Transcript David A. Lepay, M.D., Ph.D. Emerging Issues in FDA’s

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
Safety; Efficacy
Standards of Research Conduct (GCP)
International Harmonization
Quality Improvement
Quality Improvement:
Inspection of US CI’s
(CDER)
FY’77
20%
38%
FY’00
5%
2%
20%
OAI
VAI
NAI
Pending
60%
55%
n = 15
n = 399
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
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
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 decisionmaking on product applications and labeling
Based on complete and accurate information from
well-designed, ethically-conducted, and wellmonitored clinical research
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
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
Colleagues within government
OHRP: Leadership role in human subject
protection for DHHS
NSTC Committee on Science, Human Subject
Research Subcommittee (HSRS)
ORCA (VA), NBAC, NHRPAC
FDA also has unique GCP responsibilities
Relating to decision-making on applications
Answering these Calls:
FDA’s Approach
Initiatives
Protection
Responsibility
Reporting
Education/Outreach
Infrastructure (OGCP)
Collaborations; Leveraging
Protection
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
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
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 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 !!
Protection
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: Nonprescriptive (creates no new regulatory
requirements)
Intended to assist sponsors in determining when
a DMC is needed for optimal study monitoring,
Protection
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
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
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 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
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
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
Non-US data is an increasing proportion of
data submitted to NDA’s
Current criteria for accepting non-US, nonIND data are vague (rooted in ethical
principles of the Declaration of Helsinki)
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, nonIND data
Important as well is attention to expanding
harmonization efforts (WHO, PAHO,
GHTF/ISO) and support for capacity-building
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:
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
Infrastructure:
Establishing a new office to
coordinate GCP across FDA and
beyond...
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
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
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
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
“Reforms” are underway both at FDA
and in the oversight of clinical trials
The best systems can only emerge from
the broadest possible participation