Regulatory Authority Governing Clinical Trials

Anthony J. Minisi, MD

Director, Cardiology Fellowship Program

Regulatory Authority Governing Clinical Trials

Current trials governed by: Good Clinical Practices Good Laboratory Practices Good Manufacturing Practices

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]

Good Laboratory Practices

An array of standards and regulations to guide the planning, performance, monitoring, recording, reporting, and archiving of laboratory studies

Designed to assure that data are reliable and can be used

Good Manufacturing Practices

A collection of standards regulating the manufacturing, processing, packaging, and storage of drugs or devices

Designed to assure that these processes are consistent and reproducible

US Food, Drug, and Cosmetic Act--1938

Developed in response to elixir of sulfanilamide tragedy First statutory regulation of cosmetics

and therapeutic devices Required drug manufacturers to provide

scientific proof that new products were safe

Provided specific authority for factory inspections

Nuremburg Code--1947

Developed in response to unethical medical experimentation on human subjects by German scientists during WW II

First set of standards for the review and conduct of human research requiring: Voluntary consent of subjects Justifiable reason for experimentation Protection of participants

US Kefauver-Harris Drug Amendment--1962

Developed in response to thalidomide tragedy requiring: Manufacturers prove efficacy as well as

safety before marketing a new product Informed consent be obtained from all

participants Outlined a process for clinical testing

that still applies today

Declaration of Helsinki--1964

Defined ethical standards for the conduct of human research Research in humans should be based on

results of laboratory and animal experimentation

Research protocols should be reviewed by an independent committee prior to initiation

Risks should not exceed benefits

Declaration of Helsinki--1964

Defined ethical standards for the conduct of human research Informed consent should be obtained in

all research subjects Only medically and/or scientifically

qualified individuals should conduct human research

US National Research Act--1974

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research Defined basic ethical principles for the

conduct of human research 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

The Belmont Report--1979

Outlines basic ethical principles developed by the National Commission Respect for persons Beneficence Justice

Addresses distinction between medical practice and research

The Belmont Report--1979

Respect for Persons Individuals should be treated as

“autonomous agents” whose freedom to act on opinions, choices, and considered judgments should be given priority

Individuals with diminished autonomy are entitled to additional protections

The Belmont Report--1979

Beneficence Obligation to conduct research in a

manner that maximizes potential benefits and minimizes possible risks

Justice Selection of subjects should be

equitable and the burdens of research should be borne by those most likely to benefit from the research results

International Conference on Harmonisation (ICH)--1990

Convened to devise a unified standard governing clinical research in the US, European Union, and Japan

Designed to facilitate the mutual acceptance of data generated from clinical trials by regulatory authorities in each jurisdiction

ICH Principles

Studies should be conducted in accordance with the Declaration of Helsinki

Risks and benefits should be carefully scrutinized

Rights, safety, and well-being of study subjects of paramount importance

ICH Principles

Information from preliminary studies of the investigational product should support the study

Studies should be scientifically rigorous and outlined in a formal protocol

All studies should be reviewed and approved by a convened IRB

ICH Principles

A qualified physician should be responsible for all medical care and decisions

All study staff should have appropriate education, training, and experience

All study subjects should freely give informed consent prior to participation

ICH Principles

Study data should be recorded and stored in a manner that allows its accurate reporting, interpretation, and verification

Confidentiality of records should be protected

Investigational products should be manufactured, handled, and stored in accordance with GMP

QA procedures should be in place

Investigator Responsibilities

Hire study staff with appropriate qualifications

Delegate study tasks appropriately

Use investigational product per protocol

Comply with GCP and other regulatory requirements

Participate in data monitoring, auditing, and site inspection

Provide sufficient resources

Provide medical care Conduct study

procedures per protocol Obtain IRB approval Obtain informed consent Maintain records and

submit reports Safety reporting

Investigator Responsibilities

FDA Form 1572—Section 9 “Commitments” 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

I agree to personally conduct or supervise the described investigation

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

FDA Form 1572--Commitments

I agree to report to the sponsor adverse experiences that occur in the course of the study

I have read and understand the information in the Investigator’s Brochure, including the potential risks and side effects of the drug

I agree to ensure that all study staff are informed in meeting the above commitments

I agree to maintain adequate and accurate records and to make those records available for inspection

FDA Form 1572--Commitments

I agree that an IRB will be responsible for the initial and continuing review and approval of the clinical investigation

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

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

Sponsor Responsibilities

QA and QC Medical expertise Trial management Selection of

investigators Financial support Compliance with

regulatory issues Protocol generation and

amendment

Confirmation of IRB review and approval

Supply investigational product with appropriate information

Case report forms Safety monitoring Data monitoring Site audit/inspection Report submission