Felicity Grzemski PhD DABT

Drug development is an expensive, highly regulated, and complex process. One noted potential issue with early drug development is a disconnect between the preclinical research phase and the clinical development phase where the translation has a success rate of less than 10%. In addition to factors including poor drug-like properties, lack of strategic planning and commercial need, the major causes of attrition are poor clinical efficacy and safety which are typically investigated with preclinical pharmacology and toxicology studies respectively. What is critical to determine the best strategy based on your product and the intended indication to support clinical success?

Consider Druggability and Developability

At the onset, the preclinical development plan should consider both the druggability of the target and the developability of the asset; both of which have the potential to reduce drug attrition in later development stages.

The druggability evaluation, in general, investigates likelihood of being able to modulate a target, whether the target is accessible to the asset,  whether the target has a key role in a disease, the feasibility of developing an asset with high affinity to the target (target engagement) and that modulation of target function is therapeutically effective in treating a clinical indication.  In contrast, the developability assessment has focus on the asset itself and its potential to be developed as a successful drug candidate. While nonclinical performance is measured in safety, efficacy, and pharmacokinetic studies, how the asset is formulated and manufactured, physiochemical properties and patient convenience and compliance are also considered. Additionally, the developability assessment compares the asset to the current clinical standard of care and other competitors for the proposed indication and thereby address a recognised unmet medical need. The druggability and developability of an asset is mostly investigated via preclinical studies. A well thought out preclinical development plan helps you know your asset and the drug product it will become adding significant value to the project.

Consider a Target Product Profile

A Target Product Profile (TPP) is a document that outlines the minimal and ideal profile or characteristics of a drug product interacting with a specified target for a particular indication. While TPP generally provides groundwork for the label and clinical development, it is never too early to start your TPP. It can be used as a communication tool and provide focus for your team on the goals of the program. It can help determine what preclinical studies are required to enter the clinic. Preparing a TPP helps uncover challenges to your development program, maintain future vision and can prevent investing resources, including time and money in an asset that may not achieve your development goals. 

As you plan and perform nonclinical studies, development challenges such as lack of an animal model to confirm efficacy, an unexpected toxicity, need to expedite manufacturing concerns or lack of clinical biomarkers can be identified. Studies can be prioritized to derisk development issues. Your TPP is a living document and should be adjusted to accommodate incoming information.  Importantly, it can enable developing the right developmental and regulatory strategy and a higher probability for success transitioning of research data into clinical practice. And allows readiness for external evaluation, either by investors or regulatory authorities

Consider your Development Strategy

When preparing your development strategy, it is important to start with the end in mind. Is there an exit point? If the exit strategy includes development of the asset with a partner, then a fit-for-purpose quality data package with no scientific or regulatory gaps, and with no need to repeat studies, maximizes value of the program. 

Importantly, the strategy must also identify when discontinuation of the program is the next logical step. Preclinical studies may show that the safety and/or efficacy may not be superior to that of other therapeutics either marketed or further along in development - at least for the current intended indication. 

Consider the Indication

It is important that the proposed indication has a solid clinical and/or commercial rationale. The prevalence, incidence and market size for the indication should be determined. Also, what does the competitive environment look like? Is there an unmet medical need? There is no point in developing an asset where there is already a comparable drug. Will the physician prescribe the asset? It must be clear what your asset offers, be it novel first-in-class status, orphan drug designation, scientific innovation or having superior efficacy and/or safety when compared to competitor products or it is not inferior if other developability factors are being considered. 

Now the Preclinical Development Plan

Preclinical studies form the basis for confidence in the safe and efficient progression of a new molecular entity into clinical testing. It is clear that the druggability and developability of a candidate is mostly evaluated in fit-for-purpose preclinical studies. And well-designed nonclinical studies can allow an asset to segue into other therapeutic areas which would add a significant value to the project.

There is no prescribed set of studies for regulatory approval of an asset. While the preclinical program should be designed according to global and regional regulatory guidelines, it should not be considered a box checking exercise. Preclinical studies should be  necessary, streamlined, cost effective and fit for purpose. They cannot be reviewed in isolation of each other and together must tell a story to support the planned clinical study. Ultimately, there should be neither clouding of data with too much extra information nor a requirement to repeat a study done without the correct endpoints. A truly novel asset with no class or chemotype history in humans is typically considered a high commercial risk and therefore preclinical development tends towards a conservative approach.

Pharmacological efficacy data should be provided in appropriate in vitro and/or in vivo models supporting both proof of concept and potential clinical efficacy. Preclinical safety studies should characterize potential toxicities, identify target organs of toxicity, investigate dose exposure relationship and safety margins with respect to planned clinical doses and also the potential reversibility of toxicity findings. Nonclinical safety studies assist in justifying a safe clinical dose and the clinical monitoring plan for clinical trials. The risks associated with insufficient data quality and the lack of documentation are very well recognized. Therefore, nonclinical toxicology studies supporting clinical dose selection and safety should be performed to Good Laboratory Practice which provides the highest confidence of scientific quality and integrity. 

Your preclinical development strategy may have the opportunity to be discussed with regulatory authorities e.g conducting a pre-IND meeting or an interact meeting with US FDA. If so, take the opportunity to discuss any identified challenges which can help your development, save time and money, and improve your overall chances of regulatory success. The importance of a well-crafted nonclinical development plan cannot be understated.  

In conclusion, a robust preclinical development plan provides information on the safety and tolerability of the asset, and that the pharmacology is related to the desired therapeutic outcome providing a strong rationale for clinical success. In addition to patient benefit, a safe and efficacious asset is worth more to investors, and failure of candidates should be determined as early as possible. It is not only the qualities of your asset that will ultimately determine the success of your program, but also on the early recognition of failure, the effective management of key resources of effort, time, and cost and how the preclinical drug development was performed.