Guidance for Industry, Investigators, and Reviewers Exploratory IND Studies

The guidance for Industry, Investigators, and Reviewers on Exploratory Investigational New Drug (IND) Studies seeks to clarify the quantity of data required for IND submissions, particularly for exploratory studies involving limited human exposure and no therapeutic intent, such as screening or micro dose studies. It highlights that sponsors frequently furnish more information than mandated by regulations, which can be resource-intensive and may not be essential for early exploratory studies.

Purpose:

The guidance document explains that the objective of exploratory IND studies is to conduct initial phase 1 clinical evaluations of experimental new drugs and biological agents. These studies aim to assess the feasibility of further developing these therapeutic candidates. They are defined by their limited involvement of human participants and absence of therapeutic or diagnostic goals. The main objectives of these studies are to determine if the mechanism of action observed in preclinical models is applicable to humans, to examine the product's distribution within the body, and to identify the most promising leads for further research and development. This approach can result in a more efficient use of human participants and resources in identifying potential drugs, particularly for those targeting severe or life-threatening conditions..

?Difference between Traditional and Exploratory IND studies:

?Traditional:

The traditional Phase 1 approach typically involves a more extensive preclinical testing program to ensure the safety of the candidate drug before it is administered to humans. This includes comprehensive toxicological studies in animals to determine a safe starting dose for human trials, understand potential organ toxicity, and estimate safety margins. The data from these studies are used to predict pharmacokinetic and pharmacodynamic parameters in humans.

?Exploratory:

1. The preclinical testing program for exploratory IND studies can be less comprehensive, as these studies typically involve administering sub-pharmacologic doses or doses that are expected to produce a pharmacologic effect without causing toxicity.
2. The potential risks to human subjects are lower, allowing for a more flexible approach to preclinical testing and a reduced preclinical database.
3. Exploratory IND studies are intended to be concluded after the specified study or studies are completed, whereas traditional IND studies are part of a longer-term development plan.
4. The dosing duration in an exploratory IND study is expected to be limited, such as 7 days, and is not intended to establish the limits of tolerability

Content of IND submissions:

Chemistry, Manufacturing, and Controls (CMC) Information:

The regulations at 21 CFR 312.23(a)(7)(i) highlight the progressive nature of chemistry, manufacturing, and controls (CMC) information needed as an IND application advances. Each phase requires sufficient details to ensure the investigational candidate's proper identification, strength, quality, purity, and potency, with the amount of information varying based on the phase, investigation duration, dosage form, and existing data. An exploratory IND application should provide CMC information in a summary report for safety assessment. It must address any potential human risks from the candidate product and describe steps to monitor these risks. General product information should include a description of the candidate, its dosage form, manufacturing method, composition, and stability. For analytical characterization, if the same batch is used in both toxicology studies and clinical trials, the focus is on CMC information and toxicology results. If different batches are used, analytical testing should demonstrate that the clinical batch is representative of the toxicology batch.

Pharmacology and Toxicology Information:

Pharmacology and toxicology information in exploratory IND studies are primarily derived from preclinical safety testing in animals and in vitro studies, with specific guidelines for small molecules (ICH M3) and biologics (ICH S6). The recommended toxicology evaluation for exploratory INDs is more limited compared to traditional INDs due to the reduced scope of clinical studies. These studies are not designed to establish maximally tolerated doses but focus on specific objectives like confirming mechanisms of action, assessing pharmacokinetics and metabolism, or comparing therapeutic effects. Examples include micro dose studies for pharmacokinetics or imaging, clinical trials for pharmacologically relevant doses, and studies to evaluate mechanisms of action related to efficacy. The preclinical safety programs are tailored to the study design and may involve extended single-dose toxicity studies, repeat dose trials, and modified toxicity studies to select safe starting doses for clinical trials, with a focus on relevant endpoints for clinical safety evaluation.

Clinical Development Plan:

Clinical Information in exploratory IND studies focuses on a specific study or group of studies rather than a comprehensive clinical trial program. The application should justify the selection of the compound(s) and outline the rationale for the study, as future development plans depend on these initial results. The IND should specify that it will be withdrawn after the study's completion. Study designs can include single- and multiple-dose studies, where single-dose studies administer sub-pharmacologic or pharmacologic doses to a small group to gather pharmacokinetic data or perform imaging studies. Repeat dose studies should have limited duration, such as 7 days, and focus on pharmacologic or pharmacodynamic endpoints. Escalating dose studies should aim to explore pharmacodynamic outcomes rather than determining tolerability limits.

Previous Human Experience:

Since exploratory IND studies are typically first-in-human studies, previous human experience is not pertinent and is not discussed in the guidance.

?In summary, exploratory IND studies facilitate a more streamlined approach to early-phase clinical trials by concentrating on limited human exposure and specific study objectives. This can result in more efficient resource utilization and a faster evaluation of a candidate's potential.

References:

https://www.fda.gov/media/72325/download