1. Regulatory Authority Governing Clinical Trials Anthony J. Minisi, MD Director, Cardiology Fellowship Program

2. Regulatory Authority Governing Clinical Trials Current trials governed by: l Good Clinical Practices l Good Laboratory Practices l Good Manufacturing Practices

3. Good Clinical Practices “A standard for the design, conduct, performance, monitoring, auditing, recording, analysis, 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.” ICH-GCP [1.24]

4. Good Laboratory Practices l An array of standards and regulations to guide the planning, performance, monitoring, recording, reporting, and archiving of laboratory studies l Designed to assure that data are reliable and can be used

5. Good Manufacturing Practices l A collection of standards regulating the manufacturing, processing, packaging, and storage of drugs or devices l Designed to assure that these processes are consistent and reproducible

7. US Food, Drug, and Cosmetic Act--1938 l Developed in response to elixir of sulfanilamide tragedy n First statutory regulation of cosmetics and therapeutic devices n Required drug manufacturers to provide scientific proof that new products were safe n Provided specific authority for factory inspections

8. Nuremburg Code--1947 l Developed in response to unethical medical experimentation on human subjects by German scientists during WW II l First set of standards for the review and conduct of human research requiring: n Voluntary consent of subjects n Justifiable reason for experimentation n Protection of participants

9. US Kefauver-Harris Drug Amendment--1962 l Developed in response to thalidomide tragedy requiring: n Manufacturers prove efficacy as well as safety before marketing a new product n Informed consent be obtained from all participants l Outlined a process for clinical testing that still applies today

10. Declaration of Helsinki--1964 l Defined ethical standards for the conduct of human research n Research in humans should be based on results of laboratory and animal experimentation n Research protocols should be reviewed by an independent committee prior to initiation n Risks should not exceed benefits

11. Declaration of Helsinki--1964 l Defined ethical standards for the conduct of human research n Informed consent should be obtained in all research subjects n Only medically and/or scientifically qualified individuals should conduct human research

12. US National Research Act--1974 National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research n Defined basic ethical principles for the conduct of human research n Formulated guidelines to ensure that human research is conducted in accordance with these ethical principles Required establishment of an IRB at all institutions conducting human research

13. The Belmont Report--1979 l Outlines basic ethical principles developed by the National Commission n Respect for persons n Beneficence n Justice l Addresses distinction between medical practice and research

14. The Belmont Report--1979 l Respect for Persons n Individuals should be treated as “autonomous agents” whose freedom to act on opinions, choices, and considered judgments should be given priority n Individuals with diminished autonomy are entitled to additional protections

15. The Belmont Report--1979 l Beneficence n Obligation to conduct research in a manner that maximizes potential benefits and minimizes possible risks l Justice n Selection of subjects should be equitable and the burdens of research should be borne by those most likely to benefit from the research results

16. International Conference on Harmonisation (ICH)--1990 l Convened to devise a unified standard governing clinical research in the US, European Union, and Japan l Designed to facilitate the mutual acceptance of data generated from clinical trials by regulatory authorities in each jurisdiction

17. ICH Principles l Studies should be conducted in accordance with the Declaration of Helsinki l Risks and benefits should be carefully scrutinized l Rights, safety, and well-being of study subjects of paramount importance

18. ICH Principles l Information from preliminary studies of the investigational product should support the study l Studies should be scientifically rigorous and outlined in a formal protocol l All studies should be reviewed and approved by a convened IRB

19. ICH Principles l A qualified physician should be responsible for all medical care and decisions l All study staff should have appropriate education, training, and experience l All study subjects should freely give informed consent prior to participation

20. ICH Principles l Study data should be recorded and stored in a manner that allows its accurate reporting, interpretation, and verification l Confidentiality of records should be protected l Investigational products should be manufactured, handled, and stored in accordance with GMP l QA procedures should be in place

22. Investigator Responsibilities l Hire study staff with appropriate qualifications l Delegate study tasks appropriately l Use investigational product per protocol l Comply with GCP and other regulatory requirements l Participate in data monitoring, auditing, and site inspection l Provide sufficient resources l Provide medical care l Conduct study procedures per protocol l Obtain IRB approval l Obtain informed consent l Maintain records and submit reports l Safety reporting

23. Investigator Responsibilities FDA Form 1572—Section 9 “Commitments” l I agree to conduct the study in accordance with the protocol and will only make changes to the protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects l I agree to personally conduct or supervise the described investigation l I agree to inform any study subjects that the drugs are being used for investigational purposes and I will ensure that the requirements related to obtaining informed consent and IRB review and approval are met

24. FDA Form 1572--Commitments l I agree to report to the sponsor adverse experiences that occur in the course of the study l I have read and understand the information in the Investigator’s Brochure, including the potential risks and side effects of the drug l I agree to ensure that all study staff are informed in meeting the above commitments l I agree to maintain adequate and accurate records and to make those records available for inspection

25. FDA Form 1572--Commitments l I agree that an IRB will be responsible for the initial and continuing review and approval of the clinical investigation l I agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others l I will not make any changes in the research without IRB approval, except where necessary to eliminate hazards to human subjects WARNING: A willfully false statement is a criminal offense USC Title 18, Sec 1001

26. Sponsor Responsibilities l QA and QC l Medical expertise l Trial management l Selection of investigators l Financial support l Compliance with regulatory issues l Protocol generation and amendment l Confirmation of IRB review and approval l Supply investigational product with appropriate information l Case report forms l Safety monitoring l Data monitoring l Site audit/inspection l Report submission