IND Requirements and Exemptions

Does my product require an Investigational New Drug (IND) application? It’s a simple question, but the answer can have extensive consequences for your development program. In this post, we will provide insights into various IND requirements and exemptions.

What is an Investigational New Drug Application?

IND requirements are codified in Title 21 of the Code of Federal Regulations, Part 312 (21 CFR 312). From a regulatory standpoint, an IND acts as a technical exemption from certain Federal restrictions regarding the transportation and distribution of drugs across state lines. An IND also effectively allows a Sponsor to legally ship an investigational product to clinical sites across the country. However, while this is a necessary function of the IND, the true impact is considerably more far-reaching. The IND process is central to the core mission of the FDA, which is, in part, to protect the public’s health by ensuring the safety, efficacy, and security of human drugs and biological products. The FDA supports this mission during the IND process by reviewing information provided by the Sponsor, ensuring the safety of clinical trial participants, and supporting science-based decision making, while also having the authority to take enforcement action (e.g., clinical hold [21 CFR 312.42]) if things go awry. The purpose of an initial IND submission is to present the FDA with the general investigational plan and protocols for specific human studies. It is also meant to provide preliminary support for the safety, efficacy, and quality of the investigational product. This typically includes evidence from nonclinical studies and published literature, as well as initial product quality parameters and manufacturing information. Once the IND is submitted, the FDA has 30 days to review the application and decide whether to allow the proposed clinical trial to proceed or to place a clinical hold. Following the initial submission, IND updates are provided by the Sponsor and may include protocol amendments, IND safety reports, information amendments, and annual reports. The purpose of these updates is to inform the FDA about new safety findings, the results of clinical investigations, important changes to manufacturing or quality processes, and other program related information.

When is an IND Required?

To help provide clarity on IND requirements and potential IND exemptions, the FDA has published a guidance document that relays its current thinking on these topics. So, when is an IND required? The short answer is that an IND is required for any clinical investigation involving administration of a drug to humans, unless the study is exempt. That seems like a fairly straightforward statement, but there is a lot to consider there. Essentially, this requirement breaks down to three key parts: the definition of a clinical investigation, the definition of a drug, and what it means to be exempt. Let’s look at these one at a time. Definition of a Clinical Investigation. A clinical investigation is any study or experiment where a drug is given to one or more human subjects except for the use of a marketed drug in the course of medical practice. Importantly, this definition does not discriminate whether study subjects are healthy or have a disease/disorder, whether the study involves an approved or investigational product, or whether the study includes lots of subjects or only one. The one thing it does exclude is use of a marketed drug in the course of medical practice, which means that a visit to the doctor for your annual flu shot won’t make you part of a clinical trial. Definition of a Drug. Federal law defines drugs as articles (except food) intended for use in the diagnosis, cure, treatment, mitigation, or prevention of disease or intended to affect the structure or function of the body. Note that the term “articles” is not limited to chemical compounds. Which means that biological products such as antibodies, peptides, microorganisms, vaccines, and cellular therapies are also considered drugs. It is also worth noting that drugs do not necessarily have to be therapeutic. Non-food items designed to affect the structure or function of the body are also considered drugs under the statutes (e.g., birth control pills, male pattern baldness treatments). Exempt Clinical Investigations. Whether a clinical investigation is exempt often comes down to the motivation and the risk involved in the study. If there is an intent to use the study results commercially or there is a high or heightened risk to study participants, then an IND will be required. Clinical studies that are exempt from IND requirements include:

• Certain Research with Marketed (Approved) Drugs. To be exempt [21 CFR 312.2(b)], 1) the drug must be lawfully marketed in the US, 2) the study cannot be intended to support a new indication or other significant change in product labelling, 3) the study cannot be intended to support a significant change in advertising for the drug or be used to promote the drug, and 4) the study cannot significantly increase risks for those taking the drug. In addition, the investigation must follow Institutional Review Board (IRB; 21 CFR 56) and informed consent requirements (21 CFR 50).
• Bioavailability/Bioequivalence Studies. BA/BE studies compare unapproved (often generic) versions of drugs to approved drugs (see our post on BA/BE studies for more information). In order for a BA/BE study to be exempt (21 CFR 320.31), 1) the drug product must not contain new chemical entities*, 2) be radioactively labeled, or be cytotoxic, 3) dosing of both the reference and investigational drugs must follow the approved drug label for the reference product, and 4) the Sponsor must retain test article samples and adhere to safety reporting requirements. *21 CFR 314.108(a): New chemical entity means a drug that contains no active moiety that has been approved by FDA in any other NDA submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act.
• Radioactive or Cold Isotopes. Use of drugs with radioactive or cold isotopes can be IND-exempt if they are used in basic research (e.g., metabolism, physiology, or biochemistry studies). For radioactive isotopes, use must be approved by a Radioactive Drug Research Committee (RDRC), must involve doses not known to cause pharmacological effects in humans, and must include total radiation in the smallest amount practical. For cold isotopes, studies are exempted when 1) the isotope-containing product is used for basic research, 2) the dose is not known to cause pharmacological effects in humans, 3) the product adheres to regulatory standards for quality, and 4) the study follows IRB and informed consent requirements.
• Dietary Supplements and Food. Dietary supplements and food are not considered drugs. Unlike drug trials, clinical investigations involving dietary supplements or food do not require an IND to investigate effects on body function or structure but only to investigate an effect on disease. For example, studying the effect of fiber on bowel regularity would not require an IND but investigating the ability of fiber to treat chronic diarrhea would.

Note, however, that even if a clinical study is found to be IND-exempt, a Sponsor cannot simply proceed with wild abandon. An IRB still needs to approve the study, informed consent regulations still need to be followed, and additional requirements may apply.

Conclusions

The primary responsibilities of the FDA during development of an investigational product include minimizing the safety risk to clinical trial participants and helping to support the collection of meaningful clinical data. The IND process is one of the primary ways that the FDA fulfills these responsibilities. While most investigational drugs and biologics require an IND, there are exceptions, including certain clinical studies involving approved drugs, BA/BE studies, and studies focused on basic research. Whether or not a particular study is exempt from IND requirements most often depends on the commercial intent of the study and the level of risk to study subjects. Whether an IND is required or not, every drug development program must meet certain regulatory requirements, including IRB and informed consent requirements (and possibly others depending upon the particular study and/or drug product).

Questions about your drug development program? Contact one of our experts today to learn how Allucent can help you efficiently navigate the regulatory landscape, optimize your study design and data analysis, and get your product to market faster.