Collaborating with regulatory authorities to implement our innovative methodologies

Marieke De Bruin (professor Drug Regulatory Science, Utrecht University) is member of the management team of the workstream Regulatory Innovation within the Oncode Accelerator program. Marieke was trained as a pharmacist (Utrecht University) and an epidemiologist (Erasmus University Rotterdam). She combined academic research with working for the regulatory authorities since 2008, both nationally as a Pharmacovigilance expert for the Dutch Medicines Evaluation Board (2008-2016), and internationally as an independent Scientific Expert of the Pharmacovigilance Risk Assessment Committee (PRAC) appointed by the European Commission at the European Medicines Agency (2012-2018).

Why does the National Growth Fund require Oncode Accelerator to involve regulatory bodies early on in the preclinical drug development process and why is this so important?

“An important step in the translation from bench to bedside is the authorization, or regulatory approval, of a new drug. The developer needs to show that their new drug is safe, effective and of good quality, according to a set of standardized experiments. In the Oncode Accelerator program, novel techniques are developed to test new drugs. Take for instance the work of the Organoids platform within the program. If successful, organoids could replace animal models in the future. However, it is important to ensure regulatory acceptability of these novel tests. The techniques are new to researchers, but also to regulators, who evaluate the evidence for approval. By involving regulators at an early stage, knowledge is disseminated as soon as possible, and regulators will get the chance to learn without unnecessary delays. In the end, this will also accelerate the pace of drug approval.”

What is the goal of the Regulatory innovation workstream in Oncode Accelerator?

“The ambition of the Regulatory innovation workstream is two-fold. Firstly, we will perform research on how the regulatory system is currently functioning. We will measure the regulatory readiness of the system for the innovations that are part of the Oncode Accelerator program - artificial intelligence, organoids, real-time and real-world patient data and samples. We will look for opportunities to further improve the system. Secondly, stakeholder involvement will play a crucial role. We plan to interact both formally and informally with regulatory authorities. For instance, we will interact informally with them by attending stakeholder workshops where knowledge will be exchanged. We will interact formally in so-called scientific advice meetings that will be facilitated between the developers and the authorities.”

The National Growth Fund Advisory Committee wants to see sufficient progress regarding the regulation of new applications in the preclinical phase prior to approval of the conditional part of the subsidy. What results from the Oncode Accelerator program do you expect to see in the coming years?

“I hope to see informal interactions early on in Oncode Accelerator. Both in the form of knowledge exchange workshops as well as active involvement of MEB-employees in the supervisory teams of the PhD projects. An important form of generating joint output by regulators and academic/clinical researchers will be the co-creation of scientific publications. Oncode Accelerator’s techniques need to be somewhat further developed for the formal interactions with regulatory authorities. That being said, I expect these to take place later in the program.”

Can you give examples of regulatory involvement in initiatives that successfully employed similar innovative technologies for the therapy development?

“Let’s look at animal studies, for a moment. The MEB is actively involved in (and co-funds) so called 3Rs research - Replacement, Reduction and Refinement of animal tests. One such research project was about reproductive toxicity. Since thalidomide, reproductive toxicity testing needs to be performed in 2 different species (both rat and rabbit). Taking a retrospective look at the performed studies  the added value of the second species (over the first) was very limited. This knowledge was incorporated when international regulatory requirements were revised. Now, a complete set of reproductive toxicity studies can be deferred until large scale (phase 3) clinical trials and a single animal test complemented with and advanced in vitro test is sufficient until that time. This potentially saves the large scale use of animals for products that, due to high drug attrition, never reach phase 3.

Another example of successful regulatory innovation came out of the Trials@Home project. In this EU-funded IMI project, academia and industry collaborated to explore the potential of digital technologies for use in ‘decentralized clinical trials’ (DCTs). This is a way of generating evidence about the impact of these innovative approaches on conduct of clinical trials. Doing trials in a home setting would allow a more diverse group of patients to participate, than if patients need to go to the hospital for all check-ups. Regulators were actively involved in this project, both as ‘study subjects’ being interviewed about their opinions, and as stakeholders reviewing outcomes of the project. The open dialogue and information sharing between the project members and regulators occurred during drafting of a recommendation paper with new guidance on how to best perform decentralized clinical trials published on the European Medicines Agency’s website. This guidance as well as openly sharing of experiences from the Trials@Home project allows drug developers to better understand the regulatory aspects related to these novel methods and use them in their application dossier.”