The document summarizes key aspects of clinical trial protocols, including: 1) Protocols include sections like the title page, objectives, study design, safety reporting, and informed consent. Well-written protocols use clear, unambiguous language and define all abbreviations. 2) Eligibility criteria should be minimized but ensure scientific validity and safety. Criteria must be clearly defined and verifiable. 3) Institutional review boards (IRBs) are responsible for protecting human subjects. IRBs must have at least five members from varied backgrounds to review protocols and ensure ethical standards are followed.

1. Masters of pharmacy, Pharmaceutical technology (Pharmaceutics)
Subject- Drug regulatory affairs (MPT-104T)
Lesion no- 4, CLINICAL TRIALS by- Drx JAYESH M RAJPUT
Points:-
1) Developing clinical trial protocols
Protocol writing- is a complete written description and scientific rationale for a research activity involving human
subjects which includes objectives, design, and methodology.
Who reads protocols?
The protocol language/content should be understood by other physicians, nurses/CRAs, IRB members, scientific
reviewers, IC for a lay person.
Parts of the protocol
1. Title page
2. Signature page
3. Content page
4. List of abbreviations
5. Introduction/Abstract
6. Objectives
7. Background/rationale
8. Eligibility criteria
9. Study design/ methods (including drug/device info)
10. Safety/ adverse events
11. Regulatory guidance
12. Statistical section (including analysis and monitoring)
13. Human subjects protection/informed consent
1) Title page:- title page introduce the document, its title , precise number, sponsor and author to the reader. Protocol
identifying number and date any amendment should also bear the amendment number and date. The protocol number
must clearly indicate the version number, whether it is final or draft and date of this version. Title page should include
A) full title should include summary study design, medicinal products, nature of treatment (eg:- treatment, prophylaxis
and diagnosis) comparator placebo, indication patient population setting (eg:- in-patient, outpatient) randomized double

2. bind multiple studies, name and address of sponsor and monitor. Sponsor names and list of responsibilities with agreed
allocations, name and address of the person authorized to sign the protocol amendment for the sponsor. Generally chief
investigator for multicentric trial or principle investigator for single center trials. Name, title, address and telephone
number of the sponsor medical expert for the trial.
Name, title, address and telephone number of the sponsor medical expert for the trial
Name and title of the investigator who is responsible for conducting the trial, and the address and telephone number of
the trial site
Name, title, address and telephone number of the qualified physician who is responsible for all trial site related medical
decisions
Name and address of the clinical laboratory and other medical and/ or technical and/ or institutions involved in the trial.
2) Signature page:- signature page of all healthcare professionals in the trial including contact details of participating
site, sponsor and sponsor medical advisor if not already given above.
3) content page:- this help navigation through the document by large number of different people that will be needed
throughout the life of the trial.
4) list of abbreviations:- all abbreviations used should be listed and defined. Accepted international medical
abbreviations should be standardized within each project
5) introduction/abstract:- this summary should be only one to two pages long. It should give the reader sufficient
information to understand the rationale for the trial, its objective and the methods that will be used to achieve these
objective.
6) Objectives:- objectives should be stated clearly as hypotheses to be tested. Each objective should have a
corresponding discussion in the statistical section.
7) Background and rationale:- all protocols require a section detailing the scientific rationale for a protocol and the
justification in medical and scientific literature for the hypothesis being proposed. Introductory section should be
organized in a logical, sequential flow.
Double check all citations, common mistakes, name misspellings (including wrong initials), wrong journal names, wrong
years of publication and wrong volume numbers.
8) Eligibility criteria- definition:- inclusion and exclusion criteria are the conditions that must be met in order to
participate in a clinical trial. The most important criteria used to determine appropriateness for clinical trial participation
include age, sex, the type and stage of a disease, treatment history, and other medical conditions.
Writing eligibility criteria for patient
Eligibility criteria are the largest barrier to clinical trials, there is no guideline for writing these criteria, poorly written or
poorly conceived criteria may affect the scientific validity of CT. reasons for imposing eligibility criteria includes scientific
rationales, safety concerns, regulatory issues, and practical considerations,
The points to be considered to write a good eligibility criteria

3. The number of eligibility criteria should be kept to a minimum, criteria should include only those absolutely necessary to
ensure scientific validity and patient safety, eligibility criteria should be clearly defined and verifiable by an external
auditor. Eligibility criteria should be straightforward and unambiguous. Which of these criteria is better understood?
A) pregnant and/or nursing women are not eligible
b) all women of childbearing age are required to have a negative serum pregnancy test
c) nursing women are not eligible for this study. All women of childbearing potential must have a negative serum
pregnancy test within 2 weeks of study enrollment.
Failure to write eligibility criteria properly:-
Leads to failure to mimic clinical practice, increased study complexity, increased costs, less number of patient getting
recruited
9) study design:- the study design section of the protocol should contain a stepwise description of all procedures
required by the study, a good study design section includes sufficient information for the participating site.
Parts of the study design section may include:-
Initial evaluations, screening tests, required lab tests, details of treatment or procedures, device specifications, dose
scheduling and modification, calendars.
10) Safety:- adverse effect and side effect are terms commonly associated with drugs. They are used by nurses and
doctors, to refer to undesirable effects of a medication on a patient, the safety (or adverse events) section should
include:- detailed information for reporting adverse events, including reporting to the FDA and/or the sponsor,
unblinding processes (if applicable), lists of expected adverse events.
11) The statistical section:- the study objectives and study design elements in the statistical section should be described
in the objectives section, the descriptions and definitions of toxicities in the safety/AE section.
12) Human subjects protection:- this section includes discussion of:- subject selection and exclusion, proposed methods
of patient recruitment, minority representation, recruitment (or exclusion) of special subjects, including vulnerable
subjects, lists of potential risks and benefits, including justification for risks.
Informed consent
Disclosure of relevant information to prospective research subjects, comprehension of the information provided to the
subject, voluntary agreement of the subject
The protocols informed consent must
Be thorough and complete, be written in simple, nontechnical language, be carefully worded to avoid complexity
The protocols informed consent must provide
Statement that the study involves research, purpose of the research and the length of the study, description of risks and
benefits, discussion of alternative therapies, confidentiality policy, compensation for injury, contact for further
questions/information, statement of voluntary participation.

4. Tools for better writing: proofreading
Working too long on a protocol may habituate eyes and brains to mistakes, simply because they’ve been there all along
Spell-checkers, etc.
A document should be checked by automatic software
The document should be proof read.
2) Institutional review board.
Experimentation on human being is subject to ethical standards that promote respect for all and protect their health and
rights.
Research requiring ethical review:
Research involving living human subjects and use of their medical records, research involving human remains, cadavers,
biological fluids, tissues, embryos, fetuses and etc.
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.
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.
 Chairperson-appointed (who is from outside the institution)
 1-2 basic medical scientists
 1-2 clinicians from various institutes
 One legal expert or retired judge
 One social scientist
 One philosopher or ethicist
 One lay person from community
 Member secretary- appointed
Quorum of IRB
For reviewing and making decision on each protocol the quorum of IRB should be at least FIVE members with the
following representations:
 Basic medical scientists (preferably one pharmacologist)
 Clinicians
 Legal expert
 Social scientist/ representative of non-governmental voluntary agency/ philosopher/ ethicist/ theologian or a
similar person
 Lay person from the community

5.  In any case, the IRB must include, at least one member whose primary area of interest/ specialization Is
nonscientific, at least one member who is independent of the institution/ trial site
 Besides, there should be appropriate gender representation on the IRB
 If required, subject experts may be invited to offer their views
 Further, based on the requirement of research area, eg, AIDS, genetic disorders etc, specific patient groups may
also be represented in the IRB.
Functions and operations of the IRB
 Only those IRB members who are independent of the clinical trial and the sponsor of the trial should vote/ provide
opinion in matters related to the study
 Only members who participate in the IRB/IEC review and discussion should vote/ provide their opinion and /or
advise
 The IRB should perform its functions according to written standard operating procedures, should maintain written
records of its activities and minutes of its meetings and should comply with GCP and with the application
regulatory requirements.
 Ensuring that the IRB promptly notify in writing the investigator/ institution concerning
 Its trial related decisions/ opinions
 The reasons for its decisions/ opinions
 Procedures for appeal of its decisions/ opinions
Responsibility of IRB
 An IRB should safeguard the rights, safety and well-being of all trial subjects
 The IRB should obtain the following documents
 Trial protocols/ amendments written informed consent forms
 Subject recruitment procedures (e.g.:-advertise)
 Written information to be provided to subjects
 Investigators brochure IB
 Available safety information
 Information about payments and compensation
 Investigators current curriculum vitae
 Any other may need to fulfill its responsibilities
 Approval/ favorable opinion
 Modifications required prior to its approval/ favorable opinion
 Disapproval/ negative opinion
 Termination/ suspension of any prior approval/ favorable opinion
 The IRB should ensure that information regarding payment to subjects, including the methods, amounts, and
schedule of payment to trial subjects, is set forth in written informed consent form any other written information
to be provided to subjects
3) Independent ethics committee
An independent ethics committee consisted of medical and professional members, whose responsibility it is to
ensure the protection of the rights, safety, and well being of human subjects involved in biomedical research and
to provide public assurance of that protection by among other things, reviewing and approving providing

6. favorable opinion on the research protocol, the sustainability of the investigator/ researcher facilities, and the
methods and material to be used in obtaining and documenting informed consent of the research subjects.
Responsibilities of IEC
o Safeguard the rights, safety, and well-being of all trial subjects
o Reviews a proposed clinical trial within a reasonable time and document its views in writing
o Conducts continuing review of each ongoing trial at least once per year
o 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
An IEC should safeguard the rights, safety and well-being of all trial subjects. Special attention should be paid to
trials that may include vulnerable subjects.
Procedures of IEC
Determines its composition and authority under which it is established
Schedules, notifies its members of, and conducts its meetings
Conducts initial and continuing review of trials
Specifies that no subject should be admitted to a trial before the IRB/IEC issues its written approval /
favorable opinion of the trial
Specifies the information that the investigator should promptly report to the IRB/IEC ( like deviations from
the protocol, adverse drug reactions, etc)
Informed consent process:- the IEC may request more information to be given to subjects when, in the judgment of
the IEC the additional information would add meaningfully to the protection of the rights, safety and well-being of the
subjects.
Informed consent form
 A major component of GCP is the method by which the researchers will obtain voluntary and informed consent
from subjects
 Informed consent is a process, not just a form
 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 subject population in
terms that they can understand
In seeking informed consent the following information should be provided to the subject
Statement that the study involves research and explanation of the purpose of the research
Expected duration of the subject’s participation
Description of the procedures to be followed, including all invasive procedures
Description of any reasonably foreseeable risks or discomforts to the subject
Description of any benefits to the subject or others reasonably expected from research. If no benefit is
expected subject should be made aware of this
Disclosure of specific appropriate alternative procedures or therapies available to the subject

7. Statement description the extent to which confidentiality of records identifying the subject will be maintained
and who will have access to subject medical records
Trial treatment schedule and the probability for random assignment to each treatment
Compensation and treatment available to the subject in the event of a trial related injury
An explanation about whom to contact for trial related queries, rights of subjects and in the event of any
injury
The anticipated prorated payment, if any, to the subject for participating in the trial
Subjects responsibilities on participation in the trial
Statement that participation is voluntary, that the subject can withdraw from the study at any time and that
refusal to participate will not involve any penalty or loss of benefits to which the subject is otherwise entitled
Formulation of IEC
IEC consists of members, who collectively have the qualifications and experience to review and evaluate the science,
medical aspects, and ethics of the proposed trials, it includes at least five members, of which at least one member whose
primary area of interest is nonscientific, and at least one member who is independent of the institution/ trial site.
Landmark document
 The Nuremburg code: - permissible medical experiments “trials of war criminals before the nuermberg military
tribunals under control council law no.10, 1949.
 Helsinki declaration:- world medical association general assembly, Edinburgh, Scotland, October 2000
The world medical association (WMA) has developed the declaration of Helsinki as a statement of ethical
principles for medical research involving human subjects, including research on identifiable human material and
data the first version was adopted in 1964 and has been amended six times since, most recently at the general
assembly in October 2008. The current (2008) version is the only official one.
 Belmont report of 1979:- report of the national commission for the protection of human subjects of behavioral
research, DHEW, April 1979.
4) HIPAA- Health insurance portability and accountability act. (1996)
Health insurance portability and accountability act goal is to make law easier for people to keep health insurance,
protect the confidentiality and security of health care information, and help healthcare industry to control
administrative cost. HIPAA consist of:- 1. Standardized electronic data interchange transaction and codes for all
covered entities 2. Standards for security of data systems 3. Privacy protections for individual health information 4.
Standard national identifiers for health care.
Why HIPAA comes in picture?
 In 2000, many patients that were newly diagnosed with depression received free samples of anti-depressant
medications in their mail
 This left patients wondering how the pharmaceutical companies were notified of their disease
 After a long and thorough investigation, the physician, the pharmaceutical company and a well-known
pharmacy chain were all indicated on breach of confidentiality charges
 This is one of the many reasons the federal government needed to step in and create guidelines to protect
patient privacy

8. HIPAA: - is divided into two different sections those are:-
1. Portability:- this section allows individuals to carry their health insurance from one job to another, so that
they do not have a lapse in coverage, it also restrict health plans requiring pre-existing condition of an
individuals who switch from one health plan to another.
2. Administrative simplification:- this section is the establishment of a set of standard for receiving,
transmitting and maintaining the healthcare information, ensuring the privacy and security of individuals
identifiable information.
HITECH and ARRA rules
 HITECH is designed to encourage health care providers to adopt health information technology in a standardized
manner and to protect private health information
 ARRA is a direct result of modifications in the HIPAA privacy, security and enforcement rules and strengthens
health information privacy and security protections. ARRA specifically addresses:- 1. Breaches, 2. Electronic health
records (EHR), 3. Personal health records (PHR).
The privacy rule:- the privacy rule is designed to protect individuals health information (PHI) and allows individuals to
1. Get a copy of their medical records
2. Ask for changes to their medical records
3. Find out and limit how their PHI may be used
4. Know who has received their PHI
5. Have communications sent to an alternate location or by an alternate means
6. File complaints and participate in investigations
5) HIPPA- new requirement to clinical study processes

9. HIPPA 5 basic principles:-
1) Consumer control: patient rights
 Right to access health record
 Right to have health record amended or corrected
 Right to request confidential communications
 Right to request restrictions on access to medical records
 Right to complain of violations
 Right to an accounting of disclosures
2) Boundaries: - health information should be used for health purposes only, including treatment and payment
3) Accountability: - HIPAA imposes civil and criminal penalties for violation of a person’s privacy rights, civil monetary
penalties=$100/per failure with $25,000 year cap for multiple identical violations, criminal penalties= $50,000/ 1 yr in
prison, or $100,000/ up to 5 yrs in prison for false pretenses, or up to $250,000/up to 10 yrs in prison for intent to sale.
4) Public responsibility: - balancing act between protecting the privacy of patients and protecting the public health.
5) Security: - organizational responsibility to protect the privacy of patients
6) Pharmacovigilance: safety monitoring in clinical trials
Pharmacovigilance:- is a science and activities relating to the detection, assessment, understanding and prevention of
adverse effects or any other possible drug-related problems (eg. Interactions, misuse, medication errors, abuse,
overdose, addiction potential), vigilance means watching carefully in order to avoid danger.

10. Adverse event/ adverse experience (AE)- any untoward medical occurrence that may occur during treatment with a
pharmaceutical product but which does not necessarily have a casual relationship with this treatment
Eg: - undesirable signs and symptoms, disease or accidents, abnormal lab funding
Side effect: - any unintended effect of a pharmaceutical product occurring at doses normally used in man, which is
related to the pharmacological properties of the drug
Adverse drug reaction (ADR): - a response to a drug which is noxious and unintended, and which occurs at doses
normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for modification of physiological function-
casual role is suspected.
SAE: - (serious adverse event)-an AE or ADR that is associated with
Death, life threatening, results in hospitalization/prolongs existing hospitalization, persistent or significant disability or
incapacity, congenital anomaly or birth defect, medically significant.
SUSAR: - (serious, unexpected, suspected adverse reaction)
Serious, not included in product core safety data sheet, suspected link to the drug
SERIOUS VS SEVERE: - the term “severe” is often used to describe the intensity SEVERITY of a specific event (as in mild,
moderate, or severe pain), the event itself, however, may be of relatively minor medical significance (such as severe
headache), this is not the same as “serious” which is based on patient/event outcome or action criteria usually associated
with events that pose a threat to a patient’s life or functioning
Safety signal: - information on a possible casual relationship between an adverse event and a drug, the relationship being
unknown or incompletely documented previously, usually more than a single report is required to generate a signal
depending upon the seriousness of the event and the quality of the information
Rationale for continued Pharmacovigilance: - tests in animals are insufficiently predictive of human safety, in clinical
trials patients are selected and limited In number, conditions of use in trials differ from those in clinical practice, duration

11. of trials is limited, information about rare but serious adverse reactions, chronic toxicity, use in special groups or drug
interactions is often not available.
Classification of ADRs
 Type A: - augmented reactions- pharmacologically predictable from the known activity of the drug, and are
usually discovered during early research, they are common, dose related, but are usually begin with a low
mortality and morbidity.
 Type B: - bizarre reactions which are unpredictable and are rare, often at rates of less than 1:1000 patients per
annum, are usually dose-dependent, have a high morbidity or mortality, eg- agranulocytosis with clozapine,
anaphylaxis with penicillins.
 Type C: - chemical reactions are those reactions whose biological characteristics can be either rationalized or even
predicted based on the chemical structure of the parent drug, or of reactive intermediates and metabolites.
 Type D: - delayed effects, eg- the development of vaginal cancer of the offspring where the mothers had received
the drug DIETHYLSTILBESTROL during pregnancy between 1938 and 1971.
Pharmacovigilance aims: -
 Early detection of unknown safety problems
 Detection of increases in frequency
 Identification of risks
 Quantifying risks
 Preventing patients from being affected unnecessarily
Pharmacovigilance MAH responsibilities
 Timely collection of data, recording and notification (reporting)- PV systems and processes, safety database
 Appropriate assessments (data completeness, seriousness, relatedness, expectedness, medical significance,
reporting requirements and timelines)
 Expedited and periodic reporting to RA
 Signal detection and proactive risk management
Assessing adverse reactions
 Nature, organ/system involved, severity, duration
 Serious/ not serious
 Causality-relationship to the drug (definite, probable, possible, unlikely)
 Expected/ unexpected (as per known safety profile of the drug)
 Medical significance (significant/ not significant)
Regulatory reporting of adverse reactions
Why report? Ethical requirement, regulatory requirement, legal requirement
Who reports? Company (post marketing), company and investigator joint responsibility (clinical trials)
When to report? Expedited-7 to 15 days, periodic- depending on when launched/region

12. Reporting ADR
What to report?
 Patient details: pt. identifier, initials, sex, age, etc
 Suspected drug: generic name, indication, dates of admin, dose, starting and stopping date and time
 Other treatments
 Details of suspected ADR- nature, severity, duration, relationship to drug, action taken
 Outcome
 Details about the reporter/investigator
 Formats for reporting: - expedited reports- ICSR, med watch 3500A, CIOMS 1 and 2 , periodic reports- annual
safety reports, reports, PSUR, NDA PADER
Minimum data for a reportable ADR
 Identifiable patient
 AE/ADR
 Suspected medicinal product
 Reporter (HCP)
PV regulations
Main players- EMEA(EU), US-FDA, MHRA (UK), TGA (Australia), Japan, slightly different regulations, based on ICH
guidelines

13. __________________________________________Thank you … __________________________________________