Ensuring efficient development of personalized medicine by addressing regulatory needs: What role can research infrastructures play?

Abstract

Personalized Medicine is a novel medical practice that uses an individual's genetic profile to guide decisions made regarding the prevention, diagnosis, and treatment of disease. Knowledge of a patient's genetic profile is crucial to support doctors in selecting the proper therapy and administer it using the correct dose or regimen. Personalized Medicine is a great opportunity to turn the “one size fits all” approach to diagnostics, therapy, and prevention, into an individualized approach. In this paper we analyze the most recent achievements and regulatory challenges in Personalized Medicine and the role that research infrastructures can play in advancing its development.

Introduction

Over the last several years, Personalized Medicine (PM) has generated a significant change in the drug development process. PM—unlike traditional medicine, which applies the same treatment approach to all patients affected by a disease—puts the patient at the center of health care. This involves the development of targeted diagnostic, treatment, and prevention strategies, that consider differences in patients’ genetic make-up and environment. PM offers the opportunity to tailor the appropriate therapeutic strategy for the right person at the right time.

By targeting prevention and by making treatment more effective, PM aims to reduce the burden of disease. Improving the ability to better target treatment to patients who are likely to benefit from it and avoiding patients who may be at risk of being harmed, will increase success rates of treatment, improve product development times, and potentially reduce overall health care costs. As with the evolution of many innovative technologies including Advanced Therapy Medicinal Products (ATMP), the enthusiasm surrounding PM, however, is hindered by many unknown factors in the regulatory pathways. Identifying and addressing these regulatory hurdles that hinder the progress of developing PM products and treatments is essential to making PM a clinical reality and not just a concept. Changes and adjustments are needed now from all parties involved in bringing personalized medicine to the market and using it to ensure that the new tools provided by science can be applied to achieve the full benefits that PM has to offer.

Here we outline some of the regulatory challenges in the development of PM and provide an overview of some of the support that currently exists for the researcher. Specifically, we look at the role of European Union (EU) research infrastructures such as EATRIS, the European Research Infrastructure for Translational Medicine,^1–3 and the support it can offer in driving the necessary changes to overcome the challenges in implementing PM, including the regulatory hurdles that severely slow down the path to the clinic.

The challenges: One size does not fit all

The success of PM depends on the development of accurate and reliable diagnostics and, in some cases, on the identification of novel predictive biomarkers. The presence or absence of a biomarker may predict whether and how a particular patient or subset of patients will respond to an experimental drug.

In recent years we have witnessed a rapid development of new regulations in the biomarkers field that is closely linked to the development of PM. The regulatory landscape for biomarkers is evolving rapidly, with ongoing developments for both publicly reported biomarkers and biomarkers used in individual development programs. The distinction between a potential biomarker and a reliable biomarker that can be useful to guide important decisions, both clinical and commercial, is one of the main challenges in the biomarker field. Scientific justification behind biomarkers and interpretation of biomarker measurements are not always reliable and appropriate. New concepts of biomarker qualification and validation have been developed as a response to the increasing need to address quality and suitability of biomarkers and the appropriate technology platforms to develop them, but more efficient and reproducible technologies are needed.

In another aspect, classical clinical trials harvest only a small number of measurements from a great number of people. Precision medicine requires different ways of testing interventions. In order to identify factors that discriminate groups of individuals that might benefit more from one or another intervention, large data collections are needed, and this could create concerns about privacy that the data of those individuals might be used for misdirected purposes. For this reason, it is crucial to implement the data protection regulations and establish ethical standards regarding the collected genetic and biochemical data, in order to create a legal framework that establishes an appropriate balance between facilitating the safe and secure use of personal data in health research and the rights and interests of individuals. Creating such legal frameworks remains at the core of European Research Infrastructure's missions such as EATRIS and ELIXIR, which unite Europe's leading life science organizations in managing and safeguarding the increasing volume of data being generated by publicly funded research.

Clinical researchers are increasingly conducting more complex trials with smaller and focused patient populations that are greatly dependent on the identification of specific biomarkers. This has resulted in new regulatory challenges as we attempt to apply robust standards that work well for classical trials but fail to keep up with the pace in which scientific innovation is evolving. In this context, different designs from the classical randomized controlled trials may be needed. In fact, the traditional approach to drug development, where drugs were evaluated in three phases of clinical trials, has gradually proved not to be effective, and stratification may imply studying much smaller populations in which the epidemiology of the disease might potentially be different. New clinical trial designs such as Basket studies, Umbrella studies, or Platform trials have to be considered for PM. ⁴

Of note, EATRIS is the co-coordinator in the EU patient-centric clinical trial platform initiative (EU-PEARL), ⁵ which brings together patients, clinicians, industry, researchers, and authorities to create an open and trusted environment for knowledge sharing and science-driven debate on innovative clinical trials. This involves extensive cooperation among all stakeholders to improve health outcomes for patients and represents the driving force behind EU-PEARL. This innovative and challenging enterprise aims to create a framework for patient-centric integrated research platform (IRP) trials. With the growing complexity of clinical trials, new frameworks such as EU-PEARL for stronger and faster collaboration between all stakeholders in drug development must be established.

Making the necessary changes at the research and policy level

By improving our ability to predict and account for individual differences in disease diagnosis and therapy response, PM offers hope to diminish the duration and severity of illness and to improve success rates. At the same time, it may reduce health care costs by improving our ability to select quick and reliable effective therapies for a given patient while minimizing costs associated with ineffective treatment and avoidable adverse events. Existing barriers can be overcome by bringing about key changes in the setting, including at least the following examples: (a) making the required changes in regulation and reimbursement pathways for PM; (b) modifying mechanisms for research and for incentives to make biomarkers integral to all health care research rather than merely optional; (c) involving the patient to address regulatory uncertainty; (d) educating the PM Developer about the specific regulatory requirements. Of note, several European Medicines Agency (EMA) initiatives provide guidance on the development of PM products such as ATMPs ⁶ through specific guidelines including flowcharts to guide the researcher through the required regulatory steps and the availability of multiple webinars and resources available from the EMA website to support the researcher; in addition, the EATRIS ADVANCE Initiative, an EU training project supported by Erasmus Plus, aims to educate the next generation ATMP expert in regulatory needs ⁷ ; the objective of this project was to develop a three-stage blended learning program to support early-career biomedical scientists in developing currently missing scientific knowledge, transversal skills, and competences to meet the key challenge areas existing in the ATMP development cycle; (e) Promoting enhancements to data acquisition to ensure that PM approaches in health care continue to advance; and (f) ensuring synergy in European health care policy such as in regulatory regulations; for example, EMA versus national competence. As an example, STARS, ⁸ an EU funded project on Strengthening Training of Academia in Regulatory Science recently concluded; they had the objective to complement, coordinate, and harmonize regulatory efforts among Member States and at the European level to support academic health research for the benefit of patients.

In a new era of tailored medical products, the regulators need to advance with and anticipate this evolving science. Regulators should keep up with rapid advances in innovative science and technology and work together with scientists, government agencies, companies, standards organizations, practicing physicians, and patients to evaluate and validate new diagnostics and therapeutics. Furthermore, they should always strive to provide clarity, predictability, and guidance to industries to help encourage development of medical products in promising new areas. Streamlining regulatory processes will help advance technology development in a more efficient and cost-effective manner that will help drive innovation in the PM field.

It is becoming clear that PM requires a new mental attitude, putting the patient at the center of health care and demanding innovation in the way medicines are developed and health care systems are structured to deliver care. The policies on informed consent and the use of personal data, and concrete steps like electronic patient records, integrated into a system that has practical benefits for people must now become standard. Europe needs to create a new ecosystem among research institutions, patients, health care practitioners, and governments to exploit the growing range of data resources to prevent disease, or when disease does strike, to manage it better. Finally, PM must attract venture capital funds and philanthropic foundations to invest long term in health.

The role of EU research infrastructures in driving the necessary changes to overcome the regulatory challenges in implementing personalized medicine

Research infrastructures have direct relevance for PM and can play a crucial role in its development. In particular, EATRIS, over the past 3 years with its flagship project EATRIS-Plus ⁹ has worked, and continues to work, towards building EU capabilities to support the long-term sustainability strategies for PM. The main goals of the EATRIS-Plus project are to: (a) consolidate EATRIS capacities across the 150 institutions within 14 EU countries in the field of PM (particularly omics technologies) to better serve academia and industry, and to augment the number of EATRIS Innovation Hubs with large pharma; (b) drive patient empowerment through active involvement in the infrastructure's operations; and (c) expand strategic partnerships with research infrastructures and other relevant stakeholders that can address the regulatory and developmental challenges at the research policy level.

In the context of driving best practice in regulatory science, EATRIS has set up a dedicated EATRIS Regulatory Task Force and Regulatory Expert centers that can support researchers by acting as an intermediary contact point with EMA and/or the National Competent Authorities (NCA) where and if needed. With projects that are supported by EATRIS, the Regulatory Support team can help researchers with early definition of a regulatory strategy including the preparation for a Scientific Advice (SciAd) meeting if required with the most relevant Regulatory authority. During the SciAd meeting it can be discussed with the EMA or NCA what type of information the Regulators expect for the investigational medicinal product and the companion diagnostic product, which can further be supported by EATRIS or another research infrastructure if required. In addition, it can be specified during the SciAd meeting what kind of gene testing and which -omics profile is needed to identify a patient as suitable for a given personalized medicinal product. With this information at hand the EATRIS project management/operations team can then set up a product development plan that is perfectly tailored to meet the regulatory “must haves.” Subsequently, the EATRIS team can provide further support and services to the academia group where and when needed. Supporting best practice in regulatory science and working closely with the regulatory authorities is fundamental to the EATRIS mission. As a result, using this knowledge and relationship, and providing efficient regulatory support for researchers in PM and beyond, can support faster, more efficient, and less costly translation of PMs to the clinic.

In conclusion, European researchers continue to be at the forefront of major scientific health care discoveries. However, the challenge is to translate this knowledge and expertise into medical advances that improve outcomes and enhance wellbeing for patients. The key to success will be the promotion of international research by improving cooperation and collaboration in health care research. This can be accomplished by creating simplified, harmonized, and more predictable regulatory procedures, and reducing unnecessary costs and administrative burdens. EU Research Infrastructures fosters such efficient cooperation and collaboration in health care research by providing the researcher access to not only the scientific expertise, but also the regulatory expertise, health technology expertise, and future sustainability expertise where and when needed.