By William Salminen, Madelyn Huang, & Andrew Emanuel

Without concrete guidelines, it can be confusing when determining what nonclinical studies are needed for a Pre-Investigational New Drug application (PIND) meeting. However, in our experience, the answer is this:  it is critical that the nonclinical program provides sufficient data to allow the FDA to provide meaningful feedback on the proposed IND-enabling nonclinical program, but it should not be so extensive that time and money are wasted by conducting studies that may not be required for an IND or may need to be reconducted due to inappropriate study designs.

In this blog, we will go into more detail about the unwritten nonclinical requirements for the PIND meeting. We will use the term, nonclinical, to refer to any in vitro, ex vivo, or animal study conducted to support any stage of research and development of a new drug, such as proof-of-concept pharmacology studies through Good Laboratory Practice (GLP) toxicology studies.

Figure 1:

Focus on Safety

It is natural to emphasize the therapeutic potential of a drug, such as in vitro and in vivo proof-of-concept studies since that is often the primary driver for establishing a biotechnology company. From a business standpoint, these studies are critical for obtaining funding and being reassured that the drug will show promise once it enters the clinic. However, when it comes to an IND and supporting a clinical trial, FDA’s primary focus is on healthy volunteer and patient safety. It is critical that the nonclinical program outlined in the PIND briefing document is presented in a manner that allows FDA to provide relevant input on the required IND-enabling studies. For example, if the nonclinical data presented in the PIND briefing document lacks information on the potential toxicity profile of the drug (e.g., non-Good Laboratory Practice [GLP] range finding studies in one or more species), it will be difficult for FDA to provide input on the types and designs of the required GLP toxicology studies since the drug may have unique safety issues (e.g., neurotoxicity) that require special assessments. These special assessments will help ensure that an appropriate starting dose and dose escalation protocol is used to ensure healthy volunteers and patients are not harmed. Even for repurposed drugs being developed under the 505(b)(2) New Drug Application (NDA) pathway, it is critical to review the existing nonclinical and clinical data on the drug to determine what nonclinical studies may be beneficial to conduct prior to the PIND meeting and include this information in the package. For example, a new fixed dose combination product using two FDA-approved active pharmaceutical ingredients (APIs) may benefit from a preliminary drug-drug interaction (DDI) screen to rule out possible pharmacokinetic (PK) interactions and facilitate a more informed discussion with the FDA regarding the necessity of GLP combination toxicity studies.

Make It Fit-For-Purpose

There is no one-size-fits-all approach because the nonclinical program is intimately tied to the pharmacology (PD), PK, and toxicology of the individual drug and the intended IND-opening study. The nonclinical program needs to be fit-for-purpose, taking into consideration data generated with each study and determining when enough data has been generated to support the key questions that will be asked at the PIND meeting. The nonclinical data often impacts the CMC, clinical, and regulatory questions; therefore, it is important to take a holistic view of the nonclinical program and how it plays into all the PIND questions. For example, a drug may produce hepatotoxicity that appears to be species specific. It would likely be valuable to generate additional data on the species specificity and have an informed discussion with the FDA regarding additional data required to avoid a clinical hold or an exposure cap restricting clinical dose escalation.

Look at the Big Picture

It is important to look at the big picture and determine how to best design a nonclinical program that meshes with obtaining valuable FDA feedback and takes into consideration time, money, resources, and risk tolerance. This is where an experienced toxicologist comes in. They should have the expertise to tailor the nonclinical program to obtain the input needed at the PIND meeting but also keep the program lean if funding is limited, accelerate data generation by using alternative methods if meeting a milestone is critical, or generate larger and more robust nonclinical datasets for clients that have a lower risk tolerance.

Embrace Alternatives

The combination of experience and technical ability is great for determining a potential drug development path. However, it is also important to embrace alternative methods and approaches that may be contrary to past experience to efficiently address unique issues, reduce the overall nonclinical program, or provide multiple development options that can best meet the company’s key objectives.

Premier Consulting toxicologists partner with clients to develop their nonclinical strategy, PIND key questions, and briefing document to maximize FDA input and ensure a clear and streamlined path to the clinic. Contact us today to discuss your nonclinical program with one of our toxicologists.