1. Principles of Good Clinical Practice (GCP) – What is it all about and who is responsible for adherence?
GCP and QA All SIAC Call
Mar 14, 2008
Munish Mehra, PhD
Managing Director,
Global Drug Development Experts,
Washington D.C

2. What is GCP? ICH E6 Introduction (10th June 1996):
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. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

3. ICH E6 – Guidelines for Good Clinical Practice
1. GLOSSARY
2. THE PRINCIPLES OF ICH GCP
3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)
3.1 Responsibilities
3.2 Composition, Functions and Operations
3.3 Procedures
3.4 Records
4. INVESTIGATOR
4.1 Investigator's Qualifications and Agreements
4.2 Adequate Resources
4.3 Medical Care of Trial Subjects
4.4 Communication with IRB/IEC
4.5 Compliance with Protocol
4.6 Investigational Product(s)
4.7 Randomization Procedures and Unblinding
4.8 Informed Consent of Trial Subjects
4.9 Records and Reports
4.10 Progress Reports
4.11 Safety Reporting
4.12 Premature Termination or Suspension of a Trial
4.13 Final Report(s) by Investigator

4. ICH E6 – Guidelines for Good Clinical Practice
5. SPONSOR
5.1 Quality Assurance and Quality Control
5.2 Contract Research Organization (CRO)
5.3 Medical Expertise
5.4 Trial Design
5.5 Trial Management, Data Handling, and Record Keeping
5.6 Investigator Selection
5.7 Allocation of Responsibilities
5.8 Compensation to Subjects and Investigators
5.9 Financing
5.10 Notification/Submission to Regulatory Authority(ies)
5.11 Confirmation of Review by IRB/IEC
5.12 Information on Investigational Product(s)
5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)
5.14 Supplying and Handling Investigational Product(s)
5.15 Record Access
5.16 Safety Information
5.17 Adverse Drug Reaction Reporting

5. ICH E6 – Guidelines for Good Clinical Practice
5.18 Monitoring
Purpose
Selection and Qualifications of Monitors
Extent and Nature of Monitoring
Monitor's Responsibilities
Monitoring Procedures
Monitoring Report
5.19 Audit
Purpose
Selection and Qualification of Auditors
Auditing Procedures
5.20 Noncompliance
5.21 Premature Termination or Suspension of a Trial
5.22 Clinical Trial/Study Reports
5.23 Multicentre Trials

6. ICH E6 – Guidelines for Good Clinical Practice
6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)
6.1 General Information
6.2 Background Information
6.3 Trial Objectives and Purpose
6.4 Trial Design
6.5 Selection and Withdrawal of Subjects
6.6 Treatment of Subjects
6.7 Assessment of Efficacy
6.8 Assessment of Safety
6.9 Statistics
6.10 Direct Access to Source Data/Documents
6.11 Quality Control and Quality Assurance
6.12 Ethics
6.13 Data Handling and Record Keeping
6.14 Financing and Insurance
6.15 Publication Policy
6.16 Supplements

7. ICH E6 – Guidelines for Good Clinical Practice
7. INVESTIGATOR’S BROCHURE
7.1 Introduction
7.2 General Considerations
7.2.1 Title Page
7.2.2 Confidentiality Statement
7.3 Contents of the Investigator’s Brochure
7.3.1 Table of Contents
7.3.2 Summary
7.3.3 Introduction
7.3.4 Physical, Chemical, and Pharmaceutical Properties and Formulation
7.3.5 Nonclinical Studies
7.3.6 Effects in Humans
7.3.7 Summary of Data and Guidance for the Investigator
8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL

8. GCP – EU GCP Directive
EU – GCP Directive; Commission Directive 2005/28/EC; 8 April, 2005
CHAPTER 2
GOOD CLINICAL PRACTICE FOR THE DESIGN, CONDUCT,
RECORDING AND REPORTING OF CLINICAL TRIALS
SECTION 1
GOOD CLINICAL PRACTICE
Article 2
The rights, safety and well being of the trial subjects shall prevail over the interests of science and society.
Each individual involved in conducting a trial shall be qualified by education, training, and experience to perform his tasks.
Clinical trials shall be scientifically sound and guided by ethical principles in all their aspects.
The necessary procedures to secure the quality of every aspect of the trials shall be complied with.

9. GCP – EU GCP Directive (Contd.)
Article 3
The available non-clinical and clinical information on an investigational medicinal product shall be adequate to support the proposed clinical trial.
Clinical trials shall be conducted in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, adopted by the General Assembly of the World Medical Association (1996).
Article 4
The protocol referred to in point (h) of Article 2 of Directive 2001/20/EC shall provide for the definition of inclusion and exclusion of subjects participating in a clinical trial, monitoring and publication policy.
The investigator and sponsor shall consider all relevant guidance with respect to commencing and conducting a clinical trial.
Article 5
All clinical trial information shall be recorded, handled, and stored in such a way that it can be accurately reported, interpreted and verified, while the confidentiality of records of the trial subjects remains protected.

10. GCP – WHO
World Health Organization, WHO Technical Report Series, No. 850, 1995, Annex 3
Guidelines for good clinical practice (GCP) for trials on pharmaceutical products*
The purpose of these WHO Guidelines for Good Clinical Practice (GCP) for trials on pharmaceutical products is to set globally applicable standards for the conduct of such biomedical research on human subjects
A formal basis for mutual recognition of clinical data generated within the interested countries.
No question arises, however, of challenging or replacing existing national regulations or requirements.
The Guidelines are addressed not only to investigators, but also to ethics review committees, pharmaceutical manufacturers and other sponsors of research and drug regulatory authorities.

11. GCP – WHO (Contd.)
These Guidelines not only serve the interests of the parties actively involved in the research process, but protect the rights and safety of subjects, including patients, and ensure that the investigations are directed to the advancement of public health objectives.
The Guidelines are intended specifically to be applied during all stages of drug development both prior to and subsequent to product registration and marketing, but they are also applicable, in whole or in part, to biomedical research in general.

12. Overview of WHO GCP
1. PROVISIONS AND PREREQUISITES FOR A CLINICAL TRIAL
1.1 Justification for the trial
1.2 Ethical principles
1.3 Supporting data for the investigational product
1.4 Investigator and site(s) of investigation
1.5 Regulatory requirements
2. THE PROTOCOL
3. PROTECTION OF TRIAL SUBJECTS
3.1 Declaration of Helsinki
3.2 Ethics committee
3.3 Informed consent
3.4 Confidentiality
4. RESPONSIBILITIES OF THE INVESTIGATOR
4.1 Medical care of trial subjects
4.2 Qualifications
4.3 Selection of trial subjects
4.4 Compliance with the protocol
4.5 Information for subjects and informed consent
4.6 The investigational product
4.7 The trial site
4.8 Notification of the trial or submission to the drug regulatory authority

13. Overview of WHO GCP 4.9 Review by an ethics committee
4.10 Serious adverse events or reactions
4.11 Financing
4.12 Monitoring, auditing and inspection
4.13 Record-keeping and handling of data
4.14 Handling of and accountability for pharmaceutical products for trial
4.15 Termination of trial
4.16 Final report
4.17 Trials in which the investigator is the sponsor
5. RESPONSIBILITIES OF THE SPONSOR
5.1 Selection of the Investigator(s)
5.2 Delegation of responsibilities
5.3 Compliance with the protocol and procedures
5.4 Product information
5.5 Safety information
5.6 Investigational product
5.7 Trial management and handling of data
5.8 Standard operating procedures
5.9 Compensation for subjects and investigators
5.10 Monitoring
5.11 Quality assurance

14. Overview of WHO GCP 5.12 Study reports 5.13 Handling of adverse events
5.14 Termination of trial
6. RESPONSIBILITIES OF THE MONITOR
6.1 Qualifications
6.2 Assessment of the trial site
6.3 Staff education and compliance
6.4 Data management
6.5 Case-report forms
6.6 Investigational product
6.7 Communication
6.8 Notification of the trial or submission to the regulatory authority
6.9 Reports
7. MONITORING OF SAFETY
7.1 Handling and recording adverse events
7.2 Reporting adverse events
8. RECORD-KEEPING AND HANDLING OF DATA
8.1 Responsibilities of the investigator
8.2 Responsibilities of the sponsor and the monitor
8.3 Archiving of data

15. Overview of WHO GCP 9. STATISTICS AND CALCULATIONS
9.1 Experimental design
9.2 Randomization and blinding
9.3 Statistical analysis
10. HANDLING OF AND ACCOUNTABILITY FOR PHARMACEUTICAL PRODUCTS
10.1 Supply and storage
10.2 Investigational labelling and packaging
10.3 Responsibilities of the investigator
10.4 Responsibilities of the sponsor and the monitor
11. ROLE OF THE DRUG REGULATORY AUTHORITY
11.1 General responsibilities
11.2 On-site inspections
12. QUALITY ASSURANCE FOR THE CONDUCT OF A CLINICAL TRIAL
13. CONSIDERATIONS FOR MULTICENTRE TRIALS
REFERENCES
APPENDIX 1. World Medical Association’s Declaration of
Helsinki
APPENDIX 2. Model list of items to be contained in a clinical trial protocol
APPENDIX 3. Considerations for multicentre trials

16. U.S Regulatory Framework
Laws or Statutes – FD&C Act of 1938 and approved by Congress (Legislative Branch of US Govt.)
Regulations – 21 CFR Parts 50, 54, 56, 312, 314 etc – Written by FDA to implement the FD&C Act
Guidelines – Defined in 21CFR and provided guidance to assist with compliance to regulations as well as establish principles or practices - Non binding and non-enforceable – Not laws or regulations but interpretation of the laws
Guidances – Not defined in CFR – Less formal than Guidelines and provide general recommendations on how to meet regulations – Non binding and non-enforceable – Not laws or regulations but interpretation of the laws
Case Law – Court Decisions
FDA Clinical Information Sheets (See example at )
FDA Letters to Industry
Public presentations and publications (e.g. at DIA etc.) indicating individual interpretations and current status or thinking on relevant issues

17. IOMs
Field Inspector Operations Manuals (IOM) - The IOM is the primary guidance document on FDA inspection policy and procedures for field investigators and inspectors – Very detailed manual for FDA inspectors. PDF versions can be downloaded from

18. CPGMs Compliance Program Guidance Manuals
FDA compliance programs provide guidance and instructions to FDA staff for obtaining information to help fulfill agency plans in the specified program area
– Institutional Review Boards
– Sponsors/Monitors/CROs
– Clinical Investigators
– Electronic Records / Electronic Signatures Enforcement

19. CFR – Code of Federal Regulations
CFR Title 45, Part 46 (45 CFR 46) is also known as the “Common Law” or “HHS Regulations” or “Basic DHHS Policy” and covers human subject protection for any research conducted, supported or otherwise subject to regulations from a U.S. federally agency (NIH, DOJ, DOE, NASA. Focuses on IRB and Informed Consent Standards and is similar to 21CFR50 and 21CFR56
21 CFR is what FDA is responsible to oversee and covers all research using Pharmaceutical products, Biologics and Medical devices.

20. Regulations Regulations US 21CFR
Part 11 – Electronics Records; Electronics Signatures
Part 50 – Protection of Human Subjects
Part 54 – Financial Disclosure by Clinical Investigators
Part 56 – Institutional Review Boards
Part 58 – Good Laboratory Practices for NonClinical Laboratory Studies
Part 312 – Investigational New Drug Application
Part 314 – Application for FDA Approval to Market a New Drug

21. Regulations vs. Guidances (Contd.)
Regulations are Laws of the Country and Legally Binding.
Regulations are broad and could be interpreted in different ways
Guidelines and Guidances represent FDA’s current interpretation of the Regulations and can change over time
21CFR Part 11
Original guidances, Repeal of the guidances and issue of new guidance (CSUCT)
Possible change in the regulation
Changing Regulations takes much longer

22. FDA Guidances Arranged by Subject Some Examples
Check out:
Arranged by Subject
Some Examples
Acceptance of Foreign Clinical Studies
General Considerations for the Clinical Evaluation of Drugs in Infants and Children
Financial Disclosure by Clinical Investigators
Monitoring of Clinical Investigations
Testing of Glycerin for Diethylene Glycol

23. FDA Regulations vs. Declaration of Helsinki
21CFR (c)(4) incorporated declaration of Helsinki (DOH) through 1989 revision of DOH.
Most current revision of DOH from 2004 has two controversial issues

24. Controversy over Two items in the Declaration of Helsinki (2004)
Section C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE
Item 29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.
Item 30. At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.

25. FDA GCP vs. HHS Regulation (Common Rule)
See
Example: 50.23(a)-(c) Exception from general requirements: Describes an exception from the general requirements for obtaining informed consent in circumstances that are life-threatening; informed consent cannot be obtained from the subject; time is not sufficient to obtain consent from the subject's legal representative; and there is available no alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the life of the subject. There is nothing similar under HHS Regulations.

26. FDA Requirements vs. ICH GCP
Some Examples
ICH GCP Guidelines Requirements (No such provision under FDA regulations or guidances)
Recommend that the patient’s primary care physician be notified when the patient is enrolling in a clinical trial
States that any source documentation required directly on the CRF should be specified in the protocol
Requires a staff delegation of responsibilities form
Requires the Informed Consent Form given to the subject is one that is signed by the subject and the investigator
FDA Regulations require completion of a Financial Disclosure Form (1572) by all Investigators and collection of this by sponsors and reporting to FDA

27. Standard Operating Procedures SOPs
Specific to each company on how they ensure adherence to regulations, guidances, etc.
Standardize processes within a company to minimize errors and increase efficiencies
Working Practices, Operating Guidelines, Work Processes
Templates, Forms, Process Maps

28. GCP - Whose Responsibility is it?
Everyone

29. References http://www.fda.gov/oc/gcp/guidance.html#guidance

30. Global Drug Development Experts Washington D.C., U.S.A
Thank you
Questions?
Munish Mehra, PhD
Managing Director
Global Drug Development Experts
Washington D.C., U.S.A
U.S
Feel free to or call me