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Research Study Protocol Template

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									  Protocol Mechanics

• Why do we write one?
• How to begin
• Requirements for submitting a
  research protocol and types
  - Nuts and Bolts
• Basic elements of informed consent
• IRB protocol review standards
• ProtoType
          Protocols: Why do we write them?

• CFR Title 21 Food and Drugs
   – Several other Manuals, Reports
• European Directive on GCP 2001/20/EC
• ICH guidelines
   – Guidance developed the Expert Working Group of the
     International Conference on Harmonization of Technical
     Requirements for Registration of Pharmaceuticals for Human
     Use (ICH)
   – Recommended by EU, Japan, and the US.
   – Published in the Federal Register May 9, 1997 (62 FR 25692)
   – Represents the Agency’s current thinking on good clinical
      • Alternative approaches can be used if they meet the requirements
Title 45 – Code of Federal Regulations – Part 46
• Subpart A: Federal Policy for the Protection of Human Subjects:
  IRB membership, functions, and records.

• Subpart B: Additional DHHS Protections Pertaining to Research,
  Development, and Related Activities Involving Fetuses, Pregnant
  Women, and Human In Vitro Fertilization.

• Subpart C: Additional DHHS Protections Pertaining to
  Biomedical and Behavioral Research Involving Prisoners as

• Subject D: Additional DHHS Protections for Children Involved as
  Subjects in Research.
          Code of Federal Regulations
                   (21 CFR)

 Part 50: Protection of human subjects including
  informed consent
 Part 56: Regulates the conduct of the IRB
 Part 312: Investigational New Drug (IND)
  application to the FDA
 Part 11: Regulates management of electronic
             International Guidelines
                 The rules for Clinical Research

International Conference on Harmonization (ICH)
Unified International standard to facilitate the mutual
acceptance of clinical data by regulatory authorities
E6- Guidelines for Clinical Practice
E2A- Clinical Safety Data Management
    Definitions and Standards for Expedited
E8- General Considerations for Clinical Trials
If you plan to do clinical research
you need a copy of the regulations
         Thinking about writing a Protocol?
 Protocol- “ …a complete written description of, and
  scientific rationale for, a research activity involving
  human subjects.” (Protomechanics NIH)
 3 general types of protocols:
  – 1. Retrospective review- usually with data
  – 2. Natural History study- may get tissue samples, DNA
  – 3. Interventional – Phase I/II most common, Phase III, Phase IV
         Writing a Protocol – First steps
 As PI, you usually are the one who has an idea
  – Is it reasonable? Do we have the resources?
  – Significant risks?
  – Do you have the patient population?
 Include those important to the conduct of the
  protocol as an Associate Investigator
 IND request, outside investigators, COI
 Initially most ICs will ask you to write an abbreviated
  conceptual sheet outlining what you wish to do- to
  the Pre-IRB committee
      What happens to your protocol when

                Pre-IRB               Dr Gallin
New Protocol    committee

Continuing                   IRB     Office of
Review or                            Protocol
Amendment                            Services
Writing a Protocol
 Nuts and Bolts
An 1195 that
begins every
Protocol at
the NIH

               June 2006
A continuing
Review 1195
Filled in for
every Protocol

                 June 2006
       The major topics to be covered in a
 Face Sheet                          Study Analysis
 Glossary                            Adverse Event Reporting
 Précis-Abstract
   • Objectives, study population,    Data and Safety Monitoring
     design and outcome                Plan
 Introduction & Background           Human Subject Protection
   •    Background, references            • Monitoring subjects,
                                            criteria for withdrawal
 Hypothesis & Objectives
                                            from study
   • What you are testing
 Study Design and Methods            Pharmaceutical, Biologic &
   • Benefits and                      Device Info
         Importance of study          References & Appendices
 Subject Enrollment                  Consent/Assent Forms
   • Inclusion and exclusion
          Protocols for INDs (312.23 CFR)

 Statement of objectives
 Name/address/qualifications of investigators
 Criteria for patient selection
 Description of the design of the study
 Method for determining doses
 Description of observations and measurements to be
 Description of the clinical procedures and lab tests
        Protocols for INDs (312.23 CFR)
           Required by FDA but need not be in the protocol but usually is

 Chemistry, manufacturing, and control
 Pharmacology and toxicology information
 Previous human experience with the
  investigational drug
 Additional information such as radioactive
  drugs, pediatric studies,
 Consent Forms

Why all the fuss?
                                 The Doctors Trial at

   KARL       KARL       OSKAR       PAUL          SIEGFRIED      WOLFRAM    HELMUT         JOACHIM     KARL

                                                                                             The EXPERIMENTS
                                                                                             •High Altitude Exps
                                                                                             •Freezing Exps
                                                                                             •Malaria Exps
                                                                                             •Lost (Mustard) Gas Exps
                                                                                             •Sulfanilimide Exps
                                                                                             •Bone, Muscle, and Nerve
   KURT       RUDOLF     GERHARD     SIEGFRIED    HANS WOLFGANG    VIKTOR    GEORG AUGUST    Regeneration and Bone
                                                                                             Transplantation Exps
   BLOME      BRANDT     ROSE        RUFF         ROMBERG          BRACK     WELTZ
                                                                                             •Sea Water Experiments
                                                                                             •Epidemic Jaundice Exps
                                                                                             •Sterilization Exps
                                                                                             •Spotted Fever Exps
                                                                                             •Experiments with Poison
                                                                                             •Incendiary Bomb Experiments

            WILHELM                  HERTA           FRITZ        KONRAD      HERMANN        •Crimes against Humanity
WALDEMAR                 ADOLF
                The Nuremburg Code
• Voluntary consent is essential     • Degree of risk never outweighs
• The experiment should yield          the results of the experiment
  fruitful results for the good of   • Proper care to prevent adverse
  society, unprocurable by other       events
  methods or means of study          • Experiment should be conducted
• Design of study based on animal      only by scientifically qualified
  work and natural hx of disease       persons
  and the results justify the        • Subject has the right to stop at
  experiment                           any time
• Avoid all undue physical and       • The PI should be prepared to stop
  mental pain                          exp if patient is at risk of harm.
• No exp to be done with death as
  endpoint (except if MD)
           Not only in Germany-The Tuskegee Exps

• From 1932-1972, the Tuskegee Public Health Study was
  conducted by the U.S. Public Health Service to observe
  400 sharecroppers with untreated syphilis to document
  the course of the disease in African-Americans and the
  racial differences in the clinical manifestation of the
• These men were not informed of their disease status nor
  given counseling to avoid the spread of the disease
• In 1972, the study was disclosed to the public
      Consent form and discussion requirements:
                                   ICH 4.8.10

•   Trial involves research                • Participation is voluntary; subject may
                                             refuse or withdraw at any time
•   Purpose of trial
                                           • Who will be granted access to the
•   Treatments and Randomization             subject’s original files; subject’s legal
•   Trial procedures                         representative has access also
•   Subject’s responsibilities             • Records kept confidential; if published
•   Experimental aspects                     identity is confidential
•   Risks or inconveniences to subject     • Subject will be informed in a timely
    or fetus                                 fashion of information important to the
•   Expected benefits if any                 conduct of the trial
•   Alternative therapies                  • Contact information re rights,
                                             complaints, injuries
•   Compensation or rx for trial related
    injury                                 • Reasons why subject could be
                                             terminated from the study
•   Prorated payment if any
                                           • Duration of participation in study
•   Expenses to the subject if any
                                           • Approximate number of subjects in the
                NIH Informed Consent
•Introduction                     • Compensation
  Purpose of the study            • Costs to participants
  Duration of study               • Procedures for
  Research tests or procedures      withdrawal
  Research drugs or treatments    • Confidentiality concerns
•Risks and discomforts            • Genetics research:
•Benefits                         risks to family
•Alternatives to participation    members
•Uses of samples or information   • Financial or other
                                  conflict of interest
                                  • Assent procedures
    Part of the Protocol submission

Conflict of Interest of the Clinical Researchers
  A Guide to Preventing Financial and Non-financial Conflicts of Interest
                  In Human Subjects Research at NIH
                     (Last Revised, December 2006)

 Avoiding financial and other conflicts of interests is important for
  NIH, where the trust and protection of research subjects is vital
  to our mission to improve the public health.
 This specific guide applies to all investigators who substantively
  participate in the development, conduct, or analysis of clinical
  research protocols, both diagnostic and therapeutic, and are
  listed as investigators on the front sheet of protocols
 The Principal Investigator is responsible for assuring that each
  investigator listed on the protocol front sheet receives a copy of
  the Guide. In addition, the PI is responsible for providing his or
  her IC Deputy Ethics Counselor (DEC) with a list of all
  investigators on the protocol before beginning the scientific
                  Examples of Investigator COI
•   Serving as a director, officer or other decision-maker for a commercial sponsor
    of the human subjects research;
•   Holding any stock or stock options in a commercial sponsor of the human
    subjects research (unless held in a diversified, independently managed mutual
•   Receiving compensation for service as consultant or advisor to a commercial
    sponsor of the human subjects research (excluding expenses);
•   Receiving honoraria from a commercial sponsor of the human subjects
•   Personally accepting payment from the human subjects research sponsor for
    non-research travel or gifts (government receipt of in-kind, research-related
    travel is not included);
•   Obtaining royalties or being personally named as an inventor on patents (or
    invention reports) for the product(s) being evaluated in the human subjects
    research or products that could benefit from the human subjects research
    (special rules apply in this case when NIH holds the patent);
•   Receiving payments based on the research outcomes;
•   Having other personal or outside relationships with commercial sponsors of the
    human subjects research
•   Having financial interest in companies with similar products known to the
    investigator to be competing with the product under study.
  Institutional Review Board (IRB)/
Independent Ethics Committee (IEC)
CFR 56.102 and ICH 3.1 This is set in law in the US

 An IRB/IEC should safeguard the rights, safety, and well-being of all
  trial subjects. Special attention should be paid to trials that may
  include vulnerable subjects

 IRB functions in accord with the NIH (Institution’s)
       Multiple Project Assurance.

 CFR 56.107. IRB should have at least 5 Members of varying
  background. The choices should promote respect for its advice and
  counsel in safeguarding the rights and welfare of human subjects.
  At NIH need to include a biostatician, bioethicist,and nonscientist.

 PIs are expected to present new protocols
  and to respond directly to questions.

 CFR 56.109: An IRB shall review and have authority to approve,
  require modifications in (to secure approval), or disapprove all
  research activities covered by these regulations
    Some Protocol Elements the IRB looks for
•    The proposed research design is scientifically sound and will not expose subjects to
     risk unnecessarily.

•    Risks are reasonable relative to anticipated benefits: minimize risks to subjects?

•    Subject safety is maintained

•    Subject selection is equitable: rationale for inclusion and exclusion criteria

•    Safeguards to protect vulnerable subjects are in place.

•    Informed consent is obtained from research subjects or their legally authorized

•    Will the research contribution to generalizable knowledge be worth exposing
     subjects to risk?

•    Equipoise (Benjamin Friedman): A trial can be ethical if there is equal uncertainty
     among groups
 Some Protocol Elements the IRB looks for
• Subject privacy and confidentiality are

     • Will personally-identifiable research data be
       protected to the extent possible from unauthorized
       access or applications?

     • Are special privacy and confidentiality issues
       properly addressed, e.g., use of genetic
    Regulatory Elements for IRB Review:
        Additional Considerations
• Ionizing radiation: Is the use of ionizing radiation
  medically indicated or for research purposes only?

• Collaborative research: Is this an international or
  domestic collaborative project? Are FWAs or other
  assurances in place?

• FDA-regulated research: Is an IND or IDE involved in
  this protocol?
 IRB Minutes

• Attendance

• Actions

• Votes

• Discussion

• Stipulations
                              Notification of NEI/IRB Action

Principal Investigator: Robert Nussenblatt, MD
Protocol Title: Treatment of Severe Eye Disease
Protocol Number:          TBD
IND or IDE Number:                                      Commercial Sponsor:
                                     Type of Review
      Full IRB Review Meeting on: 1/7/05                 Expedited Review on:
                                   Reason for Review
        Initial Review                 Protocol, version/date: Specify if checked.
        Continuing Review              Consent, version/date: Specify if checked.
        Amendment:                     Patient information, version/date: Specify if checked.
        Risk Determination             Recruiting Materials, version/date: Specify if checked.
        Response to Stipulations       Other, specify: Specify if checked.
                                        IRB Action
       Approve: 00/00/00                    Research Risk Determination:
       Not Approved/Tabled (see below)          Minimal Risk        More Than Minimal Risk
       Approved with comments
This certifies that the NEI IRB chair has reviewed the material referenced above.

The IRB has tabled this protocol until December. They have provided a separate list of the
stipulations that must be met in order to gain approval. [These are attached.] Responses to the
stipulations should be addressed directly to the Chair of the IRB.

__________________________________                            ___________________________________
Edmond FitzGibbon, MD                                         Frederick L. Ferris III, MD
Chair, NEI/IRB                                                Clinical Director, NEI

       1/21/05                                                1/21/05
 ____________________________________________________         _____________________________________________________
Date Signed                                                   Date Signed

  1971     Principal Investigator
              Writes Protocol
Review             IRB
               Revisions to
            Protocol Requested

                 Final IRB
2003 Protocol Review Process
The Automated Protocol Writing System

             An Overview

     Warren Grant Magnuson Clinical Center
          National Institutes of Health
                Bethesda, MD

               February, 2007
                       Tools to Facilitate Clinical Research
 Conflict-of-Interest          Assisted protocol writing system           NLM
Report of Investigators                                   
                               Scientific and Regulatory Document
       (to ICD)                        Basic Clinical Care Plan
                                                                           Adverse Events
  CC Depts & ICD                                                          Reporting System
                                 Protocol Mapping System

    Cost Projections                                                       CD & SD

  Protocol Monitoring

                                    Results / data tagged            Regulatory Agencies
     Data Mining                                                       (FDA, OBA,etc)
  Institute Research                  Data Warehouse
Data Collection Systems

     Management                    Advanced Rules Engine            DSMB
                                 CRIS AE Reporting Template
Hospital Epidemiology                                                                      2
Value Added:
 Maximizes use of IT . . . employs a paperless system
 Standardizes the process – while offering flexibility
 Provides a standardized template for investigators and
 Improves resource allocation
 Enhances patient care and safety
 Facilitates the process for all
   • Increases speed of protocol writing and review
   • Consolidates other protocol-management programs
                                                       ProtoType (the Protocol Typewriter)
  NIH/Clinical Center                       A web-based clinical protocol-writing application
Customization and Flexibility
 Format is NIH Institute-specific
 Only relevant fields appear
  • e.g., Natural history study vs. Clinical Trial study

 Recommended language is available, but can be
  modified as the Investigator sees fit.

                                                ProtoType (the Protocol Typewriter)
   NIH/Clinical Center               A web-based clinical protocol-writing application
. . . Welcome to ProtoType, and Your Protocols:
Create a protocol:
Select Interventions:

                           NIH Pharmacy
                        Formulary pre-loaded
                           to choose from
(Presentation of interventions in the protocol)
Reflecting interventions in the Study Timeline:
Using standard-language cassettes (Consent Form)

                                              Edit capabilities
     Language pre-                             can be held on
      loaded when                                  special
    consent created.                            components
Using the Edit mode and inserting references and figures
An electronic Comments feature:
Compare protocol versions, with markup:

                     New Text    Old Text Crossed
                     Bracketed         Out
Electronic approval signaturing:
Value Added                 for the Researcher
 Online archives of all protocols
 Amendments immediately placed into protocol
 Helps mapping protocols
 Protocol moves electronically to IC, IRB, CC, etc.
 Tracks states of the protocol, i.e. Amendment, Continuing Review, etc.
 Updated regulatory needs automatically there, i.e. COI
 Wizard and/or direct links to additional forms, i.e. IND
 Continuing review report - List of amendments and protocol changes
 Cassettes of recommended language for consent forms and procedures

                                                    ProtoType (the Protocol Typewriter)
  NIH/Clinical Center                                                                 17
                                         A web-based clinical protocol-writing application
Program Status

  ProtoType, Ver. 2.1 & CRIS AE: May, 2005
  ProtoType, Ver. 2.2: July, 2005
  ProtoType, Ver. 2.4: October, 2005
     ProtoType, Ver. 3.0: February, 2007

                                         ProtoType (the Protocol Typewriter)
NIH/Clinical Center           A web-based clinical protocol-writing application
New Features v3.0 (coming soon)
Single Sign-on
Full Screen Text Editing
Enhanced Version Compare Features
Much More Robust Reference Management
  Supports import from 3rd parties
Attachments Accessible From Exported Documents
…And much more!

                                       ProtoType (the Protocol Typewriter)
NIH/Clinical Center         A web-based clinical protocol-writing application
                      Lists to Avoid
• FDA list of Clinical Investigators: Disqualified/Totally restricted
  list; Debarred list

• We encourage you to use ProtoType. The
  training link is at:
• To set up an account call Philip Lightfoot at
  (301) 496-0744 or you can email him at:
• An account will be set up in an hour

                                           ProtoType (the Protocol Typewriter)
 NIH/Clinical Center            A web-based clinical protocol-writing application
Protocol Contacts
    Phil Lightfoot
    (301) 496-0744

             Brian Chamberlain
             (301) 402-3299

                       Kim Jarema
                       (301) 496-0744

                              Robert Nussenblatt
                              (301) 496-3123

                                                         ProtoType (the Protocol Typewriter)
 NIH/Clinical Center                          A web-based clinical protocol-writing application
                      Thank you

• Joel Moss NHLBI          • Karen Charron
                           • Eric Zimmerman
• Kim Jarema               Johns Hopkins Bloomberg
• Brian Chamberlain          School of Public Health
• Phil Lightfoot

                                        ProtoType (the Protocol Typewriter)
NIH/Clinical Center          A web-based clinical protocol-writing application

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