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)

OAI

VAI

NAI

Pending

n = 15

60%

20%

20%

55%

38% 5%

2%

n = 399

FY’77 FY’00

A Changing Clinical Trial “Landscape”

More clinical investigatorsMore studiesMore participation of vulnerable populations

Children, Elderly, Ethnic Groups, etc.

More “outsourcing” (CRO’s, SMO’s)New technologiesGlobal 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 decision-making on product applications and labelingBased on complete and accurate information

from well-designed, ethically-conducted, and well-monitored 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 ChallengesFunctions 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 CommitteesFDA 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

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 inspectionsLeveraging with OHRP, VA, othersQuality 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, non-IND 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, non-IND 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: StructureSmall OfficeStrategically 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 TableCenter 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