The Role of Regulation in Clinical Trials: An FDA Perspective

1
The Role of Regulation in Clinical Trials An
FDA Perspective

• David A. Lepay, MD PhD
• Senior Advisor for Clinical Science
• Director, Office for GCP
• Office of the Commissioner, FDA
• June 13, 2002

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Regulation Benefits vs. Burdens

• Do we share a common understanding ?
• Of mission and linkage of regulation to mission
• Of definitions What is regulation and what is
  required by regulation
• Of what is being done beyond regulation and why

3
Regulation Benefits vs. Burdens

• Is regulation adding value ?
• Is inconsistency an issue how much and where
• As clinical research evolves, is regulation
  evolving accordingly and appropriately ?

4
FDA Regulates Products

• Drugs, biologics, medical devices (diagnostic and
  therapeutic), foods nearly 25 of the U.S.
  economy
• FDA has responsibility for clinical
  investigations of FDA-regulated products
• Irrespective of study funding
• Irrespective of study location within the U.S.
• Irrespective of whether for commercialization/
  marketing or for scientific knowledge

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FDA is All About Protection

• Protection of Participants in Clinical Research
  of FDA-regulated Products
• Broad Public Protection Mission
• To promote safe use of products that are
  themselves safe and efficacious
• To advance public health through evidence-based
  medicine (and the integrity of research data)

6
The Value of Clinical Trials in Product Approval
is Recognized

• Fully 83 of all adults believe it is
  essential (43) or very important (40) that
  all new prescription drugs or other treatments
  should be tested on human beings in clinical
  trials before they are approved for general use
• Only 1 think it is not important and only 14
  think it is only somewhat important
• Harris Interactive Survey, March 26, 2002

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But Public Confidence is at Issue...

• Confidence that patients in clinical trials
• Are treated as patients, not as guinea pigs
• 24 Very Confident 13 Not Confident
• Are told honestly and clearly of the risks
• 25 Very Confident 18 Not Confident
• Are Not Just Recruited so MDs/Hospitals can Make
  More Money
• 20 Very Confident 20 Not Confident

8
Levels of Authority at FDA

• Law Passed by Congress Governs FDA and the
  U.S. public
• Regulation Promulgated by FDA to implement the
  law Carries the force of law
• Guidance FDAs best advice Alternate methods
  may be used to meet regulation

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Public Comment and Contribution

• In general, FDA regulations and guidances are
  initially published as draft for public comment
• Implementation occurs after review and assessment
  of these comments
• FDA may also issue an advance notice of proposed
  rule making where the Agency recognizes an
  important concern but wants to first solicit
  comments on the need for regulation or its
  contents

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Key Regulations Governing the Conduct of Clinical
Trials

• Regulations directed toward protection of human
  research subjects
• 21 CFR Part 50 Informed Consent
• 21 CFR Part 56 IRB Regulations
• These regulations are near-identical to the
  Common Rule (codified in 45 CFR Part 46 and
  elsewhere) which governs protection of subjects
  in federally funded research

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Key Regulations Governing the Conduct of Clinical
Trials

• Regulations supporting FDAs unique product
  application review responsibilities and the
  Agencys broad public protection mission
• 21 CFR Part 312 IND Regulations (drug)
• 21 CFR Part 812 IDE Regulations (device)
• 21 CFR Part 314 NDA Regulations (drug)
• 21 CFR Part 814 PMA Regulations (device)
• 21 CFR Part 11 Electronic Records/Signatures
• 21 CFR Part 54 Financial Disclosure

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How does FDA Oversee Clinical Research

• In-house Review Process
• Applications and amendments
• Safety reports
• Annual reports
• Bioresearch Monitoring Program
• On-site inspections

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Serious Noncompliance has Decreased over Time
FY77
FY00
20
3
38
3
20
60
56
n 400
n 15
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Compliance as an Evolving Challenge for FDA -1-

• Sponsor-Investigators
• Who monitors the study ?
• Non-U.S. studies
• How to ensure quality over what FDA can not
  regulate in real-time ?
• Noncommercial investigations of FDA-regulated
  products

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Compliance as an Evolving Challenge for FDA -2-

• Designing trials so compliance makes sense
• Protocol design should be as simple as possible
  to promote collection of quality data without
  compromising study objectives
• Study sites should be consulted to make maximum
  use of indigenous record-keeping systems

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Compliance as an Evolving Challenge for FDA -3-

• Dealing with the growth in large multi-center
  trials
• Effective sharing of information
• Adequacy of oversight
• Reducing redundancies
• Regulation vs. Guidance vs. Anecdote
• Back to basics

17
Compliance Alone is Not at the Core of Public
Concern

• From the Harris Survey
• Distrust of systems of medical care
• Not unique to clinical trials
• Too little information or unbalanced information
  (safety risks vs. benefits)
• Too little communication/transparency
• Concerns over conflicts of interest
• Interests of investigator/institution over
  interests of subjects

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The Challenges for FDA

• Upholding and increasing confidence in a system
  that largely works well
• Understanding, shaping, and adapting to the
  evolution of this system
• Focusing on quality, capacity, performance, and
  added value
• Leveraging (resources culture)

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FDA is Striving to Meet these Challenges

• Infrastructure
• Initiatives
• Collaboration
• Communication