How to create a smart integrated drug development plan including considerations for cell and gene therapies

by Diane Seimetz

The transition from R&D stage to clinical stage is an important phase in drug development. While R&D focuses on identifying promising product candidates, drug development requires a diligent approach across various disciplines in a highly regulated environment to bring promising drug candidates to the commercial stage. On this path, an integrated drug development plan (IDP) is an extremely useful tool to increase the overall success rate. This is true for the development of all drugs but is even more important for cell and gene therapies, where conventional development paradigms often don’t apply, and where more tailored approaches are needed.

For the creation of an IDP all development disciplines such as manufacturing, nonclinical and clinical development as well as regulatory affairs should be involved (see Figure 1). Even for early-stage programs commercial aspects such as target countries for commercialization, the competitive environment as well as pricing / reimbursement aspects should be considered. The IDP is a living document that will need to be updated as the development progresses. Therefore, starting as early as possible is more important than striving for the most perfect and complete document from the beginning.

A useful way to start creating an IDP is by having the goal in mind, i.e. the product intended to be developed for commercialization in defined countries /regions. This goal can be visualized in the form of a target product profile (TPP). The TPP comprises, often in a tabular format, the value proposition under consideration of the competitive environment, target indication(s) and population(s) for development incl. desired efficacy and safety profile, route of administration as well as dosing strategy. Furthermore, target countries or regions and pricing should be considered. A TPP template is provided in [1].

For cell and gene therapies which are based on a particular platform a platform specific TPP can be a useful starting point for an IDP. The platform specific TPP can be leveraged for all product candidates derived thereof.

The quality part of an IDP outlines the proposed manufacturing approach as well as the control strategy for the drug substance and the drug product. The manufacturing approach will need to consider the involvement of potential contract manufacturing organizations (CMOs) for the entire product or parts of it that are not manufactured inhouse.

Important points to consider for the manufacturing approach of cell and gene therapies are the source and quality of starting and raw materials. As the manufacturing process has limited capacity to clear adventitious agents or impurities, a high quality of input materials will have to be ensured. For allogeneic cells as starting materials specific regulatory requirements for cell sources and testing requirements should be considered from the beginning (for example, products derived from embryonic stem cells may not be approvable in some countries due to ethical/legal reasons).

For the control strategy a diligent approach including a phase appropriate plan towards the potency assay will be needed. While for early phases of drug development a surrogate measure of functionality may be considered appropriate, a potency assay measuring the biological activity of the drug will be needed. As these assays are truly product specific and challenging to develop, this should be planned well ahead.

The nonclinical part of an IDP outlines the proposed in vitro and in vivo studies planned to address pharmacology, safety and toxicology. Important questions guiding the nonclinical development are for example (1) how does the drug work and for how long, (2) are there relevant animal models available for pharmacology and safety assessment (3) what is an appropriate dose and regimen, (4) what are potential safety concerns and uncertainties, and (5) how can the risks and uncertainties be mitigated when progressing to the first in human clinical studies.

For cell and gene therapies animal models are often not readily available or not meaningful at all due to the lack of target expression or substantial differences in the functionality of the immune system. Therefore, in vitro and in silico models (e.g. for off-target predictions) should be considered as useful tools for tailored nonclinical development.

The clinical part of an IPD outlines at least the first in human study and, depending on the stage of development, further clinical studies up to approval and beyond for potential follow-up commitments. For cell and gene therapies the first in human study is typically performed in an indicated population. The limitations of the nonclinical development program will need to be reflected in the clinical study design, e.g. by defining the most appropriate starting dose and sequencing between patients. In the case of autologous cell-based therapies the patient is part the manufacturing process. This requires a dedicated and diligent set-up of a patient to patient logistics chain. This is often underestimated in terms of complexity and cost. Furthermore, all concomitant procedures required for the collection of patient cells as well as administration of the product itself (e.g. depletion therapies) have to be considered for the overall benefit-risk of the product.

Due to the long, sometimes life-long, persistence of certain cell and gene therapies the safety follow-up time can be considerable and will need to be planned well ahead. E.g. for genetically modified cell products the commonly requested follow-up time is 15 years. The effect size that can be achieved with gene therapies is remarkable. Therefore, early approval strategies which include post-approval commitments are warranted. While this is a huge strategic advantage, it poses challenges on the set-up of the manufacturing and control strategy.

The regulatory part of an IDP outlines the regulatory tools that are available in the target territories and assesses the suitability and most favorable timing of these tools for the product candidate. The IDP typically comprises the regulatory interaction strategy, dedicated regulatory programs as well as submission strategies. Of note for cell and gene therapies, due to the innovative nature, several regulatory agencies offer early interactions, e.g. pre-scientific advice in EU member states or the INTERACT meeting with the FDA. Furthermore, regulatory interactions on platforms and innovative manufacturing strategies are offered. In a highly regulated field such as drug development the regulatory strategy is of utmost importance. Crafting the most successful strategy is artwork.

Biopharma Excellence has comprehensive expertise with the creation of smart IDPs. Interested in learning more about how YOUR program can benefit from our expertise? Get in contact with us.

References:

[1] Seimetz, D. The key to successful drug approval: an effective regulatory strategy. In: Life Science Venturing. Wiesbaden: Springer Fachmedien Wiesbaden; 2017:139–165.