HM6: Innovation in regulatory science – The path from data to evidence and the promise to streamline the regulatory lifecycle

Key points:

• There is a global evolution in drug development and RWE policy, increasing contribution of RWD/RWE to clinical evidence generation.
• This evolution has been particularly accelerated by COVID-19 pandemic.
• Collaboration and dialogue are essential to establish what is needed for multi-stakeholder confidence in RWE and alignment around fitness for purpose of evidence in a given decision-making context.

One month following the release of the FDA’s latest guidance on ubmitting documents using RWE, Fortunato Fred Senatore shared the FDA’s perspective on use and challenges of RWD and RWE. RWD from various sources (registries, patient records, patient experience, etc) can be utilised for regulatory decision-making, and analysis of RWD leads to the generation of RWE which, if relevant and reliable, can be used to apply for approval. He presented several examples of clinical developments using RWD to generate RWE such as Blincyto, supporting the conclusion that the FDA acceptance of RWE in support of a regulatory decision has been limited, and mainly in oncology and rare diseases settings.

Challenges for use of RWD/ RWE include meeting the statutory requirements for substantial evidence of efficacy. RCT remain the gold standard; recent efforts have been made to derive algorithms to use RWD from observational studies to match results with RCT. This has provided mixed results: some showed concordance between RCTs and observational studies but others, divergence. As part of its RWE program, the FDA will evaluate how observational studies could contribute evidence to drug effectiveness. Efforts to replicate the results of RCTs using more rigorously designed observational studies may provide insight into the opportunities and limitations of using these designs in regulatory decisions.

Almath Spooner next presented industry’s perspective on the RWE regulatory landscape. Clinical evidence generation focuses on leveraging all available data – recognising decision-making should be informed by the totality of evidence. The COVID-19 pandemic accelerated the development of effective strategies to address questions using the right tools. Regulatory recognition of RWE value is facilitated by enabling legislation and policy development globally.

Spooner highlighted that in the interest of further harmonisation, the ICMRA can play an important role by catalysing increased cooperation on RWE use for regulatory decision-making. In a co-chaired ICMRA workshop, the EMA, the FDA, and Health Canada shared experiences on accomplishments and challenges of RWE in medicines regulation and opportunities for future regulatory collaboration. Connectivity with other legislations, such as the General Data Protection Regulation, should be considered.

Despite efforts made over the last decade, major gaps between the US and Europe versus the rest of the world in terms of patient access to innovative medicines are still visible

Spooner shared experience on working with the EMA on DARWIN EU®. This federated network of data, expertise and services supports better decision-making throughout the product lifecycle by generating reliable evidence from RWD. It automatically expands the EMA’s capabilities to analyse data and will be fully operational by 2024. Industry had the opportunity to provide perspectives at the DARWIN EU Advisory Board and emphasised the importance of predictability and transparency on how DARWIN EU is used to generate RWE, and engagement on data sources, study design, methodologies and analytical approaches.

Despite efforts made over the last decade, major gaps between the US and Europe versus the rest of the world in terms of patient access to innovative medicines are still visible. According to Dominique Lagrave, the ways in which submission are processed and marketing applications are reviewed should evolve.

As an alternative to the current eCTD structure for example, Lagrave presented the work of Accumulus Synergy – a global, non-profit organisation founded in 2020 aiming to dramatically accelerate access to critical therapies. He explained that to enable collaboration, efficiency and deeper insight generation between industry and global HAs, Accumulus Synergy is working to develop a secure, private, collaborative, and transformative data exchange platform that can be used by both industry and HA. This way of working would benefit HAs who could learn from each other and support reliance, and industry who could receive consolidated agency feedback and leverage lifecycle management and information access. The question of security compliance that meets all government requirements and data privacy was also discussed.

…the ways in which submission are processed and marketing applications are reviewed should evolve

In opening the panel discussion, Christian Gartner mentioned that RWD are composite data containing different perspectives of time and regions and can be used at pre-filing, filing or post-approval stages. Senatore highlighted that RWD could allow generating hypotheses to be tested and help identify the difference between observations in clinical trials and the real-world setting: eg, to justify the hypothesis of intermediate endpoint for accelerated approval.

Karl Hamilton mentioned that achieving standards and high-quality remain a challenge of RWD use. At the EU level, the EMA is looking at the reuse of data for real product lifecycle, data management from old submissions and their inclusion in decision-making processes. Hamilton also specified that, at the EU level, there is now a need to simplify data management processes, while keeping them working. Spooner pointed out that the clear initial focus of RWD use is to inform regulatory decision-making. This is likely to be extended to the health technology assessment.