GCP: An international ethical and scientific quality standard for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects. PV: The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.

1. PRESENTATION
ON
GOOD CLINICAL PRACTICE
&
PHARMACOVIGILANCE
Presented By:
MD. ZAKARIA FARUKI
ORION Pharma Ltd.
ORION
1

2. PRESENTAION
Abbreviations
Pharmacovigilance Practices
Pharmacovigilance Process & Life Cycle
Drug Discovery & Development
Good Clinical Practices
Risk Management Plan
Cross Functional Teams & Pharmacovigilance
Periodic Safety Update Report
References
ORION
Drug Safety in Clinical Trials & Post Marketed Drugs
Conclusion
2

3. ABBREVIATIONS
■ GCP – Good Clinical Practices
■ NDA – New Drug Application
■ IND – Investigational New Drug Application
■ ANDA - Abbreviated New Drug Application
■ RCT - Randomized Controlled Trials
■ IRB/IEC - Institutional Review Board /Independent Ethics Committee
■ PV/PVG – Pharmacovigilance
■ QPPV - Qualified Person for Pharmacovigilance
■ ADR - Adverse Drug Reaction
■ SAE – Serious Adverse Events
■ CIOMS - The Council for International Organizations of Medical Sciences
■ RSI - Reference Safety Information
■ PSUR - Periodic Safety Update Report
■ DSUR – Development Safety Update Report
■ RMP - Risk Management Plan
■ DSMB - Data Safety Monitoring Board
■ OHRP - The Office for Human Research Protections
■ DHHS - Department of Health and Human Services
■ FAERS – FDA Adverse Events Reporting System
■ REMS – Risk Evaluation & Mitigation Strategy
■ CFR – Code of Federal Regulations
■ CDER – Center for Drugs Evaluation & Research
3
ORION

4. DRUG DISCOVERY & DEVELOPMENT
 Drug discovery is an iterative process.
According to FDA 5 steps are involved in the drug development
which are-
■ Discovery / Screening
■ Pre-clinical Research
– In-vivo
– in-vitro
■ Clinical Research
– Phase I
– Phase II
– Phase III
– Phase IV*
■ FDA Review
■ Post Marketing Monitoring*
4
ORION

5. 5
NEW DRUG APPLICATION PROCESSES ORIONThe physiological, cellular and/or generic basis of diseases is studied to identify potential
Therapeutic Targets
New compound are isolated and purified from natural sources of synthesized
In-vitro (cell-based) laboratory assay are developed to measure the effect of potential
therapeutics
Using the in-vitro laboratory assay 5,000 - 10,000 new previously developed compounds are
tested for biological activity
On average 250 of the compounds are tested possess the desire activity and are now designated
as Hits
A handful of the most promising hits are chosen to chemical modification to improve the
specificity, potency, chemicam & metabolic stability, water solubility & other
pharmacological parameters. Improved Hits are now known as “Lead Compounds”
Lead Compounds are tested in-vivo for safety and efficacy in laboratory animals such as
mice & rats (Pre-clinical)
Before moving to testing in humans, an Investigational New Drug (IND) Application must
be filled with the FDA.
Clinical Trials (Phase-I, II & III)
Phase 1: Clinical Trial consist of drug safety studies in healthy humans
(No. of subjects 20-100)
Phase II: Clinical Trial whether a drug works in small number of patients affected by
diseases (No. of subjects 100-300)
Phase III: Clinical Trial on large number of patients (No. of subjects 1000 - 3000)
New Drug Application (NDA) Approval by US FDA
Phase IV: Post-Marketing Drug Safety & Pharmacovigilance

6. 6
DRUG DISCOVERY & SCREENING ORION

7. Once researchers identify a promising compound for development,
they conduct experiments to gather information on:
 How it is absorbed, distributed, metabolized, and excreted.
 Its potential benefits and mechanisms of action.
 The best dosage.
 The best way to give the drug (such as by mouth or
injection).
 Side effects or adverse events that can often be referred to
as toxicity.
 How it affects different groups of people (such as by gender,
race, or ethnicity) differently.
 How it interacts with other drugs and treatments.
 Its effectiveness as compared with similar drugs.
7
DRUG DEVELOPMENT ORION

8. 8
PRE-CLINICAL RESEARCH ORION
■ In-Vitro Study ■ In-Vivo Study
Before testing a drug in people, researchers must find out whether it has the
potential to cause serious harm, also called toxicity. A system of quality assurance
oversight for each study to help assure the safety of FDA-regulated product

9. Drug developers, or sponsors, must submit an Investigational New Drug (IND)
application to FDA before beginning clinical research. In this application
developers must include:
■ Animal Pharmacology and Toxicology Studies (side effects that cause great
harm) data
■ Manufacturing information
■ Clinical protocols (study plans) for studies to be conducted
■ Data from any prior human research
■ Information about the investigator
Then developers need to-
■ Asking for FDA Assistance
■ FDA IND Review Team: Project Manager, Medical Officer, Statistician,
Pharmacologist, Pharmakineticist, Chemist, Microbiologist
■ FDA Approval: The FDA review team has 30 days to review the original IND
submission. The process protects volunteers who participate in clinical trials
from unreasonable and significant risk in clinical trials.
9
INVESTIGATIONAL NEW DRUG
(IND)
ORION

10. 10
CLINICAL RESEARCH ORION
While preclinical
research answers basic
questions about a
drug’s safety, it is not a
substitute for studies of
ways the drug will
interact with the human
body. “Clinical research”
refers to studies, or
trials, that are done in
people.
But unlike with
animals; the sponsor
cannot just go ahead
and run testing in
humans without
supervision.

11. 11
GOOD CLINICAL PRACTICES
Good Clinical Practice (GCP) is defined as a ‘standard for the design,
conduct, performance, monitoring, auditing, recording, analyses and
reporting of clinical trials that provides assurance that the data and
reported results are credible and accurate, and that the rights, integrity
and confidentiality of trial subjects are protected’.
It is the compilation of accepted ethical and scientific standards
governing clinical research that ensure the integrity of data obtained and
the protection of human research subjects. The objectives of GCP are-
 Mainly focused on the protection of human rights in clinical trial.
 Provide assurance of the safety of the newly developed compounds.
 Provide standards on how clinical trials should be conducted.
 Define the roles and responsibilities of clinical sponsors, clinical
research investigators, Clinical Research Associates, and monitors.
 Compliance with GCPs provide public assurance that the rights and
safety of participants in human subject research are protected and
that the data that arises from the study is credible
ORION

12. 12
EVOLUTIONOFREGULATIONS,
GUIDELINES& LAWS OF GCP
ORION
2016
ICH E6 (R2)
Addendum

13. 1 Clinical trials should be conducted in accordance with the ethical principles
that have their origin in the Declaration of Helsinki, and that 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 subject 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 the trial subjects are the most important
considerations and should prevail over interests of science and society
4 The available non clinical 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 the protocol that has received
prior institutional review board (IRB)/independent ethics committee (IEC)
approval/favorable opinion
13
The Core of the Consolidated GCP
Guidance (Principles of GCP)
ORION

14. 7 The medical care given to, and medical decisions made on behalf of,
subjects should always be the responsibility of a qualified physician or,
when appropriate, of 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 tasks
9 Freely given informed consent should be obtained from every subject 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 subjects should be
protected, respecting the privacy and confidentiality rules in accordance
with the applicable regulatory requirements
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
14
ORION
Principles of GCP Contd…

15. 15
ORIONPLAYERS IN CLINICAL RESEARCH

16. 16
ORION
SPONSORS RESPONSIBILITIES
•Obtain Regulatory
approval
•Update IB / Study
Protocol
•Selection of
qualified
Investigators
•Control of test
article disposition
•Monitoring of the
conduct of study at
site

17. 17
ORION
SPONSORS RESPONSIBILITIES

18. 18
ORIONINVESTIGATOR RESPONSIBILITIES
Responsibility for following GCPs is shared among the following:
• Institutional Review Board (IRB)
• Investigator (study team)
• Sponsor
• Monitor
■ Follow Approved Protocol
o Responsible for research team’s adherence as well
■ Protect Human Subjects
o Ensure informed consent
■ Control Investigational Product
■ Document Study Progress
o Submit appropriate reports
o Retain records

19. 19
ORIONINVESTIGATOR RESPONSIBILITIES
• Qualifications & agreements (Form 1572/ undertaking/ FDs)
• Adequate Resources
• Medical care of the patient
• Communication with Ethics Committee
• Compliance with protocol
• Handling storing and accounting for IP
(including randomization and unblinding)
• Quality Data–(Informed consent/Source/Lab/CRFs)
• Filing and archiving (Records and Reports)
• Progress Reports
• Safety Reporting
• Premature termination/ suspension of a trail
• Final Reports by Investigator

20. 20
ORION

21. 21
ORION

22. 22
ORION

23. 23
ORIONCASE REPORT FORM (CRF)
The collection of forms where all the clinical data is going to be collected for
a patient
– Designed according to the protocol
– A blank CRF is always submitted to the FDA for approval before the trial must be run
– These documents are used to record the information derived from study activities that
will be used as data
– CRFs are NOT source documents unless stated as such in the study protocol
– CRFs require a supporting source document to assure the validity of the data recorded
– CRF entries must accurately match the Source Documentation
– Any errors in entry will be queried, and must be corrected promptly
CRF COMPLETION:
– Should be done in a timely manner
– With adequate source documentation
– By appropriate study personnel
– Data transcription from SD to CRF should be
– accurate and precise

24. 24
ORIONFORMAT OF INFORMED CONSENT

25. ■ Delegate IP handling & accountability to appropriate study personnel
■ Storage as per protocol (temperature etc.)
■ Safe & secure location
■ Restricted access (only study personnel)
■ Maintain documents -receipts, forms, temperature logs
■ Given to patient only after consent
■ Return IP
■ Destroy at site according to institutional policies
25
ORIONINVESTIGATIONAL PRODUCT (IP)
IP ACCOUNTABILITY:
 An Investigator is required to maintain adequate records of the
disposition of the drug, including dates, quantity and use by
subjects.
REMEMBER
IP is NOT dispensed before patient consent/ EC approval
IP is NOT dispensed by unauthorized persons / to non-study patients
IP IS Dispensed as per randomization list
IP IS stored securely under required conditions

26. ■ Should safeguard the
rights, safety and well-
being of all trial subjects
■ Only those members who
are independent of the
clinical trial and the
sponsor should vote
■ The principal investigator
can also present the
protocol to the EC but
cannot vote for His / Her
own study
26
ORIONInstitutional Review Board (IRB) /
Independent Ethics Committee (IEC)

27. 27
ORION
ETHICS COMMITTEE COMPOSITION &
RESPONSE
EC response-
 Clearly identifying the trial by
title, Protocol No. and version
 A list of members present at
the review meeting
(chairperson, member
Secretary, other EC members)
 Date, time and place of the
review/meeting
 A list of documents reviewed;
in particular, Patient
Information Sheets and
Informed Consent Forms in
different languages (if
translated)
 The decision of the Ethics
Committee

28. Researchers design clinical trials to answer specific research questions related to a
medical product. There are mainly four Clinical trails which are-
• Phase I: Emphasis on drug safety & determine dosage range
 Typically involves 20-80 healthy volunteers (no women of child bearing potential)
 Lasts about 1 year and about70% of drugs will pass this phase
• Phase II: Emphasis on drug effectiveness
 Typically involves 100-300 individuals who have the target disease
 Lasts about 2 year and about 33% of drugs will pass this phase
• Phase III: Emphasis on drug safety, effectiveness & adverse reaction
 Typically involves 1000-3000 patients
 Lasts about 3 year and about 25-30% of drugs will pass this phase
 New Drug Application (NDA): Regulatory Review
In cases where FDA determines that a drug has been shown to be safe and effective for its intended
use, it is then necessary to work with the applicant to develop and refine prescribing information
(Labeling) & approval for marketing.
• Phase IV: Long-term Safety & effectiveness of Marketed Drug
 Post-market surveillance of the drug to continually assess the safety of the drug.
 Several thousand volunteers in disease/condition to identify Drug risks, Benefits, Optimal use of Drug
 May include incidence and severity of rare adverse reactions, cost-effectiveness analyses, comparative trials,
and quality of life studies
28
ORIONCLINICAL TRIALS

29. SUMMARY OF DRUG DEVELOPMENT
29
ORION

30.  Pharmacovigilance is the science and activities relating to
the detection, assessment, understanding, and prevention
of adverse effects or any other drug-related problems.
 To market a drug, the manufacturer must provide evidence
of its efficacy and safety to the FOOD AND Drug
Administration (FDA)
 In Premarketing testing, the numbers and type of patient
used to demonstrate a drug`s efficacy and safety are limited
as compared with the numbers and type of patient who will
eventually be prescribed the drugs after it is marketed.
 Post-marketing surveillance of drug therefore play an
important role to discover an undesirable effect that might
present at risk.
 It provide additional information on the benefit and risk of
the drugs.
30
ORIONPHARMACOVIGILANCE

31. Post-marketing
drug safety
surveillance
refers to the
monitoring of
drugs, once they
reach the market
after clinical trials
through a
process which
evaluates drugs
taken by
individuals under
a wide range of
circumstances
over an extended
period…
31
ORIONPRODUCT SAFETY & PV LIFECYCLE

32. Information obtained prior to first marketing is inadequate to cover all aspects of drug safety:
■ 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 of trials is limited
■ Information about rare but serious adverse reactions, chronic toxicity, use in special groups (such
as children, the elderly or pregnant women) or drug interactions is often not available.
32
ORIONRATIONALE FOR
PHARMACOVIGILANCE
To be sure to detect an ADR that occurs
once per 2000 patients treated, we need to
treat:

33. 33
ORION

34. 34
ORION

35. 35
ORION

36. 36
ORION
PHARMACEUTICAL POST-MARKETING
SURVEILLANCE SYSTEM

37. 37
ORIONPHARMACEUTICAL POST-MARKETING
SURVEILLANCE SYSTEM

38. 38
ORIONPHARMACEUTICAL POST-MARKETING
SURVEILLANCE SYSTEM

39. 39
ORIONPHARMACEUTICAL POST-MARKETING
SURVEILLANCE SYSTEM

40. 40
ORIONROUTINE POST-MARKETING
PHARMACOVIGILANCE

41. 41
ORIONIndividual Case Safety Reports (ICSRs)

42. 42
ORIONREGULATORY ACTIONS

43. 43
ORIONPHARMACEUTICAL POST-MARKETING
SURVEILLANCE SYSTEM

44. ■ Marketing & Sales Department
■ Quality Assurance Department
■ Quality Control Department
■ Financial Department
■ Regulatory Affairs
■ Legal Department
■ IT Department
44
ORIONCROSS FUNCTIONAL TEAMS
(CFTs)
ROLES & RESPONSIBILITIES OF CFTS
 Medicinal products are subjected to regulations designed
by the respective governments to protect public health.
 The Regulatory Affairs (RA) department of
Pharmaceutical / Biotech companies ensure that their
companies comply with all of the regulations and laws
concerning their business.
 Regulatory requirements need to be considered when
drafting the pharmaceutical, preclinical and clinical
development plan.
 RA develops the regulatory strategy, arrange agency
meetings and manage all communication with the
agencies.
 Since the regulatory requirements are constantly
changing, the regulatory team provides advice on
necessary adaptations to development plans and target
product profiles.

45. 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-authorisation.
Periodicity of Based on International Birth Date (IBD):
45
ORIONPeriodic Safety Update Report (PSUR)
6 Months 1 Year 2 Years 3 Years 4 Years 5 Years ……7 Years

46. ■ ADVERSE EVENT: Any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical product and which does not
necessarily have a causal relationship with this treatment.
■ An adverse event (AE) can therefore be any unfavorable and unintended
sign(including an abnormal laboratory finding), symptom, or disease temporally
associated with the use of a medicinal (investigational) product, whether or not
related to the medicinal (investigational) product.
■ ADVERSE DRUG REACTION (ADR): A response to a drug which is noxious &
unintended, and which occurs at doses normally used for prophylaxis, diagnosis, or
therapy of a disease, or for modification of a physiological function.
■ SERIOUS ADVERSE EVENT (SAE): According to ICH-E2A guideline, any untoward
medical occurrence that at any dose results in:
46
ORION
Drug Safety in Clinical Trials &
Post Marketed Drugs
• Death •Is life-threatening •Requires hospitalization or prolongation of existing
hospitalization •Results in persistent or significant disability/incapacity
•Congenital anomaly/birth defect •Any event, in investigator’s medical judgment,
requiring immediate intervention to prevent the subject from meeting SAE criteria.

47. 47
ORIONDrug Safety in Clinical Trials &
Post Marketed Drugs

48. 48
ORIONPHARMACEUTICAL POST-MARKETING
SURVEILLANCE SYSTEM

49. 49
ORIONADVERSE EVENT REPORTING CIOMS FORM

50. 50
ORION
FDA ADVERSE EVENT REPORTING
MEDWATCH FORM
A noticeable
(notably out of
the ordinary,
eminent,
remarkable,
memorable) sign
(or a token, an
indication or a
foreshadowing)m
ade for the
purpose of giving
notice (or
conveying
information or
communicating)
to a person of
some occurrence,
command, or
danger.

51. Life Cycle of Drug Safety Knowledge
51
ORION

52. 52
ORIONRisk Management Plan (RMP)
■ A RMP is a detailed description of a risk management system.
■ RMPs contain:
—A description and analysis of the safety profile of the medicine
—A set of pharmacovigilance and risk minimization activities.
—Covers the entire lifecycle of the medicine.
 An RMP must accompany all applications for:
• New chemical entities
• Biosimilar medicines
• Vaccines
• Class 3 and 4 biological products
• Previously registered medicines where there is a significant change to registration
status (e.g. expanded target population, new disease, extension into paediatricuse,
new dosage form).

53. 53
ORIONCONCLUSION
■ Even though clinical trials provide important information on a drug’s
efficacy and safety, it is impossible to have complete information
about the safety of a drug at the time of approval.
■ Post marketing surveillance is defined broadly as any information-
gathering activity that is performed after product approval.
■ Post marketing surveillance (PMS) is the practice of monitoring the
safety of a pharmaceutical drug which is on the market.
■ PSURs ensure that a product’s benefits continue to outweigh its risks,
and facilitate the weighing and monitoring of such events at
predetermined time points.
■ Despite the rigorous steps in the process of drug development,
limitations exist. Therefore, the true picture of a product’s safety
actually evolves over the months and even years that make up a product’s
lifetime in the marketplace.

54. 1. The Drug Development Process; US FDA
2. Drug Discovery, Development and Deployment; National Institutes of Health
3. Guideline for Good Clinical Practice E6(R1); EMA/722239/2018
4. ICH E6 (R2) Good clinical practice; EMA/CHMP/ICH/135/1995
5. ICH Efficacy Guidelines; https://www.ich.org/products/guidelines/efficacy/article/efficacy-
guidelines.html
6. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products
7. Guideline on good pharmacovigilance practices (GVP);
https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guidelines-
good-pharmacovigilance-practices-gvp-introductory-cover-note-last-updated-chapter-
piv_en.pdf
8. Introduction to Post marketing Drug Safety Surveillance: LT Andrew Fine, Pharm.D., BCPS
9. Post market Drug Safety Information for Patients and Providers (FDAAA 915):
https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandP
roviders/default.htm; https://www.fda.gov/Safety/MedWatch/default.htm
10.Arthur N et al. The Importance of Pharmacovigilance – Safety Monitoring of Medicinal
Products. WHO2002.
11.ICH E6: Good Clinical Practice: Consolidated Guidance.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM073122.pdf 54
ORIONREFERENCES

55. 55
ORION