New Draft Guidance for Industry: INDs – Determining Whether Human Research Studies Can Be Conducted Without an IND

By Dara Katcher Levy & Diane B. McColl - 

Last week, FDA issued a draft guidance intended to assist sponsors and investigators with decisions as to whether human research studies can be conducted on products without an investigational new drug application ("IND").  The draft guidance explains  when an IND is  or is not required.  The draft guidance also provides FDA’s responses to  common questions regarding application of the IND regulations to several types of research involving various types of products.  The draft guidance does present some confusion, however, on the application of the IND regulations to clinical studies assessing certain products’ effects on the structure or function of the body.   

With regard to studies that may be exempt from the IND requirement, the draft guidance clarifies such issues as the following: 

• what is meant by a “drug product that is lawfully marketed in the U.S.”; 
• criteria for assessing whether the risks associated with the proposed investigation of a marketed drug significantly increase the risk or decreases acceptability of the risk compared to approved use of  the marketed drug; and
• when an investigation might be used to support a new indication, change the drug’s labeling, or support a significant change in advertising such that it would require an IND.

The guidance also discusses the use of radioactive and cold isotopes for research.  FDA clarifies that although there are no regulations that specifically address clinical investigations using cold isotopes of unapproved drugs, the agency will exercise its enforcement discretion and will not object to these studies being conducted without an IND, provided certain conditions (modeled after the criteria for studies of radiolabeled drugs articulated in 21 C.F.R. § 361.1) are met.

Of particular note is FDA’s position on the clinical investigation of certain products that are not being investigated for therapeutic purposes, but do affect the structure or function of the body.  Provocation or challenge studies, in which an endogenous compound is administered to evoke a physiologic response, characterize a disease, or establish the mechanism of action, require an IND even though the endogenous compound is plainly not being used for a therapeutic purpose.  FDA reasons that in such studies there is an intent to affect the structure or function of the body, so the compound would be considered a drug and the studies need an IND, unless they meet the criteria for an exemption.  

FDA indicates that an IND is also required for challenge studies in which a live organism (e.g., virus, bacteria, or fungi that is modified or wild-type) is administered to study pathogenesis of disease or  response to the organism.  Acknowledging that the challenge organism is not intended to have a therapeutic purpose, FDA concludes that there is intent to affect the structure or function of the body so the organism is a biological product and a drug, and an IND is required for the clinical investigation, unless the criteria for exemption are met. 

Curiously absent from the guidance is any discussion of  clinical studies of medical foods, which are intended for the dietary management of disease or certain conditions.  FDA does speak to dietary supplements, advising that an IND is not required if the investigation is intended only to evaluate the  effect of the dietary supplement or its dietary ingredients on the structure or function of the body.  The draft guidance cites calcium as an example – a clinical study evaluating calcium’s effect on bone mass would not be subject to an IND, but a clinical study evaluating calcium’s effect on osteoporosis would require an IND.   

Also of interest is FDA’s process for addressing inquiries concerning the application of the IND requirements.  FDA will categorize inquiries as either “formal” or “informal,” specifically stating that “informal” inquiries and responses are nonbinding and will not be tracked.  Further, “formal” inquiries may not receive “formal” responses. 

Comments on the draft guidance must be submitted by January 12, 2011.  Comments on the information collection burdens proposed must be submitted by December 13, 2010.