The Role of IND-enabling Studies

IND-enabling studies are crucial for advancing a New Chemical Entity (NCE) from preclinical evaluation to its first-in-human clinical trial. These studies comprehensively assess the NCE’s safety, pharmacology, and manufacturing processes, leading to the submission of an Investigational New Drug (IND) application to regulatory agencies like the FDA.

Successful planning and execution of IND-enabling studies are vital for navigating the drug development process efficiently and increasing the chances of IND approval. This involves assembling a multidisciplinary team and collaborating with an experienced Clinical Research Organization (CRO) to optimize the process.

In this blog post, we explore the intricacies of IND-enabling studies, their strategic importance in planning Phase 1 clinical trials, the roles of pharmacological and toxicological studies, considerations in chemistry, manufacture, and control (CMC) studies, regulatory aspects, and the benefits of partnering with an experienced CRO like BioPharma Services. 

Before a New Chemical Entity (NCE) can be tested in clinical trials, its safety profile and pharmacological properties should be elucidated in preclinical studies. In the United States, this process of in vitro and in vivo preclinical characterization of an NCE is concluded with the filing of an Investigational New Drug (IND) application with the United States Food and Drug Administration (US FDA). An IND application contains pharmacological, toxicological, and manufacturing data on the NCE as well as a protocol for the planned clinical trial and investigator information. Once an IND application is approved by the FDA, a first-in-human clinical trial can be initiated.

Comprehensively planning preclinical studies that will be included in an IND application (IND-enabling studies) can help study sponsors avoid delays in the drug development process and increase the likelihood of approval of their IND application. However, the successful design and execution of IND-enabling studies requires the efforts of a multidisciplinary team with know-how in the fields of pharmacology, pharmacokinetics, toxicology, chemistry, regulatory science, and biostatistics. Working with an experienced clinical research organization (CRO) with expertise in all these areas can aid study sponsors to streamline and optimize their IND-enabling studies.

Using IND-enabling Studies to Strategically Plan for Phase 1 Clinical Trials

IND-enabling studies should be clinically relevant and should collect preclinical data aligned with the rationale of future clinical trials. Therefore, it is important to clearly define the therapeutic target of an NCE early on in IND-enabling studies. In addition, the intended disease indications in planned future clinical trials should be kept in mind when selecting the most appropriate preclinical models to acquire data for an IND application.

Overall, IND-enabling studies help determine whether an NCE is reasonably safe for the initiation of a first-in-human clinical trial and whether its pharmacological activity supports further development. By the time an IND-enabling study is completed, study sponsors should demonstrate that the use of an NCE in a first-in-human clinical trial will not expose study volunteers to an unreasonable risk.

The Role of Pharmacological IND-enabling Studies

Pharmacological IND-enabling studies collect preclinical data on both the pharmacokinetic and pharmacodynamic effects on an investigated NCE and provide a proof of concept for its use. The sampling schedule, biodistribution, and dose-response relationship of the NCE should be established. To optimally support potential future clinical development of an NCE, the used dosing regimen and route of administration should resemble the ones planned in individuals with the disease of interest as closely as possible. In addition, pharmacological IND-enabling studies should demonstrate whether an NCE binds to the target of interest and exerts the intended pharmacological effects and may provide biomarker information.

Both in vitro and in vivo experiments are generally included in pharmacological IND-enabling studies. The in vivo experiments are typically performed in animal models that mimic pathophysiological features and symptoms of the disease, for the treatment of which an NCE may be tested in future clinical trials.

A variety of factors may affect the results of pharmacological IND-enabling studies and should be considered during their planning. They include the specific characteristics of an NCE formulation, the time of day or season during which the experiments will be conducted, the characteristics of the experimental environment, and the body position and strain of the experimental animals.

The Significance of Toxicological IND-enabling Studies

Preclinical toxicological/safety studies assess the safety profile of an IND using both in vitro and in vivo models. They provide information on the type and reversibility of adverse effects an NCE exerts (especially at high doses) and may identify potential biomarkers of toxicity. In addition, preclinical toxicological studies determine the safety margin of an NCE in the investigated species, estimated by the difference in NCE doses associated with efficacy and toxicity. 

A variety of assessments are performed within the scope of toxicological IND-enabling studies, such as evaluations of general toxicity; toxicity on critical organ systems (including the respiratory, cardiovascular, and central nervous systems); and genotoxicity. Eventually, the organs most vulnerable to the toxicity of an NCE are identified, and an exposure-response relationship is established. If the findings of preclinical toxicological studies demonstrate an acceptable safety profile, an initial dose for a first-in-human clinical trial can be selected.

Several aspects should be considered when planning toxicological IND-enabling studies. A sufficiently wide dose range should be evaluated. In addition, the selected route of administration should correspond as closely as possible to the one that will be employed in potential future clinical trials. Finally, the sample size should be determined carefully to ensure sufficient power of the study.

The Role of IND-enabling Chemistry, Manufacture, and Control (CMC) Studies 

CMC studies are used to perform a comprehensive analytical characterization of an NCE, including its composition, stability, and impurities. They also ensure that the manufacturing process complies with good manufacturing practices (GMP) and is sufficiently scalable.

Regulatory Aspects of IND-enabling Studies

IND-enabling studies should adhere strictly to regulatory requirements, designed to ensure the safety and adequate pharmacological activity of an NCE. In the United States, relevant regulations include comprehensive guidelines from the FDA and Title 21 of The Code of Federal Regulations (CFR). However, regulatory authorities around the world have specific sets of regulatory requirements that study sponsors should consider if they want to enter their drug markets.

Special Considerations for Phase 1 Clinical Trials

Since Phase 1 clinical trials, and particularly first-in-human clinical trials, are the first stage of drug development during which an NCE is administered to humans, they are associated with safety risks, and ensuring the safety of study participants should be an utmost priority. Accordingly, before being administered in a first-in-human clinical trial, an NCE is characterized extensively in preclinical studies that should demonstrate the purity, quality, and potency of the analyzed NCE formulation. However, the extrapolation of findings of preclinical studies to clinical investigations is challenging due to the existence of pharmacokinetic and pharmacodynamic differences among species, and the fact that in vivo preclinical models do not encompass all relevant characteristics of human diseases.

How Working with an Experienced CRO Can Advance IND-Enabling Studies

Due to the complex nature of IND-enabling studies, they require the collaborative efforts of a multidisciplinary team of experts. Working with an experienced CRO can help study sponsors strategically plan their IND-enabling studies in a manner that is aligned with potential future clinical trials and enhances the likelihood of an IND approval.

In the United States, initiating a Phase 1 clinical trial requires an IND approval by the FDA. However, filing a CTA with Health Canada may allow study sponsors to initiate clinical trials faster due to its more streamlined approach for early-phase evaluation. Eventually, this would enable study sponsors to submit to the FDA data from a Phase 1 study conducted in Canada along with the overall drug development program. Thus, study sponsors can address safety concerns early in the drug development process.

Study sponsors whose final goal is to enter the United States drug market typically compile an IND application and initiate a first-in-human clinical trial after its approval by the FDA. However, the IND application review by the FDA is based not only on preclinical data but also on an overview of the entire drug development plan. An alternative strategic approach is filing a clinical trial application (CTA) with Health Canada. Since Health Canada primarily assesses the protocol design based on preclinical data, its review approach for early-phase evaluation is more streamlined. Conducting their Phase 1 clinical trials in Canada allows study sponsors to start collecting clinical data faster and to shift their IND-related interactions with the FDA until after they have collected clinical data. Using this strategy, study sponsors may be able to discuss expectations for a Phase 2 study protocol, rather than the requirements for a safe first-in-human study, during their initial meeting with the FDA.

Why Choose BioPharma Services for Your Next Drug Development Project?

BioPharma Services is an experienced full-service CRO with expertise in both preclinical studies and early-phase clinical trials. Our multidisciplinary team has extensive know-how in the fields of pharmacology, pharmacokinetics, toxicology, chemistry, biostatistics, and regulatory science, which allows us to optimally support study sponsors in their IND-enabling studies. In addition, our medical and safety teams have successfully led over 2,200 early-phase clinical trials and have both broad know-how across therapeutic areas and niche expertise in human abuse potential (HAP) studies and clinical trials involving complex medical procedures.

Thus, we can competently support the transition of preclinical into first-in-human studies across a variety of therapeutic areas, formulations, and routes of administration. Finally, the strategic location of BioPharma Services in Toronto positions us well to conduct Phase 1 clinical trials, including first-in-human clinical trials, in Canada, to collect clinical data faster, and to help study sponsors demonstrate a safety profile established during a Canadian Phase 1 study at the time of an IND application.

If you want to collaborate with an award-winning clinical partner who can competently and efficiently support your drug development program, complete the form below to schedule a discovery call with a member of BioPharma’s scientific and medical team.

BioPharma Services, Inc., a HEALWELL AI and clinical trial services company, is a full-service Contract Clinical Research Organization (CRO) based in Toronto, Canada, specializing in Phase 1 clinical trials 1/2a, Human Abuse Liability(HAL) and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma Services conducts clinical research operations from its Canadian facility, with access to healthy volunteers and special populations.