Preclinical Toxicology Considerations for a Successful IND Application

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Preclinical toxicology is a critical component of the drug development process. The goal of toxicology testing is to support the transition of a new drug candidate to patients in Phase I clinical studies through an investigational new drug (IND) filing.

The IND application consists of information on Preclinical Safety & Toxicology, and Chemistry & Manufacturing to support initiating a clinical trial. These include:

  • Pharmacology and Toxicology Studies—This is done to assess safety of a new drug/ drug product in humans.
  • Manufacturing—This is done to assess if the sponsor can produce and supply consistent batches of new drug/drug products.

Planning of Preclinical Toxicology Program

First and foremost, a clinical development strategy should be in place. A good understanding of the human therapeutic target, likely treatment schedule, disease indication, and clinical trial design to correctly identify the toxicology and safety assessment studies needed to support first-in-human trials. Aligning preclinical and clinical development facilitates adjustments and changes along the way to ensure the success of an IND toxicology program.

The toxicology studies include single-dose, repeated-dose, reproductive, developmental, and genotoxicity and have different schedules. The time required depends on the clinical indication and the routes supported.

Preclinical toxicology programs are unique to each molecule and category small molecules and biologics. Small molecule drugs usually refer to synthetically derived organic compounds, but also include inorganic compounds. Biologics include peptides, antibodies, fusion proteins, antibody-drug conjugates, and gene therapy.Small molecule  Biologics-1

Small Molecules  Biologics
– Metabolism as a primary factor for species selection (rodent and non-rodent) – Pharmacology as a primary factor for species selection
– Dose selection based on toxicity – Dose selection is based on pharmacology
– Pivotal Toxicology is required in two species for a duration ranging from two weeks to three months – Pivotal toxicology is required for one species for up to six months in duration
– Standalone Safety Pharmacology studies are required – Safety Pharmacology studies may be part/all in toxicology studies
– Genetic Toxicology is required – Genetic Toxicology may not be required


Species selection: species selection is based on pharmacological relevance for target receptor expression and distribution. The patient population, drug formulation, and methods of administration meant for humans are all considered while choosing a species. Two mammalian species – rodent and non-rodent, are required for small molecules, according to The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) rules. The rat and the dog are the rodent and non-rodent species of choice because metabolic processes are generally similar across mammalian species. The choice of the animal species is made in accordance with the biological target for which the drug is being developed. While rats and dogs are most used for toxicology studies, other species may be selected depending on the therapeutic area. For example, monkeys are often chosen instead of dogs for treatments of metabolic diseases since non-human primates more closely mimic humans for these disease targets.

Route of administration and dosing regimen: the toxicology study design is aimed at evaluating the toxicity of a new molecule in the test species using the intended clinical route of delivery and dosing regimen. The dose range for assessment of safety or toxicity in animals is from minimum efficacious dose to maximum tolerated (or feasible) dose.

Toxicology studies are aimed at identifying and characterizing target organ toxicity related to dose and exposure. This information is useful for clinicians to set up appropriate monitoring and the potential for reversibility after a dose-free period. Consequently, it is a common practice to include recovery groups during preclinical toxicology testing, although the recovery period time can vary for various reasons.

Analytical and bioanalytical methods are needed for the quantitative evaluation of analytes (i.e., drugs, including biologic products, and their metabolites) in biological samples (e.g., blood, plasma, serum, or urine). These methods must be validated to assure the validity, integrity, and reliability of data submitted for regulatory examination and approval; most nonclinical toxicological studies must follow good laboratory principles (GLPs).

Considerations for a Successful IND Submission

A successful IND application is dependent on a variety of factors. It takes 18 months of preparation before starting the IND program. If you are planning for an IND submission, here are a few key considerations before you begin your IND program.

  • Start with the end goal: the goal of IND is to get into human trials. Use that to map out what studies and data are needed to get there.
  • Know the molecule: knowing the characteristics and mechanism of action will aid appropriate study design and make it easier to assemble data for the IND application.
  • Reach out early to regulators: get a pre-IND meeting to get feedback, validate your approach, and optimize your strategy to get your drug into human trials.
  • Find competent CRO partners and/or consult with appropriate experts: if you lack the expertise, it is critical to consider partnering with a credible consultant or contract research organization.

Noble Life Sciences’ established experience in toxicology testing guarantees that you have comprehensive safety testing results to support the advancement of your program. Our team of experts is well-equipped to collaborate on the general principles and designs of your toxicology tests, including the species to be tested, the size of the treatment group, the duration of treatment, the frequency of administration, and the route of administration, as well as relevant in-life observations and terminal endpoints based on the properties of your test article and intended clinical use.

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Yongping Chen, M.D., Ph.D.

Yongping Chen, M.D., Ph.D.

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