Transcript Clinical Trial Quality and Compliance: An FDA Perspective

FDA Regulatory Requirements
and FDA’s Bioresearch
Monitoring (BIMO) Program
Constance Lewin, M.D., M.P.H.
Associate Director for Human Subject Protection
Acting Branch Chief, Good Clinical Practice Branch 1
Division of Scientific Investigations
Office of Medical Policy
Center for Drug Evaluation and Research
University of Miami Statewide Conference
Miami, Florida
April 21, 2006
Center for Drug Evaluation and Research
Office of the Center Director
Steve Galson, M..D.
Director
Office of Medical Policy
Robert Temple, M..D.
Director
Division of Drug Marketing,
Advertising & Communication
Thomas Abrams, R.Ph., MBA
Director
Division of Scientific Investigations
VACANT
Director
Division of Scientific Investigations (DSI)
PHONE #301-594-0020
FAX #301-594-1204
Director
VACANT
Deputy Director
Joseph Salewski
Good Clinical Practice
(GCP) Branch I
C. Lewin MD, MPH
Good Clinical Practice
(GCP) Branch II
Leslie Ball, MD
GLP/BEQ Branch
C. Viswanathan, PhD
Agenda
FDA regulatory requirements for clinical
investigators (CIs), sponsors and
institutional review boards (IRBs)
involved in FDA-regulated clinical
research
 Overview of FDA’s Bioresearch
Monitoring Program

Clinical Research Balance
•Scientific
advancement
•Product
development
•Regulatory
oversight
•Human subject
protections
FDA GCP Regulations
Applies to:
Clinical research involving products
regulated by FDA
Regulatory
oversight of:
IRBs, Sponsors, CRO/Monitors, Clinical
Investigators
Relevant
CFR include (but
not limited to):
21 CFR 50, 56
Part
50: Protection of Human Subjects
Part 56: IRBs
21 CFR 312 (IND)
21 CFR 314 (NDA)
IRBs: 21 CFR 56.120, 56.121
Penalties for noncompliance include Sponsors: Reject data; Clinical Holds; WL;
(but not limited to): Terminate IND; Application Integrity Policy
CI: 21 CFR 312.70, Warning Letters,
NIDPOE
Clinical Trials Oversight:
FDA vs. OHRP

FDA oversight



Sponsors, monitors, clinical investigators, contract
research organizations involved in IND studies
IRBs reviewing clinical research involving any FDAregulated product (IND and non-IND studies)
OHRP oversight


Institutions where clinical research is conducted or
supported by HHS or
Institutions that agree to assume responsibility for
the research in accordance with 45 CFR 46
regardless of the funding source
When Do I Need an IND?
CFR 312.2 (b) Exemptions
The clinical investigation of a drug product that
is lawfully marketed in the United States is
exempt from the requirements of this part if all
of the following apply:
(i) The investigation is not intended to be reported to FDA as
a well-controlled study in support of a new indication for
use or not intended to be used to support any other
significant change in the labeling for the drug;
(ii) If the drug that is undergoing investigation is lawfully
marketed as a prescription drug product, the investigation
is not intended to support a significant change in the
advertising for the drug;
When Do I Need an IND?
CFR 312.2 (b) Exemptions (continued)
(iii) The investigation does not involve a route of
administration or dosage level or use in a patient
population or other factor that significantly increases the
risks (or decreases the acceptability of the risks)
associated with the use of the drug product;
(iv) The investigation is conducted in compliance with the
requirements for institutional review set forth in part 56
and with the requirements for informed consent set forth
in part 50; and
(v) The investigation is conducted in compliance with the
requirements of CFR 312.7 (Promotion and charging for
investigational drugs).
Who Do I Contact to Find Out if I Need
an IND?
Contacts:
Drugs:
Biologics:
Devices:
Foods:
Barry Poole
Robert Yetter
IDE Staff
David Hattan
(301) 827-3454
(301) 827-0373
(240) 276-0125
(202) 436-1293
Call, and then submit the request in writing (FAX or email).
FDA plans to issue a guidance for this question.
DSI’s BIMO Program Responsibilities


Good Clinical Practice (GCP)

Clinical Investigators

Sponsor-Monitors, CROs
Human Subject Protection Program
(IRB)

Good Laboratory Practice (GLP)

In vivo Bioequivalence
GCP BIMO Program
Clinical Investigator Inspection Program
 Sponsor/Monitor/CRO Inspection
Program

These two programs collectively allow the
agency to determine:



Adherence to applicable regulations
Validity of studies in support of pending marketing
applications
Whether the rights and safety of subjects have
been protected
DSI’s BIMO Responsibilities

DSI is responsible for all BIMO
inspections for CDER
Developing assignments, often in
consultation with CDER review divisions
 Issuing assignments to Office of
Regulatory Affairs (ORA) field
investigators and participating on
inspection when scientific or medical
expertise is required
 Evaluating the results of inspections from a
scientific and regulatory perspective.

DSI’s BIMO Responsibilities

DSI is responsible for all BIMO
inspections for CDER
Recommending scientific follow-up
 Recommending and implementing
regulatory actions
 Providing expert advice on program
design, policy issues and guidance
 Educating and informing program
constituents

What we do in the DSI GCP Branches
For the CDER Review Divisions
DSI will arrange for routine data audit GCP inspections to
determine data integrity and safety of subjects in pivotal
clinical trials, and provide the inspection reports to the
review division prior to the Division Action Goal Date
For the Public
DSI will investigate complaints related to the conduct of
clinical trials, including arranging for directed or “for
cause” GCP inspections, and take appropriate
regulatory action.
About BIMO Inspections

BIMO inspections can be conducted at any point in the drug
development process

Inspections during IND phase are generally “for cause =
directed”

Inspections during the NDA phase are generally “routine”,
but can be “for cause” or “directed”

May include Clinical Investigator (CI), Sponsor/Monitoring
(S/M), Contract Research Organizations (CRO), Institutional
Review Boards (IRB), Good Laboratory Practice (GLP), and
Bioequivalence (BEq) inspection of FDA regulated research.
About BIMO Inspections
Routine

Inspections assigned for NDAs
Directed (“for cause”)


Problems identified during FDA review process
Complaints reported to DSI from
 FDA, other Agencies
 Sponsors/monitors
 Institutions/IRB’s
 Site personnel
 Subjects/Public
Clinical Investigator Responsibilities*





Follow the current protocol
Personally conduct or supervise investigation(s)
Ensure that all persons assisting in conduct of
studies are informed of their obligations.
Ensure informed consent (21 CFR 50) and IRB
review, approval , and reporting (21 CFR 56)
requirements are met.
Obtain the informed consent of each human
subject to whom the drug is administered.
*(Form FDA 1572: #9. Commitments)
Clinical Investigator Responsibilities*






Notify the sponsor before making changes in
the protocol.
Notify the IRB and obtain IRB approval before
making changes in the protocol.
Report adverse events to the sponsor.
Maintain adequate and accurate records.
Make records available for inspection.
Comply with all other requirements in 21 CFR
312.
*(Form FDA 1572: #9. Commitments)
Clinical Investigator Inspections
What do we look for during the inspection?
The FDA Inspection (Audit) compares
 Source
Medical Record Data
vs
 Case
Report Forms
vs
 Data
Listing Submitted to NDA
Clinical Investigator Inspections
What do we look for during the inspection?
 Clinical Investigator inspection determines
 Source of subjects
 Did subjects exist?
 Did they have the disease under study?
 Did they meet inclusion/exclusion
criteria?
 Consent obtained?
 IRB Review Obtained?
Clinical Investigator Inspections
What do we look for during the inspection?

Clinical Investigator inspection determines
 Was the protocol followed?
 Did the subjects receive the assigned study drug
in the dose, route and frequency specified by the
protocol?
 Are the case report forms complete and in
agreement with source data? Compare with NDA
data listing
 Are adverse experiences reported to sponsor
and IRB?
 Adequacy and completeness of records?
Clinical Investigator Inspections
All Centers - 2004
CDER: 351
 CBER: 71
 CDRH: 178


Total:
600
Criteria for Assigning International
Inspections
International sites may be audited

if there are insufficient domestic data;

only foreign data are submitted to support an
application;

domestic and foreign data show conflicting results
pertinent to decision-making; or

there is a serious issue to resolve, e.g., suspicion
of fraud, scientific misconduct, significant human
subject protection violations.
Clinical Inspections - International
CDER, FY 1992 – 2005**
90
*
91-95*
96
97
98
99
2000
2001
2002
2003
2004
2005**
80
70
60
50
40
30
20
10
0
**FY05 to date
10/05
Clinical Investigator Deficiencies
CDER Inspections - FY 2005*
80%
74%
70%
63%
57%
51%
60%
48%
50%
36%
40%
30%
17%
10%
Protocol
NAI
Foreign n = 65
Domestic n = 261
Record
AEs
9% 11%
Consent
20%
5%
10%
10%
Foreign
0%
Domestic
Drug
Acct
*FY05 to date
10/05
Prevalence of OAI Inspections (DSI Data)
Total number of FDA
inspections
(1/77-9/2005*): = 7,909
Total OAI cases = 241
Total Inspected
Percent OAI = 3%
Total OAI
*FY05 to date
10/05
Prevalence of OAI Inspections (DSI data)
Routine FDA inspections
(1/77-9/2005*) = 7023
Total OAI cases = 85
Percent OAI = 1.2%
Routine Inspections
Total OAI
Directed Inspections
Total OAI
Directed FDA inspections
(1/77-9/2005*) = 886
Total OAI cases = 156
Percent OAI = 17.6%
*FY05 to date
10/05
Complaints to DSI
The number of complaints about clinical
investigators/clinical trials continues to
increase
 DSI encourages such reporting (new
Electronic Complaint Form)
 Follow-up on complaints is of vital
strategic importance

Real-time follow-up of real-time issues
 Public protection; Public confidence

What Are They Complaining About?








Informed Consent Issues
Falsification
Failure to report adverse
events
Failure to follow the protocol
Inadequate Records
Qualifications of persons
performing physicals
Failure to get IRB approval,
report changes in research
Failure to follow FDA
regulations









Drug accountability
Recruitment Practices
Poor Supervision
No active IND
Violations of GLP regs
Monitoring practices
Blinding
Charging for the test article
Misleading advertisements
Complaints Received: 1992-2005*
250
200
150
100
50
0
92 93 94 95 96 97 98 99 00 01 02 03 04 05**
*Calendar Years
**FY05 to date
10/05
CI “For Cause” Inspection Assignments
(CDER, FY 1992 – 2005*)
120
100
80
60
40
20
0
FY
92
93 94 95 96 97 98 99 00 01 02 03 04 05*
*FY05 to date
10/05
Sponsor Responsibilities

A sponsor shall not begin a clinical investigation
until the IND is in effect (21 CFR 312.20), which
means:
after notification by FDA to begin investigation
 OR
 30 days after FDA receives the IND


A sponsor shall not begin a clinical investigation if
FDA places the study on clinical hold, which is an
order to delay or suspend an investigation (21
CFR 312.40)
Sponsor Responsibilities

21 CFR 312.50 - General responsibilities of
sponsors
Selecting qualified investigators
 Providing investigators with the information
they need to conduct an investigation properly
(e.g., protocol, IB, safety reports)
 Ensure proper monitoring of the investigation

Sponsor Responsibilities

21 CFR 312.50 - General responsibilities of
sponsors
 Ensure that the investigation is conducted
in accordance with the investigational
plan
 Maintain an effective IND (e.g., annual
reports, safety reports, amendments,…)
 Ensure that FDA and investigators are
promptly informed of significant new
adverse effects or risks (e.g., safety
reports)
21 CFR 312.53-Selecting investigators and monitors
Sponsors shall select only investigators
qualified by training and experience as
appropriate experts to investigate the drug
(b) Sponsors shall only ship drug to
participating investigators
(c) Sponsors shall obtain 1572, a statement of
qualifications, and financial disclosure info.
(d) Sponsors shall select qualified monitors
(a)
Human Subject Protection Program
IRB inspection program
 Consults from review divisions
 Inquiries from IRBs and public

Institutional Review Board (IRB)
Formally designated by an institution to
review, approve initiation of, and
conduct periodic review of biomedical
research involving human subjects
 Primary purpose is to assure the
protection of the rights and welfare of
the human subjects
 Scientific considerations included but
not primary

IRB Inspections: What’s done?


Purpose: to assess compliance with 21 CFR Part 56
IRB and study-specific records reviewed

Written procedures



Initial and continuing review
Reporting findings and actions to CI and institution
Ensuring prompt reporting of








Research changes
Unanticipated problems involving risk
Serious or continuing non-compliance
Suspension or termination of IRB approval
Meeting minutes: attendance, actions taken, votes, basis for
requiring changes or disapproval, controverted issues and
resolution
Continuing review activities
All correspondence w/CI
Membership list(s)
IRB Inspections: What’s done?

FDA-regulated studies are selected
Criteria for IRB approval (risks minimized,
reasonable; equitable subject selection;
informed consent; compliance with Part 50,
Subpart D as appropriate; add’l safeguards for
other vulnerable populations)
 Documentation related to study approvals,
continuing review, suspensions/terminations,
unanticipated problems involving risk to
subjects or others
 Informed consent documents
 Use of expedited review

IRB Inspections
Center for Drug Evaluation & Research
FY 2000 - 2004
300
250
200
150
100
50
0
00
01
02
03
04
IRB Inspections: What deficiencies are
commonly found?
(FY’04: CDER assigned)
37%
40%
33%
35%
30%
25%
20%
15%
17%
15%
9%
10%
5%
0%
02/05
N=100
IRB inspections: Perspective

Major differences among IRBs:
Local vs. central
 Expertise and number of IRB members
 Number of studies reviewed
 Type of studies reviewed
 Potential risk to human subjects
 Trial population

Evaluation of IRBs
Friend, not Foe
FDA has traditionally viewed IRBs as allies
in human subject protection
 Official Action (OAI) is a last resort

What is Generated After an Inspection
Form FDA 483: Inspectional
Observations
Left with inspected party at close of inspection
 Immediately available under the Freedom of
Information Act

Establishment Inspection Report (EIR)
Prepared by field investigator after inspection
 Includes exhibits supporting observed
deficiencies

What is Generated After an Inspection
DSI Review of EIR
Point-by-point review of 483 items, additional
deficiencies, limitations of inspection
 Confirmation of supporting documentation
 Assessment of any response from the inspected
party
 For GCP inspections, often include assessment
of impact on acceptability of data for the drug
approval review
 Final compliance classification

Compliance Classifications
NAI - No Action Indicated

Firm is in compliance
VAI - Voluntary Action Indicated


Minor deviation(s) from the regulations
Voluntary correction requested
OAI - Official Action Indicated

Serious non-compliance requiring regulatory
or administrative action by FDA; Data
Unacceptable
What is Generated After an Inspection
Clinical Inspection Summary Report



Summary of all inspections assigned for an
application
Provided to review division in advance of
PDUFA action goal date
Recommends acceptance or rejection of site data
Letter to the inspected party

Emphasizes deviation from regulations, if any.

Copied to the review division
What is Generated After an Inspection
Where Official Action is Indicated




Recommendation to Reject Data
 enforcement option for non-U.S., non-IND sites
Warning Letter
Disqualification of a clinical investigator (21 CFR 312.70)
 Notice of Initiation of Disqualification Proceedings and
Opportunity to Explain (NIDPOE) letter
 Informal Conference
 Notice of Opportunity for Hearing (Formal)
 Consent Agreement
 Part 16 Disqualification Hearing
Referral for criminal prosecution (OCI)
BIMO Inspections Completed
800
700
683
678
723
690
692
627
600
500
400
300
549
556
553
05
*F
Y
04
FY
03
FY
02
FY
01
FY
00
FY
99
FY
98
FY
FY
97
200
100
0
S-M
CI
IRB
BIOEQ
GLP
*FY05 to date
10/05
CDER BIMO Inspections (FY 2005*)
S-M GLP
BEQ
IRB
CI
CI = 326
BEQ= 84
IRB = 90
GLP = 34
S-M = 19
Total = 553
*FY05 to date
10/05
Helpful Websites

DSI Homepage: www.fda.gov/cder/offices/dsi
Includes links to the Clinical Investigator Inspection List
(NEW), Bioresearch Monitoring Information Systems
(BMIS) files (NEW), Warning Letters, NIDPOE Letters,
Lists of Disqualified or Restricted or Debarred
Investigators, Code of Federal Regulations, etc.

FDA Homepage: www.fda.gov
Includes links to the Federal Register Notices, FDA
guidance documents.

Compliance Programs:
www.fda.gov/ora/compliance_ref/default.htm