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

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

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?

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

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

Is it a Drug that is Lawfully Marketed in the U.S. for Another Use? 21 CFR 312.2 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

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)

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 312.7 (promotion and charging)

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

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

Clinical Holds

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

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

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

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

Data Monitoring Committees (DMCs)

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

Regulatory Requirements Requirement for sponsor to monitor progress of clinical trials [21 CFR 312.56] 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

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

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)

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