1. 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

2. 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

3. 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

4. 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

6. FDA GCP Regulations Applies to: Regulatory oversight of: Relevant
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)
Penalties for non-compliance include (but not limited to):
IRBs: 21 CFR ,
Sponsors: Reject data; Clinical Holds; WL; Terminate IND; Application Integrity Policy
CI: 21 CFR , Warning Letters, NIDPOE

7. 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 FDA-regulated 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

8. 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;

9. CFR 312.2 (b) Exemptions (continued)
When Do I Need an IND?
CFR (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 (Promotion and charging for investigational drugs).

10. Who Do I Contact to Find Out if I Need an IND?
Contacts:
Drugs: Barry Poole (301)
Biologics: Robert Yetter (301)
Devices: IDE Staff (240)
Foods: David Hattan (202)
Call, and then submit the request in writing (FAX or ).
FDA plans to issue a guidance for this question.

11. 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

12. Clinical Investigator Inspection Program
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

13. 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.

14. 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

15. 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.

16. 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.

17. 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

18. 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)

19. 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)

20. Clinical Investigator Inspections
What do we look for during the inspection?
The FDA Inspection (Audit) compares
Source Medical Record Data vs
Case Report Forms
Data Listing Submitted to NDA 18

21. 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? 19

22. 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? 20

23. Clinical Investigator Inspections All Centers - 2004
CDER: 351
CBER: 71
CDRH: 178
Total:

24. 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.

25. Clinical Inspections - International CDER, FY 1992 – 2005**
**FY05 to date /05

26. Clinical Investigator Deficiencies CDER Inspections - FY 2005*
74%
63%
57%
51%
48%
36%
17%
10% 9%
11%
10% 5%
Foreign n = 65
Domestic n = 261
*FY05 to date /05

27. Prevalence of OAI Inspections (DSI Data)
Total number of FDA inspections
(1/77-9/2005*): = 7,909
Total OAI cases = 241
Percent OAI = 3%
*FY05 to date /05

28. Prevalence of OAI Inspections (DSI data)
Routine FDA inspections (1/77-9/2005*) = 7023
Total OAI cases = 85
Percent OAI = 1.2%
Directed FDA inspections (1/77-9/2005*) = 886
Total OAI cases = 156
Percent OAI = 17.6%
*FY05 to date /05

29. DSI encourages such reporting (new Electronic Complaint Form)
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

30. 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

31. Complaints Received: 1992-2005*
CAVEAT: The complaints in CA’s log are ones that CA received and, thus, may not include every complaint that came into DSI, simply because there was no central coordination or tracking.
--1 complaint in 1999 is from a sponsor who turned in 8 clinical investigators. **
*Calendar Years
**FY05 to date /05

32. CI “For Cause” Inspection Assignments (CDER, FY 1992 – 2005*)
*FY05 to date /05

33. Sponsor Responsibilities
A sponsor shall not begin a clinical investigation until the IND is in effect (21 CFR ), 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 )

34. Sponsor Responsibilities
21 CFR 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

35. Sponsor Responsibilities
21 CFR 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)

36. 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

37. Human Subject Protection Program
IRB inspection program
Consults from review divisions
Inquiries from IRBs and public

38. 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

39. 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)

40. 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

41. IRB Inspections Center for Drug Evaluation & Research FY 2000 - 2004
The number of clinical investigator inspections assigned and completed for CDER has shown a parallel increase --- to a record 402 in FY 96 and 334 in FY 97. Preliminary estimates indicate that we will be near 350 for FY98.
Updated figures are as of 11/25/99. May be revised as additional EIRs are received from field staff.

42. IRB Inspections: What deficiencies are commonly found
IRB Inspections: What deficiencies are commonly found? (FY’04: CDER assigned)
37%
33%
17%
15% 9%
Research
Review
Written
Procedures
Quorum
Minutes
Members
02/05
N=100

43. 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

44. Evaluation of IRBs Friend, not Foe
FDA has traditionally viewed IRBs as allies in human subject protection
Official Action (OAI) is a last resort

45. 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

46. 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

47. 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

48. 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

49. 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 )
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)

50. BIMO Inspections Completed
723
678
683
690
692
627
549
556
553
*FY05 to date /05

51. CDER BIMO Inspections (FY 2005*)
CI = 326
BEQ= 84
IRB = 90
GLP = 34
S-M = 19
Total = 553
*FY05 to date /05

52. 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:
Includes links to the Federal Register Notices, FDA guidance documents.
Compliance Programs: