The Food and Drug Administration (FDA or the Agency) has been working with the Department of Health and Human Services, Office for Human Research Protections, to harmonize the agencies’ regulatory requirements and guidance regarding human subject research. As part of this ongoing initiative, FDA finalized recently two guidance documents related to the responsibilities of institutional review boards (IRBs) and requirements for investigational new drug applications (INDs). The purpose of both guidances is to clarify existing regulatory requirements by consolidating former policies and guidance on the same topics and providing answers to frequently asked questions from academia and industry.

Responsibilities of IRBs
At the end of August, FDA announced the availability of final guidance clarifying the responsibilities of IRBs to ensure appropriate protection of the rights and welfare of human subjects involved in biomedical research.¹ In particular, the guidance addresses the IRB’s role in reviewing the qualifications of clinical investigators, evaluating the adequacy of research sites, and determining whether an IND or investigational device exemption (IDE) is necessary. Many of the recommendations are not new, having appeared in various other FDA policies and guidance documents; however, the final guidance, summarized below, consolidates these principles and confirms the role and responsibilities of IRBs.

Clinical investigators — Although FDA regulations make sponsors responsible for the selection of clinical investigators who conduct FDA-regulated research, the final guidance reconfirms the IRB’s responsibility, already established by regulation, to review the investigators’ qualifications. Such review may be straightforward or involved, depending upon the proposed research and relationship of the IRB to the investigator. FDA recommends that IRBs pay special attention to an investigator’s qualifications where the study involves a sponsor-investigator, a study that is outside of the investigator’s area of expertise, and/or any study design features that may significantly increase risks to subjects.

Research sites — Per FDA regulations, an IRB must have sufficient information to ascertain the acceptability of the proposed research, including the research institution or site. As with the review of clinical investigator qualifications, the review of research sites may be straightforward or involved depending on the nature and risks of the proposed research and IRB’s familiarity with the research site.

Applicability of IND or IDE — An IRB should ask the investigator whether an IND or IDE is required and the basis for such determination. If the IRB disagrees with the assessment, it should follow its procedures for resolving controverted issues, including delaying approval, as necessary.

IND Requirements and Exemptions
On September 10, FDA announced the availability of a related final guidance document intended to assist IRBs, clinical investigators, sponsors, and sponsor-investigators in determining whether human research studies must be conducted under an IND.² This new guidance provides an overview for determining whether an IND is required for a clinical study, describes the types of studies that are generally exempt from IND requirements, addresses a range of different questions commonly asked by FDA about IND exemptions, and provides a process for seeking advice from the Agency concerning the application of the IND requirements to a planned clinical study. The guidance addresses only whether an IND is needed, and does not address IDE requirements for medical devices.

FDA regulations state that a human research study must be conducted under an IND if all of the following conditions are met:

1. The research involves a “drug,” as defined under the Federal Food, Drug, and Cosmetic Act (FDCA or the Act);
2. The research is a “clinical investigation,” as defined by FDA regulation; and
3. The clinical investigation is not otherwise exempt from FDA’s IND requirements.³

For these purposes, it is important to understand that a “drug” includes, among other things, “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” (also known as “therapeutic use”) and “articles (other than food) intended to affect the structure or any function of the body of man or other animals” (also known as “structure/function”).⁴ The latter structure/function definition does not include foods used primarily for taste, aroma, or nutritive value, or dietary supplements intended only to affect the structure or function of the body. These differences are important to distinguish between clinical studies of foods, including dietary supplements, for which an IND may not be required.

In addition, a “clinical investigation” is defined as:

[an] experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of [the IND regulations], an experiment is any use of a drug [whether approved or unapproved] except for the use of a marketed drug in the course of medical practice.⁵

This definition appropriately carves out the use, including any unapproved use, of a drug in the course of the practice of medicine where the primary intent of such use is to treat a patient.

The above definitions are fundamental to any determination of whether a clinical study is exempt from FDA’s IND requirements. The following summarizes general categories of human-based research for which the requirement for an IND has been evaluated.

Certain Research Involving Marketed Drug Products — Whether an IND is required for a clinical study of a marketed drug depends primarily upon the purpose of the study and degree of risk associated with the use of the drug. Under FDA regulations, a marketed drug is exempt from IND requirements when all of the following criteria are met:

1. The drug product is lawfully marketed in the U.S.;
2. The study is not intended to be reported to FDA to support a new indication or other significant change in the product’s labeling; For prescription drugs, the study is not intended to support a significant change in the product’s advertising;
3. The study does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of risk) associated with use of the drug;
4. The study conforms to requirements for IRB review and informed consent; and
5. The study is not being conducted as a means to promote or commercialize the product.⁶

FDA’s guidance provides clarification on the application of the first four elements of the exemption criteria. Specifically, the requirement that the drug is lawfully marketed in the U.S. permits some latitude to modify the marketed version of the drug in a clinical study; however, such modifications must be low-risk, meaning that they should not increase risks beyond risks associated with the approved use. Similarly, for the fourth criterion, an evaluation of whether product risks are significantly increased in a clinical study should consider carefully risks that deviate from the conditions of use described in the approved labeling, with particular focus on the route of administration, dose, and patient population. Finally, the guidance clarifies that a clinical study that will be reported to FDA to support a new indication or any other significant change in the product’s labeling or advertising will require an IND regardless of the entity that conducts the study.

Bioavailability or Bioequivalence Studies in Humans — The guidance clarifies that bioequivalence and bioavailability studies may be exempt from IND requirements even if they are not intended to facilitate the development of generic drugs.

Radioactive or Cold Isotopes — FDA regulations describe conditions under which radioactive drugs (i.e., drugs containing unstable isotopes) may be used for certain research without an IND. On the other hand, although used for the same or similar research purposes, cold isotopes (which lack radioactivity) are not expressly exempt from IND requirements. The guidance confirms FDA’s past enforcement policy to not object to studies of cold isotopes of unapproved drugs without an IND, provided that certain conditions are met.

Endogenous Compounds — The guidance clarifies FDA’s position that provocation or challenge studies in which an endogenous compound is administered to subjects to evoke a physiologic response, characterize a disease, or establish a mechanism of action are subject to IND requirements because, although not a therapeutic use, there is an intent to affect the structure or function of the body.

Live Organisms — Like endogenous compounds, clinical studies involving live organisms also require an IND because, even if there is not a therapeutic intent or use, there is an intent to affect the structure or function of the body.

Cosmetics — As a general matter, ingredients or products marketed as cosmetics require an IND if they are being studied for a therapeutic or structure/function use, regardless of whether the study is intended to support only a cosmetic claim (as opposed to a drug claim, for which the product would also require FDA approval).

Conventional Foods — As a general rule, a clinical study intended to evaluate the effect of a food on a disease (i.e., a therapeutic use) will require an IND, regardless of whether the purpose of the study is to support a health claim or drug approval. On the other hand, because foods by their nature affect the structure and function of the body, a clinical study evaluating a structure/function use does not require an IND provided that the intended effect is derived from the product’s character as a food — that is, its taste, aroma, or nutritive value. Clinical studies intended to evaluate the safety of a food ingredient generally do not require an IND, even if there is a structure/function effect that is in addition to the taste, aroma, or nutritive effect.

Dietary Supplements — Whether an IND is required for a dietary supplement depends on the purpose of the clinical study. Because a dietary supplement may be marketed for a structure/function use without FDA approval as a drug, a clinical study intended to evaluate the dietary supplement’s effect on a structure or function of the body does not require an IND; however, any intent to evaluate a therapeutic use will require an IND.

Process
The recent FDA guidance further clarifies frequently asked questions, including that IND requirements are not affected by the commercial or noncommercial intent of a clinical study, the size of the subject population, or clinical condition of study subjects (e.g., healthy volunteers). If there is still uncertainty about whether an IND is required for a clinical study, an IRB, sponsor, or investigator may seek advice from FDA on the applicability of the relevant regulations and requirements. The guidance sets forth processes for making informal and formal inquiries based on the medium in which a request is submitted, the complexity of the inquiry, and the type of FDA response requested. 

References

1. Guidance for IRBs, Clinical Investigators, and Sponsors – IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE is Needed (August 2013), available at http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm328855.pdf; see also Notice, 78 Fed. Reg. 52932 (Aug. 27, 2013).
2. Guidance for Clinical Investigators, Sponsors, and IRBs – Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND (September 2013), available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm229175.pdf; see also Notice, 78 Fed. Reg. 55262 (Sept. 10, 2013).
3. See generally 21 C.F.R. Part 312.
4. 21 U.S.C. § 321(g)(1).
5. 21 C.F.R. § 312.3.
6. See generally id. § 312.2(b).

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Heather Bañuelos is counsel in the Washington, D.C. office of Hunton & Williams LLP (www.hunton.com) and a member of the Firm’s Food and Drug Practice. She can be reached by email at [email protected].