BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr.

Shaheen Sultana

Unit: IV
The clinical study protocol is defined as the procedures by which clinical research is conducted.
Clinical research is conducted according to a plan (a protocol) or an action plan. The protocol
demonstrates the guidelines for conducting the trial. It illustrates what will be made in the study by
explaining each essential part of it and how it is carried out. It also describes the eligibility of the
participants, the length of the study, the medications and the related tests.
Purpose of a Research Proposal
1. To raise the question to be researched and clarify its importance.
2. To collect existing knowledge and discuss the efforts of other researchers who have worked on the
related questions (Literature view).
3. To formulate a hypothesis and objectives.
4. To clarify ethical considerations.
5. To suggest the methodology required forsolving the question and achieving the objectives.
To discuss the requirements and limitations in achieving the objectives.
A defined protocol must address (cover) the proposed medical question and protect the safety and
rights of the clinical trial participant/patients

Writing The Protocol

1. Title of the study
2. Administrative details
3. Project summary
4. Introduction to the research topic, background (Literature view)
5. Study objectives and/or questions.
6. Methodology: Study design, study population and methods of recruitment, variable list, sample
size, methods of data collection, data collection tools, plan of analysis (analysis of data)
7. Project management: Work plan (Timeline-proposed schedule)
8. Strengths and limitations of the study
9. Issues for ethical review and approvals
10. Statistical Section (Including Analysis And Monitoring)
11. Human Subjects Protection/Informed Consent

1. Title of the study

Title of proposal should be accurate, short, concise, and identify. What is the study about, Who are
the targets, Where is the setting of the study and when it is launched, if applicable. It should make
the main objective clear, convey the main purpose of the research and mention the target population.
Carry maximum information about the topic in a few words; it is a good practice to keep the title to
within12-15words. It should convey the idea about the area of research and what methods are going
to be used in a compact, relevant, accurate, attractive, easy to understand, and informative way.

2. Administrative Details

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The following administrative details and a protocol content summary should follow the title page:
a. Contents page list of relevant sections and sub-sections with corresponding page number.
b. Signature page is signed by senior members of the research team and dated to confirm that the
version concerned has been approved by them.
c. Contact details for the research team members listing postal and e-mail addresses and telephone
numbers for members of the research team.

3. Project summary
The summary should be distinctive, concise and should sum up all the essentials of the protocol.

4. Background
The background to the project should be concise and refer to the subject (research problem) straight
forwardly. In writing there view, attention should be drawn to the positives, negatives and
limitations of the studies. Introduction is concluded by explaining how the present study will benefit
the community. The literature view should logically lead to the statement of the aims of the proposed
project and end with the aims and objectives of the study. There view should include the most recent
publications in the field and the topic of the research is selected only after completing the literature
review and finding some gaps in it. Introduction should briefly answer the importance of the topic,
the gaps in the literature, the purpose of the study and benefits for the society, from the study. The
research question should be described precisely and concisely. It is going to be the basis of designing
the project.

5. Study objectives (Aims)

a. Specific Aims: Specific aims one by one should be listed concisely. It is good practice not to
include too many aims in the study (2-5 best); too many objectives often lead to in accurate and
poorly defined results. Furthermore, aims should be achievable, realistic and specific with no general
and ambiguous statements. They should be stated inaction verbs that illustrate their purpose: i.e., “to
determine, to compare, to verify, to calculate, to reduce, to describe, etc.
b. Secondary objectives (optional): These are referred to as ancillary and minor objectives that
could be studied during the course of the study the formulation of objectives helps to focus the study
and to avoid the collection of any unnecessary data and hence organize the study in clear and distinct
stages.
c. Hypothesis: It is a statement based on sound scientific theory that recognizes the predicted or
relation between two or additional assessable variables.
It is always developed in response to the purpose statement or to answer the research questions
posed. Furthermore, hypothesis transforms research questions into a statement that predicts an
expected outcome. Aims should be logically linked and arranged according to the tested hypothesis
statement.
Example:
• Research question: Is there a difference in control and treatment group

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Null Hypothesis: There is no difference.

Alternate Hypothesis: There is a difference
• The statement of the problem should provide a summary of exactly what the project is trying
to achieve.
• What exactly do you want to study?
• Why is it worth studying?
• Does the proposed study have theoretical and or practical significance?
• Does it contribute to a new understanding of a phenomenon?
• How does the research relate to the priorities of the region and the country?
• What knowledge and information will be obtained?
• What is the ultimate purpose that the knowledge obtained from the study will serve?
• How will the results be disseminated? How will the results be used, and who will be the
beneficiaries?

6. Methodology
Methods and Materials
It should describe in detail the ‘Where’, ‘Who’, ‘How’ the research will be conducted. It explains the
study design and procedures and techniques used to achieve the proposed objectives. It details the
proposed methodology for data gathering and processing.
a. Study design (cross-sectional, case-control, intervention study, Rct, etc.)
• Proper explanation should be given as to why a particular design was chosen (on the basis of
proposed objectives and availability of resources).
• A study design is in fact the researcher’s general plan to acquire the answer(s) to the
hypothesis being tested.
• Here, strategies will be applied to develop balanced, correct,
• objective and meaningful information.
• It explains the methods that will be used to collect and analyze data.

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BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

b. Study population (Study subjects)

• Where are you going to do the research and who is the study population (why doing research
in this place and why selecting this population?).
• It describes in detail about the study subjects, all aspects of the selection procedure and
sample size calculation.
• Proper definition of eligibility, inclusion, exclusion and
• discontinuation criteria of the study subjects should be stated. Allocation of subjects to study
should be explained and described in details bearing in mind the concealment and
randomization process.

c. Sample size
Sample size calculation is recommended for economical and ethical reasons. The calculation of the
sample size must be explained including the power of the sample. The sampling technique should be
mentioned, e.g., randomization that will be used in order to obtain a representative sample for your
target population. Each step involved in the recruitment of the study subjects should be described
according to the selection criteria (inclusion and exclusion criteria). “Informed consent” should be
mentioned (Permission granted in full knowledge of the possible consequences).

d. Proposed intervention
Full description of proposed intervention should be given. Here, all the activities and actions should
be recorded and thoroughly explained in their order of occurrence.
When using drugs, both scientific and brand name should be mentioned followed by the name of the
manufacturing company, city, and country.
Drug route, dosage, frequency of administration, and total duration of treatment with the drug should
be mentioned.
Involved personnel should precisely define:
• Who will be responsible for the interventions?
• What activities each personnel will perform and with what frequency and intensity?

e. Data collection methods, instruments used:

Data collection tools are:
• Retrospective data (medical records)
• Questionnaires
• Interviews (Structured, Semi-Structured)
• Laboratory test (literature or personal knowledge should be referenced, if established test; or
description should be provided in details, if not established)
• Clinical examinations
• Description of instruments, tools used for data collection, as well as the methods used to test
the validity and reliability of the instrument should be provided.

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BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

f. Data Managements and Analysis Plan

This section should be written following statistical advice from a statistician. The analysis plan and
which statistical tests will be used to check the significance to the research question/hypothesis with
appropriate references should be described. Names of variables that will be used in the analyses and
the name of statistical analysis that will be performed to assess the outcome should be listed. If
computer programs are to be applied, it is important to mention the software used and its version.

7. Project Management
Work plan-A work plan is an outline of activities of all the phase of the research to be carried out
according to an anticipated time schedule. Proper time table for accomplishing each major step of
the study should be defined. Assigning time frame to each step in the trial will be helpful in
organizing the structure of the research trial. The personnel (investigators, assistants, laboratory
technicians etc.) involved in the study or data collection should be properly trained.

8. Strengths and limitations:

It is important to mention the strengths or limitations of the study, i.e., what study can achieve or
cannot achieve is important, so as to prevent wasteful allocation of resources.

9. Ethical considerations (issues for ethical Review and Approvals)

It should indicate whether the procedures to be followed are in accord with the Declaration of
Helsinki. In any case, study should not start unless approval from ethics committee is received.
The following points should be explained:
-The benefits and risks for the subjects involved. The physical, social and psychological implications
of the research.
-Details of the information to be given to the study patients including alternative
treatments/approaches.
- Information should be provided on the free informed consent of the participants.
Information form should contain: Justification for research, outline of study, risks, confidentiality,
and voluntary participation should be told patients about the freedom to withdraw from the study
whenever they wish to.
Confidentiality indicates show the personal information obtained from the patient will be kept secret
(Data safety).

10. Operational Planning and Budgeting (Budget summary)

Outline the budget requirement showing head wise expenditure for the study-man power,
transportation, instruments, laboratory tests and cost of the drug. Budget estimate is to be attached in
the annexure. All costs including personnel, consumables, equipment, supplies, communication and
funds for patients and data processing are all included in the budget. Each item should be justified.

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

Institutional Review Board: The “Institutional Review Board” (IRB) is a local administrative body
established to protect the rights, safety, and well-being of human research subjects recruited to
participate in a clinical research. The IRB has the authority to approve, require modification in, or
disapprove all research activities that fall within its jurisdiction. The IRB provides assurances to
research subjects that every reasonable attempt has been made to protect their rights and safety as
subjects.

Responsibilities of IRB/IEC
• Safeguard the rights, safety, and well-being of all trial subjects
• Reviews a proposed clinical trial within a reasonable time and document its views in writing
• Conducts continuing review of each ongoing trial at least once per year
• Ensures that information regarding payment to subjects (including the methods, amounts,
schedule of payment) is set forth in the written informed consent form and any other written
information is provided to the subjects

CONSTITUTION OF IRB
The IRB should consist at least SEVEN members, who collectively have the qualifications and
experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. viz.
1. Chairperson-Appointed (who is from outside the institution)
2. 1-2 basic medical scientists
3. 1-2 clinicians from various institutes
4. One legal expert or retired judge
5. One social scientist
6. One philosopher or ethicist
7. One lay person from community
8. Member secretary – Appointed

The Quorum (i.e. the minimum number of individuals required to conduct a meeting) has 5 persons
minimum. As per revised Schedule Y of medicine & Cosmetics Act, 1940 which is amended in
2005, they are:
1. One basic medical scientist (pharmacologist).
2. One clinician.
3. One legal expert or retired judge.
4. One social scientist/ representative of nongovernmental organization/Philosopher/ ethicist/
theologian or an identical person.
5. One lay person from the community
6. Further, based on the requirement of research area (AIDS, genetic disorders etc…) specific
patient groups may also be represented in the IRB

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FUNCTIONS AND OPERATIONS OF IRB

Operation:
• The IRB/IEC should perform its functions according to written operating procedures, should
maintain written records of its activities and minutes of its meetings, and should comply with
GCP and with the applicable regulatory requirement(s).
• An IRB/IEC should make its decisions at announced meetings at which at least a quorum, is
present.
• Only members who participate in the IRB/IEC review and discussion should vote/provide
their opinion and/or advise.
• The investigator may provide information on any aspect of the trial, but should not
participate in the deliberations (thought process) of the IRB/IEC or in the vote/opinion of the
IRB/IEC.
• An IRB/IEC may invite nonmembers with expertise in special areas for assistance.

RESPONSIBILTIES OF IRB
1. An IRB should safeguard the rights, safety and well-being (health) of all trial subjects.
The IRB should obtain the following documents.
a) trial protocol(s)/amendment(s),
b) written informed consent form(s) and consent form updates that the investigator proposes for
use in the trial, subject recruitment procedures (e.g. advertisements), written information to
be provided to subjects,
c) Investigator’s Brochure (IB),
d) available safety information,
e) information about payments and compensation available to subjects,
f) the investigator’s current curriculum vitae and/or other documentation evidencing
qualifications, and
g) any other documents that the IRB/IEC may need to fulfill its responsibilities.
h) 2. The IRB/IEC should continuing review of each ongoing trial at intervals appropriate to the
degree of risk to human subjects, but at least once per year.
i) 3. The IRB may request more information than is given to study subjects when, in the
judgment of the IRB the additional information would add meaning to the protection of the
rights, safety and/or well-being of the subjects.
j) 4.The IRB should review both the amount and method of payment to subjects to assure
neither compulsion nor effect on the trial subjects.
k) 5. The IRB/IEC should consider the qualifications of the investigator for the proposed trial,
as documented by a current curriculum vitae and/or by any other relevant documentation the
IRB/IEC requests.
l) Payments to a subject should be prorated (day basis) and not on completion of the trial by the
subject.

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m) The IRB should ensure that information regarding payment to subjects, including the
methods, amounts, and schedule of payment to trial subjects, is should be in the form of
written information.

TYPES OF REVIEWS IN IRB

The IRB’s member secretary shall screen the proposals for their completeness and depending on the
risk involved categorize them into;
• EXEMPT REVIEW Includes anonymous (no unusual features) surveys.
• EXPEDITED REVIEW Includes interviews and surveys.
• FULL BOARD REVIEW includes any work with vulnerable (risk) populations, involving
sensitive questions etc........

EXEMPT REVIEW
If the proposed research involves less than minimal risk to participants and involves any of the
following, it may qualify for exempt status.
a) Research conducted in established or commonly accepted educational institutions that
specifically involve normal education practices that are not likely to adversely affect students
educational content.
b) Research that only includes interactions involving educational tests, survey procedures,
interview procedures or observation of public behavior.
c) Taste and food quality evaluation and consumer acceptance studies.

EXPEDITED REVIEW
If the proposed research presents no more than minimal risk, does not involve any vulnerable
populations like children, prisoners, individuals with impaired decision making capacity and
economically or educationally disadvantaged persons. and involves any of the following, it may
qualify for Expedited review.
a) Collection of data from voice, video, digital or image recordings made for research purposes.
b) Collection of data through noninvasive procedures routinely employed in clinical practice
(X-rays).
c) Research involving already approved drugs.
d) When an adverse event or unexpected adverse reaction is reported.

FULL BOARD REVIEW

All research proposals presenting with more than minimal risk requires full board review.
a) Projects that involves vulnerable population.
b) Collection of blood samples.
c) Prospective collection of biological specimens like sputum, skin appendages, excreta, saliva,
amniotic fluid.
d) Procedures that might cause significant psychological or emotional distress.

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e) Collection of information about highly sensitive topics.

f) Collection of information that could seriously harm the participant legally, socially,
financially etc...

DECISIONS OF IRB
a) Out right approval (at most, only very minor changes are suggested. The application
contained all necessary information)
b) Approval with modification ( there is enough information to judge the study, but clarification
or changes are needed)
c) Resubmit with more information ( there is not enough information to judge the application
appropriately)
d) Outright disapproval ( there is no way the researcher can ethically do study)

INFORMED CONSENT FORM

• Informed consent is the process in which a health care provider educates a patient about the
risks, benefits, and alternatives of a given procedure or intervention.
• Information must be presented to enable persons to voluntarily decide whether or not to
participate as a research subject.
• The procedures used in obtaining informed consent should be designed to educate the
subjects population in terms that they can understand.

Goals of the informed consent process

• Give the subject information about the research
• Make sure the subject has time to consider all options
• Answer all of the subject’s questions before the decision is made
• Make sure that all information is understood by the subject
• Obtain the subject’s voluntary informed consent to participate
• Continue to inform the subject throughout the research study
• Continue to re-affirm subject consent to participate throughout the research study

Some general guidelines for writing consent form

• Consent forms should be written in simple, non-technical language for readers of a seventh-
grade reading level who may not have taken science courses in school.
• Use the term “subject” rather than “patient” (the term “participant” may be used in some
behavioral research).
• Avoid statements that suggest any waiver of subject rights or release from liability of the
investigator or sponsor.
• Write all of the consent form except the consent section in the second person (“you are asked
to”) rather than first person or third person.
• The consent section should be written in first person (“I consent to…”).

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• Do not make claims of safety or efficacy for investigational articles or procedures

Consent form elements

Introductory Information and Purpose
• Explain the research study and the expected duration of subject participation, and include the
approximate number of subjects involved in the study.
• Reassure readers that it is appropriate to ask questions, and that they may take the form home
for consideration (if appropriate for the given research).
• State clearly that the study is research.
• State the purpose(s) of the research; for example, drug protocols usually test for safety,
tolerability and effectiveness.
• State why the person is being asked to participate in the study; for example, “You are being
asked to participate in this study because you have been diagnosed with…”

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• State the status of the test article based on the country where the research is being conducted;
for example, in the U.S., drugs are “approved,” vaccines are “licensed,” and devices are
“approved for marketing,” otherwise they should be designated as “investigational.”

Description of Study/Procedures
• Describe the visits and procedures (in agreement with the protocol), indicating which
procedures are experimental.
• Briefly describe the study’s design; for example, “This is a dose escalation study. As subjects
participating in the study tolerate a specific dose level, the new subjects entering the study
will be given a higher dose of the study drug.”
• Explain the method used for determining if subjects will receive study drug or placebo, the
method for assigning them to a group, and explain the chance of assignment to each group in
the study.
• State the number of visits.
• Explain the length of study participation.
• Explain what happens at the visits.

Content of informed consent form

Risks and Discomforts
Describe any reasonably foreseeable risks and discomforts to the subject. Risks and discomforts
must be stated in non-technical, layperson’s language.
Provide the risks related to all drugs required by the protocol, including rescue medications, over-
thecounter analgesics, and approved control group drugs.
Include the possibility of allergic reactions and that serious allergic reactions can be life-threatening.
Describe the risks and discomforts of invasive or unusual procedures, including protocol- required
biopsies.
Describe the risks and discomforts of blood draws, if subjects will have blood drawn.
Include a statement explaining that there may be risks of participation and side effects which are still
unknown.
• Whether known or unknown, explain the risks to women who are pregnant or who become
pregnant during the study.
• Include a statement that unknown risks and discomforts are possible; if appropriate, include
unknown risks to an embryo or fetus if a subject (or a subject’s partner) is or becomes
pregnant.

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• Where applicable, include the risk that the subject’s condition may worsen while they are in
the study (whether assigned to active drug or placebo).

Expected Benefits
Describe any possible benefits to the subject or others; indicate that benefits are not guaranteed. If
statements regarding direct benefits of participation are included, they should be qualified as
“possible” or that they “may” occur.

Costs
Describe any known or anticipated costs to the subject. State who is responsible for the costs of the
study-related items such as medications, procedures, device, visits, hospitalization and treatment for
possible side effects. Indicate which procedures and items will be provided at no charge. If insurance
will be billed for anything, include information about possible costs to the subject or their insurance.
If anything is being billed to insurance, discuss what happens if the insurance does not pay.

Payment for Participation

• Describe the planned prorated payment for participation, if any.
• Any money or other incentive of monetary value should be listed in this section rather than
the benefit section.
• If subjects are to be paid, state specifically for which visits subjects will receive payment and
when such payment will be made; for example, “payment will be made at the end of each
study visit,” “payment will be made at the end of the last study visit” or “payment will be
made within one month after the last study visit.” Be as specific as possible to minimize
confusion.
• Compensation for Injury
• Outline the plans for compensation and/or medical treatment for research-related injury or
illness, including who will be responsible for the costs.
• Explain what will happen if the subject gets injured. Explain how they will get treatment.
• Clearly state who will pay for treatment if the subject is harmed.
• Address what will happen if the subject’s insurance is billed for the treatment, but refuses to
pay.

GCP obligations of Investigators, sponsors & Monitors

Investigator
Investigator’s Qualifications and Agreements
The investigator(s) should be qualified by education, training, and experience to take responsibility
for the proper conduct of the trial, should meet all the qualifications specified by the applicable
regulatory requirement(s), and should provide evidence of such qualifications (such as CV)

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The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by
the appropriate regulatory authority(ies).

Roles of investigators
1. Adequate Resources
• The investigator should recruited the required number of suitable subjects within the agreed
recruitment period.
• The investigator should have sufficient time to properly conduct and complete the trial within
the agreed trial period.
• The investigator should have available an adequate number of qualified staff and adequate
facilities to conduct the trial properly and safely.
• The investigator should ensure that all persons involve with the trial are adequately informed
about the protocol, the investigational product(s), and their trial-related duties and functions.

2. Medical Care of Trial Subjects

• Investigator should be responsible for all trial-related medical (or dental) decisions.
• During and following a subject’s participation in a trial, the investigator/institution should
ensure that adequate medical care is provided to a subject for any adverse events, including
clinically significant laboratory values, related to the trial.
• The investigator should inform a subject when medical care is needed for inter current
illness(es) of which the investigator becomes aware.
• It is recommended that the investigator inform the subject’s primary physician about the
subject’s participation in the trial if the subject has a primary physician and if the subject
agrees to the primary physician being informed.

3. Communication with IRB/IEC

• Before initiating a trial, the investigator/institution should have written and dated approval
from the IRB/IEC for the trial protocol, written informed consent form, consent form
updates, subject recruitment procedures (e.g., advertisements), and any
• other written information to be provided to subjects.
• The investigator/institution should provide the IRB/IEC with a current copy of the
Investigator’s Brochure.
• If the Investigator’s Brochure is updated during the trial, the investigator/institution should
supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
• During the trial the investigator/institution should provide to the IRB/IEC all documents
subject to review.

4. Investigational Product(s)
• Responsibility for investigational product(s) accountability at the trial site(s) rests with the
investigator/institution.

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• The investigator/institution and/or a pharmacist or other appropriate individual, who is

designated by the investigator/institution, should maintain records of the product’s delivery
to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor
or alternative disposition of unused product(s).
• These records should include dates, quantities, batch/serial numbers, expiration dates (if
applicable), and the unique code numbers assigned to the investigational product(s) and trial
subjects.
• The investigator should ensure that the investigational product(s) are used only in accordance
with the approved protocol.

5. Randomization Procedures and Unblinding

• The investigator should follow the trial’s randomization procedures, if any, and should
ensure that the code is broken only in accordance with the protocol.
• If the trial is blinded, the investigator should promptly document and explain to the sponsor
any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse
event) of the investigational product(s).

6. Informed Consent of Trial Subjects

• In obtaining and documenting informed consent, the investigator should comply with the
applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles
that have their origin in the Declaration of Helsinki.
• Prior to the beginning of the trial, the investigator should have the IRB/IEC’s written
approval informed consent form and any other written information to be provided to subjects.
• Prior to a subject’s participation in the trial, the written informed consent form should be
signed and personally dated by the subject

7. Records and Reports

• The investigator/institution should maintain adequate and accurate source documents and
trial records that include all pertinent observations on each of the site’s trial subjects.
• The investigator should ensure the accuracy, completeness, legibility, and timeliness of the
data reported to the sponsor in the CRFs and in all required reports.
• Any change or correction to a CRF should be dated, initialed, and explained. The investigator
should retain records of the changes and corrections.
• The financial aspects of the trial should be documented in an agreement between the sponsor
and the investigator/institution.
• Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator
should make available for direct access all requested trial-related records.

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8. Progress Reports
• The investigator should submit written summaries of the trial status to the IRB/IEC annually,
or more frequently, if requested by the IRB/IEC.
• The investigator should promptly provide written reports to the sponsor, the IRB/IEC and,
where applicable, the institution on any changes significantly affecting the conduct of the
trial, and/or increasing the risk to subjects.

9. Safety Reporting
• All serious adverse events (SAEs) should be reported immediately to the sponsor except for
those who not needing immediate reporting.
• The investigator should also comply with the applicable regulatory requirement(s) related to
the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies)
and the IRB/IEC.
• For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any
additional requested information (e.g., autopsy reports and terminal medical reports).

10. Premature Termination or Suspension of a Trial

• If the trial is prematurely terminated or suspended for any reason, the investigator/institution
should promptly inform the trial subjects.
• If the investigator terminates or suspends a trial without prior agreement of the sponsor, the
investigator should inform the institution, the sponsor and the IRB/IEC, and should detailed
written explanation of the termination or suspension.
• If the sponsor terminates or suspends a trial, the investigator should promptly inform the
institution and IRB/IEC with detailed written explanation of the termination or suspension.
• If the IRB/IEC terminates or suspends its approval/favorable opinion of a trial, the
investigator should inform the institution and sponsor and provide detailed written
explanation of the termination or suspension.

11. Final Report(s) by Investigator

• Upon completion of the trial, the investigator, should inform the institution; the
investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome,
and the regulatory authority(ies) with any reports required.

Sponsor
1. Quality Management
• The sponsor should implement a system to manage quality throughout all stages of the trial
process.
• Sponsors should focus on trial activities essential to ensuring human subject protection and
the reliability of trial results.

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

• The sponsor should ensure that all aspects of the trial are operationally feasible and should
avoid
• unnecessary complexity, procedures, and data collection. Protocols, case report forms, and
other operational documents should be clear, concise, and consistent.

2. Critical Process and Data Identification

• During protocol development, the sponsor should identify those processes and data that are
critical to ensure human subject protection and the reliability of trial results.

3. Risk Identification
• The sponsor should identify risks to critical trial processes and data. Risks should be
considered at both the system level (e.g., standard operating procedures, computerized
systems, personnel) and clinical trial level (e.g., trial design, data collection, informed
consent process).

4. Risk Evaluation
• The sponsor should evaluate the identified risks, against existing risk controls by
considering:
• (a) The likelihood of errors occurring.
• (b) The extent to which such errors would be detectable.
• c) The impact of such errors on human subject protection and reliability of trial results.

5. Risk Control
• The sponsor should decide which risks to reduce and/or which risks to accept. Risk reduction
activities may be incorporated in protocol design and implementation, monitoring plans,
defining roles and responsibilities, systematic safeguards to ensure adherence to standard
operating procedures, and training in processes and procedures.

6. Quality Assurance and Quality Control

• The sponsor is responsible to ensure that trials are conducted and data are generated,
documented (recorded), and reported in compliance with the protocol, GCP, and the
applicable regulatory requirement(s).
• The sponsor is responsible to ensure direct access to all trial related sites, source
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and
inspection by domestic and foreign regulatory authorities.

7. Medical Expertise
• The sponsor should designate appropriately qualified medical personnel who will be readily
available to advise on trial related medical questions or problems. If necessary, outside
consultant(s) may be appointed for this purpose.

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

8. Trial Design, Trial Management, Data Handling, and Record Keeping

• The sponsor should utilize qualified individuals (e.g. biostatisticians, clinical
pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, for
designing the protocol, CRFs, to supervise the overall conduct of the trial, to handle the data,
to verify the data, to conduct the statistical analyses, and to prepare the trial reports.

9. Investigator Selection
• The sponsor is responsible for selecting the investigator(s)/institution(s). The sponsor should
provide the investigator(s)/institution(s) with the protocol and an up-to-date
• Investigator’s Brochure, and should provide sufficient time for the investigator/institution to
review the protocol and the information provided.

10. Compensation to Subjects and Investigators

• If required by the applicable regulatory requirement(s), the sponsor should provide insurance
or othe legal and financial coverage to the subjects and investigator against claims arising
from the trial, except for claims that arise from malpractice and/or negligence

11. Information on Investigational Product(s)

• When planning trials, the sponsor should ensure that sufficient safety and efficacy data from
nonclinical studies and/or clinical trials are available to support human exposure by the route,
at the dosages, for the duration, and in the trial population to be studied.

12. Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)

• The sponsor should ensure that the investigational product(s) (including active comparator(s)
and placebo, if applicable) is characterized as appropriate to the stage of development of the
product(s), is manufactured in accordance with any applicable GMP, and is coded and
labelled in a manner that protects the blinding, if applicable.
• The sponsor should determine, for the investigational product(s), acceptable storage
temperatures, storage conditions (e.g. protection from light), storage times, reconstitution
fluids and procedures, and devices for product infusion, if any. The sponsor should inform all
involved parties (e.g. monitors, investigators, pharmacists, storage managers) of these
determinations.
• The investigational product(s) should be packaged to prevent contamination and
unacceptable deterioration during transport and storage.
• In blinded trials, the coding system for the investigational product(s) should include a
mechanism that permits rapid identification of the product(s) in case of a medical emergency,
but does not permit undetectable breaks of the blinding.

13. Supplying and Handling Investigational Product(s)

• The sponsor should:

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

• a) Ensure timely delivery of investigational product(s) to the investigator(s).

• b) Maintain records that document shipment, receipt, disposition, return, and destruction of
the investigational product(s)
• c) Maintain a system for retrieving investigational products and documenting this retrieval
(e.g. for deficient product recall, reclaim after trial completion, expired product reclaims).
• d) Maintain a system for the disposition of unused investigational product(s) and for the
documentation of this disposition.

14. Record Access

• The sponsor should ensure that the investigator(s)/institution(s) provide direct access to
source data/documents for trial related
• monitoring, audits, IRB/IEC review, and regulatory inspection.
• The sponsor should verify that each subject has consented, in writing, to direct access to
his/her original medical records for trial-related monitoring, audit, IRB/IEC review, and
regulatory inspection.

15. Adverse Drug Reaction Reporting

• The sponsor should expedite the reporting of all adverse drug reactions (ADRs) that are both
serious and unexpected to the IRB(s)/IEC(s), where required, and to the regulatory
authority(ies)

Monitor:
• Purpose
• The purposes of trial monitoring are to verify that:
• (a) The rights and well-being of human subjects are protected.
• (b) The reported trial data are accurate, complete, and verifiable from source documents.
• (c) The conduct of the trial is in compliance with the currently approved
protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).

Selection and Qualifications of Monitors

• (a) Monitors should be appointed by the sponsor.
• (b) Monitors should be appropriately trained, and should have the scientific and/or clinical
knowledge needed to monitor the trial adequately. A monitor’s qualifications should be
documented.
• (c) Monitors should be thoroughly familiar with the investigational product(s), the protocol,
written informed consent form and any other written information to be provided to subjects,
the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).

Extent and Nature of Monitoring

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

• The sponsor should ensure that the trials are adequately monitored. The sponsor should
determine the appropriate extent and nature of monitoring.
• The determination of the extent and nature of monitoring should be based on considerations
such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial.
• In general, there is a need for on-site monitoring, before, during, and after the trial.
• Two types of monitoring:
a. On-site monitoring is performed at the sites at which the clinical trial is being conducted.
b. Centralized monitoring is a remote evaluation of accumulating data, performed in a timely
manner, supported by appropriately qualified and trained persons. Ex: investigators’ training and
meetings, and review of statistical analysis.

Monitor’s Responsibilities.
• The monitor(s) in accordance with the sponsor’s requirements should ensure that the trial is
conducted and documented properly by carrying out the following activities :
a. Acting as the main line of communication between the sponsor and the investigator.
b. Verifying that the investigator has adequate qualifications and resources (laboratories, equipment
and staff) remain adequate.

c. Verifying, for the investigational product(s):

i. That storage times and conditions are acceptable, and that supplies are sufficient throughout
the trial.
ii. That the investigational product(s) are supplied only to subjects who are eligible to receive it
and at the protocol specified dose(s).
iii. Those subjects are provided with necessary instruction on properly using, handling, storing,
and returning the investigational product(s).
iv. That the receipt, use, and return of the investigational product(s) at the trial sites are
controlled and documented adequately.
v. That the disposition of unused investigational product(s) at the trial sites complies with
applicable regulatory requirement(s) and is in accordance with the sponsor.

d. Verifying that the investigator follows the approved protocol.

e. Verifying that written informed consent was obtained before each subject’s participation in the
trial
f. Ensuring that the investigator receives the current Investigator’s Brochure, all documents, and all
trial supplies needed to conduct the trial properly and to comply with the applicable regulatory
requirement(s)
g. Ensuring that the investigator and the investigator’s trial staff are adequately informed about the
trial.

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

h. Verifying that the investigator and the investigator’s trial staff are performing the specified trial in
accordance with the protocol and any other written agreement between the sponsor and the
investigator/institution
i. Verifying that the investigator is enrolling only eligible subjects
j. Verifying that source documents and other trial records are accurate, complete, kept up-to-date and
maintained.
k. Verifying that the investigator provides all the required reports, notifications, applications, and
submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the
trial.

l. Checking the accuracy and completeness of the CRF entries, source documents and other trial-
related records against each other. The monitor specifically should verify that:
• i. The data required by the protocol are reported accurately on the CRFs and are consistent.
• ii. Any dose and/or therapy modifications are well documented for each of the trial subjects.
• iii. Adverse events, concomitant medications and inter current illnesses are reported in
accordance with the protocol on the CRFs
• v. All withdrawals and dropouts of enrolled subjects from the trial are reported and explained
on the CRFs.
m. Determining whether all adverse events (AEs) are appropriately reported within the time periods
n. Determining whether the investigator is maintaining the essential documents

Monitoring Plan
The sponsor should develop a monitoring plan that is tailored to the specific human subject
protection and data integrity risks of the trial. The plan should describe the monitoring strategy, the
monitoring responsibilities of all the parties involved, the various monitoring methods to be used,
and the rationale for their use. The plan should also emphasize the monitoring of critical data and
processes. Particular attention should be given to those aspects that are not routine clinical practice
and that require additional training. The monitoring plan should reference the applicable policies and
procedures.
Audit
If or when sponsors perform audits, as part of implementing quality assurance, they should consider:
Purpose
The purpose of a sponsor’s audit, which is independent of and separate from routine monitoring or
quality control functions, should be to evaluate trial conduct and compliance with the protocol,
SOPs, GCP, and the applicable regulatory requirements.

Selection and Qualification of Auditors

a) The sponsor should appoint individuals, who are independent of the clinical trials/ systems, to
conduct audits.

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

b) The sponsor should ensure that the auditors are qualified by training and experience to conduct
audits properly. An auditor’s qualifications should be documented.
Auditing Procedures
a) The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance
with the sponsor’s written procedures on what to audit, how to audit, the frequency of audits, and the
form and content of audit reports.
b) The sponsor’s audit plan and procedures for a trial audit should be guided by the importance of
the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and
complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).
c) The observations and findings of the auditor(s) should be documented.
d) When required by applicable law or regulation, the sponsor should provide an audit
certificate.

Pharmacovigilance may be a process of constant monitoring and evaluation of all adverse events
during drug development process, to make sure the security of the participants (subjects) and a
continuing assessment of the risk and benefit. Pharmacovigilance is the process of monitoring the
effects of drugs, both new and existing ones. This includes collecting data, analyzing it, and taking
steps to prevent any negative effects. Pharmacovigilance must happen throughout the entire life
cycle of a drug, from when it is first being developed to long after it has been released on the market.

Aim of Pharmacovigilance
• To improve patient care & safety
• To contribute to assessment of benefit, harm & effectiveness of medicine
• To Identify previously unrecognized adverse effects of the drugs
• To Promote rational & safe use of medicine
• To Promote education & clinical training
• To Identify patient related risk factors of ADR such as dose, age, gender
• Any response to a drug which is unintended, occurs at particular doses
• To diagnose or therapy of disease, or for the modification, of physiological function.

Pharmacovigilance - safety monitoring in clinical trials

• Clinical monitoring is the oversight and administrative efforts that monitor a participant’s
health and efficacy of the treatment during a clinical trial.
• Both independent and government-run grant-funding agencies, such as the National Institutes
of Health (NIH) and the World Health Organization (WHO), require data and safety
monitoring protocols for Phase I and II clinical trials.

Safety monitoring
• Safety monitoring of a clinical trial is conducted by an independent physician with relevant
expertise.

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

• This is accomplished by review of adverse event, immediately after they occur, with timely
follow-up through resolution.
• Responsibility for data and safety monitoring depends on the phase of the study and may be
conducted by sponsor or Contract research organization (CRO) staff or contractor, and/or by
the Principal clinical investigator/project manager conducting the study.
• Regardless of the method used, monitoring must be performed on a regular basis.
• Oversight of the monitoring activity is the responsibility of the sponsor.
• Pharmacovigilance looks at all available information to assess the safety profile of a drug
• Pharmacovigilance should also take the benefit of the drug in account.
• Pharmacovigilance works by
-ADR Sharing
-Suspicion Reporting
-Analysis of Findings

Adverse Drug Reactions

• ADR is a response to drug, which alters the normal physiological function of the body,
factors which causes ADR includes mainly multiple drug therapy, age & gender.
• They are mainly two types of ADR
TYPE A: These are common, predictable, dose dependent, they are seldom fatal
TYPE B: These are uncommon, unpredictable, dose independent; they involve relatively high
rates of serious morbidity.
• India is a hub of Global Clinical trials & a destination for Drug Discovery & Development.
• However, whether patients in India receive safe drugs or not is still very much in question
Rapid induction of NCEs and high tech Pharma products in the market throw up the
Challenges of monitoring Adverse Drug Reactions (ADRs) over large multiethnic population
base.

Who Should Report Safety Data

• Physicians
• Pharmacists
• Pharmaceutical companies qualified persons-(Pharmacovigilance/Regulatory manager)
• Investigators (clinical trials)
What to Report?
• It is important to report serious unexpected ADRs.
• Most cases of unexpected ADRs are associated with medicines newly introduced on the
market.
• All suspected adverse reactions.
• Every single problem related to the use of a drug.
• ADRs associated with radiology contrast media, vaccines, diagnostics, drugs used in
traditional medicine, herbal remedies, cosmetics, medical devices and equipment.

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

Importance of Pharmacovigilance
• Complete safety data (especially for unexpected and serious adverse events) can only be
captured through Pharmacovigilance.
• It cannot be captured through clinical trials which are conducted in an “artificial
environment.”
• In clinical trials
-patients are not taking any other medications
-do not have concomitant diseases
-are taking the drug short-term (during the duration of the trials only) and
-are not part of vulnerable groups (e.g., children, pregnant women, elderly, etc.)

Pharmacovigilance programme of India (PVPI)

It officially starts on 23rd November 2004 at New Delhi, is under the control of CDSCO (Central
Drug Standard Control Organization), Directorate general of health services, Indian
pharmacopeia commission (Ghaziabad).
The program is conducting by NCC (National Coordinating Centre) to ensure that the benefits of
use of medicine against the risks.
It was Launched by the MoHFW, Govt. of India in the year 2010 at AIIMS New Delhi as
National Coordinating Centre (NCC). The Programme transferred to IPC as NCC in April, 2011
by a Notification issued by the MoHFW, Govt. of India.
IPC-PvPI became the NCC for Materiovigilance Programme of India (MvPI) from July, 2015.
IPC, NCC-PvPI became a WHO Collaborating Centre for Pharmacovigilance in Public Health
Programmes & Regulatory services from July, 2017

Objectives:
• To monitor ADRs
• To create awareness among health care professionals about ADRs
• To monitor benefit-risk profile of medicines
• Support the CDSCO

Sponsor’s responsibilities in Pharmacovigilance:

• Use and adopt Pharmacovigilance procedure(s) to monitor adverse reactions occurring in
clinical trials.
• Modifications in protocol due to safety or efficacy concerns (e.g., dosage changes, changes in
study inclusion criteria, intensification of monitoring);
• Restrictions in study population or indications;
• Changes to the informed consent document relating to safety issues;
• Formulation changes for safety reasons; • Addition of a special reporting requirement;
• plans for new safety trials;

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

• On going safety evaluation of the investigational medicinal products;

• Immediate notification of finding from the clinical trials that could adversely affect the health
of subjects;
• Reporting of ADRs in Clinical Trial

Investigator’s responsibility in Pharmacovigilance

• The investigator shall report all SAEs immediately to the sponsor except for those that the
protocol or IB identifies as not requiring immediate reporting.
• For reported deaths of a subject, the investigator shall supply the sponsor and the Ethics
Committee with any additional information requested.
• The sponsor shall keep detailed records of all AEs reported to him by the investigator.
• In blinded clinical trials, Pharmacovigilance role of investigator gets extended to the
management of blinded therapy cases.

Safety update reports

• Development Safety Update Report (DSUR) should serve as a “stand-alone” document
suitable for submission to ethics committees and other stakeholders, if required by local
regulations.
• The primary focus should be on the investigational drug (s) and information on comparators
is provided only where relevant to the safety of trial subjects.
• SURs present safety profile of an investigational drug and actions proposed (viz early
termination of the trial, ongoing status, addition of any extra visit for patient for evaluation of
safety etc)

Galgotias College of Pharmacy B. Pharm (VIII Sem)