Most of us know that a BA/BE study of a generic can be done without an IND (the exception, called a Bio-IND, is when the drug being studied is cytotoxic or a radioactive labeled drug). In 505(b)(2) drug development we often are studying the BA/BE of a test drug versus an RLD as part of the process and it can sometimes be confusing to the client as to whether an IND is required. 21 CFR 312 lays out the regulations, but we all know that regulations can be subject to some interpretation and that is the reason the FDA provides guidances. In this case, FDA has just issued a new draft guidance entitled “Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND”.

An IND is required when a drug is involved in a clinical investigation that is not exempt from the regulations. The new guidance gives greater clarity to what is a ‘drug’, what is a ‘clinical investigation’ and which clinical investigations are exempt for the IND process.

Based on our experience, perhaps the most useful discussion concerns the exemption provision of 21 CFR 312.2. Let me quote from the draft guidance and then comment:

A clinical investigation of a drug is exempt from the IND requirements if all (emphasis mine) of the criteria for an exemption in § 312.2(b) are met:

• The drug product is lawfully marketed in the United States.
• There is no intent to report the investigation to FDA as a well-controlled study in support of a new indication and no intent to use it to support any other significant change in the labeling of the drug.
• In the case of a prescription drug, the investigation is not intended to support a significant change in the advertising for the drug.
• The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
• The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
• The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the investigation is not intended to promote or commercialize the drug product).

In most case of commercial development there is intent to report the study as part of an FDA filing. However, exploratory studies might be within the exemption if all of the other factors are met. An example would be studies in support of the development of an anti-abuse technology for a narcotic. In this case, where the intended drug product is to be exactly like the RLD except for the presence of a known, GRAS, ingredient that will cause nausea when the product is abused, it may be feasible to conduct limited studies without an IND.

While we can think of other examples, they are rare and most likely an IND is required. As stated in the guidance, ask FDA when in doubt. How to ask the FDA isn’t addressed, but the usual rule of thumb applies here — ask the right question supported by good information.

Premier Consulting has had assignments from sponsors where we have not used any IND. In these cases, the new product approval was based on the literature and the only study required was a phase 1 bridging study. The studies have been done without an IND and the projects proceeded directly to NDA submissions.