CLINICAL RESEARCH HANDBOOK by oROMUF

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									Clinical Research Handbook




         Palmetto Health
     Research Administration




             June 2011
                                  TABLE OF CONTENTS

                                                                                                Page
Overview                                                                                          4
Protection of Human Subjects in Research                                                          6
        Historical Overview                                                                      6
        Ethics and Federal Regulations                                                           7
Developing a Clinical Research Project                                                            8
        Clinical Research                                                                        8
        Basic Steps in Planning the Research Project                                             9
        Examples of Study Designs                                                               13
IRB Submission Guidance for Investigators Conducting Clinical Research                           16
        What is the purpose of the Institutional Review Board?                                  16
        Authority of the Committee                                                              17
        Privacy of Protected Health Information                                                 17
        Scientific Review Committee                                                             18
        Training in the Protection of Human Subjects in Research – CITI Training                18
        What are the Federal definitions pertaining to research with Human Subjects?            20
        How do I determine if my project is considered Human Subjects Research?                 21
        Human Subjects Research and Quality Improvement                                         22
        When should Human Subject Research Projects be submitted for IRB review?                23
        Presentation of Case Reports                                                            23
        What Conditions require submitting my project to the Palmetto Health IRB for review?    23
        Review mechanisms used by the Institutional Review Board                                24
                            Exempt from IRB Review                                               24
                            Expedited IRB Review                                                 25
                            Full IRB Review                                                      25
        Accessing the Electronic Institutional Review Board (eIRB) Submission System            25
                            What do I need to do?                                                25
                            Your Personal Workspace                                              26
                            Study Workspace                                                      26
                            Creating a New Application                                           26
                            Submitting an Application                                            26
                            Uploading Documents                                                  26
                            Editing and Deleting Study Documents                                 27
                            Informed Consent Documents                                           27
                            Responding to Reviewer Comments                                      27
                            Continuing Review                                                    28
                            Amendments                                                           28
                            Reportable Events                                                    28
                            Printing an Application                                              29
        What does it mean when my research is exempt from IRB review?                           29
        Key points to remember when submitting projects exempt from IRB review                  31



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        How do I know if my research qualifies for expedited IRB Review?             32
        What materials should be provided for expedited IRB review?                  33
        Full IRB review (Convened Meeting)                                           36
        What materials should be provided for Full IRB review?                       36
        Continuing Review: Renewals & Study Status Changes                           38
        Amendments: Study Modifications                                              39
        Unanticipated Problems or Adverse Events or Other Complications              40
        Informed Consent Document                                                    41
        Obtaining Informed Consent                                                   42
        Study Auditing                                                               43
        Corrective Action Plan                                                       44
IRB Administration                                                                    45
Who are the persons responsible for the operations of the IRB?                        45
Regulatory Compliance                                                                 46
Good Clinical Practice                                                                47
Responsibilities of the Investigator                                                  48
Responsibilities of the Study Coordinator                                             48
Responsibilities of the Research Team                                                 49
Where can I learn more about the requirements of research involving Human Subjects?   50
Registration of clinical trials through ClinicalTrials.gov                            50
Appendix A: Outline for Writing an Observational Study Proposal                       51
Appendix B: Outline for Writing a Clinical Research Protocol                          52
Appendix C: Privacy of Protected Health Information - Accounting of Disclosures       56
Appendix D: Resources for Investigators                                               57
Appendix E: Index of Abbreviations                                                    58




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                                              Overview
About this Overview
This two page overview is designed to give some quick answers to questions that investigators
frequently have. For more detailed information, please consult the appropriate sections in this
handbook and the links and references that it contains.

Compliance with Federal Regulations
The ethics of human subject research and federal regulations have evolved over the past 50
years. Compliance with the requirements of the federal regulations, even for non-federally
sponsored/regulated research, protects the rights and welfare of subjects. Palmetto Health (PH)
requires compliance with federal regulations for all human subject research regardless of source
of support.

Proposal Development
Clinical research takes two primary forms. One is an experimental approach (i.e., clinical trials)
in which a factor of interest is introduced and its effect on the subjects is observed at a later point
in time. The other is an observational approach in which outcomes typically have already
occurred and interest is on establishing associations with other factors. Because the allocation of
treatment in experimental research is under the control of the investigator (through the protocol),
there are issues that must be addressed in the study document (e.g., stopping rules) that are not
required in observational studies. For both classes of studies there are some frequent design
issues that result in approval delays and include failure to justify the sample size, as well as a
vague or missing statistical section which describes the proposed analysis. In addition, care
must be taken to ensure that the inclusion criteria, design and analysis are all consistent with the
stated study purpose. Appendices A and B give the format for observational and experimental
studies respectively. Appendix D lists the resources that Palmetto Health makes available to
investigators to assist in their research. You can find in Appendix E a list of abbreviations used
in this document.

Scientific Review
All proposed human subject research must receive scientific review prior to submission for IRB
review, with the exception of research qualifying for exemption from the requirements of 45
CFR 46.101(b) and industry initiated and sponsored research and clinical trials. Principal
investigators of other proposals that have had scientific review elsewhere should submit a copy
of the review report in eIRB. Scientific review is an assessment of the scientific merit of the
research design. IRB review shall not begin until the protocol has secured SRC review.

Institutional Review Board
Generally, investigative projects at Palmetto Health fall into one of the following categories:
    1. Not Human Subjects Research - “Human Subject" is defined as "a living individual about
         whom an investigator (whether professional or student) conducting research obtains data
         through intervention or interaction with the individual; identifiable private information."
         “Research” is defined as "a systematic investigation, including research development,
         testing and evaluation, designed to develop or contribute to generalizable knowledge.”
         The usual situations where a project at PH may not be human subjects research include
         some quality improvement activities and studies where the investigator is given a de-



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      identified dataset by an individual having access to the data but who is not part of the
      study team. In this scenario the investigator will not have viewed individual identifiers.
      The investigator may submit the proposal through eIRB and obtain a determination
      indicating that the project is not human subjects research.
   2. Exempt research in our setting usually involves the collection or study of existing data,
      documents, records, pathological specimens, or diagnostic specimens, 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. At PH the determination that a study
      is exempt is made by submitting the proposal through eIRB.
   3. Expedited research involves projects where perhaps the data is prospectively collected or
      contains individual identifiers but is still minimal risk (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).
   4. If the proposal does not qualify for one of the above review mechanisms, it will be
      considered requiring full board review.

Human Subjects Protection Training
Investigators and Key Study Personnel are required to complete training on ethical principles and
regulations pertaining to research with human subjects. Key Study Personnel include any person
who is actively involved with human subjects through one or more of the following categories:
1) The informed consent process, 2) Performs study related interventions on human subjects, or
has 3) Access to study subjects’ identifiable private health information for research purposes.
Research personnel must affiliate with Palmetto Health and complete required training modules
through the Collaborative Institutional Training Initiative (CITI) prior to conducting research
with human subjects. Research personnel should log onto the CITI website at
www.citiprogram.org. Every two years research personnel are required renew their training by
completing designated refresher modules from the CITI.

Electronic Institutional Review Board (eIRB) Submission System
Investigators seeking IRB review of their proposals must submit through eIRB. Prior to
submitting an IRB application, you must register at eirb.healthsciencessc.org. The registration
form can be completed in a few minutes, and will be validated by Palmetto Health Information
Technology (IT). Once you are able to login, you will be given the option to create an IRB
application by selecting “Create New Study”.




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Protection of Human Subjects In Research

Historical Overview

There are three events that have had significant impact on federal regulations for the protection
of human research subjects. These are: the 1946 Nuremberg Doctors Trial, the 1960s
Thalidomide Tragedy, and the 1972 Tuskegee Syphilis Study Exposé.

Because of the atrocities that were committed in the name of medical science by the Nazi
doctors, the Nuremberg Code was internationally adopted in 1947 as the first code for the
protection of human subjects in research.

The Code stated that:

      Informed consent of volunteers must be obtained without coercion in any form.
      Human experiments should be based upon prior animal experimentation.
      Anticipated scientific results should justify the experiment.
      Only qualified scientists should conduct medical research.
      Physical and mental suffering and injury should be avoided.
      There should be no expectation of death or disabling injury from the experiment.

Thalidomide was approved as a sedative in Europe in the late 1950s. It had not been approved
by the U.S. Food and Drug Administration (FDA) in the United States; but the manufacturer
supplied “samples” to U.S. physicians, who were paid to study its safety and efficacy in what
was loosely termed “research” by giving the experimental drug to patients. This was common
practice at that time. Thalidomide also produced an anti-nausea effect and, thus, some
physicians were using it to treat morning sickness in pregnant women. What was not known
about this drug at that time was that it also inhibits the growth of small blood vessels in fetuses,
particularly during the first trimester of pregnancy. Thousands of babies were born with grossly
underdeveloped arms and legs. In the U.S., congressional hearings led to the passage of the
Drug Amendments of 1962. This statute required the following:

      Documentation of efficacy and safety before licensing a new drug.
      Informed consent of study subjects.
      Systematic reporting of adverse events.

Note: Because of the action of thalidomide on the development of small blood vessels, it is now
being used again as an anti-tumor agent in clinical trials. Protocols and consent forms for these
trials include substantive safeguards to prevent the drug from being given to women who might
be pregnant and to emphasize that women who are receiving the drug and are sexually active
must use at least two reliable methods of birth control.

In 1932, the U.S. Public Health Service (now the Centers of Disease Control and Prevention, or
CDC) initiated a syphilis program for Negro males in a rural county in Alabama. This study
started out in response to a genuine concern about minority health problems, and also because
the known treatment for syphilis at that time was dangerous and inadequate (the use of the



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mercury and arsenic). Initially, the subjects were to be given complete physical examinations, a
thorough medical history, and then followed for six to eight months; however, no treatment was
to be given. At the end of that time, non-therapeutic spinal taps were to be performed and the
study was to be stopped. Instead, the study went on for a little more than 40 years. During this
time, the men were never told that any of the procedures were non-therapeutic. Even after
penicillin was accepted as the curative treatment for syphilis in 1943, none of these men received
it. A public exposé in 1972 by an investigative reporter for the Associated Press finally led to
discontinuance of the study on 1973, and the remaining men in the study received treatment. (In
addition, the CDC extended free medical care to these men, the wives who had contracted
syphilis, and the children who had been born with congenital syphilis for the rest of their lives.
This money continues to be paid to these citizens today. In a formal White House ceremony in
1997, President Clinton apologized to study subjects and their families and called for renewed
emphasis on research ethics.)

In 1974, Congress passed the National Research Act which mandated regulations for the
protection of human subjects that included requirements for informed consent and review of
research by institutional review boards (IRBs). This Act also created the National Commission
for the Protection of Human Subjects of Biomedical and Behavioral Research. In 1979, the
National Commission wrote the Ethical Principles and Guidelines for the Protection of Human
Subjects of Research, commonly called the Belmont Report, which is the cornerstone statement
of ethical principles upon which the federal regulations for the protection of subjects are based.
Based on the Belmont Report, further regulations were mandated by the Department of Health
and Human Services (DHHS) and FDA in 1981. After 10 years of negotiation and coordination,
17 federal agencies agreed to adopt the basic human subject protections. These were published
in 1991 and are referred to as the “Common Rule” and established three main human subject
protection mechanisms: 1) Review of research by an institutional review board; 2) Informed
consent of subjects; and 3) Institutional assurance of compliance.

Ethics and Federal Regulations

The ethics of human subject research and federal regulations have evolved over the past 50
years. Compliance with the requirements of the federal regulations, even for non-federally
sponsored/regulated research, protects the rights and welfare of subjects. Most research
institutions (including Palmetto Health) require compliance with federal regulations for all
studies regardless of source of support.

The Belmont Report describes three basic principles relevant to the ethics of human subject
research: respect for persons, beneficence, and justice. The Belmont Report may be accessed at:
www.hhs.gov/ohrp/humansubjects/guidance/belmont.html.




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                             Developing a Clinical Research Project

                                          An Introduction

                                    Rudolph S. Parrish, Ph.D.
                                      Vista Research, LLC

I. Clinical Research

Clinical research takes two primary forms. One is an experimental approach in which a factor of
interest is introduced and its effect on the subjects is observed at a later point in time. The other
is an observational approach in which outcomes typically have already occurred and interest is
on establishing associations with other factors.

Clinical research designs provide a systematic framework within which scientific research in
human subjects can be carried out efficiently and ethically and in which experimental
conclusions are reached in a manner that is statistically defensible.

Clinical trials: A clinical trial is a prospective controlled experiment in human subjects which
involves an intervention and observation of the subsequent effect of that intervention on the
subject. Interventions may be therapeutic, prophylactic or diagnostic, and they may be
introduced as pharmacologic agents, treatment regimens, procedures, or devices. In a clinical
trial, the investigator selects and assigns the “exposure” (i.e., the intervention) and then follows
the subject to determine the effect or outcome for that individual. The three types of clinical
trials and their typical objectives are:

       Phase I: Determine safety and maximally tolerated dose (MTD)
       Phase II: Determine efficacy and further evaluate safety
       Phase III: Establish relative efficacy compared to another intervention

The purpose of a Phase I trial may be to assess how well a drug or procedure can be tolerated in
humans and to determine a reasonable dose or technique for the intervention. In a Phase II trial,
one seeks to estimate biologic activity or effect (efficacy) and to assess rates of adverse events
(toxicity). Phase III trials are comparative, usually seeking to show that a new procedure is
better (more effective) or at least as good as (equivalent to) the standard treatment, or at least
better than no treatment (placebo). Phase I and II trials are usually one-arm (i.e., single treatment
group) studies and usually involve a relatively small number of subjects. Phase III trials usually
involve two arms and a large number of subjects. They are commonly called “randomized
controlled trials”.

Observational studies: An observational study differs from a clinical trial or an experimental
study in that the researcher does not control who has the exposure of interest. The primary
hypothesis tested in any observational study is whether there is an association between an
exposure (e.g. smoking) and an outcome (e.g. lung cancer). The three main types of
observational studies are cross-sectional, case-control, and cohort. A cross-sectional study is
often used to quickly determine an association between an exposure and an outcome, which are



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measured at the same time. One obvious disadvantage of a cross-sectional study is that it is not
possible to determine if the exposure occurred prior to the outcome of interest. A case-control
study design is often used when the outcome is rare, such as in studies looking at cancer. In
these studies, subjects with and without the outcome are admitted to the study and a history of
the exposure is determined. Lastly, a cohort study follows a group of individuals with and
without an exposure until the outcome occurs. This type of study allows for the study of rare
exposures and also allows for the determination of multiple outcomes. Temporal sequence is
more clearly established in a cohort study than with the other two study designs. Other study
types include case studies and chart reviews. The primary objective of an observational study is
to establish an association between an exposure factor and an outcome variable, but may also
seek to ascertain the prevalence of a given factor.

II. Basic Steps in Planning the Research Project

Several issues need to be resolved prior to writing a clinical research protocol. The effort can be
delineated into several steps. One needs to consider each of the following:

       1.   Research questions
       2.   Study population
       3.   Measures of response, or exposure and outcome
       4.   Testable hypotheses or estimable parameters
       5.   Experimental design
       6.   Sample size
       7.   Statistical data analysis

When all of these have been dealt with, the actual protocol development can be accomplished.

Forming the research question: In simple studies, it is best to focus on a single primary
research question. Additional secondary questions might also be considered, but the design of
the study will be based mostly on the primary question. The simpler the research question, the
more easily the trial can be designed, conducted, analyzed, and interpreted. Research questions
should be of sufficient scientific interest to merit expenditure of funds and investigator efforts
and to justify enrollment of patients. Research questions should be answerable, in a statistical
sense, with the resources available. That is to say, they should be important and practical
questions. They should be stated clearly before the trial is conducted. They should lead
naturally to the primary hypothesis stated in the context of a primary response or outcome
variable.

In small-scale clinical trials, it is usually best to work with interventions that are expected to
produce large effect sizes. Effect size refers generally to the magnitude of the mean change due
to the intervention divided by the standard deviation. The anticipated effect size usually should
be based on prior knowledge and what also might be considered as of clinical and practical
interest.

A research question can be stated in general terms but must be more explicitly specified in terms
of an endpoint of interest for use in designing the trial. For example, one might postulate that



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Drug X will be effective in treating a given medical condition, whereas it would be necessary to
indicate what is meant by “effective”, as well as providing the dosing and administration details.
If patient response is well defined, then the research question might be posed in a form such as
“Drug X will produce a 40% response rate”. This relates the intervention to the endpoint that
will be measured, the endpoint being the response rate for the group of subjects determined by
evaluating each subject as to whether or not the response was achieved. Other situations might
involve measurement of variables that change over a continuum, such as blood pressure. If Drug
Y is meant to lower blood pressure, one might postulate that “Drug Y will lower systolic BP by
10 points”. This would translate into a mean change in systolic BP of 10 points for the group of
patients. Time-to-event endpoints also are continuous and are often expressed in hypotheses in
terms such as “median survival time”.

A thorough literature review is very helpful in ascertaining whether a research question has been
addressed by other investigators, and it is often helpful in gathering information on expected
levels of response and variability of observations.

Specifying the study population: The study population is innately tied to the research question.
It may be defined as “the subset of the population having the condition or characteristics of
interest defined by the eligibility criteria (inclusion/exclusion)”. This is the population to which
an inference is desired to be made. Eligibility criteria, together with the characteristics of the
subjects that actually are enrolled, define the study sample and the population to which the
inference may truly be valid [external validity]. Subjects will be entered into the study in various
ways depending on the experimental design type and other factors. Sometimes it is of interest to
ensure that subjects from different classes are equally represented in the sample. Examples
include gender, race, and age. When a specified number of subjects are selected on the basis of
factors such as these, the sampling is said to be “stratified”. Consulting a statistician will help in
determining when stratification is needed, but generally one would stratify on factors that are
suspected of being predictive of outcome. Another aspect of the study sample is the actual
selection process which includes recruitment approaches. Essentially, the objective is to recruit
in an objective manner so that the inferences that are drawn from the sample data will apply to
the study population in an unbiased manner.

Selecting response variables: Response variables specify the actual observations that are made
on each individual subject following the intervention. They should be selected to correspond to
the endpoints in the stated hypotheses, so that if a value for the response variable is obtained for
each subject, the relevant endpoint can be calculated. If a response rate for the group is utilized
as an endpoint, each individual subject must be evaluated for the corresponding response (e.g.,
CR, PR, NR) and such responses need to be carefully and objectively defined. If continuous
endpoints are used, the variables that go into the calculation must be defined (e.g., hormone level
in serum, time to death).

Selecting exposure and outcome variables: An exposure variable refers to the presence or
absence (or sometimes the level) of an uncontrolled factor which an individual has experienced.
Examples include: smoking, BrCa1, UV radiation, aspirin use. Exposure variables are selected
because of a scientific suspicion that they might be associated in some manner, possibly
causative, with an outcome of interest, such as a diagnosis of cancer or other disease or



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condition. The exposure and outcome variables will be mentioned in the hypotheses as being
related in some way. For a case-control study, one would postulate that there is a significant
association between them, as measured by an odds ratio. For a cohort study, subjects with the
exposure factor might be postulated to have a higher or lower risk of experiencing the outcome
of interest. Exposure factors are not considered to be interventions because they are not assigned
to the subjects through the experiment.

Forming a hypothesis that can be tested: The research question is posed technically in the
form of a null hypothesis (H0) and a corresponding alternative hypothesis (Ha). The null
hypothesis is usually given as the hypothesis of “no difference” or “no effect”, which is desired
to be rejected if the research question is true, and the alternative hypothesis specifies what is
actually postulated in the research question. Moreover, the alternative hypothesis should specify
quantitatively what is expected to occur, as in the examples above. For example, “H0: The mean
response rate using Drug X will not be different from zero, Ha: The mean response rate using
Drug X will be at least 40%”. When specified in this manner, the collected data should enable
the estimation of the mean response rate and its standard error, from which an appropriate test
statistic can be formed to test the null hypothesis.

Identifying parameters that can be estimated: With some types of studies, all that is needed
are simple statistics (such as the mean, median, or proportion) which are used to summarize the
findings for the study sample. This is typical for cross-sectional studies that involve a
questionnaire or other survey tool. Interest might center on ascertaining the proportion of
subjects that have a certain characteristic, for example. Typically, the values computed from the
study data are “inferred” to be the values for the greater study population. The statistics from the
study group are said to be “estimators” of the corresponding population parameters. Once a
population parameter is identified as something that is desired to be known, there is usually an
optimal sample statistic that does the best job of estimating that parameter value. You can
consult a statistician to determine what statistic to use and how the calculations should be done.

Selecting the correct experimental design: After hypotheses and parameters of interest are
determined, there may be several options for selecting an appropriate experimental design that
will be used to conduct the study and collect the necessary data. The design must be such that
the objectives can be achieved, hypotheses can be tested, and parameters can be estimated. If
conducting a clinical trial, it will usually be obvious which Phase will be used. For observational
studies, the same will be true. It is very important to develop a good plan, and this step generally
should be discussed with a statistician. If the research question is well thought out, endpoints are
known, hypotheses are specified, and the study population is identified, it will be easier to
address the design issue.

There are several aspects to specifying the experimental design beyond selecting the basic form
of the study. These include items that are listed in the appendix. Of particular note is the
selection of control groups, when applicable. The randomized controlled trial (RCT) and the
case-control study both use control groups. In the RCT, subjects are entered into the study and
then randomized to a treatment or control arm. There are many different approaches for
implementing randomization and a statistician usually should be consulted about the options. In
the case-control study, a control group should be selected carefully to ensure the best possible



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referent group. The intent is to select a control group that would be the same for all
characteristics except for the factor under study. This is another are where consulting a
statistician or epidemiologist is worthwhile. It is often useful to employ a blinding methodology
to prevent the introduction of biases from either the patient or investigator side.

Clinical trial designs often employ stopping criteria that are meant to end the trial early if either
too high a rate of adverse events occurs or if ample evidence for or against the primary
hypothesis is established early in the accrual/treatment period. A statistician can help design
specific tests that can be applied at either specific times or after a given number of subjects have
been enrolled and evaluated. For adverse events, the investigator needs to decide what rate is
acceptable and how high a rate would be considered unacceptable. Stopping criteria may be
implemented also as part of an interim monitoring plan, but this usually must be considered at
the design stage rather than after the study has been started. Stopping a trial altogether is
different than withdrawing a patient because of safety concerns for that individual. In the latter
case, specific criteria need to be specified to accommodate removing a patient from the study.
These are usually based on clinical considerations and not statistical matters, but there will be
implications as to how the data are analyzed when subjects have dropped out. A statistician
should be consulted for this situation when the analysis plan is being developed.

Determining the number of subjects needed: The number of subjects needed to conduct a
study will depend on several factors. The question of sample size is closely tied to the type of
design being used, hypotheses being tested, endpoints, and desired power or confidence interval.
Thus, these issues should be resolved before asking for a sample size calculation. Some
preliminary data are almost always needed before a determination of sample size can be made
(a.k.a., power analysis). For example, one needs to know the response rates expected in the
control and treatment groups, or the anticipated median survival time in the groups. Preliminary
information also needs to include measures of the variability expected in the observations (from
subject to subject). Two main ways to get this preliminary information is through a literature
review and through a pilot study. If there is insufficient information to do a proper power
analysis, it is often better to conduct a small pilot study with the purpose of estimating the rates
or means etc., and the variability among observations that will be needed in the power analysis.
A statistician should be consulted about this issue.

Type I error: Reject Ho when Ho is true
Type II error: Do not reject Ho when Ho is not true

Significance level refers to the probability of a Type I error.
Power refers to the probability that Ho will be rejected when Ho is false.

Developing a plan for analyzing the data: A statistical analysis plan should be developed in
such a way that it is clear how the data analysis will be conducted on order to address the
research questions. More particularly, the analysis should correspond to the hypotheses to be
tested and/or quantities to be estimated. The plan will be a roadmap to how the data will be
treated and processed to conduct a statistical test or to estimate a population parameter. For each
type of study, a different approach will be necessary in general. For Phase I trials, the analysis
will describe how to estimate the MTD and assess safety issues. For Phase II trials, hypotheses


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concerning response rates, means, medians, or survival times typically will be tested to
determine whether the alternative hypotheses are plausible given the data, and these quantities
will be estimated along with associated confidence intervals. For Phase III trials, similar
hypotheses will be tested to compare an experimental therapy group versus a control group,
usually. In case-control studies, one seeks to estimate and test odds ratios with or without
adjustment for other factors. In cohort studies, the emphasis is on assessing relative risks. In
cross-sectional studies, one might want to know prevalence or rates or means, for example, of
particular groups. The end result of the analysis should be to obtain an objective answer to the
research questions in light of the available data. The analysis plan details how that will be
approached.

Putting the protocol together: After the planning of the study is completed, a formal written
protocol should be created. The overall structure of it will vary depending on the study design,
but generally it will contain several sections that correspond to those given in Appendix A.

III. Examples of Study Designs

Phase II Clinical Trial:

        A new drug is being tested to determine whether it can provide symptomatic relief for
patients suffering from irritable bowel syndrome (IBS). From the literature, it is known that
other available drugs are known to have a success rate of about 60%. The research question is
“Does the new drug have a success rate of at least 0.60?”. The study population will consist of
adults aged 18 and above who are diagnosed with IBS at a local clinic. All subjects who are
recruited will be provided with the new drug and instructed to follow prescribed guidelines for
self-administration which consists of two doses: taken once after supper and once before
bedtime. The endpoint will be whether diarrhea and abdominal pain have subsided by morning.
Each subject will be contacted by telephone the next morning to obtain the patient’s response
which will be recorded as a complete response (CR) or no response (NR). Thus, the response is
dichotomous. Subjects will be recruited in a consecutive manner until the desired sample size
has been achieved.

        The research hypothesis that will be tested is whether the proportion of subjects who
respond is at least 0.60. This may be stated formally as Ho:  < 0.60 versus Ha:   0.60. An
estimate of the true response rate  will be computed as p = x/n where x = number of subjects
who report a CR and n = total number of subjects in the study. In this study, 61 subjects will be
required to achieve a power of 0.80 when the true response rate is 0.75, given a significance level
of 0.05. The null hypothesis will be tested using a one-sided binomial test in which the null
hypothesis will be rejected if at least 43 subjects report a CR. An appropriate 95% confidence
interval on the response rate will be calculated.

Phase III Clinical Trial:

        A new oral steroidal drug is to be compared with a topical medication for use in
transplant patients who develop extensive skin rash. The subjects are to be recruited from four
transplant clinics and will be randomized to one of the two treatments. Randomization will be



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performed within each clinic (i.e., randomization will be stratified by clinic). The skin rash will
be measured as a percent of body surface area involved at presentation and again at 24 hours post
medication. The response to be measured is the relative change in the skin surface area that is
involved with rash (this is calculated as 100 x [baseline – post-med]/baseline). The null
hypothesis is that there will be no difference in response between the two treatment approaches.
The research hypothesis is that the oral medication will be better than the topical medication. It
is desired to have power of 0.80 to detect a clinically meaningful relative change of 10% using a
one-tailed t test to compare the two group means at a 0.05 level of significance. That is, if there
is a true difference of 10% in the level of responses for the two treatments, there should be an
80% chance that this will be detected by the statistical test. The significance level implies that
there will be a 5% chance of erroneously declaring that a difference exists when in fact there is
no difference. The t test will compare the mean responses between the two groups. From
preliminary studies, the topical treatment produced an improvement in the rash (i.e., a relative
change) of approximately 50% and had a standard deviation of 20%. In view of this data, a total
of 100 subjects will be required, with 50 subjects on each treatment arm.

Cross-sectional Study:

A researcher is interested in the association of human papillomavirus (HPV) infection and
cervical dysplasia in sexually active women who attend an STI clinic. Patients are admitted
sequentially into the study who meet the eligibility criteria. Patients have cervical samples taken
to test for the presence of HPV (exposure) which is positive or negative, and cervical dysplasia
(outcome) which is also positive or negative. The prevalence of HPV can also be determined
from this type of study design.

The research hypothesis to be tested is:

               Ho: HPV is not associated with cervical dysplasia (Odds Ratio=1)
               Ha: HPV is associated with cervical dysplasia (Odds Ratio ≠ 1)

Sample size would be based on the expected association (O.R.) based on previous studies as well
as prevalence of the outcome in the unexposed group. If we expect the Odds Ratio to be 5 and
the prevalence of cervical dysplasia in the unexposed group to be 10%, the sample size needed
would be 96 or 48 in each group. This is based on 80% power and alpha=0.05.

Cohort Study:

A research team is interested in looking at the association of a certain gene (Gene A) and risk for
eclampsia in patients who get their prenatal care from the health department. Patients are
enrolled sequentially in the study and testing for the specific gene is done at the start of the
study. Patients are followed until delivery to determine how many develop eclampsia. The
exposure is Gene A (dichotomized as yes/no), and the outcome is eclampsia (yes/no).

The hypothesis to be tested is:

               Ho: Gene A is not associated with eclampsia (Relative Risk=1)



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               Ha: Gene A is associated with eclampsia (Relative Risk ≠ 1)

Sample size would be based on the expected association (R.R.) based on previous studies as well
as prevalence of the outcome in the control group. If we expect the association to be 3 and the
prevalence of eclampsia in the control group to be 5%, the sample size needed would be 318 or
159 in each group.

Case-Control Study:

A researcher is interested in whether or not smoking is associated with lung cancer. She recruits
a group of subjects with newly diagnosed lung cancer (cases) and a group of subjects who are
similar to the cases except for having the disease (controls). Each subject (case and control) is
asked to recall smoking history by questionnaire or in-person interview. In this study the
exposure is smoking history (yes/no) and the outcome is lung cancer (yes/no) which are both
dichotomous variables.

The research hypothesis to be tested is:
              Ho: smoking is not associated with lung cancer (Odds Ratio=1)
              Ha: smoking is associated with lung cancer (Odds Ratio ≠ 1)

Sample size would be based on the expected association (O.R.) based on previous studies as well
as prevalence of the exposure in the control group. If we determine that the expected association
is 20 and the prevalence of smoking in the controls is 5%, the sample size needed would be 22 in
each group or 44 total subjects. This is based on 80% power and alpha=0.05.


See Appendix A for an Outline for Writing an Observational Study Protocol. Appendix B
(Outline for Writing a Clinical Research Protocol) is more detailed and contains elements
that would be required for a clinical trial.




                                          Page 15 of 58
                                  Institutional Review Board

         IRB Submission Guidance for Investigators Conducting Clinical Research

This guide has been developed to assist investigators conducting human subject research through
Palmetto Health. It is designed to answer questions about how to submit research projects to the
Institutional Review Board (IRB) for either, Full IRB Review (convened meetings), Expedited
IRB Review or Exempt from IRB Review. The information provided below is derived from but
not limited to Federal Policy from the Department of Health and Human Services (DHHS), Food
and Drug Administration (FDA), and Office of Civil Rights (OCR).

All clinical investigations regulated by the Food and Drug Administration that support
applications for research for human use including drugs, medical devices, biological products,
electronic products, and food and color additives are applicable to Federal Policy, 21 CFR 50;
56; 312; 600; and 812. These Federal guidelines can be found at the following FDA link:
www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm.

Palmetto Health holds a Federalwide Assurance (FWA00000128) with the Office of Human
Research Protections (OHRP) in which the Institution assures that all human subject research,
regardless of sponsorship, will comply with the Federal Policy for the Protection of Human
Subjects, 45 CFR 46 and its Subparts A (Basic DHHS Policy for Protection of Human Research
Subjects), B (Additional Protections for Pregnant Women, Human Fetuses and Neonates
Involved in Research), C (Additional DHHS Protections Pertaining to Biomedical and
Behavioral Research Involving Prisoners as Subjects), D (Additional DHHS Protections
Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects) and E
(Registration of Institutional Review Board). The IRB exercises due caution and special
consideration in review of research protocols involving prisoners, children, pregnant women,
human fetuses and neonates, and individuals institutionalized as mentally disabled and other
groups that may be classified as vulnerable. These Federal guidelines can be found at the
following DHHS link through OHRP: www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html.

Our current Federalwide Assurance (FWA) with OHRP can be found by searching the following
link: ohrp.cit.nih.gov/search/search.aspx?styp=bsc. FWA00000128 is our Federal registration
number with OHRP. Our Federal registration number and FWA number are one in the same.

What is the purpose of the Institutional Review Board?

The Institutional Review Board is guided by the ethical principles regarding all research
involving humans as subjects as set forth in the report entitled “The Belmont Report, Ethical
Principles and Guidelines for the Protection of Human Subjects of Research” which includes:

   Respect for Persons. That individuals should be treated as autonomous agents; and that
    persons with diminished autonomy are entitled to protection.

   Beneficence. Persons are treated in an ethical manner not only by respecting their decision
    and protecting them from harm, but also by making efforts to secure their well being. The



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    two general rules formulated, as complementary expressions are (1) do not harm, and (2)
    maximize possible benefits and minimize possible harms.

   Justice. The selection of subjects for research should be equitable and the fruits of the
    research should be distributed equitably.

Palmetto Health acknowledges and accepts its responsibilities for protecting the rights and
welfare of human subjects of research covered under its Federalwide Assurance agreement. The
institution acknowledges that it and its investigators bear full responsibility for the performance
of all research covered under this agreement, including full responsibility for complying with
federal, state, and local laws as they may relate to such research.

This institution recognizes that before human subjects are involved in research, proper
consideration must be given to:

   The risks to the subjects;
   The anticipated benefits to the subjects and others;
   The importance of the knowledge that may reasonably be expected to result; and
   The informed consent process to be employed.

Authority of the Committee

A. The Committee may approve, disapprove or modify research protocols and consent/assent
   documents referred to its review.

B. The Committee may conduct continuing review of all protocols, consistent with federal
   regulations.

C. The Committee may observe and verify changes to protocols and consent/assent documents,
   consistent with federal regulations.

D. The Committee may suspend or terminate approval on any protocol subject to its review.

Privacy of Protected Health Information

The Health Insurance Portability and Accountability Act of 1996 (HIPAA), 45 CFR 160 and 164
has specific elements that apply to research with human subjects, living and deceased, for
privacy of protected health information. Certain requirements apply to the use (inside) and
disclosure (outside) the covered entity, Palmetto Health, of protected health information (PHI) in
connection with all research involving human subjects.

The Palmetto Health Institutional Review Board (IRB) has taken adequate measures to comply
with these regulations. Research requiring access, use or disclosure of PHI, i.e. medical records,
physician notes, and laboratory tests, must receive review by the IRB. The IRB may allow for
the use and disclosure of PHI by use of one or more of the following categories:
1) Research Authorization, 2) Waiver of Authorization, 3) Reviews Preparatory to Research,



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4) Limited Data Set, 5) Research on Decedents, and 6) Complete De-Identification.

When completing an IRB application in the eIRB Submission System, investigators will need to
indicate the methods by which PHI will be utilized. Please see the corporate policy entitled
“Research Uses and Disclosures of Protected Health Information” for further guidance.

Scientific Review Committee

All proposed human subject research must receive scientific review prior to IRB review, with the
exception of:

       (i) Research qualifying for exemption from the requirements of 45 CFR 46.101(b).
       (ii) Industry initiated and sponsored research and clinical trials.

Scientific review is an assessment of the scientific merit of the research design. The review
addresses the following questions:

   1. Are the design, methods, and procedures of the proposed research appropriate to answer
      the research questions?
   2. Are the design, methods, and procedures appropriate to ensure risks to participants are
      minimized?
   3. Is the sample size appropriate to answer the research question?
   4. Are the data collection and analysis methods appropriate to answer the research
      question?
   5. Are there are adequate data and safety monitoring measures to protect participants?
   6. Whenever possible, are research procedures designed to maximize potential benefits?

Documentation of prior scientific review, conducted external to Palmetto Health should be
submitted along with the proposed protocol in e-IRB.

Note: IRB review shall not begin until the protocol has secured SRC review.

Training in the Protection of Human Subjects in Research – CITI Training

Investigators and Key Study Personnel are required to complete training on ethical principles and
regulations pertaining to research with human subjects. Completion of training is required for all
research personnel listed on the IRB application prior to issuance of IRB approval for a project.

Key Study Personnel include any person who is actively involved with human subjects through
one or more of the following categories: 1) The informed consent process, 2) Performs study
related interventions on human subjects, or has 3) Access to study subjects’ identifiable private
health information for research purposes. It is the responsibility of the principal investigator to
identify persons considered key study personnel for a particular research project. Key study
personnel commonly include principal investigators, sub-investigators, co-investigators, study
doctors, project directors, research associates, study coordinators and research nurses.




                                           Page 18 of 58
The Palmetto Health IRB uses the Collaborative IRB Training Initiative (CITI) which is an
Internet-based set of educational modules on the protection of human subjects in research.
Coursework is designed for all personnel that have significant involvement in the planning,
conduct, and analysis of any research activity that employs human subjects. Coursework
consists of training modules divided into Biomedical Research and Social & Behavioral
Research.

Research personnel must complete required CITI training modules prior to conducting research
with human subjects. Research personnel should log onto the CITI website at
www.citiprogram.org and affiliate with Palmetto Health. Research personnel involved in clinical
research should complete the Biomedical Research Investigator module. Research personnel
involved in psychosocial research should choose the Social & Behavioral Research Investigator
module.

A minimum score of 80% must be obtained. Those not reaching a passing score will need to
review the content of the modules and re-take the exam until a score of ≥ 80% is obtained. All
investigators who wish to conduct research at Palmetto Health should complete CITI training
regardless of whether their research qualifies for Exempt, Expedited or Full IRB Review.

   Initial CITI Training: Complete the online training program entitled “CITI Course in The
    Protection of Human Research Subjects”. This web based online training program is
    available at www.citiprogram.org. Select “Register for the CITI Course”, under “All
    Others” select your affiliation with “Palmetto Health” then choose your username and
    password. Once registered you must choose between Biomedical or Social & Behavioral
    Research and then choose “Basic CITI Course”. Completing the required modules will take
    approximately 4 to 6 hours of your time. You are encouraged to complete your training in
    multiple visits.

   Refresher CITI Training: Complete the online training program entitled “CITI Course in
    The Protection of Human Research Subjects”. This web based online training program is
    available at www.citiprogram.org. Login using your previously selected username and
    password. Once logged in, choose “Refresher Course”. Completing the required modules
    will take approximately 1 to 2 hours of your time. You are encouraged to complete your
    refresher training in multiple visits. The Refresher Course must be completed within 2 years
    from the date of your initial CITI training. You cannot complete the Refresher CITI Training
    without first completing the Initial CITI Training. You are encouraged to complete your
    training in multiple visits.

Every two years research personnel are required to renew their training by completing designated
refresher modules from the CITI Biomedical 201 or CITI Social & Behavioral Research 101
courses.

Research personnel who have completed CITI training through another institution must login to
CITI and affiliate themselves with Palmetto Health. They will then be instructed to possibly
complete additional training modules as required by the Palmetto Health IRB.




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Note: IRB approval for a study will be withheld until all research personnel identified on the
IRB application have completed their Initial CITI Training and/or Refresher CITI Training in
affiliation with Palmetto Health.

What are the Federal definitions pertaining to research with Human Subjects?

Federal guidelines at 45 CFR 46.102 provide us with definitions to help determine when a
project should be considered research.

“Research” is defined as "a systematic investigation, including research development, testing and
evaluation, designed to develop or contribute to generalizable knowledge.” This definition
applies to research activities involving human subjects undertaken by students for purposes of
independent study, theses or dissertations where the results will be publicly disseminated through
publication or presentation, including pilot and exploratory research, and therefore must receive
IRB review.

“Human Subject" is defined as "a living individual 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."

Any research that collects data from or about human beings is considered to involve human
subjects. Whether the research involves direct intervention in a person's life, or indirect
involvement by observation, interview or survey, there is a requirement for IRB review. This
includes basic, applied, social science, and medical research involving subjects; review of
records; and collection of biological specimens.

“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.

“Children” are defined in the HHS regulations as ``persons who have not attained the legal age
for consent to treatments or procedures involved in the research, under the applicable law of the
jurisdiction in which the research will be conducted.''

Unless the research is exempt according to 45 CFR 46.101(b), Palmetto Health does not become
"engaged" in research with human subjects, unless its employees or agents intervene or interact
with living individuals specifically for research purposes or to obtain individually identifiable
private information specifically for research purposes. The Institution is not considered
"engaged" in research with human subjects when its employees or agents:

   Act as consultants on research but at no time obtain, receive, or possess identifiable private
    health information.
   Perform routine services for investigators and adhere to commonly recognized professional
    standards for maintaining privacy and confidentiality.
   Do not obtain subjects' consent or act as authoritative representatives of the investigators.




                                           Page 20 of 58
Palmetto Health becomes “engaged” in research with human subjects, when its employees or
agents perform invasive or noninvasive procedures such as drawing blood; collecting biological
samples; dispensing drugs; administering treatments; employing medical technologies; utilizing
physical sensors; utilizing measurement procedures, which are considered non-routine or above
standard of care.

How do I determine if my project is considered Human Subjects Research?

To determine if your project is human subjects research, you must answer “Yes” to questions one
and two below.

   1. Is the project Research? 45 CFR 46.101(d) “Research means a systematic investigation,
      including research development, testing and evaluation, designed to develop or contribute
      to generalizable knowledge. Activities which meet this definition constitute research for
      purposes of this policy, whether or not they are conducted or supported under a program
      which is considered research for other purposes. For example, some demonstration and
      service programs may include research activities.”

       O Yes or O No

       Projects which employ systematic data collection with the intent to contribute to
       generalizable knowledge are considered research. A key aspect of research is that there
       be a systematic design in advance, generally utilizing a scientific approach or protocol,
       for the defined purpose of contributing to generalizable knowledge. The following two
       components must be in place to meet the definition of research:

       a. A systematic investigation involves having a method or plan which includes a
          detailed or careful examination, exploration, or to learn the facts about something
          complex or hidden. Attempting to answer a question or prove/disprove a hypothesis
          are indications that an activity is a systematic investigation. The absence of a
          hypothesis does not automatically mean an activity is not a systematic investigation.

       b. Generalizable knowledge is acquired knowledge that can be applied to both the
          population being studied and possibly to other populations or situations. If there are
          no intentions to develop or contribute to generalizable knowledge, IRB review is not
          required. During the process of data collection or analysis, if it becomes clear that
          findings could be generalizable or benefit others, then the project should receive IRB
          review.

   2. Does the research involve Human Subjects? 45 CFR 46.101(f) “Human subject means a
      living individual 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.”

       O Yes or O No




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       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.”

Human Subjects Research and Quality Improvement

Most quality improvement (QI) activities usually are not research subject to federal regulations
pertaining to the protection of human subjects when purposes of the activities are limited to:

   1. Implementing a practice to improve the quality of programs, improve services or improve
      medical care, and
   2. Collecting patient or provider data regarding the implementation of the practice for
      clinical, practical, or administrative purposes.

If the quality improvement activity is intended to evaluate an existing practice and attempt to
improve it, and the data from the evaluation will not be applied to populations other than the
population under study, then the activity would not be subject to the federal regulations for the
protection of subjects in research, 45 CFR Part 46.

Such activities do not satisfy the federal definition of “research” under 45 CFR 46.102(d), which
is “a systematic investigation, including research development, testing and evaluation, designed
to develop or contribute to generalizable knowledge. Activities which meet this definition
constitute research for purposes of this policy, whether or not they are conducted or supported
under a program which is considered research for other purposes. For example, some
demonstration and service programs may include research activities.”

Quality improvement projects are usually performed for internal purposes within the institution.
Quality improvement activities, generally referred to as program evaluation or quality
improvement, are normally not intended to have any application beyond the specific organization
in which they are conducted.

However, in some cases quality improvement activities are designed to accomplish a research
purpose as well as the purpose of improving the quality of care and therefore fall under the
federal definition of research requiring IRB review. Usually in such cases the information to be
collected would contribute to generalizable knowledge. Generalizable knowledge is acquired
knowledge that can be applied to both the population being studied and possibly to other
populations or situations. If there are no intentions to develop or contribute to generalizable
knowledge, IRB review is not required. During the process of data collection or analysis, if it



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becomes clear that findings could be generalizable or benefit others, then the project should
receive IRB review.

Quality improvement activities undertaken to test a new, modified, or previously untested
intervention, service, or program for purposes which include improving the quality of care and
also collecting information about patient outcomes for the purpose of establishing scientific
evidence to determine how well the intervention achieves its intended results, then that quality
improvement project likely constitutes human subjects research.

Planning to publish an account of a quality improvement project does not necessarily mean that
the project fits the definition of research. Conversely, a quality improvement project may
involve research even if there is no intent to publish the results.

When should Human Subject Research Projects be submitted for IRB review?

All research involving human subjects must be submitted to the IRB for review. Final
determination of whether an activity is human subjects research will be made by the IRB Chair
or his designee.

Presentation of Case Reports

Case reports do not meet the definition of research although they contribute to generalizable
knowledge. Case reports are not systematic investigations. The clinician is simply sharing
information about interesting cases for educational purposes. Case reports are usually limited to
no more than a few patients. Once you start to exceed three subjects and you are attempting to
prove a point or answer a question, then you are performing a systematic investigation and IRB
may be required. If at any time a case report attempts to answer a question, or prove/disprove a
hypothesis, the clinician may no longer be just presenting a case report but possibly conducting
research.

What conditions require submitting my project to the Palmetto Health IRB for review?

The Board reviews all research activities that involve human subjects in order to protect the
rights and welfare of subjects and evaluate the risks and benefits of the proposed research. An
investigator should submit a proposal for IRB review regardless of what review category the
project may be eligible. It is the decision of the IRB Chair or his designee to determine how a
research project should be reviewed either as exempt, expedited or full board and not that of the
investigator.

Research activities include a variety of procedures such as, but not limited to, review of medical
records, collection of data through surveys or observation, research using existing pathological
specimens, discarded tissue or secretions, use of approved drugs or devices, investigational drugs
or devices, and randomized trials. It is necessary to submit a project to the IRB when the:

1. Research is sponsored in any part by Palmetto Health;




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2. Research is conducted by or under the direction of any employee or agent of Palmetto Health
   in connection with his or her institutional responsibilities;

3. Research is conducted by or under the direction of any employee or agent of this institution
   using any property, facilities, or services of the institution;

4. Research is conducted by or under the direction of an investigator with privileges through the
   institution using any property, facilities, or services of the institution;

5. Research involves the use of the institution’s nonpublic information to identify or contact
   human research subjects or prospective subjects;

6. Research may be conducted by any employee or agent of the institution provided that at least
   one member of the research team is a member of the professional staff of the institution;

7. Research may be proposed and sponsored by individuals who are not employees or agents of
   the institution provided that at least one member of the research team is a member of the
   professional staff of the institution.

If the investigator is a student, the research must be performed under the supervision of a
member of the faculty with privileges through Palmetto Health, who by his or her approval
assumes responsibility for the conduct of that research with respect to the proper safeguards of
the rights of subjects.

Review mechanisms used by the Institutional Review Board

The Palmetto Health Institutional Review Board reviews all biomedical and behavioral research
activities including but not limited to clinical, psychosocial, epidemiological and biological
protocols. There are essentially three basic methods of review utilized by the IRB which
include:

   1. Exempt from IRB Review
   2. Expedited IRB Review
   3. Full IRB Review

Protocols for IRB review are classified as either Full IRB Review or Expedited Review. Exempt
Reviews are performed administratively by the Chair or his designee.

Exempt from IRB Review

Research activities can be considered Exempt from IRB Review when the project falls under one
or more of six defined categories according to 45 CFR 46.101(b).

Research performed on information such as medical records, patient charts, diagnostic test
results, laboratory-pathology test results, and radiological test results may be Exempt from IRB
Review as long as certain conditions are met such as when the data already exists and



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

Certain research activities involving the use of educational tests (cognitive, diagnostic, aptitude,
achievement), survey procedures, interview procedures or observation of public behavior may
also be Exempt from IRB Review, unless: (i) information obtained is recorded in such a manner
that 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. Protocols believed to be exempt from IRB review must be
submitted to Research Administration. Investigators cannot make this determination themselves.

Expedited IRB Review

Research activities considered no more than minimal risk may qualify for Expedited Review.
Psychological, social, and behavioral research may qualify for Expedited Review, by the Chair
or his designee, dependent upon the study interventions as well as research conducted with tissue
and blood samples. Requirements for informed consent do apply for expedited review.

Full IRB Review (Convened Meeting)

Clinical research involving the use of any FDA approved or investigational drugs, biologics or
devices for treatment related purposes, must receive Full IRB Review. Research projects
involving any clinical treatment related procedures should be assessed as greater than minimal
risk. When assessing the risk of a protocol, one must take into consideration not just physical
risks to patients, but also psychological, emotional, privacy, confidentiality, employment and
financial risks.

Accessing the Electronic Institutional Review Board (eIRB) Submission System

Palmetto Health has implemented an electronic IRB submission system developed through
collaboration with Health Sciences South Carolina. New study applications are to be submitted
through eIRB. Once an application is processed in the eIRB system, all activities related to the
submitted study (e.g., continuing reviews, amendments, and reportable events) will be processed
electronically. Currently approved studies can be transferred into the eIRB system at any time
by completing a study conversion. You should submit your conversion at least 90 days before
the next continuing review.

What do I need to do?

   1. Register – Prior to submitting an IRB application, you must register at
      eirb.healthsciencessc.org/. The registration form can be completed in a few minutes, and
      will be validated by Palmetto Health Information Technology (803-434-4357).
   2. Change Password – Change your password in response to the validating system
      generated password.




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   3. Create New Study – Upon login, go to “My Home”, you will be given the option to
      “Create New Study” application.

Your Personal Workspace

Your Personal Workspace – “My Home” displays all eIRB submissions that are associated with
you.

Study Workspace

When you open an existing study application, amendment, or continuing review from your
Personal Workspace, you will be taken to the study workspace. The Study Workspace is the area
where all activities associated with the study are performed.

Creating a New Application

Applications for new research studies must be submitted by the Principal Investigator (PI). Study
Coordinators and/or co-Investigators may complete, but not submit applications.

   1. Click the “Create New Study” button to initiate a new IRB application.
   2. Fill in the first screen of the application.
   3. Click “Continue” to advance to the next page of the application (Clicking “Continue”
      automatically saves your changes).
   4. When you are finished, click “Save” to save your changes and then “Exit” to leave the
      application form and return to the study workspace.

Submitting an Application

The “Submit Application” activity can only be performed by the PI. Once the PI submits the
application, an e-mail will be sent to study team members (Study Coordinator and co-
Investigators), notifying them of the submission.

After submission, the Study Team will not be able to edit the application unless it is returned
with changes requested by the IRB Staff.

   1. From the Study Workspace, click the “Submit Application” button.
   2. Complete all questions on the Submit Application screen.
   3. Click “OK” at the bottom of the Submit Application screen.

Uploading Documents

   1. Click the “Add” button and a new window will appear.
   2. Enter a title for the document you are uploading (otherwise, the system will use the
      filename).
   3. Click “Browse” and select the file you want to attach.
   4. Click “Open”



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   5. Click “OK”

Editing and Deleting Study Documents

An application cannot be edited while it is under IRB review.

Editing previously uploaded documents:
   1. Open the document on your computer or network drive.
   2. Make the necessary changes.
   3. Save the document.
   4. In the eIRB application, select the checkbox beside the name of the currently uploaded
       version of the document.
   5. Click the “Edit” link to upload the revised copy.

Deleting uploaded documents:
   1. Select the checkbox beside the document name.
   2. Click the “Delete” button.

Informed Consent Documents

Informed consent instructions and templates can be found at www.palmettohealth.org/IRB:
    1. Save the informed consent template to your computer or network drive.
    2. Open the template and modify the body of the template as required for your study.
    3. Save the document.
    4. In the eIRB application, use the “Add” button to upload the informed consent document
       in the “Consent Forms” section of the application.

Editing informed consent documents:

An application cannot be edited while it is under review.

   1. Open the informed consent document on your computer or network drive.
   2. Turn on change tracking and modify the body of the document as needed.
   3. Save the redlined document.
   4. Accept all changes, turn off change tracking, and save a separate clean copy of the
      document.
   5. In the eIRB application, use the “[Edit]” link to attach the revised clean copy in the
      “Consent Forms” section.
   6. Use the “Add” button to upload the redlined version of the informed consent form.

Responding to Reviewer Comments

   1. Use the “Jump To” drop down list to navigate to the section of the application where
      notes have been added.
   2. Make the necessary changes.




                                          Page 27 of 58
   3. Use the “Click here to respond” link at the top of the page to summarize your response to
      the reviewer.
   4. Select the appropriate category and give your response.
   5. Click “OK”.
   6. When finished, “Save” and “Exit” the application form and return to the Study
      Workspace.
   7. Click the “Submit Response to Reviewer” button to return the application to the reviewer.

Continuing Review

Study team members will receive a system generated e-mail reminder that their application is
due for a continuing review 60 and 30 days prior to the study expiration date.

Continuing reviews can be submitted only for approved active studies.

A continuing review cannot be created while an amendment is in progress.

   1.   Navigate to the Study Workspace of the approved active study.
   2.   Click the “New Continuing Review” button to start a new continuing review submission.
   3.   Provide the required information on each page of the continuing review form.
   4.   Click “Finish” at the end of the continuing review.
   5.   Submit the continuing review.

Amendments

Amendments can be submitted only for approved active studies.

Only one amendment can be in process at a time for each study.

There are two parts to submitting an amendment using the eIRB application:
    Completing the Amendment form, outlining the changes that need to be made.
    Making these changes in the main application itself.

           1. Navigate to the Study Workspace of the approved active study.
           2. Click the “New Amendment” button to start a new amendment submission.
           3. Complete the required information on each page of the amendment form.
           4. When you reach the “Summary of Amendment Changes” screen, click
              “Continue”
           5. Make required changes to the study application.
           6. Return to the Amendment Workspace.
           7. Click “Submit Amendment”

Reportable Events

Unanticipated Problems, Adverse Events and Protocol Deviations can be submitted only for
approved active studies.



                                         Page 28 of 58
Reportable events must meet the following criteria to be submitted through eIRB for review:
    The event must be considered serious.
    The event must be considered unanticipated (unexpected).
    The relationship of the event to the study must be study related or possibly study related.
    Making these changes in the main application itself.

           1.   Navigate to the Study Workspace of the approved active study.
           2.   Click the “Reportable Event” button to start a new submission.
           3.   Complete the required information on each page of the event form.
           4.   When you reach the final page of the report “Click Finish”.
           5.   If the event requires changes to the study, an Amendment must be submitted.
           6.   Return to the Reportable Event Workspace.
           7.   Click “Submit” for the Reportable Event.

Printing an Application

   1. Navigate to the Study Workspace.
   2. Click the “Printer Version” button.
   3. Select a printer and click “Print”

Specific pages of the application can be printed by:

   1.   Viewing the study.
   2.   Navigating to the desired page.
   3.   Clicking “Print” at the top of the page.
   4.   Selecting a printer and clicking “Print”

If further assistance is required, please contact Research Administration at 803-434-2884 or by
e-mail to eIRB@palmettohealth.org.

What does it mean when my research is exempt from IRB review?

Although your project may be human subjects research, it may meet one or more of six specific
categories for exemption. You are still required to submit your project to the IRB for review,
and the determination of exemption will be made by the IRB Chair or his designee.

45 CFR 46.101(b) – Unless otherwise required by department or agency heads, research
activities in which the only involvement of human subjects will be in one or more of the
following categories are exempt from this policy:

1. 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.




                                           Page 29 of 58
2. 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.

3. 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 paragraph (b)(2) of this section, 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.

4. Research involving the collection or study of existing data, documents, records, pathological
   specimens, or diagnostic specimens, if these sources are publicly 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.

5. Research and demonstration projects which are conducted by or subject to the approval of
   department or agency heads, 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; or (iv) possible changes in methods or levels of payment for benefits or services
   under those programs.

6. Taste and food quality evaluation and consumer acceptance studies, (i) if wholesome foods
   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 Food and Drug Administration or
   approved by the Environmental Protection Agency or the Food Safety and Inspection Service
   of the U.S. Department of Agriculture.

Proposals of the above types which cannot protect subjects' anonymity and pose no more than
minimal risks to subjects may be suitable for Expedited IRB Review.

Once a study is created, the eIRB submission system will ask you series of questions to help
identify whether your research qualifies for an exemption.

The following documents will need to be uploaded to your eIRB application:

1. A protocol with information explaining the purpose, procedures and endpoints for the study
   must be uploaded into eIRB (See Appendix A).

2. Surveys, Questionnaires, or Data Collection Tools.



                                           Page 30 of 58
3. Study Advertisements, Recruitment Brochures, Web Sites or other documents used for study
   recruitment and/or education.

If the study requires access to protected health information (PHI) such as medical records, lab
test results or pathology results, then the study is applicable to the Privacy Rule (HIPAA)
meaning the study requires access to personal health information. Research falling under
category 4 for exemption, commonly requires IRB approval for use of a Waiver of Authorization
which will allow you access to medical records without first having to contact subjects for their
permission, but only if your application has satisfied the criteria specified by 45 CFR 164.512.

When using a waiver of authorization, an accounting of disclosures may be required for releases
of protected health information that go outside of Palmetto Health where the subject has not
signed an authorization. An accounting of disclosures form for individual and/or multiple
patients may need to be completed. See Appendix C for details.

Key points to remember when submitting projects exempt from IRB review

   Projects believed to be Exempt from IRB Review must still be submitted to Research
    Administration for review.

   If you believe your study is exempt, you must submit a written protocol along with a
    completed IRB Application through eIRB indicating why you believe the research is exempt.

   You must obtain written documentation from Research Administration confirming your
    research is Exempt from IRB Review. Decisions concerning exemption will be made by the
    IRB Chair or his designee.

   Research involving vulnerable subjects may not qualify for an exemption*.

    * The exemptions at 45 CFR 46.101(b) do not apply to research involving prisoners,
    subpart C. The exemption at 45 CFR 46.101(b)(2), for research involving survey or
    interview procedures or observation of public behavior, does not apply to research with
    children, subpart D, except for research involving observations of public behavior when the
    investigator(s) do not participate in the activities being observed.

   If you are claiming an exemption, you should justify it in your application.

   Even if your research is Exempt from IRB Review, you should address whether the project
    will involve the inclusion of women, minorities, and children in your protocol.

   Exempt reviews may require up to 4 weeks for review and approval dependent upon response
    times, quality of the submission materials and complexity of the study. If you have questions
    regarding your submission to the IRB, please don’t hesitate to contact Research
    Administration in order to facilitate the IRB review process.




                                          Page 31 of 58
How do I know if my research qualifies for expedited IRB Review?

Certain categories of research defined by Federal Policy 45 CFR 46.110 may qualify for
Expedited IRB Review.

Please refer to the following links for specific guidance on expedited review procedures:

Office for Human Research Protections (OHRP) Guidance on the Use of Expedited Review
Procedures can be found at: http://www.hhs.gov/ohrp/humansubjects/guidance/exprev.htm

Expedited review procedures for certain kinds of research involving no more than minimal risk,
and for minor changes in approved research can be found at:
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.110

Categories of research that may be reviewed by the Institutional Review Board through an
Expedited Review Procedure can be found at:
http://www.hhs.gov/ohrp/humansubjects/guidance/expedited98.htm

Research activities that present no more than minimal risk to human subjects, involve only
procedures listed in one or more of the following summarized categories, regardless of the age of
subjects, except as otherwise noted, may qualify for Expedited IRB Review. Standard
requirements for informed consent (or its waiver, alteration, or exception) apply regardless to
Expedited IRB Review and Full IRB Review. The following categories pertain to initial and
continuing IRB review as well as minor changes in previously approved research:

1. Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture 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 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, 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 in an 8 week period and collection
   may not occur more frequently than 2 times per week.

2. 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.



                                           Page 32 of 58
3. 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.

4. 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).

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

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

Expedited IRB Review consists of a review of research involving human subjects by the IRB
Chair or by one or more experienced reviewers designated by the Chair from among members of
the IRB. IRB expedited review is normally quicker than Full IRB Review as the protocol is
reviewed administratively through our office by the Chair or his designee.

What materials should be provided for expedited IRB review?

Submissions requiring Expedited IRB Review must be submitted through the eIRB Submission
System located at eirb.healthsciencessc.org. Once a study is created, the eIRB submission
system will ask you series of questions to help identify whether your research qualifies for an
expedited review.

The following materials should be submitted for IRB review:

1. An electronic IRB application should be completed indicating that the study is no more than
   minimal risk.

2. An Informed Consent Form developed by following the template “Development of Informed
   Consent for Research” and meeting the requirements of the “Consent Checklist”. Sometimes




                                          Page 33 of 58
   a sponsor will provide a model consent form template which will need to be modified to meet
   the requirements of these two named documents.

3. A complete Protocol with references. Protocols from sponsors often already come with
   Amendments. Locally developed research must be reviewed and approved by the Palmetto
   Health Scientific Review Committee (SRC). If your protocol has had prior scientific review,
   please upload in eIRB documentation of the review. SRC approval should be secured prior
   to IRB review and approval. Please contact SRC@palmettohealth.org for details on how to
   submit your protocol for SRC review.

4. All Surveys, Questionnaires, Data Collection Instruments, etc.

5. Study Advertisements, Recruitment Materials such as Study Brochures, Flyers, Web Sites or
   other documents used for study recruitment and/or education.

6. If applicable, documentation from the Sponsor (if the project has a Sponsor) such as a Study
   Budget and Contract(s) between the Sponsor, Principal Investigator and Palmetto Health.

7. Proof of documentation of training in the protection of human subjects through CITI Training
   in affiliation with Palmetto Health.

8. An Impacted Services Agreement should be completed and signed and uploaded into eIRB
   under the General Comments section of the application. Common impacted services include
   Pathology, Laboratory, Pharmacy, Nursing and Radiology.

If the study requires access to Protected Health Information (PHI) such as medical records, lab
test results or pathology results, then the study is applicable to the Privacy Rule (HIPAA)
meaning the study requires access to personal health information. In such case the following
information should be completed in eIRB:

9. Application for access to health information is achieved by using at least one method from a
   total of six methods as described in the Privacy Rule. For Expedited IRB Review, the most
   commonly used methods of accessing health information are by use of:

   a. A Research Authorization specifically developed for the study. Subjects signing a
      Research Authorization are granting you permission to access to their health information
      specifically for the research. For research using protected health information that will
      involve patient contact, a Research Authorization should be obtained. You will need to
      follow the template “Development of Informed Consent for Research” to make sure all
      required elements of authorization are included in this document.

   b. A Waiver of Authorization granted by the IRB for access to medical records which
      prevents the investigator from having to contact patients for their permission to review
      their records. Commonly a Partial Waiver of Authorization will be utilized to help
      identify subjects eligible for the research through a search of medical records. Once
      potential subjects are identified and contacted, and if willing to participate in the research,



                                           Page 34 of 58
        they would then need to sign a Research Authorization. When using a waiver of
        authorization, an accounting of disclosures may be required for releases of protected
        health information that go outside of Palmetto Health where the subject has not signed an
        authorization. An accounting of disclosures form for individual and/or multiple patients
        may need to be completed. See Appendix C for details.

   c. Data Use Agreement for a Limited Data Set. This method allows the investigator access
      to only certain limited identifiers as agreed upon between the investigator and the
      institution. This method is not as commonly utilized. A template for development of a
      Data Use Agreement is available.

Under special conditions a Waiver of Informed Consent may be utilized according to 45 CFR
46.116(d). Such a request should be submitted within the eIRB application for your new study.

An IRB may approve a consent procedure which does not include, or which alters, some or all of
the elements of informed consent set forth in this section, or waive the requirements to obtain
informed consent provided the IRB finds and documents that:

   1.   The research involves no more than minimal risk to the subjects;
   2.   The waiver or alteration will not adversely affect the rights and welfare of the subjects;
   3.   The research could not practicably be carried out without the waiver or alteration; and
   4.   Whenever appropriate, the subjects will be provided with additional pertinent information
        after participation.

Under special conditions a Waiver of Documentation of Informed Consent may be utilized
according to 45 CFR 46.117(c). Such a request should be submitted within the eIRB application
for your new study.

An IRB may waive the requirement for the investigator to obtain a signed consent form for some
or all subjects if it finds either:

   1. That the only record linking the subject and the research would be the consent document
      and the principal risk would be potential harm resulting from a breach of confidentiality.
      Each subject will be asked whether the subject wants documentation linking the subject
      with the research, and the subject's wishes will govern; or
   2. That the research presents no more than minimal risk of harm to subjects and involves no
      procedures for which written consent is normally required outside of the research context.

In cases in which the documentation requirement is waived, the IRB may require the investigator
to provide subjects with a written statement regarding the research.

Expedited Reviews may require up to 4 weeks for review and approval dependent upon response
times, quality of the submission materials and complexity of the study. If you have questions
regarding your submission to the IRB, please don’t hesitate to contact Research Administration
in order to help speed up the IRB approval process.




                                          Page 35 of 58
Full IRB review (Convened Meeting)

Research activities that involve clinical treatment utilizing any drugs or devices (approved or
investigational) are considered greater than minimal risk, therefore require Full IRB Review by
the convened Board. Research on human subjects that does not qualify as Exempt from IRB
Review or for Expedited IRB Review shall be reviewed by the convened Board. Any research
considered greater than minimal risk, does not qualify for an exemption or expedited review.
For complete details on the Full IRB Review process, please review the Palmetto Health IRB
Policy and Procedures document which can be found at www.palmettohealth.org/IRB.

Protocols submitted through eIRB should be accompanied with the appropriate submission
materials. Submissions for Full IRB Review must be received at least twenty one (21) days prior
to the scheduled meeting. The principal investigator (or designated co-investigator) will be
scheduled to present a summary of the proposed protocol at an IRB meeting. The investigator
will be asked questions concerning the protocol by members of the Committee. The investigator
will be thanked for the presentation and then be excused from the meeting.

The Principal Investigator will be notified by the Chair in writing of the decision of the IRB. If a
response is required, it too must be in writing. When the IRB requests very specific revisions
that simply require the concurrence of the investigator, the revised documents may be referred to
the IRB Chair or designated reviewer for approval. IRB approval for those affected protocols
will not officially begin until the concerns raised by the Committee from the convened meeting
have been adequately addressed and approved by expedited review.

When substantive clarifications are necessary for the protocol or informed consent document, the
IRB will table the protocol, and the acceptability of changes and revisions will be determined at
a subsequently convened meeting.

What materials should be provided for Full IRB review?

Submissions requiring Full IRB Review must be submitted through the eIRB Submission System
located at eirb.healthsciencessc.org. Once a study is created, the eIRB submission system will
ask you series of questions to help identify whether your research requires full board review.

The following materials should be submitted for IRB review:

1. An electronic IRB application should be completed indicating that the study is greater than
   minimal risk.

2. An Informed Consent Form developed by following the template “Development of Informed
   Consent for Research” and meeting the requirements of the “Consent Checklist”. Sometimes
   a sponsor will provide a model consent form template which will need to be modified to meet
   the requirements of these two named documents.

3. A complete Protocol with references. Protocols from sponsors often already come with
   Amendments. Locally developed research must be reviewed and approved by the Palmetto



                                           Page 36 of 58
   Health Scientific Review Committee (SRC). If your protocol has had prior scientific review,
   please upload in eIRB with your protocol the documentation of the review. SRC approval
   should be secured prior to IRB review and approval. Please contact
   SRC@palmettohealth.org for details on how to submit your protocol for SRC review.

4. All Surveys, Questionnaires, Data Collection Instruments, etc.

5. Study Advertisements, Recruitment Materials such as Study Brochures, Flyers, Web Sites or
   other documents used for study recruitment and/or education.

6. Documentation from the Sponsor (if the project has a Sponsor) such as a Study Budget and
   Contract(s) between the Sponsor, Principal Investigator and Palmetto Health.

7. Current Investigator’s Brochure from the Sponsor which can include Package Inserts.

8. Proof of documentation of training in the protection of human subjects through CITI Training
   in affiliation with Palmetto Health.

9. An Impacted Services Agreement should be completed and signed and uploaded into eIRB
   under the General Comments section of the application. Common impacted services include
   Pathology, Laboratory, Pharmacy, Nursing and Radiology.

If the study requires access to Protected Health Information (PHI) such as medical records, lab
test results or pathology results, then the study is applicable to the Privacy Rule (HIPAA)
meaning the study requires access to personal health information. In such case the following
information should be completed in eIRB:

10. Application for access to health information is achieved by using at least one method from a
    total of six methods as described in the Privacy Rule. For Full IRB Review, the most
    commonly used methods of accessing health information are by use of:

   a. A Research Authorization specifically developed for the study. Subjects signing a
      Research Authorization are granting you permission to access to their health information
      specifically for the research. For research using protected health information that will
      involve patient contact, a Research Authorization should be obtained. You will need to
      follow the template “Development of Informed Consent for Research” to make sure all
      required elements of authorization are included in this document.

   b. A Waiver of Authorization granted by the IRB for access to medical records which
      prevents the investigator from having to contact patients for their permission to review
      their records. Commonly a Partial Waiver of Authorization will be utilized to help
      identify subjects eligible for the research through a search of medical records. Once
      potential subjects are identified and contacted, and if willing to participate in the research,
      they would then need to sign a Research Authorization. When using a waiver of
      authorization, an accounting of disclosures may be required for releases of protected
      health information that go outside of Palmetto Health where the subject has not signed an



                                          Page 37 of 58
       authorization. An accounting of disclosures form for individual and/or multiple patients
       may need to be completed. See Appendix C for details.

    c. Data Use Agreement for a Limited Data Set. This method allows the investigator access
       to only certain limited identifiers as agreed upon between the investigator and the
       institution. This method is not as commonly utilized. A template for development of a
       Data Use Agreement is available.

Please visit www.palmettohealth.org/IRB for access to all forms and templates noted above. All
documents are available here for download in Microsoft Word.

Continuing Review: Renewals & Study Status Changes

Each protocol will be reviewed periodically and no less frequently than once every twelve (12)
months. The investigator shall complete an application for continuing review through eIRB in a
timely manner with enough time to allow for the submission to receive IRB review and approval
prior to the current date of expiration. Information provided will be processed for Full IRB
Review or by Expedited IRB Review, whichever is appropriate.

IRB Approval may be delayed if there are any modifications or corrections to be made to the
study under continuing review. The investigator has the option of submitting the continuing
review application 30+ days prior to their given submission deadline to avoid the possibility of
expiration of IRB approval. If the investigator fails to submit for continuing review in a timely
manner, then IRB approval will expire, effective at the end of the current approval period
meaning the research must cease. A study submitted for continuing review may be reviewed by
the expedited procedure if the study is closed to accrual, patients are no longer receiving protocol
treatment, and patients are in normal follow-up.

Federal guidelines direct that the Committee must review all ongoing human subjects research at
least once a year. It is the responsibility of the investigator to see that their research is submitted
for continuing review before IRB approval lapses.

Continuing Review submissions submitted through eIRB must include:

1. A completed eIRB application for Continuing Review.

2. A clean copy of the Informed Consent Form should be uploaded into eIRB. This consent
   will be stamped with IRB approval for use over the next approval period.

In eIRB a Study Status Change should be submitted under Continuing Review when:

   The research is permanently closed to the enrollment of any additional subjects;

   All subjects have completed all research-related interventions;

   The research is no longer following subjects for data collection.



                                            Page 38 of 58
Amendments: Study Modifications

Changes to the protocol, informed consent form or other study materials cannot be initiated by
the investigator without prior IRB review and approval, except where necessary to eliminate
apparent immediate hazards to the subject. In this case, the IRB must be notified of this action
within 24 hours.

The investigator is responsible for submitting changes to the protocol through eIRB, no matter
how minor the changes may be in comparison to the original IRB approved protocol, the changes
must be submitted to the Board for review and approval prior to their incorporation into the
research.

Investigators should note that only those procedures specifically approved by the IRB may be
carried out. Any new information that would affect the potential risk to subjects must be brought
to the IRB’s attention in a timely way. Any negative or adverse reactions by subjects should be
reported to the Board immediately.

When submitting changes in eIRB, an Amendment request form should be completed with the
following information:

1. A complete description of the changes made to the protocol, consent form, or other study
   documents.

2. Copies of the changed documents showing exactly what was added or removed. The
   changes should be underlined, highlighted and/or struck through. If the documents are in
   Microsoft Word, you may use the markup feature for tracking changes. Clean copies of the
   changed documents should also be provided.

When an investigator submits an amendment to the study for IRB review, the Board must
determine if the changes are minor or major. In most cases, minor changes to previously
approved protocols can be reviewed by Expedited IRB Review such as:

   The principal investigator plans to leave the institution and intends to continue the research
    activities at another institution.

   If the research activities are to be continued under the direction of a new principal
    investigator.

   Change of location of program activity.

   Addition or deletion of study personnel to the research protocol.

   Editorial or administrative changes (i.e. changes in names, addresses, telephone numbers,
    etc.).




                                           Page 39 of 58
   Minor changes that have no substantive effect upon an approved protocol or a reduction of
    protocol risks already approved by Full IRB Review as acceptable research risks.

   Scientific and/or therapeutic changes that leave the research population at the same or lower
    risk than risk(s) already approved.

   Changes to the consent form that reflect changes in the scientific/therapeutic changes as
    noted above.

   Adding additional subjects of the same type of population indicated in the original protocol
    (i.e. expanding accrual goals).

   Extending the duration of the study beyond the period of time initially approved by the IRB;

   Change in the title of the protocol.

   Addition or deletion of questions from assessment tools, survey instruments or patient
    questionnaires.

Changes to a protocol that may increase the risk to the research population or are of questionable
risk must receive Full IRB Review. The IRB has the authority to require any changes or
modifications to a study be submitted for Full Board review. The following major changes must
receive Full IRB Review:

   Adding a subject population different from those already approved.

   Adding question(s) to assessment tools, survey instruments or patient questionnaires that may
    increase risk to the subject.

   Changes in consent procedures where someone other than a physician will be obtaining
    informed consent for a protocol deemed greater than minimal risk.

   Adding an element that may breech the confidentiality of the subject.

   Change in the way subjects are compensated for their participation in the research.

   An increase in risk or questionable risk to the research population.

Unanticipated Problems or Adverse Events or Other Complications

Investigators are responsible for immediately reporting to the IRB and, if applicable, the FDA,
any injuries to subjects, deaths associated with the research procedures, or any unanticipated
problems which involve risks to the human research subjects or others. The DHHS requests
investigators to report any “significant deviations” from protocols. Other criteria may be
included as per individual protocols. The Palmetto Health IRB Policy titled “Reporting and



                                           Page 40 of 58
Reviewing Unanticipated Problems Involving Risk to Subjects or Others and Adverse Events”
should be reviewed for detailed information on the requirements for reporting events to the IRB.

A Reportable Event should be submitted in eIRB with the following information:

   A complete description of the nature of the unanticipated problem or adverse event;

   An assessment stating that the event was serious, unanticipated, related or possibly related to
    the research;

   Any correspondence from the sponsor detailing the event; if applicable, a discussion of the
    implications for continuation of the study; and an autopsy report if available.

The report is reviewed by the Chairperson, designated representatives, and/or the full IRB
committee. If the reaction is severe, the investigator may be requested to discontinue the study
pending further review by the IRB.

Informed Consent Document

The informed consent document is only one part of the larger process of informed consent that
occurs between the potential research participant and members of the research team. The
informed consent document should ideally be written in language understandable to all research
participants involved (6th to 8th grade reading level).

The informed consent process should involve an ongoing dialogue between investigators and
research participants. Investigators should address the research participants' concerns and
questions and should confirm that research participants understand the basic purpose and conduct
of the study. Only in this way can researchers ensure that the rights of research participants are
protected and that the integrity of the informed consent process is maintained.

The Committee will evaluate proposed informed consent/assent documentation with regard to
the following elements:

1. A statement that the study involves research, an explanation of the purposes of the research
   and the expected duration of the subject’s participation, a description of the procedures to be
   followed, and identification of any procedures which are experimental.

2. A description of any reasonably foreseeable risks or discomforts to the subject.

3. A description of any benefits to the subject or to others which may reasonably be expected
   from the research.

4. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might
   be advantageous to the subject.




                                           Page 41 of 58
5. A statement describing the extent, if any, to which confidentiality of records identifying the
   subject will be maintained and that notes the possibility that the Food and Drug
   Administration may inspect the records.

6. For research involving more than minimal risk, an explanation as to whether subjects will be
   eligible for any compensation and an explanation as to whether any medical treatments are
   available if injury occurs and, if so, what they consist of, or where further information may
   be obtained.

7. An explanation of whom to contact for answers to pertinent questions about the research and
   research subjects’ rights, and whom to contact in the event of a research-related injury to the
   subject.

8. A statement that participation is voluntary, that refusal to participate will involve no penalty
   or loss of benefits to which the subject is otherwise entitled, and that the subject may
   discontinue participation at any time without penalty or loss of benefits to which the subject
   is otherwise entitled.

Additional elements of informed consent, when appropriate, one or more of the following
elements of information shall also be provided to each subject:

1. A statement that the particular treatment or procedure may involve risks to the subject (or to
   the embryo or fetus, if the subject is or may become pregnant) which are currently
   unforeseeable.

2. Anticipated circumstances under which the subject’s participation may be terminated by the
   investigator without regard to the subject’s consent.

3. Any additional costs to the subject that may result from participation in the research.

4. The consequences of a subject’s decision to withdraw from the research and procedures for
   orderly termination of participation by the subject.

5. A statement that significant new findings developed during the course of the research which
   may relate to the subject’s willingness to continue participation will be provided to the
   subject.

6. The approximate number of subjects involved in the study.

Obtaining Informed Consent

The investigator must obtain legally effective informed consent of subjects prior to their
involvement in research unless waived by the IRB. The Physician (Principal Investigator) must
be the one responsible for obtaining informed consent from patients for protocols that involve
medical treatment. Research protocols that do not involve medical treatment authorized by a
physician may utilize qualified personnel to obtain informed consent upon IRB approval.



                                           Page 42 of 58
It is important that the physician be the person to obtain informed consent from patients for
protocols that involve medical treatment. Non-physician professional personnel may assist with
the consenting process but cannot obtain the informed consent. They may obtain patient
signatures and witness the consenting process.

Investigators or co-investigators listed under the study personnel for a protocol may obtain
informed consent if the procedures specified in the protocol are within the scope of their
professional practice. Non-physician professional personnel may assist with the consenting
process but cannot obtain informed consent from patients for protocols that involve medical
treatment.

Research protocols that do not involve medical treatment authorized by a physician may utilize
qualified personnel to obtain informed consent. A person can obtain informed consent if the
procedures specified in the protocol and consent form are within the scope of that person’s
practice. For example, nursing protocols should allow nursing investigators to obtain informed
consent since this would be in the scope of their practice. The same practice is in effect for
pharmacists, nurse practitioners and other medical professionals.

Non-physician professional personnel may obtain patient signatures and witness the consenting
process but cannot obtain informed consent from patients for protocols that involve medical
treatment. The principal investigator (physician) should document the consenting process in the
patient’s record.

Unless the research falls within the purview of the Food and Drug Administration (FDA), the
investigator is responsible for retaining the signed consent and assent documents for at least three
years after termination of IRB approval.

For research which falls under FDA authority, the investigator is responsible for retaining the
signed documents for the period specified in the applicable FDA regulations.

All non-exempt research approved by the Committee must obtain informed consent from
subjects either through the use of a written consent form or through an alternative oral procedure.
An exemption may be requested for survey and interview procedures or observations of public
behavior but not for research with children as subjects.

Study Auditing

A. The IRB is charged with the responsibility to ensure that human subjects involved in research
   are adequately protected. A representative of the IRB will review research studies conducted
   through Palmetto Health on an ongoing basis for federal compliance. Study auditing is one
   method used by the IRB to ensure adequate patient protection.

B. The following elements may be reviewed during a study audit:




                                          Page 43 of 58
1) Validation that the informed consent document has been properly signed by the research
   subject and those authorized to obtain consent. (Signature dates on the informed consent will
   be compared to the date the subject was actually enrolled.)

2) The consenting conference/process between the investigator and the research subject has
   been documented in the patient’s chart.

3) Documentation that proper informed consent was obtained in the medical chart or patient
   record of the study participant. (Records should indicate that the patient was given the
   opportunity to have questions about the research study answered by the
   investigator/physician.)

4) Review of the investigator’s protocol file showing documentation of all correspondence
   between the investigator, sponsor and the IRB have been properly reviewed by the IRB.

5) Use of a survey/questionnaire by the IRB for auditing investigators and/or their research
   staff. If willing, patients may be asked to complete a survey/questionnaire for the IRB to
   evaluate the effectiveness of their consent conference.

6) Review of patient records to ensure that the trial is being conducted in compliance with the
   protocol as approved by the IRB.

7) Review of records for compliance of clinical trials consistent with good clinical practice
   (ICH GCP) and Medical and Dental Staff Bylaws, Rules, and Regulations for the institutions
   of Palmetto Health.

Corrective Action Plan

The IRB will be responsible for implementing and maintaining an education program on the
ethical principles and regulatory requirements for the protection of human subjects for all IRB
members, all IRB professional staff, and all research investigators.

This may require periodic in-service training of all research investigators and/or interactive or
didactic training from expert consultants working in the field of human subject protections.
A satisfactory corrective action plan may involve a restructuring of the institutional system for
protecting human subjects, including an enhanced institutional commitment, implementation of
additional IRBs, and the appointment of additional IRB Chair(s) and/or members. It may also
mean changes in leadership.

Investigators suspected of being non-compliant with their research will be audited. The IRB will
take corrective actions under the following circumstances:

1) When the subject has been placed at intentional or unintentional harm without immediate
   corrective actions by the investigator. (This includes offering prompt medical treatment and
   the possibility of stopping all protocol therapy.)




                                          Page 44 of 58
2) When improper documentation of informed consent has been discovered.

3) When evidence indicating any injury or harm to subjects has occurred either due to the
   protocol therapy or due to improper procedures or practices conducted by the investigator.

4) When the protocol therapy has been found to be ineffective and places subjects at undue risk
   with little or no benefit.

5) When any of the federal regulations governing the protection of humans subjects involved in
   research have been violated as listed in 45 CFR 46 and 21 CFR 50.

The severity of the act of non-compliance will determine how the IRB reports violations to the
FDA and OHRP. In the event an act of non-compliance cannot be resolved between the
investigator and the IRB, then the appropriate authorities from the FDA and/or OHRP will be
notified.

IRB Administration

Palmetto Health corporate office of Research Administration is assigned the responsibility to
provide staff support to the IRB as well as to coordinate administrative and record keeping
activities between the staff of the institution, the IRB, and other organizations, including
collaborating institutions. Research Administration will retain IRB records relating to specific
research activities for at least three (3) years after termination of the project.


The Chair shall in writing notify the Principal Investigator of the recommendations of the
Committee. The Principal Investigator is required to respond in writing to any requests for
changes or clarification, which will be made a part of the protocol.

Who are the persons responsible for the operations of the IRB?

Edward W. Catalano, M.D. serves as the IRB Chair for Palmetto Health. Dr. Catalano provides
strong leadership in the ethical operations of the IRB, critical and equitable review of protocols,
strategic planning, appointment of members and determination of the need for outside expertise
where required.

Rebecca Marigliano, Ph.D. is the Director of Research. Dr. Marigliano has extensive experience
in research and IRB administration and provides leadership to the Clinical Trials and Research
Administration departments. You can reach Dr. Marigliano by phone at 803-434-4898 or
contact her through e-mail at rebecca.marigliano@palmettohealth.org.

Mary Prather, R.N., M.P.H. is the Human Research Protections Program (HRPP) Manager in
Research Administration. Ms. Prather has an extensive background as a nurse. She provides
oversight for the IRB and is involved in the development of research related policies. You can
reach Ms. Prather by phone at 803-434-6983 or contact her through e-mail at
mary.prather@palmettohealth.org.



                                           Page 45 of 58
Regulatory Compliance

When the DHHS awards an assurance of compliance (FWA) to an institution, the institution has
agreed to apply federal regulations for the protection of human subjects and to be guided by the
ethical principles of the Belmont Report. The Office of Human Research Protections (OHRP) is
the office within the federal government that negotiates Assurances for DHHS and oversees the
compliance of the institutions with these assurances. FWAs must be renewed every three years.

The IRB is charged with promptly reporting to the appropriate institutional officials, OHRP,
FDA, and any federal agency that is sponsoring a particular study any of the following actions:

      Injuries to human subjects or other unanticipated problems involving risks to subjects or
       others.
      Serious or continuing noncompliance with regulations or requirements of the IRB.
      Suspension or termination of IRB approval for research.

Should an IRB fail to comply with these mandates, OHRP is charged with applying sanctions to
the IRB. These sanctions may range from the withdrawal of the institutional assurance, to
placing limitations on the institutional assurance, and to temporary suspension of federal
research at the institution. In the past, OHRP has enforced sanctions at some major research
institutions which suspended all human subject research across the entire institution until
violations could be rectified. In these cases, the IRBs were required to rework their policies and
procedures as well as re-review and re-approve every previously approved study protocol before
the suspension was lifted.

OHRP also has the authority to impose sanctions on individual researchers. Included among the
sanctions that may be imposed on an individual researcher are:

      Recommending to the DHHS that the researcher be barred from receiving federal funds
       for conducting research.
      Requiring OHRP approval for each study conducted by the researcher.
      Requiring the researcher to undergo remedial training or education.
      Placing certain restrictions on the researcher’s ability to conduct research (e.g., requiring
       supervision of the researcher).

For research studies which involve the use of investigational drugs (INDs) or devices (IDEs), the
FDA provides oversight and regulation. The FDA inspection program, the Bioresearch
Monitoring Program (BIMO), conducts routine randomized audits of investigators, research
sites, sponsors, and IRBs to assess compliance with federal regulations. BIMO conducts “for
cause” audits when noncompliance with federal regulations is suspected. FDA sanctions
correlate to the level of risk to which research subjects are placed at risk by the violations of the
federal regulations. In some instances, disqualification/debarment proceedings are implemented,
and may be temporary or permanent.




                                           Page 46 of 58
As a condition for accepting federal funding for research, institutions are required by Public
Health Service (PHS) regulations to have written policies and procedures for investigating
scientific misconduct. The PHS definition of scientific misconduct is as follows:

   Misconduct in science means fabrication, falsification, plagiarism or other practices
   that seriously deviate from those that are commonly accepted within the scientific community
   for proposing, conducting, and reporting research. It does not include
   honest error or honest differences of interpretations or judgments of data.

When an allegation of scientific misconduct is made, the regulations require that the institution
initiate an inquiry to determine whether or not there may be a basis to believe that misconduct
could have occurred. If, after the inquiry, institutional officials believe that misconduct may
have occurred, the institution is required to conduct a more in-depth investigation. It is also
required that the Office of Research Integrity (ORI) be notified of the intent to conduct the
investigation. The ORI is a division of the PHS which oversees investigations of allegations of
scientific misconduct. At the conclusion of the investigation, the institution is required to write a
report of its findings and its determination as to whether or not the accused individual did
commit scientific misconduct. The report is submitted to institutional officials, who determine
the final action to be taken. The report is also submitted to ORI, which has the authority to either
accept or reject the findings. If an individual is found guilty of scientific misconduct, there is a
range of penalties that the institution and ORI may utilize. These penalties are similar to those
mentioned above that may be imposed by OHRP and FDA. Additionally, in some instances, the
institution or ORI may require that any publication related to the research in question be
retracted or corrected.

The Palmetto Health IRB policy regarding scientific misconduct (and all IRB policies) can be
found at the following web address: www.palmettohealth.org/IRB.

Good Clinical Practice (GCP)

Good Clinical Practice (GCP) is an ethical and scientific quality standard for designing,
conducting, monitoring, recording, auditing, analyzing, and reporting drug trials that involve
participation of human subjects. In the United States, GCP has been based primarily upon FDA
policy and regulation. In recent years, however, a movement toward international GCP
standards has occurred. The International Conference on Harmonization (ICH) is composed of
expert working groups from industry and regulatory bodies in the European Union, Japan, and
the United States. The ICH has now published standards for GCP which apply to the clinical
trials of drugs. There is no one source of guidance for GCPs. They are embodied within laws,
regulation, and guidelines such as:

       Ethical codes
       IRB and consent regulations
       Guidelines on the obligations of investigators, sponsors, and monitors
       Code of Federal Regulations pertaining to drugs and devices
       ICH Guidelines
       Official guidance documents



                                           Page 47 of 58
Compliance with GCPs during clinical trials will ensure that:

      The rights and safety of human subjects are not compromised.
      Appropriately and adequately trained staff are managing the study.
      The study is carefully documented.
      Protocol is strictly adhered to.

GCPs, therefore encompass all aspects of a clinical trial including (but not limited to):

      Obtaining informed consent.
      Documenting accurate case histories.
      Maintaining complete “paper trails” for all study documents.
      Reporting adverse events.
      Proper record retention.

Responsibilities of the Investigator

Investigators share the responsibility with research institutions and sponsors for ensuring that
study subjects are adequately protected. Studies must be properly designed so that they are
scientifically sound and likely to yield valid results. Investigators must be appropriately
qualified to conduct the research. The investigator is responsible for ensuring that the research is
conducted according to the protocol that was approved by the IRB.

The ultimate responsibility for the acceptable conduct of research with human subjects rests with
the investigator. Only sound professional judgment can ensure the protection of study subjects.
It is up to the investigator to see that:

      The personal dignity and autonomy of the research volunteer are respected.
      Subjects are protected from harm by maximizing anticipated benefits and minimizing
       possible risks.
      The benefits and burdens of research are shared fairly.

The investigator is personally responsible for the conduct of the research project and for the
actions of personnel under his/her supervision. Study-specific tasks may be delegated to various
research team members, but the level of responsibility must coincide with the experience and/or
capabilities of those team members. The investigator should always document in writing the
responsibilities delegated to all members of the research team.

Responsibilities of the Study Coordinator

The study coordinator is a specialized research professional who works under the direction of the
investigator and is responsible for the day to day clinical trial activities.

These activities may include (but are not limited to) the following:
    Screening and recruiting subjects.



                                           Page 48 of 58
      Setting up and organizing study files.
      Training the people involved.
      Obtaining subjects’ signatures on the informed consent forms.
      Ensuring that all necessary data are gathered and recorded in the appropriate source
       documents (i.e., patient charts) and the case report forms.
      Reviewing source documents and case report forms for adverse events that may have
       been missed.
      Collaborating with other departments (e.g., laboratory, pharmacy, etc.) as necessary.
      Ensuring that study documents are complete, current, and filed correctly.
      Problem-solving and resolving data queries.
      Completing study closeout activities at the end of the study.

Responsibilities of the Research Team

Anyone who is providing treatment and/or documenting in accordance with the study protocol
for a patient becomes a member of the research team. It is imperative that these health
professionals receive education and training regarding the study protocol and the specific
treatment(s) to be given. Meetings with these staff members are usually arranged by the study
coordinator. Training may be done by the investigator, the study coordinator, and/or a
representative from the sponsor, if there is one.

Information about the process of data collection must be included in the educational training for
research team members. Specifically, the method for documenting on case report forms (CRFs)
and the importance of source documents must be emphasized.

A source document is any document where the data are first recorded. This includes the
electronic documentation of clinical data. Thus, all of the forms that can be found in a patient’s
medical record (electronic or hard copy chart forms) have the potential for being source
documents if they contain information which is pertinent to the protocol of the study. CRFs are
forms that are specifically tailored to the documentation needs of the protocol. These forms
contain the data that will be kept in the investigator’s study files for each patient in the study.
These data will be analyzed and used to determine the outcomes of the trial. The information
found on each case report form must be consistent with information which is found on pertinent
source documents. It is not necessary for every entry in a CRF to have a matching entry in a
source document; but where the data do appear in both, they should agree. If there is a
discrepancy between the case report form and the source document, the source document most
often takes precedence. However, the investigator and/or the study coordinator are the
appropriate persons to decide which documentation will be accepted as accurate and to authorize
the correction. The person who makes the change should sign and date the document, including
an explanation, as appropriate. As with all legal documents, it is never acceptable to use white-
out, to erase an entry, to correct an entry by writing over it, or completely obliterate an entry by
any method. Anyone reviewing the documentation must be able to see what was changed, when,
and why the change was made.

As you receive education for specific clinical trials in which you will be involved, be sure to
clarify which documents are source documents and which one(s) are case report forms.



                                           Page 49 of 58
Where can I learn more about the requirements of research involving Human Subjects?

Federal guidance regarding the Department of Health and Human Services regulations for the
protection of human subjects can be found at Title 45, Part 46 of the Code of Federal Regulations
(45 CFR part 46). The Office for Human Research Protections (OHRP) provides leadership on
human research subject protections and implements a program of compliance oversight. Please
visit their web site at www.hhs.gov/ohrp for an abundance of information.

Guidance for Institutional Review Boards and Clinical Investigators from the Food and Drug
Administration relating to approved or investigational drugs, biologics or devices, can be found
in the FDA Information Sheets located at
www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationShee
tsandNotices/ucm113709.htm.

For further information on submission requirements for the Palmetto Health Institutional Review
Board, please visit www.palmettohealth.org/IRB.

Registration of clinical trials through ClinicalTrials.Gov

ClinicalTrials.gov is a mandatory registry of federally and privately supported clinical trials
conducted in the United States and around the world.

Please visit www.clinicaltrials.gov for instructions on how clinical trial investigators/sponsors
should register.

ClinicalTrials.gov allows the registration of trials that are approved by a human subject review
board (or equivalent) and conform to the regulations of the appropriate national health
authorities. Clinical investigators with primary responsibility for initiating and conducting
clinical trials should submit trial data to ClinicalTrials.gov using a web based data entry system
called the Protocol Registration System (PRS). Publications of the results of the research cannot
be published unless the trial is registered prior to the start of the study. This responsibility is
solely that of the principal investigator and not the institution.

Frequently Asked Questions about ClinicalTrials.gov can be found at:
www.nlm.nih.gov/services/faqctgov.html

A Fact Sheet on ClinicalTrials.gov can be found at:
www.nlm.nih.gov/pubs/factsheets/clintrial.html




                                           Page 50 of 58
                                          APPENDIX A

                     Outline for Writing an Observational Study Proposal


TITLE PAGE: complete formal project title, principal investigator, co-investigators,
corresponding addresses

1. ABSTRACT

2. BACKGROUND/JUSTIFICATION FOR STUDY
       Current Status of Research in the area being investigated
       Data in the literature with references
       Reasons for conducting the project in light of current knowledge

3. RESEARCH AIMS
       Clear statement of the clinical/scientific question
       Main objective
       Secondary objective(s) (optional)

4. RESEARCH METHODS
       Number of subjects
       Study Population: Inclusion/Exclusion criteria
       Study procedures (clinical and biological procedures with the time schedule): what is
        done, who does it, when
       Duration of the entire study and the duration of participation for each included subject

5. VARIABLES MEASURED AND MEASUREMENT METHODS
       Clinical or biological variables measured
       Identify how the variables relate to the research objectives
       Variable type (e.g., continuous) and expected typical values
       Data management, including software and security

6. STATISTICAL ANALYSIS
       Justification of sample size estimate
       Statistical tests used for each analysis and the rationale for the analysis
       Person in charge of the statistical analysis

7. STUDY BUDGET

8. BIBLIOGRAPHIC REFERENCES

9. APPENDICES
       Questionnaires, surveys, assessment tools, consent form, diaries/journals, quality of
        life, and/or data collection forms.

Note: If statistical design support or analysis is needed after first draft, please see Appendix D of
this handbook.




                                           Page 51 of 58
                                          APPENDIX B

                       Outline for Writing a Clinical Research Protocol

Before performing a research project, a formal research protocol must be written. All scientific,
organizational, administrative and financial aspects of the protocol should be established at this
point. The aim of these guidelines are to provide investigators with a general outline on how to
write a clinical research protocol. The list of recommendations given below will facilitate the
approval of your research project by the Palmetto Health Institutional Review Board. One must
keep in mind that the success of a research project depends on a clear and clinically pertinent
definition of the project that includes scientific, organizational, administrative and financial
aspects of the project. All locally developed research projects will be reviewed by the Palmetto
Health Scientific Review Committee prior to receiving review by the IRB. You will need to
provide an electronic copy of your protocol to the SRC at SRC@palmettohealth.org so your
proposal may be forwarded to the committee for scientific and statistical review.

TITLE PAGE: complete formal project title, principal investigator, co-investigators,
corresponding addresses, and name of sponsor

1. ABSTRACT
       Objectives: Materials, methods and evaluation criteria
       Research Plan
       Methodology
       Expected results and possible implications

2. RATIONALE
       Protocol Summary
       Statement of the Problem
       Hypothesis or Key Questions
       Specific Objectives of the Program
       Significance of this Research
       Current Status of Research in the area being investigated
       Data in the literature with references
       Reasons for conducting the project in light of current knowledge

3. OBJECTIVES
       Main objective
       Hypothesis or hypotheses to be tested
       Secondary objective(s) (optional)

4. TECHNICAL DATA ON MATERIAL OR DRUGS TO BE TESTED (optional)
       Investigator's brochure for drugs, devices or materials, which have not received FDA
        approval.




                                          Page 52 of 58
5. EXPERIMENTAL DESIGN
       Volunteers (healthy subjects and/or patients), number of subjects, source of
        recruitment.
       Inclusion criteria (clinical, biological, demographic)
       Exclusion criteria
       Concerning past history, concomitant diseases
       Concerning the study product
       Experimental protocol
       Type of trial (controlled or uncontrolled; open, blind, double-blind; cross-sectional or
        longitudinal)
       Study design (optional)
       Treatment(s) tested (formulation, dosage, times per day, duration)
       Reference treatment or placebo
       Randomization method
       Study procedures (clinical and biological procedures with the time schedule): what is
        done, who does it, when
       Criteria for discontinuing the study for a participating subject
       Associated treatments: (always anticipate)

6. VARIABLES MEASURED AND MEASUREMENT METHODS
       Biological variables
       Parameters measured
       Place where analyses are performed
       Method(s) used
       Person in charge of the analyses
       Clinical variables
       Parameters measured
       Place where analyses are performed
       Method(s) used
       Person in charge of the analyses

7. NUMBER OF SUBJECTS INCLUDED
    The sample size, or the number of subjects included, depends on the alpha and beta risks
    accepted, on the degree of difference between the evaluation criterion to be demonstrated
    between the groups, and on the variance of this criterion in the control group.

8. SAMPLE LABELING, PRESERVATION AND TRANSPORTATION

9. ANALYSIS METHODS AND PARAMETERS MEASURED
      9.1. Strategy for statistical analysis (which parameter should be compared and correlated
           with which other parameter)
      9.2. Statistical tests used for each analysis and the rationale for the analysis.
      9.3. Place where data analysis is performed and software used.
      9.4. Person in charge of the statistical analysis.




                                         Page 53 of 58
10. ADVERSE EVENTS
     Modalities for detecting and recording an adverse event
     Severe adverse events must be reported to the IRB and Sponsor
     Names and telephone numbers of persons to be contacted in the event of a serious
      adverse event

11. ADDITIONAL ASPECTS
       Subject Compliance to Treatment (assessment method) (as applicable)
       Observation Diary/Journal (who keeps the diary; who comments)
       Surveys, Questionnaire or Other Assessment Tools
       Drug routing via the Hospital Pharmacy (if applicable)
       How Written Informed Consent will be obtained
       Authorized Persons to obtain Informed Consent
       How Protocol Amendments will be processed
       Sponsor Contact Information
       Study Monitoring/Quality Assurance
       How is Patient Anonymity Guaranteed?
       Maintenance of Records and Archives
       Stipends which may be provided for participating Study Volunteers

12. STUDY DURATION
      Indicate the planned duration of the entire study and the planned duration of participation
      for each included subject .

13. LOCATION OF PROGRAM ACTIVITIES
      Indicate all locations and sites participating in the study.

14. PUBLICATION(S)
      Indicate the form of the publication (official report, scientific article) and who will write
      the final report of the study in accordance with legal requirements. Give the names of the
      authors of the final report and if possible the order of authorship.

15. CLINICAL TRIALS AGREEMENT

16. STUDY BUDGET

17. FINANCIAL SOURCES

18. BIBLIOGRAPHIC REFERENCES

INFORMED CONSENT

   The form must be written in easily understood non-technical terms (lay language). The
   information and consent form may be given as a single document; the volunteer is to initial
   each page and sign the document at the end. The original consent form is placed in the
   patient’s medical record. Copies of the signed consent document are given to the volunteer,


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   the sponsor, and kept with your study records. Please review the Development of Informed
   Consent template for guidance on how to write your consent form.

ADDITIONAL APPENDICES
  Include as needed such as questionnaires, surveys, assessment tools, diaries, journals, quality
  of life, data collection forms.

All of the sections indicated above in these guidelines may not be pertinent for all projects and
other pertinent sections necessary for specific trials have not been mentioned. However, we
hope that these guidelines will be helpful for investigators.

The protocol need not be lengthy but the above components should be included; if not
applicable, so note. All questionnaires and surveys should be included as appendices.

You may also wish to visit the web site of the Office of Human Subjects Research (OHSR)
through the National Institutes of Health and view Information Sheet #5, Guidelines for Writing
Research Protocols. Their web site is listed at http://ohsr.od.nih.gov.




                                          Page 55 of 58
                                          APPENDIX C

                           Privacy of Protected Health Information
                                  Accounting of Disclosures


In accordance with the HIPAA Privacy Rule, an accounting of disclosures may be required for
releases of protected health information (PHI) that go outside of Palmetto Health where the
subject has not signed an authorization. For disclosures of protected health information for a
particular research purpose for 50 or more individuals, the accounting of disclosures must be
performed to include:

A) The name of the protocol and protocol number (Reason/Purpose Section);

B) A brief lay description and purpose of the research and criteria for selecting particular records
(Reason/Purpose Section);

C) A brief description of the type of PHI that was disclosed (PHI Disclosed Section);

D) The date or period of time during which disclosure(s) occurred (Date Disclosed Section);

E) The name, address, telephone number of entity that sponsored the research and of the
researcher to whom the information was disclosed (To Whom Disclosed Section)

(F) A statement that the protected health information of the individual may or may not have been
disclosed for a particular protocol or other research activity.


Please visit www.PalmettoHealth.org/IRB for access to the following two tracking forms:

      Palmetto Health Accounting of Disclosures of PHI Tracking Log (Individual Patient)
      Palmetto Health Accounting of Disclosures of PHI Tracking Log (Multiple Patients)




                                           Page 56 of 58
                                        APPENDIX D

                                 Resources for Investigators

Research Design and Statistical Consultation

Investigators seeking assistance in developing a research protocol should contact Martin Durkin,
MD for design support with their study. Dr. Durkin can help the investigator with the protocol
prior to submission in eIRB. Data analysis assistance is also available.

Initial contact should be to:
Martin Durkin, MD, MPH
SRC Vice Chair
Medical Director, Clinical Research
Palmetto Health
803.434.6963
E-mail: martin.durkin@palmettohealth.org


IRB Submission:

Once the protocol has been developed under the guidance of these professionals, Investigators
should submit their protocol to Palmetto Health for review through the eIRB. The submission
should include the Protocol with all Appendices including any Data Collection Tools and
Surveys/Questionnaires.

Questions regarding IRB should be directed to:
Mary Prather
Research Administration
Research Manager
803.434.6983; Fax: 803.434.6754
E-mail: mary.prather@palmettohealth.org


Regulatory and Study Coordination:
Investigators may choose to contract with the Palmetto Health Clinical Trials Department (CTD)
if assistance with data collection, study coordination, budget, and/or regulatory assistance is
needed.

To learn more about how the CTD may be able to assist you please contact:
Adreane Burgess, RN, BSN, CCRP
Manager, Clinical Trials Department
Phone: 803-434-7311
Email: Adreane.Burgess@PalmettoHealth.org




                                         Page 57 of 58
                                            APPENDIX E

                                       Index of Abbreviations


CDC     Centers of Disease Control and Prevention
CFR     Code of Federal Regulations
CITI    Collaborative Institutional Training Initiative
CR      Complete response
CRF     Case report forms
DHHS    Department of Health and Human Services
eIRB    Electronic Institutional Review Board
FDA     U.S. Food and Drug Administration
GCP     Good Clinical Practice
H0      Null hypothesis
Ha      Alternative hypothesis
HIPAA   Health Insurance Portability and Accountability Act of 1996
ICH     International Conference on Harmonization
IRB     Institutional Review Board
MTD     Maximally tolerated dose
NIH     National Institutes of Health
NR      No response
OCR     Office of Civil Rights
OHRP    Office of Human Research Protections
OHSR    Office of Human Subjects Research
OR      Odds ratio
PH      Palmetto Health
PHI     Protected health information
PRS     Protocol Registration System
RA      Research Administration
RCT     Randomized controlled trial
RR      Relative risk
SRC     Scientific Review Committee




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