1. Special Topics in IND Regulation
David Roeder, M.S.
Associate Director for Regulatory Affairs
Office of Drug Evaluation IV
Center for Drugs, FDA
April 14, 2005

2. Special Topics in IND Regulation
When Is an IND Needed?
Clinical Holds
Data Monitoring Committees (DMCs)

3. When is an IND Needed? Questions to ask Is it a drug?
Is it being used in a clinical investigation?
Is it a drug that is lawfully marketed in the U.S. for another use?

4. Is it a Drug?
“articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease…” and
“articles (other than food) intended to affect the structure or any function of the body…” (21 USC 321(g)(1)(B) and (C))
The second prong of the definition does not apply to dietary supplements
Note that a drug is defined by intended use, not the nature of the substance

5. Is it a Clinical Investigation?
A “clinical investigation” is “any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects.”
An “experiment” is “any use of a drug except for the use of a marketed drug in the course of medical practice.”
Not limited to commercial development

6. Is it a Drug that is Lawfully Marketed in the U.S. for Another Use?
21 CFR provides for exemptions for certain clinical studies of approved drugs for unapproved uses
Most cases can be determined by the sponsor or investigator
An exemption letter from the FDA is generally not necessary
When in doubt, consult with the FDA

7. IND Exemptions for Lawfully Marketed Drug Products (must meet all criteria)
Study is not intended to be reported as a well-controlled study for a new indication or significant labeling change
Study is not intended to support significant change in advertising
Does not involve a route of administration, dosing level, or patient population that significantly increases the risk (or decreases the acceptability of risk)

8. IND Exemptions for Lawfully Marketed Drug Products (cont.)
Conducted in compliance with 21 CFR 56 (IRB) and 21 CFR 50 (informed consent)
Conducted in compliance with 21 CFR (promotion and charging)

9. Other IND Exemptions
Certain studies with in vitro biologic diagnostic products
Blood grouping serum
Reagent red blood cells
Anti-human globulin
In vitro or laboratory research animals
Certain bioavailability studies
Radioactive drugs for certain research uses

10. Difficult Cases “Provocation” or “challenge” studies Stable isotopes
“Shelf chemicals”
Drug vs. nutritional supplement
Foreign studies

11. Clinical Holds

12. Clinical Holds
Study cannot proceed until 30 days from FDA receipt (new INDs only)
Can be imposed at any time subsequent to 30-day safety review
Unless accompanied by a clinical hold, agency comments are advisory only
Partial clinical hold vs. full clinical hold

13. Grounds for Imposing a Clinical Hold: Phase 1
Human subjects at unreasonable and significant risk
Unqualified investigator(s)
Investigator brochure misleading, erroneous or incomplete
Insufficient information to assess risk
Exclusion by gender if for life-threatening condition

14. Grounds for Imposing a Clinical Hold: Phase 2 or 3
Any reason cited in previous slide
Protocol deficient in design to meet stated objective

15. Grounds for Imposing a Clinical Hold: Other
Treatment IND or protocol
Certain studies that are not designed to be adequate and well-controlled
Certain investigations involving exception from informed consent

16. Data Monitoring Committees (DMCs)

17. FDA Guidance
Guidance for Clinical Trial Sponsors on the Establishment and Operation of Clinical Trial Data Monitoring Committees (draft guidance) November 2001
Final guidance pending

18. Regulatory Requirements
Requirement for sponsor to monitor progress of clinical trials [21 CFR ] can be partly addressed with DMC
DMC required if exception from informed consent for emergency research [21 CFR 50.24(a)(7)(iv)]
Otherwise, no requirement for DMC

19. Considerations for Assessing the Need for a DMC
Risk to trial participants
Practicality of DMC review
Short-term trials normally not practical
If DMC is used for short-term study, “pauses” can be incorporated
Assurance of scientific validity

20. Examples of Studies for Which DMCs are Often Recommended
Cardiovascular trials with morbidity/mortality endpoints
HIV, HBV, sepsis trials
Some rare and unpredictable serious infections (e.g., draft guidance for vaccinia complications)

21. Special Considerations
DMC models based on federally funded trials are acceptable
DMC should be multidisciplinary
DMC members should be free of conflict of interest