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Emerging Issues in FDA’s Oversight of Clinical Research. David A. Lepay, M.D., Ph.D. Senior Advisor for Clinical Science FDA Science Board Meeting November 16, 2001. Achievements in Clinical Research (1975-2000). Ethical Principles and Infrastructure (IRBs) Evidence-Based Decision-Making

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Emerging issues in fda s oversight of clinical research

Emerging Issues in FDA’s Oversight of Clinical Research

David A. Lepay, M.D., Ph.D.

Senior Advisor for Clinical Science

FDA Science Board Meeting

November 16, 2001

Achievements in clinical research 1975 2000
Achievements in Clinical Research (1975-2000)

  • Ethical Principles and Infrastructure (IRBs)

  • Evidence-Based Decision-Making

    • Safety; Efficacy

  • Standards of Research Conduct (GCP)

  • International Harmonization

  • Quality Improvement

Quality improvement inspection of us ci s cder
Quality Improvement: Inspection of US CI’s (CDER)










n = 399

n = 15

A changing clinical trial landscape
A Changing Clinical Trial “Landscape”

  • More clinical investigators

  • More studies

  • More participation of vulnerable populations

    • Children, Elderly, Ethnic Groups, etc.

  • More “outsourcing” (CRO’s, SMO’s)

  • New technologies

  • Global expansion

    • Countries/areas new to GCP

Some calls to action
Some Calls to Action

  • June 1998: IG Report “IRBs: A Time for Reform”

  • May 1999: NY Times, “Research for Hire. A Doctor’s Drug Studies Turn into Fraud”

  • September 1999: Death in gene therapy trial

  • December 2000: Washington Post series “The Body Hunters”

  • (June 2001: Death in lung physiology trial)

Answering these calls fda s mission
Answering these Calls: FDA’s Mission

  • FDA has a broad public protection mission

    • Ensure the safe use of regulated products that are themselves safe and efficacious

    • Underlying this mission is FDA decision-making on product applications and labeling

      • Based on complete and accurate information from well-designed, ethically-conducted, and well-monitored clinical research

Fda s mission in clinical research is also broad
FDA’s Mission in Clinical Research is Also Broad

  • Ensure Implementation of Good Clinical Practice (GCP) Standards

    • GCP is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects

    • GCP embraces trial objectives, trial design, study oversight, data collection and quality assurance, study analysis, as well as human subject protection in studies that support product applications

Good clinical practice
Good Clinical Practice

  • GCP is most fundamentally a System of Shared Responsibilities

    • Clinical Investigators

    • Institutions/Institutional Review Boards

    • Industry (Sponsors/Monitors)

    • Government Regulators

Human subject protection is one facet of gcp
Human Subject Protection is One Facet of GCP

  • Colleagues within government

    • OHRP: Leadership role in human subject protection for DHHS

    • NSTC Committee on Science, Human Subject Research Subcommittee (HSRS)


  • FDA also has unique GCP responsibilities

    • Relating to decision-making on applications

Answering these calls fda s approach
Answering these Calls: FDA’s Approach

  • Initiatives

    • Protection

    • Responsibility

    • Reporting

    • Education/Outreach

  • Infrastructure (OGCP)

    • Collaborations; Leveraging


  • Strengthening our systems for human subject protection

    • IRB’s/Institutions

    • Real-time oversight of safety

    • Effective sponsor monitoring

    • Clinical investigators and site staff

    • Responsiveness to subject concerns/complaints

Strengthening the irb system
Strengthening the IRB System

  • IRB Registration: Defining an inventory and developing communications links

  • Voluntary IRB accreditation

    • FDA is working closely with OHRP, HSRS, and IOM toward piloting voluntary IRB accreditation

    • Raising the floor above minimal regulatory requirements

  • Reducing unnecessary burdens where these add little to human subject protection and/or are otherwise better covered

The challenges
The Challenges

  • Functions need to be adequately covered

    • Review of protocol ethics and informed consent

    • Scientific review

    • General monitoring

    • Safety monitoring

    • Reduction and management of conflicts of interest

    • Maintenance of privacy/confidentiality

The challenges1
The Challenges

  • But who best to do these

    • Need to define/redefine/clarify roles

    • Need to establish an effective but reasonable level of redundancy

  • And how to ensure the performance of those assigned each of these roles

    • Education

    • Quality assurance !!


  • Real-time oversight of safety

    • Primacy of the clinical investigator and site staff

      • Education and institutional culture

    • Appropriate use of Data Monitoring Committees

      • FDA will shortly issue guidance on DMC’s: Non-prescriptive (creates no new regulatory requirements)

      • Intended to assist sponsors in determining when a DMC is needed for optimal study monitoring, and how such committees may operate

    • Safety databases


  • Attention to Vulnerable Populations

    • Interim Rule (“Subpart D”; Effective April 30, 2001): Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products

    • Directed at IRB review of protocols: Safeguards must be commensurate with risk/benefit category to approve a protocol

    • Consistent with FDA Pediatric initiatives to obtain more data/labeling information

    • FDA is also looking at PHS “Subpart B”: Additional protections for pregnant women, human fetuses, and neonates involved in research

Protection enhancing fda s bioresearch monitoring program
Protection: Enhancing FDA’s Bioresearch Monitoring Program

  • Priority Planning

    • Assuring integrity of data submitted to applications, but also

    • Following up “real-time” complaints

    • “State of the field” inspections (gene therapy, pediatric trials,...)

  • More resources for on-site inspections

  • Leveraging with OHRP, VA, others

  • Quality assurance of FDA’s inspection program

Responsibility ensuring understanding
Responsibility:Ensuring Understanding

  • Clinical Investigators, IRB’s, and institutions need a thorough understanding of when an IND/IDE is required

    • Definition of “Drug” includes “articles (other than food) intended to affect the structure or any function of the body of man or other animals

    • “Clinical Investigation” means “any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects”

Responsibility ensuring understanding1
Responsibility:Ensuring Understanding

  • Challenge studies and physiology studies of unapproved drugs, biologics, and devices meet the definitions for FDA jurisdiction

    • Understanding the nature and scope of such activities in the academic community

    • How to balance level of oversight with level of risk ?

Responsibility ensuring responsibility
Responsibility:Ensuring Responsibility

  • Attention to ambiguities in the lines of responsibility

    • Investigator/subinvestigator

    • Sponsor-investigators

    • Sponsors/contractors

    • Institutions/Institutional Review Boards

  • Recent cases have brought attention to inadequacies in the “culture” of institutions

Responsibility conflicts of interest
Responsibility:Conflicts of Interest

  • Financial and non-financial conflicts of interest are a growing concern in clinical research

    • Payment of investigators

    • Compensation to subjects

    • Authorship on papers; publication of negative results

    • Financial interests of institutions; pressure on IRBs

  • FDA is working together with OHRP, NHRPAC, HSRS and others to develop guidance that will minimize and manage conflicts of interest

Responsibility standards for non us trials
Responsibility:Standards for Non-US Trials

  • Non-US data is an increasing proportion of data submitted to NDA’s

  • Current criteria for accepting non-US, non-IND data are vague (rooted in ethical principles of the Declaration of Helsinki)

Responsibility standards for non us trials1
Responsibility:Standards for Non-US Trials

  • FDA has made great progress in GCP harmonization

    • The Agency is moving toward GCP as a more concrete standard for accepting non-US, non-IND data

  • Important as well is attention to expanding harmonization efforts (WHO, PAHO, GHTF/ISO) and support for capacity-building

Reporting research misconduct
Reporting:Research Misconduct

  • For FDA to do its job, FDA believes sponsors should promptly report:

    • Any information they have that any person involved in human subject trials committed research misconduct

    • Whenever the sponsor discovers misconduct

    • Not just for clinical investigators and not just when a clinical investigator is terminated

      Regulations should reflect these standards...


  • Education is the key to improving trial quality

  • Education must target ALL who participate in clinical trials and must be a process of “lifelong learning”

    • Standards for clinical investigators and site staff

  • Technology should be embraced

    • New GCP Web site at FDA: www.fda.gov/oc/gcp


  • Establishing a new office to coordinate GCP across FDA and beyond...

Naming the office too cold too hot and just right
Naming the Office: Too Cold, Too Hot, and Just Right

  • (Office of Clinical Science)

    • Not adequately reflective of what we will do

  • (Office for Human Research Trials)

    • Too easily confused with the Department’s Office for Human Research Protections

  • Office for Good Clinical Practice !!!

Ogcp structure
OGCP: Structure

  • Small Office

  • Strategically located

    • Office of the Commissioner and its Office of Science Coordination and Communication

  • Key Positions

    • David A. Lepay, MD PhD: Senior Advisor for Clinical Science and Director

    • Stan W. Woollen: Associate Director for Bioresearch Monitoring

    • Bonnie Lee: Associate Director for Human Subject Protection Policy

Ogcp functions
OGCP: Functions

  • Centralized (Commissioner’s Office) Role in:

    • GCP Policy (bridging the Centers and ORA)

    • Bioresearch Monitoring of Clinical Trials

    • GCP Initiatives

    • International GCP (harmonization) activities

    • GCP Education and Outreach

Ogcp operations
OGCP: Operations

  • Success through leveraging

    • Across FDA

      • Agency GCP/Human Subject Protection Steering Committee (medical policy)

      • BIMO GCP Round Table

      • Center and ORA Infrastructures

    • With OHRP and other Colleagues

    • With Stakeholders

Working together plentiful opportunities
Working Together: Plentiful Opportunities

  • “Reforms” are underway both at FDA and in the oversight of clinical trials

  • The best systems can only emerge from the broadest possible participation