RSNN workshop report

17 to 17 April 2019
Villa Jongerius, Utrecht
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 “The future of clinical trials and evidence generation, and their use in regulatory decision making”

We live in an era of unprecedented scientific innovation. Digital technologies and highly personalised therapies are about to make their way into clinical practice. Not only the scientific landscape is changing. Society is changing as well and increasingly asks for faster access to therapeutic innovations, better assessments of the efficacy of medicines, and cost-effectiveness of treatments. These factors – amongst others – drive us to review how we generate evidence from clinical trials for regulatory decision making. This topic concerns multiple stakeholders: from patients to pharmaceutical companies, from regulators to academia.

A multi-stakeholder approach is needed that benefits all parties involved. Therefore, the Regulatory Science Network Netherlands (RSNN) organised a workshop titled “The future of clinical trials and evidence generation, and their use in regulatory decision making”. The workshop was organised on the 17th of April 2019 and took place at Vila Jongerius, Utrecht.

The meeting was opened by Prof. Bert Leufkens, chair of the RSNN. Prof. Leufkens’ opening was followed by four speakers with different backgrounds (Prof. Joop van Gerven – Chairman Central Committee on Research Involving Human Subjects (CCMO); Prof. Rolf Groenwold – Leiden University Medical Centre; Prof. Ton de Boer – Chairman CBG-MEB; Dr Rebecca Lumsden – Director Europe and International Regulatory Policy at Pfizer) who shared their views on this subject in a plenary session. In the afternoon, the attendees split up into four smaller workshop groups to discuss the topic more in-depth. All relevant stakeholders (patients, payers, academia, industry, health technology assessors, regulators and healthcare professionals) were represented at the event, and the discussions were taking place in an open and constructive manner. This report provides a summary of the key discussion points and most important outcomes, both from the plenary speakers as well as the smaller workshops.

What drives the need to innovate clinical trials?

Historically speaking, clinical trials were used to answer two key questions: how efficacious is this medicine, and how safe is it for the average user? For decades, the randomised controlled trial (RCT) has been considered the gold standard to answer these questions: a clinical trial in which highly selected patients are randomised over treatments, and which is performed under stringent conditions, so as to optimally tease out the treatment effects – both the good as well as the “bad” ones.

However, over the past years it became clear that RCTs do not always work for all populations and struggle to deliver the answers that we need to decide whether a medicine is safe and effective. In addition, there is an increasing focus from other stakeholders to draw more information from clinical trials than just safety and efficacy, e.g. long-term effects and comparative effectiveness.

During the plenary sessions, several different factors that drive the need to transform clinical trials were discussed. A key driver is scientific innovation: for studies that concern digital technologies, Artificial Intelligence (AI), gene therapies, highly personalised treatments and Advanced Therapy Medicinal Products (ATMPs), the classical RCT sometimes falls short in proving the safety and efficacy.

Societal changes were also mentioned as drivers that ultimately result in different requirements for clinical trials. These include for example the increased attention for orphan diseases and paediatric indications, where it can be difficult to find a sufficient number of patients to include in a study. Heterogeneous aging populations with multiple comorbidities and treatments can also pose challenges for classical RCTs. Another example is the increased attention for value-based healthcare and (comparative) cost-effectiveness of the treatment, topics that are often not included as outcome measures in clinical trials.

Almost paradoxically, regulations themselves were also identified as drivers behind the need for a revision of the clinical trial assessment system. The industry is increasingly faced by multi-layer regulatory pathways (such as ethical committees, global and local regulators and Health Technology Assessment bodies) that all have their own procedures and requirements. The intention of the different regulatory bodies is good, as they strive to protect the patient from any potential harm to their best extent. However, as a consequence, obtaining approval for market access and reimbursement has become a time-consuming and expensive process which translates to higher costs and delayed access to new drugs for society. Furthermore, it drives academic groups and small companies, that do not have the resources or infrastructure for these costly processes, out of the drug development market.

Prof. De Boer raised the issue of the limited applicability of the way we currently conduct pre-marketing and post-marketing research. “Pre-marketing studies focus on efficacy and are performed in a highly controlled setting, and often do not represent the real-world situation. As such, the effectiveness of a treatment in clinical practice is never as good as in its registration study. Post-marketing studies primarily focus on safety. As a consequence, we miss information on the effectiveness of medicine in real-world practice and fail to identify the value of a new treatment compared to existing therapies.”

These examples underline the need to transform the clinical trial landscape. But how can we best do this?

Innovating clinical trial designs: what are the options?

All speakers put forward possible solutions that could improve the ways clinical trials are used for regulatory decision making. The common denominator in the proposed solutions was the issue of trade-off. For every modification we make to clinical trial designs to gain something, we often lose something on the other end. Or, as Prof. Groenwold phrased it: “There is plenty of choice, but there is no free lunch”.  

Prof. Groenwold presented several alternative approaches to traditional trial designs and explained what the trade-off of these are. For example, it is possible to perform multiple studies in one study participant, which can help to increase recruitment numbers for study populations with generally low subject numbers. The trade-off here is that it can be burdensome to the subject to take part in several studies at the same time. Prof. Groenwold indicated that academia can help with designing trials that answer a specific question, or tackle a specific issue, such as low recruitment possibilities.

Both Prof. Groenwold and Prof. De Boer discussed the possibilities of “real-world data” (RWD) or “real-world evidence”. Collecting RWD in pre-marketing and post-marketing studies would aid us in assessing how medicines perform in routine clinical practice and in daily-life situations. It can also help to guide choices amongst different therapeutic alternatives. The trade-off here is that RWD runs the risk of being incomplete or of questionable quality, and by definition contains “known unknown” factors. This can complicate analyses. In addition, the collection of RWD requires a suitable infrastructure and resources to do so.

Another possibility put forward by Prof. Van Gerven and Prof. De Boer was to re-assess the current rules and regulations and look for areas where it is possible to make regulations more flexible, making it easier to perform a clinical study. This is a process that would require careful review, as most rules and regulations initially served the purpose of protecting the rights and wellbeing of study participants. Dr Lumsden added that harmonisation of rules and regulations across different regulatory spheres (locally as well as globally) would greatly aid the pharmaceutical companies in innovating their clinical trials. She pointed out that trial designs other than RCTs are already being applied in medicines development, but that companies prefer to “play it safe”: If there is uncertainty around the acceptability of study trial results by regulators to allow for market access, companies will not take that risk and go for a more traditional design. She also pointed out that, even though there is a lot to gain from innovative trial designs, operational challenges sometimes stand in the way of applying these.

Innovating clinical trials: Where are we at?

There are several developments that drive the unmet need of innovating clinical trials. If all stakeholders commit to finding the best fitting trial for each research question, there is a lot to gain for patients, the healthcare system and pharmaceutical companies. Willingness amongst the several stakeholders to explore this is not the limiting factor, but to take this process a step further, we need to collectively agree on a few key questions: How do we find the optimal trial for each research question? How do we determine which questions need to be addressed during development, in which order, and which questions will be left for health care? How do we harmonise the process of agreeing on optimal trial designs across all stakeholders? And maybe most importantly, how do we find balance between assessing the safety and efficacy, the effectiveness in real life, and time and resources spent on investigating this? Regulatory science can help to answer these questions.

During the break-out sessions, stakeholder views on the above topics were collected. On the one hand, from a company perspective the reduction of total development time, impact on the value proposition for a new medicine, and costs, are crucial considerations for the implementation of new evidence generation strategies. On the other hand, for public stakeholders, the reproducibility, predictability and transparency of study results were key determinants for the acceptability of innovative study designs.

To overcome certain thresholds for progress in this field, a dynamic drug development plan could help to address any uncertainties and issues once identified during the process. This may potentially take away unnecessary layers of complex regulations.  Also, the early involvement of patients and health technology assessors in the design of new trials can help to create awareness of potential barriers and feasibility issues. The participants agreed that there should be openness to a ‘case by case’ trial design, addressing the specific needs for testing a particular medicinal product. However, non-standard and complex new trial designs must be understandable to patients, regulators and ethics advisors, and therefore appropriate education of relevant parties is key. Furthermore, the cost-benefit balance for study sponsors needs to be acceptable – especially when performing costly real-world evidence studies (e.g., using remote monitoring with wearable devices). Ultimately, the consequence of working with real-life evidence is the acceptance of an increased diversity in study designs and populations. The use of these new types of data may go hand in hand with other innovations such as the use of artificial intelligence for regulatory decision making.

Sabine Straus (Chair of the Pharmacovigilance Risk Assessment Committee at EMA, CBG-MEB), closed the event with a dinner speech. She reflected on the current developments in the clinical trial and medicines development landscape, both its promises as well as its challenges. Her concluding words nicely summed up the outcome of this workshop: “It’s not always easy to balance the safety of patients versus the potential of innovations. But we need to keep aiming for better assessments, in all interventions, and at the same time find a way to guard the safety of patients in the best way possible. Always.

The RSNN will use the conclusions of this workshop to further explore this topic and to formulate new research questions. Outcomes will be published in relevant peer-reviewed journals.

Presentation Joop van Gerven

Presentation Rebecca Lumsden

Presentation Rolf Groenwold

Presentation Ton de Boer