Good Clinical Practice: Are We There Yet ? And What Comes Next ?

1
Good Clinical Practice Are We There Yet ? And
What Comes Next ?

• David A. Lepay, MD PhD
• Senior Advisor for Clinical Science
• Office of the Commissioner, US FDA
• July 25, 2007

2
What This Talk Will Cover

• Introduction to FDA
• FDA Expectations and Oversight in Clinical
  Research
• New Challenges in Clinical Research
• FDA GCP Strategies and Initiatives

3
FDA Key Facts

• Oldest consumer protection agency in the U.S.
• Workforce of nearly 10,000 with an annual budget
  of approximately 1.9 billion
• Regulates nearly 25 of the U.S. economy
• Pharmaceuticals
• Biologics (including blood products, vaccines)
• Medical devices (diagnostic and therapeutic)
• Veterinary medicines
• Foods

4
FDA Logistics

• Based in Rockville, MD (15 miles from DC)
• 20 District Offices across the U.S.
• Dallas District Office
• Resident Post in Houston
• General inquiries 1-888-INFO-FDA
• Website www.fda.gov
• Note link to Clinical Trials pages for
  Consumers and for Professionals

5
FDAs Authority over Clinical Research

• FDAs authority derives from the movement of
  investigational drugs/biologics/devices across
  U.S. national/state borders
• An IND (research permit) must be in effect to
  lawfully ship an investigational drug within the
  U.S. for purposes of a clinical investigation
• FDA regulations establish direct authority over
  all investigators, sponsors, monitors, contract
  research organizations, and IRBs/institutions
  conducting research under a U.S. IND

6
Levels of Authority

• FDA must operate in accordance with the law
  (principally the Food Drug and Cosmetic Act)
• Executes provisions of the law
• Cant exceed authorities granted under the law
• FDA can promulgate regulations to implement the
  law these carry the force of law
• FDA can develop guidance ( FDAs best
  thinking) guidance is not legally binding

7
Application Review at FDA

• Review of research applications (IND/IDE)
• Review of marketing applications (NDA/ BLA/PMA)
• Postmarketing review

8
Review of Research Applications (IND/IDE)

• Conducted by review teams in FDAs Centers
• Organized by therapeutic area
• Focus is on subject safety and on the ability of
  proposed studies/protocols to meet their stated
  objectives
• Applicants/sponsors are responsible for the
  protocols (including the design of protocols)
  submitted to FDA applications
• Application/protocol may proceed unless FDA
  imposes a hold

9
Dispelling Some Myths

• FDA does not approve protocols
• FDA does not approve informed consent documents
• FDA does not certify clinical investigators,
  clinical sites, sponsors, or IRBs
• FDA does not directly regulate clinical
  laboratories (GLP preclinical (animal) testing)
• FDA does not regulate the practice of medicine

10
FDA Inspection of Clinical Research

• FDA has authority to inspect any party involved
  in clinical investigations of FDA-regulated
  products
• Investigators, sponsors, monitors, CROs,
  institutions, IRBs
• Most often to validate data submitted to FDA in
  support of marketing applications
• But also systems inspections and for cause
  inspections at any phase of testing

11
FDAs Regulations for Clinical Research

• Small subset of the over 1300 parts to Title 21
  of the Code of Federal Regulations
• 21 CFR 312/812 IND/IDE Regulations
• 21 CFR 314/814 NDA/PMA Regulations
• 21 CFR Part 50 Informed Consent
• 21 CFR Part 56 IRB Regulations
• 21 CFR Part 54 Financial Disclosure by Clinical
  Investigators
• 21 CFR Part 11 Electronic Records Electronic
  Signatures

12
Good Clinical Practice (GCP)

• Ethical and scientific quality standard for
  designing, conducting, recording, and reporting
  clinical investigations/research
• Embraces FDA regulations at a minimum
• Elaborated upon in FDA guidance documents
• Including internationally harmonized guidance
  (e.g., ICH E6 GCP Consolidated Guideline)
• System of shared responsibilities sponsor,
  investigator(s), IRB(s)/institution(s),
  regulators

13
What FDA Expects Sponsors -1-

• Includes sponsor-investigators of
  investigator-initiated studies)
• Understand when an application to FDA (IND/IDE)
  is required

14
When is an IND/IDE Required ?

• In general An IND/IDE is required when an
  unapproved drug (biologic or significant risk
  device) is used in a clinical investigation

15
When is an IND/IDE Required ?

• An IND may be required when an approved product
  is used in a clinical investigation based on use
  of the study information (e.g., to support a new
  indication, change in labeling, or change in
  advertising) or based on increased risk
• Even when exempt from an IND, IRB review and
  Informed Consent are required

16
What FDA ExpectsSponsors -2-

• Select qualified sites/investigators
• Provide investigators with the information they
  need to conduct the investigation properly
• Monitor conduct of the investigation
• Prompt correction or termination/reporting
• Safety monitoring and reporting (to FDA and to
  investigators)

17
What FDA ExpectsInvestigators

• Understand what you are agreeing to the FDA Form
  1572

18
The Investigators Signed Attestation (1572) -1-

• Personally conduct or supervise the investigation
• Read and understand the Investigators Brochure
• Ensure that an IRB compliant with FDA
  requirements will be responsible for the initial
  and continuing review and approval of the study

19
The Investigators Signed Attestation (1572) -2-

• Obtain IRB approval prior to initiating the study
• Inform subjects and obtain informed consent in
  accordance with Part 50
• Promptly report to the IRB all changes in the
  research activity and all unanticipated problems
  involving risks to human subjects and others

20
The Investigators Signed Attestation (1572) -3-

• Follow the protocol
• Report adverse events to the sponsor
• Ensure that those assisting in the conduct of the
  studies are informed about their obligations
• comply with all requirements regarding the
  obligations of clinical investigators and all
  other pertinent requirements in this part

21
What FDA ExpectsIRBs -1-

• Understand your importance, your authority, and
  your responsibility under the regulations
• Understand your most fundamental roles
• Protection of research subjects
• Ethical review of protocols (and assurance of
  scientific review)
• Informed consent
• Ensuring through continuing review that the study
  remains ethical to continue and that informed
  consent is current

22
What FDA ExpectsIRBs -2-

• Understand the roles of others
• Investigator as the contact point with subjects
• Expectation that the investigator will (and
  therefore is able) to personally conduct or
  supervise the study
• Sponsor bears primary responsibility for
  monitoring and analyzing safety reports/data from
  the study
• FDA is available to answer questions (including
  whether an IND/IDE is needed)

23
What FDA ExpectsFor All Parties

• Understand the Basic Elements of Data Quality
  Remember ALCOA
• Attributable
• Legible
• Complete/Contemporaneous
• Original
• Accurate

24
The Times They Are A- Changin

• FDA regulations remain a floor for the conduct
  of regulated research
• FDA continues in its most basic expectations for
  sponsors, investigators, and IRBs
• BUT

25
Changing Clinical Trial Landscape Studies

• More and varied clinical studies/study designs
• Novel therapeutic modalities proof of concept
• Broader range of subject populations
• Greater use of information technology
• Electronic record-keeping
• Electronic patient-reported outcomes
• Remote monitoring

26
Changing Clinical Trial Landscape Investigators

• Smaller base of experienced clinical
  investigators (CIs)
• Reported decline in number of CIs
• Increasing proportion of CIs who do only a single
  study
• More delegation
• More sponsor-investigators/investigator-
  initiated studies

27
Changing Clinical Trial Landscape Study Sites

• More clinical sites per study
• More private clinics vs. academic centers
• More sites are not meeting subject accrual
  targets/timeframes
• Sponsors reporting a greater proportion of sites
  that contribute only one subject or dont/cant
  contribute even a single subject
• Start-up costs average 30K per site

28
The Fear Factor

• Greater financial investments bring greater
  implications of failure
• Growing concerns about litigation
• Growing public fear and distrust
• More information less informed

29
Public Confidence in Clinical Research

• Harris Interactive Survey
• Online
• May 6-17, 2004 April 19-26, 2005
• Previous surveys in 2000, 2001, and 2003
• N 5,822 (04 survey) N 2,261 (05)
• Adults 18 (General Public)
• Slides courtesy of Jill Guary, MS, CCRC,
  Director, Clinical Research, Harris Interactive
  (www.harrisinteractive.com)

30

Subjects who participate in clinical trials are
making a contribution to science
31

Subjects who participate in clinical trials are
taking a gamble with their health
32

Subjects who participate in clinical trials are
like guinea pigs
33
Compliance Has Improved Over Time (FDA CI
Inspections)
FY06
FY77
20
48
6
NAI
20
OAI
NAI
OAI
VAI
VAI
60
46
n 596 Classified
n 15
34
Complaints to FDA are Increasing, FY 1998-2006
354
266
214
202
155
132
127
93
10
98 99 00 01 02 03 04
05 06
3/2/07
35
Good Clinical Practice at FDA

• Public Concerns Strategic Objectives
• Safety
• Information to the Individual Subject
• An Ethical, Understandable, Transparent System
• Rapid Recognition and Resolution of Problems

36
Themes

• Quality Systems
• Risk Management
• Critical Path
• Less Can Be More

37
Some Specifics

• Subject Safety
• Establishment and Operation of Clinical Trial
  Data Monitoring Committees (final guidance
  issued March 2006)
• Adverse Event Reporting Improving Human
  Subject Protection (issued for public comment on
  April 9, 2007)
• Supervisory Responsibilities of Investigators
  (issued for public comment on May 10, 2007)

38
Some Specifics

• A Strong IRB System
• IRB Registration (Proposed Rule)
• Using a Centralized IRB Review Process in
  Multicenter Clinical Trials (Final guidance
  issued March 2006)
• Coordination among government agencies
• (Non-governmental, voluntary accreditation
  programs)

39
Some Specifics

• Advancing Technology
• Computerized Systems Used in Clinical Trials
  (final guidance issued May 10, 2007)
• Opening a Dialogue on Quality
• DIA-FDA Workshop, Developing and Implementing
  Quality in Clinical Investigations From Design
  to Completion, May 10-11 in D.C.
• Public docket established to receive additional
  comments to FDA

40
Next Step Building Confidence in Clinical
Research

• FDA needs your help
• Talking to subjects
• Setting standards for all who engage in clinical
  research
• Focusing on quality
• Reporting when serious problems occur
• Actively participating in dialogue to promote
  participant protection and build capacity for
  future research

41
Closing Perspective

• You Too Are On This Road
• GCP is Not So Far Away But We Will Get
  There Only If We Look Out for Each Other and Head
  There Together