The US Food and Drug Administration (FDA) has released a new final guidance document intended to assist sponsors in determining whether a research study involving human subjects may be conducted without first filing an investigational new drug (IND) application with US regulators.

Background: The FMT Precedent

In recent months, FDA has proven to be somewhat amicable to the idea of extending enforcement discretion-that is, expressing that it won't punish an entity-when human research is conducted without an IND, which are reviewed by FDA to ensure that human research is safe and likely to benefit patients.

The most notable expression of that policy has come with respect to fecal microbiota transplants (FMT), an emerging treatment option for persons afflicted with infections of Clostridium difficile (C. diff), a hardy bacteria that is often difficult to treat with antibiotics. FMT transplants work by taking desirable bacteria from a healthy person's bowels and then implanting the (usually processed) bacteria into the bowels of the patient affected by C. diff, which then have the chance to overpower the existing infection.

FDA had originally said it would require an IND to be submitted for the procedure, but later tempered this position after receiving withering criticism from patient advocates who said the change would make conducting FMTs onerous and unaffordable.

"Some health care providers have stated that applying IND requirements will make FMT unavailable and have suggested that an alternative regulatory approach is needed to ensure the widespread availability of FMT for individuals with C. difficile infection unresponsive to standard therapies," FDA explained. "The agency acknowledges these concerns and intends to exercise enforcement discretion regarding the IND requirements for the use of FMT to treat C. difficile infection not responding to standard therapies provided the treating physician obtains adequate informed consent from the patient or his or her legally authorized representative for the use of FMT products."

 But the FMT approach is just one instance of when an IND won't be required-what about other disease areas? Could they stand to benefit from a similar enforcement approach as well?

New Guidance: When is an IND Not Required?

FDA's new final guidance document, Investigational New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND, is intended to clarify when an IND isn't required as well as "specific situations" that could confuse sponsors of human research.

The guidance notes a number of specific instances in which it may not be clear if use of an FDA-regulated product might trigger a required IND filing. Those include:

• clinical investigations using 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

Generally, any investigation involving the administration of a drug to a human is subject to an IND per 21 CFR 312. That requirement is in effect if all three of the following conditions exist simultaneously:

• 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)).
• The research is a clinical investigation as defined in the IND regulations (21 CFR 312.3).
• The clinical investigation is not otherwise exempt from the IND requirements in part 312.

It is important to note that the term "drug" can also mean "biological products," such as allergenic extracts, gene therapy products, monoclonal antibodies and more.

Specific Exemptions

But the meat of the guidance comes in its fourth section, in which FDA describes which policies are exempt from the IND requirements of 21 CFR 320.31(b).

For example, research involving already-marketed drug products can be exempt, provided the research meets the following conditions:

• The drug maintains lawful marketing status.
• The study is not intended to support a new indication or other labeling change.
• The study won't support "significant" advertising changes.
• The study does not involve an unsafe route of administration (but can involve different doses, forms, patient populations, and safe routes of administration).
• The study is otherwise compliant with all requirements under 21 CFR 56 (institutional review board) and 21 CFR 50 (informed consent).

The key here, FDA explains, is that any changes be "low risk modifications" that keep patients safe and are considered in light of the inherent risks and complexities of the drug product.

" For example, minor variations to solid oral dosage forms, such as changing the color, scoring, or capsule size of the marketed dosage form for blinding purposes, would generally be low risk, provided the changes did not involve major manufacturing or formulation changes," FDA wrote.

Bioequivalence and bioavailability studies can also be exempt from IND submissions. Such exemptions may be granted if:

• The drug being studied is not a new chemical entity.
• The drug dosage does not exceed currently approved standards on the drug's label.
• The study meets IRB and informed consent requirements per 21 CFR 50, 56.
• The sponsor adheres to safety reporting requirements.

Other examples of potential IND exemptions include: radioactive isotopes, cold isotopes, endogenous compounds, live organisms, cosmetics, dietary supplements and conventional foods.

The guidance also includes a multi-page frequently asked questions (FAQ) section. Perhaps the most notable of the questions: Even if a study enrolls only a small number of subjects, that does not exempt it from IND requirements.

"The number of subjects enrolled has no bearing on whether the study is subject to the IND regulations," FDA explained. "The definition of clinical investigation specifically includes studies with as few as one subject."

The full guidance is available on FDA's website.

Investigational New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND

Federal Register