TOPRA Human Medicines Symposium 2022
17th ‑ 19th October 2022 - Vienna, Austria.
by Dr Hannah Lewis, Senior Consultant at Scendea
The focus of the TOPRA annual symposium, hosted this year in Vienna, was Regulatory Science – leading the way to the future.
Accordingly, the sessions covered the relevance of innovative clinical trials, expedited procedures, digital health, real-world evidence and data (with emphasis on the DARWIN EU project), but also ventured into the arenas of Health Technology Assessment (HTA) and patient engagement, to consider the impact of these elements on current and future clinical development programmes. The key discussion points and implications for sponsors are summarised below.
The Use of Innovative Clinical Trials Under the Clinical Trials Regulation.
The Accelerating Clinical Trials in the EU (ACT EU) initiative has been developed by the European Medicines Agency (EMA), Heads of Medicines Agencies and the European Commission (EC) to foster innovation in clinical trials in Europe. ACT EU, launched in January 2022, has been designed to build on the newly implemented Clinical Trials Regulation (CTR) and Clinical Trials Information System (CTIS) to promote the conduct of large multinational trials in Europe. This will first focus on trials addressing unmet medical needs and rare diseases, and provide specific support for small and medium-sized enterprises (SMEs).
As part of this programme of work, the use of innovative clinical trial designs and methodologies has been evaluated by the respective working parties. In May 2022, the ACT EU Steering Group published a Q&A document on complex clinical trials (CCTs) under the EU CTR which explores the scientific and operational implications of such trials. As more applications are submitted through the CTIS, user feedback will be crucial to drive the effective implementation of the system to support CCTs. For example, the CTR allows for the submission of only one substantial modification at a time, which could be problematic when managing CCTs. Therefore, to avoid or pre-empt any limitations for the submission and/or amendments of CCTs (as these may require, amongst other elements, the inclusion of master and sub-protocols), user feedback should be considered for system improvements. Moreover, the aforementioned Q&A document is intended to be updated with evolving experience. This EU discussion on innovative trial designs echoes the FDA’s implementation of the Complex Innovative Trial Design Pilot Meeting Program which considers the use of complex adaptive, Bayesian and other novel clinical trial designs.
The Clinical Trials Coordination Group (CTCG; previously Clinical Trials Facilitation Group [CTFG]) will also support sponsors making submissions under the CTR via CTIS. The CTCG have the responsibility of issuing guidance on innovative clinical trial designs and decentralised clinical trials (DCTs) in Europe. On this topic, it is expected that guidance on the conduct of DCTs (designed to offer maximum flexibility and convenience to facilitate participation e.g., home health visits, study medicine home shipments and use of electronic consent) will be published by the end of 2022 (EU DCT Project).
Are Expedited Programmes Delivering on Their Promise?
Representatives from the Agencies (Food and Drug Administration [FDA], Medicines and Healthcare products Regulatory Agency [MHRA] and EMA) were able to share their reflections regarding their respective expedited programmes and the ability of said programmes to accelerate drug development and patient access. Whilst the FDA’s Priority Review and Breakthrough Therapy Designation were considered to confer a tangible benefit, the US Accelerated Approval pathway is not considered to be fully delivering on its promise, as it enables products to remain on the market despite the failure of the post-approval trial. There are considerable challenges with the programme, including completion of the post-approval trial within predefined timeframes, inclusion of placebo‑controlled arms and the terminology associated with accelerated endpoints. A review of the programme is planned for late 2022; follow-up on the completion of agreed post-approval trials was considered the main point to be addressed in the immediate term.
From the EMA perspective, positive data from the PRIority Medicines (PRIME) 5-year analysis was highlighted. Eighteen of the 21 PRIME products were granted marketing authorisation, and PRIME products incurred significant reductions in clock-stops and overall assessment periods compared with non-PRIME products. However, EMA conceded that improvements could be made to ensure continuity of scientific advice from Rapporteurs and (as mentioned below) to improve the interaction with HTAs during the development process to avoid post-approval delays.
It was emphasised that the expedited programmes need to consider not only marketing authorisation, but also delivery, reimbursement and access to patients. Although the MHRA Innovative Licensing and Access Pathway (ILAP) is considered too premature to provide meaningful metrics at this time, it has been designed to reflect this critical need. One of the aims of the pathway is to align the marketing authorisation application (MAA) and HTA review dates and ensure that discussions are ongoing throughout development, given that the data requirements are not the same for both assessments.
Integration of Health Technology Assessments.
Health Technology Assessments contextualise the use of a product within a healthcare system considering the currently available products. The assessment is distinct from the evaluation for MAA and cannot always rely upon the same evidence. Research from the Centre for Innovation in Regulatory Science (CIRS) showed that parallel submission of HTA and MAA improved speed to market after approval while delays occurred in EU countries where a sequential process was undertaken. However, even when sponsors take advantage of expedited procedures for regulatory approval, they don’t necessarily deliver the product earlier to patients because sponsors are not always prepared for HTA submissions (particularly SMEs). This was a key (and recurring) theme for discussion throughout the symposium.
The implementation of the EU HTA Regulation (HTAR) (Regulation (EU) 2021/2282) in January 2022, for applications submitted from January 2025 onwards, is expected to improve this. The framework covers joint clinical assessments and scientific consultations, the identification of emerging health technologies and voluntary co‑operation aimed at supporting evidence-based decision-making. This framework will be available across the EU-27 states; however, appraisals will remain at the member state level (whilst the clinical assessments are joint, individual member states can have a sub‑analysis/economic analysis specific to their country). The intention is to begin with oncology products, before moving onto advanced therapy medicinal products (ATMPs), Orphan drugs and then full product scope.
Joint scientific consultations (with EMA and HTA bodies) will be available upon request, but unlike the previous open call under the European Network for Health Technology Assessment (EUnetHTA), priority criteria will be applied to eligible requests when the number exceeds the number of consultations: unmet medical needs; first in class; potential impact on patients, public health, or healthcare systems; significant cross-border dimension; major Union-wide added value or Union clinical research priorities. The utility of such joint consultations during development is discussed by Jansen et al and emphasises the value of pre-approval joint advice procedures for all stakeholders.
Planning for Patient (or Patient Representative) Involvement in a Development Plan.
Patient engagement is increasingly recognised as a critical element of a product’s development plan, particularly in designing clinical trials for the intended patient population. The patient voice can be presented in multiple forms, as individual patients, patient representatives, advocates and experts, who can each deliver nuanced and meaningful input. Patients are often not involved until post‑marketing or HTA stage; whereas it is recommended that their input should be implemented into the programme early and should continue throughout the product’s lifecycle. Patients and caregivers can convey the day-to-day challenges and the benefits (or lack thereof) of the current standard of care. When developing the clinical development plan, patient and regulator inputs can inform the trial design to ensure it is fit for purpose and not overburdensome. Aspects to consider include relevance of endpoints (e.g., quality of life versus progression free survival and the meaningfulness of exploratory endpoints to patients); patient reported outcomes (appropriateness of number of questionnaires requested for completion), the schedule of events (appropriateness to the population, necessity to perform all proposed visits); comparators (appropriateness or meaning to patients) and finally the true unmet medical need(s) (for example, the symptom being targeted may not always be one that patients feel the need to address). Moreover, a protocol that is patient‑focussed can improve recruitment and compliance, particularly if the need for compliance is well-communicated to the patient.
Patient engagement can begin as early as the preclinical phase and should start as early as possible for conditions where there may not be an appropriate patient or patient representative. In this case, sponsors may need to provide training to ensure this resource is available. Organisations to support these interactions include EUPATIConnect (connecting patients with researchers) and EURORDIS Open Academy (for training patient advocates).
Patient engagement is already implemented at the EMA level both during scientific advice (see EMA case study) and Pharmacovigilance Risk Assessment Committee (PRAC) meetings. Interestingly, EMA are also piloting patient engagement during MAAs; input is requested from Day 1 of the MAA process and is provided to both Rapporteurs and the sponsor to support the assessment of the dossier.
To summarise, the sessions held provided valuable insight into current and relevant regulatory topics impacting developers of medicinal products. Key emphasis was placed on the roles of patients and HTAs to ensure that clinical trial designs are fit for purpose and able to support earlier patient access. Additional discussions focussed on the steps being taken by regulators to adopt innovative aspects of drug development, including CCTs, and although not discussed in this summary, strategies for the use of digital health and the relevance of real-world evidence for regulatory decision-making.
Do you need support with you product development and regulatory activities,
get in touch to speak to a member of our team