Module 4 Design of trials

Clinical Trial Design

The most important scientific accomplishment of the 20th century was the application of
the Scientific Method to solve the mysteries of Nature. With this methodology, we were able to
find out answers to many of the unanswered questions that we had about scientific issue during
the last.
The application of the scientific method requires the formulation of a question about
some natural phenomenon. Once we have formulated the question, the next step is to generate
hypothesis, a hypothesis that could explain why this phenomenon exists. When you have your
hypothesis, you hypothesis, you go to the next step : posing a question to probe this hypothesis.
Then we move to the most important step : deciding the most appropriate trial design to answer
this question.
We have three major types of study designs that can respond to these questions. The
first type is the descriptive trial. This type of trial basically generates hypotheses. It does no
answer anything. The second type is the analytic or observational trial in which we try to relate
associations between causes and diseases. the third type, is the experimental trial, in which
efficacy and safety are demonstrated.
There are various categories of clinical research : scientific trial, observational trials and
the experimental trials. This division depends on the actions that the investigator takes during of
association. or some type of description of what is happening, or we can take an active
intervention in the trial, in which case we would be talking about an experimental trial . The
observational trial can be divided in to two groups: descriptive, and analytic or explanatory trials.
The descriptive trial. The examples here: case reports, series of cases, cross-sectional
studies, the surveys, basically describe what we see in nature. These types of trials are very
important because they have generated most of the information that we have about human
diseases.

The analytic or explanatory trial. Basically, with the application of the bio-statistics we can
find answers about relationships between risk factors and diseases. They can be case control
studies, cohort studies, or natural experiments.
Finally, the experimental trials are those in which an active intervention by the investigator has
occurred to try to modify the behavior of a disease, trying to see if there is efficacy and safety in
this therapeutic measure. These trials can also be divided into two major groups: the clinical
trials and the meta-analysis.
The descriptive trials are very useful for generating hypotheses. They do not give you definitive
answers, but they are simple to do, they are inexpensive, and basically they are the ones that
have given the most information about the characteristics of human diseases, about the
personal experiences of physicians, about unexplained phenomena, and about innovative
treatments. These trials do not have the power or design to establish cause/effect relationships;
however, most of the information we have about human diseases come from these types of
trials.
In Analytic trials, what we do is apply the Scientific Method and statistical methodology in order
to seek for causes, etiologies, predictors, better diagnoses, or a test therapy for different
diseases. The investigator in these cases is observing nature rather than controlling treatment.
We do not do any type of allocation. We can do it either looking backwards, in which case we
would be dealing with a case control study. We can look at it now, and we would be doing a
cross-sectional study, or we can look forward, and we will have a cohort study. The meta-
analysis basically compares groups, groups of subjects either exposed or unexposed to a
specific risk factor to establish relationships between the potential cause and the effect using
statistical methodology.
The case control studies, which are part of this analytic group, go from the disease to the risk
factor. We basically look for subjects who have the disease, find a control group that is
comparable to the group we are studying, and look backwards to see if there was exposure to
the risk factor or not. It begins with cases, people with the disease, and goes retrospectively
from the disease to the risk factor. The controls are selected from the same population of
people that the study group was selected from, and we try to determine the presence or
absence of risk factors in the two populations. The association in this case is determined by a
statistic relationship called the odds ratio. If the odds ratio is more than one, we have a positive
association. If the odds ratio is below one, we do not have the association.

What are the advantages of the case control studies? They are efficient, they permit collection
of cases in a relatively easy way, and we can use them in diseases that are not very frequent.
They do not have the problem of cohort studies for which one has to wait years before reaching
the answer. The answer is found right away. They are particularly useful in the trials of
uncommon conditions, especially to develop a hypothesis about the cause of the problem.
They are less expensive, but they have some disadvantages. First of all, sometimes it is difficult
to assure comparability between the cases and the controls. Sometimes difficulties arise in
assuring the comparability of the exposure in both groups because data is being looked at
retrospectively.

Potential requirements for multiple-control populations to validate the observations are another
problem with these studies.
In the case of the cohort studies, we go the opposite way. We go from the risk factor to the
disease. We take a population that is exposed to a risk factor and we follow this population
prospectively, sometimes for years. Then at the end, we assess the outcome. We try to
determine if those people that were exposed to the risk factor have a higher incidence of the
problem
than the ones that were not exposed. The outcome is measured often years after the study
began. These trial are much more expensive than the case control studies. The association in
this type of trial is determined by a statistical relationship called the relative risk. As with case
control studies. The association in this type of trial is determined by a statistical relationship
called the relative risk. As with case control studies, in the case of cohort studies, the relative
risk has to be above one if there is a positive association. Cohort studies have their advantages.
Exposure data can be established more easily because a population is being followed from the
very beginning. The study will show who has been exposed and who has not.
Cohort studies are a more robust study design than case control studies, although they
can have some disadvantages. First of all, there is selection bias in choosing the cohort. The
other major problem that the cohort studies have is that there will be a significant impact in loss
of follow-up because many of the subjects followed in the cohort will be lost during the study.
The other problem of the cohort study is the fact that there may be changes in subject
characteristics during this period. Maybe some of the people that were exposed to the risk
factor changed their behavior and they are not exposed to the risk factor anymore. Or some of
the ones who were not exposed to it at the beginning can get exposed during the study. Also
there is a surveillance bias in changing the diagnostics criteria or methodology for diagnosis in
these subjects. Because of advances in science, we might have a new test to diagnose a
disease that appears during the course of the cohort study, and that might completely change
the criteria that we are using to include or exclude subjects in the study. The most important
problem these trials have is that they require years to complete the study. They are usually very
expensive compared to a case control study.
Another type of study that is more descriptive than analytic is the cross-sectional or
prevalent study. In this of study, we are looking at the present. We are not looking forward or
backward. A study population is created that will determine exposure to a specific risk factor,
and classify the population in terms of the presence or absence of the outcome, trying to
determine the prevalence of the abnormality. There are secondary goals also. for instance,
determining what risk factors have been present in the two groups, They are often succeeded
by initiating a secondary case control study, so they usually serve as the seed of a case control
study in which we can have a statistical analysis and try to determine whether or not there is an
association between the risk factor and the disease.
 Comparative Comparative Features of Case-Control and Cohort Studies

Features of Case-Control and Cohort

Studies
Case Control Cohort
Retrospective Prospective
Unit of measure: Unit of measure: Relative Risk
Odds Ratio Higher cost
Lower cost Larger sample
Smaller sample Cause >> Effect
Effect >> Cause

Advantages of the cross-sectional studies: they are efficient; all of the information can
be collected at once; you do not have to wait years for a response. The cross-sectional studies
may be repeated at intervals, and the results combined to determine the behavior of the
disease.
They also have some disadvantages: subject selection bias. Is the population studies
truly representative ? Truly random? The response form the subject is also a problem. If there is
not a sufficient response form the subject, it may be that the population is not representative of
the population being studied. The lack of cooperation by subjects can destroy the design and
effectiveness of a study that was being performed to determine the presence or absence of a
specific problem in a population. A response rate of at least eighty percent is required to have a
valid study. Time-ordered relationships are not always will determined in these types of studies.
There is always an issue whether the exposure was before or after your had the problems. That
is something that cannot be addressed in these types of studies
The controlled randomize double- blind trial is the gold standard in clinical research.
Such trials have had a major impact on science in the last century.
How do we categorize the clinical trials? We can categorize them according to different
characteristics, according to the number of participant centers, according to the control group,
by randomization, blinding, or by format, If the trials are categorized according to the participant
centers, the trials can be either a single-center study or a multi-center study. Other criteria can
be used, such as domestic or international studies.
How is the control group selected? It is possible not to select a control group and instead
have a non-comparative study, Historical controls could be used, taking subjects that were
treated in the past for the same condition and try to compare the historical controls with the
subjects that are being treated now. Many people think this design, using historical controls, is
like having no controls. Why is this? Historical controls are very difficult to evaluate. or compare
with the current subjects. It requires that we assume that those subjects were diagnosed with
the same criteria or that they received treatment in the same way. It is very difficult to assure
comparability among the two groups. Concurrent controls are the most used modality of control
groups. In this modality you are comparing both groups, and treating them at the same time,
providing assurance that both groups are receiving the treatment with the same criteria. Self-
controls can also be used in which every subject is his or her own control. Obviously, This is a
modality that will require some specific conditions to be applicable.
Randomization. How do we allocate the subjects to the arms of the trial? It is possible to
have a non-randomized trial. In this case, the investigator decides to which arm the subject is
going to be treated. The subject could go to arm A or arm B according to the investigator's
decision. A simple randomization technique can also be employed. A coin toss or a statistical
table could be used to decide which subject is going to receive which treatment. In a balanced
or stratified randomization, there is a balanced distribution of the study. In a centralized
randomization trial, each new subject that enters any of the canters around the world is
allocated according to a single criteria or statistical table.
The type of blinding is another important element in the classification of clinical trials. We
can have an open or non-blind clinical study. This might be necessary in some conditions. for
instance, it is very difficult to blind a surgical procedure; either the subject was operated on or
he was not We can use a single-blinded situation in which the subject does not know what
treatment he or she is receiving, but the investigator does know which treatment is being given.
We can use a double - blind strategy in which neither the subject nor the investigator knows
what the treatment is. We can even use what is called the double-dummy design. The double-
dummy design is a modality that is very useful to preserve the blind, when different
presentations of medications are being used in each of the groups. If one of the groups is
receiving intravenous medication and the other one is receiving oral medication, the blind is
preserved by using IV placebo and an oral placebo. Both groups receive drugs, an IV
formulation and an oral formulation, in which case one will be active and one will be placebo.
Studies can be conducted with parallel groups, where both groups are treated
simultaneously. The trial can be designed with a crossover design or a factorial design or a
square, or method analysis.
Parallel group trials. In this case, population of subjects is selected with some with
inclusion and exclusion criteria. Next, the subjects are randomized to one of the two arms of the
study, treatment A, treatment B. The outcome of the two groups is then evaluated. Finally the
efficacy of the two treatments is compared. Crossover design, we select the population, we do
the allocation, also in two groups, group A and group B. When both groups have been treated
for a period of time, the subjects enter a washout, and the process is reversed. The group that
received treatment B will receive treatment A and vice versa. With this modality, each subject
becomes his or her own control. This method provides the best control that can be used, that is,
every subject will be his own control.
However this study design has limitation in that it cannot be applied in acute disease. It
can only be applied in chronic stable diseases, in which there is an assurance that the disease
is not going to change in a short period of time, such as the period of time between treatment in
group A and the treatment in group B.
In factorial design, there are several arms and in one of the arms you combine the
treatments. For example, the first and second arms could be treatment A and treatment B. the
third arm would be treatment A + B and the fourth arm could be placebo. This allows you to
evaluate the synergy between different treatments.
Meta- analysis has become very popular because it increases the statistical power by
using a pool of clinical trials. Meta- analysis combines the results of several clinical trials and
analyses the sum of all the subjects that participated in these trial. From a statistical point of
view, it is very good because the sample size and the statistical power are increased. However,
there are many weakness that should be pointed out. First, it is very difficult to assure that all
the groups used for the meta analysis were treated with the same diagnostic and therapeutic
criteria that were used in the current group. Medicine changes, the diagnostic criteria change,
consequently, it is difficult to have homogeneity among the different groups that you are being
analyzed. The other important bias that Meta analysis has is a publication bias. We tend to
publish positive results. We tend to publish successful studies. Negative results are either not
published or very rarely published. When a meta- analysis of the publications of that specific
situation is performed, only the successful studies are being analyzed, that may not be
representative of the entire population that you wish to analyze.
Parallel Group Trial

Cross-over Design

RCT: Factorial Design Trial

The Power of Clinical Trials: Ranking by Trial Design
 The Protocol as a Clinical Tool
Success in clinical research is very simply defined. Success in clinical research is a project that
is completed on time, on budget, and to a high standard that meets the objectives it was
designed to achieve.
What is a failed clinical trial? A failed clinical trial is a trial that fails to appropriately assess
safety and/or effectiveness of a new treatment. Failed clinical trials provide inadequate or
misleading information about the best ways to use a new therapy. They do not contribute to the
development of the drug; they do not help regulators evaluate the drugs; and they do not help
the patients or the prescribers in indicating the safe way of using the drug. Surprisingly a rather
large percentage of clinical trials fail to produce useful conclusions. That is not so bad, but what
is worse is that inaccurate or failed clinical trials can produce the wrong conclusions that are
then followed. That is what is meant here by misdirection and failure of future clinical
development.
Pharmaceutical sponsors have abandoned good drugs because they could not detect their good
properties. They routinely develop drugs that should be abandoned. They develop them a little
too long, which takes a lot of money. If they could identify, at the earliest possible time, those
drugs that are going to fail they would save an enormous amount of money and reduce the cost
of drug development. Because of all those errors, drug development times are longer than they
should be and the end result is that the drugs are introduced too late.
Clinical trials fail for a variety of reasons and they are presented here. It is not possible to
separate those reasons. The reasons mentioned here overlap with each other, but lets look at
item one: "errors in hypothesis testing". Very simply, we try to see differences between one
treatment and another: the old treatment and the new one, the new treatment and nothing at all,
no treatment before the introduction of the new one. Such things as noise and variability and
errors in data collection sometimes blur these differences.
We have a false positive type of error when we wrongly conclude that the drug is active but
actually is not. We have a false negative type of error when we wrongly conclude that it is
inactive when in fact it was active. Unfortunately, we do make those errors.
Often those errors are due to the fact that we are not careful in putting together our
development plan. We are not careful in asking the right questions, in defining the indications,
in selecting the populations that are most sensitive to the drugs and in selecting sites that are
likely to observe the new properties of the drug. We make errors in trial design. We are
sometimes imprecise in selecting our endpoint measures. Sometimes we do not put enough
resources into a trial to detect differences or signals. When there is noise it takes more
resources or more subjects to see a difference and sometimes we cannot afford it.
Some trials fail because we have tremendous difficulties with recruitment of subjects. We move
away from the original recipe, that describes those subjects with precision. With every move
away from the original hypothesis, we create noise which contributes to the blurring of that
hypothesized difference. At times we deal with investigators who do not follow the protocols that
also contributes to noise. All of these errors contribute to poor data quality. The process of a
clinical trial is a stepwise process. First we define the study objectives and we include many
partners at that step. We can include subjects, representatives of patients’ organizations,
physicians, insurance companies at times to define the study objectives. Once the study
objectives are defined, we use them in a plan that is the design phase of the clinical trial. When
the plan is approved by all the stakeholders, we start enrolling subjects and collecting data.
That data is managed by specialists in data management, who collect that data, summarize it,
put it together in tables and forms the basis or the core of the study reports for pharmaceutical
companies. Those study reports for pharmaceutical companies are internal reports. They are
shared with the investigators who participated in the clinical trials, so that publications can be
issued.
The critical issues in study planning are as stated. The objectives have to be clear and as
narrow as possible. The standards for data collection have to be very clear. There should be
quality checks at each step of the process. On the previous slide you saw the successive steps
in the clinical trial process. Resource allocation is a very important thing. It is unethical to start a
clinical trial without the resources to complete it. It is a waste of time. The subjects are exposed
to a new drug that could have safety problems and society will not benefit from that trial.
There are many participants in a clinical trial and defining their responsibilities is very important.
Boston consulting firm has a system that puts participants in four different bins or categories.
One category contains participants who are accountable for starting and completing tasks.
Another category holds those participants who have the right to authorize or veto tasks or
expenses. Another category contains participants who have the duty to support, to train, to
teach, to provide the materials and so forth. Finally, the last category contains participants who
have the right to be informed in time to react appropriately. There are many such participants in
the pharmaceutical companies. Clarifying those interfaces always helps in study planning and
execution.
the protocol is a document that the pharmaceutical sponsor usually prepares with the
participation of many other experts outside the company: physicians, patients’ advocates, and
academics. The collective product is put together by the sponsor, and describes why the trial is
being conducted, the rationale for the trial, the objectives, and how the trial will be executed. It
also describes the procedures and measurements used to evaluate the safety and effectiveness
of the drug, the treatments to be administered, as well as the control treatment, and the new
treatment to be used. A section on regulatory requirements must also be included: Generic
regulatory requirements and sometimes country-specific regulatory requirements that may be
more stringent.
A few key points to consider: investigators are responsible for complete adherence to the
protocol. A corollary of this is that any deviation from the protocol constitutes non-
compliance. Another corollary of this is that the investigators should not make any changes
to protocols without first notifying the sponsor with whom they have a contract, and the
Institutional Review Board, or IRB, or Ethics Committee. The only exception to this is if it
becomes necessary to protect the rights or safety of the subject. If changes are made, a full
report is required to be submitted as soon as possible to the sponsor and the IRB or Ethics
Committee.
The International Conference on Harmonization, Good Clinical Practices (GCP), lists the
requirements for a GCP-compliant protocol, most of which are quite intuitively obvious. There
has to be a title page with the protocol title and the date it was written. (This is important
because there may be several versions of this protocol,) The title page should also include the
name and address of the pharmaceutical firm; (the sponsor), the name and address of the
monitoring organization, especially if the monitoring organization is different; such as when the
sponsor, contracts monitoring to a Clinical Research Organization (CRO). Also included on the
title page is the name and address of clinical laboratory, and the name and title of investigators
and co-investigators. Finally, there is a little section called the Confidentiality Statement. This
reminds the users of the protocol that the intellectual property in the protocol is the property of
the sponsor and cannot be distributed or shown to people who are not part of the contractual
relationship with the sponsor.
What are the requirements for a protocol under ICH-GCP? As you would expect, there has to
be a description of the inclusion and exclusion criteria for the patients that would be in the trial; a
specification of the safety measures that would be used to monitor the safety and tolerability of
the drug; a precise description of the efficacy endpoints or efficacy variables, that should include
the methods and the timetable for those assessments. Also there has to be a full description of
the statistical methods that would be used as the trial is conducted, for interim analysis for
instance, and when the trial ends.
Safety reporting and the communication lines for safety reporting have to be well described in
the protocol. The clinical laboratory parameters have to be described. What is allowed and
what is not allowed in terms of concomitant therapy has to be described, and there should be
some room for extra information that may help the investigator. There may be, for instance, a
reminder of the standard diagnostic criteria for a particular disease or a helpful flow chart.
There may also be a reminder that the investigator is responsible and accountable for being in
compliance with the Department of Transportation regulations on handling of hazardous
materials. This is something that the investigators are responsible for.
Responsibility of sponsor is to make sure that they know the regulations and point them to
training sources if they are not familiar with those regulations. Investigators and the subjects
that they treat have to have direct access to the sponsor 24 hours a day. The phone numbers
have to be there. Ideally it should be one number for everybody to simplify things, and the
organization or the group that would be on the receiving side in the pharmaceutical company
has to be described. There should be a section on ethics.
The financial aspects of the contract between the sponsor and the investigator have to be
described, and made transparent to the institution where the investigator works. It also needs to
be made transparent to the ethics committee or Institutional Review Board (IRB). There must be
a statement of insurance in the protocol. There also needs to be a description of the
understanding with regards to publication: when will the data be made available to the
investigator; what should be the type of journal where the study should be published; who will
be the authors.
ICH is rather formal and prescriptive about the formatting of the protocol. The sections of the
protocol are as follows and again this is prescribed by ICH. There has to be:
• A section describing the trial type and design, whether it is double blind, single blind, dose
response, for example
• A section on the primary end points and the exploratory or secondary end points

• A description of the method to allocate the treatments, the randomization method, and the
method that will be used to prevent the participants and the investigators or the sponsors’
agents from determining who is receiving the new treatment and who is receiving the control
treatment.

• A section to deal with the description of the treatments, the dosage regiments, the dosage
forms, the packaging methods and the labeling methods.
• A section on the duration of subject participation
• A section on the criteria to discontinue subjects if they do not tolerate the drug, or wish to
withdraw from the trial, and what to do with those subjects and the data they have provided
• A methods section describing what circumstances one would discontinue the trial, usually
when certain safety signals have emerged.
• A section on how often the sponsor will monitor the investigator sites. Some trials require low
frequency monitoring, some require high frequency monitoring - this has to be described
with precision.
The subjects are expected to take the drugs, and follow their treatments as prescribed. In
normal practice, subjects are not always compliant and there is no reason to believe that
subjects participating in a clinical trial would be more compliant. We need methods to monitor
this. Pill counts can help. We can calculate how many pills have been used between visits.
There are other methods such as measuring the exposure to the drug by pharmacokinetic
measurements, plasma measurements. There are other methods that look at the number of
times subjects open their bottles of pills, but the important thing here is that these procedures
have to be described in advance.
You also have to describe in advance what is expected of investigators when the sponsor sends
auditors to the site or what is expected of investigators when the regulatory agency send
auditors to the site. That has to be described in advance.
Trials generate a lot of data, a lot of paperwork, a lot of documents. Some of them have to be
kept for a long time, (and this is also prescribed by regulatory agencies,). What has to be kept
and what can be discounted has to be described in the protocol.
Finally there has to be a record of the contract between the sponsor and the investigator,
so-called signature page or investigator page. This binds the investigator and the sponsor.
The contract stipulates that the investigator should conduct the trial in compliance with the
protocol that was agreed to with the sponsor and approved by the Institutional Review Board
or Ethics Committee. The investigator should not deviate from the agreement by the
sponsor except when necessary to eliminate the immediate hazard to the trial subject.
Situations may occur when the investigator may feel compelled to deviate from the protocol.
For instance, when it becomes necessary to interrupt the treatment because there is a strong
suspicion that the new treatment is dangerous to a particular subject or subjects in general. In
that case, the investigator may have no other choice but to implement that change, document
the reason, notify the sponsor for the agreement and then notify the Institutional Review Board
or the Ethics Committee for review and approval. These are rare circumstances but there is
room for such actions.
In conclusion, the clinical trial protocol documents the requirements for conduct of the trial. It
must be approved by the IRB or Ethics Committee. Deviations must be agreed upon and
documented by the investigator and the sponsor, and submitted to the IRB or Ethics Committee
where required and strict compliance is required. If those conditions are met, there is a high
likelihood of meeting the business and scientific objectives of the study; to have a quality plan;
to be in a good position for publishing in a good journal and to stay within budget. It is important
for the pharmaceutical sponsor and it is also important for the investigator. If all those
conditions are met, it is a win-win situation, one of the great benefits of clinical research. It is a
win for the investigator, it is a win for the sponsor, and last but not least, it is a win for the
participant.
 1 INTRODUCTION TO PROTOCOL DESIGN
The word RESEARCH means "finding out" or "discovery", by use of systematic effort,
information or answers to something you want to know. You 'research' by asking questions and
by searching for answers to those questions, which are satisfactory, methodologically valid, and
balanced. You cannot research if you do not want to know anything, that is, you must have
something you would like to know more about before you can do research. You begin with a
question or questions. If you have none, you will find no answers or will not know when you
have found one.
A clinical trial (also called medical research) is a research study to answer specific questions
about a new drug or new therapies or new ways of using known treatments and to know
whether new drugs or treatments are both safe and effective.

The planning of a clinical trial depends on the question that the Sponsor/investigator is
addressing. The general objective is usually obvious, but the specific question to be
answered by the trial is often not stated well. Stating the question clearly and in advance
encourages proper design. One would like answers to several questions, but the study should
be designed with only one major question in mind, i.e. primary question and that should be
adequately answered. For example,
n Does the new therapy work as well as a current standard care but with less discomfort
to patients?
n Will the new treatment work better or faster than standard care?
n Will the new treatment possibly be or lead to a cure?
A clinical trial or study protocol is essentially a self-contained document or booklet of
rules that outline in detail what the trial hopes to accomplish, how the trial will be
carried out, and how the progress of the treatment program will be assessed, how the final
data will be analyzed and who will be assuming the role of 'the buck stops here'. The
protocol is developed from extensive consideration of how best to conduct the study from
both a clinical and statistical point of view. The success of any project depends greatly on this
stage of development of protocol which generally takes several weeks or months.
The medical writer is the person who designs the protocol. Inputs from the physicians (or
dentists), medical personnel from the sponsor company (in case the protocol is asked to be
written by a CR0), representatives from the study monitoring, safety monitoring, data
management, quality assurance, statistics and drug logistics team.
Though inputs are taken from many individuals and departments/ divisions of the
organisation, the medical writer should have a first hand clinical knowledge of the disease
that is being evaluated to choose the appropriate clinical trial design in order to address the
objectives. A medically trained (physician) individual would be preferable to write a
protocol.
Though CRAs (Monitors) are not involved in writing a protocol, it is important for
them to have an understanding of protocol basics to make their job more effective
and easy.
2 PROTOCOL TEMPLATE INSTRUCTONS
The protocol template is a tool to facilitate rapid protocol development. No two
protocols are the same. Formats will vary from company to company and among
different medical writers in the same company. This may be dictated by the
company's standard operating procedure (SOP). All sections may be modified as
necessary to meet the scientific aims of the study and development of the protocol.
The protocol template consists of the Main Body and Appendices. They generally
include the following items in the sequence as below, but these may be modified or
reordered to meet the requirements of specific situations effectively.
2.1 COVER PAGE

The cover page shall contain the following:

n Protocol title, identifying number, version number and effective date

The title should be specific so as to distinguish the intended study from similar
protocols. By title, a person should be able to understand the study design in
brief. For example,

"A 24- week, Multi- centric, Randomised, Double- Blind, Placebo- controlled, Phase 3
clinical trial to evaluate the Safety and Efficacy of Arcatol® in patients with Chronic
Myeloid Leukemia – An Equivalence Trial"

"A Multi- Centric, Randomised, Double- Blind, Comparative, Phase 3 Clinical Trial to
evaluate the Safety and Efficacy of AAAAA TM in Cancer patients with Mild to Moderate
Cancer Chemotherapy- Induced Neutropenia – An Equivalence Trial"

"A Multi- Centric, Open Label, Phase 3 Clinical Trial to evaluate the Safety and Efficacy of
AAAAATM in Chemosensitive Cancer Patients with Mild to Moderate Chemotherapy- Induced
Neutropenia"

A unique numbering procedure can be followed by a certain sponsor. For example: ACT-
Suven- IND- B-013/2006. ACT denoting Asian Clinical Trials, Suven for Suven
Pharmaceuticals Ltd, IND for Indian company, B for Biotech product and numbering of
the project for that year or in sequence since the opening of the company.
All protocols should have the versions and the date of effect which also becomes a part of
the identifiers. Any amendments shall also bear the amendment/version number(s) and
date(s). Other details include:
n Name of the Sponsor and/or CRO
n Name of the Coordinating center (if applicable)
n Name, address (of institution where trial will be done), telephone, fax and email
address of the Principal Investigator(s)
n Name, address (of institution where trial will be done), telephone, fax and
email address of the Co-Investigator
n Name, address (of institution where trial will be done), telephone, fax and email
address of the IRB/EC
 n Name, address (of Sponsor/ CRO), telephone, fax and email address of the
Project Safety Officer
n Signature of PI
2.2 INNER PAGE

The inner page (i.e. the one after the title page) can have details of the study team.
n Name, address (of Sponsor/ CRO), telephone, fax and email address of the
Project Biostatistician
n Name, address (of institution where trial will be done), telephone, fax and email
address of the responsible Research Nurse or the Study Coordinator
n Name, address (of Sponsor/ CRO), telephone, fax and email address of the
Project Clinical Research Associate (or Monitor)
2.3 CONFIDENTIALITY STATEMENT

A confidentiality statement instructing the Investigator/recipients to treat it as a confidential

document can also be included apart obtaining a Nondisclosure and Confidentiality Agreement.

2.4 SYNOPSIS
An overview of the study is given here. The summary will provide enough information for potential
investigators to determine if they are interested in and have capability to conduct the study.
A typical synopsis runs not more than 2-3 pages and typically includes:
n Study title
n Description of the study medication and comparator (generic and trade name): Their
dosage form (tablets or capsules), route of administration (oral or parenteral), dose
and regimen (10 mg bid) and duration of the treatment
n Study population (for e.g. male or female only or both genders, cancer patient of
mild to moderate type with intended age group also)
n Sample size: Anticipated patient enrolment break- up with percentage of
drop outs
n Phase of study
n Study design: Blinding-open, or single or double; randomised or not, controlled with
placebo or with innovator or other marketed product, parallel or crossover
n Objective(s) of the study: Efficacy end points and evaluation criteria
n Rationale for the conduct of study
n Data Analysis: Brief summary of the statistical analysis plan
n Inclusion and Exclusion criteria
n Name of potential responsible Investigator and participating
institution/site(s)
n Study flow chart: A general description of the procedures, tests, and timelines
in a tabulated format
2.5 TABLE OF CONTENTS

A protocol should include a table of contents, outlining relevant sections of the

documentation.
2.6 LET OF ABBREVIATIONS
The abbreviations that are made use of in the protocol are listed herein, alphabetically.
2.7 INTRODUCTION

2.7.1 BACKGROUND INFORMATION ON THE D/SEASE/CONDIIDN

A brief summary of the incidence of the disease/condition, etiology, pathogenesis, and

clinical features on the disease/condition being evaluated should be mentioned. In
addition, a brief description of the methods of diagnosis, and the approved and
available treatments available should be mentioned.

References to literature and data that are relevant to the trial, and that provide the
background and rationale for the trial can also be provided here either as foot note or
numbered appropriately with full details at the end of the document.
2.7.2 BACKGROUND INFORMATION ON THE NVESTIGATIONAL PRODUCT

A concise summary of the available data on the investigational product(s) from pre- clinical
studies, and the effect in humans (pharmacology, bioavailability, clinical effects,
and justification for the route of administration, dosage form, dose regimen, treatment
period, known and potential risks and benefits) should be given. A summary of findings from
clinical trials that are relevant to the trial shall be included. Added advantage/limitation of the
investigational product over the existing drug/therapy or parent compound shall be
mentioned.
This section also shall describe the contents and quantities of the active ingredients in the
investigational product(s), comparator (identical, marketed product). In addition, the
details of all inactive ingredients and additives (e.g. adjuvant, preservatives, etc.) in the
formulation shall be included.
In brief, describe the background, including human subject or animal research and
references that are relevant to the design and conduct of the present study
.

2.7. SCIENTFIC RATIONALE FOR THE STUDY

The protocol must include:

n A rationale for research subject selection based on a review of
g e n d e r / e t h n i c / r a c e c a t e g o r i e s a t r i s k f o r t h e d i s e a s e / c o n d i t i o n being
studied
n Strategies/procedures for recruitment (including advertising, if applicable)
n Justification for exclusions, if any
If the protocol is of a phase 3 or 4 clinical trial, a discussion of how the trial will be
carried out to conduct valid results analyses of differences by gender and ethnicity must
be included.

Explain the rationale for the involvement of special classes of subjects, if any, such as
fetuses, pregnant women, children, cognitively impaired individuals, prisoners or
other institutionalized individuals, or others who are likely to be vulnerable. Discuss
what, if any, procedures or practices will be used in the protocol to minimize their
susceptibility to undue i n f l u e n c e s and unnecessary risks (physical,
p s y c h o l o g i c a l , e t c . ) a s research subjects.
Rationale for the conduct of the proposed study should be backed with references
to literature.

2.8 STUDY OBJECTIVES

A d e s c r i p t i o n o f t h e o b j e c t i v e s a n d p u r p o s e ( g o a l s ) t h a t t h e t r i a l i s designed
to answer should be detailed:

n Main objective (Hypothesis or hypotheses to be tested)

The primary objectives of any study should be clear and explicitly stated. The
primary question may be framed in the form of testing a hypothesis b e c a u s e m o s t o f
t h e t i m e a n i n t e r v e n t i o n i s p o s t u l a t e d t o h a v e a particular outcome that, on
the average, will be different from the outcome in a control group. The outcome
may be a beneficial action such as ameliorating an illness, reducing symptoms or
improving quality of life. The primary variable should be the variable capable of
providing the most clinically relevant and convincing evidence directly related to the
primary objective of the trial. There should generally be only one primary variable. This
will usually be an efficacy variable, because the primary objective (for most
confirmatory trials) is to provide strong scientific evidence regarding efficacy. There
should be sufficient evidence that the primary variable can provide a valid and
reliable measure of some clinically relevant and import ant t reat ment benef it in
the patient population described by the inclusion and exclusion criteria. The primary
variable should generally be the one used when estimating the sample size.
The primary variable should be specified in the protocol, along with the rationale for its
selection. Redefinition of the primary variable after unblinding is unacceptable, since
the biases this introduces are difficult to assess. When the clinical effect defined by
the primary objective is to be measured in more than one way, the protocol should
identify one of the measurements as the primary variable on the basis of clinical
relevance, importance, objectivity, and/or other relevant characteristics, whenever
such selection is feasible

 Secondary objective(s) (optional)

Secondary variables are either supportive measurements related to the primary

objective or measurements of effects related to the secondary objectives. Their
predefinition in the protocol is also important, as well as an explanation of their
relative importance and roles in interpretation of trial results. The number of
secondary variables should be limited and should be related to the limited number
of questions to be answered in the trial.
 S t a t e w h e t h e r t h e s t u d y i s i n t e n d e d t o s h o w s u p e r i o r i t y , equivalence or
non- inferiority over the comparator

Trials to Show Superiority

Scientifically, efficacy is most convincingly established by demonstrating s u p e r i o r i t y t o
p l a c e b o i n a p l a c e b o - c o n t r o l l e d t r i a l , b y s h o w i n g superiority to an active control
treatment or by demonstrating a dose-response relationship. For serious illnesses,
when a therapeutic treatment which has been shown to be efficacious by superiority
trial(s) exists, a placebo-controlled trial may be considered unethical. In such case the
scientifically sound use of an active treatment as a control should be considered.
Active comparators should be chosen with care. An example of a suitable active
comparator would be a widely used therapy whose efficacy in the relevant indication
has been clearly established and quantified in well designed and well documented
superiority trial(s) and which can be reliably expected to exhibit similar efficacy in
the contemplated active control trial. To this end, the new trial should have the
same important design features (primary variables, the dose of the active
comparator, eligibility criteria, etc.) as the previously conducted superiority trials in
which the active comparator clearly demonstrated clinically relevant efficacy, taking
into account advances in medical or statistical practice relevant to the new trial.

Trials to Show Equivalence or Non- inferiority

In some cases, an investigational product is compared to a standard treatment
without the objective of showing superiority. This type of trial is divided into two
major categories according to its objective;

a. One is an 'equivalence' trial, and the other is a

b. 'Non- inferiority' trial.
Bioequivalence trials fall into the former category. Many active control trials are
designed to show that the efficacy of an investigational product is no worse than
that of the active comparator, and hence fall into the latter category.
Active control equivalence or non- inferiority trials may also incorporate a placebo, thus
pursuing multiple goals in one trial; for example, they may establish superiority to
placebo and hence validate the trial design and simultaneously evaluate the degree
of similarity of efficacy and safety to the active comparator. There are well known
difficulties associated with the use of the active control equivalence (or non-
inferiority) trials that do not incorporate a placebo or do not use multiple doses of
the new drug. These relate to the implicit lack of any measure of internal validity (in
contrast to superiority trials), thus making external validation necessary. The
equivalence (or non- inferiority) trial is not conservative in nature, so that many flaws
in the design or conduct of the trial will tend to bias the results towards a conclusion of
equivalence. For these reasons, the design features of such trials should receive
special attention and their conduct needs special care. For example, it is especially
important to minimise the incidence of violations of the entry criteria, non-compliance,
withdrawals, losses to follow- up, missing data and other deviations from the
protocol, and to minimise their impact on the subsequent analyses.
It is vital that the protocol of a trial designed to demonstrate equivalence or non-
inferiority contain a clear statement that this is its explicit intention. An equivalence
margin should be specified in the protocol; this margin is the largest difference that
can be judged as being clinically acceptable and should be smaller than differences
observed in superiority trials of the active comparator. For the active control
equivalence trial, both the upper and the lower equivalence margins are needed,
while only the lower margin is needed for the active control non- inferiority trial. The
choice of equivalence margins should be justified clinically.
Trials to Show Dose- response Relationship
Another possibility is a trial in which multiple doses of the investigational drug are
compared with the recommended dose or multiple doses of the standard drug. The
purpose of this design is simultaneously to show a dose- response relat ionship
for the investigational product and t o compare the investigational product with the
active control.

How response is related to the dose of a new investigational product is a question to

which answers may be obtained in all phases of development, and by a variety of
approaches. Dose- response trials may serve a number of objectives, amongst which
the following are of particular importance:
n the confirmation of efficacy
n the investigation of the shape and location of the dose- response curve
n the estimation of an appropriate starting dose
n the identification of optimal strategies for individual dose
adjustments
n t h e d e t e r m i n a t i o n o f a m a x i m a l d o s e b e y o n d w h i c h a d d i t i o n a l benefit
would be unlikely to occur

These objectives should be addressed using the data collected at a number of

doses under investigation, including a placebo (zero dose) wherever appropriate. For
this purpose the application of procedures to estimate the relationship between dose
and response, including the construction of confidence intervals and the use of
graphical methods, is as important as the use of statistical tests. The hypothesis
tests that are u s e d m a y n e e d t o b e t a i l o r e d t o t h e n a t u r a l o r d e r i n g o f d o s e s o r
t o particular questions regarding the shape of the dose- response curve (e.g.
monotonicity). The details of the planned statistical procedures should be given in the
protocol.

2.8.1 EFFEACY PARAMETERS

The endpoints are used to satisfy the objective of the study. Although many
efficacy measurements for most diseases are known, a specific test(s) should be
used to provide the most definitive data. This should be acceptable, available and
reproducible. Primary endpoints are usually the key efficacy parameters to be
studied. Secondary endpoints usually contain efficacy variables with lower clinical
significance and also the safety parameters of the trial. Various types of criteria may
be used to measure efficacy parameters.
n Presence or absence or reduction of a symptom, sign or lesion within a
timeframe
n Graded or scaled criteria, for e.g. visual scale or questionnaire
n Relative change criteria, for e.g. biochemical measurements
n Change in quality of life
In chemoprevention studies, endpoints usually fall into the following categories.
Depending on the study hypotheses and design, efficacy endpoints may include an
incidence of invasive or pre-invasive disease.
e.g., polyp incidence); clinical response (e.g., change in number and severity of
leukoplakia by physical examination); and histological or cytological response (e.g.,
change in severity of dysplasia in biopsy materials).

Methods for assessment must be described briefly and referenced in this section with detailed
descriptions of laboratory and/or other procedures.

2.9 STUDY DESIGN

Study design, by definition, incorporates matters of the scientific issues that are relevant to
completion of the study and the patient care.

2.9.1 TYPE OF TRIAL

n Pilot, efficacy or pharmacokinetics

2.9.2 DESIGN

· Parallel, crossover, factorial design, or black- box design

The most common and most straight forward statistical design used in clinical trials is the
parallel design. Here the patients are assigned to one of two or more arms, each arm being
allocated a different treatment. These treatments will include the investigational product at
one or more doses, and one or more control treatments, such as placebo and/or an active
comparator.
In crossover design, each group will receive both treatments, so each group can be
compared with itself as well as to the other group. It starts off like a parallel design, but
halfway through; the groups switch to the other treatment. Since many drugs have residual
effect or a long half life, a wash out period before the onset of the second part of the study
is needed. This simple manoeuvre is attractive primarily because it reduces the number of
subjects and usually the number of assessments needed to achieve a specific power, sometimes
to a marked extent. In the simplest 2x2 crossover design each subject receives each of two
treatments in randomised order in two successive treatment periods. When the crossover
design is used it is therefore important to avoid carryover. This is best done by selective and
careful use of the design on the basis of adequate knowledge of both the disease area and the
new medication. The disease under study should be chronic and stable. The relevant
effects of the medication should develop fully within the treatment period. The washout
periods should be sufficiently long for complete reversibility of drug effect.
A common, and generally satisfactory, use of the 2x2 crossover design is to demonstrate the
bioequivalence of two formulations of the same medication.

In a factorial design, two or more treatments are evaluated s i m u l t a n e o u s l y

t h r o u g h t h e u s e o f v a r y i n g c o m b i n a t i o n s o f t h e treatments. The simplest
example is the 2x2 factorial design in which subjects are randomly allocated ID one
of the four possible combinations of two treatments, A and B say. These are: A alone; B
alone; both A and B; neither A nor B. In many cases this design is used for the specific
purpose of examining the interaction of A and B. The statistical test of interaction may
lack power to detect an interaction if the sample size was calculated based on the
test for main effects. This consideration is important when t his design is used f or
examining the joint effects of A and B , in particular, if the treatments are likely to
be used together.
The study of traditional medicine can also be undertaken in a "black- box" manner. This
means that the treatment and all of its components are delivered as they would be
in the usual clinical situation. In this type of study, no component of the treatment
"package" is isolated and studied independently. This allows the effectiveness of
traditional medicine to be determined either within its own theoretical framework or within
that of conventional medicine.
2.9.3 RANDOMISATION SCHEME

Randomisation is the method by which study patients are randomly assigned to

treatment groups. A code scheme can be generated by a validated computer
program (MS Excel® or SampsizeC). Randomisation minimizes bias by ensuring that
there is no determined pattern in the way patients are assigned to the treatment
groups. A blind can also be broken during a SAE without having to break other patient's
blinds.
2.9.4 CONTROLLED OR UNCONTROLLED

Control groups are used in clinical trials as a baseline against which to compare a
new treatment to test that is both safe and effective. The different types of control
groups used are – placebo, active comparator or hist orical cont rol. I n some
countries and hospitals, there are et hical issues that restrict the use of clinical
trials. In some cases, the use of a placebo is even illegal, particularly for patients
suffering from certain illnesses, such as cancer. Therefore, clinical trials must
always be conducted within the framework of the prevailing law in a given country or
state.
The version of Declaration of Helsinki adapted in Edinburgh in October 2000 states
in section 29: 'The benefits, risks, burdens and effectiveness of a new method
should be tested against those of the best current prophylactic, diagnostic and
therapeutic methods. This does not exclude the use of placebo, or no treatment
in studies, where no proven p r o p h y l a c t i c , d i a g n o s t i c o r t h e r a p e u t i c m e t h o d
e x i s t s . I n a c t i v e comparator controlled trials, the treatment group is compared
to an already marketed drug or an innovator.

Patients receiving placebo do not merely receive an inert substance but a l s o

r e c e i v e s u p p o r t , c o n c e r n , a n d r e a s s u r a n c e t h a t a s s i s t s t h e therapeutic alliance
and encourages the positive attitude that forms the basis of cognitive treatment.
Response to non-specific factors is seen in all fields of medicine but is particularly
potent in psychiatry. Placebos have been reported to improve subjective and
objective outcomes in up to 30 to 40 percent of patients with a wide range of clinical
conditions, such as pain, asthma, high blood pressure, and even myocardial
infarction'. The placebo response is variable across settings and across time and is
unpredictable. Historical data cannot therefore provide an adequate control for
treatment effects in studies of new drugs.
Sometimes using a placebo would be unethical (infectious disease known to
respond to dug). Attention to diagnosis, severity of illness, and to possible
comorbid conditions is needed in the design and conduct of placebo-controlled
studies in order to optimise the chance of obtaining valid data.
2.9.5 SNGLE SITE OR MULTEENTER

Multicenter trials are carried out for two main reasons. Firstly, a multicentre trial is
an accepted way of evaluating a new medication more efficiently; under some
circumstances, it may present the only practical means of accruing sufficient subjects
to satisfy the trial objective within a reasonable time-frame. Multicenter trials of this
nature may, in principle, be carried out at any stage of clinical development. They may
have several centers with a large number of subjects per centre or, in the case of a rare
disease; they may have a large number of centers with very few subjects per centre.
Secondly, a trial may be designed as a multicenter (and multi- investigator) trial
primarily to provide a better basis for the subsequent generalization of its findings.
This arises from the possibility of recruiting the subjects from a wider population and
of administering the medication in a broader range of clinical settings, thus
presenting an experimental situation that is more typical of future use. In this case
the involvement of a number of investigators also gives the potential for a wider
range of clinical judgment concerning the value of the medication.
If a multicenter trial is to be meaningfully interpreted and extrapolated, then the
manner in which the protocol is implemented should be clear a n d s i m i l a r a t a l l
c e n t e r s . P r o c e d u r e s s h o u l d b e s t a n d a r d i z e d a s completely as possible.

2.9.6 BLINDED OR OPEN

• Single or double or triple- blind
Blinding is those methods to reduce bias by preventing observers and/or experimental
subjects involved in an analytic study from knowing the hypothesis being
investigated, the case-control classification, the assignment of individuals or
groups, or the different treatments being provided. The Investigator, subject,
Monitor and the statistician can be blinded. With blinding, introduction of bias by
the investigator (in terms of enrolment) and by the subject (in terms of
response to the treatment) can be reduced.

2.9.7 SCHEMATIC DIAGRAM

n Software like Microsoft Visio® can be used to illustrate the study design

2.9.8 INCLUSION / EXCLUSION CRITERIA

Inclusion/exclusion criteria constitute the definition of patient characteristics
required for entry into the study. Care should be taken while defining the criteria.
If the inclusion criteria is too broad, a heterogeneous group of patients may be
enrolled which may dilute the objective of the study. If the limits are too narrow,
enrolment of patients may take a longer time but a homogenous population may
be included. For phase 2 clinical trial, a homogeneous population would provide more
meaningful data and interpretations.
Some of the criteria used to determine patient inclusion/exclusion are listed
below:
n Age
n Gender
n Race or ethnic background
n Education
n Occupation
n Weight
n Social and economic status
n Pregnancy and lactation
n Use of tobacco, caffeine, alcohol, narcotics –their abuse or misuse
n Diet and nutritional status
n Physiological limitations or congenital anomalies
n Genetic disorder
n Concomitant medications
n Washout of concomitant drugs or of the investigational drug (in case of
crossover studies)
n Allergy to a particular drug or agent
n Co-existing or previous history of diseases or conditions relevant to the
present disease/condition
n Surgery or other interventions
n Willingness to participate and comply with the study and/or drug intake
n Previous participation in similar trials
n Window period (for e.g. < 6 hours after the onset of symptoms)
n Relevant abnormal hematology or biochemistry values

2.9.8.1 AGE

Some trials are specific to age, for e.g. paediatric (<12 years), adult (=18 to =65
years) and elderly (>65 years). A 'minor' i.e. below 18 years of age may be included in
the trial with consent from the parent or the legally accepted guardian. Children above
7 years of age must also give their 'assent' or 'affirmation' (verbally and in the
presence of a witness) in addition to consent of the parent.
It has been well known that elderly respond to many of the drugs differently
(pharmacokinetically, and pathologically) than adult. But usually, elderly are
included in many of the trials due to the decrease in the organ function resulting in
frequent adverse effects and events. Some of the drugs which are used in
diseases/conditions prevalent among the elderly (for e.g. dementia) are evaluated in
these groups. It would be necessary to add in more laboratory/clinical investigations
to be on safer side.
2.9.8.2 GENDER

Certain clinical trials are focused on a particular gender (prostate or uterine

diseases). Women of child bearing potential are usually checked for pregnancy
before participation to make doubly sure that they are not pregnant. A pregnancy
waiver form can be used to take an undertaking that appropriate contraceptive
methods will be followed by the trial participant and their partners to avoid
pregnancy. Some drugs are eliminated thru semen which can in turn cause
congenital anomalies in the fetus, so it should also be borne in mind that both the
gender that should avoid pregnancy.
2.9.8.3 RACE OR ETHNIC BACKGROUND

There are racial and ethnic differences in the causes, expression, and prevalence of
various diseases. While obtaining data (demography), information about patient's
ethnic or racial group is imperative for the identification, tracking, and investigation
of the reasons for racial and ethnic dif f erences in t he prevalence and severit y of
disease and in responses to treatment.
Definitions of race and ethnic background have often been applied
inconsistently. The classification scheme used in the 2000 U.S. Census, which is often
used in biomedical research, includes five major groups:

 Black or African American  American Indian or Alaska native

 Asian  Native Hawaiian or other Pacific
 White  Islander

In general, this classification scheme emphasizes the geographic region of origin

of a person's ancestry.

Historically, the greatest force influencing genetic differentiation among humans has
been geography. Great physical distances and geographic barriers (e.g., high
mountains, large deserts, and ocean) have imposed impediments to human
communication and interaction and have led to geographically determined
endogamous (i.e., within-group) mating patterns resulting in a genetic
substructure that largely follows geographic lines. The past two decades of
research in population genetics has also shown that the greatest genetic
differentiation in the human population occurs between continentally separated
groups.
E n d o g a m o u s m a t i n g w i t h i n c o n t i n e n t s h a s g i v e n r i s e t o f u r t h e r subdivisions,
often corresponding to ethnic groups. This subdivision is again partially attributable
to geography but is also associated with social factors, including religion, culture,
language, and other sources of group identification.
The racial or ethnic groups described above do not differ from each other solely in
terms of genetic makeup, especially in a multiracial and multicultural society such
as the United States but not in India.

Socioeconomic status is strongly correlated with race and ethnic background

and is a robust predictor of access to and quality of health care and education,
which, in turn, may be associated with differences in t h e i n c i d e n c e o f d i s e a s e s a n d
t h e o u t c o m e s o f t h o s e d i s e a s e s ' . F o r example, black Americans with end-stage
renal disease are referred for renal transplantation at lower rates than white
Americans.
There are estimated to be at least 15 million genetic polymorphisms 4 , and as yet
undefined subgroups of these polymorphisms underlie variation in normal and
disease traits. The importance of such variation is underscored by the fact that
a change of only a single base pair is required to cause many well- known inherited
diseases, such as sickle cell disease, or to increase the risk of common disorders,
such as Alzheimer's disease.
"Complex" genetic disorders such as asthma, cancer, diabetes, and
atherosclerosis are most likely due b multiple, potentially interacting, genes and
environmental factors and are thus more challenging to study.

The genetic determinants of the majority of these disorders are currently poorly understood, but
the few examples that do exist demonstrate clinically important racial and ethnic differences
in gene frequency.

One of the best- known examples of a gene that affects a complex disease is APOE
(apolipoprotein allele). A patient harboring a variant of this gene, APOE E4, has a
substantially increased risk of Alzheimer's disease. APOE E4 is relatively common and is seen
in all racial and ethnic groups, albeit at different frequencies, ranging from 9 percent in
Japanese populations to 14 percent in white populations to 19 percent in black American
populations'.
Critical examination of the more recent data on multiple sclerosis (MS) prevalence leads to some
revisions of previously held concepts, the most interesting of which is the appreciation of the
greater influence of genetic factors on disease acquisition. The rarity of MS among Samis,
Turkmen, Uzbeks, Kazakhs, Kyrgyzis, native Siberians, North and South Amerindians,
Chinese, Japanese, African blacks and New Zealand Maoris, as well as the high risk among
Sardinians, Parsis and Palestinians, clearly indicate that the different susceptibilities of distinct
racial and ethnic groups are an important determinant of the uneven geographic
distribution of the disease6.
2.9.8.4 EDUCATION

Although a trial subject's education is not usually addressed in the inclusion criteria,
there are studies in which knowing a subject's education becomes significant, for e.g.
trials involving extensive use of questionnaire. The translation from the original questionnaire to a
local language becomes difficult and the knowledge of English could be needed.
2.9.8.5 OCCUPATION

It is necessary to exclude subjects whose occupations involves driving or use of dangerous

machinery in a trial involving drugs causing drowsiness or sedation. If the investigational
drug is meant specifically for occupational health hazard, for e.g. bagassosis (alveolitis
caused by inhaling bagasse – sugarcane dust), then the population involved in that occupation
need to be recruited.
2.9.8.6 WEIGHT

Inclusion or exclusion of a subject based on weight is not a major concern except in

bioavailability, bioequivalence studies and phase 1 clinical trial. The accepted range is
body mass index (BMI) 18-23 kg/sq meter. To be safe, it is better to exclude
extremely thin or obese individuals. Knowing weight as baseline can help in
knowing if there is any loss during the trial period or follow up if the trial is conducted
for a longer duration (year or so).

2.9.8.7 SOCIAL AND ECONOMIC STATUS

Certain diseases and drug abuse are more common in specific social or economic
groups. For e.g. Multiple sclerosis and Sickle-cell disease is prevalent more in the
Zoroastrians (Parsis). Drug abuse is high in the north- eastern states of India.
2.9.8.8 PREGNANCY AND LACTATION

Most clinical trials exclude pregnant and nursing mothers. It is necessary t o t e s t

f o r p r e g n a n c y i n c h i l d b e a r i n g p o t e n t i a l s u b j e c t s a n d u s e pregnancy waiver
forms. Information should be given in the protocol as to w h a t t o d o a n d w h o m t o
r e p o r t i n c a s e a f e m a l e s u b j e c t b e c o m e s pregnant during the trial period or during
follow up.
Specific clinical trials may be conducted in pregnant or lactating mother, for e.g. HN.
The inclusion criteria must be defined with extreme care and caution. Ethical
consideration must be carefully evaluated.
2.9.8.9 USE OF TOBACCO, CAFFIEN, ALCOHOL, NARCOTICS - THEIR ABUSE OR
MISUSE

S o m e t i m e s i t i s n e c e s s a r y t o e x c l u d e s u b j e c t s f r o m t h e t r i a l , i f interactions
between the investigational drug and tobacco or caffeine, alcohol or narcotics
are known and thought to happen. Caffeine is a known CNS stimulant. A restriction
or the amount that is allowable can be mentioned since it could highly impossible for a
person to stop overnight the consumption of caffeine, tobacco, alcohol or narcotics
since all these are addictive substances.
2.9.8.10 DIET AND NUTRITIONAL STATUS

Dietary evaluation is important, as well as assessment of any physical characteristics

that could indicate a nutritional deficiency, such as generalized weakness, fatigue,
muscle wasting, oedema, smooth tongue, mental confusion, paralysis, diarrhoea,
and low haemoglobin and hematocrit levels. Food or specific nutrients may interfere
with the drug action and its bioavailability.
2.9.8.11 WINDOW PERIOD

It is necessary to fix a definite window period for certain trials, for e.g. < 6 hours
after the onset of chest pain for inclusion in to a trial evaluating drug for acute
myocardial infarction since the therapeutic effect may be less as the symptom gets
prolonged.

2.9.8.12 PHYSIOLOGICAL LIMITATIONS OR CONGENITAL ANOMALIES

The criterion of physiological limitations refers to the use of results of certain tests
(laboratory or clinical) as a basis for patient inclusion or exclusion.

2.9.8.13GENETIC DISORDER
Based on the type of trial, patients with genetic disorders (for .e.g. G6PD deficiency)
may or may not be included in the study.

2.9.8.14 CONCOMITANT MEDICATIONS

This section should include the policy on the use of concomitant medications,
including OTC mediations, herbal products or vitamin supplements. Names or
classes of drugs may be exclusively mentioned that the trial subject needs to be
excluded from taking. If a particular drug is known to cause interaction with the
study drug, then that drug must be clearly mentioned in the protocol for
exclusion. Usually concomitant medications are not allowed during phase 1
clinical trial. Care should be taken when trial subjects usually above 40 years of
age are included for a study as they may be taking antihypertensive or oral
hypoglycemic agents concomitantly. Emphasize that all the conmeds be recorded.
2.9.8.15 WASHOUT OF CONCOMITANT DRUGS OR OF THE INVESTIGATIONAL DRUG

Whenever patients are taken off one treatment and a new drug (investigational)
is initiated, for e.g. antihypertensive agents, wash out may be necessary.
Depending up on the half life of the original drug that the patient was taking, a
period of time must elapse to eliminate the effects before the start of the
investigational drug. This could be about four to five half lives. But necessary
precaution should be taken, as the underlying disease or condition may flare up, for
e.g. blood pressure going up when one class of antihypertensive is stopped. In
such cases, tapering of the original drug with slow induction of the trial medicine can
be acceptable.
2.9.8.16 ALLERGY TO A PARTICULAR DRUG OR AGENT

If the trial subject is known to have allergies to the class of drugs that is been
investigated, the same can be mentioned for exclusion.

2.9.8.17 CO- BUSTING OR PREVIOUS HISTORY OF DISEASES OR CONDITIONS

RELEVANT TO THE PRESENT DISEASE CONDITION

History of diseases other than the one been studied may be considered as an
entrance criterion in few trials. Certain patients should be excluded for a trial
because of safety considerations. During phase 4 clinical trials, certain patients
with renal or hepatic disease can be taken as 'special population' and the effects of
the new drug can be studied.
2.9.8.18 SURGERY OR OTHER INTERVENTIONS

Trial subjects who have undergone surgical interventions in the recent past are
usually excluded from the study.

2.9.8.19 IMWNGNESS TO PARTICIPATE AND COMPLY IMTH THE STUDY AND OR

DRUG INTAKE
Willingness to participate in a clinical trial is understood if the trial s u b j e c t s i g n s
t h e i n f o r m e d c o n s e n t f o r m . I f a s u b j e c t i s e x p e c t i n g relocation or is thought not
to be complying with the study visits and requirements, it is better to exclude him/her
from the study.

2.9.8.20 PREVIOUS PARTICIPATION IN SIMILAR TRIALS

It is advisable to exclude any patient who has participated in another similar trial
within a period of 3-6 months to minimize the chance of any carryover effect from the
preceding trial.

2.9.8.21 RE_EVANT ABNORMAL HEMATOLOGY OR BOCHEMISTRY VALUES

C r i t e r i a f o r i n c l u s i o n o r e x c l u s i o n o f a p a t i e n t c a n b e b a s e d o n abnormalities in
the hematological, urine or other related investigations. Sufficient investigations for
safety must be conducted to include or exclude a patient from a trial as baseline and
thereafter to see variations.

In addition to the above, types and details of the equipment to be used for various
tests (physical examination, and laboratory investigations) must be mentioned, for
e.g. stadiometer for measuring height.

2.9.9 CLINICAL EVALUATIONS AND PROCEDURES

2.9.9.1 SCHEDULE OF EVENTS
A tabular depiction of the visits, procedures and activities to be performed at
each visit makes an Investigator or the Research Nurse to easily identify the events
at a particular point of time. A similar tabular format can be inserted after synopsis
page also.

Pre W W Wk W W W W W W Wk Wk Wk Off
- k k2 3 k4 k5 k k k k 9 10 11 12 Study`
Informed
X
consent
Demographics X
Medical
X
history
Concurrent
X X X
meds
Physical exam X X X X X X
Vital signs X X X X X X
Performance
X X X X X X X
status
CBC w/diff X X X X X X X X X X X X X X
Serum
X X X X X X X X X X X X X X
chemistry*#
EKG X X
Study drug
X X X X
admin
 X X
Tumor
X X X X X X X X X X X X X
measurements
Radiologic Radiologic measurements should be performed every
X X`
evaluation week
*Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium,
chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT
[AST], SGPT [ALT], sodium
#: Serum pregnancy test (women of childbearing potential)
c: Off- study evaluation. Two consecutive measurements taken 4 weeks apart must
be used to document progressive disease if the patient is removed from study
(Schedules shown in the Study flow chart/Calendar above are provided as an example
and should be modified as appropriate)

2.9.9.2 PRE- INTERVENTION PROCEDURES OR SCREENING PROCEDURES

Describe in detail all procedures that must be completed for a subject before the
study intervention can be initiated. Include description of run- in procedures, if
applicable. Specify timing relative to tests, meals or start of the treatment.
2.9.9.3 EVALUATIONS DURING THE STUDY INTERVENTION

Indicate what procedures will be completed, and at what stage of the study,
while subject is receiving the study drug(s).

2.9.9.4 EVALUATIONS AT COMPLETION OF STUDY INTERVENTION

Specify what evaluations must be performed when a subject discontinues use of

study agent. These evaluations should be consistent with the endpoints described
in the objectives and statistical analysis sections of the protocol.

2.9.9.5 FOLLOW UP EVALUATIONS

If applicable, specify what evaluations must be performed when a subject is on

follow- up. Follow- up is a protocol-specific evaluation period that occurs after the
subject stops taking the study agent. The section should carefully define and justify the
follow- up period for the protocol. These evaluations should be consistent with the
endpoints described in the objectives and statistical analysis sections of the protocol.
2.9.10 STUDY POPULATION AND TARGET POPULATDN

The main characteristics of the study subjects with particular reference to medical
condition and demographic characteristics and the number of subjects (sample size)
who shall be screened and those who shall be enrolled into the study should be
detailed. The sample size depends on the alpha and beta risks accepted, on the
degree of difference between the principal evaluation criterion to be demonstrated
 between the groups, and on the variance of this criterion in the control group.
These figures should be established before consulting a statistician.
T h i s s e c t i o n s h o u l d i n d i c a t e t h e n u m b e r a n d t h e t y p e o f s u b j e c t s targeted.
The maximum number of patients to be screened and the minimum number of
subjects required to meet the protocol objectives should be given.
2.9.11 WITHDRAWAL / DISCONTNUATION CRITERM

Explain when and how to withdraw subjects
treatment, the type and timing of the data to
whether and how subjects are to be replaced
from trial/Investigational product treatment. If
should specify how replacement subjects would
2.9.12 DOSING SCHEDULE / ADMPDSTFIATDN
from the trial/Investigational product
be collected for withdrawn subjects,
and follow- up for subjects withdrawn
replacement is allowed, the protocol
be assigned to treatment groups.

Description of dosage, frequency and route of administration of the investigational

product(s), and/or comparator should be mentioned in the protocol. Treatment plans
should explicitly identify when treatment (typically dosage) modifications are
appropriate. Treatment modifications and the factors predicating treatment
modification should be explicit and clear. If dose modifications are anticipated,
provide a dose de-escalation schema with treatment modifications expressed as a
specific dose or amount rather than as a percentage of the starting or previous dose.
2.9.13 COMPLANCE
Poor compliance shall always be considered a possible cause of
therapeutic failure so it is necessary that adequate procedures be taken to reduce
this failure. Regimens shall be simplified (e.g., synchronizing multiple medications)
and matched to the patient and parents' schedules, w h e r e p o s s i b l e . C r i t i c a l
a s p e c t s o f t h e t r e a t m e n t p l a n s h o u l d b e emphasized. Early follow- up visits or
phone calls (e.g., in 3 to 4 days) assesses progress and allows prompt correction of
problems.

2.9.14 STUDY DECONTNUATION

A description of the "stopping rules" or "discontinuation criteria" for individual
subjects, parts of trial, and entire trial should be clearly indicated. In the event of
discontinuation, the date of the last treatment, date and time of the latest contact
between Investigator and study subject, and reason for and name of the person who
made the decision to discontinue should be mentioned. Procedures should also be
mentioned if the study is prematurely terminated by the Sponsor.
· When and how to withdraw subjects?
· What i s t h e t y p e a n d t i m i n g o f t h e d a t a t o b e c o l l e c t e d f o r
withdrawn subjects?
· Are subjects replaced? If so, how?
· What is the follow- up, if any, for subjects withdrawn?

2.9.15 MONITORNG
General methods to be followed for monitoring should be defined [whether
monitoring will be conducted by the Sponsor or by an independent group]. The
protocol should indicate the extent, nature and schedules of monitoring visits on
considerations such as the objective, design, complexity, sample size and end point
of the study.

2.10 PIVEST1GATIONAL PRODUCT MANAGEMENT

Detailed description of the optimal procedures for labelling, packaging, storage and
dispensing of the study medication should be dealt in this section.

2.10.1 PRODUCT DESCRFMN

Include the available dosage forms, ingredients, and packaging, as appropriate. If
applicable, state the name and address of the third party (Clinical Trial Management
Company) if it is involved in supplying the investigational drug from a different site.
2.10.2 SOLUTDN PFtEPAFtATKIN (How THE DOSE IS TO BE PREPARED)
Include reconstitution directions and directions for further dilution, if appropriate.

2.10.3 STORAGE PROCEDURES AND STABLITY CONSIDERATIONS

Include the requirements for the original dosage form, reconstituted solution, and
final diluted product, as applicable. If reconstituted, the stability in the reconstituted
forms should be specified.

2.10.4 ROUTE OF ADMNISTFtATION

Include a description of the method to be used and the rate of administration, if
applicable, for example, continuous intravenous infusion over 24 hours, short
intravenous infusion over 30 to 60 minutes, intravenous bolus, etc. Specify the infusion
rate. Describe any precautions required for safe administration.

2.10.5 DOSAGE REGIMEN

Clarify the duration of administration, including any medication-free periods or
washout periods. As appropriate, specify the timing of dosing in relation to meals or
conmeds.

2.10.6 DRUG SHIPMENT

The agent must be shipped directly to the institution where the trial is ongoing. The
transfer of study drug between institutions is not permitted. This has to be mentioned
in the protocol.

2.10.7 DRUG ACCOUNTABLITY

The Investigator, or a responsible party designated by the Investigator, must

maintain a careful record of the inventory and disposition of all agents received
from suppliers name using the Drug Accountability Record Form. Describe
instructions for the receipt, storage, dispensation, a n d r e t u r n o f t h e
investigational products to ensure a complete accounting of all
investigational products received, dispensed, and returned/destroyed. Describe
policy and procedure for handling unused investigational products.
2.10.8 BLNDING AND UN- BLNDNG DURNG EMERGENCES

Description of the procedures for maintenance of study randomization codes and

procedures for breaking the codes should be detailed here.

2.11 ADVERSE EVENT (AE)/ SERIOUS ADVERSE EVENT (SAE)

MANAGEMENT

This section should include:

2.11.1 DEFINITION
An Adverse Event (AE) is an unanticipated problem involving "risk" to
subjects that ultimately results in harm to the subject (impacts on
subject's morbidity and mortality) or others. "Adverse Reaction" and
"Adverse Event" are not synonymous.
AE is any unfavorable and unintended sign (including an abnormal
laboratory finding, for example), subjective and objective symptom, or
disease temporally associated with the use of a medicinal product, whether or
not considered related to the medicinal product. "Adverse Event" implies that the
event may be coincidental, whereas "Adverse Drug Reaction" implies that the event was
caused by the drug in question.
Adverse drug reaction is a causal relationship between a medicinal product and
an adverse event is at least a reasonable possibility, i.e., the relationship cannot be
ruled out.

2 . 1 1 . 2 C L A S S F E A T I O N AND ASSESSMENT OF INTENSITY

The intensity and grade of AE/SAES can be assessed accordingly as described

below.
0. None
1. Mild: An experience that is usually transient, & requires no special
treatment or intervention. The experience does not generally interfere with
usual daily activities. Includes transient laboratory test alterations
2. Moderate: An experience that is alleviated with simple
therapeutic treatments. The experience impacts usual daily
activities. Includes laboratory test alterations indicating injury,
but without long-term risk
3 . S e v e r e : A n e x p e r i e n c e t h a t r e q u i r e s t h e r a p e u t i c intervention. The
experience interrupts usual daily activities. If hospitalization is required for
treatment it becomes a serious adverse event

2 . 1 1 . 3 EXPECTED ADVERSE EVENTS

Include a comprehensive list of all known risks and any potential risks (such as the
toxicities seen with another agent of the same class or risks seen in animals
administered this agent).

2.11.4 PROCEDURES AND MIELPIES

The Principal Investigator (PI) is responsible for tracking events, including new soft
risks, physical and psychological symptoms, for all subjects in a research study. It is
only through diligent recording of these events and/ or symptoms that serious and
unexpected side effects or reactions can be identified. Describe the procedures
(including the hotline number) for recording adverse events and also the timelines for
reporting of AEs or SAES. Give numbers (day and night) on which the investigator can call
for emergencies.
Any serious and unexpected adverse events associated with the study
intervention that occur on-site must be reported to the IRB

2 . 1 1 . 5 INTERPRETATION OF CAUSALITY

Assessments of whether a given study drug causes a particular adverse reaction

vary from the casual observation to the carefully controlled study. An assessment
that a particular report was possibly due to the administration of a vaccine is not an
indication that there should be a concern about immunization, but more often
represents a rare but expected event that is known to occur with the vaccine. By
reviewing a large number of cases in a careful manner, a potential signal (indicating a
suspicion that a vaccine may be causing a particular event that previously has not
been well described) can be identified.
The degree of certainty with which an adverse event can be attributed to Study
administration (or alternative causes, e.g. natural history of the underlying diseases,
coexisting disease, concomitant therapy, etc.) will be determined by how well the event
can be understood.
The relationship of an adverse event b Investigational products can be classified as
below:
n Definite: The adverse event is clearly related to the intervention and can be
confirmed by improvement on stopping or reducing the dosage of the
Investigational products, with reappearance of the reaction on repeated
exposure (rechallenge)
n Probable: The adverse event is likely related to the intervention
n Possible: A causal relationship to the intervention cannot be ruled out
n Unrelated: The adverse event is clearly not related to the
intervention

2 . 1 1 . 6 ASSESSMENT OF OUTCOME

The outcome can be assessed as:

1 = Recovered with or without treatment
2 = Event continuing with or without treatment
3 = Died
 4 = Unknown causes

2.11.7REPORTNG

All adverse events (AEs) occurring with any patient participating in the clinical
trial must be reported to the Sponsor or CR0 responsible. The details (contact
person and address) of the same should be given. AE reports must be filed with the
Sponsor and the Institutional Review Board (IRB) when any of the following happens to a
subject on a study:
· Death
· U n a n t i c i p a t e d " r i s k " r e q u i r i n g t r e a t m e n t , h o s p i t a l i z a t i o n o r prolongation of
existing hospital stay
· Any suspicious findings that may have relationship to the study
· A d v e r s e p r e g n a n c y o u t c o m e b e f o r e , d u r i n g a n d a t t h e t i m e o f delivery
· Birth defects or congenital anomaly
· Loss of research records that contain identifiable information
· Overdose of drug
· Unusual frequency or intensity of expected effects described in the informed consent
document or trends in one type of AE event toward within a protocol (serious or
not)
· Breach of confidentiality
· Unanticipated problems involving risks to "others" (Example: A nurse in a
research study is inadvertently stuck by a needle c o n t a i n i n g a
c h e m o t h e r a p e u t i c a g e n t t h a t i s t e r a t o g e n i c , mutogenic, etc.)
· Abnormal test results that is critical to evaluate the "risk" or "safety" of subjects
· U n e x p e c t e d – a n y a d v e r s e e x p e r i e n c e t h a t i s n o t i d e n t i f i e d i n nature,
severity or frequency in the consent form and is not due to a disease process.
The sponsor should expedite the reporting to all concerned
investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the
regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious
and unexpected. Such expedited reports should comply with the applicable
regulatory requirement(s) and with the ICH Guideline for Clinical Safety Data
Management: Definitions and Standards for Expedited Reporting. The sponsor should
submit to the regulatory authority(ies) all safety updates and periodic reports, as
required by applicable regulatory requirement(s). Schedule Y of Drugs & Cosmetics Act,

2.12 DATA MANAGEMENT AND STATETICAL ANALYSE

This section should include:
n Indicate specific documents in which the original patient data will be
captured (e.g. source document given by the sponsor or the hospital
records) and the methodology for completing the same
n Data collection and processing
n The selection of subjects to be included in the analyses (e.g. all randomized
subjects, all dosed subjects, all eligible subjects, evaluable subjects, drop-
outs, etc)
n Specify the study design and primary endpoints
n If secondary endpoints are included in this study, specify how they will be
 analyzed. In particular, brief descriptions should be given of analyses of
pharmacokinetic, biologic, and correlative laboratory endpoints
n Specify the planned sample size and accrual rate (e.g., total target accrual and
annual target accrual. Justify the choice of sample size and the power
calculation. In multicenter trials, the numbers of enrolled subjects projected for
each trial site should be specified

Clinical trials should have sufficient statistical power to detect differences between
groups considered to be of clinical interest. It should be remembered that a
sample size calculation provides only an estimate of the needed size of a study.
Because of the approximate nature of sample s i z e c a l c u l a t i o n s , t h e i n v e s t i g a t o r /
b i o s t a t i s t i c i a n s h o u l d b e a s conservative as can be justified while still being
realistic in estimating the parameters used in the calculation. If the sample size is
drastically overestimated, the trial may be judged as unfeasible, may waste time,
resources and money. If the sample size is underestimated, there is a good
chance the trial may lead to inaccurate results. In general, as long as the
calculated sample size is realistically obtainable, it is better to overestimate the size
and possibly terminate the trial early than to underestimate and arrive at incorrect
conclusions.
Sample size estimation depends on assumptions made about variability of the
response, level of response in the control group, and difference anticipated or
judged to be clinically relevant. Reliable estimates can be obtained from previous
studies, if not pilot or feasibility studies may be conducted to obtain these data.

n Level of significance to be used

In normal English, "significant" means important, while in statistics "significant"
means probably true (not due to chance). A research finding may be true without
being important. Significance tests are performed to s e e i f t h e n u l l h y p o t h e s i s c a n
b e r e j e c t e d . I f t h e n u l l h y p o t h e s i s i s rejected, then the effect found in a sample
is said to be statistically significant. If the null hypothesis is not rejected, then the
effect is not significant. When statisticians say a result is "highly significant" they
mean it is very probably true. They do not (necessarily) mean it is highly important.
Significance levels show you how likely a result is due to chance. The most
common level, used to mean something is good enough to be believed, is 0.95.
This means that the finding has a 95%chance of being true. The 95%confidence
level means you can be 95%certain. However, this value is also used in a
misleading way. No statistical package will show you "95% or ".95" to indicate this
level. Instead it will show you ".05," meaning that the finding has a five percent
(.05) chance of not being true, which is the converse of a 95% chance of being true.
The significance level is most commonly set at 5%or p=0.05, where p stands for
probability.
n Procedure for accounting for missing, unused, and spurious data
n P r o c e d u r e s f o r r e p o r t i n g a n y d e v i a t i o n ( s ) f r o m t h e o r i g i n a l statistical
plan
n Give complete details of how the results will be analyzed and reported along
with the description of statistical tests to be used to analyze the primary and
secondary endpoints defined above
n Rationale and conditions for any interim analysis if planned
n Any deviation(s) from the original statistical plan shall be described
 and justified in protocol and/or in the final report, as appropriate
n D e s c r i b e s t a t i s t i c a l c o n s i d e r a t i o n s f o r P h a r m a c o k i n e t i c ( P K ) analysis, if
applicable

2.13 ETHICAL CONSDERATIONS AND ISSUES

All research involving human subjects should be conducted in accordance with the
ethical principles contained in the current version of the Declaration of Helsinki.
Three basic ethical principles should be respected, namely justice, respect for
persons, and beneficence (maximizing benefits and minimizing harms and
wrongs) or non-maleficence (doing no harm), as defined by the current revision of the
International Ethical Guidelines for Biomedical Research Involving Human Subjects or the
laws and regulations of the country in which the research is conducted, whichever
represents the greater protection for subjects.
An ethics committee, according to each institution's guidelines should review each
trial.

Prior to initiating the study, the Principal Investigator should provide a signed
Investigator Statement Form stating that the study will be conducted in compliance
with regulations for clinical investigations.

2.13.1 INSTITUTIONAL REVEVV BOARD (MB) APPROVAL

Prior to initiating the study and receiving drug, the PI must obtain written approval to
conduct the study from the appropriate IRB. Should changes to study protocol
become necessary, protocol amendments should be submitted in writing by the PI to
the Sponsor and, when approved, to the IRB for approval prior to implementation.

2.13.2 INFORMED CONSENT

The investigator should be emphasized to obtain consent in written prior t o
s u b j e c t ' s i n v o l v e m e n t i n a n y o f t h e s t u d y r e l a t e d a c t i v i t y . T h e investigator
should be informed that all potential candidates for the study be given a copy of the
study Informed Consent to read. The investigator should explain all aspects of the study
in lay language and answer all the candidate's questions regarding the study. If the
candidate decides to participate in the study, he/she should be asked to sign the
Informed Consent Document.
2.13.3 DATA AND SAFETY MON1TORNG

If Data and Safety Monitoring Board is necessary to oversee the trial, then it should
be mentioned in the protocol. The purpose of the data and safety monitoring plan
is to insure the safety of participants, the validity of data, and the appropriate
termination of studies for which significant benefits or risks have been uncovered or
when it appears that the trial cannot be concluded successfully. The essential
elements of the Data and Safety Monitoring Plan include:
n Monitoring the progress of trial and the safety of participants
n P l a n s f o r a s s u r i n g c o m p l i a n c e w i t h r e q u i r e m e n t s r e g a r d i n g t h e reporting of
adverse events
n Plans for assuring data accuracy and protocol compliance
The names, occupation and address of all the members constituting the DSMB
should be mentioned. The time plan as when the interim safety analysis will be
conducted should be chalked.
2.14 QUALITY ASSURANCE

Quality assurance and control techniques to ensure compliance should be as

detailed below:
n Appropriate and required association with the Institutional Ethics Committee
n Adherence to the protocol
n Allow the regulatory authorities to access the records, facilities and other trial-
related resources
n Keeping all data related to the clinical trial accessible to Monitor and
Sponsor's audit
2.15 PUBLICATION POLLY

Procedures and policies, relating to publication of clinical trial results should be

described here if not in a separate agreement. 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.
2.16 PRIVACY OF PERSONAL DATA

Statements shall be drafted to describe the confidentiality of subject data

2.17 CONTRACT AND NSURANCE

D e t a i l s o f f i n a n c i n g t h e s t u d y a n d I n s u r a n c e , i f n o t a d d r e s s e d i n a separate
agreement shall be incorporated here
2.18 ARCHIVAL OF DATA

n Details of the archiving procedures at the study site, and ACT shall be
mentioned. In case, the study site is not able to handle the large volume of
documents, arrangements to archive the same shall be mentioned
2.19 REFERENCES

n List all references

The style of references should be that of Index Medicus. References should be
numbered consecutively in the order in which they are first mentioned in the text.
Also foot note can also be inserted at the bottom of each respective page. List all
authors by their last name first followed by their first name in initials when there
are three or fewer; when there are four or more, list the first three, then "et al." The
following is a sample reference:
1. Lahita R, Kluger 3, Drayer DE et al. Antibodies to nuclear antigens in patients treated
with procainamide or acetylprocainamide. N Engl 3 Med 1979; 301: 1382-5
2.20 APPENDICES
n List of laboratory reference (normal) values
n Laboratory procedures
n Labelling details/procedures
n Declaration of Helsinki (October 2000)
n Classification of disease/condition
n ICH- GCP E6 guidelines
n CDSCO Good Clinical Practice guidelines for Clinical Research in India
n Information to patient and Consent Form
n Adverse Event terminology (Common Toxicity Criteria, WHO-ART)

Informed Consent
Informed consent in ICH is defined as a process by which a subject voluntarily confirms his or
her willingness to participate in a particular trial after having been informed of all aspects of the
trial that are relevant to the subject's decision to participate. Informed consent is documented
by means of a written, signed, and dated informed consent form. Process is as important, or
more important, than the documentation, but both elements need to be present.
In obtaining and documenting informed consent, the investigator should comply with the
applicable regulatory requirements. The investigator should also adhere to good clinical
practices and to the ethical principles that have their origin in the Declaration of Helsinki.
Prior to the beginning of a trial, the investigator must obtain from the Institutional Review Board
(the IRB) written approval and favorable opinion of the written informed consent form and any
other written information to be provided to the subject. This is not a one-time event. In the
conduct of clinical research new information frequently becomes available that is relevant.
Accordingly, revisions to the informed consent will need to be submitted to the IRB for re-
approval and then taken, once they are approved, to the subject for re-consenting.
The intention of the informed consent process is to transmit study information from the
investigator to the subject or his or her legal representative. It requires that the subject clearly
understands the risks, the alternative treatments, the potential benefits, the obligations as a
subject, and that the study involves research. It must be emphasized that reading and signing
the consent form does not assure comprehension, and to provide the information necessary to
assure comprehension is a major responsibility of the investigator and the investigator's
research team.

The subject must be treated as an autonomous agent. The subject must be allowed to make a
voluntary decision without coercion, and consent must be obtained prior to any study-related
procedures. The consent should not contain any language waiving the subject's legal rights.
Adequate information must be provided. One must also provide an opportunity for the subject
to consider options and ask questions. The individual administering the consent process must
be assured that the individual that is being asked comprehends what is going on. The clinical
investigator must obtain voluntary agreement and must supply ongoing information.
The final step is documentation of the subject's agreement to participate. The consent form
must be approved by the IRB, and the investigator is ultimately responsible for obtaining
consent.
All oral and written information must be understandable to the subject. Information must be
provided in a language in which the subject is fluent. Medical terms must be clearly explained in
language that is understandable to non-medical individuals. The subject will be provided a copy
of the consent form. As previously mentioned, if amendment of the consent form is necessary it
needs to be reapproved by the IRB and then re-signed by all ongoing subjects.

Trials that have no anticipated direct clinical benefit for the subject should be conducted in
subjects who can personally give consent and who can sign and date the written informed
consent form. Trials which have no anticipated direct clinical benefit may be conducted in a
subject with the consent of a legally-acceptable representative provided the objectives of the trial
cannot be met by means of a trial in a subject who can give informed consent personally.
Additionally, the risks to the subject must be very low; the negative impact must be minimal.
The trial must not be prohibited by law, and, perhaps most important, the IRB has given written
approval and a favorable opinion of the trial.

In an emergency situation, when prior consent of the subject is not possible, the consent
of a legally acceptable representative should be requested if one is available. If a legally
acceptable representative is not available, the subject can still be enrolled if it is to the subject's
best clinical interest. The subject and/or the legally acceptable representative should be informed
of the trial and sign a written informed consent form as soon as possible.

When a subject can only be included in a trial with the consent of a representative, for
example, if children or persons with severe mental disabilities or dementia are involved, the
subject still should be informed about the trial to the extent of his or her understanding. If
capable, the subject should sign and date the informed consent form.

If the subject or representative is unable to read, an impartial witness should be present

during the entire informed consent discussion. After the subject has orally consented to the trial,
or he or the representative have signed and dated the consent form, the impartial witness then
signs, attesting
that all trial information was clearly explained to the subject or representative.

The elements that must be included on the informed consent document.

it should be clearly stated that the trial involves research. The purpose of the trial should
be outlined. The possibility of random assignment and the trial procedures that will be
necessary, including follow-up visits, must be clearly stated. The experimental aspects of the
trial and the possible risks and the reasonably expected benefits should be clearly stated, along
with the alternative procedures available to the subject if he or she chooses not to take part in
the trial.

Available compensation in the event of injury should be clearly stated. Payment, if any, to
the subject for participation in the trial should be outlined. Anticipated expenses, if any,
should be clearly stated. It should be stated that the subject's involvement in the trial is voluntary
and, of great importance, it should be clear that the subject may withdraw from the trial at any
particular time.
 it should be clearly stated in the document that the persons who will be granted direct
access to the subject's medical information are clearly outlined, that the identification of the
individual subjects will be kept confidential, and that the subject and/or his or her representative
will be informed when any new information becomes available.

The name of a person or persons to contact for further information or for emergency
situations should be made available on the document and on a separate piece of paper, if
requested by the subject, in which telephone contact numbers and/or e-mail addresses are
provided. Also, it is important to state any reasons that a subject might be terminated from the
trial.
The expected duration of the trial should be defined, and the approximate
number of subjects that will be included in the trial should be outlined. The subject needs to
understand and agree that the data collected will be reported and transferred as part of the
trial analysis but that the subject will not be uniquely identified and that his/her data will be
used even if the subject withdraws from the trial.

Once the informed consent document is signed and the study has progressed, an issue
that comes up commonly is document retention. The rules are very clear. A master copy of
each version of the informed consent form should be filed along with its approval with the trial
documents. The signed, completed informed consent form should be filed with the subject's trial
file or medical records, as is appropriate.

The International Conference on Harmonization has legislated that all trial documents
must be retained for at least two years after the last approval of a marketing application. In
truth, one should be very reluctant to ever discard or destroy trial documents. If you do wish
to discard or destroy trial documents, you should seek a discussion about the subject with the
sponsor of the trial.

Introduction:

What is informed consent?

When most people hear the phrase “informed consent,” they think of the legal document that
explains the study and contains the required dated signatures. However, informed consent is
first and foremost a process by which a person voluntarily agrees to participate in a research
study after being fully informed about it.

The informed consent document should contain all of the information that the person needs to
make an informed decision about taking part in the study. Many research teams use the
consent document to guide the verbal explanation of the study to potential participants.

The participant must sign and date the informed consent document before taking part in any
study procedures. Signing the consent form is NOT the final step in the informed consent
process. The participant may withdraw consent and decline to participate in the study at any
time before or after signing the consent document until their participation in the study is
completed.

Part 1 of this module deals with the informed consent document. Part 2 deals with the informed
consent process.

Part 1: The informed consent document

A close look at a sample consent form (1)

1. Study purpose
The consent document must state (ICH GCP 4.8.10).

a. That the trial involves research.

b. The purpose of the trial.

Study purpose

You are invited to take part in a research study involving pregnant substance users.

The purpose of this study is to compare two types of alcohol/drug counseling. One type of
counseling is called Motivational Enhancement Therapy. The other is standard care as provided
at Hospital, referred to as Treatment as Usual.

The study is being done to find out if one method works better to keep patients in treatment and
to help them stop using alcohol or drugs.

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2. Study treatment and randomization
The consent document must state (ICH GCP 4.8.10).

c. The trial treatment(s) and the probability for random assignment to each treatment (if a
randomized clinical trial).

Study Treatment

If you enroll in the study, you will be randomly (by chance, like the flip of a coin) assigned to
either Treatment as Usual or Motivational Enhancement Therapy. You have an equal chance of
being assigned to either treatment group.

Treatment As Usual
If you are assigned to Treatment as Usual, you will receive the treatment normally given at this
clinic. This will include at least 3 individual sessions that will focus on helping you to understand
the requirements of the treatment program and helping you with overcoming alcohol or drug
use.

You may also receive other individual or group counseling that is standard at Anytown
Community Mental Health Center and not part of this study. The clinic staff will explain the
program to you.

Motivational Enhancement Therapy

If you are assigned to Motivational Enhancement Therapy, you will be asked to attend 3
individual counseling sessions within a 4-week period.

During these sessions, you will be asked about what you see as problems connected with your
substance use. If you express a desire to change, you will be encouraged to make a plan for
changing your behavior. Each of these sessions will be about 1 hour long. In addition to these 3
counseling sessions, you may also receive other individual or group counseling that is standard
at Hospital and not part of this study. The clinic staff will explain the program to you.

3. Study procedures

The consent document must state (ICH GCP 4.8.10).

d. The trial procedures to be followed, including all invasive procedures.

e. The participant’s responsibilities.

f. Those aspects of the trial that are experimental.

s. The expected duration of the participant’s participation in the trial

Study procedures

If you agree to be in this study, you will attend a total of 8 research visits, including today’s visit.
This section describes these research visits, the study treatments, and additional study
procedures.

Research Visits

Research Visit 1
Today’s visit is the first research visit. This visit should take about 2 hours. After you sign this
informed consent form, study staff will ask you questions and do some tests to find out if you are
eligible (able) to take part in the study. This will include finding out that

 You are pregnant, as confirmed by a positive urine pregnancy test,

 You are 18 years of age or older, and

 You are likely to be able to attend the treatment sessions.

Study staff will also ask you questions to find out whether you meet any of the conditions that
would make you ineligible for the study (unable to take part). These include

 You are likely to enter residential treatment,

 You are unlikely to complete the entire study (e.g., you are planning to move away from
the area, you are facing legal charges likely to result in a jail sentence, etc.),

 You are in danger of harming yourself or another person.

In addition, we will ask questions and do some tests that will be repeated at future visits. These
will include questions about

 Your recent alcohol and drug use. You will be asked to give a urine sample and take a
test for alcohol on your breath.

 Your thoughts and attitudes about quitting and your thoughts and beliefs about whether
you can remain alcohol and drug free after you quit.

We hope to do all these things today. If we do not finish today, we will ask you to come back on
another day.
Research Visit 2
You will be asked to attend Research Visit 2 within 7 days of Visit 1. This visit should take about
1-1½ hours. Research Visit 2 will include

 Questions to find out if you have an alcohol or drug problem.

 Questions about any problems you are having or have had in any of the following areas:
medical, school or work, alcohol or drug use, legal, family, and mental health.

 Questions about behavior that could lead to HIV infection.

Research Visits 3, 4 and 5

You will be asked to attend research visits weekly for 3 weeks. These will be Visits 3, 4, and 5.
Each visit should take about 30-45 minutes. At each of these visits you will be asked questions
about

 Recent alcohol and drug use. You will be asked to give a urine sample and to take a test
for alcohol on your breath.

 Your attendance at treatment and the treatment services that you have received.

In addition, during one of these visits you will be asked how you feel about your clinician.

Research Visit 6
You will be asked to attend Research Visit 6 one to two weeks after Research Visit 5 . This visit
should take about 1-1½ hours. During this visit you will be asked questions about

 Recent alcohol and drug use. You will be asked to give a urine sample and to take a test
for alcohol on your breath.

 Your thoughts and attitudes toward quitting and your thoughts and beliefs about whether
you can remain alcohol and drug free after you quit.

 Any problems you are having or have had in any of the following areas: medical,
school/work, alcohol/drug use, legal, family, and mental health.

 Behavior that could lead to HIV infection.

 Your attendance at treatment and the treatment services you have received.

 Your satisfaction with the treatment you have received.

Research Visit 7 and 8
You will be asked to attend Research Visit 7 about 1 month after Visit 6. You will be asked to
attend Research Visit 8 about 2 months after Visit 7. Each of these visits should take about 1
hour. At each of these visits, you will be asked questions about

 Recent alcohol and drug use. You will be asked to give a urine sample and take a test
for alcohol on your breath.

 Any problems you are having or have had in any of the following areas: medical, school
or work, alcohol or drug use, legal, family, and mental health.

 Behavior that could lead to HIV infection.

 Your attendance at treatment.

Other Procedures

Contact Information
You will be asked to give the names and telephone numbers of several people who are likely to
know where you are in case we need to find you for follow-up visits. These people will be
contacted only if we have looked for you and not been able to find you. You will need to sign a
separate release that gives research staff your written permission to contact these people.

The people whose names you give us will be asked only about where we might be able to find
you. They will not be asked about your drug use or other personal issues. They will not be told
about this study, or about the fact that you are in the study, unless you want us to share this
information with them.

If you want to share information about this study with your contacts, you will need to sign a
separate release that gives research staff your written permission to do so.

Release of Information
The researchers who are doing this study would like to get information about your attendance at
prenatal care appointments. You will be asked to sign a release that allows them to read your
prenatal care records.

The researchers would also like to get information about your attendance at treatment at
Hospital and about efforts that have been made to encourage you to attend. You will be asked
to sign a release that allows the researchers to read your clinical records at Hospital.

Audiotaping
You have been asked to consent to audiotaping of your treatment sessions. All 3 sessions will
be audiotaped.
The sessions are being taped to make sure your clinician is carrying out the treatment properly.
The audiotapes will not be used for any other purpose. Only members of the research team will
listen to the tapes.

You have the right to stop the taping at any time during a session. You also have the right to
request at any time during the trial that all existing tapes of your sessions be erased.

To protect your privacy, audiotapes will be identified by a numeric code only. Your name and
other information that identifies you will be kept confidential. The audiotapes will be kept at Any
State University for 3 years and then will be destroyed.

Your records may also be reviewed for audit purposes by authorized employees of Any State
University or their agents. An audit means that your records or accounts will be examined for
accuracy. Under federal law, anyone who reviews your records must keep the information
confidential.

By signing the consent form for this study, you are giving your consent for your treatment
sessions to be audiotaped.

4. Risks of taking part in the study

The consent document must state (ICH GCP 4.8.10).

g. The reasonably foreseeable risks or inconveniences to the participant and, when

applicable, to an embryo, fetus, or nursing infant.

Risks of taking part in the study

Taking part in the study may present some risks.

 Being in this study has the same risks as being in any outpatient alcohol or drug
treatment program. Stopping substance use can be quite difficult. There is no guarantee
that you will be able to stop using because you are in this study.

 You may feel hassled or embarrassed about giving urine samples and answering
questions about your personal habits, lifestyle, and alcohol or drug use. You may refuse
to answer any questions that you do not want to answer. You may unexpectedly meet
friends or associates while in the treatment program or study.

 Loss of confidentiality (people by chance finding out personal information about you) is
another risk of being in this study. For example, a neighbor or friend may see you at the
clinic. We have made every effort to keep your personal information private. For
example, instead of identifying you by name, we use a numeric code. We store your
records in a secured, locked area. However, we cannot absolutely guarantee your
confidentiality.
  Being in the study may present risks and discomforts that are not yet known.

5. Benefits of taking part in the study

The consent document must state (ICH E6 GCP 4.8.10).

h. The reasonably expected benefits. When there is no intended clinical benefit to the
participant, the participant should be made aware of this.

Benefits of taking part in the study

Agreeing to take part in this study may not result in any direct benefit for you. The researchers
hope that the information learned from this study will benefit other substance users in the future.
Potential benefits to you may include help in controlling your alcohol or drug use.

6. Alternatives to taking part in the study

The consent document must state (ICH E6 GCP 4.8.10).

i. The alternative procedure(s) or course(s) of treatment that may be available to the

participant, and their important potential benefits and risks.

Points to note: IRBs often want the informed consent document to list other therapies available
for the condition under treatment, in addition to other treatment options at the facility where the
study is being conducted.

Alternatives to taking part in the study

If you do not want to be in this study, you can still receive the treatment to which you are entitled
at Hospital.

7. Costs of participation and compensation in the event of injury

The consent document must state (ICH E6 GCP 4.8.10).

j. The compensation and/or treatment available to the participant in the event of trial-
related injury.

l. The anticipated expenses, if any, to the participant for participating in the trial.

Points to note: When research involves more than minimal risk to the participant, the consent
document must describe the treatment and compensation that will be provided in the event that
a participant sustains a research-related injury. The language in the consent cannot appear to
limit the participant’s rights in seeking damages related to injury in a trial.
Federal regulations do not limit the definition of “injury” to a physical injury. An injury may be
psychological, social, financial, or of another nature

Costs and compensation

Taking part in this study may lead to added costs for you or your health insurance provider.

If you are physically injured as a result of taking part in this study, you will receive any
necessary medical treatment, which will be billed as part of your medical expenses. You will
have to pay any costs that are not covered by your insurance. You are expected to know, or to
find out, what health insurance you have.

The clinic does not offer money as compensation for injuries. However, by taking part in this
study you are not giving up any legal rights or benefits to which you are otherwise entitled.

8. Payment for taking part in the study

The consent document must state (ICH GCP 4.8.10).

k. The anticipated prorated payment, if any, to the participant for participating in the trial.

Points to note: Payment to participants for their participation in a research study must
never be coercive in either amount or method of distribution.

Payment

You will be paid for taking part in this study. You will be paid ------ for longer research visits
(Visits 1, 2, 6, 7, and 8) and $25 for shorter research visits (Visits 3, 4, and 5). If you complete
all of the study visits, you will be paid a total of ------. Payment will be given as coupons or
vouchers that can be used to buy things at local stores.

9. Voluntary nature of study

The consent document must state (ICH E6 GCP 4.8.10).

m. That the participant’s participation in the trial is voluntary and that the participant may
refuse to participate or withdraw from the trial, at any time, without penalty or loss of
benefits to which the participant is otherwise entitled.

r. The foreseeable circumstances and/or reasons under which the participant’s

participation in the trial may be terminated.

Voluntary nature of study

Taking part in this study is voluntary. You may choose not to take part in the study. You may
also choose to leave the study at any time. Leaving the study will not result in any penalty or
loss of benefits to which you are entitled. You may be required to receive treatment at this
center, but you are not required to take part in this study.

Dr. ABC, the doctor in charge of the study here at Clinic, may stop your participation in the study
at any time. This may be for reasons related solely to you or may be because the entire study
has been stopped.

10. Confidentiality of personal information

The consent document must state (ICH E6 GCP 4.8.10).

n. That the monitor(s), the auditor(s), the IRB, and the regulatory authority(ies) will be
granted direct access to the participant’s original medical records for verification of
clinical trial procedures and/or data, without violating the confidentiality of the participant,
to the extent permitted by the applicable laws and regulations and that, by signing a
written informed consent form, the participant or the participant’s legally acceptable
representative is authorizing such access.

o. That records identifying the participant will be kept confidential and, to the extent
permitted by the applicable laws and/or regulations, will not be made publicly available. If
the results of the trial are published, the participant’s identity will remain confidential.

Confidentiality

Every effort will be made to keep your personal information confidential.

All personal information, including the audiotapes of your treatment sessions, will be coded and
stored in a locked cabinet. Your identity will be held in confidence in any reports of the study
that may be published. However, we cannot guarantee absolute confidentiality. Your personal
information may be disclosed if required by law.

Persons and organizations that may inspect or copy your research records are

 The Principal Investigator (doctor in charge of the study) and his/her research associates
and contracted agents,

 The Lead Investigator and his/her contracted agents,

 Agents of the National Institute on Drug Abuse and of Any State University Institutional
Review Board or its designees.
To provide you with the best ongoing care and to safely treat you if you have an emergency
while you are enrolled in this study, staff at Anytown Community Mental Health Center must be
able to share clinically important information about you.

Staff will share information about you with the treating clinician and necessary medical
personnel only if you have a medical emergency. Information about your participation in this
study, your attendance at treatment sessions, efforts made to encourage your attendance, and
discussions you have with your clinician during treatment sessions will be shared only if
necessary.

Two sets of records will be kept concerning your care: research records and regular clinical
records. Regular clinical records will not include information about your being a participant in
this study. The research record will include authorized information from your clinical records
such as information about your treatment attendance and efforts made to encourage your
treatment attendance.

To help us protect your privacy, we have obtained a Certificate of Confidentiality from the
National Institutes of Health.

With this Certificate, the researchers cannot be forced to disclose information that may identify
you, even by a court subpoena, in any federal, state, or local civil, criminal, administrative,
legislative, or other proceedings. The researchers will use the Certificate to resist any demands
for information that would identify you, except as explained below.

The Certificate cannot be used to withhold information from employees of the United States
Government that is used for auditing or evaluation of Federally funded projects. Nor can it be
used to withhold information that must be disclosed to the U.S. Food and Drug Administration
(FDA).

The Certificate of Confidentiality does not prevent the researchers from disclosing without your
consent information that would identify you as a participant in the research in the following
circumstances:

 Matters such as child abuse or neglect,

 Reportable communicable diseases, or

 Threatened violence or harm to yourself or others.

If keeping information private would put you or someone else in immediate danger, the
researchers will release information to protect you or another person.

A Certificate of Confidentiality does not prevent you or a member of your family from voluntarily
releasing information about yourself or your involvement in this research. If an insurer,
employer, or other person obtains your written consent to receive research information, the
researchers may not use the Certificate to withhold that information.

11. New information that may affect study participation

The consent document must state (ICH GCP 4.8.10).

p. That the participant or the participant’s legally acceptable representative will be informed
in a timely manner if information becomes available that may be relevant to the
participant’s willingness to continue participation in the trial.

New information

You will be told promptly if the researchers find out any new information that might affect your
health, welfare, or willingness to remain in the study.

At any time that you are told of new information about the study, you will be asked to sign a new
consent form to indicate your willingness to continue taking part in the study. You do not have to
continue taking part if you do not want to. You may withdraw from the study at any time without
penalty or loss of benefits to which you are entitled.

12. Study contacts

The consent document must state (ICH GCP 4.8.10).

q. The person(s) to contact for further information regarding the trial and the rights of trial
participants in the event of trial-related injury.

Contacts for questions or problems

For questions about the study or about a research-related injury, contact the site Principal
Investigator, Dr. Jones, at (123) 456-7890.

If you have a medical emergency, please call the Crisis Intervention Team at (987) 654-4321
and ask to have Dr. Jones paged, or call 911, or go to the nearest emergency room.

For questions about your rights as a research participant, contact the patient representative at
Memorial Hospital at (111) 222-3333.

13. Duration of participation and number of people taking part in the study
The consent document must state (ICH GCP 4.8.10).

s. The expected duration of the participant's participation in the trial.

 t. The approximate number of participants involved in the trial

Length of the study and number of people taking part

If you agree to be in this study, you will be one of about 30 to 90 participants in this area. In
total, about 200 people from all over the country will be taking part in the study. It will take about
5 months to complete all 8 research visits.

Special requirements concerning the consent of pregnant women

When a research activity involves pregnant women as participants

 Both mother and father must be informed about any potential impact of the research on
the fetus.

 Both mother and father must consent to the woman’s participation in the research.
However, the father’s consent is not required in the following circumstances:

o The purpose of the research is to meet the health needs of the mother.

o The father’s identity or whereabouts cannot be determined.

o The father is not reasonably available.

o The pregnancy resulted from rape.

Special requirements concerning the consent of children (1)

The CFR defines children 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.” (45 CFR 46.402)
The legal age for consent in most states is 18; persons under age 18 are considered minors.
However, in some jurisdictions, persons under age 18 can consent to treatment for substance
abuse or dependence.

Special requirements concerning the consent of children (2)

When children or minors are involved in research, both the assent of the child or minor and the
permission of his or her parent(s) are usually required.
Permission means the agreement of parent(s) or a legal guardian to the participation of their
child or ward in research.

Assent means a child’s agreement to participate in research. Failure to object is not assent.

In most cases, both parents must give their permission for their child or minor’s participation in
research. However, exceptions to this requirement are permitted in certain circumstances. An
exception is also permitted in the case of an emancipated minor.

Special requirements concerning the consent of children (3)

Although children may be legally incapable of giving informed consent, they may nevertheless
be able to assent to or dissent from participation in research.

Out of respect for children as developing persons, children should be asked whether or not they
wish to participate in the research, particularly if

 The research does not involve interventions that are likely to benefit the participants, and

 The child can understand what it means to be a volunteer for the benefit of others.

A child’s assent should be sought when the child is capable of providing such assent, taking into
account his or her age, maturity, and psychological state. The age that a child needs to attain to
give assent varies from state to state. In certain circumstances, the IRB may determine that
research can proceed without the assent of the children involved.

Special requirements concerning the consent of prisoners (1)

Because of their incarceration, prisoners may be under constraints that potentially affect their
ability to make a truly voluntary decision about whether or not to participate in a study.

45 CFR 46.303 defines a prisoner as

“Any individual involuntarily confined or detained in a penal institution. The term is

intended to encompass individuals sentenced to such an institution under a criminal or
civil statute, individuals detained in other facilities by virtue of statutes or commitment
procedures which provide alternatives to criminal prosecution or incarceration in a penal
institution, and individuals detained pending arraignment, trial, or sentencing.”
Special requirements concerning the consent of prisoners (2)

Additional safeguards for the protection of prisoners involved in research (set forth in 45 CFR 46
C) include the following:

 The IRB must approve the study as prisoner research.

 The IRB that reviews and approves the study must include a prisoner or prisoner
advocate in its membership.

 A majority of the IRB members (exclusive of prisoner members) must have no

association with the prison(s) involved in the research, apart from their membership on
the IRB.

 The study must present no more than minimal risk to the participants.

 The proposed research must involve the study of

o The possible causes, effects, and processes of incarceration and criminal

behavior.

o Prisons as institutional structures or prisoners as incarcerated persons.

o Conditions that particularly affect prisoners (e.g., vaccine trials; research on

hepatitis, which is more prevalent in prisons than elsewhere; research on social
and psychological problems such as alcoholism, drug addiction and sexual
assault).

o Practices intended to improve the health or well-being of the participants.

Elements of the informed consent process

Part 1 of this module examined the informed consent document in detail. Part 2 will examine the
process of obtaining informed consent from potential study participants.

To be valid, informed consent must be based on the following:

Capacity to give informed consent

Before the informed consent process can begin, the potential participant must be deemed
capable of understanding his or her actions and making a reasoned decision. If the person lacks
capacity because he or she is a minor, is ill, or for any other reason, special provisions must
apply (such as a life-threatening emergency), or the person may not be included in the study.
A person who has a court-appointed legal guardian or who has been determined by a court to
be legally incompetent cannot sign an informed consent form even if he or she the capacity to
make a decision. This determination is made by the legal system and not by clinicians.

Disclosure of all relevant information

The research team must disclose all relevant information about the study to the potential
participant. The information disclosed must be sufficient to enable the potential participant to
make an informed reasoned decision about whether to participate. This information generally
includes

 The purpose of the study.

 The nature of the procedure or intervention that is being studied.

 Reasonable alternatives to participation in the study.

 The potential risks and benefits, as well as the uncertainties, of study participation.

Comprehension by the participant

The potential participant must understand the information disclosed to him or her about the
research study. The research team must be able to evaluate the potential participant’s ability to
understand what his or her participation in the study would involve.

Voluntary agreement by the participant

The participant must agree to participate in the research study and his or her agreement must
be voluntary and free from coercion or undue influence.

Right to withdraw
The participant must be informed that he or she has a right to withdraw from the study at any
time and for any reason, without penalty or loss of benefits that he or she would otherwise be
entitled to receive.

If a participant wishes to withdraw from a study in which an experimental drug is being tested,
he or she must be informed of any procedures that are recommended to ensure safe withdrawal
from the study drug. The participant must also be advised of any consequences of withdrawal,
such as the inability to continue taking the study medication.

Inviting potential participants to enroll in a research study

Written documentation of Institutional Review Board approval of the study, consent document(s)
and recruitment materials (where appropriate) must be obtained and provided to the sponsor.
NIDA and the CTN Lead Investigator must give their approval before recruitment can begin at a
study site.
Members of the research team may find it helpful to keep the following questions in mind as
they go through the process of recruiting participants for a study.

 Is the participant capable of understanding information about the study and giving
voluntary, informed consent?

 Has the participant been given sufficient, accurate information about the study?

 Does the participant understand the information he or she has been given about the
study?

 Is the participant’s decision to participate in the study entirely voluntary or has he or she
been coerced or influenced in any way (e.g., by circumstances or by other people)?

 Does the participant understand that signing the informed consent document indicates
agreement to participate in the study?

Inviting potential participants to enroll in a research study

 Is the participant capable of understanding information about the study and giving
voluntary, informed consent?

Adults have the capacity to consent when they possess sufficient mental capability to

 Understand information given to them,

 Appreciate the relevance of the information to their circumstances, and

 Make a reasoned decision about whether or not to participate in a particular study.

Capacity to consent may be affected by several factors, including

 Age

 Cognitive (mental) impairment

 Illness

 Treatments
Capacity to consent is study-specific. A person may have sufficient capacity to carry out daily
activities and make personal decisions, but he or she may not have sufficient capacity to
appreciate the relevance of a given research study to his or her circumstances. On the other
hand, a person may be incapacitated in daily activities but still have the capacity to consent to
study participation

 Is the participant capable of understanding information about the study and giving
voluntary, informed consent?

For some participants or groups of participants, the investigator or the IRB may decide to obtain
an independent capacity assessment. This may involve consulting a psychiatrist or neurologist
for a determination of an individual’s cognitive ability and ability to understand the details and
implications of a study protocol.

If a person is unable to provide informed consent, a legally authorized representative may in

some circumstances give permission for the individual to participate in research. A legally
authorized representative may be

 A parent (for children only).

 A legal guardian, as determined by state law, who can make health care decisions for a
person who is unable to consent.

 An individual who holds a valid durable power of attorney for health care. However, be
aware that legal opinions about the authority of the holder of a durable power of attorney
for health care are evolving. The investigator should clarify whether institutional and IRB
policies permit the holder of a durable power of attorney for health care to give informed
consent for participation in research on a participant’s behalf.

 Has the participant been given sufficient, accurate information about the study?

To be informed means to have thorough knowledge of a matter. To be able to give informed

consent, participants must have sufficient, accurate information about a study. This means that
participants should be able to answer the following questions:

1. What is the purpose of the research?

2. Does the study involve an experimental treatment or procedure?

3. Does the study involve random assignment to one treatment or another?

4. What must I do as a study participant?

 5. What are the anticipated risks and benefits of participation in the study?

6. What alternative treatments or procedures are available?

7. Will participants in the study receive any compensation?

8. Will I have any expenses for participating in the study?

9. How long will my participation in the study last?

10. Will my study records be kept confidential?

11. Will I be informed in a timely manner about any issues that might affect my willingness to
continue taking part in the study?

12. Who is in charge of the study?

13. Will I receive treatment whether I participate in the study or not?

14. May I withdraw from the study at any time if I change my mind and no longer wish to
take part?

 Has the participant been given sufficient, accurate information about the study?

To ensure that a participant has been given sufficient, accurate information about a study, a
member of the research team should

 Talk with the participant about the study’s purpose and requirements.

 Provide fliers or brochures that describe the study or provide general information about
clinical research.

 Invite the participant to ask questions and respond to questions asked by the participant.

 Give the participant plenty of time to read the informed consent document and ask
questions about it.

 Give the participant a copy of the informed consent document to take home and read
before signing it. Also give the participant a copy of the consent form after he or she has
signed it.
  Invite the participant to call with questions later and provide the names and phone
numbers of people to call.

 Has the participant been given sufficient, accurate information about the study?

Potential participants in CTN studies may be sick or in withdrawal or may have difficulty
focusing for an extended period of time. Information must be presented in language they can
understand, at a pace they can keep up with, and in a manner that invites questions.

Sometimes information about a study may be presented to a group of potential participants. In

this situation, it is important to meet individually with each participant so that he or she has the
opportunity to ask questions in private.

 Does the participant understand the information he or she has been given about the
study?

The research team must be satisfied that the participant understands what he or she has been
told about the study. Participants who are in withdrawal, depressed, manic, or otherwise
psychiatrically or cognitively impaired may not be able to give informed consent.

The best way to be sure that the participant understands the information he or she has been
given about the study is to review the consent document with the participant, line by line. Then,
ask the participant questions about the study to ascertain what information he or she has
absorbed.

It may be helpful to prepare a quiz to test the participant’s understanding of the study. Such a
quiz would have to be prepared in advance and submitted to the IRB for review and approval
along with the other consent documents.

 Does the participant understand the information he or she has been given about the
study?

It is particularly challenging to be sure that participants understand the information they have
been given when the following is true.

A participant has limited speaking ability in English

45 CRF 46.116 requires that

“the information given to the participant or the representative shall be in language

understandable to the participant or the representative.”
In practice, most IRBs require the informed consent document to be translated for potential
participants who have limited or no understanding of spoken English. Researchers must follow
the procedure approved by the IRB for obtaining consent from these participants.
It is also important to be aware of specific language differences that may be confusing to
participants who are not fluent in English. For example, in Spanish, the word “once” means the
number 11. An instruction to “take this medication once daily” might be confusing to a Spanish-
speaking participant.

A participant has limited reading ability

45 CRF 46.117 states:

“[the consent] form may be read to the participant or the participant’s legally authorized
representative, but in any event, the investigator shall give either the participant or the
representative adequate opportunity to read it before it is signed.”
Both 45 CRF 46.117 and ICH E6 GCP 4.8.9 state that if a participant is unable to read, a witness
must be present throughout the informed consent discussion and must sign the consent form(s).

 Is the participant’s decision to participate in the study entirely voluntary or has he or she
been coerced or influenced in any way (e.g., by circumstances or by other people)?

Coercion occurs if an individual perceives that he or she could be harmed or punished for
refusing to take part in a study.

Historically, individuals in relationships of dependence or unequal power have been particularly

vulnerable to coercion. Coercion occurred in the 1960s at Willowbrook State School when some
parents could not admit their child to the school unless they agreed to the child’s participation in
studies in which children were deliberately infected with hepatitis.

Blatant coercion such as this is rare today because of the vigilance of research teams and IRBs.
However, in some cases, coercion may occur subtly and unintentionally. This kind of coercion
can be more difficult to detect.

 Does the participant understand that signing the informed consent document indicates
agreement to participate in the study?

In most cases, the dated signature of the participant, or his or her legally authorized
representative, on the informed consent document indicates that the participant understands the
study and is willing to participate. Signing the informed consent document should be the final
step in the informed consent process.

A member of the research team must sign the consent form to confirm that

 To the best of the team member’s knowledge, the participant has understood the
information given to him or her about the study and is volunteering without coercion.

 The informed consent process followed the procedures authorized by the local IRB.
The participant should be given a copy of the signed consent document. The original must be
kept on file in the research offices per local IRB guidelines.

Part 2: The informed consent process

Quality control in the informed consent process (1)

Protection of human research participants is the primary goal of the IRB and the Informed
Consent process. Failure to comply with general requirements for informed consent (45 CFR
46.116) and documentation of informed consent (45 CFR 46.117) may result in suspension of a
study. Errors in the informed consent process are considered protocol violations and, as such,
must be reported to the relevant IRBs, along with a description of the action taken to correct the
error and prevent it from occurring again.

If violations of the informed consent process are severe or continuing, penalties may be
imposed and the IRB may report the problem to the regulatory authorities. It is therefore
important to ensure that the process of obtaining informed consent from participants is carried
out carefully and with due attention to every detail. This section describes common errors that
can occur in the informed consent process and discusses how they can be prevented.

Remember, mistakes will happen. The most important thing to remember is to deal with them
openly and honestly and report them immediately upon identification. The study staff will help
you identify methods to prevent them happening again.

Part 2: The informed consent process

Quality control in the informed consent process (2)

The following are examples of some of the most common errors that can occur in the informed
consent process.

The participant signs the informed consent form after study procedures have begun.

How does this happen?

Some studies may involve clients as they come into the clinic. The eager staff sees that the
person who usually conducts consent interviews is busy and tries to help by having the client
“just fill out some forms” while waiting.

Another staff member later assumes, without checking and without seeing the completed forms,
that the participant has already completed the informed consent documentation and proceeds to
enroll the person into the study.
How can this error be prevented?

 Never assume anything. Always check that a participant’s informed consent

documentation is complete before beginning a study procedure.

 Never perform any study assessments on potential participants before informed consent
has been obtained.

Corrective Action: Review the study and the consent form with the participant as soon as the
failure is identified. Document all steps to correct the situation, attach them to the signed
consent form and notify your supervisor as soon as possible.

The consent form is signed by the participant but is missing the initials or signature of
the investigator or witness (if applicable), or is not dated.

How does this happen?

The investigator may have become distracted. Perhaps the phone rang or another client needed
attention. Perhaps the participant asked a question about another aspect of the study and the
investigator turned the page, forgetting to sign or initial the form as required or to check that the
participant has written the date on the form next to his or her signature.

How can this error be prevented?

 Conduct consent interviews in a quiet, separate room.

 When reviewing a consent form with a participant, focus on that task. Don’t answer the
phone or respond to distractions unless there is a genuine emergency.

 The person obtaining the participant’s consent must be present when the consent form
is signed. Having the investigator sign the consent form later is unacceptable. Never
backdate a consent form.

 Create and use a checklist to ensure that every detail in the informed consent process is
completed. (Refer to the Regulatory Affairs guidance documents on LiveLink for a
sample checklist prepared by the CTN)

Whiteout is used to correct an error on the consent form.

How does this happen?

Failure to follow Good Clinical Practice or Good Medical Record correction techniques is the
only reason for this error. Whiteout should never be used on any research or medical record
document.
How can this error be prevented?
If an error occurs while the consent form is being completed, use Good Clinical Practice or
Good Medical Record correction techniques to correct it: Cross out the error, initial and date the
crossing-out, and enter the correct information. (See also Good Medical Record practices to
observe when writing progress notes in the Documentation and Record-Keeping module.)

An out-of-date version of the consent form is used.

How does this happen?

Several versions of a consent form may be developed before IRB approval is received. Or, if the
study has been in progress for more than 1 year, a new version of the consent form (most likely
with a different date stamp) will have been prepared. In either case, a staff member may
mistakenly pull out and use an out-of-date version of the form.

How can this error be prevented?

 Ensure that the current version of the consent form is readily identifiable (e.g., color
coded, marked with a prominent date stamp).

 Keep copies of the current version of the consent form in a different place than older,
archived versions. Destroy copies of old, unused consent forms and mark the old
original as obsolete in the regulatory binder.

 Put up notices to remind research staff where to find, and how to identify, the most
current versions of the consent forms.

Corrective Action: When the issue is identified reconsent the participant using the appropriate
consent form. Attach a memo identifying the issue and the corrective action to the new consent
form.

A new consent form is required, but not all participants signed it.

How does this happen?

 Some participants were absent from the clinic during the week when most participants
signed new consent forms. When the absent participants returned the following week,
the need for them to sign new consent forms was overlooked.

 A staff member assumes that a colleague had already had the participant sign a new
consent form.

How can this error be prevented?

 Again, never assume anything. When a new consent form is required, check on each
participant’s next clinic visit to ensure that he or she has signed the new form.
  Devise a system for flagging the files of participants who have not yet signed new
consent forms.

 Use a tracking spreadsheet.

Corrective Action: When the issue is identified have the participant review, sign and date the
new consent form. Document the reason for the delay and attach it to the new consent form.

The original consent form has been lost.

How does this happen?

 A staff member may mislay a participant’s consent form among other papers on his or
her desk.

 The form may have been filed incorrectly.

 The original of the consent form may have been given to the participant by mistake.

How can this error be prevented?

 Devise written procedures for the handling of informed consent documentation and train
all staff in the use of these procedures.

Corrective Action: Report the loss of a consent form immediately to the IRB and/or the sponsor
and get another signed as soon as possible. To avoid the appearance of fraud, carefully
document the sequence of events that led to the loss of the first consent form.

Overview of regulations on documentation of informed consent (1)

Informed consent shall be documented by the use of a written consent form.

 The IRB must approve the consent form.

 The participant or the participant’s legally authorized representative must sign the
current version of the IRB approved consent form.

 A copy of the form must be given to the person who signs it. The study site must keep
the original on file.
The consent form may take one of two organizational structures.

 A written document that embodies the elements of informed consent required by 45 CFR
46.116. This form may be read to the participant or the participant’s representative. The
investigator should give the participant or representative ample time to absorb the
content of the form before signing it.

 A short-form written document stating that the elements of informed consent were
presented orally to the participant or the participant’s representative. When the short
form document is used

o A witness must be present at the oral presentation.

o The IRB must approve a written summary of what is to be said to the participant
or representative.

o The participant or representative must sign only the short form itself.

o The witness must sign both the short form and a copy of the summary.

o The person obtaining the participant’s consent must also sign a copy of the
summary.

o A copy of the summary, in addition to a copy of the short form, must be given to
the participant or the participant’s representative.

Researchers must not waive or appear to waive any legal rights of participants.
For example, care must be taken when describing what compensation (beyond the provision of
immediate or therapeutic intervention) the institution is voluntarily willing to provide in an event
such as a research-related injury.

Participants should understand that, regardless of what the institution may agree to provide as
compensation for a research-related injury, they retain the right to take legal action against the
institution and/or those responsible for the injury.

The consent form must be revised when new information becomes available that may be
relevant to the participant’s consent.
If a new adverse event appears to be related to the study medication (e.g., a severe allergic
reaction that occurs shortly after a medication is given), this risk should be added to a revised
consent form.

 The revised consent form must be approved by the IRB.

  The participant must be informed of the new information in a timely manner.

 The communication of the new information to the participant must be documented.

Summary of key points

 Informed consent is a process by which a person voluntarily agrees to participate in a

research study after being fully informed about it.

 The informed consent document should contain all of the information that the participant
needs to make an informed decision about participating in the study.

 The participant’s signature on the informed consent document confirms his or her
voluntary agreement to take part in the study. This is the final step in the informed
consent process.

 The general requirements for informed consent in federally funded research are spelled
out in 45CFR.46.116 and 21 CFR 50.20. Some states have enacted requirements for
informed consent that go beyond federal regulations.

 All CTN members have a responsibility to ensure that the process of obtaining informed
consent from research participants not only conforms to federal, state, and local
regulations but also respects each individual’s right to make a voluntary, informed
decision.

 The first step in the process of informed consent is preparing the consent document for
presentation to the Institutional Review Board that must review and approve the study
and consent document. The IRB must review and approve the consent document before
the study can begin.

 Consent documents should be written in nontechnical language that the proposed

participants would understand. The language should be consistent with the proposed
participants’ educational level, cultural views, and familiarity with research.

 The information that must be provided in an informed consent document is pecified in 45

CFR 46.116, 21 CFR 50.20, and ICH GCP 4.8.10.

 The legal age for consent in most states is 18; persons under age 18 are considered
minors. Additional protections for children involved as participants in research are set
forth in 45 CFR 46 Subpart D. In most cases, both parents and the child himself or
herself must consent to the child’s participation in research.

 If a person is unable to provide informed consent, a legally authorized representative

may in some circumstances give permission for the individual to participate in research.
 Only one person gives consent – if the participant is capable and is not court ordered
legally incompetent then he or she should sign. If the participant is not capable or is
legally incompetent, then the legal representative or guardian should sign. Child and
their parents sign, but children assent and parents consent.

 Participants must not be coerced or unduly influenced. Coercion occurs if an individual

perceives that he or she could be harmed or punished for refusing to take part in a
study. In some cases, coercion may occur subtly and unintentionally.

 The value of an incentive for participation in a study should not be so high that it could
be considered an undue influence on an individual’s decision to participate.

 It is important to ensure that the process of obtaining informed consent from human
participants is carried out carefully and with careful attention to every detail. Failure to
comply with general requirements for informed consent (45 CFR 46.116) and
documentation of informed consent (45 CFR 46.117) may result in suspension of a study
as well as fines and penalties.