Title: Good Clinical Practice: Are We There Yet ? And What Comes Next ?
1Good 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
2What This Talk Will Cover
- Introduction to FDA
- FDA Expectations and Oversight in Clinical
Research - New Challenges in Clinical Research
- FDA GCP Strategies and Initiatives
3FDA 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
4FDA 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
5FDAs 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
6Levels 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
7Application Review at FDA
- Review of research applications (IND/IDE)
- Review of marketing applications (NDA/ BLA/PMA)
- Postmarketing review
8Review 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
9Dispelling 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
10FDA 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
11FDAs 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
12Good 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
13What FDA Expects Sponsors -1-
- Includes sponsor-investigators of
investigator-initiated studies) - Understand when an application to FDA (IND/IDE)
is required
14When 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
15When 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
16What 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)
17What FDA ExpectsInvestigators
- Understand what you are agreeing to the FDA Form
1572
18The 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
19The 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
20The 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
21What 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
22What 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)
23What FDA ExpectsFor All Parties
- Understand the Basic Elements of Data Quality
Remember ALCOA - Attributable
- Legible
- Complete/Contemporaneous
- Original
- Accurate
24The 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
25Changing 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
26Changing 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
27Changing 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
28The Fear Factor
- Greater financial investments bring greater
implications of failure - Growing concerns about litigation
- Growing public fear and distrust
- More information less informed
29Public 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
33Compliance 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
34Complaints 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
35Good 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
36Themes
- Quality Systems
- Risk Management
- Critical Path
- Less Can Be More
37Some 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)
38Some 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)
39Some 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
40Next 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
41Closing 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