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