being
   made about the safety and/or efficacy of the product with adverse
   consequences for future patients."

   c. Examples of Protocol Deviations

   •   Non-adherence to exclusion and inclusion criteria
   •   Failure to comply with dispensing or dosing requirements
   •   Incorrect storage of study medications
   •   Use of prohibited concomitant medication
   •   Subjects not following the prescribed treatment cycle - not coming in a
       timely manner, yet still receiving drug
   •   Test requirements not being followed - either tests not done, incorrect
       tests done, or not done in a timely manner
   •   Failure to report Adverse Events in a timely manner
   •   Failure to follow specific instructions about subjects who terminate or
       withdraw - for example, final study visits required for safety reasons,
       or follow-up after the subject is off the medication
   •   Issues around the consent form and process - Failure to obtain consent
       prior to beginning of the study, failure to use the appropriate consent
       form, failure to use the currently approved consent form, failure to

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    update the consent form with new risks, failure to re-consent patients
    when new risks are known
•   Revising the consent form and using the revised form without IRB
    approval
•   Over-enrolling - adding more subjects than the number specified on
    the IRB submission form without receiving approval to enroll
    additional subjects
•   Using a protocol as an umbrella - having a vague description in the
    protocol submission and using that to allow a variety of tests or
    procedures that go beyond a simple consent form
•   Failure to follow the statistical plan
•   Failure to amend the protocol and inform the IRB through the revision
    process before revisions are implemented and failure to document
    changes in the protocol in a systematic way
•   Failure to document deviations from the protocol agreed upon by the
    sponsor and investigator for specific patients

d. How to Report Protocol Deviations, Violations or Suspected
Deviations

Use the Protocol Deviation Form which is available on the SCRIHS
website.

Deviation Description: What occurred? Describe the incident fully. If
appropriate, identify the patient with initials. Give a date when the
incident occurred.

Explain Why the Deviation Occurred? For example: Was the
coordinator new and unfamiliar with the protocol? Was the investigator
unavailable and not offering guidance? Did the pharmacy dispense the
wrong drug?

Outcome: Describe what happened. What remedies were taken to rectify
the deviation? For example, if the wrong drug was given, did someone call
the patient and tell them?

Harm to Subjects: Were any subjects harmed by the deviation? How do
you know? Was an Adverse Event report also filed with the IRB?

Sponsor Response: Was the sponsor notified? When? Did the sponsor
document this event? Did the sponsor suggest how to avoid this in the
future? Forward the appropriate documentation to the IRB for review.

Preventing Future Occurrences: Explain what will be done to prevent
this from happening again.


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e. Who Reports Protocol Deviations?

•   Self Report - Principal Investigator and staff
•   Monitor or auditors find them and they are reported
•   Whistleblower reports
•   Patient reporting

f. How the IRB Processes Protocol Deviations

SCRIHS staff will divide protocol deviations into two categories, those of
a minor nature, and those of a more serious nature. Minor deviations are
reviewed administratively by the SCRIHS staff and signed by the IRB
Chair for final approval. In the process of the initial review, SCRIHS may
ask for additional information to clarify specific elements of the deviation.

Protocol deviations of a more serious nature are forwarded to the IRB for
review and discussion; where a decision will be made on what actions to
take. Depending on the seriousness of the violation, remedies are
considered that will help the investigator not jeopardize subject safety, be
in compliance in the future, and understand the regulations.

If the investigator provides a valid action plan to assure that the deviation
will not occur again, the Board may simply acknowledge and accept the
receipt of the Deviation. In the case of multiple offenses, the IRB may
recommend training for study staff and the investigators. SCRIHS staff is
available to meet with study personnel to review requirements,
procedures, study records, and compliance issues in general may provide
training. Other times the IRB may recommend that training be conducted
at an accredited training facility outside the School of Medicine. It is also
the right of the IRB to audit an investigators study files and procedures to
identify and rectify potential problem areas.

If the violation is extremely serious, the investigator may be contacted to
discuss the issue with the Board or the IRB Chair

g. What Investigators and Study Staff Can Do to Avoid Protocol
Deviations

Everyone involved in the study should be familiar with the protocol and
fully understand their role in the study. The delegation of tasks should be
perfectly clear to all personnel. The PI is the responsible party and must
understand his/her role in control and conduct of the study.

Research staff should have a procedure in place for discussing protocol
deviations. Investigators should have procedures in place for handling
protocol deviations as they occur. For example: What kind of

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   documentation will the sponsor require? Who will notify the IRB? What
   remedies are considered for common protocol deviations?

   Be sure the investigator and research staff is familiar with the regulations
   regarding protocol deviations.

6. Terminations

When a research study has been completed, a Termination Form must be
submitted to SCRIHS. A Termination Form can be submitted at any time.

The Principal Investigator should not delay the process of terminating a study to
coordinate with the time that a continuing review is due.

If a study is industry-sponsored, normally the company will provide a “close-
out” letter indicating that the study may be closed with the IRB. Often a
“close-out” visit will occur with a monitor reviewing the study files ensuring
all records are complete. If the study is federally sponsored and a multi-site
study, the Data Coordinating Center is responsible for indicating when the
study may be closed at the local site. Sometimes studies (multi-site) are closed
when data is still being analyzed at a national level. When a study is closed
locally there is a "data lock" on the data gathered and the data will be turned
over to the Data Coordinating Center or study sponsor. If investigators are
uncertain about whether to close the study, they can discuss this with SCRIHS
staff.

Termination Forms will be reviewed and approved administratively by the
SCRIHS staff and IRB Chair. Investigators will receive a signed copy of the
Termination Form once it is approved.

Following the termination of a study, study materials must be stored for the
time specified by the sponsoring agency or per GCP guidelines. This ranges
from a minimum of three years up to seventeen years depending on the type of
study, the sponsor, and the FDA regulations regarding drug studies.

Definition of Termination:
No further contact with human subjects is planned; no subjects are or will be
treated or followed; all data are gathered and analyzed; and any final reports
or publications are complete. Subsequent use of any data from this study will
require a new submission to the IRB.

Suspension or Termination of IRB Approval: It is the responsibility of the
investigator to report administrative suspension or termination of IRB approval
as directed by 21 CFR 56.108(b) to the following FDA Offices if appropriate:

For Drug Products: Division of Scientific Investigations (HFD-45)

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Office of Medical Policy
Center for Drug Evaluation and Research
7520 Standish Place
Rockville, MD 20855
Phone: 301-594-0020 Fax: 301-594-1204

For Biologic Products: Bioresearch Monitoring Branch (HFM-664)
Division of Inspections and Surveillance
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research/FDA
1401 Rockville Pike, Room 400S
Rockville, MD 20852-1448
Phone: 301-827-6221 Fax: 301-827-6748

For Medical Devices: Division of Bioresearch Monitoring (HFZ-310)
Office of Compliance
Center for Device and Radiological Health (CDRH)
2094 Gaither Road
Rockville, MD 20850
Phone: 301-594-4718

7. Continuing Reviews

   a. Regulations

   The requirement for continuing review and the criteria are defined in two
   regulations: DHHS 45 CFR 46.109(e)
   http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.109
   and FDA regulations: 21 CFR 56.111
   www.fda.gov/oc/ohrt/irbs/appendixc.html.

   Additional guidance is available at:
   http://ohrp.osophs.dhhs.gov/humansubjects/guidance/contrev2002.htm.

   b. When is a Continuing Review Required?

   A continuing review is required at least once a year. Depending upon the
   evaluation of risk/benefit ratios and other monitoring, the IRB has the
   right to request a review be conducted more than once a year. When an
   investigator receives an approval letter for a new study, the review period
   is given in the letter. If the approval period is for less than a year, it is
   because there are concerns regarding risks to the subjects that the IRB
   would like to monitor closely. The approval period may also be shorter
   than one year if an investigator has had incidence of non-compliance. The
   approval time period is determined by the IRB on a case-by-case basis.

   IRB approval must be maintained as long as human subjects are, in any
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way, involved with the study. Therefore, until long-term follow-up, long-
term data collection, or data analysis is completed, the study must
continue to be submitted for continuing review.

Federal regulations do not allow for any extension or "grace" period
in extending a study beyond the expiration date.
c. What is Expected

It is the responsibility of the investigator to submit the continuing review
before the expiration date. Waiting until the last possible review date to
submit puts your study at risk for expiration. It’s possible that the study
will not be placed on the agenda due to an incomplete submission, or it
could be reviewed and expire due to the time required to address issues or
concerns brought up by the Board. Investigators are encouraged to make
sure there is adequate time for review and changes.

A reminder: In order to be reviewed prior to the expiration date, the study
must arrive in the office by the deadline of the meeting that PRECEDES
the expiration date, or earlier.

SCRIHS will make a reasonable effort to notify investigators 60 days prior
to the expiration date (first notice) that the study is due for review.
Notification letters are sent by mail. Upon receiving the notification,
investigators should immediately begin preparation of the periodic review
form for submission. If there is no response to the first notice, SCRIHS
will make a reasonable effort to send a second notice 30 days prior to the
expiration date. In the week preceding the expiration of the study or
shortly thereafter, SCRIHS will send a termination notice to the
investigator.

This termination notice must be signed by the investigator and returned. If
a study inadvertently expires, and you wish to continue your research, you
must resubmit the expired study as a new study.

Investigators are required to include the last two patient signed consent
forms with their continuing review submission. This requirement can
provide the investigator with an opportunity to be sure that study files are
in order, which includes checking that there are signed consent forms for
each participant.

The SCRIHS consent template is updated periodically throughout the year.
These changes can be a consequence of a change in regulations, attempts
to bring greater consistency to the consent form template, and the
introduction of new topics. The IRB requires investigators to use the most
current consent form template; therefore, it is required that investigators
update their consent form each year to ensure the most current consent


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template posted on the SCRIHS website at the time of continuing review,
is being utilized.

d. What to Report

The Continuing Review Form outlines all the items that are needed when
filing a continuing review submission. They include updating study sites, a
summary of progress to date, the most currently approved consent form,
an update on subject enrollment, a summary of Amendments, a summary
of Adverse Events, request for any new literature, documentation from any
external auditing, etc. In addition, investigators are asked to update the
personnel section of the form and submit it with their continuing review.
All individuals working with human subjects must complete SCRIHS
training and an updated personnel list in the study files allows SCRIHS to
ensure that all personnel have completed training.

e. Collating Instructions for Continuing Review Submissions

Please clip each individual packet together -

22 Packets will have the following:
One (1) copy of the completed Continuing Review Statement
One (1) clean copy of the most currently approved Informed Consent Form *
One (1) copy of the Authorization to Use and Disclose Protected Health
Information for Research Purposes *
One (1) copy of the protocol summary
One (1) copy of any attachments
One (1) copy of any publications

The 23rd packet will have the following:
One (1) copy of the completed Continuing Review Statement
One (1) clean copy of the most currently approved Informed Consent Form *
One (1) copy of the Authorization to Use and Disclose Protected Health
Information for Research Purposes *
One (1) copy of the protocol summary
One (1) copy of the complete protocol
One (1) copy of the Investigator’s Brochure (If issued since last continuing
review date and has not been approved administratively)
One (1) copy of any attachments
One (1) copy of any publications
Leave a note indicating that this is the 23rd packet

The 24th packet will have the following:
The original completed Continuing Review Statement
Four (4) clean copies of the most currently approved Informed Consent Form *



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Four (4) copies of the Authorization to Use and Disclose Protected Health
Information for Research Purposes. *
One (1) Copy of the last two (2) signed Informed Consent Forms
One (1) copy of the protocol summary
One (1) copy of any attachments
One (1) copy of any publications
Leave a note indicating that this is the 24th packet

* If enrollment for your study has been completed, you will not need to
submit any Informed Consent Forms OR Authorizations to Use and Disclose
Protected Health Information for Research Purposes.

f. Letter of Justification for Continuing Review Submissions

If your study has had SCRIHS approval for three (3) consecutive years or more,
has no subjects enrolled, and is now up for its fourth year (or more) continuing
review, you need to submit a letter of justification with your continuing review
materials. This letter should address the following points:

               1. Reasons for lack of subject enrollment
               2. Future plans for the study
               3. Adequate justification for the study to remain open

This letter will be your means of convincing the committee that your study should
not be administratively terminated. If the justification is not adequate, in the
committee’s opinion, you will be allowed a second chance to defend your
position. If the committee decides again that this justification is inadequate, your
study will be terminated. If your study has had approval for three (3) years
consecutively without enrollment and you do not send a letter of justification,
your study will be automatically terminated.

You must submit 24 copies of your letter, collated with the copies of your
required continuing review materials.

g. Turnaround Time After Review

If continuing reviews are submitted in a timely manner, they will not
expire before the IRB has an opportunity to review them. If changes have
been requested, the investigator will receive a letter explaining the
necessary changes. If the continuing review is approved as submitted, the
investigator will receive the original continuing review form with the
Chair’s signature. They will also receive a consent form stamped with the
new approval and expiration dates. Upon receipt, study staff should
discard old consent forms, and immediately begin to use the newly
stamped consent forms.



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h. What Are the Consequences of Not Responding?

The Federal Regulations mandate that all studies be reviewed by the IRB
at least once every calendar year. No provisions are provided for
extending a study beyond the expiration date. It is important that deadlines
regarding periodic review submissions be observed. The volume of studies
reviewed by the IRB is such that it is important to submit as soon as the
first notice is received.

Failure to maintain current approval may disqualify data from being
accepted by a sponsor. Further, the IRB may place sanctions on the study,
including the use of data gathered after the expiration date is passed.

For the safety of patients receiving medications or other interventions, it is
important that continuing approval be maintained. If the study expires, the
study is effectively closed, whether or not a notice is received from
SCRIHS. The expiration date on the consent form is also an effective tool
in monitoring when your study expires. When the investigator realizes that
the study has lapsed, he/she should notify SCRIHS immediately for
instructions on how to proceed. A new study submission must be prepared
and submitted if the study expires and the investigator wishes to continue
with the research. Until that application is reviewed and approved, no
further research may be done.

Performance of study procedures during a lapse in approval may result in
sanctions for the investigator. Under no circumstances should an
investigator continue to do research. Because there are no active consent
after a study expires, there is no possible way to legally obtain informed
consent. ALL RESEARCH MUST STOP.

Data gathered during the time period when a study has lapsed may not be
used in the data analysis without special consideration by the IRB.
Investigators wishing to use the data will have to make a special request to
the IRB. Since gathering the data during the lapse is a serious violation of
federal guidelines, regarding human subjects, the IRB is usually not
comfortable allowing investigators to use the data.

Please note that an expired study takes additional time for all concerned
parties. Further, the IRB is concerned that studies that are abruptly closed
may impact the health and safety, and the willingness of subjects to
participate. Investigators must be vigilant and be sure that studies do not
expire.

i. The Review Process

Federal guidelines recommend that a "substantive and meaningful" review


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       be undertaken at the time of continuing review. A study usually merits the
       same level of review in continuing review as it received originally. As in
       the initial review, the IRB may require revisions in the protocol or the
       consent documents.
       What is a meaningful and substantive review?

       The criteria for continuing review are defined in 21 CFR 56.111 and
       include:

       •   Risks to subjects are minimized;
       •   Risks to subjects are in relation to anticipated benefits;
       •   The selection of subjects is equitable;
       •   Informed consent will be utilized and documented appropriately (if a
           waiver was not granted);
       •   When appropriate, the privacy of subjects and the confidentiality of
           data will be protected and maintained;
       •   When appropriate, mechanisms will be set up that make provision for
           monitoring the data as it is collected.
       •   When appropriate, additional safeguards are in place if subjects are likely to
           be vulnerable to coercion.

D. Administrative Review

Administrative review is review and approval of an IRB submission by the SCRIHS staff
and the IRB Chair. Submissions that are reviewed administratively do not require review
by the full board. Below are examples of when administrative review is employed.

   •   Local and multi-center adverse event reports that do not impact the risk/benefit
       ratio of the study or would not require the IRB to reconsider the approval of the
       study, require protocol modifications, or to review the study more than once a
       year.

   •   SCRIHS staff will administratively review Amendments to the consent form that
       do not substantially alter procedures, or present an increased risk.

       Minor revisions (e.g., protocol or consent changes, changes in personnel, changes
       in telephone numbers, corrections, small increases in the study population, etc.)
       are reviewed administratively. Updated Investigator Brochures are also reviewed
       administratively. In cases where changes present new information about risks, a
       revised consent form that includes those risks should be included in the
       submission. If it is not, the investigator will be contacted in writing explaining the
       changes that must occur before the amendment can be approved.

       Changing Primary Investigators can be reviewed administratively, provided the
       submission includes a sign-off by the relinquishing investigator.


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   •   Protocol deviations/violations
   •   Revisions made as a result of pending approval by the IRB
   •   Exempt studies

Materials that are reviewed administratively ultimately receive their final approval by the
Chairman. Approval letters are not issued for items reviewed administratively.

E. Communication from the IRB

   1. How Does the IRB Communicate Various Actions to Investigators?

   Continuing Review Letters:

   Reminder letters are sent to the Principal Investigator when their studies are 60 days
   from review and 30 days from review. If the Continuing Review is not submitted, a
   termination letter will be sent 30 days after the due date of the Continuing Review.

   Approval letters:
   Approval letters indicate the meeting date the study was reviewed, that the
   study was approved in the form submitted, and the frequency with which the
   study will be reviewed.

   Pending Letters:
   A pending letter will indicate the meeting date the study was reviewed, that
   the study was approved pending revisions, and how frequently the study will
   be reviewed. Pending letters detail the necessary steps that an investigator
   must take to obtain full approval of their submission according to the IRB
   requirements. Approval will be done administratively if the investigator
   completes the required steps. The study approval will date back to the first
   IRB meeting at which the study was considered. Thus, if an investigator takes
   six weeks to complete the required steps in a pending letter, then the
   expiration date will be (approximately) one year less six weeks.

   Pending letters and re-reviews by the initial reviewers:
   Sometimes, reviewers will ask for specific revisions/clarifications to be made
   which they want to re-review before final approval is granted. In this case the
   investigator will be notified, in writing, that the reviewer has requested to
   review the stated revisions once they are made. Once the initial reviewers
   agree that the revised materials are sufficient, final approval can be issued.
   Such reviews often take more time, as the materials have to be delivered to the
   reviewer and picked up after the review is complete. This is done outside of
   the scheduled meeting.

   Tabled:
   Letters for tabled studies will indicate the meeting date the study was

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reviewed, that the study was tabled pending revisions and/or clarifications,
and what the investigator needs to submit in order for the study to be placed
on the next agenda. Tabled letters will describe the extensive revisions that are
required for the study to be reconsidered. The study will be reconsidered at the
first possible meeting after the necessary submissions are received. The date
and time of the next month’s meeting are given in the letter. Responses must
be received by the appropriate deadline in order for the study to be reviewed
at that meeting.

Disapproval Letters:
Letters disapproving a study are sent when the Board has reached a final
determination that the study cannot be approved in its current form. The letter
will detail the reasons the committee decided not to approve the study.

Other communications:
Other communications may be sent by e-mail such as to address a minor issue
that does not require a formal letter. Both SCRIHS and the investigator should
copy the e-mail and place it in the study file to provide an audit trail.
IRB Approval Dates:
The IRB Approval date is the date of the first consideration of the study (the
IRB meeting date) unless the study was tabled.

Tabled Studies:
The IRB Approval date for a study that is initially tabled is the IRB meeting
date when the study was reconsidered and finally approved.

2. What Do IRB Stamps Mean?

IRB documents are stamped in various ways to affirm review and approval. The
stamps described below are used in addition to approval letters to indicate review and
approval.

Consent forms for distribution to subjects must be copied from the officially stamped
version of the most recently approved consent form. The stamp is on the signature
page of the consent with the approval and expiration dates of the consent.

Receipt Date:
Stamped on all materials received in the office to note when the materials arrived.
The receipt date is used to triage how materials are processed and forwarded for
review.

Approval Stamps:

   a. “This consent is valid” stamp: (found on the signature page of the
   consent form)



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       Approval Date: The IRB meeting date the submission was initially
       considered and approved (including approved pending revisions), OR for
       studies that have gone for continuing review, it is the IRB meeting date the
       continuing review was considered and approved.

       Approval Expires: The date, one year from the initial (or continuing
       review) consideration and approval. The expiration date is the date by
       which the next continuing review must be reviewed and approved. There
       are no extensions to expiration dates.

       (In the case of tabled studies, the approval date is the IRB meeting date the
       study was finally approved)

       b. Amendment Summary approval stamp: (found on the front page of
       the consent form or HIPAA authorization)

This stamp includes an Amendment number and an approval date. The Amendment
number serves as a tracking a filing device for the SCRIHS office. The SCRIHS staff
issue an amendment number to every amendment submitted for a study. The only forms
an investigator will get back with an amendment stamp are consent forms or HIPAA
Authorization when they have been amended. The approval date for these stamps is the
date the Chair signs for approval.

F. Guidance for Investigators working with the IRB and with SCRIHS Staff

   1. General Guidance

   For a researcher to be clear on their responsibilities, it is advisable to be familiar with
   this manual and to review governmental regulations that pertain to the type of
   research that is being proposed before preparing submissions to the IRB.

       •   When preparing submissions, investigators and study staff should approach
           this process with the same care they use in submitting grant applications to
           funding agencies.
       •   Utilize the most current forms available on the SCRIHS website. Contact
           SCRIHS staff for guidance.
       •   Answer all questions - if you don't know what the question means, call the
           SCRIHS office for assistance.
       •   The SCRIHS staff is responsible for communicating the regulations of the
           federal government, University policy and guidance, and the deliberations of
           the IRB Boards.
       •   Timely communication helps speed the process along.
       •   Be sure to provide as much contact information as possible (e.g., e-mail
           address, phone numbers, fax numbers, and a pager number.) This will aid in
           processing your submission in a timely manner.


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   •   All communications with SCRIHS must be typed - handwritten materials will
       not be accepted.

2. Who Can Help Me?

SCRIHS is happy to advise any investigator or new research staff member through
the IRB process. Call SCRIHS and ask for assistance. A designated staff member will
be glad to meet with you about the process.

3. Who Handles My Study Once it has Been Submitted?

Studies submitted to SCRIHS are divided among staff for the pre-review process.
Investigators are contacted if items are missing or if additional information about
their submission is required.

Pre-review by SCRIHS staff is not the same as the Board review. Pre-review by staff
is only to point out readily obvious missing elements in the consent form, items that
should have been submitted (e.g. questionnaires, data collection forms, recruitment
materials), and other information that may render your submission incomplete. IRB
members have asked the SCRIHS staff to conduct this pre-review so that incomplete
submissions are not forwarded to the IRB for review.

4. Deadlines

Deadlines for submission are posted on the SCRIHS website. Investigators are
strongly encouraged to submit their studies prior to the deadline. This will provide
additional time for corrections or to obtain submission elements that are missing
before the materials are sent out to Board members.

It is especially important that periodic reviews be submitted in a timely fashion. If
studies are not submitted on time they will expire. When this occurs, additional
research cannot be carried out until the study is re-approved.

5. Guidance on IRB Submission Packet

   •   A complete packet must be submitted. Copies of all documents must be in
       each packet.
   •   Make enough copies and collate the submission into individual packets.
       These individual packets must be clipped together. For full board review,
       twenty-three (23) complete packets are required; for expedited review, three
       (3) complete packets are required. SCRIHS will not make copies of
       submissions.
   •   Signatures of Principal Investigator, Co-Investigators and Department Chair
       are required on the Application for Approval. One copy must include the
       original signatures. Signature stamps are not accepted. Be sure the copy


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       containing the original signatures is marked to draw the attention to the
       SCRIHS staff.
   •   Recruitment materials should be enclosed if there are intentions of using them.
   •   All appropriate attachments should be included, (e.g., survey instruments,
       questionnaires, or other research instruments) 1 copy for each packet.
   •   If something is missing from the packet, a cover note should provide an
       explanation. Missing items will only delay the review.
   •   Check for typos and spelling errors.

6. Where are the forms I need for submission?

Forms can be found on the SCRIHS website: www.siumed.edu/adraf/scrihs1.html

When preparing your submission, use only the most up-to-date version of the
appropriate form. Investigators should not download forms to their computers
for continual use. It’s the responsibility of the investigator to visit the SCRIHS
website to be sure a new version has not been posted. Under no circumstances
will handwritten forms be accepted.

7. Can I submit forms via the Web?

Because of the need for original signatures, forms cannot be submitted via the Web.

8. Turnaround Time

   •   Turnaround time is related to the completeness of the submission.
   •   Timely communication helps speed the process.
   •   To inquire about the status of your submission, please e-mail SCRIHS staff.
       Include the submission date, the investigator's name, and a SCRIHS protocol
       number.
   •   Pending and approval letters are generally prepared in the week following an
       IRB meeting. Approval letters, pending letters and tabled letters are mailed to
       investigators but draft copies can be email or faxed if requested.
   •   After receiving a "pending" letter requiring changes to the consent form or
       other clarifications, prompt response by the investigator will undoubtedly
       speed up the approval process.

9. Responses to Pending Letters

   •   Responses to letters should be sent to the SCRIHS office. They should include
       a complete response with all points addressed. If changes are requested that
       you do not agree with, you need to explain in writing why you don't agree.
       Ignoring a request slows down the review and approval process. If the
       changes are of an editorial nature, a memo will not be necessary. You can
       attach a copy the pending letter and indicate that the requests have been
       satisfied.

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      •   If changes to the consent form were requested, appropriately update the
          version date on the consent form to differentiate it from the original
          submission.
      •   Do not submit an Amendment Summary Form with the revisions.
      •   Responses to "pending letters" are required within ninety (90) days of the
          receipt of the letter. SCRIHS can provide better service when revisions are
          submitted in a timely fashion.

G. IRB Decisions and the Appeal Process

   1. Investigators Attending the IRB meeting

   Investigators may request, or may be invited, to attend an IRB meeting to explain
   their study, to provide background, or offer additional information. The Board, on
   occasion, invites investigators to the IRB meeting when a study has complex ethical
   issues or if the investigator wishes to undertake a large-scale study.


   2. What Does Disapproval of a Study or of an Amendment Mean? Can It Come
   Back as a New Study?

   When a study is disapproved, it means that the study cannot be implemented as
   described in the submission. Sometimes disapproval is based on profound ethical
   objections or the investigator did not adequately address issues raised by the IRB.

   Occasionally a study can be redesigned and resubmitted under a new protocol
   number. This requires that the previous issues be presented in a substantive and
   fundamentally different way. If the study is sponsored by industry, the company
   representatives may be unwilling to change the protocol.

   Disapproval of a full-board amendment most often occurs when an investigator is
   proposing to add procedures to a study that radically alters the original proposal.
   Sometimes a sub-study may be approved as a complete new study.

   3. Criteria for Appeal

   If a study has been tabled, the Investigator is advised to fully answer all questions and
   concerns raised by the Board. The investigator will be notified of these questions and
   concerns in writing immediately after the studies initial review. Usually appeals are
   not necessary when a study has been tabled only once and the investigator has fully
   complied with the Board's request for changes or information.

   Sometimes a study is rejected due to a misunderstanding or incomplete information
   about the study. When this occurs, the IRB will make every effort to review the study
   carefully and suggest changes that would make the study acceptable for
   implementation.


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   4. How the Appeal is Resolved

   To resolve an appeal, it is helpful for the investigator to attend the IRB meeting to
   present additional information that the IRB may need in order to make a decision on
   whether a study can move forward. In some cases it will be clear that, despite
   additional information, the IRB agrees that the study simply cannot be approved. This
   can take a considerable amount of time.

Section IX: Consent

A. Overview

   1. Participation in Research is Voluntary

   Truly effective, legally informed consent occurs when the information presented in
   the consent form is comprehended and when the subject decides voluntarily to
   participate in the study.

   The consent form is the vehicle to provide the information for potential subjects and
   the consent process is the expansion of the information in a voluntary setting allowing
   for give and take in the exchange of information about what will happen in the
   research. In addition to what is written in the consent form, the “give and take”
   should provide the potential subject with adequate information to make an
   “informed” decision about whether or not to participate in the research study. The
   setting and the amount of time for the consent interview has an effect on whether the
   subject feels coerced and whether the consent given is truly voluntary.

   2. Disclosure of Benefits and Risks

   When people are ill and looking for a potential cure for their disease, they may not
   read or hear the disclosure of risks and benefits in the same way that a normal healthy
   subject might. It is important when writing consent forms that risks and benefits are
   described exactly. This is full disclosure. Since the nature of research is to find
   answers, it is often difficult to say that the benefits can really be known.

   3. Federal Regulations and Guidelines

   The federal regulations address consent in a complete and simple manner.
   Investigators and research staff should be familiar with the federal regulations
   regarding informed consent.
   They can be found at: 45 CFR 46.116

   The Office of Human Research Protections has prepared a checklist that is useful to
   be sure all required elements of consent are in the consent form. “Informed Consent
   Checklist - Basic and Additional Elements”
   http://ohrp.osophs.dhhs.gov/humansubjects/assurance/consentckls.htm


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      FDA Regulations about Informed Consent

   For studies that are subject to FDA regulation, additional and/or different regulations
   apply to the consent form and process. SIU School of Medicine’s regulations are
   based on melding all the regulations together. See the sections listed (Section 5—
   Items 34-45; Section 6—Items 46-53) in the FDA INFORMATION SHEETS:
   Guidance for Institutional Review Boards and Clinical Investigators.

   A chart comparing the differences between DHHS regulations and FDA regulations is
   available at:
   http://www.fda.gov/oc/ohrt/irbs/appendixe.html

      Good Clinical Practice Guidelines about Informed Consent

   FDA regulations relating to good clinical practice are available at:
   http://www.fda.gov/oc/gcp/regulations.html
   The consolidated guidelines that constitute “Good Clinical Practice appeared in the
   Federal Register on May 9, 1997

B. Constructing the Consent Form

   1. Elements of Consent

   Every consent form should contain a separate paragraph heading for the following sections
   and include the basic elements of informed consent and additional elements, as appropriate.
   They are found in 45 CFR 46.116.

   Consent Form Section                       Required Elements

   Introduction/Purpose                      Study involves research, purpose(s) of study,
                                             duration, and why they are asked to participate

   Procedures                                 Description of procedures to be performed and
                                              identification of any procedures that are
                                              investigational

   Risks                                      Description of any foreseeable risks or
                                              discomforts. Full disclosure in simple terms.
                                              *When appropriate: A statement that the treatment
                                              or procedure may involve risks to the subject (or
                                              embryo or fetus should the subject become
                                              pregnant), which are currently unforeseeable

   Benefits                                   Any benefits to the subject or others which
                                              might be reasonably expected


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Alternatives                      A disclosure of appropriate alternative procedures
                                  or courses of treatment that may be advantageous.
                                  You must state that the subject may choose not to
                                  participate in the research study

Confidentiality                    A statement describing the extent to which
                                   confidentiality of records identifying subjects will
                                   be maintained

Costs                              If subjects are paid, the amount of payment, a
                                   description of the method of disbursement and the
                                   timing of payments.
                                   * When appropriate: Disclosure of any additional
                                   costs to the subject that may result from
                                   participation in research

Research-related injury            For research involving more than minimal risk, an
                                   explanation as to whether any compensation and
                                   medical treatments are available if injury occurs,
                                   what they consist of and where further information
                                   may be obtained, including who to contact to report
                                   such injury.

Subject’s Rights                   Participation is voluntary, refusal to
                                   participate will involve no penalty or loss of
                                   benefits to which the subject is otherwise
                                   entitled, and the subject may discontinue
                                   participation at any time without any penalty
                                   or loss of benefits.
                                   *When appropriate: Anticipated
                                   circumstances under which participation
                                   may be terminated by the investigator
                                   without regard to the subject’s consent
                                   and/or consequences of a subject’s decision
                                   to withdraw from the research and
                                   procedures for orderly termination of
                                   participation. A statement that significant
                                   new findings developed during the course of
                                   the study, which may relate to the subject’s
                                   willingness to participate, will be provided.

Contact Persons                    An explanation of whom to contact for answers to
                                   pertinent questions about the research and about
                                   subjects’ rights.



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Consent and signatures                    A statement that the subject agrees to participate in
                                          the research, and will receive a copy of the consent
                                          form. Dated lines for the subject (or authorized
                                          representative) and authorized study personnel
                                          obtaining consent to sign indicating agreement to
                                          participate in the study.
Additional elements if appropriate to the study should also be included.

The IRB requires use of the consent form template. The template includes a format,
suggested language, and other requirements. The IRB also has a template for tissue
banking consent forms and blood-collection consent forms. All of the templates are
available at the SCRIHS website.

2. General Guidance for Developing an Informed Consent Form

•   The SCRIHS consent template must be used. Do not submit sample consent forms
    provided by a study sponsor. The template includes the format, the section headings, and
    all required language.
•   Use simple (lay) language - the form should be written at no higher than 8th grade level
    (see section on readability if you wish to see what reading level your consent form is in.)
•   Avoid scientific or technical terms. If they must be used, provide an explanation in lay
    terms.
•   Use second person throughout, with the exception of the consent agreement to
    participate. (e.g. You will be asked…)
•   Include only pertinent information. Avoid redundancies. Sometimes it helps to outline the
    consent and make sure you have covered everything once.
•   Exculpatory language--Do not use qualifying phrases such as “you understand that”, “you
    acknowledge that”, etc., or references to understanding. Avoid language which may
    appear to waive any rights to which the subject is entitled.
•   Check spelling and grammar.
•   Include the SCRIHS protocol number on the top of each page.
•   Call the SCRIHS office for guidance when you have questions.
•   Section headings should be underlined or bolded.
•   Use size 12 point font or larger throughout the consent form.
•   Number pages “page x of y” on each page. (e.g., page 2 of 4)
•   Include header or footer with current version date on each page of the consent form.

3. Consent Forms for Studies Involving Children or Others Unable to Give Informed
Consent

•   If children are involved and are between 12 and up to 18 years of age, provide for consent
    of parent and assent of child.
•   For younger children, add a sentence stating that the study has been discussed with them
    and they agree to participate.



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   •   If other persons are involved in the procedures (caregiver, spouse, parent, teacher),
       consent must be obtained from each via an additional consent form.

   4. Glossaries and Lay Language

   The glossaries, dictionaries and writing aids listed below have been compiled by
   other IRBs and organizations to provide guidance and suggestions for using lay
   language in consent forms. In addition, a multilingual glossary is provided to help in
   preparing consent forms in languages other than English or to check the translation of
   an already prepared consent form.

   "Alternative Lay Language for Medical Terms for Consent Forms" is copyrighted
   from the University of Kentucky and is provided here for your use.
   http://healthcare.partners.org/phsirb/irbforms/dict2.pdf

   "MedTerms.com is the medical reference for MedicineNet.com, containing easy-to-
   understand explanations of over 10,000 medical terms. This online medical dictionary
   provides quick access to hard-to-spell medical definitions through an extensive
   alphabetical listing." Descriptions of terms, diseases, medical procedures that may
   assist in writing in lay language. www.medterms.com/Script/Main/hp.asp

   "The Plain Language Action & Information Network is a government-wide group of
   volunteers working to improve communications from the federal government to the
   public." www.plainlanguage.gov/library/smpl1.htm

   Multilingual Glossary of Technical and Popular Medical Terms in Nine European
   Languages:
   http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

C. The Consent Process

   1. Who Should Obtain Consent—Authorized Study Personnel

   The Application for Approval requires all authorized study personnel to be listed and
   their roles defined. Those persons who will be assigned to obtain consent in the study
   must have this role indicated on the Application. In order to obtain consent the study
   personnel should be very familiar with the protocol, very familiar with the consent
   form, and trained in obtaining consent.

   If there are changes in personnel, when the study is active, investigators should
   submit an Amendment Summary Form along with a Revision to Authorized Study
   Personnel Form describing the changes in personnel.

   *Investigators are reminded that new personnel must have fulfilled the SCRIHS
   education requirements before being able to participate in the research study.



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2. PIs Role in Consent

The principal investigator is responsible for either personally obtaining consent from
prospective subjects, or designating an approved authorized study personnel to obtain
informed consent. Ultimately, the PI is responsible for whoever is enrolled in the
study.

Sign-off on the consent form by the person obtaining consent should occur at the
same time the subjects is signing the consent. Since consent and the initial visit could
take place at the same time, it is important that the eligibility for participation be
reviewed by the PI in a prompt manner.

3. Training to Obtain Consent

Research staff, vested with this important task, must have training specific to
obtaining informed consent because this is one of the critical elements of human
subjects’ protections - assuring that all elements of the consent process have been
honored (voluntariness, comprehension, information, competency to understand).

Consent is a process and not merely the presentation of a form or a reading aloud of a
form. Research staff and investigators should not assume they know how to obtain
consent. Practice, reading, and discussion among staff are important elements in
moving toward a more complete process.

Research staff may wish to practice obtaining consent by role-playing. When a new
study is about to start, research staff may wish to review the consent form aloud and
think of the questions that a potential subject might have about the study.

4. Taking the Consent Form Home Prior to Signing

Sometimes it is important that a subject be given the opportunity to take the consent
form home to discuss it more fully with family members, their personal physician, or
others. This should be encouraged as truly informed consent takes place when all
questions have been asked by the subject and answered by the investigator or the
research staff. If a subject requests to take the consent form home, this request must
be honored.

An investigator should never be so eager to reach an enrollment goal that they do not
allow the subject adequate time to consider enrollment in the study. Subjects are more
inclined to stay enrolled if they fully understand everything that will be happening
during the course of the study.

There are some low risk studies that probably don’t require lengthy or measured
consideration about whether to enroll or not. Sometimes the study itself takes as long
as the consent process. This may be true when total participation is answering a single



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questionnaire or participating in a single blood draw. A subject, though, has the right
to review the consent form in a manner that is appropriate to ensure understanding.

5. Debriefing

When a study has utilized deception in the conduct of the study, subjects must be
debriefed after the procedures of the study have been completed to explain what
actually happened in the study. The debriefing has the goal of disclosure; repairing
the breach of the informed consent process, minimizing concerns or tension that the
subject may have as a result of learning they have been deceived, and offering
additional discussion if necessary.

Further it is important when deception has been used in a study that debriefing occur
so that subjects involved in future studies don’t make assumptions that perhaps the
use of deception is common and occurs in many research studies.

A debriefing plan will include an oral discussion and some written materials
including an expression of regret that the use of deception was necessary, explaining
why it was necessary, and reviewing what really happened in the study. It is
important to emphasize that the approval of the use of deception was granted by the
IRB.

Subjects must be offered a chance to ask questions and discuss any confusion or
concerns they have about the study. In addition, in the case of a potential significant
reaction, information about additional support or counseling that subjects may need as
a result of the deception must be offered.

6. Regulations About Which Consent Form to Use

The most recently approved consent form must be the one offered to the research
subject for signing. Subjects must not be offered a consent form that has expired.
Expiration dates are written on the consent form to assist investigators in remaining in
compliance.

If, for some reason, a study’s approval has lapsed, investigators may not enroll
subjects using an expired consent. If the subject shows up and the outdated consent is
discovered, the consent interview will have to be postponed for a later time. Such
delays cause problems in subject recruitment and retention. Investigators are urged to
regularly monitor that their study is in compliance and fully approved. In preparing
for a consent interview and signing, it is a good idea to check that the consent form
has not expired prior to scheduling the subject visit.

7. Re-consenting Subjects When the Consent Form Has Changed

Subjects must be re-consented when the consent form has changed and the changes in
the consent form directly affect the subject. Examples of changes that would affect


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the subject include changes in the contact information for the Principal Investigator,
the addition of another blood draw, or other procedures, a change in existing
procedures, the addition of a study visit, new risks as a result of adverse events, new
side effects, the addition of a questionnaire, the addition or subtraction of drugs used
in the study, and changes in confidentiality (who can see the data). Usually re-
consenting can take place at the next study visit. The timing and methods need to be
discussed with SCRIHS to advise how the new consent should be presented to the
subjects.

There are some instances when all participants have completed a study but new risks
are later discovered through data analysis or through reporting at other active sites
that are still enrolling subjects. In the case where new risks are very serious or
complicated or could be long-term effects of the drug or device, it may be necessary
to bring the subjects back to the clinic to explain the risks in a face-to-face discussion
and re-consent. A letter can sent to participants explaining the information and then
participants can be offered a return visit or a group session to further discuss new
risks and re-consent.

If the change might impact the health or well-being of the active subject, re-
consenting should occur immediately. This means that subjects must be contacted to
come to the clinic before their next study visit to discuss the new risks and sign a new
consent form. Contacting subjects should be done with care so as not to alarm
participants.

If the changes are easily explained, it is possible to mail the consent form to the
subjects to inform them of the change, yet have them discuss and sign the actual
consent form when they come in for their next study visit. The changes could be
outlined in a letter to study subjects that accompanies the consent form. It should
indicate clearly in the letter that subjects should not sign and send the consent form
back. A letter such as this and a description of this process needs to be approved by
SCRIHS prior to implementation.

Changes that occur in the protocol, such as lab values or screening criteria, do not
usually impact the consent form and therefore the consent form would not be
changed. If there are changes, they must be submitted for IRB review as an
amendment.

Sometimes when a finding is issued before the end of the study, an information letter
may be sent to all study participants explaining what was discovered. This would not
mean that persons would be re-consented but it does provide them with additional
information to judge whether they wish to remain enrolled in the study.

In some cases, investigators should inform subjects by certified letter. Whether a
certified letter is sent depends on the type of information communicated and its
importance. Such a letter is not in place of a consent form. Sometimes a letter will be
sent to participants and then the information incorporated into the consent form at a


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later time. Other options include creating addendum consent. This option is not
utilized more than once or twice during a study because the subjects may get
confused with multiple additions to a consent form. Each study’s unique situation is
considered when additional information must be shared with subjects, but the
standard procedure will be to change the consent form.

Study subjects do not have to be re-consented when a version date changes as a result
of a continuing review. If no changes were made to the consent form, then it is not
necessary to re-consent them because of the IRB review. If the only changes made are
to comply with changes to the consent form template, the subject does not have to be
re-consented. Additionally, changes such as the title, the addition of a co-investigator,
and small corrections, do not require that subjects be re-consented.

Each sponsor may have different regulations regarding re-consenting. Investigators
can discuss sponsor requirements with SCRIHS.

Note: The consent form cannot be altered by crossing out sentences if something
is eliminated.

8. Regulations About Signing and Storing Consent Forms

Consent forms must be fully signed and dated before filing. The subject should have
received a photocopy of the signed consent immediately upon completion of the
consent interview. If consent is done in a location without a photocopier available,
two copies of the consent should be signed and one labeled as the copy and given to
the subject.

By maintaining a study log, investigators and research staff can easily track that
consent forms are signed and dated as appropriate. This may be especially useful in a
study with multiple consent forms or a study that has updated consent forms on a
regular basis.

Original copies of the consent forms should be kept in the study binder, subject file,
or with the research records. Memorial Medical Center and St. John’s Hospital
require a photocopy of the consent form in each patient’s hospital medical chart.

9. Witnesses

SCRIHS requires a witness to the consent process only when there may be some
concern regarding comprehension on the part of the subject. When a study enrolls
subjects with cognitive impairment, investigators should consider using a witness in
addition to the person obtaining consent.

The inclusion of a witness line on the consent form sometimes indicates that the
subjects may have some comprehension problems. The use of a witness needs to be



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   fully explained in the Application for Approval in the section on how consent is
   obtained.

   10. Consent by Someone Other than the Patient

   When adults are enrolling in research studies and are not competent to understand
   consent and enroll themselves, the same rules that apply to regular patients apply to
   research subjects. If the subject is competent to consent and enroll themselves, then
   they may do so. If the subject cannot participate in that process then, under various
   laws in Illinois, a legal representative would be used in the following order:
   1- A Guardian of the Person. A copy of the court order appointing the guardian and
   the order must give the guardian powers over all health care decisions must be
   provided. The copy should be kept with the consent form.

   2 - An agent under a Durable Power of Attorney for Health Care. A copy of the
   document is needed and the document must be reviewed to ensure that there are no
   limitations in it that would preclude consent to a research protocol. The copy should
   be attached to the consent form.

D. Special Types of Consent and Additional Consent Templates

   1. Blood Withdrawal Qualifying for Expedited Review

   (No long term storage or genetic testing)

   In some instances, the collection of blood samples may be considered to present no
   more than minimal risk to research participants and may be reviewed through an
   expedited review process (45 CFR 46.110). In other instances, the collection of blood
   samples may be considered as greater than minimal risk and must be given full board
   review. These guidelines are for simple blood withdrawal with minimal risk
   according to federal guidelines. This category may not be used for long term storage
   of blood, unspecified future research, or genetic testing if the risk level of the study
   does not qualify for expedited review. Other consent forms are available to address
   those types of situations.

   2. General Requirements for Blood Withdrawal

   •   There are no special health reasons (e.g., severe anemia, pregnancy) to
       contraindicate blood withdrawal.

   •   In patients from whom blood is already being drawn for clinical purposes, there
       are no other health reasons to preclude additional blood collection.

   •   In subjects from whom blood is not already being drawn for clinical purposes, the
       withdrawal method is by cutaneous sticks (e.g., heel, ear or finger) or by standard
       venipuncture in a reasonably accessible peripheral vein.

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•   Experienced professional or technical personnel carry out all blood withdrawals
    and collections.

•   The patient has signed a consent form and understands what the study is about,
    how the blood will be collected, and what will be done with the blood.

3. Specific Requirements for Minimal Risk Blood Collection Qualifying for
Expedited Review

Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as
follows:

A. Blood samples may be collected for research purposes from healthy, non-pregnant
adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not
exceed 550 ml in an 8 week period (Note that a pint is 480 ml) and collection may not
occur more frequently than 2 times per week; or

B. From other adults, considering the age, weight, and health of the subjects, the
collection procedure, the amount of blood to be collected, and the frequency with
which it will be collected. For these subjects, the amount drawn may not exceed the
lesser of 50 ml or 3 ml per kg of body weight in an 8 week period and collection may
not occur more frequently than 2 times per week (45 CFR 46.110).

4. Specific Requirements for Minimal Risk Blood Collection Qualifying for
Expedited Review Involving Children

Blood samples may be collected under the following conditions:

1. No more than three (3) skin punctures are to be made in any single attempt to draw
blood solely for research purposes.

2. The volume drawn per specimen, including blood drawn for clinical purposes,
should not exceed one percent (1%) of the child’s total blood volume. A child’s blood
volume is usually estimated to be 80cc/kg, thus volume drawn per specimen should
generally be < 0.8cc/kg. (For example, for a child weighing 20kg, the maximum
volume of blood that could be drawn for research as well as for clinical purposes
would be 20x0.8=16cc).

3. The cumulative volume of blood withdrawn for clinical or research purposes over
an eight week period should not exceed ten percent (10%) of the child’s total blood
volume. A child’s blood volume is usually estimated to be 80cc/kg, thus volume
drawn should be < 8cc/kg/8weeks. (For example, for a child weighing 20kg, the
maximum volume of blood that could be drawn for research and clinical purposes
together over 8 weeks would be 20x8=160cc).



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5. Conversion of Teaspoons, Tablespoons, Ounces, Milliliters (mls), Cups, Pints

                         Ounces            Milliliters     Tablespoons         Pints
    1 teaspoon                             5 ml
    3 teaspoons          1/2 ounce         15 ml           1 Tablespoon
    1 Tablespoon         1/2 ounce         15 ml
    2 Tablespoons        1 ounce           30 ml
    4 Tablespoons        2 ounces          60 ml
    8 Tablespoons        4 ounces          120 ml
    1/2 cup              4 ounces          120 ml                              1/4 pint
    1 cup                8 ounces          240 ml                              1/2 pint
    2 cups               16 ounces         480 ml                              1 pint

For consent forms, if blood is being drawn, use at least two descriptions of the
amount of blood (e.g., milliliters and teaspoons, tablespoons, or ounces) At the end of
the Procedures section, list the total number of times blood will be drawn, the
frequency of draw (e.g., at each study visit), and total amount: You will have
(amount) of blood withdrawn (number of times drawn, and frequency). The total
amount of blood drawn for the entire study will be (amount).

6. Oral Consent

In some instances, oral consent may be appropriate or even preferred.

In instances where the notation of a person’s identity could compromise issues of
privacy and confidentiality or could adversely harm their employability or
insurability, oral consent might be appropriate. In other instances, the study may be of
such low risk as to not warrant written consent.

Investigators wishing to waive written consent should review the Waiver of Consent
Guidelines and Form to determine if they have adequate justification to submit a
waiver of consent request.

A script is always required when written consent is waived. The elements of consent
are included in the script but can be written in a more informational manner. An
information sheet describing the study and giving contact information is also
required.

7. Children and Assent

Special regulations apply to enrolling children in research studies. The chart below
indicates how investigators can prepare the appropriate form, script, or consent form
for the appropriate age group.




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Below Age 5
As appropriate and depending on the study, some explanation can be given to the
child about what is involved in the study.

5-11 year olds
Verbal consent (directed to the child) should be given by the investigator. This verbal
discussion should include the following:
    child-friendly language
    what the child will experience (risks)
    what will be done
    statement that results will be private
    if they get paid
    they have a choice to participate or not participate

Parent(s) will sign the consent form. On the assent form, parent(s) will sign verifying
that a verbal consent was delivered and the child should sign their name if possible.

12 year olds up to 18 year olds:
During the consent process, the investigator should direct the discussion to the
parent(s) and the child. The discussion should be based on the consent template and
in age appropriate, child friendly language.

Parent(s) will sign the consent form. The assent form will have the following
statement:

“I have read this form and the research study has been explained to me. I had the
chance to ask questions. If I have more questions, I know who to call. I agree to be in
the research study described above and will get a copy of this assent form.

If the child agrees to participate, the child must sign the assent form. If the child does
not or cannot sign for some reason, the investigator should provide an explanation for
the lack of assent.

Please note: If the assenting children declines participation in the study, the parents or
legally authorized representative cannot force the child to participate. Also, mere
failure to object should not be construed as assent.

Consent Form for Parents:

   If the adult is also a participant, the consent should be in “you and your child”
   language. There should be an assent form but it does not have to say “you and
   your parent.”
   If the adult is not a participant, the consent should be in “your child” language.
   Subjects Rights section to read as follows: “Your child’s participation in this
   study is voluntary and s/he is free to withdraw at any time. Even though you have
   given permission to your child to be in our study, if he or she shows any


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       reluctance to participate, we will not include them. Similarly, if he or she starts
       the study but becomes bored, or uncomfortable with it, we will stop. Participation
       or withdrawal will not affect any rights to which your or your child is entitled.
       Withdrawal will in no way affect any present or future involvement with SIU
       School of Medicine or its services.”

   8. Pharmacokinetic Studies as Part of a Clinical Trial

   Pharmacokinetic studies are often added to a clinical trial as an amendment or sub-
   study to evaluate drug metabolism. The IRB prefers a separate consent form when
   participation in the pharmacokinetic phase of the study is optional. Since pharma-
   cokinetic studies often involve additional blood draws and other lab tests, it is
   important that the subject can easily differentiate between the main study and the sub-
   study. Often pharmacokinetic studies are a means of evaluating gender or age
   differences in drug efficacy and therefore are not open to all persons enrolled in a
   trial. In some circumstances, the IRB may approve the use of the sponsor’s model
   consent for the pharmacokinetic studies.

E. Waiver of Consent

   1. Regulations and Overview

   Informed consent is mandated by Federal policy (45 CFR 46 Section 116). Informed
   consent is also one of the fundamental principles of ethical conduct in the use of
   human subjects. Occasionally there are reasons to waive written consent or to alter
   the requirements of consent. Only the IRB can make the determination to waive some
   (written) or all (written and verbal) consent requirements. Under some circumstances,
   described in the Federal Regulations, an investigator may feel that his/her study
   justifies a request to waive consent. The essential conditions of a waiver that must be
   justified are:

   •   that the research pose no more than minimal risk to subjects;
   •   that no adverse effects will occur as a result of the waiver or alteration;
   •   that without the waiver or alteration the research in question could not be carried
       out; and
   •   that information will be provided after participation is completed, if appropriate.

   Investigators may wish to consult the federal regulations: Federal Policy for the
   Protection of Human Subjects §46.116 General requirements for informed
   consent; §46.117 Documentation of informed consent: (Section 116(d) and 117)

   2. Examples of Situations Where a Request for Waiver of Consent Would Not
   Be Approved by the IRB:

   1. I don’t have enough money in my research grant to print consent forms and
   distribute them and file them.

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2. These are my patients so I see them anyway and they trust that I will not involve
them in something that might harm them.
3. I already have access to the patient records.
4. There isn’t any risk even though it would be possible to get consent.
5. I don’t have a staff member who can handle all the paperwork involved in
obtaining informed consent.
6. If I consent people, they will not want to participate in the study.
7. The consent form will scare people. It seems so legalistic.
8. It’s an inconvenience and a lot of added time to get all the consents signed.

3. Waiver of Written Informed Consent

The requirement for a written, signed consent form may be waived by a Human
Subjects Review Committee if the criteria below are met:

•   the signed consent form itself might compromise the confidentiality of the data
    describing the subject and the subject prefers that no signed consent form be used;
    or
•   the research presents no more than minimal risk and involves no procedures for
    which written consent is normally required outside the research context.

    a. Verbal Consent and Script Still Required

    Though waiver of written informed consent may be appropriate, this does not
    mean that verbal consent cannot be utilized in situations where the investigator or
    study staff will be meeting with the subject. A script for verbal consent should be
    submitted to the IRB for review. A verbal consent script provides all of the
    elements of consent in a more informal style. In addition, each subject should be
    provided with an information sheet that describes the study and gives contact
    names and numbers.

    Normally, investigators will be asked to keep a log of those who were approached
    about the study, and offered verbal consent. A simple chart can indicate the
    subjects as subject 1, subject 2, and subject 3. A column can indicate that verbal
    consent was given and a date. Since a specific number of study subjects have been
    requested in the IRB application, it is important that investigators keep some
    record to indicate that they are not enrolling more subjects than they originally
    requested.

    b. Passive Consent

    Occasionally passive consent is allowed in certain low risk studies. Passive
    consent is consent that is implicit in the participation or that does not require the
    potential subject to return a card, sign a consent form, or call to indicate a
    willingness to participate. Generally passive consent is not an acceptable practice.
    Federal regulations and state regulations require “legally effective informed

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consent” to participate in research. The IRB must approve passive consent
procedures.

Examples of when is passive consent might be allowed

Passive consent may be allowed in a study, where for example, a sample
population is mailed a survey and a letter (see sample letter below) describing the
study, and they are asked to complete the survey and mail it back. No identifiable
information is collected. The subjects are not signing a consent form prior to
answering the survey. They can, on the other hand, not answer the survey and
simply throw it away. This raises questions as to whether another round of
surveys can be mailed to non-respondents. Investigators need to plan ahead and
carefully describe in the study description what means will be used if there are not
enough respondents to the first survey. Investigators should discuss their plans
with the SCRIHS staff to get a reading on whether the proposed passive consent is
reasonable. Ultimately, the IRB decides if the consent process is acceptable.

A letter accompanying a questionnaire or survey should include the
following elements:

•   Introduction and identification of Researcher
•   Purpose of the research
•   Where the person’s name was obtained
•   What will subject be asked to do and how long will it take
•   Privacy and Confidentiality
•   Risks if there are any
•   Agreement to participate voluntarily
•   Contact Persons and information

Template with Sample Language
Date
Dear (Give name of respondent):

I am a graduate student working under the direction of Professor (Give the full
name of the Faculty Member who is serving as the Faculty Advisor on this study),
in the (give Department's name) Department at Southern Illinois University) or a
professor in the Department of (give Department's name) at SIU School of
Medicine)

I am conducting a research study to (state purpose of study - e.g., how young
people obtain summer jobs in Springfield and what the experience of interviewing
for a job is like or your opinion about whether the restaurants in Springfield
contribute to the litter problem and what business owners should do about litter.

I obtained your name and address from (describe the source of the name - e.g., the
local YMCA teen chapter, or the community directory of recycling club

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   presidents).


   I am asking you to participate by (describe what is being asked of the participant.
   Describe length of time it will take to do the task).

   It will take about 20 minutes to answer the questionnaire that is enclosed. When
   you are done with the questionnaire, please mail it back in the enclosed self-
   addressed, stamped envelope.

   Your participation in this study is voluntary. If you choose not to participate or to
   withdraw from the study at any time, there will be no penalty.

   The results of the research study may be published, but your name will not be
   used. [If anonymous questionnaires are completed, include statement that "The
   questionnaire is anonymous. The results of the study may be published but your
   name will not be known."].

   If you have any questions concerning the research study, please call me [or
   Professor _____] at ( ) ___-_____.

   Return of the questionnaire will be considered your consent to participate.

   Sincerely,

   Signature
                                    Signature
   Researcher's name
                                    Faculty Advisor's Name
   Address
                                    Address
   Phone and E-mail


4. Waiver or Alteration of All Elements of Consent (no verbal and no written
consent)

A request to waive written and verbal informed consent must be accompanied by a
complete explanation in response to the four statements below. All of the criteria
must be met to qualify for a waiver of both written and verbal consent.

a. The proposed research presents no more than minimal risk of harm to subjects.
b. The waiver or alteration of consent will not adversely affect the rights and welfare
    of the subjects.
c. The research could not practicably be carried out without the waiver or alteration.
d. Whenever appropriate, the subjects will be provided with additional pertinent
    information after participation.
5. Definition of Minimal Risk


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   An individual is considered to be at more than minimal risk if exposed to the
   possibility of harm -- physical, psychological, social, legal, or other -- as a
   consequence of participation as a human subject in any research activity which
   departs from the performance of routine physical or psychological examinations and
   tests, or which departs from established and accepted procedures necessary to meet
   the individual's needs, or which increases the probability or magnitude of risks
   ordinarily encountered in daily life.

Section X: HIPAA

A. Summary of the HIPAA Privacy Rule

The HIPAA Privacy Rule governs the use and disclosure of “protected health
information.” Protected health information (PHI) is information that is created or
received by a health care provider, a health plan or health care clearinghouse that relates
to the past, present or future physical or mental health of an individual. Information about
the payment for health care also may be PHI. To qualify as PHI, the information must
identify the person directly or be sufficiently specific that the person could be identified.
The Privacy Rule governs all PHI in all forms, whether electronic, paper, medical media,
or conversation.

Regulations in the HIPAA Privacy Rule are founded on the principle that patients should
be aware of all the uses and disclosures of their protected health information. Patients are
informed about an entity’s use of their information in three ways:

   •   Through receipt of the entity’s Notice of Privacy Practices
   •   By written authorization prior to certain uses and disclosures, when specified by
       the law
   •   By exercising their right to receive an accounting of disclosures of their
       information

Another guiding principle of the Privacy Rule is that of “minimum necessary.” Health
care entities must use only the minimum necessary information to accomplish the
intended purpose of the use or disclosure. Exceptions to the minimum necessary standard
include uses and disclosures related to treatment, disclosures to the individual patient, and
certain disclosures required by law.

B. Policy Regarding the Use or Disclosure of Patient Data for Research

The HIPAA Privacy Rule outlines the conditions under which health care data may
lawfully be used for research purposes. SCRIHS will be responsible to ensure HIPAA
compliance related to research at SIU SOM. The investigator is responsible for providing
the SCRIHS with the appropriate HIPAA forms necessary for each submission. SCRIHS
may require all subjects sign an HIPAA authorization, grant a waiver of authorization,
partial waiver or determine the project is exempt from HIPAA. Further, SCRIHS may
require a data use agreement be provided for any person or entity that receives or used

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PHI in the course of performing requested services for the Investigator or SIU SOM. As
with IRB review, no individual with conflict-of-interest relevant to a specific protocol
may vote on that protocol at the meeting.

Any research use of PHI must meet one of two conditions and receive written approval
from SCRIHS:

       1. Authorization is granted by the patient, through a written authorization
          form

               OR

       2. One of the following criteria is met:

           a) the information is completely de-identified and no longer governed by
           HIPAA
           b) a waiver of the individual authorization requirement is obtained from the
           Cleveland institutional review board (IRB) or privacy board
           c) the information is compiled into a “limited data set” and a data use
           agreement is executed
           d) the activity qualifies as “preparatory to research”
           e) the researcher is accessing information solely on decedents

C. Written Authorization

Written authorization from the patient is the default requirement for use of protected
health information in research. Prospective research, such as a clinical trial, generally
requires prior authorization. The authorization differs from informed consent in that the
authorization obtains specific authorization to use and disclose protected health
information for the research study. For purposes of clinical research at SIU SOM, the
HIPAA authorization is a separate document from the informed consent template.

The authorization must be written in plain language, and the subject must receive a copy
of their signed authorization. Authorizations must be study-specific. For projects that
have sub-studies, an authorization also must be obtained for the sub-study. Research
subjects may revoke their authorization at any time during the research. If authorization is
revoked, the Privacy Rule allows continued use and disclosure of the information that
was obtained prior to the revocation, to preserve the integrity of the study. For example,
the researcher may use the information to account for study withdrawals, to report
adverse events to FDA, or to comply with study audits.

Procedures:

   •   All new subjects enrolled into previously–IRB approved studies, on or after April
       14, 2003, must sign a HIPAA privacy authorization.



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   •   Subjects who are re-consented on or after April 14, 2003 must sign the HIPAA
       authorization.
   •   Data from subjects who were enrolled prior to April 14, 2003 is “grandfathered
       in.” In other words, no additional privacy authorization is required, unless those
       subjects are re-consented after the compliance date. At that time, a HIPAA
       authorization will be signed.
   •   Authorization forms for ongoing studies will be reviewed by SCRIHS
   •   When the study is reviewed by SCRIHS, the letter to the investigator will also
       include the review and possible approval/waiver or exempt status of the HIPAA
       authorization.

D. De-identification

Certain research projects can be accomplished through the use of de-identified data. For
example, a de-identified data set might include age, gender, marital status, ethnicity, and
relevant medical data or an unidentified tissue sample. Totally de-identified data is not
subject to HIPAA regulations.
To qualify as being de-identified under the Privacy Rule, the following data elements
about the individual and the individual’s relatives, employers, or household members
must be removed:

   Names;
   All geographic subdivisions smaller than a State, including street address, city,
   county, precinct, zip code, and their equivalent geocodes, except for the initial three
   digits of a zip code if, according to the current publicly available data from the
   Bureau of the Census:
           (1) The geographic unit formed by combining all zip codes with the same
           three initial digits contains more than 20,000 people; and
           (2) The initial three digits of a zip code for all such geographic units
           containing 20,000 or fewer people is changed to 000;
   All elements of dates (except year) for dates directly related to an individual
   including:
           - birth date
           - admission date
           - discharge date
           - date of death; and
           - all ages over 89 and all elements of dates (including year) indicative of such
           age,
           except that such ages and elements may be aggregated into a single category
           of
           age 90 or older;
   Telephone numbers;
   Fax numbers;
   Electronic mail addresses;
   Social security numbers;
   Medical record numbers;

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   Health plan beneficiary numbers;
   Account numbers;
   Certificate/license numbers;
   Vehicle identifiers and serial numbers, including license plate numbers;
   Device identifiers and serial numbers;
   Web Universal Resource Locators (URLs);
   Internet Protocol (IP) address numbers;
   Biometric identifiers, including finger and voice prints;
   Full face photographic images and any comparable images; and
   Any other unique identifying number, characteristic, or code.

If the investigator receives only de-identified data or samples, then the Privacy Rule does
not apply. However, if the investigator him/herself views records that contain identifiable
information and from those records extracts a de-identified data set, then the project must
undergo human subjects review and must qualify for a waiver of authorization. The
investigator must submit a HIPAA De-Identified Certification Form with the IRB
submission. This form can be found on the SCRIHS website.

E. Waiver of Individual Authorization

An investigator also may apply for a waiver of authorization. In planning a study that
employs a waiver of authorization, the investigator should consider their responsibility to
comply with the minimum necessary standard of the Privacy Rule. Only the minimum
amount of protected health information should be used and disclosed, as necessary to
accomplish the goals of the research. For example, date of birth should not be recorded if
age will suffice.

SCRIHS will approve a waiver of the privacy authorization if the research meets the
following criteria:

   •   The use or disclosure of protected health information involves no more than a minimal
       risk to the privacy of individuals based on, at least, the presence of the following
       elements;

               An adequate plan to protect the identifiers from improper use and disclosure;
               An adequate plan to destroy the identifier at the earliest opportunity consistent
               with conduct of the research, unless there is a health or research justification for
               retaining the identifiers or such retention is otherwise required by law; and
               Adequate written assurances that the protected health information will not be
               reused or disclosed to any other person or entity, except as required by law, for
               authorized oversight of the research study, or for other research for which the use
               or disclosure of protected health information would be permitted by the Privacy
               Rule;

   •   The research could not practicably be conducted without the alteration or waiver; and

   •   The research could not practicably be conducted without access to and use of the
       protected health information.

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HIPAA regulations require that when a medical record is used or disclosed via a Privacy
Board waiver of authorization, the investigator’s use or disclosure must be recorded in
the patient’s accounting of disclosures. Studies that are approved as exempt studies by
SCRIHS will usually require a HIPAA waiver, if the researcher must access the entire
medical record to perform the data collection. However, if the holder of the medical
record performs the data extraction and delivers only de-identified data to the researcher,
no HIPAA waiver is required and only a HIPAA De-Identified Certification Form must
be submitted. The Request for Waiver of Authorization form can be found on the
SCRIHS website.

F. Limited Data Set

Certain research projects involve the use of data or tissue samples that do not meet the
HIPAA standards for de-identification. The Privacy Rule allows the use of a “limited data
set” for research purposes. A limited data set is one in which direct identifiers have been
removed, but certain potential identifiers remain. For example, a limited data set might
include the subject’s zip code, date of birth, hospitalization dates, and relevant medical
information. Use of a limited data set is contingent upon the investigator and covered
entity entering into a data use agreement.

A limited data set is protected health information that excludes the following direct
identifiers of the individual and of relatives, employers, or household members of the
individual:

       Names;
       Street address/Postal address information, other than town or city, State, and zip
       code;*
       Telephone and fax numbers;
       Electronic mail addresses;
       Social security numbers;
       Medical record numbers, health plan beneficiary numbers or other account
       numbers;
       Certificate/license numbers;
       Vehicle identifiers and serial numbers, including license plate numbers
       Device identifiers and serial numbers;
       Web universal resource locators (URLs) or Internet protocol (IP) address
       numbers;
       Biometric identifiers, including finger and voice prints; and
       Full face photographic images and any comparable images.

       *Unlike de-identified data, the limited data set may include five-digit zip code or
       any other geographic subdivisions, such as State, county, city, precinct and their
       equivalent geocodes. These geographic designations are permitted in order to
       support a range of research and public health activities, such as the analysis of
       local variations in disease burdens or statistics on the provision of health care
       services.

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While the Privacy Rule dictates the identifiers that must be removed in a limited data set,
the minimum necessary standard of the regulation remains in effect for any other health
information. Researchers are responsible for requesting only the information that is
necessary to accomplish the research purpose. For example, if age expressed in years,
months, or days will suffice, date of birth should not be requested.

A limited data set is considered to be protected health information under the Privacy
Rule. Prior to using the limited data set, the investigator must provide a data use
agreement. The agreement must contain the following elements:

   •   The permitted uses and disclosures by the recipient
   •   The approved users and recipients of the data
   •   Agreement by the recipient not to re-identify the data or contact the individuals
   •   Assurances that the recipient will use appropriate safeguards to prevent use or
       disclosure of the limited data set other than as permitted by the data use
       agreement
   •   Agreement that the investigator will report to the covered entity any uses or
       disclosures of the limited data set which were not specifically allowed
   •   Agreement to require that any agents and subcontractors adhere to the same
       safeguards

Because certain potential identifiers are allowed, research employing a limited data set is
subject to human subjects regulations. The study must be approved by SCRIHS.

Disclosures in the form of a Limited Data Set are exempt from the HIPAA requirements
for accounting of disclosures. In other words, accounting or tracking of the use or
disclosure is not required by the record holding department. Call the SCRIHS office for
guidance with submissions of a data use agreement and limited data set.

G. Reviews that are Preparatory to Research

The Privacy Rule allows a researcher to access protected health information if he/she
attests that:

   •   The information is being sought solely to prepare a research protocol or for
       similar purposes preparatory to research.
   •   No protected health information will be removed from the medical record offices.
   •   The information being sought is necessary for research purposes.

This provision may be useful for examining medical records in order to formulate
hypotheses, assess feasibility of a project, or determine the availability of data or a patient
base. Investigators may review identifiable data in order to make these determinations;
however, HIPAA requires that any information recorded during that review must meet
de-identification standards. The preparatory review may not be used for recruitment


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purposes. For example, researchers may not record names and contact information during
the review.

HIPAA privacy regulations do not require IRB or privacy board review of activities
preparatory to research. As a general rule, this pre-research activity will not require IRB
submission because no formal protocol exists. Questions about the necessity of IRB
review should be directed to the SCRIHS office.

HIPAA regulations require that when a medical record is accessed for activities
preparatory to research, the researcher’s access must be included in the patient’s
accounting of disclosures

H. Research on Decedents

Research on decedents is not subject to human subject regulations; however, it is subject
to the HIPAA Privacy Rule. In order to access medical records on decedents, the
researcher must provide the holder of the medical record with assurances that:

   •   The information being sought is solely for research on decedents
   •   The information being sought is necessary for research purposes

The holder of the medical record has a right to require documentation of the death of the
individuals. HIPAA regulations require that when a medical record is accessed for
research on decedents, the investigator’s access must be included in the patient’s
accounting of disclosures.

I. Research Recruitment under HIPAA

The requirements of the Privacy Rule impact the way in which potential subjects are
identified and recruited for studies. According to the rule, health care providers involved
in the treatment of an individual are allowed to talk with their patient about enrolling in a
research study. This discussion would not require an authorization. However, if the health
care provider shares the patient’s information with an investigator who is not involved in
the patient’s care, either signed authorization from the patient or SCRIHS approved
Request for Partial Waiver of Authorization for Recruitment Purposes is necessary. This
partial waiver allows investigators to view the patient’s protected health information in
order to make a determination about study eligibility. The Request for Partial Waiver of
Authorization for Recruitment Purposes form can be found on the SCRIHS website.

Once a potential subject has been identified, research staff should follow appropriate
ethical standards about contacting the patient. The initial contact should come from
someone who is known to the patient as having legitimate knowledge of their health
status, based on an established clinical relationship.
Allowable Recruitment Practices




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   •   Health care providers who are conducting a study may talk with their own
       patients about the option of study enrollment.

   •   Health care providers may use their own knowledge of the patient’s condition and
       their knowledge about a colleague’s study to inform their patients about a study.
       At that point, two possibilities exist:

                   The provider gives the investigator’s contact information to the
                   patient, and the patient initiates the contact.
                   The patient signs an authorization so that the provider can give the
                   patient’s name to the investigator.

   •   Health care providers may release their patient records to an investigator, if the
       investigator obtains a waiver of authorization from SCRIHS. Then the
       investigator can review the chart, determine eligibility, and work with the
       provider on contacting potential subjects.

   •   The investigator posts SCRIHS-approved flyers or advertisements, and eligible
       patients directly contact the investigator.

J. Accounting for Research Disclosures

Under the Privacy Rule, patients have the right to receive an accounting of certain
disclosures of their protected health information. The accounting process was established
so that patients could learn about how their information was used or disclosed in cases
where written authorization was not required. Disclosures from a patient’s medical record
that are made under a waiver of authorization, for activities preparatory to research, or for
studies on decedents must be included in the accounting process. Investigators are
responsible for assisting the holder of the medical record in fulfilling their accounting
duties.

K. Research Subjects’ Access to Research Records

Under the HIPAA Privacy Rule, patients have a right to access their information that is
maintained in a “designated record set.” The designated record set is the collection of
medical and billing information that is used, in whole or in part, to make clinical
decisions about a patient. The Office of Civil Rights has given guidance that research
records would not necessarily be considered as a designated record set.

L. Record Retention

Investigators are responsible for appropriate record retention to meet HIPAA and other
compliance requirements. The Privacy Rule requires that all documentation concerning
patient privacy must be maintained for six years from the date it was last in effect.
Clinical trial data should be retained at minimum for six years, and longer if required by
the sponsor and/or FDA.

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Section XI: Subject Recruitment

A. What are Subject Recruitment Materials?

Subject recruitment materials are advertisements, brochures, scripts, and other materials
that are used to “directly recruit” subjects for a research study. These include written ads
to be taped for broadcast, notices to be posted on the World Wide Web, and any other
materials to be seen and/or heard by potential subjects.
Subject recruitment materials are viewed as an extension of the consent form. They are
often the first contact a subject may have with information about a study. They must
accurately represent any information that is explained in the consent form.

B. Advertising Guidelines for Subject Recruitment Materials

   •   The procedure for recruitment should not be coercive. Coercion can be defined as
       any undue use of position, authority or inducement to persuade a subject to enroll
       in a study.

   •   Do not state or imply a certainty of favorable outcome or other benefits beyond
       what is outlined in the informed consent document and the protocol. Usually
       research means that a hypothesis is being tested and therefore favorable outcomes
       are uncertain.

   •   Do not make claims, either explicitly or implicitly, that a drug, biologic, device,
       or procedure is safe or effective for the purposes under investigation or that the
       test article is known to be equivalent or superior to any other drug, biologic,
       device, or procedure.

   •   Do not use terms such as “new treatment,” “new medication,” or “new drug”
       without explaining that the test article is investigational, not yet FDA approved.
       The terminology “novel treatment” is not acceptable due to the possibility some
       subjects may think the treatment sounds enticing. You may not use the
       terminology “treatment” for interventional studies. Treatment relates to medical
       care and not to research.

   •   Do not promise “free medical treatment” when the intent is only to say that
       subjects will not be charged for taking part in the study.

   •   Advertisements may state that subjects will be compensated but should not
       emphasize the payment or the amount to be paid. Compensation is something,
       such as money, given as payment for a service, or in this case, for the time a
       person is dedicating to the study. A simple statement of “Compensation will be
       provided” is acceptable.



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   •   If reimbursement will be provided, this may be stated. Reimbursement is defined
       as paying back or compensating for money spent. Acceptable phrases for
       reimbursement: “You will be reimbursed for your parking expenses.” or “All
       travel expenses will be reimbursed.” or “You will be provided with a reduced fee
       parking sticker for the hospital parking garage.” or “Travel expenses up to $25 for
       each completed visit will be provided.”

   •   When advertisements are to be taped for broadcast, the IRB should review and
       approve the wording of the advertisement prior to taping. When physicians are
       being interviewed on general medical topics, not in relation to a research study,
       the IRB is not involved.

   •   It is assumed that when subjects are used in an interview for purposes of
       recruiting additional subjects, the subject has signed an approved consent form,
       for the study that is being advertised, prior to participating in the interview. In
       addition, subjects are often asked to sign media releases. Enrolled subjects who
       may be approached to give a testimonial about their participation in a study must
       not feel coerced. Subjects must not be encouraged to make claims about the
       efficacy of the study especially since the study is in progress and such claims are
       largely anecdotal.

C. What Subject Recruitment Materials must be Reviewed by the IRB?

All materials and methods for subject recruitment must be reviewed and approved by the
IRB before use. They can be reviewed at the time of the original submission or submitted
during the course of the study as an Amendment Summary. No materials may be posted
or used without prior IRB review and approval. The purpose of the review is to ensure
that the information is not misleading to potential subjects, that it reflects information
stated in the consent form accurately, and that it complies with SIU School of Medicine
guidelines.

D. Procedures for Investigators

To gain further understanding of the procedures for submitting recruitment materials for
IRB review, the following guidelines have been provided:

   •   Prepare the materials for broadcast, advertisement, or distribution. (See section Y
       “Guidelines for Press Releases”)
   •   Submit the materials with the Application for Approval. If the materials are not
       included, note in the Application that they will be sent later.
   •   If sent after study approval, submit the materials with a completed Amendment
       Summary Form.
   •   If the study is industry sponsored be sure the sponsor has seen the materials
       before submission to avoid any conflict with contractual obligations.



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   •   If materials are to be used for more than one study, please submit an Amendment
       Summary and copies of the materials for each study so that each study file can be
       kept up-to-date.
   •   Because recruitment materials are considered an extension of consent, the consent
       form must be approved first or the recruitment materials can be reviewed and
       approved in conjunction with the consent form review.
   •   When submitting revisions to the consent form during the course of the study, be
       sure to check that the recruitment materials don’t need updating too.



E. Tone and Style of the Recruitment Materials

Since many potential subjects may not have previously participated in a research study or
clinical trial, it is important to leave a positive impression from the first contact with the
idea of participating in research. Investigators must remember that participation in
research is voluntary. If one potential subject has a bad experience they often tell their
friends and family about the difficult experience. This can impact the ability of future
researchers to recruit persons into studies.

SIU School of Medicine wishes to convey in their recruitment materials the quality of the
University, a professional demeanor, and an honest statement about the study.

Recruitment materials should include just enough information to interest prospective
subjects. Detailed inclusion and exclusion criteria should not be included, as it is the
physician’s responsibility to appropriately screen subjects, though age ranges and gender
criteria may be included.

Pictures or designs should be tasteful and appropriate to the study. For example, a study
for an arthritis drug should not include a picture of an old, bent-over woman.

F. Recruiting Strategies and Methods

Patient recruitment strategies need to balance accuracy, subject comprehension, and
voluntariness. In addition, HIPAA regulations must be considered when planning
recruitment strategies.

In the case of a funded study, the recruitment strategy can actually be considered a part of
a business plan. Investigators have contractual agreements that indicate how many
patients they think they can enroll, and because of this, the recruitment strategy must be
structured so there is a reasonable expectation of success. With this in mind, it is easy to
understand why the IRB wants to know how people will be recruited into studies, and
how they will be compensated (if at all).

“IRBs must consider whether paid participants in research are recruited fairly, informed
adequately, and paid appropriately. Taking into consideration the subjects' medical,

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employment, and educational status, and their financial, emotional, and community
resources, the IRB must determine whether the rewards offered for participation in
research constitute undue inducement.
(IRB Guidebook found at: http://ohrp.osophs.dhhs.gov/irb/irb_guidebook.htm)

G. FDA Rules on Recruitment and Payment for Study Subjects

The FDA has very specific guidelines on recruitment and payment for human subjects.
Investigators who conduct studies with FDA oversight should be familiar with the two
documents listed below.

Recruiting Study Subjects: http://www.fda.gov/oc/ohrt/irbs/toc4.html#recruiting
Payment to Research Subjects: http://www.fda.gov/oc/ohrt/irbs/toc4.html#payment

H. Inclusion of Women, Minorities, and Children

The Belmont Report principle of justice requires that the benefits and burdens of research
be fairly distributed, that no group be singled out as participants in research nor that any
one group might be the sole beneficiary of the outcomes of research. Therefore, the
government has established regulations regarding balancing race and gender of subjects
in clinical research.

NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical
Research - Updated August 1, 2000.
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm

Inclusion of Women and Minorities as Participants in Research Involving Human
Subjects - Policy Implementation Page.
http://grants.nih.gov/grants/funding/women_min/women_min.htm

I. Use of Vulnerable Populations as Potential Research Subjects

Vulnerable populations are those persons who may not be competent to understand the
information presented to them, who may be susceptible to coercion or undue influence
either because of their status, a disability, or some other factor, and who in some cases
are unable to consent for themselves.

To provide maximum protection when recruiting vulnerable populations, both
recruitment strategies and the consent process must be carefully considered and explained
in the Application for Approval. Often legally authorized representatives participate in
the recruitment and consent processes if the subject is cognitively impaired or cannot
provide consent.

Vulnerable populations may include persons from the following groups:

       Prisoners                               Persons with Low Literacy


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       Institutionalized Persons              Drug Addicts
       Cognitively Impaired Persons           Prostitutes
       Comatose Persons                       Elderly Persons
       Children                               Employees
       Minorities                             Students
       Terminally Ill Persons                 Pregnant Women
       Fetus

In some instances there are specific federal regulations regarding the use of persons from
these groups as research subjects. In other instances a basic understanding of ethical
principles will inform the investigator that special precautions need to be in place. Often
persons have more than one quality that makes them a vulnerable population.

Issues regarding recruiting vulnerable populations vary according to the particular
vulnerability. Investigators are encouraged to discuss recruitment strategies with SCRIHS
staff when proposing research involving such populations.

The federal regulations specifically address particular vulnerable populations in Subparts
of Title 45, Part 46 of the Code of Federal Regulations including the policy on research
that involve: fetuses, pregnant women, and human in vitro fertilization (Subpart B);
prisoners (Subpart C); children (Subpart D).

J. What is Coercion and Undue Influence?

An agreement to participate in research constitutes a valid consent only if voluntarily
given. This element of informed consent requires conditions free of coercion and undue
influence. Coercion occurs when an overt threat of harm is intentionally presented by one
person to another in order to obtain compliance. Undue influence, by contrast, occurs
through an offer of an excessive, unwarranted, inappropriate or improper reward or other
overture in order to obtain compliance. Also, inducements that would ordinarily be
acceptable may become undue influences if the subject is especially vulnerable.

An understanding of the concept of coercion will help investigators clarify why some
recruitment procedures and strategies are considered unacceptable. Researchers, whether
clinicians or university faculty, may have an elevated status in the minds of many
potential subjects.

Investigators must keep in mind the importance of maintaining the voluntary nature of a
subject’s participation in research. Voluntariness means that there is agreement about the
terms of the relationship. Subjects should be encouraged to ask questions. Full disclosure
by the investigator is part of the voluntary relationship. The investigator cannot expect
that fully informed legal consent has taken place if information about the study is either
withheld or if procedures and risks are glossed over.
Incentives to participate in research may affect the voluntary nature of the agreement.
Other elements that compromise voluntariness may be pain, the fear of death, a chronic



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illness, a power relationship such as employer/employee or faculty/student relationships,
a lack of education, or illiteracy.

Compensation, other than payment for the amount of time to participate in the study, can
also be viewed as coercive.

K. Competing Studies by the Same Investigator

When an investigator has more than one study for a similar patient population, and it is
not clear if there are different inclusion and exclusion criteria, the investigator must
explain to the IRB how patient enrollment will be handled in the two competing studies.
The investigator will also need to provide a complete and thoughtful explanation why
there is a need for two competing studies.

One problem with competing studies is that there may not be a sufficient number of
subjects to carry out both studies. When this occurs, it may not be possible to make
statistically sound conclusions in one or both of the studies. This, in turn, by diminishing
what might be possibly learned from the study, may warrant undertaking the studies in
the first place. Without sufficient enrollment, the generalizability of the research (or
statistical significance) may not warrant the risk that subjects take on.

The concern of the IRB is that whoever is enrolled will receive the greatest possible
benefit from their participation in the studies. Investigators, who receive varying amounts
of reimbursement for each patient enrolled, might favor one study over the other when
considering who to enroll in which study, if there is more money to be gained.

Generally, the IRB discourages competing studies by the same investigator for the same
patient population. Sponsors often ask investigators to sign a non-compete clause.

L. Recruitment Registries

Registries are useful in collecting potential research subjects either with particular
diseases or conditions, or a general willingness to be contacted about participation in
research studies.

Registries must be reviewed and approved by the IRB in the same fashion as a clinical
study. Registries take time to set up and require maintenance. Policies must be in place
regarding the information contained in the registry. What is described in the consent form
to the potential registry participant must parallel the policies described to the IRB,
including who has access, how long information will be kept, how often registry
participants may be contacted, and what information will be shared with those requesting
use of the registry. All persons in registries must have given consent to be in the registry.


Other issues that may be appropriate to address, depending on the type of registry are:



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1.   How are deaths updated in the registry?
2.   How are persons re-contacted if the “rules” regarding the registry change?
3.   Is there a mechanism to track how many times a person is contacted about studies?
4.   What is the process by which someone can request the their removal from the
      registry?

Investigators should contact SCRIHS for guidance in setting up a registry. Samples of
materials from other registries can be shared with those who are interested in developing
this recruitment tool.


M. Disease Registries

 Disease registries may be used for recruitment when the consent that is in place, when
the subject was initially approached, indicates that investigators will be placing the
participant’s name in a registry; so they can be contacted at a future date about other
studies or to track the course of their disease. Often disease registries pool data from
many sites and offer investigators additional resources to learn more about disease
progression. Disease registries often involve collecting, storing, and analyzing blood or
tissue samples.

If an investigator with a new study wishes to use a registry where prior consent is not in
place, the gatekeeper of the registry must become an intermediary and agree to send a
letter to registry participants to inquire if they wish to be contacted. Confidentiality
concerns prohibit new investigators from taking names and sending an inquiry to registry
participants without an intermediary. The new investigator does not “inherit” access to
the names, only the agreement to be contacted for the particular study in question.

N. Contacting SIU Employees about Participation in Research Studies

SIU School of Medicine does not allow the University e-mail system or University-
produced mailing labels to be used for broadcast announcements for human subjects
recruitment. The use of mailing lists from Human Resources is not an acceptable method
for recruiting SIU School of Medicine employees into research studies. SIU School of
Medicine employees have the right to not be solicited for participation in research
studies. They may wish to respond to flyers and notices that are posted on campus. It is
important that employees not feel as though they are a captive pool of research subjects.

O. Accessing Student Information and Records

Accessing student records for the purposes of recruitment poses restraints on researchers.
There are several laws in place that protect the confidentiality of student records.
Whether a researcher is studying elementary school children, high school students, or
college students, the Family Education Rights & Privacy Act (FERPA) Regulations limit
access to confidential school records. The three fundamental rights covered by FERPA
are:


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     1. The right to review and inspect education records;
     2. The right to request to amend education records;
     3. The right to limit disclosure of personally identifiable information.

Additional information about FERPA can be found at the website:
http://www.ed.gov/offices/OM/fpco/

P. Privacy and Confidentiality

Phrases such as “your confidentiality will be protected” are sprinkled in the language of
research studies, consent forms, information sheets, and recruitment advertisements.
What exactly such phrases mean is open to varying degrees of understanding both by the
investigator, the research staff, and the subject.

A process to protect the confidentiality of names and contact information collected from
potential subjects must be planned ahead of time. This information must be maintained in
a confidential manner.

For purposes of recruitment, researchers should not have access to any confidential or
private information about a prospective subject without the subject's prior consent; this
includes school children and their parents, clients of private or public assistance
programs, and patients. Under certain circumstances, researchers may be required to
obtain the permission of agencies responsible for the care of the prospective subjects
before recruiting them. When obtaining the names of potential participants from third
parties, the investigator must consider whether any breach of confidentiality or privacy
laws has occurred. For example, doctors must contact their patients for permission before
releasing their names to a third party.

The third party does not have the right to access the names in the future if the potential
subjects do not indicate that they do not wish to participate. In other words, the condition
of receiving names is for the specific study in question and may not be stored for contact
about other studies.

Investigators are responsible for ensuring that approved procedures are followed by any
third parties (e.g., therapists, teachers, or social-service providers) who may be aiding in
the recruitment, advertising, and/or informed consent process.

Q. Screening Patient Data

An Investigator can review his/her own patients data (e.g., medical records, X-rays,
EKGs, etc.) to identify potential subjects for a research study. However, if an
investigator wishes to review records of patients other than his/her own (another covered
entities records) to identify potential subjects, HIPAA compliance must be considered.
The investigator must submit a Request for Partial Waiver of Authorization for
Recruitment Purposes to the SCRIHS office. This request must be approved by the IRB


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Chair and the investigator must receive a signed copy of the form before proceeding to
review any records. This form can be found on the SCRIHS website.

Investigators may not employ other types of indirect or circuitous techniques to identify
potential research subjects.

R. Payment for Participation

When investigators propose payments for research subjects they should be clear about
why they are paying the subject. It is acceptable to pay subjects for their time and
discomfort, but the payment should be commensurate with the amount of time they will
be involved in the study.

SCRIHS does not use a formula to calculate how much subjects should be paid but
SCRIHS does weigh the factors mentioned above in determining if the proposed payment
is reasonable.

Payment as an incentive to participate in research must be approached with great care.
Financial incentives are often used when health or other benefits to subjects are remote or
non-existent. The use of incentive pay is looked at closely, to make sure that subject
populations are not coerced to participate as a result of their financial situation. All
incentive pay must be distributed equally to all subjects — control subjects, normals and
those with a disease or condition.

Payments cannot be withheld until the end of the study. All payments should be pro-rated
to reduce coercion. This is to say, that payment should follow each visit or phase of the
study and the rationale for the timing of when and how much a subject is paid should be
fully explained in the protocol and consent form.

For example, a study with ten visits might offer $25 after each visit for a total of $250 for
participation. On the other hand, the same study with ten visits, offering $10 after each
visit and a lump sum payment after the final visit of $150 is offering the same amount of
money but in a more coercive manner.

Subjects have the right to stop participating in the study at any point in time. Therefore, it
is less coercive if subjects are paid as they participate in the study.

Payment for participation cannot be listed as a benefit in the consent form.

S. Compensation for Injury

Investigators should not confuse incentive payments as an “escrow account” for a
subject’s compensation for injury. In other words, receipt of payment does not mitigate
the need to address issues regarding compensation for injury.




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Compensation for injury is generally worked out through the contract with the sponsor.
The specifics regarding compensation for injury must be clearly spelled out in the
consent form.

SCRIHS requires a copy of the model consent form or a letter, on company letterhead,
stating the company will pay for research related injuries.

T. Incentives for Participation Other Than Payment

Many studies use incentives other than cash payments. Some incentives can be seen as
coercive and others are merely small tokens of appreciation. Investigators need to weigh
carefully whether any items given to subjects might influence the subject to buy products
from a particular pharmaceutical company because they receive many items with the
name of the company imprinted.

The use of any incentive gifts must be stated in the initial protocol submission. If the
need arises at a later point in time in the study, an Amendment Summary request must be
submitted explaining what is being handed out and its value. The incentive items do not
have to be submitted to the IRB as there is difficulty in storing such materials. They can
be described in the submission form.

Incentives cannot be listed as a benefit in the consent form.

U. Lotteries

The use of lotteries for subject incentives is acceptable only when the odds of winning
the “prize” are clearly spelled out in the consent form. Generally the IRB does not accept
lotteries where a great deal of money can be won. For example, recruitment lotteries that
offer over $100 can be considered coercive.

V. Reimbursement of Expenses

Investigators are encouraged to provide adequate reimbursement for study participants. It
is appropriate to provide funding for the cost of traveling to the study, parking, a meal
voucher if the person is at the clinic for a long period of time and any other costs that
should be borne by the study.

Often investigators think that the benefit is the participation — that a particular drug or
procedure might benefit the subject. Investigators need to keep in mind that the research
is being conducted to find out if there is a benefit. The unanticipated benefit that might
occur because one subject does feel improvement in their condition, or one subject
receives active drug instead of placebo should not be construed as a benefit and therefore
mitigate the need to reimburse subjects for the cost of their participation.
Reimbursement for expenses should relate to actual costs without placing an undue
burden on the subject or on the investigator to keep extensive records and receipts.



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W. Extra Costs for the Subject because of Study Participation

It is important that any additional cost burdens that a subject might incur by participation
in the study be fully explained to the subject at the recruitment stage of the research
study. A good time to do this is during the recruitment interview. If study subjects will
have to undergo tests, surgery, or other procedures that they would not normally do and
therefore their insurance would not pay for them, they need to be appraised of the
potential costs. Even if costs will be covered by insurance, subjects should be informed of
additional costs that will be incurred if additional visits or tests and procedures will be
completed that could result in additional insurance co-pays and out of pocket expenses
such as travel to visits, parking and missed work.

When research subjects are presented with the consent form, this should not be the first
time that they hear about additional costs that may be involved.

X. Finder's Fees/Kickbacks

Providing financial incentives to third parties for enrolling subjects is
considered coercive, and is prohibited. Finder's fees are defined as
monies, or other incentives, for referring or recruiting subjects for a
clinical investigation. This includes, but is not limited to, providing meals,
credit towards conferences, or textbook expenses, in addition to actual
cash. Receiving such incentives may be a criminal or civil violation of
federal fraud and abuse laws under 42U.S.C. §1320(a)-7b (“Anti-Kickback
Statute”) and 42U.S.C. §1395nn (“Stark Law”)

Y. Guidelines on Press Releases and Recruitment: Media Relations Departments

Most investigators choose to use the public relations department to help write recruitment
materials and press releases. All press releases must ultimately be approved by the public
relations department. When the intent of a press release or other media materials is to
generate interest in a research study that is in progress, where recruitment is continuing,
the press release must be reviewed by the IRB.

Media scripts, brochures, flyers, web site postings, and other materials designed to
describe research in progress and encourage participation must be approved by the IRB
prior to publication and distribution. These materials can be sent with the original
submission of a study or, once the study is approved, it should be submitted with an
Amendment Summary Form. When materials are produced without the appropriate
review and approval, investigators will not be allowed to use the materials.

A common error that occurs in preparing press releases or other materials is the use of
statements that the research has proven efficacious or may benefit participants. Often,
research data are not yet analyzed and compiled when research is in progress and such
statements are not accurate. They mislead potential participants and raise expectations

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that a particular disease may be “cured” by participation. It is well known that the
nuances of the phases of clinical research, efficacy, and whether something is FDA
approved or still experimental often are not understood completely by participants.

When submitting posting for websites, the SCRIHS protocol number must be included in
the listing so that SCRIHS can check approval status quickly. Further, an Amendment
Summary Form must be submitted for each study listed as each study must have a record
of active approvals in the correct file.

**Note: If you are submitting a press release for a study, it must be reviewed by the
Public Affairs office prior to submission to SCRIHS. If you are submitting a
newspaper advertisement for a study, it must by reviewed by Ann Collins in the
Marketing Dept. prior to submission to SCRIHS.

Section XII: Special Issues

A. Cognitively Impaired Policy

The predominant ethical concern in research involving individuals with psychiatric,
cognitive, developmental disorders, or who are substance abusers, is that their disorders
may compromise their capacity to understand the information presented and their ability
to make a reasoned decision about participation. In addition, for individuals with
disabilities affecting their reasoning powers who are residents of institutions responsible
for their total care and treatment, the impact of institutionalization may further
compromise their ability to exercise free choice.

Definitions

Cognitively Impaired: Having either a psychiatric disorder (e.g., psychosis or mood,
anxiety, personality or behavior disorder), an organic impairment (e.g., dementia) or a
developmental disorder (e.g., mental retardation) that affects cognitive or emotional
functions to the extent that capacity for judgment and reasoning is significantly
diminished. Others, including persons under the influence of or dependent on drugs or
alcohol, those suffering from degenerative diseases affecting the brain, terminally ill
patients, and persons with severely disabling physical handicaps, may also be
compromised in their ability to make decisions in their best interests.

Competence: Technically, a legal term, used to denote capacity to act on one's own
behalf; the ability to understand information presented, to appreciate the consequences of
acting (or not acting) on that information, and to make a choice. (See also: Incompetence,
Incapacity.)

Competence may fluctuate as a function of the natural course of a mental illness,
response to treatment, effects of medication, general physical health, and other factors.
Therefore, mental status should be re-evaluated periodically. As a designation of legal
status, competence or incompetence pertains to an adjudication in court proceedings that


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a person's abilities are so diminished that his or her decisions or actions (e.g., writing a
will) should have no legal effect. Such adjudications are often determined by inability to
manage business or monetary affairs and do not necessarily reflect a person's ability to
function in other situations.

Incapacity: Refers to a person's mental status and means inability to understand
information presented, to appreciate the consequences of acting (or not acting) on that
information, and to make a choice. Often used as a synonym for incompetence.

Incompetence: Technically, a legal term meaning inability to manage one's own affairs.
Often used as a synonym for incapacity.

Institution: A residential facility that provides food, shelter, and professional services
(including treatment, skilled nursing, intermediate or long-term care, and custodial or
residential care). Examples include general, mental, or chronic disease hospitals;
inpatient community mental health centers; halfway houses and nursing homes; alcohol
and drug addiction treatment centers; homes for the aged or dependent; residential
schools for the mentally or physically handicapped; and homes for dependent and
neglected children.

Problems of Consent and Competence

As a general rule, all adults, regardless of their diagnosis or condition, should be
presumed competent to consent unless there is evidence of serious mental disability that
would impair reasoning or judgment. Even those who do have a diagnosed mental
disorder may be perfectly able to understand the matter of being a research volunteer, and
quite capable of consenting to or refusing participation. Mental disability alone should
not disqualify a person from consenting to participate in research; rather, there should be
specific evidence of individuals' incapacity to understand and to make a choice before
they are deemed unable to consent.

Persons formally adjudged incompetent have a court-appointed guardian who must be
consulted and consent on their behalf. For incompetent persons who are institutionalized,
consent by officials of the institution in which the person resides (even if they are the
person's legal guardians) is not generally considered appropriate, since the supervisory
duties may give rise to conflicting interests and loyalties. Family members or others
financially responsible for the patient may also be subject to conflicting interests because
of financial pressures, emotional distancing, or other ambivalent feelings common in
such circumstances.

Some individuals may be incompetent and have no legal guardian, for example, geriatric
patients with progressive cognitive disorders. Typically a spouse or adult child of such
persons consents to their medical care, but no one is their legally authorized
representative. The extent to which family members may legally consent to the
involvement of such persons in research (especially if no benefit to the subject is
anticipated) is not clear.


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If the participant is not capable of giving consent due to medical condition or mental
capacity, consent must be obtained through a legal guardian or power of attorney. In this
case assent must be sought from the participant. The Assent Form for Cognitively
Impaired participants must be utilized in conjunction with the Informed Consent Form.
The Assent Form for Cognitively Impaired participants is located on the SCRIHS
website.

POLICY: Investigators must submit the following with the Application for
Approval for new studies: procedures for evaluating the mental status of
prospective subjects to determine whether they are capable of consenting;
procedures for obtaining the consent or assent of prospective subjects, if
appropriate; procedures for determining the conditions under which consent may
be provided by legally authorized representatives of prospective subjects.

Also, in studies where cognition may change during the course of the study, for
example with persons who have Alzheimer’s disease, a procedure must be set up to
evaluate the person each time they come to the study clinic to assure continuing
comprehension about study participation. In some cases, a caregiver may be a part
of the study in which case such evaluation may not be necessary. In other cases,
where the subject comes on their own, it is important that the investigator is sure
they remember their involvement and what the study is about. Sometimes Mini-
Mental Status Exams are employed; other times, specific tests that pertain to the
study may be used.

The investigator must certify there is a process for reassessment if there is concern
that the cognition status of the subject may change

Because no generally accepted criteria for determining competence to consent to research
(for persons whose mental status is uncertain or fluctuating) exist, the role of the IRB in
assessing the criteria proposed by the investigator is of major importance.

Criteria for determining competence might vary according to the degree of risk or
discomfort presented by the research procedures and the extent to which therapeutic gain
can be anticipated. Investigators should recognize that the setting in which consent is
sought as well as the person seeking the consent can influence a prospective subject’s
ability to comprehend or appreciate what is being asked. In certain cases SCRIHS may (i)
require a competency assessment by someone independent from the investigator at the
time of enrollment and during a subject’s participation in the research, if mental capacity
is likely to diminish, and (ii) appoint a consent monitor to supervise the informed consent
process.

The selection of an appropriate representative to consent on behalf of those unable to
consent for themselves must be accomplished without clear guidance from statutes, case
law, or regulations; however, within the boundaries of existing precedents, SCRIHS will
seek to help investigators formulate appropriate procedures for these uncertain areas.


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Among other things, SCRIHS may consider whether to require investigators to solicit
prospective subjects’ assent (i.e., the willing and, to the extent possible, knowledgeable
participation of those unable to give legally valid consent), and SCRIHS may consider
whether an incompetent person’s refusal to participate in research should override
consent given by a legal guardian. Such decisions may be based on the amount of risk
involved in the research and the likelihood that subjects will derive health benefits from
their participation.

Selection of Subjects

It is now generally accepted that research involving persons whose autonomy is
compromised by disability or restraints on their personal freedom should bear some direct
relationship to their condition or circumstances. Persons who are institutionalized,
particularly if disabled, should not be chosen for studies that bear no relation to their
situation just because it would be convenient for the researcher. Institutional settings can
create circumstances that may compromise the voluntary nature of participation in
research. For example, institutionalized individuals may have become emotionally
dependent on their caretakers and may acquiesce too readily to requests for their
"cooperation." Persons who are totally dependent on an institution may be vulnerable to
perceived or actual pressures to conform to institutional wishes for fear of being denied
services or privileges. If medical care, staff attention, or living conditions are inadequate,
an invitation to move into a special unit or research ward may be appealing. Finally, with
little or no opportunity to make decisions regarding their daily living, the ability of
institutionalized subjects to make choices may be further diminished. Investigators must
provide SCRIHS with sufficient justification for using an institutionalized
population.

The “Risk and Benefit Evaluation for Cognitively Impaired Persons”

Although DHHS regulations charge the IRB with ensuring that adequate safeguards are
in place to protect the rights and welfare of vulnerable subjects, including those with
mental disabilities, no additional DHHS regulations specifically govern research
involving cognitively impaired subjects. The National Commission for the Protection of
Human Subjects has, however, issued recommendations for protection of cognitively
impaired subjects similar to the recommendations made with respect to children. In light
of these recommendations, SCRIHS shall determine the level of risk and benefit the study
poses to cognitively impaired subjects.

The assigned primary and secondary reviewers of the study protocol undergoing full
board review must evaluate the level of risk and benefit the study poses and report their
recommendations to the board on the Reviewer’s Checklist. These recommendations will
be discussed during full board review and the discussion and conclusion of the board will
be documented in the minutes.

Instructions for Assessing Risk and Benefit



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Minimal risk means that the probability and magnitude of harm or discomfort anticipated
in the research are not greater in and of themselves than those ordinarily encountered in
daily life or during the performance of routine physical or psychological examinations or
tests.

Research that presents more than minimal risk should involve cognitively impaired
subjects only if there is a prospect of direct benefit from participation.

If research does not involve beneficial interventions and presents more than minimal risk
to cognitively impaired subjects, the anticipated knowledge must be of vital importance
for understanding or eventually alleviating the subjects’ disorder or condition. Research
proposals of this nature may require SCRIHS to obtain assistance from expert
consultants.

B. Children

Special procedures are in place in the Federal Regulations that provide additional
safeguards for the protection of children involved in research activities. The IRB will
adhere to 45 CFR Part 46, subpart D or 21 CFR Part 50, Subpart D.

       Definitions:

       "Children" are persons who have not attained the legal age for consent to
       treatments or procedures involved in research or clinical investigations, under the
       applicable law of the jurisdiction in which the research or clinical investigations
       will occur. In Texas, a minor can petition to be "emancipated", but must do so by
       filing a petition and meeting the statutory requirements of Sec. 31 of the Texas
       Family Code. Only if a minor were "emancipated" as described above; or was
       adjudicated to be an adult for the purpose of criminal prosecution under the
       Juvenile Justice Code would the state of Texas consider the minor an “adult.”

       "Assent" means the child's affirmative agreement to participate in research or
       clinical investigation. Mere failure to object may not, absent affirmative
       agreement, be construed as assent.

       "Permission" means the agreement of parent(s) or guardian to the participation of
       the child in the research or clinical investigation.

       "Parent" means a child's biological or adoptive parent.

       "Guardian" means an individual who is authorized under state or local law to
       consent on behalf of a child to general medical care when general medical care
       includes participation in research.




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For studies involving children where the risk is greater than minimal, the IRB may
approve only the categories of research listed below provided all applicable criteria are
met:

       (1) Research not involving greater than minimal risk (45 CFR 46.404), if the
       IRB finds that no greater than minimal risk to children is presented, approval may
       be given only if adequate provisions are made for soliciting the assent of the
       children and the permission of at least one (1) parent/guardian. Minimal risk
       means that the probability and magnitude of the harm or discomfort anticipated in
       the research are not greater in and of themselves than those ordinarily encountered
       in daily life or during the performance of routine physical or psychological exams
       or tests.

       (2) Research involving greater than minimal risk but presenting the prospect
       of direct benefit to the individual subjects (45 CFR 46.405), if the IRB finds
       that more than minimal risk to children is presented by an intervention or
       procedure that holds out the prospect of direct benefit for the individual subject,
       or by a monitoring procedure that is likely to contribute to the subject’s well-
       being, approval may be given only if the IRB finds that:

               a. the risk is justified by the anticipated benefit to the subjects, and

               b. the relation of the anticipated benefit to the risk is at least as
               favorable to the subjects as that presented by available alternative
               approaches, and

               c. adequate provisions are made for soliciting the assent of the
               children and permission of at least one (1) parent/guardian, and

               d. a data safety monitoring plan has been established to monitor
               participants.

       (3) Research involving greater than minimal risk and no prospect of direct
       benefit to individual subjects, but likely to yield generalizable knowledge
       about the subject’s disorder or condition (45 CFR 46.406), if the IRB finds
       that more than minimal risk to children is presented by an intervention or
       procedure that does not hold out the prospect of direct benefit for the individual
       subject, or by a monitoring procedure which is not likely to contribute to the well-
       being of the subject, approval may be given only if IRB finds that:

               a. the risk represents a minor increase over minimal risk, and

               b. the intervention/procedure presents experiences to subjects that
               are reasonably commensurate with those inherent in their actual or
               expected medical, dental, psychological, social, or educational
               situations, and

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               c. the intervention/procedure is likely to yield generalizable
               knowledge about the subject’s disorder or condition which is of
               vital importance for the understanding or amelioration of the
               subject’s disorder or condition, and



               d. adequate provisions are made for soliciting assent of the child
               and permission of both parents/guardians, and

               e. a data safety monitoring plan has been established to monitor
               participants.

       (4) Research not otherwise approvable which presents an opportunity to
       understand, prevent, or alleviate a serious problem affecting the health or
       welfare of children (45 CFR 46.407), if the IRB does not believe the research
       meets the requirement of 404, 405, or 406, approval may be given only if:

               a. The IRB finds that the research presents a reasonable
               opportunity to further the understanding, prevention, or alleviation
               of a serious problem affecting the health or welfare of children,
               and

               b. The Secretary of DHHS, after consultation with a panel of
               experts in pertinent disciplines and following opportunity for
               public review and comment has determined either (1) that the
               research in fact satisfies the conditions of 404, 405, or 406, or (2)
               the research presents a reasonable opportunity to further the
               understanding, prevention or alleviation of a serious problem
               affecting the health or welfare of children and the research will be
               conducted in accordance with sound ethical principles and
               adequate provisions are made for soliciting the assent of children
               and the permission of their parents or guardians, and

               c. A data safety monitoring plan has been established to monitor
               participants.

The reviewers of protocols involving children document their findings on the reviewer
checklist form and the IRB formally documents findings in the appropriate minutes.

C. Fetuses, Dead Fetuses, Placenta

To conduct research on fetal tissue or placenta, written consent must be obtained from the
women providing the tissue from abortions, miscarriages, or deliveries.



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The following Federal Law outlines the additional protections for pregnant women,
human fetuses, and neonates involved in research:

Overview of 45 CFR 46 Subpart B
§46.203 Duties of IRBs in connection with research involving pregnant women, fetuses,
and neonates.
§46.201 To what do these regulations apply?
§46.202 Definitions.
§46.203 Duties of IRBs in connection with research involving pregnant women, fetuses,
and neonates.
§46.204 Research involving pregnant women or fetuses.
§46.205 Research involving neonates.
§46.207 Research not otherwise approvable which presents an opportunity to understand,
prevent, or alleviate a serious problem affecting the health or welfare of pregnant women,
fetuses, or neonates.

For further guidance in this type of research please contact the SCRIHS office.

Additional guidance on the use of stem cells is available in “Guidance for Investigators
and Institutional Review Boards Regarding Research Involving Human Embryonic Stem
Cells, Germ Cells, and Stem Cell Derived Test Articles” .

D. Genetics and Consent

A study involving genetic analysis requires special attention to the consent form.The
issues below must be considered and addressed in the consent form.

What is the length of the storage of materials?
Who will have access to the materials? Will they be shared?
Will identifying information be shared?
What will the genetic material be tested for?
What might the genetic material be tested for in the future?
Will the subject will have access to diagnoses based on research?
Are family members involved? How will they be contacted and consented? (See OHRP
Clarification of Third Parties. (http://ohrp.osophs.dhhs.gov/nhrpac/documents/third.pdf)
What can be reasonably expected to be determined from the research?
Is a waiver of consent appropriate? If so, why?

For further guidance in this type of research please contact the SCRIHS office.


E. International Research and Consent

Considerations about informed consent and international research focus primarily on
whether consent is a culturally appropriate methodology and what language should be
used for the consent document.


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In addition to a review and consideration of the issues reviewed in the section on
International Research, investigators need to be prepared to provide adequate information
to the IRB so that a complete description of the international site is presented.

For further guidance in this type of research please contact the SCRIHS office.

F. Research Involving Medical Students

The involvement of students in research is common in the social and behavioral sciences.
Student participation in research provides researchers with readily available subjects and
students can benefit from the research experience. Although the federal regulations do
not provide explicit protections for students as subjects, their involvement may present
special concerns to SCRIHS. Potential concerns include:

   •   Potential for Coercion. Student participation in faculty research can raise
       questions regarding their ability to exercise free choice because of the possibility
       that grades or other important factors will be affected by their decisions to
       participate. To protect against coercion, faculty-investigators should advertise for
       subjects generally (e.g., through subject pools or notices posted in the school)
       rather than recruit individual students or students enrolled in their classes. In
       addition, faculty researchers need to take special care to protect prospective
       participants from adverse consequences of declining or withdrawing from
       participation.

   •   Requiring Research Participation. Requiring participation in research for course
       credit (or extra credit) is controversial. To diminish or eliminate the coercive
       aspect of student participation for course credit, students are to be given the
       choice of equitable alternative activities (e.g., write a brief research paper or
       attend faculty research colloquia). Students who do choose to participate in
       studies should be given several studies to choose from; these studies must not
       involve more than minimal risk; and students should be able to withdraw from the
       study at any time without losing the extra credit.

The oversight of educational research involving medical students and the undergraduate
curriculum is the responsibility of SCRIHS, the Carbondale Human Subjects Committee
(CHSC), the Education Policy Council (EPC), and the Associate Dean for Education and
Curriculum (ADEC). The responsibility of SCRIHS in reviewing the proposed research is
to assure that research subjects are informed of their rights and to protect their welfare.
Since students are a protected class of subjects, this aspect of research is closely
scrutinized by SCRIHS. The responsibility of the EPC and the ADEC in reviewing the
proposed research is to minimize interference with the ongoing curriculum and to protect
institutional interests.

For all research involving SIU SOM medical students and data generated in relation to
implementation and evaluation of the curriculum:

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   •   All proposed undergraduate educational research to be undertaken by SIU SOM
       faculty members, students, residents or staff must be approved by SCRIHS or
       CHSC prior to initiation of the research. The research shall have been approved
       by the ADEC, as evidenced by signature on the appropriate SCRIHS or CHSC
       document, prior to submission to SCRIHS or CHSC.
   •   All proposed undergraduate educational research undertaken solely by faculty
       members, students, residents or staff of institutions other than SIU SOM (i.e.,
       research proposals originating from institutions other than the SIU SOM and not
       having SIU SOM faculty, students, residents or staff as collaborative
       investigators) must be approved by SCRIHS or CHSC prior to initiation of the
       research. The research shall have been approved by the ADEC, as evidenced by
       signature on the appropriate SCRIHS or CHSC document, prior to submission to
       SCRIHS or CHSC. The ADEC shall inform the EPC of each of these research
       studies originating from institutions other than SIU SOM.

For research reviewed by SCRIHS, there is a signature line for the ADEC on the
Application for Approval.

Given that students can be very vulnerable to coercion, SCRIHS reserves the right to
require proposed research involving students to be reviewed by the full board, even if it
may meet the criteria for expedited review.

G. Non-English Speaking and Illiterate Subjects: Enrollment in Research Studies

   1. Regulations and Overview

   Federal guidelines (21 CFR 50.20 and 45 CFR 46.116 and 46. 117)) require that
   investigators who plan to enroll persons as subjects in studies provide consent form
   documentation in a language that is understandable to the potential subject or
   authorized representative. When the subject population includes non-English
   speaking people, the IRB requires a certified translated consent form to assure
   understanding. The investigator will need a plan to accommodate potential subjects
   who are non-English speakers. Further, the relevant sections of the protocol should
   discuss these issues.

   The protocol must fully describe how subjects who do not speak English will be
   recruited, consented, and participate in the study. Though consent may take place
   through the use of a translated consent form, investigators must consider how they
   will work with the subject during the course of the study if the subject does not speak
   English.This must be described in the protocol.

   Principal investigators should be cautious about enrolling persons who do not
   understand what they are being asked to become involved in. If the subject does not
   clearly understand the information presented in the consent form, the subject’s
   consent will not be truly informed and may not be legally effective. Further, subject
   compliance is often jeopardized by a lack of understanding about the study.

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2. Obtaining a Certified Translation of the Consent Form for a Study

There are a variety of ways to obtain a certified consent form. The easiest method is
to use a translation service. (See the links provided for translation services.) The
translation company will provide a letter or a stamp on the consent form declaring
that it is a certified translation. In some instances sponsors will provide translation
services or an already prepared translation. If the consent is provided by the sponsor,
a certifying letter must also be provided.

If investigators wish to use other persons to do the translation, they must have one
person translate the English language consent form into the required language, and
then have a second person translate the foreign language consent back into English.
This is called “back translation.” The “back translation” assures that the meaning in
the foreign language is the same as the English. The two versions of the consent
forms should be compared for accuracy. Corrections should be made if the “back
translated” consent and the original English consent do not agree.

A letter must accompany the consent forms giving the names and language
certifications of both translators. The same person cannot prepare both the original
translation and the “back translation.” To avoid a conflict of interest, it is important
that the translators not be a part of the study staff.

Investigators are encouraged to wait until the final consent form in English is
approved before having it translated. When revisions to the consent form occur
during the course of the study, the consent form that is not in English must be updated
as well.

All consent forms must be submitted to the IRB for review and approval. Consent
forms in languages other than English must have the IRB approval and expiration
stamp on the form.

See below for the names of company who provide translation of consent forms.

3. Who Can Conduct the Consent Interview if the Subject is Non-English
Speaking?

A bilingual person who is conversant with the study and with the consent form can
conduct the consent interview. Investigators are cautioned about using hospital
translation services as those persons may not be familiar with the study in question.
At all times, investigators must consider whether the consent interview results in a
legally authorized consent process.

While a translator may be helpful in facilitating conversation with a non-English
speaking subject, routine ad hoc translation of the consent document cannot be
substituted for a written translation. Further, investigators must consider how they


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will conduct the study with the non-English speaking person through the course of the
study.

4. How Does an Investigator Enroll a Subject Who Unexpectedly Shows Up and
Does Not Speak English?

Overview:
Occasionally subjects who do not speak English are appropriate persons to enroll in a
study. A non-English speaker presents special issues for the investigator in terms of
consent and the conduct of the study. Even unplanned enrollment requires planning
on the part of the investigator. Access to an appropriate translator who can do verbal
translation in addition to a translated consent form approved by the IRB prior to the
consent process are steps that must be taken beforehand. Therefore, enrolling a
subject who is a non-English speaker, when there were not plans to include those who
don’t speak English, takes time, planning, additional resources (to pay for the
translation services), and patience. The person may not be enrolled as quickly as an
English-speaking subject.

Investigators need to weigh carefully whether, even with a translator, a legally
effective consent can be obtained. Can the subject participate fully in the study if they
don’t speak English and the research team did not plan for those who don’t speak or
read English? Who will translate study procedures and instructions during the course
of the study if there was a not a plan in place to translate documents and study visits?

In unplanned enrollment, a translator must assist in an oral translation of the consent
form. A statement must be in the study records and on the English language consent
form indicating that the translation took place and identifying the translator.The
translator needs to document their belief that the subject understands the study fully
and the consent process. If the subject is a patient, a note about the translation should
be made in the patient’s chart as well. There must also be a consent form in the
subject’s native language. The subject will sign the consent from in their language
and the translator and the person obtaining consent should sign both the English
consent and the translated consent documents.

Considerations before making the decision to enroll non-English speaking subjects

While some may use clinical trials for medical care, and in some instances a clinical
trial may be the last possibility of hope as other treatments have failed, working with
a non-English speaking population requires extra care. Not only is the consent
process potentially problematic but the ongoing conduct of the study is a concern.
Will the subject understand what is expected of them? Will they be able to explain
adverse events to the study coordinator on their regular visits? Will they understand
dosing regimes? Will they be reluctant to call the investigator if they sense something
is not right because they are aware that there is not a person who speaks their
language available at all times.



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These concerns must be considered. Further the study records must include
documentation on how consent was done, who was present, who translated, and who
is available to translate during study visits as the study continues. This extra
documentation requires additional work and resources. Study coordinators and
investigators need to be aware of the additional burden that they are sure that the
study subjects understand what is happening in the research study.

Who should do the oral translation?

Investigators are cautioned against using family members as translators as they may
not have sufficient medical or scientific background to explain the study completely.
Interviewing family members about their background and knowledge may help in
verifying that the English speaking family member has enough fluency and education
to be a reasonable translator during the course of the study. Documentation of this
discussion and interview must be included in the subjects’ study records.

Translation Services

Investigators may contact any of the translation services listed below for assistance in
translating consent forms. We understand that these companies have experience in
dealing with translation of research consent forms.

AD-Ex Worldwide
http://www.ad-ex.net
Quotes: translations@ad-ex.net
1-800-223-7753

Corporate Translations
http://www.corporatetranslations.com/overview.htm
netinfo@corporatetranslations.com
(310) 376-1304 4 (310) 376-1394 or

Northwest Translations Incorporated
http://www.nwtranslations.com/
E-Mail Contact: sales@nwtranslations.com
1-800-270-5620

Multilingual Planet
http://www.multilingualplanet.com/index.html
E-Mail Contact: info@multilingualplanet.com
1-617-566-7050




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   5. What about Illiterate Persons who Understand English but Do Not Read or
   Do Not Read Well Enough to Understand the Consent Form Document?

   Enrolling subjects who do not read or do not read well enough to understand the
   consent form requires that the investigator present the consent documentation in a
   verbal format. This normally does not mean that the consent is just read to the
   potential subject. Since most consent forms are written at an 8th grade reading level,
   merely reading the consent may not provide information that is understandable to the
   potential subject. The consent description should, at the very minimum, include all
   the information in the consent form; however an additional explanation may be
   necessary. The investigator is also encouraged to probe with questions to ascertain
   understanding of the consent. During the course of the study, the investigator and
   study staff should take extra care that the illiterate person understands study
   instructions clearly.

   After the verbal presentation of the consent, the illiterate or semi-literate person
   should sign the document with an X. Sometimes illiterate and semi-literate persons
   can sign their name. The name of the subject should be printed.

   A witness to the consent process is required to verify that the study was fully
   explained and no pertinent information was omitted (intentionally or not). The
   witness must sign the consent form as well as the person obtaining consent.

   All subsequent revisions to the consent form must be explained and witnessed in a
   similar manner. The IRB must approve the written summary of what will be
   presented orally and the protocol must include a discussion on how the verbal consent
   process will be carried out.

   6. Are Illiterate Persons Considered a Vulnerable Population?

   Yes, the IRB believes that illiterate persons are a vulnerable population that could be
   subject to coercion and undue influence. Appropriate safeguards must be in place
   when enrollment of such persons is anticipated.

H. Patient Information Sheets or Booklets

Patient information sheets or booklets are viewed as extensions of the consent form,
similar to recruitment materials. They should be submitted with the Application for
Approval of a new study. It is assumed that no additional information on risks or adverse
reactions is included in the information sheet that is not already in the consent form.

Sometimes sponsors decide after a study is underway to create information brochures that
help patients understand the trial or teach them how to handle a particular procedure in
the trial, such as how to mix and self-inject a medicine. Sometimes this information is
made available in videos. These can all be submitted to SCRIHS as Amendment
Summaries.


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As extensions of consent, patient information booklets should be checked for readability
and should be prepared using lay language and at no more than an 8th grade reading level.

I. Photography and Recording

When researchers are planning to videotape, audiotape, photograph, or otherwise record
portions of research procedures, this must be fully explained in the consent form. It must
be made clear whether persons can opt in or out of the recording sessions. If subjects
must agree to be photographed or recorded, this must be stated clearly. If they can opt
out, a special section at the end of the consent form will allow them to indicate whether
they wish to participate in the photography or recording portion of the research.

In some instances, such as gait research, the point of the research is to videotape people
walking and compare the different gaits of persons. In other instances, for example,
taking photographs of recovery from a skin rash may be only for the sponsor to use in
advertising. The reasons by the recording or photography must be fully disclosed. The
disposition of the information after the research must be explained. Further, issues
regarding identification must be clarified.

J. Secondary Data

Human subjects approval is required if the data are collected from human beings. Even
when the data are used as secondary data, an IRB submission must be made. If the data
are to be stored for other uses, this must be fully explained in the original consent form.

Secondary data are gathered for other purposes, such as census, Medicare, and consumer
data. Generally it is stripped of identifying information and often some preliminary
analysis or grouping has been performed. Generally the investigator planning to use the
data was not the person responsible for the original collection or analysis of the data.
Usually the investigator has no access to identifying information.

The IRB may ask for certification that the subjects were consented when the data were
initially gathered. They may also ask for clarification that the consent form explained the
secondary uses of the data and explained whether the identifiers would be stripped from
the data.

When data sets from non-public sources are used, the IRB may ask for a certification
from the gatekeeper of the data, and verification that the potential secondary use was
fully explained in the original consent form.

K. Sensitive Information

Sensitive information is any information that by its release to “an unauthorized source”
could cause embarrassment or shame; or could potentially impact employability or
insurability or the delivery of other kinds of services.


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When this type of information is collected in a research study it requires the utmost care
to assure that the information is kept confidential. Investigators must take care on a
personal level by making sure questionnaires, mailing lists, and other data are not left
lying around an office, by a computer where data input may be done, or in a lab where
others may come and go and see the information.

Coding the names of the subjects by using a number or other code immediately offers a
layer of protection and anonymity that is important in upholding the commitments made
in the consent form about confidentiality. The list of names and codes associated with
them must be kept in a locked file inaccessible to others. Protecting subjects who provide
sensitive information places trust in the investigator that they will abide by standard data
management practices. Good data management starts with a coding plan that is
implemented as soon as data are collected.

Some examples of sensitive information that may be collected include:

   •   Information about sexually transmitted diseases
   •   Information about HIV status or other health conditions.
   •   Information about sexual preference
   •   Information about illegal activities
   •   Information about people’s psychological state
   •   Information about being the victim of abuse

L. Tissue and Blood Collection:

   1. Surgical Waste and Extra Materials

   Investigators wishing to obtain tissue or fluid should contact the Pathology Labs
   about obtaining samples, coding samples, and appropriate procedures to use samples
   in research studies. Current regulations do not allow for the collection of waste
   surgical tissue or fluids from the operating room or from other investigators without
   an appropriate IRB submission. The Pathology Labs can provide samples for any type
   of tissue or fluid study.

   All procurement procedures must be fully described in the protocol, in addition to the
   scientific justification of the intended use of the samples. Other issues that must be
   addressed prior to obtaining tissue are whether consent was obtained, whether the
   researcher expects to have access to medical records, whether the samples are made
   anonymous, and whether samples are procured in an appropriate manner.

   Investigators should not make arrangements with operating room staff to procure
   leftover surgical materials — placentas, breast tissue, foreskins, etc. without
   appropriate IRB approval.

   2. Storage for Future Use


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   In a study where there is extra tissue and blood collected that will be stored for future
   use, the proposed use must be fully described in the protocol and a tissue banking
   consent form. Subjects need to know what type of studies may be done on the stored
   blood or tissue, whether the samples will be identified, whether genetic information
   will be gathered and analyzed as part of the research, how long the samples will be
   stored, who will have access to them, and how they will be disposed of after use.
   Further, subjects need to know if they will be notified if something is discovered from
   their sample that could provide important health information. Additionally,
   clarification must be provided in the consent form about commercial potential from
   the development of the samples into a product, including whether the subjects will
   share in any profits.

M. Vulnerable Populations

When working with a vulnerable population in a research study, issues related to the
consent process, understanding fully authorized legal consent, and the possible need to
appoint a subject advocate must be considered. It is important to note that vulnerable
populations cannot be studied under an exemption certification. In the chart below, some
types of vulnerable populations are listed and some of the issues that must be considered
outlined.

   Vulnerable             Issues to consider regarding consent and how attributes of the
   Populations            vulnerable population manifests itself in the consent process.
   Children               Protected class of persons cannot voluntarily consent without parental
                          consent. Children may sign assent form depending on age; See Subpart D
                          of Title 45, Part 46 of the Code of Federal Regulations contain the federal
                          policy on research that involves children:
                          Other sections of this manual deal with assent issues.
   Cognitively            May pass in and out of understanding; ability to understand consent form
   Impaired               and ongoing participation may change from week to week; ability to
   Persons                understand consent form may be permanently impaired; judgment and
                          reasoning affected. Assessment must occur so that the investigator knows
                          the condition of each participant. Sometimes assessment must occur each
                          time subject is seen as part of the study.
   Comatose               Cannot give consent; need appropriate and legally authorized surrogate.
   Persons
   Drug Addicts           Involved in illegal activities; Certificate of Confidentiality should be
                          considered.
   Economically           May agree to be involved only for free medical care or payment made for
   Disadvantaged          participation when it may not be in the best interests of the individual.
   Persons
   Elderly Persons        Cognition levels may vary during the course of the study
   Employees              May feel coerced by employer to participate. Sometimes lab staff are asked
                          to be normal subjects. There can be no requirements of employment that
                          coerce employees to participate if they don’t want to.
   Hearing-               If a deaf person wishes to enroll in a study how will the investigator make

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Impaired            sure the consent process has been complete. It is not enough to have the
Persons             consent form for the subject to read. How will questions be handled? How
                    will future visits be handled? Does someone on the study staff know sign
                    language?
Institutionalized   May not understand consent form, may be cognitively impaired, may not
Persons             have autonomy, and may not be able to exercise free will (voluntariness).
Low Literacy        May not understand the consent form
Persons
Minorities          Not all minorities are considered vulnerable populations; the context of the
                    study, why minorities are included; whether they are the targeted focus of
                    the study are factors that must be considered and may impact consent.
Non-English         Even though consent forms must be translated into the native language,
speaking            without research staff who are fluent in the language, there is difficulty
Persons             ascertaining whether non-English speaking participants truly understand
                    their study involvement.
Persons             Could include: computer hackers, drug addicts, prostitutes, illegal
Involved in         immigrants, and those engaged in other types of illegal activities.
Illegal             Collecting data from persons who are involved in illegal activities can be
Activities          challenging. A foremost consideration must be that by signing a consent
                    form, the subject is, in effect, agreeing to participate in a study about their
                    illegal activities. Therefore the act of protecting subjects, making sure they
                    understand their rights and explaining the study, and executing legally
                    authorized consent may lead to disclosure and place the subject in more
                    harm than non-participation would. Investigators need to weigh carefully
                    what problems may be encountered if subjects are required to sign consent
                    forms. It may be appropriate to ask for a waiver of written consent and
                    employ the use of an information sheet for this type of research.
                    A Certificate of Confidentiality may be appropriate.
Pregnant            In some instances, pregnant women must be included as would any other
Women,              population; in other instances special protections for pregnant woman must
Fetuses,            be in place. Investigators who plan to use Pregnant women, Human
Neonates, In-       Fetuses, and Neonates in research should be familiar with the government
Vitro               regulations described in 45 CFR 46. Subpart B.
                    There are specific requirements for language in the consent form when
                    using pregnant women in research.
Prisoners           “In as much as prisoners may be under constraints because of their
                    incarceration which could affect their ability to make a truly voluntary and
                    uncoerced decision whether or not to participate as subjects in research, it
                    is the purpose of this subpart to provide additional safeguards for the
                    protection of prisoners involved in activities to which this subpart is
                    applicable." Prisoners may feel coerced into participating because they
                    think the authorities may grant them special privileges. They may agree to
                    participate because they think it will reduce their sentence, earn favors with
                    guards; See Subpart C of Title 45, Part 46 of the Code of Federal
                    Regulations containing the federal policy on research that involves
                    prisoners:

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                           This information was updated in May 2003.
   Students                May feel coerced because they think their grade may be affected if they
                           don’t agree to participate; the professor is always in power position over
                           the student. Must have another option for participation. Grade cannot be
                           affected by non-participation.
   Terminally Ill          “Terminally ill patients are those who are deteriorating from a life-
   Persons                 threatening disease or condition for which no effective standard treatment
                           exists. It is generally considered unacceptable to ask such persons to
                           participate in research for which alternative, not similarly burdened,
                           populations of subjects exist. Nevertheless, it may often be necessary to
                           involve terminally ill patients in research concerning their disease and its
                           treatment. Further, terminally ill persons should not be excluded from
                           research in which they may want to participate simply because of their
                           status. One can imagine that altruism and a desire to bring good from
                           adversity may well motivate persons suffering from life-threatening
                           illnesses to become involved in biomedical or behavioral research. Still,
                           terminally ill individuals are a vulnerable population of research subjects,
                           and, therefore, require additional protection against coercion and undue
                           influence [45 CFR 46.111(b)]. “ (from OHRP Institutional Review Board
                           Guidebook: Special Classes of Subjects: Chapter VI, Section G.)

N. Case Reports

A case study is a report of treatment (including innovative treatment, e.g., surgery) and,
as such, does not meet the Common Rule definition of research (a systematic
investigation, including research development, testing and evaluation designed to develop
or contribute to generalizable knowledge).

If any of the following is present, the activity is considered research rather than a case
study.

           •   There is a plan to perform the treatment on some individuals but not on
               others.
           •   Investigational drug(s) or device(s) are involved (off-label use of an
               approved drug or device is permissible).
           •   There is a clear intent before treating the patient to use systematically
               collected data that wouldn’t ordinarily be collected in the course of
               clinical practice in reporting and publishing the case study.
           •   There is intent to manipulate medications (even approved ones) to
               determine maximum effectiveness, or to test if they work consistently
               well.
           •   Extra tests are conducted for the sake of reportability.
           •   There is a protocol/study plan.
           •   Separate sets of records or data sheets are maintained (particularly with
               identifiers).
           •   The primary purpose is to answer a research question, not to provide care.

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           •   There is consideration that the treatment might yield a case series if it is
               effective in others (e.g., testing a hypothesis).

Case studies may be published; the published report must be descriptive, not analytical.

   •   Case studies that contain no PHI with identifiers do not need to be reviewed by
       either the Privacy Board or SCRIHS (note: a unique condition itself might be
       considered identifiable).

   •   Case studies that contain identifiers will be reviewed by the Privacy Board,
       which will determine the need for authorization.

Research activities with or without identifiers will be reviewed by SCRIHS. For
questions contact the SCRIHS office at 545-7602.

O. International Research

Researchers who conduct research outside of the United States are subject to the same
rules that apply to conducting research in the U.S. In addition, particular ethical codes,
government regulations, and specific local cultural norms, values, and expectations may
add additional regulatory and ethical considerations to the researcher who is doing
international research. Often governmental permission to conduct research is required. In
some instances, the country where the research will be done may have some type of
regulatory process or board that oversees human subject research. In that case,
submissions may have to be made to that regulatory agency or board, in addition to
obtaining approval from SCRIHS.

Section XIII: INDs, IDEs, Treatment INDs, Single-Patient INDs, Parallel Track,
and Gene Transfer

A. Investigational New Drug Applications (INDs)

   1. What is an Investigational New Drug Application?

   An Investigational New Drug Application (IND) is a request for Food and Drug
   Administration (FDA) authorization to administer an investigational drug to humans.
   Any use of a drug product not previously authorized for marketing in the United
   States first requires an IND to the FDA. The IND articulates the plan for developing
   the drug, including safety of manufacturing and administration in human subjects.

   2. Overview

   The overarching goal in regulating unapproved drugs is the protection of human
   subjects. The IND process requires repeated checks, reports, a complete application, a
   detailed protocol, recording keeping and reporting obligations that assist in making
   sure that drugs used in research, in the hope that they eventually come to market, are

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safe for the intended use.

"Current Federal law requires that a drug be the subject of an approved marketing
application before it is transported or distributed across state lines. Because a sponsor
will probably want to ship the investigational drug to clinical investigators in many
states, it must seek an exemption from that legal requirement. The IND is the means
through which the sponsor technically obtains this exemption from the FDA.

During a new drug's early preclinical development, the sponsor's primary goal is to
determine if the product is reasonably safe for initial use in humans and if the
compound exhibits pharmacological activity that justifies commercial development.
When a product is identified as a viable candidate for further development, the
sponsor then focuses on collecting the data and information necessary to establish that
the product will not expose humans to unreasonable risks when used in limited, early-
stage clinical studies."

3. Types of INDs

There are three types of INDs:

   Investigator IND is submitted by a physician who both initiates and
   conducts an investigation, and under whose immediate direction the
   investigational drug is administered or dispensed. A physician might
   submit a research IND to propose studying an unapproved drug, or an
   approved product for a new indication or in a new patient population.

   Emergency Use IND allows the FDA to authorize use of an experimental
   drug in an emergency situation that does not allow time for submission of
   an IND in accordance with 21CFR, Sec. 312.23 or Sec. 312.34. It is also
   used for patients who do not meet the criteria of an existing study
   protocol, or if an approved study protocol does not exist.

   Treatment IND is submitted for experimental drugs showing promise in
   clinical testing for serious or immediately life-threatening conditions while
   the final clinical work is conducted and the FDA review takes place.

4. How Do I Know if I Do Not Need to Submit an IND?

Below is a link to information describing when an investigator would be exempt from
using an IND This guidance was taken directly from the FDA webpage:
http://www.fda.gov/cder/about/smallbiz/faq.htm#IND

If you are uncertain about whether the research study you are doing requires an IND,
check with the SCRIHS office when preparing your Application for Approval. It
saves time if investigators can provide clear answers to the questions below justifying
why an IND would not be required. "Investigational use" suggests the use of an


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   approved product in the context of a clinical study protocol. When the principal intent
   of the investigational use of a test article is to develop information about the product's
   safety or efficacy, submission of an IND may be required. However, the clinical
   investigation of a marketed drug or biologic does not require submission of an IND if
   all six of the following conditions are met:

   •   It is not intended to be reported to FDA in support of a new indication for use or
       to support any other significant change in the labeling for the drug;
   •   It is not intended to support a significant change in the advertising for the product;
   •   It does not involve a route of administration or dosage level, use in a subject
       population, or other factor that significantly increases the risks (or decreases the
       acceptability of the risks) associated with the use of the drug product;
   •   It is conducted in compliance with the requirements for IRB review and informed
       consent [21 CFR parts 56 and 50, respectively];
   •   It is conducted in compliance with the requirements concerning the promotion
       and sale of drugs [21 CFR 312.7]; and
   •   It does not intend to invoke 21 CFR 50.24.

   5. How Does an Investigator Apply for an IND?

   The two most common uses of INDs are sponsor-initiated studies where the
   sponsor holds the IND and Investigator-initiated studies where the
   investigator holds the IND.

   For information on how to obtain and IND number, please refer to the
   following website:
   www.fda.gov/cder/regulatory/applications/Introduction

   6. IRB Responsibilities

   Before any study using an investigational new drug or biologic can be
   reviewed, an IND number must be obtained and submitted to the IRB.

B. Investigational Device Exemption (IDE) Application

   1. What is a Medical Device?

   A medical device is any health care product that does not achieve its primary intended
   purposes by chemical action or by being metabolized. Medical devices include
   surgical lasers, wheelchairs, sutures, pacemakers, implantable defibrillators,
   intraocular lenses and orthopedic pins. Medical devices also include diagnostic aids
   such as reagents and test kits for in vitro diagnosis of disease and other medical
   conditions such as pregnancy.

   Clinical investigations of medical devices must adhere to the Food and Drug
   Administration (FDA) informed consent and Institutional Review Board (IRB)

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regulations (21 CFR parts 50 and 56, respectively). They must also follow the federal
requirements enacted as part of the Medical Device Amendments of 1976 and the
Safe Medical Devices Act of 1990. These amendments to the Federal Food, Drug,
and Cosmetic Act define the regulatory framework for medical device development,
testing, approval, and marketing.

2. What is an Investigational Device?

An investigational device is a medical device that is the subject of a clinical study
designed to evaluate its effectiveness and/or safety. The clinical study must be
conducted according to the requirements of the IDE regulations (21 CFR 812).
Certain clinical investigations of devices may be exempted from the IDE regulations
as set forth in 21 CFR 812.2.

3. Significant Risk Devices

A significant risk device is an investigational device that:

   •   Is intended as an implant and presents a potential for serious risk to health,
       safety or welfare of subjects.

   •   Is purported or represented to be for a use in supporting or sustaining human
       life and presents a potential for serious risk to health, safety, or welfare of
       subjects.

   •   Is for a use of substantial importance in diagnosing, curing, mitigating or
       treating disease and presents a potential for serious risk to the health, safety,
       or welfare of subjects; OR

   •   Otherwise presents a potential for serious risk to the health, safety, or welfare
       of subjects.

An IRB's risk determination has important consequences for the study sponsor, the
FDA, and prospective research subjects. Significant risk device studies must be
conducted in accordance with the full IDE requirements (21 CFR 812) and may not
begin until 30 days following the sponsor's submission of an IDE application to the
FDA. The study may not start until the FDA has approved the IDE application and
the IRB has approved the study.

Examples of Significant Risk Devices: surgical lasers, tissue adhesives, epidural and
spinal catheters, jet ventilators, arterial embolization devices, cardiac assist devices,
cardiac pacemakers, extracorporeal membrane oxygenators, replacement heart valves,
cochlear implants, dialysis delivery devices, infusion pumps, intrauterine devices,
implantable prostheses.




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4. Non-Significant Risk Devices
In contrast, non-significant risk device studies do not require submission of an IDE
application to the FDA. However, the sponsor, who may be a company or an
investigator, is required to conduct the study in accordance with the "abbreviated
requirements" of the IDE regulations (21 CFR 812.2(b)). Unless otherwise notified by
the FDA, a non-significant risk device study is considered to have an approved IDE if
the sponsor fulfills the abbreviated requirements. The abbreviated requirements
address, among other things, the need for IRB approval and informed consent, record
keeping, labeling, promotion, and study monitoring. Non-significant risk device
studies may start immediately following IRB approval.

Examples of Non-significant Risk Devices: daily wear contact lenses, conventional
gastroenterology and urology endoscopes, conventional implantable vascular access
devices (ports), electroencephalography, and external monitors for insulin reactions.

5. FDA Guidance on How to Submit an IDE

The FDA provides extensive guidance and support to investigators wishing to file an
IDE. www.fda.gov/cdrh/devadvice/ide/index.shtml

6. What Does the IRB Do?

The proposed study is submitted to the IRB using the Application for Approval Form.
This form requests brief information about the device. Additional documentation may
be provided to accompany the request for review.

The IRB can agree with the sponsor's decision but can also make its own independent
decision. For example, a sponsor may determine a device is a non-significant risk
device. The IRB, however, may not agree and may require the investigator to file an
IDE. In deciding if a device presents significant or non-significant risk, the IRB will
consider the device's total risk. For example, if the device is used in conjunction with
a procedure involving risk, the IRB will consider the risks of the procedure in
conjunction with the risks of the device.

After the IRB has made a decision about the degree of risk, it proceeds to decide
whether to approve the study based on the usual guidelines for review. Because the
FDA considers any device that is classified as a significant risk device to raise the
risk level of a study, full review is required. The IRB considers the risk of the
procedures involved in using or implanting the device in addition to the risk level of
the device itself.




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C. Off-Label (Unapproved Use) of FDA-Regulated Products in Medical Practice
Versus Research

Good medical practice and the best interests of the patient require that physicians use
legally available, marketed drugs, biologics and devices according to their best
knowledge and judgment. If physicians use a product for an indication not included in the
approved labeling (i.e., off-label), they have the responsibility to be well informed about
the product, to base its use on firm scientific rationale and on sound medical evidence,
and to maintain records of the product’s use and effects.

   •   Off-label use of a marketed product in this manner when the intent is solely the
       practice of medicine does not require IRB review or the submission of an IND or
       IDE.
   •   Off-label use of a marketed product in research (i.e., as part of a systematic
       investigation designed to develop or contribute to generalizable knowledge) does
       require IRB review and approval.
   •   Off-label use of a marketed product intended to support a change in labeling (new
       indication) requires both IRB review and submission of an IND or IDE.

D. Treatment INDs, Single-Patient INDs (also called Compassionate Use) and
Parallel Track

   1. Treatment INDs

   A procedure under which promising investigational new drugs may be made available
   to patients with life-threatening or other serious diseases for which no satisfactory
   alternative drug or other therapies exist. The purpose of the Treatment IND
   exemption is to facilitate the availability of promising new drugs to desperately ill
   patients as early in the drug development process as possible (before marketing
   begins) and to obtain additional data on the drug's safety and effectiveness. A
   Treatment IND is a treatment protocol that is added to an existing investigational new
   drug application (IND). It allows physicians to treat qualifying patients according to
   the protocol.

   FDA permits Treatment INDs only for drugs that show some promise of therapeutic
   benefit. Two standards exist: For serious diseases, applications for Treatment INDs
   must show sufficient evidence of safety and effectiveness to support the use.
   Ordinarily, this standard means that a drug may be made available for treatment use
   either during Phase 3 investigations or after all clinical trials have been completed.
   For immediately life-threatening diseases, the evidence, taken as a whole, must show
   (i.e., there must be sufficient data reasonably to conclude) that the drug may be
   effective for its intended use in its intended patient population and would not expose
   the patients to whom the drug is to be administered to an unreasonable and significant
   additional risk of illness or injury. Under this standard, investigational drugs for
   treating immediately life-threatening diseases may be made available for treatment



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use earlier than Phase 3, but ordinarily not earlier than Phase 2 [21 CFR 312.34(a),
312.34(b)(2), and 312.34(b)(3)].

Treatment INDs must be reviewed by an IRB prior to their submission and must
comply with the regulations governing informed consent (21 CFR Part 50) and IRBs
(21 CFR Part 56) [21 CFR 312.34(c)].

The Role of the IRB: The primary responsibility of the IRB in reviewing a Treatment
IND is the same as in reviewing any proposed investigation involving human
subjects: to determine whether the proposed use exposes the subjects to unreasonable
or unnecessary risk, to review the informed consent forms and process, and to
monitor the progress of the Treatment IND.

Informed consent is especially important in treatment use situations because the
subjects are desperately ill and particularly vulnerable. They will be receiving
medications, which have not been proven either safe or effective, in a clinical setting.
Both the setting and their desperation may work against their ability to make an
informed assessment of the risk involved. IRBs must ensure that potential subjects are
fully aware of the risks involved in participation.

IRBs should also pay particular attention to Treatment INDs in which the subjects
will be charged for the cost of the drugs. The question here is one of equitable
selection and the involvement in research of vulnerable populations, particularly
economically disadvantaged persons [21 CFR 56.111(a)(3)]. If subjects will be
charged for use of the test article, economically disadvantaged persons will likely be
excluded from participation. The stated purpose of the Treatment IND exemption is
to facilitate the availability of promising new drugs to desperately ill patients while
obtaining additional data on the drug's safety and effectiveness. Charging for
participation may preclude economically disadvantaged persons as a class from
receiving access to test articles. IRBs will need to balance this interest against the
possibility that unless the sponsor can charge for the drug, it will not be available for
treatment use until it receives full FDA approval.

2. Single Patient Use

Another mechanism through which practitioners may obtain investigational drugs for
treatment use outside of a controlled clinical trial is what is called a "single patient
use." Usually, the patient is in a desperate situation and unresponsive to other
therapies, or in a situation where no approved or generally recognized treatment is
available. Further, there is usually little evidence that the proposed therapy is useful,
but may be plausible on theoretical grounds or anecdotes of success. Access to
investigational drugs for use by a single, identified patient may be gained either
through the sponsor under a treatment protocol, or through the FDA, by first
obtaining the drug from the sponsor and then submitting a treatment IND to the FDA
requesting authorization to use the investigational drug for treatment use [21 CFR
312.35]


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   3. Parallel Track

    The FDA has devised another mechanism to make available promising
   investigational agents as quickly as possible to persons with AIDS and other HIV-
   related diseases while generating data on the safety and effectiveness of the drug
   [Federal Register 57 (April 15, 1992): 13250-13259]. Under the FDA policy, persons
   with AIDS and HIV-related diseases who are not able to take standard therapy or for
   whom standard therapy is no longer effective, and who are not able to participate in
   ongoing controlled clinical trials, would have access to promising investigational
   drugs. Recipients of the new drugs would be participants in studies without
   concurrent control groups to monitor drug safety that are conducted in parallel with
   the principal controlled investigations. This mechanism of expanded availability is
   therefore called "Parallel Track."

   Parallel Track protocols are accomplished under the Treatment IND mechanism,
   which is described above, and should be thought of as a subset of the Treatment IND.
   They are distinguished from Treatment INDs by the amount of evidence of
   effectiveness required. Treatment INDs may be granted after sufficient data have
   been collected to show that the drug "may be effective" and does not have
   unreasonable risks, but before marketing approval has been granted. According to the
   FDA, Parallel Track protocols "might be approved for promising investigational
   drugs when the evidence for effectiveness is less than that generally required for a
   Treatment IND.

   Investigators wishing to use any of the options named above should
   prospectively contact SCRIHS for guidance.

   Occasionally, an agent or device is approved for another use but a physician feels it
   might help a single patient in an emergent situation. If this is the case, the condition
   must be life threatening. If the drug/device is used on an emergent basis, the
   guidelines for Emergency Use pre-empt the guidelines outlined here. Such use
   assumes a "treatment" use and the provisions utilized for Emergency Uses apply.

E. Gene Transfer Research

Gene transfer research involves the administration of genetic material to alter the
biological properties of living cells for therapeutic purposes. Gene transfer activities in
humans are investigational and are regulated by both the FDA and the NIH, Office of
Biotechnology Activities (OBA).

   •   FDA regulations require the submission of an IND for human gene transfer
       research.

   •   DHHS regulations specify that no individual may be enrolled in human gene
       transfer research until review has been completed by the Recombinant DNA
       Advisory Committee (RAC) at NIH, local Institutional Biosafety Committee

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       approval has been obtained, local IRB approval has been obtained, and the
       investigator has obtained all other regulatory authorizations from the subject.

   •   While the RAC is advisory to the Director of the National Institutes of Health
       (NIH), compliance with its guidelines is mandatory for all investigators at
       institutions that receive NIH funds for research involving recombinant DNA.

Section XIV: Emergency Use and Humanitarian Use Devices (HUDs)

A. Emergency Use Exemption for Drugs, Biologics, and Devices

NOTE: In order to remain in compliance with human subjects regulations, the
definition of Emergency Use will be interpreted very strictly. It should not be
confused with requests for urgent review, "compassionate use," protocol deviations,
or other instances where urgent IRB approval may be requested. Physicians are
advised to discuss an emergency use with SCRIHS staff. Investigators must proceed
with care in using this very selective category of drug/device/biologic use per
Federal regulations and IRB guidelines. Emergency Use is for one-time use only and
may not be used repeatedly. Data gathered under an emergency use cannot be used
for research reporting purposes.

   1. Definitions and Regulations

   The emergency use exemption procedure has been developed for use of an
   investigational drug, device or biologic in cases when a human subject is involved in
   a life-threatening situation or severely debilitating in which no standard acceptable
   treatment is available, and in which there is not sufficient time to file a complete
   application for IRB approval.

   From the FDA Information Sheets for Institutional Review Boards: Life-threatening,
   for the purposes of 21 CFR 56.102(d), includes the scope of both life-threatening and
   severely debilitating, as defined below. Life-threatening means diseases or
   conditions where the likelihood of death is high unless the course of the disease is
   interrupted and diseases or conditions with potentially fatal outcomes, where the end
   point of clinical trial analysis is survival. The criteria for life-threatening do not
   require the condition to be immediately life-threatening or to immediately result in
   death. Rather, the subjects must be in a life-threatening situation requiring
   intervention before review at a convened meeting of the IRB is feasible. Severely
   debilitating means diseases or conditions that cause major irreversible morbidity.
   Examples of severely debilitating conditions include blindness, loss of arm, leg, hand
   or foot, loss of hearing, paralysis or stroke.

   The emergency use provision in the FDA regulations {21 CFR 56.102(d)} is an
   exemption from prior review and approval by the IRB. It allows for one emergency
   use of a test article without prospective IRB review. Any subsequent use of the
   investigational product at the institution must have prospective IRB review and
   approval.

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When emergency medical care is provided without prior IRB review and approval,
the patient may not be considered a research subject. The emergency care data may
not be co-mingled with research data, nor may the outcome be reported as research
activity.

2. How Often Can an Emergency Use Exemption be Used?

An Emergency Use request can be used once without prior IRB review. Any
subsequent use of the test article must have prospective IRB review and approval.

3. What if the Test Article is Already Being Used in a Research Study?

If the test article is already being used in an approved IRB study at SIU, negotiations
with the Principal Investigator of the approved study, the study sponsor, and the FDA
may allow a subject to be enrolled on an emergent basis even though they may not
qualify for the study. This situation takes time for negotiation. No person may be
enrolled in a trial on an emergent basis when they do not qualify without prior
notification and approval by the IRB.

4. How is the Sponsor Involved?

The sponsor of the drug will usually add the SIU Investigator as a Clinical
Investigator on its IND application. The sponsor normally provides a copy of the
protocol and a consent form. These documents must accompany the submission to the
IRB.

The sponsor will usually ship the drug after they have received approval to proceed
from the IRB. The SIU investigator should fax the "approval to proceed" letter from
the IRB to the sponsor.

Since the approval is often done on an emergent basis, the request is reported at the
next available IRB Board meeting. At that time, the use is explained and noted. A
letter noting the deliberation is prepared and sent. It also reminds the investigator to
submit the follow-up report. Often the sponsor wants copies of this letter and
subsequent follow-up reports, too.

5. What if the Sponsor of the Drug, Biologic or Device Will Not Grant the SIU
Investigator Status as a Clinical Investigator?

The SIU Investigator may file an individual IND directly with the FDA. An IND
number is assigned and permits the sponsor to ship the drug. It is important that the
SIU Investigator document the telephone or e-mail contacts with the FDA as "memos
to file." Investigators should note who they talked to at the FDA, what was said, and
the telephone number. The documentation can take the form of an e-mail.



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   6. How is the FDA Involved? Obtaining an Emergency IND or IDE

   The emergency use of an unapproved investigational drug or biologic requires an
   IND. The usual procedure is for the investigator to contact the sponsor and determine
   if the drug or biologic can be made available for the emergency use under the
   company's IND.
   The need for an investigational drug or biologic may arise in an emergency situation
   that does not allow time for submission of an IND. In such cases, FDA may authorize
   shipment of the test article in advance of the IND submission. Requests for
   authorization may be made by telephone or other rapid communication means.



FDA Contacts for Obtaining an Emergency IND

Product                          Office/Division to Contact

                                 Drug Information Branch
Drug products                    (HFD-210)
                                 301-827-4573

                                 Office of Blood Research and Review
Biological blood products        (HFM-300)
                                 301-827-3518

                                 Office of Vaccines Research and Review
Biological vaccine products      (HFM-400)
                                 301-827-0648

                                 Office of Therapeutics Research and Review
Biological therapeutic
                                 (HFM-500)
products
                                 301-594-2860

                                 Division of Emergency and Epidemiological
                                 Operations
On nights and weekends
                                 (HFC-160)
                                 301-443-1240

   7. How is Emergency Use Handled During Business Hours?

   Although prior approval (submission to an IRB meeting for consideration) to use an
   investigational drug or device in an emergency situation is difficult to obtain because
   the need for an emergency use often arises rather quickly, the SCRIHS staff can
   provide an acknowledgment letter in advance of administration of the test article. The
   steps below outline what SCRIHS staff and the requesting physician need to do.



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To secure a waiver from prospective IRB review during business hours, please follow
the steps below.

a. The physician calls SCRIHS and notifies the Supervisor or designee about the
   request.
b. SCRIHS must determine if the test article is already being used in an IRB
   approved protocol at the institution.
c. If it is already being used in an IRB approved protocol, SCRIHS staff advises the
   physician that the test article is already being used in an approved study. The
   SCRIHS staff will help facilitate contact with the investigator of the IRB
   approved study and the sponsor to see if the patient might qualify for the trial or if
   a one-time exception can be made to the inclusion/exclusion criteria to include the
   patient. If this is the case, this now becomes an urgent review for a protocol
   deviation.
d. The SCRIHS staff instructs the physician to submit the form letter with the
   description requested, a consent form, the protocol (if available) and any other
   documentation that will help explain the situation. This should be hand-delivered
   to the SCRIHS office.
e. The SCRIHS staff contacts an IRB Chair who reviews the the letter describing the
   patient's condition, and any other documentation and gives permission for the
   drug to be used.
f. The SCRIHS staff prepares an acknowledgement letter and stamps approval on
   the consent form. The letter is available for pick-up by the physician or his/her
   staff.
g. The physician can forward this letter to the sponsor indicating that the IRB knows
   about the request.
h. The physician will work with the Hospital Pharmacy to secure shipment and
   delivery of the drug/device and meet any other hospital requirements for review
   for use and approval.
i. If the protocol and consent form were not received prior to the use of the drug, the
   physician forwards the consent form and protocol from the company after the use
   of the test article with the follow-up report. This needs to be done within five days
   after the treatment. If the treatment continues for longer than 5 days, the IRB
   should be notified of this fact and a reporting time determined in consultation
   with the SCRIHS staff.
j. Within five days following the use of the drug the physician must submit the
   follow-up report. At that time the physician will be encouraged to submit a full
   protocol if they expect to make use of the test article again.
k. All documentation is forwarded to the next IRB meeting for reporting to the IRB.
   Since the use of the test article has occurred, the IRB is not approving the use at
   this point. The IRB will send a written statement to the investigator
   acknowledging that the IRB is aware of the use and considers it to meet the
   requirements of 21 CFR Part 56.104(c) or 45 CFR 46.116(f).
l. The IRB submission may be done at anytime but investigators must be aware that
   they may not use the test article more than one time. If a complete IRB packet is
   submitted, the emergency use file should be included for the IRB reviewers. Any


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   data gathered in the emergency use of the test article may not be later used in the
   research study.

8. How is Emergency Use Handled After Business Hours or When There is Not
Time to Notify the IRB?

***First and foremost, page the SCRIHS staff member on call. The SCRIHS
emergency pager number is 467-3433.

If there is an emergency use when the IRB office is closed, the physician should be
sure the report of the patient's condition is reviewed and signed by another physician
not involved in the case stating they concur with the use of the investigational article.
If applicable, the second physician also must certify that informed consent cannot be
obtained according to the conditions that must apply. (See section below on consent)
If informed consent can be obtained, physicians must prepare a consent form.

Please note that emergency use does not mean "without consent" of the patient or the
patient's legally authorized representative (LAR) unless conditions exist where the
patient cannot give consent and the LAR cannot be contacted. In this event, the
uninvolved physician must certify this to be the case.

Within five days, the treating physician should notify SCRIHS by submitting the
appropriate paperwork. Acknowledgement from the IRB will follow after the letter
from the physician, a copy of the signed consent form, and any other supporting
documentation are received.

The acknowledgement will be an "After-the-Fact" acknowledgement from the IRB.

When a physician must employ an experimental procedure or test article to care for a
patient in a life-threatening situation, the IRB must trust that the physician is
exercising his/her best clinical judgment. The physician must then take the
appropriate steps to be sure the IRB is properly informed.

9. Informed Consent and Emergency Use

Emergency use of a drug or device does not negate the requirement to obtain
informed consent, prior to giving the drug or using the device, from the subject or the
subject's legally authorized representative.
The consent form is often provided by the sponsor. In the event that there is not
sufficient time to use the SCRIHS consent template, the sponsor's consent will be
used. It should be reviewed carefully by the SCRIHS staff and the IRB chair. In the
event that the FDA grants an emergency IND, a consent form will have to be
constructed by the Investigator.




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   10. What if the Patient Cannot Give Prior Consent?

   In rare instances, prior consent cannot be obtained. [21 CFR 50.23(a)] To handle this
   situation, both the investigator and a physician who is not otherwise participating in
   the clinical investigation must certify in writing all of the following:

   a. The subject is confronted by a life-threatening situation necessitating the use of
      the test article.
   b. Informed consent cannot be obtained because of an inability to communicate
      with, or obtain legally effective consent from, the subject.
   c. Time is not sufficient to obtain consent from the subject's legal representative.
   d. No alternative method of approved or generally recognized therapy is available
      that provides an equal or greater likelihood of saving the patient's life.

   11. Follow-up and After-Use Procedures

   It is important the follow-up be completed in the required time frame. In the unusual
   event that the emergency treatment lasts longer than the five days, the investigator
   should notify SCRIHS of the outcome of the treatment and be sure to make it clear
   that the treatment will continue for longer than five days. Notification about the
   outcome of the emergency use can be reported by letter or e-mail. If there is even the
   smallest possibility that this drug/device might be needed again, on an emergent
   basis, it is strongly recommended that a general use protocol be submitted for
   prospective IRB review and approval. Because the emergency use can be granted
   only one time for an institution, it safeguards the institutions ability to provide
   emergency medical care by having the protocol prospectively IRB approved.
   However, the FDA acknowledges that it would be inappropriate to deny emergency
   treatment to a second individual if the only obstacle is that the IRB has not had
   sufficient time to convene a meeting to review the issue. Again, in these cases, the
   IRB must be notified within five working days after any emergency use of a test
   article.

B. Guidelines for Humanitarian Use Devices (HUDs)

   1. What is a Humanitarian Use Device (HUD)?

   As defined in the Federal Food, Drug, and Cosmetic Act, a HUD is a device that is
   "intended to benefit patients in the treatment and diagnosis of diseases or conditions
   that affect fewer than 4,000 individuals in the United States per year."

   2. What is a Humanitarian Device Exemption (HDE)?

   A Humanitarian Device Exemption (HDE) is an application that exempts the device
   from the usual clinical research trials to obtain full FDA approval. That is to say that
   since there are not enough patients with the condition or disease, it would not be
   possible to conduct statistically significant trials that would support efficacy and
   safety as is required in the application for medical devices that will be used by large

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numbers of persons. FDA may grant the humanitarian device exemption ("HDE") if,
among other things, the applicant submits information to show that there is a
reasonable basis from which to conclude that the probable benefit of use of the device
outweighs the risk of illness or injury, taking into account the probable risks and
benefits of currently available devices and alternative treatments.

3. Who is Responsible for Ensuring That a HUD is not Administered to or
Implanted in a Patient Prior to Obtaining IRB Approval at a Health Care
Facility?

The healthcare provider is responsible for obtaining IRB approval before the HUD is
administered to or implanted in a patient. The HDE holder (usually the sponsor) is
responsible for ensuring that the HUD is only used in facilities having an IRB
constituted and acting in accordance with 21 CRF56.

4. What Types of Reviews are IRBs Responsible for with Respect to HUDs?

IRBs are responsible for initial as well as continuing review of the HUD. For initial
review of a HUD, IRBs are required to perform a full board review.

5. Does an IRB Have to Review and Approve Each Individual Use of the
Humanitarian Use Device (HUD)?

The IRB can require approval on a case-by-case basis but usually will not. The IRB
will track use(s) of the HUD the report in the continuing review. In the continuing
review, physicians should list the number of patients who have received the HUD in
the past year.

6. What Do I Submit to the IRB?

For the IRB to consider an HUD, the IRB must review the materials received from
the sponsor, including a protocol, the patient information booklet, and any other
materials that are received. The standard hospital surgical consent accompanied by
the patient information booklet may be sufficient. The IRB will assign the study a
SCRIHS protocol number.

7. Is Consent Required?

An IRB approved consent is not required though physicians should ensure that
adequate information is provided to the patient. It is required that the hospital surgical
consent is provided and a copy of the information brochure by the sponsor be
presented to the patient. The patient information brochure should be forwarded to the
IRB for its consideration when the IRB application is submitted. If the patient
information booklet does not provide an adequate overview, the IRB may request that
the physician prepare a clinical consent form for the HUD. In some rare instances,
consent may not be possible, in which case, the investigator needs to alert the IRB to


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this possibility when the IRB submission is prepared. A waiver of consent may be
granted based on the information presented.

8. Do I Have to Submit for Continuing Review?

Federal regulations require that an annual review be submitted to the IRB. The annual
review will be reviewed by the full board. In the continuing review you will need to
report on the total number of patients who have received the device in the previous
year. There are several sections of the Continuing Review form that may not apply. If
you have questions, please contact SCRIHS.

9. Submitting Data Safety Monitoring Reports

If there is a data and safety monitoring committee and reports are issued they should
be forwarded to the IRB as soon as they are received by the investigator. They can be
forwarded with an Amendment Summary form. In some instances the FDA has
required that a Data Safety Monitoring Committee be put into place.

10. May the Device be Used More than Once Without Notifying the IRB Each
Time?

The device may be used more than once without notifying the IRB each time.
Physicians are expected to report the uses and summarize them in the annual
continuing review. Adverse events must be reported in the usual manner as they
pertain to each use. Please remember that use of an HUD in an off-label manner is a
violation of federal laws. The IRB has been mandated to monitor HUD uses so that
off-label uses are reported to the FDA. If the HUD is held by an investigator, please
contact SCRIHS for additional assistance in handling the issue of notification. Each
use of the device should be predicated on the idea that the use outweighs the risk of
illness or injury, taking into accounts the probable risks and benefits of currently
available devices and alternative treatments.

11. Other Resources

Humanitarian Device Information
www.fda.gov/cdrh/ode/hdeinfo.htm

Humanitarian Device Exemptions (DE) Regulation: Questions and Answers; Final
Guidance for Industry
www.fda.gov/cdrh/ode/guidance/1381.html

The Humanitarian Device Exemption - Safe Medical Devices Act of 1990
www.fda.gov/orphan/humdev.htm

A listing of all devices that presently fall into the HDE category
www.fda.gov/cdrh/ode/hdeinfo.html#2


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   The original CFR that describes the intent of the FDA in the use of HUDs.
   www.fda.gov/orphan/humuse.htm


Section XV: Compliance and Quality Control

A. Compliance Policy

It is the policy of SIU School of Medicine to comply with all applicable local, state, and
federal regulations in the conduct of human subjects research. Principal Investigators and
Department/Division Chairs are required to report any regulatory non-compliance to the
Associate Dean for Research and Faculty Affairs, the IRB Chairman and the SCRIHS
office, and to participate in appropriate resolution. The SCRIHS office will investigate
and assess the non-compliance and the committee will take appropriate action, which
may include, but is not limited to, suspension of the research study or suspension of the
investigator’s research privileges. As determined by the specifics of the situation,
SCRIHS reserves the right to conduct the type of investigation it deems necessary in
order to obtain the required information. Moreover, SCRIHS may delegate any
component of the investigation to those individuals best suited to perform the functions
of the investigation; however, all final determinations and action are to be made by
SCRIHS.

The purpose of this policy is to outline the procedure for reporting and investigating
noncompliance with human research protections requirements. Noncompliance can be
defined as any violation from the study protocol approved by SCRIHS, any violation of
any conditions imposed by SCRIHS on the approval of the study or conduct of research;
or any violation of Institutional policies or federal or state laws and regulations that
govern human subjects research.

Implementation of this policy will consist of the SCRIHS staff conducting monthly
random audits of investigators’ research files. The SCRIHS office will distribute a
schedule at the first of every calendar year indicating which department will be audited
each month as well as the topic on which the review will focus (for example, informed
consent, adverse event reporting, protocol deviations, etc.). One investigator from the
designated department will be randomly selected. The SCRIHS staff will notify the
selected investigator twenty-four (24) hours in advance in order to obtain a list of study
subjects. The investigator will be expected to make all research files and regulatory
binders readily available to the SCRIHS staff and reserve a room for them to use for the
day.

B. Procedures for Handling Noncompliance

   1. Principal Investigators (PIs) are responsible, with their Department Chairs, for
   promptly reporting to SCRIHS, in writing, all incidents of noncompliance.
   Investigators may make an initial report in person, but must follow up with a written


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report. Any other person may report suspected noncompliance, in person or in
writing.

2. The IRB Chairman and Director are to obtain as much information as possible
from the individual who reports the event. If warranted, the IRB Chairman, the
Associate Dean for Research and Faculty Affairs, SIU Legal Counsel and the
SCRIHS staff will then meet to discuss the following:

   •   The incident and the facts presented to date
   •   Identification of those individuals who are to attend the soonest possible
       SCRIHS meeting after the incident is reported
   •   Whether the protocol is to be placed on temporary administrative hold, such
       that no additional patients are enrolled and/or all activities are temporarily
       suspended
   •   Whether sufficient facts exist to demonstrate serious or continuing
       noncompliance that is reportable to federal agencies. For purposes of this
       policy, serious noncompliance is defined as noncompliance that involves the
       risk of harm to a human subject, that violates the rights of a human subjects
       under applicable regulations or SCRIHS policy, or that violates the
       obligations of an investigator to seek, obtain, and comply in a timely manner
       with SCRIHS review of human subjects research. Continuous noncompliance
       is defined as a series of more that one noncompliant event, in reasonable close
       proximity, that indicates the need for evaluation of methods and systems used
       to protect human subjects.
   •   Whether research records should be sequestered during the investigation.

3. The Institutional Official (the Dean) is to be notified immediately after these initial
determinations are made.

4. A meeting will be scheduled to discuss the situation and will include the
Department Chair, the IRB Chairman, the IRB Director, the Associate Dean for
Research and Faculty Affairs, Legal Counsel, the Dean (if necessary), and any other
staff member thought to be involved in the noncompliance incident.

5. Once the SCRIHS office is notified, SCRIHS staff will collect all available
information known about the event prior to the next meeting. A list of issues and
questions, based on this information, will be prepared and distributed to the
committee members prior to the meeting (if possible) in order for the committee
members to have time to review the material and be prepared to discuss the issue at
hand. If necessary, the investigator and/or other involved individuals will be asked to
attend the meeting and cooperation with this request is expected.

6. At the next scheduled meeting, SCRIHS will discuss the incident and the actions
taken to that point. The committee members will be provided with all the information
compiled to date and will discuss the event to determine the issues to be addressed
and the action to be taken.

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7. Minutes from the meeting will include the issues, questions and decisions reached.

8. If necessary to obtain further information as to the extent of the noncompliance,
the SCRIHS staff can perform an internal audit of the investigator’s research files at
any time with 24 hours notice.

9. When and if the event is determined reportable to OHRP and/or the FDA, they
will be notified in a letter describing the incident, the actions taken to date and
whether an individual subjects were harmed as a result. If warranted, OHRP or the
FDA, will be notified immediately by phone.

10. During the course of the investigation, the investigator should continue to monitor
any clinical condition of the subjects if necessary.

11. The investigator will be informed, in writing, of the decisions made by the
committee. If the committee has more issues or questions they need clarified, the
letter will address those issues and the investigator will be expected to respond
promptly. If a final decision was made, the letter will detail the action that has been
taken by the committee.

12. The investigator will be responsible for preparing a final report that includes
explanation of the noncompliance event, answers to any questions raised by the
committee and a plan of action to ensure that similar incidents do not occur in the
future. This final report will be reviewed by SCRIHS at a convened meeting. Once all
issues are resolved and the plan of action is deemed satisfactory, a final report to
OHRP or the FDA may be necessary.

13. If necessary, the final report to OHRP or the FDA will be prepared by the IRB
Director in cooperation with the IRB Chairman and Legal Counsel and will include
the following:

   •   An overview of the noncompliance event
   •   The course of action taken to investigate the event
   •   The manner in which the investigation was conducted
   •   The findings of noncompliance
   •   The corrective action s taken for each issue of noncompliance
   •   Any sanctions made by SCRIHS
   •   The plan proposed by the investigator as well as the Institution to ensure the
       problem will not recur

14. In response to noncompliance, the actions SCRIHS can take include, but are not
limited to the following:

   •   Modification to any aspect of the conduct of a research study
   •   Requiring reconsent of enrolled subjects

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      •   Letter of reprimand
      •   Investigator and staff participation in educational and quality improvement
          activities or conferences
      •   Enhanced monitoring
      •   Suspension of research privileges
      •   Termination of research privileges

C. Investigator Requirements for Organizing Regulatory and Research
Documentation (Quality Control)

   1. Overview

   Whether you are doing a clinical research study or social science research, a federally
   sponsored study, an industrially sponsored study, a student study, or an investigator-
   initiated study, the maintenance and organization of research records and
   documentation is a required responsibility of the investigator and the research staff.
   Some sponsors have specific requirements on how files be maintained. It is the
   responsibility of the investigator to find out what those requirements are. Even when
   studies are not funded, human subjects regulatory compliance dictates the need to
   have some system for organizing documentation. Even if the study is a small study to
   be done in a short time frame, it is important that the original data, consent forms,
   regulatory documents, and other documentation be organized so that it can be
   retrieved easily.

   Organizing regulatory documents and research documentation assists investigators in
   assuring that each research study is compliant with IRB policies, and with federal
   policies governing human subjects. Data collected in research studies may be useless
   without "adequate and accurate records." (FDA documentation on 1572)

   Organizing records, creating a "reminder" calendar, and updating files regularly will
   help investigators prepare for monitor visits or a SCRIHS audit. Good record keeping
   is also helpful in making sure continuing reviews are filed in a timely manner, and
   that all correspondence with SCRIHS has been confirmed, acknowledged, or
   approved.

   It is important that a safe and secure place to is used to store the documents, such as
   the investigator's office or lab. It is also important to consider safety and security
   when transporting documents from clinical sites to the Investigator’s office.

   Depending on the level of complexity of the study, the number of subjects, the
   duration of the study, and requirements by sponsors, investigators may need to
   organize several types of documentation. If the research study is a clinical study it is
   important that "Good Clinical Practice" guidelines be followed in keeping
   documentation organized. If the research study is subject to FDA oversight there are
   additional requirements for record keeping and documentation that must be filed with
   the FDA. Specific contracts between the investigator and the sponsor may also

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specify storage and the length of time records must be kept. Investigators who are
conducting clinical trials should be aware of these regulations.

The key to successful human subject protection and compliance is adequate and
accurate record keeping.

2. Basic Procedures for Maintaining Regulatory Documents

All documents relating to the research study should be date stamped when received.
This is especially important to ensure compliance. When an audit is undertaken, often
the receipt dates of sponsor’s reports are checked against records of the materials
being submitted to the IRB. It is expected that documents from the sponsor, sent to
the IRB have a receipt date stamped on them. Date stamping is an effective method to
aid in keeping documents in regulatory binders in order.

Use pen when making notations on regulatory documents, case report forms, and
sponsor documents. Initial and date documents to identify who gathered the data, read
the memo, and acknowledged receipt. A pencil should not be used.

If a database is used to gather data during the trial, be sure that it is backed-up
properly and frequently.

When errors are made when recording information in study documents, cross out the
error with a single pen stroke, initial and date the cross out, and enter the new
information.

 Organize your study related papers on a regular basis. Don't let regulatory papers
stack up. Set aside time at the end of each week to be sure that your regulatory
binders are in order.

3. Calendar Reminder

Investigator should establish a system so that study staff and the investigator know
when items are due at the IRB, when monitors are scheduled to visit, and other
important study dates.

It is the investigator's responsibility to be sure that periodic reviews, adverse events,
and other reports are filed in a timely manner. Investigators jeopardize the
continuation of their studies when documents are not submitted within expiration
dates and other deadlines. Be sure that all study staff know the deadlines and know
how to file documents. It is not an excuse to say, we didn't know it was due. It is part
of the investigator's responsibilities to meet deadline dates without prompting.

It is recommended that investigators create a calendar to provide an overview of due
dates and expiration dates. The calendar should be created at the beginning of the
study and maintained throughout the study. Regulatory submission guidelines must


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be honored. To help track return receipt of acknowledgement or approval,
investigators may also wish to note when documents are sent to the IRB.

4. Research Staff for Maintaining Regulatory Documents

Generally it will be easier to work with the IRB and SCRIHS if the investigator
designates one member of the research staff as the person who will do regulatory
work. Keeping regulatory paperwork in good order is much easier when only one
member of the study staff has been designated to do so. Since a number of offices
and agencies are involved in filing regulatory materials, it makes sense to concentrate
the training into one person. To be sure the designated individual is aware of all the
guidelines and regulations, extra training from SCRIHS can be provided. A complete
understanding and overview of what compliance involves is essential for an
individual assuming this responsibility.

5. Regulatory Binders: Suggested Organization

Study materials should be kept in chronological order within each tab. Some files
may require several notebooks. Investigators can use file folders if they wish though,
if the study lasts a long time, the files tend to become disorganized.

Protocol and Amendments, Investigator Brochures - Master Protocol and
all revisions and amendments. All copies should be kept for the duration of
the study. Do not throw out superceded amendments but mark accordingly.

Continuing Reviews - Copy the Continuing Review Statement submission
and all attachments. Add the approval letter as well as the original, stamped
consent form.

Revisions - Copy the signed revision form that is submitted to the IRB. When
the form is returned acknowledged, add the copy to the notebook after the
copy of the original submission.

Consent Forms - All versions of the consent forms should be copied and kept
in one section, in addition to locating them with other submissions.

It is a good idea to put the latest consent form in a plastic sleeve in the
regulatory binder so it is perfectly clear what consent form is the most
currently approved version. Some investigators make extra copies of the
currently approved consent form to have them ready for patients they wish to
recruit. Investigators must be careful that they do not use an expired consent
form when this method is employed.

Advertising and Recruitment Materials - Copies of all submissions,
approvals of advertising; and recruitment scripts, posters, brochures, websites,
flyers, radio spots, and other forms of recruitment materials.


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If the study has many types of recruitment materials, the research staff may
wish to design a cover sheet that indicates where it was used and the various
arrangements, costs, etc. in placing the ad.

Correspondence - General correspondence that does not fit into other
sections.

IRB submission - Original Submission Packet - a copy of all items that were
submitted originally including protocol, consent forms, questionnaires, etc.

FDA 1572 - Copies of all filings of the 1572 should be kept in this section.

CVs - Copies of current CVs of the investigators and others listed on the 1572
should be included here.

Investigator and Site Data - If there is documentation on the site that must
be maintained as part of the research study use this section.

Screening Logs for Subjects - When subjects are approached to participate in
the study, a screening log should be maintained that indicates how they were
identified, when they were approached, the appointment time for the first visit,
whether a consent form was mailed to the potential subject to read before the
consent visit, and any other data that might be useful in explaining how many
people were screened, how they were contacted, and what the enrollment rate
for the study is.

Adverse Events - Adverse events originate at the local site or are sent as
Medwatch reports from other sites. For studies that are non-clinical and only
conducted at SIU, there will only be records of adverse events that occurred at
SIU or the affiliated hospitals.

Lab - Include copies of lab deliveries, certifications, and lab values.

Drug Records and/or Device Logs - Receipt, Dispensing, and Returning -
When drugs are shipped to research sites, there is paperwork that must be
maintained. If drugs are not dispensed by the pharmacy for a study, the study
team must have procedures in place to receive, store, dispense, and return
drugs.

Monitor Visits and Evaluations - Notification from sponsor's about monitor
visits with information on what needs to be available for review. Copies of the
signed monitor reports after the visit should be maintained in this section.

Protocol Deviations/Violations - Copies of submission of protocol deviations
and violations should be kept in this section. Correspondence from the IRB


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regarding remedies for protocol deviations and violations or documentation
that suggested remedies occurred - for example - announcements of a meeting
of study staff to review handling things so deviations will not occur in the
future. If the sponsor granted the deviation, written notification must be
maintained.

Telephone Log - A log of phone calls made during the course of the study
helps verify what things were actually done.

Miscellaneous - Anything that does not fit into the previous categories goes in
here.

6. Consent Forms

One of the safeguards expressed in consent forms is that of subject confidentiality.
Often statements to the effect that no one will know you are in the study other than
study staff, the IRB, the FDA and the sponsor are stated and must be honored. In
order to effectively comply with the consent form statement, investigators and their
research staff need to have mechanisms in place to be sure consent forms are filed
appropriately and not left lying around.

Consent forms should not have participant telephone numbers, addresses, medical
record numbers or social security numbers on them. These are considered identifying
information and may unintentionally compromise the subject's privacy

Consent forms often outline the disposition of research documentation. Investigators
must be sure they have procedures in place to be sure they are fulfilling the
obligations set forth in the consent form.

7. Subject Files

In addition to screening logs and regulatory binders, each subject may have their own
file during the course of the study. They may be assigned a number on the screening
log that may carry over to the study files and serve as a unique identifier.

Subject Files might include:

A medical history (if a medical study) - sometimes specifically filled out for the study
and other times, a copy of the subject's medical record from a clinic or their
physician.
Signed Consent Forms and Assent Form
Questionnaires
Records of materials and drugs given to the subject
Lab Test Results
Records of study visits
CRF's completed


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Physician Notes
Source Documents

8. Source Documents

Source date is defined as "All information contained in original records and certified
copies of results, observations or other facets required for the reconstruction and
evaluation of the study that is contained in source documents. Source documentation
is the location where information is first recorded including original documents, data
and records." (Centerwatch)

Some Typical Clinical Source Documents:
Signed Consent Forms
Laboratory Test Results
Information on the Laboratory doing the analysis
Range of Values for the Lab Tests
Subject Diaries
Drug or Device Receipts
X-rays

Some Typical Behavioral/Social Science Source Documents:
Questionnaires
Signed Consent Forms
Field Notes
Video Tapes
Photographs
Tape Recordings

9. Case Report Forms

Case report forms are used to summarize data collection for the sponsor. Usually,
case report forms are designed in conjunction with the protocol. The forms have
specific questions that record study data to hopefully provide answers. Case report
forms should not be used as source documents.

10. Sponsor Documents

Sponsor's often have specific systems for dealing with research and regulatory
documentation. The study training sessions will either train you, or a monitor will
assist in training you, on how documents should be organized

11. Monitor Visits

Monitors may come several times during the course of study. They need a quiet place
to work, close to the documentation. Research staff should cooperate with monitors in
their requests for information. On the occasion that a disagreement with the monitor
arises, research staff can call the SCRIHS office for clarification. Often, monitors

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have specific ideas on how regulatory documents should come from the IRB. Since
IRBs constitute local review, not all IRBs will be the same in the way they approved
studies, issue approvals, and conduct administrative review.

12. Getting Ready for an Audit - SCRIHS, FDA, Outside Monitor, OHRP, Other
SCRIHS may request to audit your materials at any time; therefore, it is extremely
important for all of your study documentation to be in order. Since the SIUSOM IRB
has an agreement with the federal government, called the Federal-Wide Assurance,
any study conducted at SIUSOM, or its affiliates could be audited by either the Office
of Human Research Protections (OHRP) or if a clinical study, by the Food and Drug
Administration (FDA), regardless of sponsorship. The SCRIHS staff has created a
form that investigators and their research staff can use to internally audit their own
research files in order help ensure compliance. SCRIHS strongly suggests that all
investigators perform this self-assessment on a regular basis.The Quality Improve-
ment Through Self-Assessment Form can be found on the SCRIHS website.

The investigator should notify the IRB when they are notified of an upcoming audit.
A copy of the audit report should be sent to SCRIHS for the study file. Investigators
can submit copies of audit reports to the SCRIHS with an Amendment Summary
Form as a cover sheet.

When an audit uncovers serious protocol violations and deficiencies, the investigator
is expected to notify the IRB within five business days with a copy of the report. It is
important that the IRB know when there are studies that are found to have compliance
deviations and violations.

13. Conclusion

Keeping research related paperwork up-to-date, and orderly is a key element in
protecting the study participants. Organizing paperwork is as important as dispensing
the right drug or the right dosage of a drug. Investigators and study staff MUST
dedicate the necessary time to maintain the organization of the paperwork for all of
their studies. First and foremost, investigators must have signed consent forms
indicating that the subject intended to enroll in the study.

14. Resources

Study Record Maintenance:
Section topics include: Regulatory Binder and Checklist, Source Documentation,
Case Report Form (CRF) Notebook, Study Closeout, Records Retention.
http://ecourse.ctsu.org/html/manage_1.htm#notebook

Essential Documents: A good chart indicating what are essential documents - from
the Cancer Support Trials Unit.
http://ecourse.ctsu.org/documents/Essential_Documents.pdf



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   Overview on Good Clinical Practice: addresses regulatory documents
   www.irbforum.org/documents/documents/Module4.pdf

   FDA guidance on Documents. Page 50
   www.fda.gov/cder/guidance/959fnl.pdf

   A good list of source documents:
   http://ecourse.ctsu.org/html/sourcedocuments.htm

Section XVI: Conflict of Interest Policy:

All members of the SIU SOM research community should be sensitive to the potential
impacts of financial interests and/or non-financial relationships with commercial
sponsors or other external entities on the conduct of research and the participation and
protection of human research subjects. In compliance with federal regulations, guidance,
and SIU SOM policy, SCRIHS considers such relationships and determines whether they
might influence or appear to influence the outcome of a research study involving human
subjects, the objectivity of the investigator during the performance of such a study, or the
investigator’s interactions with research subjects who participate in the study.
Accordingly, SCRIHS, through the Conflict of Interest Committee, solicits and reviews
relevant information regarding the financial interests of all investigators and key study
personnel participating in a protocol involving human research subjects prior to
approving a protocol or approving a continuing review of a protocol.

All investigators and key study personnel must be familiar with this policy and sign the
Application for Approval Form to indicate compliance with this policy. A Protocol-
Related Conflict of Interest Disclosure Form (“Protocol COI Form”) must be completed
and signed upon submission of an application to the Springfield Committee For Research
Involving Human Subjects (“SCRIHS”). Investigators and key study personnel must
certify that they have read the policy by signing the application for approval, continuing
review, or amendment in the space provided. If an actual or potential conflict develops
after submission of the protocol to SCRIHS, the investigator or key study person must
complete and submit an additional Protocol COI Form to SCRIHS at that time.

The full SCRIHS COI Policy and the Protocol COI Form can be found on the SCRIHS
website.

Section XVII: Social Science

Social and behavioral science research encompasses a variety of disciplines including,
but not limited to, anthropology, sociology, psychology, political science, education,
social work, art education and history, theatre, and, music. Much of this research uses
qualitative research methods such as formal and informal interviews, participant
observation, questionnaires, surveys, focus group discussions, oral history, ethnographic
research, program evaluation and collection or study of existing data, documents and
records.


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These research methods are used to measure beliefs, behaviors, attitudes, and responses,
or evaluation of the effectiveness of particular programs or instructional methodologies.
However, the research must still be carried out with due consideration of the Ethical
Principles regarding research involving human subjects.

According to federal regulations all social/behavioral research involving human subjects
as defined below must be reviewed and approved by an Institutional Review Board (IRB)
prior to initiation of the research study to assure that the rights and welfare of human
subjects are protected. Additionally, all investigators including faculty and students must
complete the required Human Subjects Protection Training for Social/Behavioral
Research prior to initiation of research involving human subjects.

       Definitions:

       Intervention includes both physical procedures by which data are
       gathered (for example, venipuncture) and manipulations of the subject or
       the subject's environment that are performed for research purposes.

       Interaction includes communication or interpersonal contact between
       investigator and subject.

       Private information includes information about behavior that occurs in a
       context in which an individual can reasonably expect that no observation
       or recording is taking place, and information which has been provided for
       specific purposes by an individual and which the individual can
       reasonably expect will not be made public (for example, a medical
       record). Private information must be individually identifiable (i.e., the
       identity of the subject is or may readily be ascertained by the investigator
       or associated with the information) in order for obtaining the information
       to constitute research involving human subjects.

Social/Behavioral Research must also apply the Ethical Principles, which guide the
protection of human subjects of research, especially when subjects are exposed to more
than minimal risk.

Minimal risk is the probability and magnitude of harm that is normally encountered in
the daily lives of healthy individuals, or in the routine medical, dental or psychological
examination of healthy individuals.

All studies involving special populations as subjects, such as children (less than 18 years
of age), prisoners, individuals with physical or mental disabilities, economically or
educationally disadvantaged persons, institutionalized individuals, pregnant women, or
fetuses require additional protections. Appropriate precautions must be taken to ensure
the confidentiality of the research subjects.




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Section XVIII: Research in Foreign Countries

Research conducted in a foreign country is subject to all of the IRB specifications in
these guidelines. In certain circumstances, IRB requirements may be modified out of
respect for the cultural and local customs of the country in which research is to be
conducted. Investigators who seek modification of any IRB requirements must provide
appropriate justification to the IRB. The regulations recognize that procedures normally
followed in foreign countries may differ from those set forth in 45 CFR 46. In such
instances, the Principal Investigator (PI) must show that the procedures prescribed by the
foreign institution assure protections that are at least equivalent to those provided in 45
CFR 46 and which are ascribed to by the SIU School of Medicine IRB.

For further information regarding research to be conducted in foreign countries, see letter
(h) of the Federal Regulations.

Investigators may contact any of the translation services listed below for assistance in
translating consent forms.

       AD-Ex Worldwide
       www.ad-ex.net
       Quotes: translations@ad-ex.net
       1-800-223-7753

       Corporate Translations
       www.corporatetranslations.com/overview.htm
       netinfo@corporatetranslations.com
       (310) 376-1304 or (310) 376-1394

       Northwest Translations Incorporated
       www.nwtranslations.com
       sales@nwtranslations.com
       1-800-270-5620

       Multilingual Planet
       www.multilingualplanet.com/index.html
       E-Mail Contact: info@multilingualplanet.com
       1-617-566-7050

Section XIX: Resources

A. Ethical Codes

Belmont Report (http://ohsr.od.nih.gov/guidelines/belmont.html)

The Belmont Report sent forth the basic ethical principles underlying the acceptable
conduct of research involving human subjects. Those principles, respect for persons,
beneficence, and justice, are now accepted as the three quintessential requirements for

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the ethical conduct of research involving human subjects. This document is the
foundation of human subject regulations in the United States.

Declaration of Helsinki (http://www.cirp.org/library/ethics/helsinki/)

In 1964 the World Medical Association developed the Declaration of Helsinki as a
statement of ethical principles to provide guidance to physicians and other participants in
medical research involving human subjects. The code of ethics has been widely adopted
by medical associations in various countries. It has been revised and amended several
times.

Nuremburg Code (http://ohsr.od.nih.gov/guidelines/nuremberg.html)

The Nuremburg Code served as the first set of principles outlining professional ethics for
human subjects research. It was developed from the Trials of War Criminals before the
Nuremberg Military Tribunals ... and defines ethical behavior in the conduct of research
using human subjects. Its development grew from the atrocities in human research
conducted by the Nazis.

B. General IRB and Human Subjects Information

Human Subject Regulations Decision Charts - Information on determining if your
research study requires IRB review.
(http://ohrp.osophs.dhhs.gov/humansubjects/guidance/decisioncharts.htm)

Comparison of FDA and HHS Human Subject Protection Regulations -
www.fda.gov/oc/gcp/comparison.html

President's Council on Bioethics - Advises the President on ethical issues related to
advances in biomedical science and technology. http://bioethics.gov/

C. Federal Agencies and Guidance

   1. DHHS Federal Regulations Governing Human Subjects

   Department of Health and Human Services (DHHS)
   45 CFR 46 - DHHS Regulations for the Protection of Human Subjects
   http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm
   OHRP - Office for Human Research Protections, DHHS, home page
   http://ohrp.osophs.dhhs.gov/

   Institutional Review Board Guidebook - OHRP guidance for IRB members and
   investigators http://ohrp.osophs.dhhs.gov/irb/irb_guidebook.htm


   2. Health Insurance Portability and Accountability Act (HIPAA) 45 CFR 46.160
   and 164 - Health Insurance Portability and Accountability Act (HIPAA) Privacy

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Office of Civil Rights
www.hhs.gov/ocr/hipaa/privacy.html and
www.hhs.gov/ocr/hipaa/guidelines/research.pdf
[45 CFR 164.501, 164.508, 164.512(i)]
[See also 45 CFR 164.514(e), 164.528, 164.532]
Complete text of all HIPAA Regulations www.hhs.gov/ocr/combinedregtext.pdf

3. Guidance from Federal Agencies and Other Organizations

   a. Center for Disease Control
   Home Page: www.cdc.gov
   Center for Disease Control Human Subjects Guidance: CDC Procedures
   for Protection of Human Research Participants (PDF document)

   b. Food and Drug Administration
   Home Page:www.fda.gov
   FDA Regulations:

          21 CFR 50 - FDA regulations for Protection of Human
          Subjects
          www.fda.gov/oc/ohrt/irbs/appendixb.html

          21 CFR 56 - FDA regulations for Institutional Review
          Boards
          www.fda.gov/oc/ohrt/irbs/appendixc.html

          21 CFR 312 - FDA regulations for Investigational New
          Drugs
          www.access.gpo.gov/nara/cfr/waisidx_00/21cfr312_00.htm
          l

          21 CFR 812 - FDA regulations for Investigational Device
          Exemptions
          www.access.gpo.gov/nara/cfr/waisidx_03/21cfr312_03.htm
          l

          21 CFR 814.100 - 126 - FDA regulations for Humanitarian
          Use Devices
          www.access.gpo.gov/nara/cfr/waisidx_03/21cfr812_03.htm
          l

          FDA Guidance for Institutional Review Boards and
          Clinical Investigators-1998 Update
          www.fda.gov/oc/ohrt/irbs/default.htm
          This document provides a valuable resource for
          investigators regarding FDA regulations for IRB operations


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       and procedures and clinical investigator requirements.
       Investigators using drugs and devices will benefit from a
       review of these rules.

       Good Clinical Practice in FDA-Regulated Clinical Trials
       www.fda.gov/oc/gcp/default.htm
       This site provides information concerning Good Clinical
       Practice (GCP) in the design and conduct of clinical trials.
       Compliance requirements and resources are included with
       links to relevant federal regulations and contact persons in
       the FDA.

       Guidance for Clinical Trial Sponsors on the Establishment
       and Operation of Clinical Trial Data Monitoring
       Committees: Draft Guidance
       www.fda.gov/ohrms/dockets/98fr/010489gd.pdf
       Though this document is only a draft, it provides
       reasonable suggestions on how to set up Data Monitoring
       Committees, what they should do, how they should operate.

c. International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH) - www.ich.org
This group provides guidance from a study of the regulatory authorities
from Europe, Japan, and US regarding drug development to harmonize the
interpretation and application of technical guidelines and requirements for
product registration and to reduce the need for duplicate testing in the
development of new drugs. Many sponsors require affirmation that the
IRB upholds these principles.

d. Office of Research Integrity - www.ori.dhhs.gov
The Office of Research Integrity (ORI) promotes integrity in biomedical
and behavioral research supported by the Public Health Service (PHS) at
about 4,000 institutions worldwide. ORI monitors institutional
investigations of research misconduct and facilitates the responsible
conduct of research through educational, preventive, and regulatory
activities.
e. Veterans Health Administration (VHA) Office of Research Oversight
(ORA) - www1.va.gov/oro/
The Office of Research Oversight (ORO) serves as the primary VHA
office in advising the Under Secretary for Health on all matters of
compliance and assurance regarding human subjects protections, animal
welfare, research safety, and research misconduct.




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D. Of Interest to Researchers and Human Subjects Protections Staff and Board
Members

   1. Ethics Organizations

   ARENA: Applied Research Ethics National Association
   www.primr.org/arena.html

   PRIM&R Public Responsibility in Medicine and Research
   www.primr.org/index.html

   AAMC American Association of Medical Colleges--AAMC Research Compliance
   Resources
   www.aamc.org/research/dbr/compliance/startcom.htm

   2. Ethical Codes of Professional Organizations

   American Anthropological Association
   www.aaanet.org/committees/ethics/ethics.htm

   American Educational Research Association
   www.aera.net/humansubjects/HRP-AERA.htm

   American Folklore Society
   www.afsnet.org/aboutAFS/humansubjects.cfm

   American Political Science Association
   www.apsanet.org/pubs/ethics.cfm

   American Psychological Association
   www.apa.org/ethics/code2002.html

   American Sociological Association
   www.asanet.org/members/ecoderev.html

   3. Listserv E-Mail Groups

   The IRB Forum: www.mcwirb.org
   The IRB Forum promotes the discussion of ethical, regulatory and policy concerns
   with human subjects research. The IRB Forum is open to past and current members of
   Institutional Review Boards (IRB) or Research Ethics Committees (REC), IRB/REC
   administrators, individuals involved in IRB/REC oversight and others with
   professional involvement in IRB/REC and/or research activities. Others will be
   admitted if their involvement in human subjects research will contribute to the
   discussion of issues pertinent to The IRB Forum. Go the website to sign up for the
   Forum.


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   OHRP Listserve: http://ohrp.osophs.dhhs.gov/list.htm
   The Office for Human Research Protections (OHRP) has created a LISTSERV in
   order to provide interested individuals with information regarding human subject
   research protection, and upcoming educational workshops and other programs. Go to
   the website for information on how to subscribe.

E. Special Topics


1. Mandated Reporting - State of Illinois Manual for Mandated Reporters
www.state.il.us/dcfs/MANDATED2002.pdf

2. Minors/Emancipation - State of Illinois
www.legis.state.il.us/legislation/ilcs/ch750/ch750act30.htm

3. Human Experimentation Resources on the Web
www.mit.edu/~dmaze/human_experimentation.html

4. National Clearinghouse on Child Abuse and Neglect Information
http://nccanch.acf.hhs.gov/pubs/factsheets/childmal.cfm

5. Human Genome Study www.ornl.gov/TechResources/Human_Genome/home.html

6. AIDS Confidentiality Act-State of Illinois -
www.legis.state.il.us/legislation/ilcs/ch410/ch410act305.htm 05.htm




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