The US Food and Drug Administration (FDA) has reopened a comment period for a guidance document that aims to clarify the circumstances in which a research study involving human subjects may be conducted without first filing an investigational new drug application (IND) with the agency.

Background: IND Basics

The draft version of the guidance was released in September 2013, and is intended to make clear the cases when an IND is not required.

In general, any investigation involving the administration of a drug to a human is subject to an IND per 21 CFR 312. In plain terms, that means that before a sponsor can begin research on a drug, it must submit an IND to FDA and await its approval.

A sponsor of a study must submit an IND if all three of the following conditions exist simultaneously:

1. The research involves a drug as that term is defined in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 321(g)(1)).
2. The research is a clinical investigation as defined in the IND regulations (21 CFR 312.3).
3. The clinical investigation is not otherwise exempt from the IND requirements in part 312.

This affords FDA the opportunity to review the IND to ensure trial participants are protected from any unnecessary harm, and that the trial meets federal regulatory requirements.

However, there are ample cases in which an IND may not be required to be submitted, even if the research must still be conducted with the oversight of an Institutional Review Board (IRB).

For example, an IND may not be required if the research involves:

• studies of already-marketed drugs
• bioequivalence/bioavailability studies
• studies using radiolabeled or cold isotopes
• studies using dietary supplements or foods
• studies using endogenous compounds
• pathogenesis studies using modified organisms
• studies using wild-type organisms in challenge models
• studies that do not have a commercial purpose

Dietary Supplement Problems

But as Focus explained in our write-up about the guidance, the document also goes into the specifics of each exemption, including those related to food products like dietary supplements.

Twelve entities submitted comments on the guidance, reflecting a range of opinions, but a general consensus: More guidance is needed.

The law firm Hyman, Phelps and McNamara (HPM), for example, noted that the guidance fails to mention medical foods or certain aspects about dietary supplements, and therefore fails to "fully explore" the scope of the IND regulation.

The Natural Products Association (NPA), Consumer Healthcare Products Association (CHPA) and Council for Responsible Nutrition (CRN) all mirrored these sentiments as well, asking for more clarity and in some cases changes to the language of the guidance.

In addition, HPM said the guidance "confuses the claims that a manufacturer may make for a dietary supplement with legitimate scientific inquiry." Under federal law, a dietary supplement is a food item distinguishable from drugs in that they do not make disease-specific claims. Rather, they claim to affect the general structure or function of the body. FDA's guidance notes that studies on the structure or function of the body would not require IND approval, but that other studies likely would.

Here, the law firm noted an odd discrepancy:

"Under FDA's dietary supplement example at lines 376-383, if the study endpoint is "bonemass," the study is exempt from the IND requirements. However, if the endpoint is "prevention of osteoporosis," the study requires an IND. The exact same patients would be given the exact same amount of the dietary supplement in both cases, but only one study is subject to an IND. This policy may lead to some creative design of endpoints, but it will not protect the rights and safety of patients, which is the purpose of an IND (21 C.F.R. § 312.22)."

The comment goes on to ask FDA if secondary endpoints might create the need for a full IND, such as if a primary endpoint was "increased bonemass" and a second endpoint was "preventing osteoporosis." HPM concluded that this would likely interfere with the practice of "scientific inquiry."

Based on those comments, as well as a range of other ones by major pharmaceutical companies, FDA has now decided to reopen its comment period on the guidance document.

"Following publication of the [guidance], we received correspondence asking us to provide for further opportunity to comment on subsection … D ("Foods") of section VI ("Specific Issues Concerning the Application of the IND Regulations") of the final guidance," FDA wrote. "The correspondence explained that more time was needed to review the guidance and consider its effect on researchers and health care providers, among others."

FDA said it agreed, and has now given industry until 7 April 2014 to comment on the guidance.

 

Federal Register Notice