Regulatory Authority Governing Clinical Trials

1
Regulatory Authority Governing Clinical Trials

• Anthony J. Minisi, MD
• Director, Cardiology Fellowship Program

2
Regulatory Authority Governing Clinical Trials

• Current trials governed by
• Good Clinical Practices
• Good Laboratory Practices
• 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

• 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

5
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

6
(No Transcript)
7
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

8
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

9
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

10
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

11
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

12
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

13
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

14
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

15
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

16
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

17
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

18
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

19
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

20
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

21
(No Transcript)
22
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

23
Investigator Responsibilities

• FDA Form 1572Section 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

24
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
  Investigators 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

25
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

26
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