IND Exemptions and Compounded Drug Research

For a clinical investigation to be exempt from IND requirements, the drug product must be lawfully marketed in the United States and meet all conditions outlined in 21 CFR 312.2(b).

Research involving modifications to the lawfully marketed drug may also be IND-exempt, provided they do not introduce risks exceeding those associated with the product’s standard, labeled use. This exemption would typically apply to low-risk modifications to the lawfully marketed dosage form, such as minor variations to solid oral dosage forms. For example, changes to the color, scoring, or capsule size of the marketed dosage form for blinding purposes would generally be considered low risk, if they do not involve significant manufacturing or formulation changes.

While sponsors are primarily responsible for determining the need for an IND (21 CFR 312.2(a)), Institutional Review Boards (IRBs) play a critical role in ensuring study compliance with regulations, protecting the rights and welfare of human subjects, and assessing that the research does not introduce new risks (21 CFR 56.101). IRBs rely on sponsors/investigators to provide the documentation to support IND exemption claims.

Compounded drugs present unique challenges. They lack FDA approval, possess an unknown safety and efficacy profile, and may have incomplete labeling. In addition, poor compounding practices can lead to serious drug quality issues, potentially resulting in patient harm or death. Consequently, compounded drugs in research studies are not in compliance with FDA regulations for IND exemption and IRBs cannot determine whether the research will not significantly increase risks associated with the use of the product (21 CFR 312.2(b)(1)(iii)).

Ultimately, the FDA has the final authority to determine what are the requirements to investigate the compounded drug in the research. Sponsors and investigators should proactively consult the FDA when studying compounded versions of lawfully marketed drugs to determine IND requirements.