Investigational New Drug (IND) studies play an essential role in the drug development journey. This testing helps researchers foresee safety concerns and estimate the most efficacious starting doses for clinical trials.
What is IND testing?
IND testing involves the rigorous examination of new drug candidates to assess their safety profile, pharmacological properties, and potential therapeutic benefits. Before a new drug can be administered in first-in-human (FIH)/Phase 1 studies clinical trials, it must undergo a series of IND-enabling tests to establish preclinical safety. These tests typically include toxicology studies in two species, safety pharmacology studies, and genetic toxicology, among others.
A comprehensive IND-enabling program requires a full clinical plan, including the drug class, administration route, dose, treatment duration, and planned indication. The application provides comprehensive data on the drug’s pharmacology, toxicology, manufacturing processes, and proposed protocols for human clinical trials.
IND and the development cycle
The progression from IND application to clinical trials marks a critical juncture in the drug development cycle, signifying the transition from laboratory research to real-world testing in human subjects. IND studies consist of seven phases, each addressing specific objectives and regulatory requirements needed before moving into clinical trials:
- Early development and discovery: Identifies potential drug candidates through laboratory research and preclinical testing.
- Nonclinical development: IND-enabling studies bridge the gap between early discovery and clinical trials. Comprehensive pharmacological and toxicological assessments of the drug candidate are completed in laboratory animals during this phase.
- Objective of IND-enabling studies: Obtain sufficient data to support the safety and feasibility of testing the drug candidate in humans during clinical trials.
- Regulatory submission: Researchers compile the data and submit an IND application to regulators. The application includes comprehensive information on the drug candidate, study protocols, preclinical data, and plans for clinical trials.
- Regulatory review: Regulatory agencies evaluate the IND application to ensure the preclinical data supports the proposed clinical trial, and that ethical standards are met.
- Clinical trials: Phase I trials focus on evaluating the safety, tolerability, and pharmacokinetics of the investigational drug in a small cohort of healthy volunteers. Subsequent phases continue testing the drug in human subjects to further evaluate safety, dosage, efficacy, and side effects.
- Post-approval activities: Successful completion of clinical trials may lead to a New Drug Application (NDA) submission for regulatory approval. Post-approval activities include ongoing safety monitoring, additional studies, and market launch.
IND-enabling studies are a critical link between early development, discovery, and human clinical trials. This process produces the data required to gain regulatory approval to test a drug candidate in humans and also ensures the potential benefits outweigh any risks. Completing an IND study is a key milestone in the drug development process.
What does IND include?
An IND application demonstrates the quality, safety, and efficacy of the investigational product with a comprehensive dossier of scientific data, regulatory documents, and supporting materials. IND-enabling studies fall into four main categories:
Drug Metabolism and Pharmacokinetics (DMPK)
DMPK studies offer insights into absorption, distribution, metabolism, and excretion (ADME) of experimental drugs. This data, gathered preclinically, guides the optimization of chemical structures and predicts in vivo PK properties and drug-drug interaction potential.
Starting with in vitro analysis, including physicochemical properties and permeability assays, DMPK progresses to in vivo studies, typically in animals, whose pharmacokinetics closely resemble humans. These may entail mass balance studies, pharmacokinetics, and metabolite identification, facilitating translation into human trials.
Toxicology
Preclinical toxicology assessments are pivotal for advancing new drug candidates. The safety assessment program strategies vary between small molecules and biologic therapies. Small molecules necessitate general toxicology studies in two species, along with mutagenicity and cytogenetic assessments to gauge genotoxicity. Metabolites formed in vivo can influence human risk. Conversely, biologics may require studies in a single species, as they don’t interact with DNA and don’t form metabolites. Instead, they degrade into peptides or amino acids and/or excreted.
Safety pharmacology
Safety pharmacology tests assess a drug’s impact on vital organ systems, such as cardiovascular, pulmonary, and CNS, with additional evaluation for effects on GI motility and renal function, as necessary. Small molecules are often completed through standalone studies, while biologics can integrate into toxicology studies.
Toxicology studies should include single and repeated doses and may require immunotoxicity and local tolerance studies for human trials. Once initial studies are completed, additional testing may be needed for reproductive and development toxicity and carcinogenicity.
Bioanalysis
Preclinical bioanalysis involves identifying and quantifying drugs and metabolites in biological matrices like blood and plasma. Regulator guidance aids developers in validating bioanalytical methods to ensure data quality. Researchers then utilize validated methods for tissue sample analysis in studies including:
- Pharmacokinetics and/or toxicokinetics
- Immunogenicity
- Biomarker assessment
Developing these methods according to guidance is a thorough process. Read more on the resources available to developers in understanding regulatory needs. [KH1] IND studies play a vital role in drug development, enabling the transition from preclinical research to clinical practice. By systematically evaluating the safety and efficacy of new therapies, IND studies pave the way for medical advancements that have the potential to transform patient care and improve health outcomes.
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