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13. DESIGNING OF CLINICAL STUDY DOCUMENTS

(Protocol, CRF, ICF)

PROTOCOL
The protocol is a document that describes how a clinical trial will be conducted
and ensures the safety of the trial subjects and the integrity of the data collected. It
describes the background, rationale, objectives, design. methodology, statistical
considerations, and organization of a clinical research project. A well-designed study
relies predominantly on a thoroughly considered, well-structured and complete

protocol.

Relevant components of Protocol:

General information:
1. Protocol title, protocol identifying number and date.
2. Name, address & contact numbers of the sponsor and the monitor/ CRO.
3. Name and title of the persons authorized to sign the protocol and the protocol
amendments for the sponsor.
4. Name, title, address and contact numbers of the sponsor's medical expert for
the study.
5. Name, title, address and contact numbers of the investigator who is/are
responsible for conducting the study, along with their consent letter.
6. Name, address and contact numbers of the institution clinical laboratories
and / or other medical and technical departments along with the particulars of
the head of the institution and the relevant department.

Objectives and Justification:

1. Aims and objectives of the study.
2. Name and description of the investigational products.
3. Summary of the known and potential risks and benefits, if any, to human
subjects.

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4. Description of and justification for the ROA, dosage regimen and treatment
periods for the pharmaceutical product being studied and the product being
used as control.
5. A statement that the study will be conducted in compliance with the protocol,
GCP and the applicable regulatory requirements.
6. Description of the inclusion & exclusion criteria of the
study population
7. References to the literature and data that are relevant to the study and that
provide background for the study.

Ethical Considerations:
1. General ethical considerations related to the study.
2. Description of how patients or healthy volunteers will be informed and how
their consent will be obtained.
3. Possible reasons for not seeking informed consent.

Study design:
The scientific integrity of the study and the credibility of the data from the study
depend upon the study design. It includes:

1. Description of the type of the study (randomized, comparative, blinded, open,

placebo-controlled), study design (parallel groups, cross-over technique),
blinding technique (double or single-blind), randomization (method and
procedure).
2. A schematic diagram of the study design, procedures, and stages.
3. Medications/treatments permitted (including rescue medications) and not

permitted before and / or during the study.

4. A description of the study treatments, dosage regimen, route of administration
and the dosage form of the investigational product and the control proposed
during the study.
5. A description of the manner of packaging and labeling of the investigational
product.
6. Duration of the subject participation and a description of the sequence of al
study periods including follow-up, if any.
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7. Proposed date of initiation of the study.
8. Justification of the time-schedules. E.g. How far the safety of the active
ingredients, medicinal products has been tested, the time course of the disease
in question.
9. Discontinuation criteria for
study subjects and instructions on terminating or
suspending the whole study or a part of the study.

Inclusion, Exclusion, and Withdrawal of Subjects:

1. Subject inclusion criteria: specifications of the subjects (patients / healthy
volunteers) including age, gender, ethnic groups, prognostic factors,
diagnostic
admission criteria, etc. should be clearly mentioned where relevant.
2. Subject exclusion criteria, including an exhaustive statement on criteria for
preadmission exclusions.
3. Subject withdrawal criteria (i.e. terminating investigational product
treatment/study treatment) and procedures specifying- when and how to
withdraw subjects from the treatment, type, and
timing of the data to be
collected from withdrawn subjects, whether and how
subjects are to be
replaced and the follow-up on the withdrawn subjects.
4. Statistical justification for the number of
Subjects to be included in the Study.

Handling of the Products:

1. Measures to be
implemented to ensure the safe handling and storage of the
pharmaceutical products.
2. System to be followed for labeling of the products (code numbering etc.)
3. The label should necessarily contain the following information:
the words
"For Clinical Studies only", the name or a code number of the
study, name and
contact numbers of the
investigator, name of the institution, subject's
identification code.

>Assessment of Efficacy:

1. Specifications of the effect parameters to be used.

2. Description of how effects are measured and recorded.
3. Time and periodicity of effect recording.
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4. Description of special analyses and/tests to be carried out (pharmacokinetics,
clinical, laboratory, radiological, etc).

Assessment of Safety:

1. Specifications of safety parameters.

2. Methods and periodicity for assessing and recording safety parameters.
3. Procedures for recording and reporting adverse drug reactions and / or adverse
events and inter-current illnesses.
4. Type and duration of the follow-up of the subjects after adverse events.
5. Information on the establishment of the study-code. where it will be kept and
when, how and by whom it can be broken in the event of an emergency.

Statistics:

1. Description of the statistical methods to be employed, including the timing of

any planned interim analysis.
2. A number of study subjects needed to achieve the study objective and other
statistical considerations.
3. Detailed break-up of the number of subjects planned to be enrolled at each
study site (in case of multi-center studies)
4. Procedures for managing missing data, unused data and unauthentic data

5. Procedures for reporting any deviations from the original statistical plan.
6. Selection of the subjects to be included in the final analyses (e.g. all
randomized subjects /all dosed subjects / all eligible subjects/ evaluable

subjects).

> Data handling and management:

A statement should be clearly made in the protocol that the investigator/institution

will permit study-related monitoring, audits, ethics committee review and regulatory
A copy of the CRF
inspections providing direct access to source data/documents.
should be included in the protocol. Besides., the following details should be given:

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1. Procedures for handling and processing records of effects and adverse
events
the product under study.
to

2. Procedures for the keeping of

patient lists and patient records for each
individual taking part in the study.
3. Records should facilitate easy identification of the
individual subjects.
Quality control and quality assurance:

1. A meticulous and specified plan for the various steps and

procedures for the
purpose of controlling and monitoring the study most effectively.
2. Specifications
and instructions for anticipated deviations from the
protocol.
3. Allocation of duties and responsibilities within the
research team and their
coordination.
4. Instructions to staff including study description (the way the study is to be
conducted and the procedures for drug usage and administration).
5. Addresses and contact numbers etc. enabling any staff member to contact the
research team at any hour.
6. Considerations of confidentiality problems, if any arise.
7. Quality control of methods and evaluation procedures.

Finance and insurance:

1. All financial aspects of conducting and reporting a study may be arranged and
a budget made out.
2. Information should be available about the sources of economic
support (e.g.
foundations, private or public funds, sponsor/manufacturer).
3. Likewise, it should be stated how the expenditures should be distributed e.g.
payment to subjects, refunding expenses of the subjects, payments for special
tests, technical assistance, purchase of apparatus.
4. Study Subjects should be satisfactorily insured against any injury caused by
the study.

Publication policy:
1. A publication policy, if not addressed in a separate agreement, should be
described in the protocol.

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Evaluation:

1. A specified account for how the response is to be evaluated.

2. Methods of computation and calculation of effects.
3. Description of how to deal with and report subjects withdrew from/dropped
out of the study.

CASE REPORT FORM

CRF is a data collection tool of printed, optical or electronic document
designed to record all of the protocol required information to be reported to
the sponsor, support investigators, and coordinators on each trial subject. A
well-designed CRF facilitates data collection and entry, and directly benefits
other facets of data management and statistical analysis.
CRFs can be classified into two types i.e. Paper CRF (pCRF) and Electronic CRF
(eCRF). Though paper CRFS are still used largely, use of electronic CRFS (eCRFs)
are gaining popularity due to the advantages such as improved data quality,
online discrepancy management, and faster database lock, etc. eCRF has
minimal chance of errors and it also avoids data redundancy. On the other
hand, pCRF designing is time-consuming, involve large amount of papers which
add to the total expense.
It collects relevant data in a specific format in accordance with the protocol
and compliance with regulatory requirements. It allows for efficient and
complete data processing, analysis and reporting and facilitates the exchange
of data across projects and organizations esp. through standardization.
This collected data is used to perform statistical analysis for the trial. Design
of individual CRFs will vary from trial to trial, but it is essential that the design
ensures that adequate collection of data has been performed proper trails can
be kept to demonstrate the validity of the trial (both during and after the trial).
CRF development is one of the most crucial steps in Clinical trials as it
preserves and maintains quality and integrity of data. CRF design should be
standardized to address the needs of all users such as investigator, site
coordinator, study monitor, data entry personnel, medical coder and
biostatistician.

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Elements of the CRF:

Header Information:

Key identifying Information.

Study Number.
Site/Center Number.
Subject identification number.
.Usually, come from a standard library.

Safety modules:
Select modules appropriate for your study.
Keep safety analysis requirements in mind.

Safety Modules usually include

1. Demographic details.
2. Adverse Events.

3. Vital Signs.
4. Medical History/Physical Exam.
5. Concomitant Medications.
6. Patient Disposition.

>Efficacy modu

1. Designed for each therapeutic area based on the protocol.

2. Considered to be "unique" modules and can be more difficult to develop.
3. Use existing examples from similar protocols where applicable.
4. Consider developing a library of efficacy pages.
5. Design modules following project standards for data collection.
6. Key efficacy endpoints
7. Additional tests for efficacy

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Data to be collected on CRF:

This will vary from trial to trial, but should include the following:

Inclusion/exclusion criteria
Baseline data and demography data.
Data specifically required by the protocol
Any dose and/or therapy (including non-trial therapy) taken and/or modify
Adverse events, concomitant medications, and intercurrent illnesses.
Visits that the participants fail to make, tests that are not conducted, and
examinations that are not performed.
All withdrawals and dropouts of enrolled participants from the trial reported
and explained.

Some data will be recorded directly onto the CRF and there will not be any prior
written or electronic record of such data. This is considered to be source data.

Designing and Development of CRF:

1. Collect the data outlined in the protocol.

2. Use of consistent formats, font style and font sizes throughout the CRF booklet.
3. Selection of portrait versus landscape versus combination layouts.
4. Use of clear and concise questions, prompts, and instructions.
5. Provide boxes or separate lines to hold the answers.
6. Separate the columns with thick lines.
7. Provide bold and italicized instructions
8. Minimize free-text responses.
9. Page numbering if necessary, should be consistent throughout.
10. Specify the unit of measurement.
11. Indicate the number of decimal places to be recorded.
12. Use standard data format (E.g., DD/MM/YYYY) throughout the CRF.
13. Use "no carbon required (NCRY" copies to ensure exact replica of CRF.
14. Provide instructions to reduce misinterpretations.

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15. Avoid duplication.

CRF Design Layout:

There are three types of data: non-time dependent, time-dependent and cumulative
data. CRE Design layout strategies based on data types and preferred database
structure. The CRE design layout strategy should be determined considering a CRF
clustered level and the time and frequency of a data review.

Non-time dependent data:

Non-time dependent data is the data collected at a snapshot in time. Such data
include subject demographics and medical history.

> Time-dependent data:

Time-dependent data is data collected repeatedly over time. A typical example is

vital signs recorded at multiple visits. With time-dependent data, there are 2 options
to the CRF layout: Single page, per visit or a Cumulative log.

Cumulative data:

Cumulative data is data collected over time but not linked to a specific visit. Adverse
events and concomitant medications are typical examples. The usual approach to
designing a CRF for cumulative data is the "cumulative log" approach described in

the previous section.

Checklist for handling CRF:

1. All data entered in a CRF must be legible, i.e. use block letters, for multiple
copy CRFs make sure that all copies are legible.
2. All data entered in a CRF should be understandable: i.e. use adequate units of
measure for laboratory results.
3. Errors must be crossed out with a single line leaving the mistake legible.
4. The correction should be initialed and dated by the investigator.
5. Correction should be distinctly different from the original, and done
consistently throughout the trial (e.g. made in a different colored ink).

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6. The source data must be
readily available and retrievable for
monitoring,
auditing, and inspection.
7. Document
everything: Errors and omissions are acceptable but not without
explanation.

Responsibility of CRF:

The design can vary between clinical research organizations (CRA, data manager,
specialty role) but include

1. All efficacy and safety parameters specified in the protocol using standards
libraries.
2. To collect only data required by the
protocol.
3. Work with protocol grid/visit schedule.

Uses of CRF:

1. Subject tracking.
2. Data analysis and reporting.
3. Reports to the FDA on subject safety.
4. Promotional materials.
5. New Drug Application submissions.

6. Support for labeling claims.

7. Articles in medical journals.

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INFORMED CONSENT FORM

Informed consent is an essential part of the design of every research project

in their research
involving human subjects. Researchers who involve human subjects
have both an ethical and legal obligation to secure the informed consent of the

potential research subjects prior to initiation of the research

Format and Style of Informed Consent Form:

The IRB strongly encourages Investigators to use the standard IRB consent. The

form is written in the 2nd person. IRE requires that the consent and assent
documents be written in the 2nd person, i.e., "You" rather than "I." Do not start

sentences with "You understand...."

Consent forms should be writen in lay language, at a level understandable to
the participants in the study. Researchers may use flowcharts and tables to

enhance reading comprehension. Also, try to avoid medical/scientific/technical

language or include simple definitions/explanations for such terms if they

must be used.
T h e use of a 12-point font is recommended. A larger type size may be
appropriate for some populations, such as children, the elderly, or the visually

impaired. Documents must be typewritten. A place for the subject and

researcher signature and date must appear on the consent document. A witness

signature is required in specific circumstances.

Instructions for Developing an Informed Consent Form:

As part of the informed consent process, the consent document is designed to

potential subjects about a research study so they can make an

provide information to

informed decision about their participation. The use of a form to document the
consent process is required unless specifically waived by the IRB. One of the most

common reasons for the delay in IRB approval is an incomplete, inaccurate, and/or
unclear consent form document.

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Purpose of the Study:

Describe the purposes of this research study in lay terms.

Include a statement that indicates why this is considered a research study.
.Provide definitions for specifie research design features (e.g.. double-blind,
randomization, placebo-controlled).

Procedures:

.Include a thorough description of the specific procedures involved in the

study.
Include detailed inclusion/exclusion criteria, length of involvement.
I f the subject will be interviewed or asked to complete a questionnaire,
describe the types of questions that he/she will be asked to answer.
Provide a procedures table if subjects would benefit from the addition of a
table.

Risks:

This element will ask if the study involves more than minimal risk.
If so you will be prompted for a detailed description of the potential risks and
discomforts involved (physical, psychological, social, and economic).
For some procedures, you may choose to use standard text (e.g., blood draw).
If applicable, include a statement that the treatment or procedure may involve
risks, which are currently unforeseeable, to the subject.

Benefits:

Describe all expected benefits and who will benefit.

Note:

Compensation for participation is not a benefit.

Provision for free drugs or procedures is not a benefit.

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Compensation, Costs, and Reimbursement:
I f subjects will be compensated for their participation or reimbursed for costs,
describe in detail the type of payment, amount, and terms.
Specify any additional costs to the subject that may result from participation in
this study that will not be reimbursed.

Withdrawal or Termination from Study:

When appicable, subjects should be informed of circumstances under which

their participation may be terminated by the investigator without the subject's
consent.

Subjects should also be informed of procedures for safe and orderly

termination should they decide to withdraw from the study before it is
completed.

Confidentiality:
Include information about the protection of the subject's privacy, method of
protecting research data, and who may have access to study records.

New Findings:

The standard text explains that significant new information will be provided to
the subject by the investigator.

Alternatives to Participation:
Include applicable information on alternative procedures or courses of
treatment that may be advantageous to the potential subject if he/she refuses
to participate or withdraws from the study.

>Compensation for Injury:

Standard non-alterable text describes the provision for
subject injury incurred
as a result of this study, if
applicable.

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Other Considerations:
. I f a research team member has a disclosable financial interest in the outcome
of this particular study or research program, a statement to that effect should
be inserted.
If the study involves the collection of specimens, the appropriate standard
language should be included.

> Contact Information:

Includes contact information to answer study questions and standard text that
instructs subjects to contact the Research Protections office if they have any
comments or questions regarding the conduct of the study and/or their rights
as research subjects.

>Voluntary Participation:
The standard text emphasizes that the decision to participate, or not
participate, is solely up to the subject.

Signature Lines:

Signature lines should be included for the subject and for the researcher
obtaining informed consent.
A Legally-Authorized Representative signature line should be included if you
will obtain surrogate consent or are developing a parental permission form for
enrollment of a minor in research.
You may obtain the assent of a minor age 13-17 (as well as parental
permission) using this consent form.

A Witness signature line must be included for specific types of research.

Waiver of Written (Signed) Informed Consent:

An IRB may waive the requirement to obtain a signed informed consent document in

two situations:

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The only record linking the participant and the research would be the consent
document.
T h e principal risk would be potential harm resulting from a breach of

confidentiality.
Each participant will be asked whether the participant wants documentation
linking the participant with the research, and the participant's wishes will
govern.

Or

The research presents no more than minimal risk of harm to participants.

The research involves no procedures for which written consent is normally
required outside of the research context.

In some cases documentation is required for informed consent is waived, the IRB
often requires the researchers to provide participants with a written statement
regarding the research.

Researchers interested in obtaining a waiver of written (signed) informed consent

should make sure that their research qualifles for one of the above options, and
should address how the research qualifies for each of the option's requirements in
the Appendix P of the electronic IRB Application.

Waiver or Alteration of Informed Consent:

An IRB may approve a consent procedure which does not include, or which alters
some or all of the elements of informed consent, or waive the requirements to obtain
informed consent provided the researcher documents in Appendix O of the
electronic IRB Application and it contains:

The research involves no more than minimal risk to the participants.

The waiver or alteration will not adversely affect the rights and welfare of the
participants.

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T h e research could not practicably be carried out without the waiver or
alteration.
Whenever appropriate, the participants will be provided with additional
pertinent information after participation.
The research is not a clinical investigation subject to FDAregulations.

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