How to correctly identify the boundary between pre-clinical and clinical development, in order to optimise the rapid translation of research towards new and innovative medicines and develop new business models for the pharmaceutical industry? The question was addressed by a joint workshop held in March 2018 by the Academy of Medical Sciences and the Association of the British Pharmaceutical Industry (ABPI), those results have been published in the summary report “Bridging the preclinical-clinical boundary”.
A two-way exchange to better define the boundary
Translational research aims to optimise the pathway of candidate medicines from the lab to the final use in the clinical practice by investing in the optimisation of early-stage clinical development. This is based, according to the report, on four key pillars: an interdisciplinary workforce that spans across sectors; a research infrastructure that supports collaboration and knowledge exchange; an agile and flexible regulatory processes; and new technologies that provide opportunities to enhance preclinical and early clinical research.
The key point to be addressed is the correct identification of the boundary between pre-clinical and clinical phase, i.e. the point where there is sufficient pre-clinical evidence available to start first-in-human clinical trials.
Phase 1 and 2 studies – focused on the determination of the safety and efficacy profile of the candidate drug – present a particularly high risk and attrition, and require a significant escalation in both resourcing and time. A robust and predictive evidence is thus needed as a prerequisite in order to successfully plan following development steps and optimise the large costs of later stage, phases 2b and 3 clinical trials.
The suggestion coming from the workshop indicates the possibility to maximise progression by mean of a ‘two way’ evidence exchange across the boundary: evidence from pre-clinical models should closely shape the design of clinical studies, while data obtain from clinical studies (e.g. data on populations or drug interactions) should be used as a feedback to run further preclinical research. The final objective should be the improvement of the initial selection and validation of the target, the evidence of efficacy and identification of biomarkers.
An interdisciplinary and integrated team approach
The two-ways exchange model requires a strong integration of both research infrastructures and skilled interdisciplinary workforces at the pre-clinical and clinical level. The traditional model of development sees a quite deep separation between the pre-clinical and clinical functions, both at the level of the dedicated facilities and interactions of the respective staff. According to ABPI, the new collaborative model overcomes this separation to achieve a better integration of disciplines and sectors, scientific evidence generation and funding models. The effort to proceed in this direction may require different incentives and ways to reward ‘success’, as well as redefining career pathways. Training may be also needed in order to fill skills gaps, i.e. in bioinformatics, statistics, clinical pharmacology and pharmaceutical science. Early development teams should include a wide array of different skills, from basic scientists, project leads and regulatory experts to clinicians and statisticians. As explained by Professor Paul-Peter Tak, Chief Immunology Officer and Senior Vice President R&D Pipeline at GSK, the focus should be on the quality of a molecule based on its physicochemical properties, and the value of identifying the right early clinical studies that can better inform late stage development.
Another issue relates to the differences in culture traditionally experienced between the academia, industry and healthcare providers, which might make it hard to integrate the different perspectives. According to the results of the workshop, early engagement and a better appreciation of the respective cultures and differing priorities might help to overcome this division and to increase permeability across sectors. An example in this direction is the Open Targets platform, created by GKS in collaboration with the Sanger Institute and European Bioinformatics Institute with the goal to share knowledge and expertise to better identify and prioritise promising therapeutic targets.
The challenges of experimental medicine
Safety and efficacy data obtained from early stage clinical trials are used to inform the decision to further proceed with clinical development. The approach typical of experimental medicine requires a strong interaction between the industry and the academia and/or hospitals where the studies are run, and who often hold the expertise in biological pathways and physiology. Permeability across sectors is a goal achievable, according to the report, working to increase research culture, skills and awareness into early medical training and establishing appropriate incentives in the wider healthcare system. Access to the best available research infrastructure may be facilitated by the availability of ‘front door’ organisations (e.g. university translational research offices (TRO) and cluster organisations) supporting research sponsors to identify the right expertise.
Mutual recognition of success in early stage research should also be encouraged in order to fill the ‘credibility gap’ mentioned by Tim Eisen, Head of Oncology (Translational Medicine Unit) at AstraZeneca and professor of Medical Oncology at University of Cambridge: for experts from the academia, for example, it might be important to evaluate the progression of a therapy to the next stage of clinical development under the same terms of a publication in a high impact journal. Pre-competitive collaborations, open science and open innovation should be a goal for industry, in order to share excellence and high-quality data, especially at the more basic levels of research.
Complex infrastructures and new technologies
Another important point relates to the easy understanding of the complex research infrastructure network by all stakeholders, and particularly by SMEs, being the ones more likely to rely on collaborations to access the needed expertise. TROs might be very useful to provide a matrixed support team to help the navigation across the many activities linked to the proper management of the preclinical/clinical translational boundary, including preclinical validation, good manufacturing practices, good laboratory practice safety testing, regulatory knowledge and clinical trial infrastructure design and management.
From the financial point of view, a better targeting of funding would be needed in order to support scale-up and proof-of-concept of early clinical research and encourage further funding from venture capitalists and industry.
Many new pre-clinical technologies are already available to support a better integration of the boundary, i.e. the microphysiological systems (MPS) known as organ-on-a-chip, that mimics the complexities of human tissues and organs. They allow the preliminary evaluation of many parameters and physiological phenomenons before testing on the actual human tissue occurs. Such models might also be used to model pharmacokinetics and pharmacodynamics (PKPD) of a drug, and possibly to identify drug interactions and contraindications. The suggestion made by the report is that in future they might also supplement or even replace animal models.
An agile regulatory framework to support early stage trials
Early stage clinical trials might benefit from the ‘devolved health systems’ model to create pilot integrated schemes at a local level and provide flexibility to rapidly assess small, iterative improvements that may be otherwise too costly, slow or risky to be managed. Patient recruitment might be improved by a better engagement with patient groups, suggests the report, especially for experimental medicine studies which might not directly benefit the participant.
Flexibility to support innovative trial design should also come from the regulatory perspective, in order to adapt the design to actual outcomes data. This might include the possibility to remove or add treatment arms, change the balance of randomisation or alter statistical methodologies, without compromising validity. A collaborative approach that includes also regulators is thus suggested, for example by a better interaction with the MHRA’s Innovation Office. It would be also important to constantly inform regulators with technological developments that are likely to feature in licensing applications, such as the above mentioned organ-on-a-chip.