Clinical research overview with emphasis on GCP from national & international perspect

1. An Insight
to
Good Clinical Practices-
National & International
Aspect
AMRITA BHATTACHARYA (MSc BIOTECHNOLOGY, PGDCR)

2. Overview
•Overview of Clinical Research
•Historical Perspective of GCP
•GCP & ICH
•Structure of ICH-Observers and Participants
•Essential Documents as per ICH-GCP E6
•Indian GCP
•Indian and Intenational GCP-A comparison
•ICMR GCP Guidelines
•WHO GCP Guidelines
•GCP International Perspective-US FDA,EU,UK,Australia,
Health Canada, Brazilian GCP
•Critical GCP Violations
•Annual inspection report 2013 by EMA

3. Clinical Research/Trial
Any investigation in human subjects intended to discover or
verify the clinical, pharmacological, and/or other
pharmacodynamic effects of an investigational product(s), and/or to
identify any adverse reactions to an investigational
product(s), and/or to study absorption, distribution, metabolism,
and excretion of an investigational product(s) with the object of
ascertaining its safety and/or efficacy-E6 GCP
 The Code Of Federal Regulations (CFR) defines a clinical trial
as the clinical investigation of a drug that is administered or
dispensed to or used involving one or more human subjects-21
CFR 312.3

4. Clinical trial-start to stop
Investigator
selection
Approv
al
Process Patient recruitment
& participation
Data entry and
review
Statistical analysis
Presentation and
publication of
report
Data filed and
registration

5. Overview of Clinical Trials
PHASE II
Efficacy & Side Effects
PHASE I
Dosage and safety determination
Preclinical Stage
Chemistry, Purification, Pharmacology, Toxicology,
Safety assessment in animals
File IND at FDA/DCGI
Preclinical Stage- 3-4 years, 5000 compounds
evaluated

6. PHASE IV
Post Marketing Surveillance
FILE NDA AT FDA & DCGI
PHASE III
Comparison of new with standard treatment & safety
PHASE I-III- 6 Years, 5 enter trials from 5000 compounds
evaluated
Approval stage- 2 years, only 1 gets approved for post
marketing

7. Historical Perspective
Nuremberg:
 During the Nuremberg
War Crimes Trials, 23 German doctors
were charged with crimes against
humanity for “performing medical experiment upon
concentration camp inmates and other living human
subjects, without their consent, in the course of which
experiments the defendants committed the
murders, brutalities, cruelties, tortures, atrocities, and
other inhuman acts.”
 First International Document which advocated
voluntary participation and informed consent.

8. The Nuremberg Code (1947)
As part of the verdict, the Court enumerated some rules
for "Permissible Medical Experiments", now known as
the “Nuremberg Code”. These rules include:
 voluntary consent
 benefits outweigh risks
 ability of the subject to terminate participation

9. Thalidomide Tragedy
 Thalidomide introduced into German market in
1957 as an over-the-counter remedy, based on
the maker’s safety claims.
 Given to pregnant women as sedative resulting in
161 babies with phocomelia (shortened, absent,
or flipper-like limbs)
 1962-US senate hearings “Kefauver
Amendments” passed into law.
 For the first time drug manufacturers were
required to prove to the FDA the effectiveness of
their products before marketing them.

10. Tuskegee Syphilis Study
 American medical research
project conducted by the
U.S. Public Health Service
from 1932 to 1972,
examined the natural course
of untreated syphilis in black
American men.
 As part of a study conducted in Macon County,
Alabama, poor sharecroppers were told they were
being treated for “bad blood.”In fact, the physicians in
charge of the study ensured that these men went
untreated. Hence nor they were told that they had
syphilis nor were offered effective treatment.
.

11. The Belmont Report
Ethical Principles and Guidelines for the
Protection of Human Subjects of Research
The National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research
April 18, 1979

12. The Belmont Report
Basic Ethical Principles:
 Respect for Persons
 Individual autonomy
 Protection of individuals with reduced autonomy
 Beneficence
 Maximize benefits and minimize harms
 Justice
 Equitable distribution of research costs and benefits

13.  Declaration of Helsinki
In 1964, the World Medical Association established recommendations
guiding medical doctors in biomedical research involving human
subjects. These guidelines influenced national legislation, but there was
no set standard between nations

14. GCP
Good clinical practice (GCP) is an international
ethical and scientific quality standard for
 designing,
 conducting,
 recording, and
 reporting trials that involve the participation of
human subjects
Public Assurance that rights, safety and well-being
of the subjects are protected

15. ICH
 International Conference on Harmonization
 Initiated on April 1990,in a meeting hosted by
EFPIA (European Federation Of Pharmaceutical
Industries and Associations) in Brussels
 1960s-1970s-Rapid increase in laws, regulations
and guidelines for reporting and evaluating the
data on safety, quality and efficacy
 Varied from country to country-need to
harmonize.
 Main Outcome-Tripartite ICH guidelines on
Safety, Quality and Efficacy

16. Structure of ICH parties
• EU (European Union)
• EFPIA (European Federation of Pharmaceutical Industries and
associations)
• US FDA (US Food and Drug Administration)
• MHLW (Ministry Of Health, Labor & Welfare Japan)
• JPMA (Japan Pharmaceutical Manufacturers Associations)
• PhRMA (Pharmaceutical Research and Manufacturers Of
America)
Six
Parties
• WHO (World Health Organization)
• EFTA (European Free Trade Association)
• Canada
Three
Observers

17. Essential Documents
 IB
 Signed Protocol and amendments
 Informed consent (SIS+ICF) all translations
 Financial aspects of the trial
 Insurance statement
 Signed agreement b/w involved parties
 Dated, Documented approval of IRB/IECs
 Composition of IRB/IECs
 Regulatory authority authorization/ approval/ notification
of protocol (where req)
 CV
 Normal range values of lab or tests included in protocol
 Certifications and accreditations
 IP sample of label attached to containers

18. Essential Documents
 Instruction for handling of IPs ( if not included in
protocol)
 Shipping records for IPs and trial related materials
 COA
 Decoding Procedures for blinded trials
 Master Randomization List
 Monitoring Report
 Subject Screening and Enrollment Log
 Subject Identification Code List
 IP accountability at the site
 Clinical Study Report

19. Indian GCP
 ICMR guidelines-2000
 Indian GCP guidelines-2001
 Principles-Essentiality, Voluntariness,Informed
consent and community agreement,
Nonexploitation,Privacy and confidentiality,
Precaution & risk minimisation ,Professional
competence, accountability and
transparency,maximization of the public interest and
distributive justice,compliance,totality of
responsilibility.

20. Structure
ICH E6
 Glossary
 Principles
 IRB/IEC
 Investigator
 Sponsor
 Protocol
 Investigator’s
Brochure
 Essential Documents
Indian GCP
 Definitions
 Pre-requisites
 Responsibilities
 Records & Data
 Quality Assurance
 Statistics
 Special Concerns
 Appendices

21. ICMR guidelines
 Ethical Guidelines for Biomedical research On Human
Participants.
 Divided into 8 chapters
 Chapter I-Statement of General Principles on Ethical
Considerations involving Human Participants
 Chapter II-Ethical Review Procedures
 Chapter III- General Ethical Issues
 Chapter IV- Statement of specific principles for Clinical
Evaluation of Drugs/Devices/Diagnostics/Vaccines/Herbal
Remedies
 Chapter V-Specific principles for Epidemiology Principles
 Chapter VI- Specific Principles for Human Genetics and
Genomics research.
 Chapter VII-Specific principles for research for
transplantation
 Chapter VIII-Specific Principles for Assisted Reproductive
Technologies.

22. WHO GCP
 based on provisions already promulgated in a number of
highly developed countries including Australia, Canada,
European Community, countries, Japan, Nordic
Countries (Denmark, Finland, Iceland, Norway and
Sweden) and the United States.
 1) Pre-requisites for clinical trial
 2) The protocol
 3) Protection of trial subjects
 4)Reponsibilities of the investigator
 5) Responsibilities of the sponsor
 6) Responsibilities of the monitor
 7) Monitoring of safety
 8) Record keeping and handling of data
 9) Statistics and calculations

23.  10) Handling and accountability of pharmaceutical
products
 11) Role of drug regulatory authorities
 12) QA for the conduct of the trial
 13) Considerations for multicentric Trials
 Appendices
 Appendix 1-World Medical Associations Declaration of
Helsinki
 Appendix 2-Model list of items to be contained in a
protocol
 Appendix 3-Considerations for multicentric trials.

24. US FDA-GCP
 Branch of the United States Department of Health and
Human Services.
 Title 21 of the Code of Federal Regulations (CFR)
 The Code of Federal Regulations (CFR) is a
codification of the general and permanent rules
published in the Federal Register by the Executive
departments and agencies of the Federal
Government.

25. CFR Title 21
Parts applicable to clinical research:
 Part 11 - Electronic Records and Signatures
 Part 50 - Protection of Human Subjects
 Part 54 - Financial Disclosure by Clinical Investigators
 Part 56 - Institutional Review Boards
 Part 312 - Investigational New Drug Application
 Part 314 - Applications for FDA Approval to Market a
New Drug or an Antibiotic Drug
 Part 600 - Biological Products
 Part 812 - Medical Devices

26. CFR Title 21
Title Volume Chapter Browse Parts Regulatory Entity
Title 21
Food and
Drugs
1 1-99 FOOD AND DRUG
ADMINISTRATION,
DEPARTMENT OF
HEALTH AND HUMAN
SERVICES
2 100-169
3 170-199
4 200-299
5 300-499
6 500-599
7 600-799
8 800-1299
9 II 1300-1399 DRUG
ENFORCEMENT
ADMINISTRATION,
DEPARTMENT OF
JUSTICE
III 1400-1499 OFFICE OF NATIONAL
DRUG CONTROL

27. Form FDA 1572
 an agreement signed by the investigator to provide
certain information to the sponsor.
 assure that he/she will comply with FDA regulations
related to the conduct of a clinical investigation
 FDA doesnot require the form to be submitted to the
agency
 two instances when it is necessary for an investigator
to complete and sign a new 1572: when an
investigator is participating in a new protocol that has
been added to the IND and when a new investigator
is added to the study.
 a 1572 is only required for studies of investigational
drugs and biologics conducted under an IND

28. EU-GCP
 Requirements for the conduct of clinical trials in the
European Union (EU), including GCP and good
manufacturing practice (GMP) and GCP or GMP
inspections, are implemented in:
 the 'Clinical Trial Directive' (Directive 2001/20/EC);
 the 'GCP Directive' (Directive 2005/28/EC).
 Looked after by EMA (European Medicines Agency).

29. 2001/20/EC
• Introduced to ensure that everyone follows the same GCP
standards
• Clarified and standardised practice for the safety of the
subject and the
 quality of the data
• Refers to the Core Principles of ICH GCP (as a scientific
guideline),
 especially Principles 5,7,11,12 and 13
• Major areas of change included:
 - The ethics review system came under the law
 - Each member state had to appoint a Competent Authority
(MHRA in UK)
 - Strengthened consent for vulnerable groups
 - Amendments required to follow a process
 - Additional safety reporting requirements

30. UK-GCP
 Looked after by MHRA (Medicines and Healthcare
Products Regulatory agency)
 GCP elements-Trial initiation, approvals and
completion, Responsibilities of organisations and
individuals, Recruitment and informed consent
processes, Documentation and data quality,
Safety reporting /pharmacovigilance.
 The European Clinical Trials Directive (2001/20/EC) is
the key piece of legislation, and this has been
transposed into UK law via Statutory Instrument
2004/1031

31. UK GCP regulations
 Statutory Instruments which govern the conduct
of clinical research in the UK.
 The Statutory Instruments are:
 2004/1031 (1 May 2004) – EU Directive 2001/20/EC
transposed into law
 2006/1928 (29 August 2006) – EU Directive
2005/28/EC transposed into law
 2006/2984 (12 December 2006) – A&E trials without
consent for adults without capacity
 2008/941 (1 May 2008) – Research Ethics Committee
membership and approval
 2009/1164 (8 May 2009) – Urgent safety measures
 2010/1882 (19 August 2010) – Advanced Therapy
Medicinal Products

32. Australian GCP
 The TGA is a division of the Australian Government
Department of Health and Ageing and is regulating
pharmaceutical .
 Adopted the EU version of the GCP guideline.
 National Statement published by NHMRC (National
Health and Medical Research Council important in
Australian GCP context.
 As ethics committee important player in assessment,
approval and monitoring trial.
 Important aspects-Clinical Safety Data Management,
Expedited reporting of adverse drug reactions.

33. Health Canada-GCP
 The Health Products and Food Branch Inspectorate
(Inspectorate) has the responsibility for the
inspections and investigations of clinical trials.
 The inspection of clinical trials will be initiated in close
collaboration with the Therapeutic Products
Directorate (TPD) and the Biologics and Genetic
Therapies Directorate (BGTD).
 Adopted ICH-GCP guidelines for conduct of trials in
1997.

34. Brazilian-GCP
 Brazil participates in GCP harmonization
together with most countries in Latin America
through efforts of the Pan American Health
Organization (PAHO).
 The GCP guidance document in development
through PAHO has its origins in the
International Conference on Harmonization
(ICH) E6, GCP Consolidated Guideline.

35. Critical GCP violations
 Fabrication or falsification of data
 Lack of or inadequate quality certification
 Updated IBs not in place
 Formal procedures/systems not in place
 Poor accountability of IPs at the site
 Poor/ Ineffective blinding system
 No/ inadequate reporting of deviations
 Activity performed without protocol training/delegation
 Use of expired/recalled IPs
 Use of translated ICDs without approval by IEC.

36. Thank you