GCP Quality Assurance and FDA David A Lepay

GCP, Quality Assurance, and FDA David A. Lepay, M. D. , Ph. D. Senior Advisor for Clinical Science, US FDA Fall 2001

GCP Quality Assurance: Then and Now z. Then: y. Always a cornerstone of sponsor success in GCP y“Silent Topic” at FDA x. No explicit regulatory requirement for auditing x. Sponsor approaches a “mystery” to the Agency x. Routine audit reports would not be requested

GCP Quality Assurance: Then and Now z. Now: y. Greater contact between FDA and industry y. More guidance x. FDA: ICH GCP Consolidated Guideline l Section 5. 19: Audit l Section 6. 11: Documents -- Quality Control and Quality Assurance

GCP Quality Assurance: Then and Now z. Now: y. More guidance x. EU: The “Engage Guideline” l European Network of GCP Auditors, Optional l Guideline for GCP Compliance and Quality Systems Auditing) x. Others: l EU Directive; (Revision to WHO GCP guideline)

GCP Quality Assurance: Then and Now z. Now y. More dialogue on quality assurance y. More transparency x. Reporting of misconduct (falsification, fabrication, compromise to subject protection) is necessary and different from reporting routine QA

Need for QA in a Changing Clinical Trial “Landscape” z More studies; more sites; greater volume at each site z Expansion and fluidity of clinical investigator pool z “New” players in new roles (CRO’s, SMO’s) z New technologies (electronic record-keeping) z More participation by “vulnerable” subjects z Global expansion (areas new to GCP)

Calls to Action are Calls for Quality Assurance z June 1998: IG Report “IRBs: A Time for Reform” Who is watching the institutions ? z May 1999: NY Times, “Research for Hire. A Doctor’s Drug Studies Turn into Fraud” Enough QA ? Effective QA ? z December 2000: Washington Post series “The Body Hunters” Where is the QA in non-US studies ?

Calls to Action are Calls for Quality Assurance z September 1999: Death in gene therapy trial z June 2001: Death in lung physiology study Who is auditing (or even monitoring) the sponsorinvestigators ? Who is auditing (or monitoring) noncommercial studies ?

Answering these Calls at FDA z. New Collaborations z. New Approaches

New Colleagues in Government z Office for Human Research Protections (OHRP) z Office of Research Integrity (ORI) z National Science and Technology Council Human Subject Research Subcommittee (HSRS) (16 Federal Departments and Agencies involved in human research) z National Human Research Protection Advisory Committee (NHRPAC)

New Collaborations z FDA is committed to public dialogue y. Meetings with Stakeholders y. Education and Outreach y. Advancements in Communication Technology z All parties participating in the clinical trial process must become engaged in identifying and implementing process improvements z Public comment is integral to the process of FDA rule-making and guidance development

New Approaches z. Initiatives y. Human Subject Protection y. Responsibility y. Reporting y. Education/Outreach z. Infrastructure

RESPONSIBILITY: Ensuring Responsibility z Attention to ambiguities in the lines of responsibility y. Investigator/subinvestigator y. Sponsor-investigators y. Sponsors/contractors y. Institutions/Institutional Review Boards z Attention to identifying, minimizing, and managing conflicts of interest

RESPONSIBILITY: Ensuring Understanding z Clinical Investigators, IRB’s, and institutions need a thorough understanding of when an IND/IDE is required y“Drug” includes a product (other than a food) that is intended to affect the structure or function of the body y“Clinical investigation” means any experiment (use except for a marketed drug in the course of medical practice) in which a drug is administered involving one or more human subjects

Marketed Drugs Can Still Be Investigational z Medical Practice y. Approved indication and use y. Off-label use z Investigational Use (IND needed) y. New route of administration y. New dosage level y. Use in way that increases risk y. Use to develop data for labeling change or NDA for new indication

REPORTING: Research Misconduct z FDA believes Sponsors should promptly report: y. Any information they have that any person involved in human subject trials committed research misconduct y. Whenever the sponsor discovers misconduct y. Not just for clinical investigators and not just when a clinical investigator is terminated z Regulations should reflect these standards. . .

REPORTING: Research Misconduct z. A Sponsor’s Responsibility but Everyone’s Duty y. As much specific information as possible x. Name of the person(s) x. Contact information x. Specific identity of the affected research l IND/IDE #, protocol, study title, and study dates

Who Complains? FY 2000 from CDER’s DSI 5% 2% 2% 14% 8% 3% 3% 11% 9% 8% 8% 9% 19% n = 118

You Are Already Helping: Classification of Follow-Up Inspections 26% (n= 27) n= 105 26% 52% n= 27

EDUCATION: z Education is the key to improving trial quality z The primary focus of FDA’s Bioresearch Monitoring program is and should be educational z Education must target ALL who participate in clinical trials and must be a process of “lifelong learning” y. Standards for clinical investigators and site staff

Information from FDA z. A New FDA Web Site to Consolidate GCP Information: zwww. fda. gov/oc/gcp/ z. Revising FDA’s Information Sheets for IRBs and Clinical Investigators y. Comprehensive review and revision expected to issue for public comment in 2002

INFRASTRUCTURE: z. Establishing a new office to coordinate GCP across FDA and beyond. . .

Naming the Office: Too Cold, Too Hot, and Just Right z(Office of Clinical Science) y. Not adequately reflective of what we will do z(Office for Human Research Trials) y. Too easily confused with the Department’s Office for Human Research Protections z. Office for Good Clinical Practice !!!

OGCP: Structure z Small Office z Strategically located y Office of the Commissioner and its Office of Science Coordination and Communication z Key Positions y David A. Lepay, MD Ph. D: Senior Advisor for Clinical Science and Director y Stan W. Woollen: Associate Director for Bioresearch Monitoring y Bonnie Lee: Associate Director for Human Subject Protection Policy

OGCP: Functions z. Centralized (Commissioner’s Office) Role in: y. GCP Policy y. Bioresearch Monitoring of Clinical Trials y. GCP Initiatives y. International GCP (harmonization) activities y. GCP Education and Outreach

OGCP: Operations z. Success through leveraging y. Across FDA x. Agency GCP/Human Subject Protection Steering Committee (medical policy) x. BIMO GCP Round Table x. Center and ORA Infrastructures y. With OHRP and other Colleagues y. With Stakeholders

OGCP and Quality Assurance z. OGCP will reflect the Agency’s Commitment to Quality Assurance y. Internally x. Coordinating QA for the Agency’s GCP BIMO Program y. Externally x. Coordinating Agency GCP policy and initiatives to enhance the quality of clinical research

GCP QA: Looking Ahead z. Quality assurance and quality improvement should become prevailing themes in clinical research z. This may include new venues for QA y. Academic Institutions y. Research hospitals and clinics y. Global expansion

GCP QA: What We Should Strive For z. Building quality in upfront z. Assuring quality throughout z. Developing capacity for continuous quality improvement now and in the future

Working Together: Plentiful Opportunities z“Reforms” are underway both at FDA zand in the oversight of clinical trials z. The best systems can only emerge from the broadest possible participation z. Quality assurance and quality improvement are integral to development of the best systems !