Dr.

Nikitha Sree K

Clinical Research and Pharmacovigilance

Q1) What is pharmacovigilance?

A1) According to WHO- Pharmacovigilance is the science and activities related to detection,
assessment, understanding and prevention of adverse effects or any other drug related
problems. In Greek, Pharmaco means 'drug' and vigilance means 'watch' It also means to keep
watch on drugs during its trial phases as well as during marketing phase

Q2) What do you mean by clinical trials and what are different phases of clinical trial?

A2) -type of research that studies on new tests and treatments and evaluates their effects on
human.

CLINICAL TRIAL PHASES

PHASE 1

-Human pharmacology trial

-It comprises healthy volunteers without any disease or concurrent medications or people with
the disease or any condition

-Evaluate the safety of the drug and the dosage .

-Determine the maximum tolerated dose, pharmacokinetics, pharmacodynamics

-Study participants -20-100, Length of study- lSeveral months

- In this phase about 70 % of the drugs move to the next phase

PHASE 2

-Therapeutic exploratory trials

-Comprises volunteers with the disease or condition

-Evalute the therapeutic efficacy and the side effects

-Determine dose and regimen

-Study participants includes several hundreds of people

-Length of study- maximum 2 years

-Approximately 33 % of the drugs move to the next phase

PHASE 3

-Therapeutic confirmatory trial or expanded clinical trials

- Comprises volunteers with the disease or condition for the trial is doing.

- Evaluate efficacy and adverse reactions

- Safety, efficacy, dose and dose regimen

- Study participants- 300 to 03000, Length of the study- +1 to 4 years

- About 25-30 % of drugs move to next phase

PHASE 4

• Main Purpose is Safety and efficacy

• Study participants- Several thousand volunteers who have the disease/condition

Q3) What is the difference between side effect and adverse drug reaction?

SIDE EFFECT

Unwanted effect but often unavoidable pharmacodynamic effect that occurs at therapeutic
doses. These are expected and are mild in nature and are self-resolving. They can be predicted
from the pharmacological profile of the drug and known to occur in a given percentage of drug
recipients. Side effect may be bad in one context and the same bad effect can be good for
someone else.

ADVERSE DRUG REACTION

According to WHO, A response which is noxious and unintended, and which occurs at normal
doses used in human for the Prophylaxis, Diagnosis or therapy of the disease or the
modification of the physiological functions. ADR is always related to the drug.

Q4) What do you understand by INDA and NDA in clinical trials? please provide full
form also.

A4) The NDA application is the vehicle through which drug sponsors formally propose that
the FDA approve a new pharmaceutical for sale and marketing in the U.S. The data gathered
during the animal studies and human clinical trials of an Investigational New Drug (IND)
become part of the NDA.The Investigational New Drug (IND) application falls into the first
category, while the New Drug Application (NDA) fall into the second category.

Investigational New Drug Process (IND)

After completion of preclinical phase and before staring the clinical phase, the company should
begin the Investigational New Drug Process (IND) and should file the INDA (Investigational
New Drug Application) to get approval from regulatory authorities before beginning the
clinical phase. This process of filing INDA is a mandatory activity, and no clinical phase can
start without approval of INDA. Drug developers/sponsors/pharma companies, must submit an
INDA to the regulatory authorities before beginning clinical research. In the INDA the
developers must include: Animal study data and toxicity (side effects that cause great harm)
data

• Manufacturing information

• Clinical protocols

• Data from any prior human research

• Information about the investigator

• After successful approval of INDA the sponsor will begin the CT phases

New Drug Application: NDA

• Before marketing of drug and after phase 4 the sponsor should file NDA

• Marketing of the drug can only be started once the company gets approval from regulatory
bodies for the NDA

• Again, NDA submission is a mandatory activity required by regulatory authorities

• NDA tells the full story of the drug, and its purpose is to demonstrate that a drug is safe and
effective for its intended use in the population studied

• The sponsor should include everything about a drug from preclinical data to phase 3 trial data

• After approval of NDA the sponsor is now ready to market the drug
Q5) What is the difference between adverse drug reaction and adverse event?

A5) Adverse drug event and adverse drugs reactions both are unintended but in ADR there will
always be a causal relationship that means it will always be related with the drug and in ADE
there may or may not a causal relationship between ADE and the drug.

Q6) What is adverse event and adverse drug reaction?

A6) ADVERSE DRUG REACTION

According to WHO, A response which is noxious and unintended, and which occurs at normal
doses used in human for the Prophylaxis, Diagnosis or therapy of the disease or the
modification of the physiological functions.ADR is always related to the drug

eg: .Liver damage with tetracycline antibiotics.and Diarrhea with amoxicillin.

DEFINITION OF ADE (ADVERSE DRUG EVENT)

A/C WHO Any untoward medical occurrence that may present during treatment with a drug,
but which may or may not necessarily have a causal relationship with this treatmen t.

Eh: The patient on cetirizine and diclofenac falls suddenly on the second day of taking
medicine. So here fall is not related to any pharmacological affect, or any ADR related to the
drugs.

Types:

A physical event ( a rash).

A psychological event (depression).

A laboratory event (increased blood sugar).

An increase in the severity or frequency of a pre-existing symptom or condition (e.g., increased

pain in a painful tooth)

Q7) What is causality assessment in Pharmacovigilance?

A7) Assessment of the relationship between the suspected product/drug and the suspected
adverse event is known as causality assessment. Causality assessment is the backbone of
Pharmacovigilance.
Q8) What is medication error, drug misuse, abuse, and drug dependence?

A8) Medication error:

Medication error are mishaps that occur during prescribing, transcribing, dispensing,
administering or monitoring a drug. Eg: misreading or Miswriting a prescription.

TYPES:

Prescription error (By Doctors)

Transcription error (Writing of what have spoken) (By Pharmacist)

Identing/printing error (Nurses / Pharmacist)

Dispensing error (By Pharmacist)

Administration error (By Nurses)

DRUG MISUSE

Drug misuse is an intentional use of a product not in accordance with the safety reference
information and product information and which is inappropriate and is not justifiable. Misuse
is for legal drugs which are used in a wrong manner and not in accordance with the prescription
and in accordance with the reference safety information.

Eg: Using someone's else prescribed medicine for example Augmentin prescribed to daughter
for dental infection was used by her mother also, considering the dental pain as dental infection.

DRUG ABUSE

Drug abuse is the habitual use of a drug to alter emotion, mood and state of consciousness and
is not limited to narcotic medications. The term drug abuse is used only in the setting of habitual
(chronic) use and not a single time use. Eg: Cough syrups are also used by the patient as a
part of drug abuse.

DRUG DEPENDENCE

Drug dependence is a compulsive or chronic need and is an addiction. The seven elements of
drug dependence are (per diagnostic and statistical manual of mental disorders IV)

-Tolerance

-Withdrawal
-More ingested then intended

-Desire to cut down

-Time involved

-Reduction in occupational, social and recreational activities and

- Continued use despite problems associated with the substance.

At least three of the seven are required to call it as drug dependence. Dependence on a drug
means that your body has become so used to having that drug regularly that you need that drug
to function normally, and if it were stopped you would feel unwell. Some drugs th at cause
dependence include nicotine, morphine, heroin (also known as diamorphine), cocaine,
amphetamine and alcohol.

Psychological dependence - means that you have a craving or are compelled to use a particular
drug to give you pleasure or to stop you from feeling bad – even though it may be dangerous
to take the drug.

Physical dependence- that if the drug is stopped suddenly, you get withdrawal symptoms.eg: if
you are dependent on heroin and stop this drug suddenly then you may get the withdrawal
symptoms

Q9) What are the different causality assessment scales available and what are the
different+ categories inside WHO-UMC assessment scale?

A9) CAUSALITY ASSESSMENT SCALES

1) WHO-UMC SCALE

2) NARANJO ADR PROBABILITY SCALE

WHO-UMC CAUSALITY ASSESSMENT SYSTEM

The WHO-UMC system has been developed in consultation with the National Centers
participating in the Program for International Drug Monitoring and is meant as a practical tool
for the assessment of case reports. It is basically a combined assessment considering the
clinicalpharmacological aspects of the case history and the quality of the documentation of the
observation

WHO-UMC CAUSALITY CATEGORIES

CATEGORY 1

CERTAIN- When your answer is completely Yes and from the initial report itself it’s clear that
the suspected AE was because of the drug only.

ASSESSMENT CRITERIA-

1) Plausible time relationship to drug intake.

2) Cannot be explain by disease or other drugs.

3) Response to withdrawal plausible (positive dechallenege)

4) Adverse event pharmacologically defined

5) Rechallenge satisfactory (positive rechallenge)

CATEGORY 2

PROBABLE or LIKELY- When your answer is Yes, but rechallenge information is not there

ASSESSMENT CRITERIA-

1) Plausible time relationship to drug intake.

2) Cannot be explain by disease or other drugs.

3) Response to withdrawal plausible (positive dechallenge)

4) Adverse event pharmacologically defined

5) Rechallenge information not provided

CATEGORY 3

POSSIBLE- Because of interaction with some other drugs or drug disease interaction.

ASSESSMENT CRITERIA-

1) Plausible time relationship to drug intake.

2) Can be explain by disease or other drugs.

3) Adverse event pharmacologically defined

4) Dechallenge positive

5) Rechallenge information not provided

6) Data in inconclusive

CATEGORY 4

UNLIKELY- Here it does not matter if we have full data or not but in this the alternate factor
(any other drug or disease) is very strong

ASSESSMENT CRITERIA-

1) Plausible time relationship to drug intake.

2) Can be strongly explained by disease or other drugs.

3) Adverse event pharmacologically defined

4) Dechallenge N/A

5) Rechallenge N/A

CATEGORY 5

UNCLASSIFIED/CONDITIONAL- When answer is no that drug could not cause that reaction
(Incomplete data).

ASSESSMENT CRITERIA-

1) Report suggesting an adverse reaction

2) More data for proper assessment needed

3) Additional data under examination

CATEGORY 6

UNASSESSABLE/UNCLASSIFIABLE- When answer is no that drug could not cause that

reaction (Incomplete data and data cannot be found on follow up also).

ASSESSMENT CRITERIA-

1) Report suggesting an adverse reaction

2) Data cannot be supplemented or verified

Q10) What do you mean by serious adverse event (SAE) and what are the different
seriousness criteria for an event to be qualifies for SAE?

A10) SERIOUS ADVERSE EVENT (SAE)

An AE is considered serious if it poses a threat to the patient’s life or functioning. The FDA
defines a serious adverse event (SAE) as any untoward medical occurrence that at any dose
may

-Results in death, life-threatening, hospitalization or prolongs existing hospitalization,

-significant disability or incapacity, or is a birth defect, or requires medical intervention to

prevent one of the above outcomes (e.g., an asthma attack that requires intensive treatment in
an emergency room, a seizure that does not result in hospitalization but requires medical
treatment). An AE needs to meet only one of the above criteria to be considered serious.

A change in vital signs, diagnostic tests (e.g., an electrocardiogram), or laboratory test results
,if the change is of sufficient magnitude to meet one of the above criteria. Eg- a patient could
be diagnosed with pneumonia in his or her doctor’s office and given antibiotics to take at home.
The pneumonia is an AE, but not an SAE However, if the patient is hospitalized for the
pneumonia, that is considered an SAE.

Q11) What do you mean by aggregate reports and what are different type of aggregate
reports?

A11) AGGREGATE REPORTS

Aggregate report is the process that reviews the cumulative safety information from a wide
range of sources, on a periodic basis and submits the findings to regulators worldwide.

PURPOSE OF AGGREGATE REPORTS

The periodic reporting of aggregate safety reports provides National Competent Authorities
(NCAs) with a comprehensive overview of the safety profile of a drug, based on the collated
evidence to date.

TYPES OF AGGREGATE REPORTS

- Periodic safety update report (PSUR)

- Periodic benefit risk evaluation report (PBRER)

- Development safety update report (DSUR)

PERIODIC SAFETY UPDATE REPORT (PSUR):

A Periodic Safety Update Report (PSUR) is a pharmacovigilance document intended to provide

an update of the worldwide safety experience of a medicinal product to regulatory authorities
at defined time points post authorization

PURPOSE OF PSUR:

The main purpose of the PSUR is to identify new or emerging safety information, as a means
of determining changes in the benefit rlisk profile of the authorized drug.

The frequency of submission is different for different countries. INDIA- Every 6 months for
the first 2 years and annually for the next 2 years

USA- Quarterly for 3 years and annually thereafter

EUROPE- Every 6 months for the first 2 years, annually for the next 2 years and 3 yearly
thereafter

PERIODIC BENEFIT RISK EVALUATION REPORT (PBRER)

A Periodic Benefit Risk Evaluation Report (PBRER) is an analysis of the safety, efficacy, and
efficiency of a drug, once it is already in the market.

DIFFERENCE BETWEEN PSUR AND PBRER

A PSUR primarily served as an interval safety report whereas a PBRER is meant to be a

cumulative benefit-risk report. Unlike a PSUR, a PBRER includes data on efficacy and
effectiveness.

DEVELOPMENT SAFETY UPDATE REPORT (DSUR)

The DSUR is the pre-marketing equivalent of the post marketing Periodic Safety Update
Report (PSUR). It is an analytical document. DSURs are internationally harmonized, safety
documents covering the safety summary of medicinal products during their clinical trial phase.

PURPOSE OF DSUR

The development safety update report (DSUR) proposed in this guidance is intended to be a
common standard for periodic reporting on drugs under development ,including marketed
drugs that are under further study
Q12) What do you mean by BA/BE study?

A12) BIOAVAILABILITY (BA) AND BIOEQUIVALENCE (BE) STUDY

• Bioavailability is defined as relative amount of drug from an administered dosage which

enters the systemic circulation and the rate at which the drug appears in the systemic
circulation.

• Bioequivalence studies are used to assess the expected in vivo biological equ ivalence of two
proprietary preparations of a drug. In bioequivalence studiies two drugs are compared to show
that they have nearly equal bioavailability and PK/PD parameters. These studies are often done
for generic drugs

Q13) What is Generic drug and what is the difference between Branded drug Generic
drug?

A13) GENERIC DRUGS

• Generic drugs are copies of brand-name drugs that have the same dosage, use, effects, side
effects, route of administration, risks, safety, and strength as the original drug. Same
pharmacological effects.

• Generic drugs are like brand drugs in composition except the excipient part.

• Do not have to conduct clinical trials to demonstrate that their product is safe and effective.

• Instead, they conduct bio-equivalence studies (BA/BE studies) and file an abbreviated New
Drug Application, to market the generic drug.

DISSIMILARITIES

- They could have different sizes, shapes, colours

- They might have different inactive ingredients.

- The generic cost less than the Brand name drug.

Q14) What do you mean by ANDA and what is the purpose of ANDA?

A14) ABBREVIATED NEW DRUG APPLICATION

• An abbreviated new drug application (ANDA) contains data which is submitted to FDA for
the review and potential approval of a generic drug product.
• Once approved, an applicant may manufacture and market the generic drug product to provide
a safe, effective, lower cost alternative to the brand-name drug it references.

Q15) What do you know about thalidomide disaster?

A15) Thalidomide disaster: It was observed that the incidence of congenital malformations of
babies had increased from 1.5% to 20% in women who had taken thalidomide during
pregnancy.Dr. Lenz suggested a correlation between malformations and thalidomide in a
convention and his suspect was published in a German Journal.

,- In 1973, a retrospective study showed the correlation between the congenital malformations
of babies and the ingestion of thalidomide during pregnancy.

- The tragedy of thalidomide brought to light many problems and critical issues and the
reliability of animal tests, the behavior of the industrial company, and the importance of
monitoring the drugs after their marketing. This tragedy changes the system of
Pharmacovigilance because the spontaneous reporting of adverse drug reactions became
systematic, organized, and regulated.

In Europe (1965), the disaster of thalidomide stimulated the development of a European

legislation with the EC Directive 65/65

Q16) What are the 13 principles of ICH GCP for conducting any clinical trial?

A16) ICH-GCP PRINCIPLES:

1) Clinical trials should be conducted in accordance with the ethical principles that have their
origin in the Declaration of Helsinki, and are consistent with GCP and the applicable regulatory
requirements

2) Before a trial is initiated, foreseeable risks and inconveniences should be weighed against
the anticipated benefit for the individual trial participant and society. A trial should be initiated
and continued only if the anticipated benefits justify the risks.

3) The rights, safety, and well-being of trial participants are the most important considerations
and should prevail over the interests of science and society.

4) The available nonclinical and clinical information on an investigational product should be

adequate to support the proposed clinical trial.
5) Clinical trials should be scientifically sound and described in a clear, detailed protocol.

6) A trial should be conducted in compliance with a protocol that has received prior institutional
review board (IRB) approval.

7) The medical care given to, and medical decisions made on behalf of, participants should
always be the responsibility of a qualified physician or, when appropriate, a qualified dentist.

8) Each individual involved in conducting a trial should be qualified by education, training,

and experience to perform his or her respective task(s).

9) Freely given informed consent should be obtained from every participant prior to clinical
trial participation.

10) All clinical trial information should be recorded, handled, and stored in a way that allows
its accurate reporting, interpretation, and verification.

11) The confidentiality of records that could identify participants should be protected,
respecting the privacy and confidentiality rules in accordance with the applicable regulatory
requirement(s).

12) Investigational products should be manufactured, handled, and stored in accordance with
applicable good manufacturing practice (GMP). They should be used in accordance with the
approved protocol.

13) Systems with procedures that assure the quality of every aspect of the trial should be
implemented.

Q17) Name few regulatory bodies/competent authorities across the world?

A17) REGULATORY AUTHORITIES WORLDWIDE:

1. The European Medicines Agency (EMA) for countries in the European Union (EU).

2. The Food and Drug Administration (FDA) for the United States.

3. Pharmaceuticals and Medical Devices Agency (PMDA) for Japan.

4.Marketed Health Products Directorate (MHPD).

5. CDSCO (central drug standard control organization) WHO is one of the primary bodies that
facilitate the sharing of data between the countries around the world.
Q18) What do you know about ICSR and its full form and which guideline of GVP is
concerned with ICSR?

A18) The individual case study report (ICSR) is an adverse event report for an individual
patient and is the source of data in pharmacovigilance. The focus of ICSRs are reports from
healthcare providers and patients in member countries of the WHO Programme.

Module VI in GVP is concerned with Collection, management and submission of reports of

suspected adverse reactions to medicinal products (Rev 2) /ICSR case processing guideline.
Only valid ICSR (Individual case safety reports) are eligible for submission to regulatory
bodies. There are basic minimum 4 criteria based on which we can say that the report is valid
or not.

MINIMUM CRITERIA FOR A REPORT TO BE VALID

1.One or more identifiable reporter

2. Identifiable patient

3. Identifiable company suspect product

4. Identifiable Suspect event

Q19) What is the role of principal investigator in a clinical trial?

A19) PRINCIPAL INVESTIGATOR

- Supervises clinical trial.

- Develops the concept

- Makes protocol

- Submits the protocol for the Institutional Review Board (IRB) approval

- Directs the recruitment of patients

- Manages the informed consent process

- Supervises data collection, analysis, interpretation, and presentation

- Right and safety of trial participant

- Medical Care of Study Participant

- Compliance with the Protocol

- Use of Investigational Products

- Randomization and Blinding

- Premature Suspension or Termination of Study

Q20) What are the basics roles and responsibilities of a sponsor in any clinical trial?

A20) ROLES AND RESONSBILITIES OF SPONSOR

1) Data and Safety Monitoring

2) Quality Assurance and Quality Control

3) Study Design and Management

4) Transfer of Trial-Related Obligations

5) Designating appropriately qualified medical personnel

Q21) What do you mean by informed consent in any clinical trial?

A21) INFORMED CONSENT IN CLINICAL TRIAL

1) This includes a person voluntarily agreeing to participate in a research study after being fully
informed about it via verbal discussion with study staff, followed by documentation in a
written, signed, and dated informed consent form.

2) A participant’s consent should be continuously sought during the study, and the participant
should be notified of any changes to the study, along with any other pertinent information that
may influence their decision to remain in the study.

3) The informed consent document should contain all the information th at the person needs to
make an informed decision about taking part in the study.

4) The participant must sign and date the informed consent document before taking part in any
study procedures.

5) Signing the consent form is NOT the final step in the informed consent process. The
participant can withdraw consent and decline to participate in the study at any time before or
after signing the consent document until their participation in the study is completed.
6) All researchers must ensure that the process of obtaining informed consent from study
participants not only conforms to federal, state, and local regulations but also respects
everyone's right to make a voluntary, informed decision.

Q22) What do you understand by protocol in any clinical trial?

A22) RESEARCH PROTOCOL

The research protocol must describe the following aspects

Why the study is being done?

What will be done in the study?

Where the study will be done?

Who is involved in the research study?

When study interventions will take place?

RESEARCH PROTOCOL INCLUDES

1.General Information

2.Background Information

3.Study Objectives and Purposes

4.Study Design

5.Selection and Withdrawal of Participants

6.Treatment of Participants

7.Assessment of Efficacy

8.Assessment of Safety

9.Statistics

10. Direct Access to Source Data or Documents

11. Quality Control and Quality Assurance

12) Ethics

13) Data Management

14) Financing and Insurance

15) Publication Policy

16) Supplements

Q23) What are the source documents and essential documents in any clinical trial?

A23) ESSENTIAL DOCUMENTS IN CLINICAL TRIALS

Essential documents are those documents that individually and collectively permit evaluation
of the conduct of a trial and the quality of the data produced. These documents serve to
demonstrate the compliance of the investigator, sponsor, and monitor with the standards of
Good Clinical Practice and with all applicable regulatory requirements.

-Essential documents may be audited or inspected by quality assurance monitors or by

regulatory authorities to confirm the validity of the study and the integrity of the data collected.
These documents are to be maintained by the site and the sponsor and are classified according
to the stage of a study at which they are normally created. These documents may be maintained
in multiple locations. 0 The sponsor and the investigator/institution should maintain a record
of the location(s) of their respective essential documents, including source documents.

SOURCE DOCUMENTS IN CLINICAL TRIALS

Source documents are original documents, data, or records that are created during a clinical
study, that relates to the medical treatment and the history of the participant, and from which
study data are obtained. Source documents are one type of essential document that is required
by GCP guidelines.

The purpose of source documents-

Document the existence of study participants. Substantiate the integrity of the study data
collected. Any document in which information, an observation, or data generated relevant to a
study is recorded for the first time is a source document. Thus, a scrap of paper, or an electronic
mail message may be a source document if it is the original form on which information relevant
to a study is recorded.

EXAMPLES OF SOURCE DOCUMENTS

1) The following are examples of source documents:

2) Adverse event and concomitant medication logs

3) Reports of diagnostic test results

4) Signed and dated Informed Consent Forms

5) Participant diaries

6) Appointment calendars

7) Progress notes

8) Paper case report forms (CRFs) on which data are entered directly onto the CRF, rather than
extracted from another source document.

Q24) What do you understand by case processing and what are the different steps in case
processing?

A24) The process of processing the cases is known as case processing and the processing
includes multiple steps. Case here means the ICSR that is the individual case safety report.

STEPS IS CASE PROCESSING

1. Case receipt

2. Data verification

3. Validity check means checking if the case is valid or not

4. Booking of cases and registration

5. Data entry

6. Coding of adverse events and Drugs

7. Causality assessment

8. Expectedness assessment

9. Case narrative

10. Self-quality check

Q25) What is MedDra and current version in use and also what all things can be coded
with help of MedDra into safety database?

A25) MedDRA (medical dictionary for regulatory activities)

1) MedDRA is a clinically validated international medical terminology used by regulatory
authorities and the regulated biopharmaceuticals industry.

2) MedDra is a standardized medical terminology, published by the international council for

harmonization, used for coding cases of adverse events in clinical study reports and
pharmacovigilance databases and to facilitate searches in these databases.

3) The terminology is used through the entire regulatory process, from pre-marketing to post

SCOPE OF MedDRA- It is used to code adverse events terms, therapeutic indications,

past medical history , past surgical history and laboratory data also.

Current Version-

MedDRA updates are bi-annual with the first release in March and the second in September
and the current version of MedDra in use is version 25.0 and was last updated in March 2022.