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

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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 – PowerPoint PPT presentation

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Title: 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
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