Developing a well–thought-out nonclinical program is an evolving process. The number and types of animal studies impact not only funding requirements, when an IND will be filed, and whether the IND will be cleared, but also what the starting dose in the clinic will be, and for long-term studies – whether submission and approval of the NDA/BLA will be affected.
ICH M3(R2), Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals, provides a blueprint for the studies needed for approval. However, the uniqueness of each drug, medical device, and biologic, as well as the clinical history of a product and whether the product results from a novel technology (e.g., nanotechnology), dictates how closely a nonclinical program must adhere to this guidance.
Frequent and open communication about the nonclinical program with the FDA at pre‑IND meetings, Type C guidance meetings, and the end‑of‑Phase 2 meetings is likely to provide a company with valuable insight on the FDA’s thinking and to help a company develop a robust program that will not be a “showstopper” late in the development process. The FDA, however, is unlikely to develop a company’s nonclinical program; rather, it is likely to shape an existing program into a successful one.
At each stage of product development, a new set of questions or points of clarification concerning results of nonclinical studies already conducted or those expected in preparation for the next stage come up. Below are some questions that should be considered as a company starts to think about one of its first interactions with the FDA (i.e., the pre-IND meeting):
- Is it worth having a pre-IND meeting at all?
- Has sufficient nonclinical work been performed to warrant a pre-IND meeting?
- Has the company been closely following FDA’s thinking on the nonclinical development for a particular kind of product and technology through FDA workshops, white papers, and news releases?
- Is there a nonclinical path of an approved product that serves as a good model for the company’s own nonclinical program?
- Is there an opportunity to engage the FDA in informal discussions before the pre‑IND meeting?
- Do results of the animal and in vitro studies provide enough background for the FDA to make meaningful recommendation for additional studies?
- Is there an opportunity to talk about the starting dose in the clinic at the pre-IND meeting?
- If the product will not reach a maximum tolerated dose or if toxicity is not observed (because of the type of product in question), what path will be proposed?
- Are there any CMC-related issues that could affect nonclinical development (e.g., impurities)?
- Can an abbreviated nonclinical program be proposed based on the clinical data available for the product?
- Are there any peculiarities about the product that should be addressed with the FDA (e.g., a combination product consisting of two active biopharmaceuticals)?
- How much money is needed to continue the nonclinical program if the FDA recommends a conservative path forward?
- Is it worth engaging a contract research organization to assist with the preparation for and conduct of the pre-IND meeting?
Overall, from a nonclinical development standpoint, the pre-IND meeting should clarify for the company what the next steps are in resolving existing issues and what studies would be considered appropriate for clearance of the IND application.
This is a post by Tariq Allana, Ph.D. Tariq is a Clinical Strategy Scientist at Cato Research and the Associate Director, Business Development.
