TOPRA Human Medicines Symposium 2023
23rd - 25th October 2023 - Lisbon, Portugal
Authored by: Dr Bethany Aykroyd, Consultant
Introduction
Held annually since 2004, the TOPRA Symposium is Europe’s premier conference for healthcare regulatory affairs. This year’s Symposium took place in Lisbon, Portugal, and was held in partnership with Infarmed, Portugal’s national regulatory authority for medicines and health products. Over the course of the three-day Symposium, the latest insights and developments in human medicines regulation were discussed with the overall theme of ‘advancing global healthcare together’. The key discussion points and implications for developers are summarised below…
Update on the new EU medicine legislation and reactions from different stakeholders
In 2020, the European Commission published a Pharmaceutical Strategy for Europe as a patient-centred strategy aiming to boost global competitiveness whilst ensuring the safety and quality of medicines. Building from this, the European Pharmaceutical Legislation framework is being reshaped to adapt to technological advances and address recent challenges, including lessons learned from the Covid-19 pandemic. The European Commission’s proposal focusses on six objectives:
1. Access to medicines
2. Availability – shortages and security of supply of critical medicines
3. Affordability
4. Regulatory simplification and future-proofing
5. Environmental sustainability
6. Combatting antimicrobial resistance
One of the proposed solutions to improve access to medicines in the EU is to modify the incentives for innovative medicines. This would adapt the current ‘one-size-fits-all’ approach for unconditional data protection and marketing exclusivity (for orphan drugs) to a more targeted approach. The level of data protection and marketing exclusivity would be dependent on meeting criteria such as market launch in all EU member states, addressing an unmet medical need or performing comparative clinical trials. If all of the criteria are met, this would increase the maximum level of data protection to 12 years, instead of 11 years today, and increase marketing protection for orphan medicines to a maximum of 13 years, compared to 10 years today. However, the baseline data/marketing protection level would be reduced. As such, this proposal attracted lots of negative comments. In particular, an industry representative stated that it would be unrealistic to achieve all of the modular components to be awarded the maximum protection. Whilst this concern is understandable, the modular elements to gain the maximum levels of protection relate to areas of major interest to patients, including improved access, which is one of the main reasons for proposing such changes.
Proposals to produce a more competitive and innovation-friendly framework with simplified procedures have been more warmly received. These include a reduction in marketing authorisation assessment and approval time by around 50 days, the possibility for the EMA to review data in phases as they become available (rolling or phased review) and simplifying regulatory requirements for authorising generic and biosimilar medicines. Proposed pre-authorisation support and future-proofing measures include improved clarity on the interplay between EU legislative frameworks (e.g. medical devices) and facilitating the use of health data, including real-world evidence, for regulatory purposes.
Real World Evidence (RWE) and the use of big data for regulatory decision making
According to the EMA’s Regulatory Network strategy to 2025, by 2025 the use of RWE will be an established reality supported by a wide spectrum of regulatory use cases. As part of delivering the 2025 RWE vision, the Data Analysis and Real World Interrogation Network (DARWIN EU®) was launched in February 2022. DARWIN EU® is a network of data, expertise and services that aim to support better decision-making throughout product lifecycle by generating reliable evidence from real world healthcare data. The current focus of DARWIN EU® is on its scale up of Data Partners, studies, pilot use cases and developing standard analytical pipelines. From the EMA’s perspective, the Agency is working on a case-by-case basis to ascertain when RWE can be used to inform regulatory decision making.
In terms of the US, a draft framework issued by the FDA in December 2018 describes sources of RWE, challenges and potential opportunities. The FDA defines RWE as clinical evidence generated through various study designs (e.g. randomised trials, externally controlled trials and observational studies) regarding the usage and potential benefits/risks of a medical product derived from the analysis of real world data (RWD; routinely collected data relating to patient health status and/or delivery of health care). The key considerations from the framework are whether the RWD is fit-for use, whether the study design used to generate RWE can provide adequate scientific evidence to answer the posed question and whether the study conduct meets the FDA regulatory requirements. Delegates were informed that the FDA is working on issuing guidance and supporting demonstration projects to help sponsors and other stakeholders better understand how RWE can be used to support regulatory decision making. Areas where RWE could be used include supporting changes to labelling about drug product effectiveness, adding or modifying an indication via a change in dose, dose regimen, or route of administration; or adding comparative effectiveness or safety information. It was strongly recommended that sponsors actively engage with the FDA prior to conducting a study utilising RWE.
US & EU paediatric alignment and updates on the EMA’s Stepwise PIP pilot
The Symposium theme of ‘advancing global healthcare together’ was emphasised during discussions on paediatric development. It was stressed that collaboration between the EMA and FDA is key to achieving a global aligned review and optimal outcome for paediatric plans. There was a push for sponsors to initiate an EMA-FDA parallel scientific advice procedure before drafting and submitting the Paediatric Investigation Plan (PIP) and initial Pediatric Study Plan (iPSP). However, aligning with Scendea’s own experience, despite the fact that the advice is in parallel, delegates highlighted that these meetings do not always lead to harmonised advice. The EMA and FDA responded that they are committed to improving alignment and have already produced joint procedural information for submitting a PIP and an iPSP for COVID-19 vaccine treatment and joint guidance on cancer medicines for use in children. Additionally, the EMA, FDA and three other regulatory agencies hold monthly teleconferences as a group known as the ‘Paediatric Cluster’ to discuss product-specific paediatric development and topics related to product classes under the terms of Confidentiality Agreement. The objectives of these exchanges are to enhance the science of paediatric trials and avoid exposing children to unnecessary trials. We were informed that items chosen for discussion at Paediatric Cluster meetings are often those that resulted in discrepancies between PIPs and PSPs. Supporting the value of these meetings, between 2014 and 2017, convergence was achieved for 73% of the issues discussed.
Additionally, the Symposium discussions also provided an update on the EMA’s Stepwise PIP pilot. The EMA is currently running a pilot to test a 'stepwise PIP' agreement which would introduce a partial development programme supporting the authorisation of innovative medicines for children. A stepwise PIP would apply to cases where there is a lack of crucial information needed to decide on certain parts of the PIP, such as whether a clinical study for a whole age group is necessary or which endpoint is suited for an indication without established regulatory precedent. This programme would be conditional on the development of a full PIP via the standard modification process once sufficient evidence becomes available. The EMA launched this pilot in February 2023 and it is due for review upon the adoption of eight initial opinions on stepwise PIPs. Sor far, the EMA has received fourteen requests across a range of therapeutic areas including oncology, metabolic disorders, cardiology and neurology and it is thought that the pilot will continue for the majority of next year until the eight opinions have been agreed. These cases will then be analysed to help shape the process for the future.
As a final note, Chrissi Pallidis from the EMA highlighted that paediatric development is still being driven by adult development. As a result, there still is not sufficient development in diseases affecting mainly the paediatric population, including neonatology. Improvements in the development and availability of medicines for children needs to be continuously expanded.
Patient engagement in the regulatory lifecycle of medicines
Interaction with patients has evolved constantly over the past years and there are now multiple discussion platforms in place. For instance, the EMA’s Patients' and Consumers' Working Party provide a platform for the exchange of information, the FDA holds Patient Listening Sessions and patient focus drug development meetings to allow a better understanding of a patient’s lived experience and the Patient Engagement Cluster allows the FDA, EMA and Health Canada to share best practices involving patients along drug and biologic regulatory lifecycles.
Industry representatives also shared their own experiences and examples where they have found patient voices to be the most valuable in their development programmes.
Support with overall clinical development:
Understand treatment journey and unmet medical needs
Identify education gaps
Input on meaningful endpoints and patient-reported outcomes
Phase I-III:
Obtain feedback on trial design and study feasibility
Understand possible challenges with product use (administration and adherence)
Ensure communication materials are clear
Understand acceptable risks and the required benefit
Post Approval:
Capture real-world data regarding effectiveness and safety
Access perceptions of standards of care
Identify patient access issues
The acceptability of patient-reported outcomes as a primary endpoint was posed to both the EMA and FDA. At present, the EMA does not have any precedent for this, meaning this would very much depend upon the case made and the indication involved, and would perhaps be a co-primary outcome. However, the EMA has previously asked sponsors to include patient-reported outcomes as secondary endpoints. Conversely, the FDA appear to have accepted patient-reported outcomes as a primary endpoint for heart failure. It was stressed that this would not have been the case five years ago, suggesting that both agencies may become more receptive in the future.
The EMA urges transition of existing clinical trials to CTIS portal
The Clinical Trials Regulation (EU) No 536/2014 repealed the Clinical Trials Directive 2001/20/EC on 31 January 2022. Clinical trials authorised under the Clinical Trials Directive are to be transitioned to CTIS by the end of the 3-year transition period (30 January 2025). On the date of the Symposium presentation, only around 300 transitional trials had been placed in the portal which means that most trials (around 5000) still need to be transitioned. It is expected that the majority of these remaining trials will be transferred between now and April 2024. Whilst the EMA is aware and planning around this, it was admitted that there may be potential issues if workload is not evenly distributed. The recommendation is to transition any remaining trials as soon as able to.
Awards and honours
During the Annual Review Meeting element of the Symposium, TOPRA recognised valued contributions to the regulatory affairs profession. Scendea’s Head of Product Development & Regulatory Consulting, Principal Consultant, Zeb Younes, was an integral member of the team awarded the ‘TopTeam Award’, for her contributions to MSc Module 9 Course Working Party, where she delivered sessions on viral safety and comparability.
Additionally, since 2010, annual international TOPRA Awards for Regulatory Excellence have recognised the inspirational work taking place across the regulatory affairs profession. Scendea’s Senior Consultant, Harriet Thomasson-Coombs, has been announced as a finalist in this year’s Horizon category which recognises outstanding ability in individuals with fewer than five years’ experience in the regulatory affairs profession. The winners will be revealed at TOPRA’s awards ceremony on 29 November 2023 at Merchant Taylors' Hall in London.
Conclusion
Collaboration between the EMA and FDA was a key topic of this year’s Symposium with both agencies expressing a shared ambition to realise the potential value of RWE through collaboration. The FDA strongly recommended that sponsors actively engage with the FDA prior to conducting a study utilising RWE. The theme of collaboration continued during paediatric discussions, and although there are still concerns from sponsors that EMA-FDA parallel scientific advice can result in divergent advice, the EMA and FDA are committed to improving alignment, partly via producing joint paediatric procedural information and through the ‘Paediatric Cluster’ monthly meetings. Additionally, patient engagement throughout the regulatory lifecycle of medicines is being encouraged, including during the licensing application review process, with patient reported outcomes having already been accepted by the FDA as a primary endpoint in heart failure. Furthermore, an important note for sponsors is that the EMA urges the transition of any outstanding existing clinical trials to the CTIS portal to avoid any potential demand related issues. Finally, whilst controversial, the European Commission’s proposals to reform the EU pharmaceutical legislation aims to address fundamental challenges with medicines authorised in the EU such as delayed patient access and unmet medical needs. The debate concerning the practical application of these proposals, however, will likely take some time to conclude.
The next TOPRA Symposium will be held in Rotterdam, the Netherlands, from 30 September to 2 October 2024.
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