By Giuliana Miglierini
Based on the review of results obtained in the first five years of implementation of the PRIority Medicines (PRIME) scheme, the European Medicines Agency has launched a set of new features to further enhance the support to developers of new medicinal products in areas of unmet medical needs (see the revised guidance for applicants seeking access to PRIME scheme).
The guideline complements contents of other documents, i.e. EMA’s Guidance on accelerated assessment, the guidance on the preparation of the PRIME kick-off meeting and submission readiness meeting, the one specific for applicants seeking scientific advice and protocol assistance, and the toolbox guidance for robust CMC data packages.
The new set of measures to speed up approval
The major goal of the PRIME scheme, introduced by EMA in 2016, is to accelerate the regulatory pathway for new medicines seeking approval and that may have a high impact on severe conditions currently lacking treatment options. The scheme aims to facilitate the generation of robust data packages supporting the compliance to regulatory requirements for all aspects of development and production of a new medicine.
A critical aspect to ensure efficiency of this process is the ability to build a constructive and continuous dialogue between regulators and sponsors, fundamental for the continuous monitoring of development activities. To this regard, EMA will establish a new roadmap for each PRI-ME development, that will parallel and complement the already existing product development tracker. The combination of the two should allow the optimisation of early scientific advice and regulatory support provided by EMA committees. It should also facilitate the prompt identification of critical aspects and emerging issues in the development, requiring further discussion between regulators and sponsors to positively solve them.
Should issues occur with a specific programme that has already received comprehensive initial advice, EMA is now entitled to provide expedited scientific advice specifically for PRIME developments. The new approach will be tested in a one-year pilot project started in March 2023. Requests of expedited scientific advice have to meet some criteria: the request is a follow-up advice, subsequent to the initial scientific advice procedure; it refers to issues with a specific, well-defined scope; and its urgency has to be justified, in comparison to standard scientific ad-vice timelines. The PRIME Scientific Coordinator is the first point of contact for sponsors to discuss these requests, which have to be submitted via IRIS, as well as all other issues referred to the PRIME scheme.
The pilot phase also includes the new roadmap and tracker to replace the previous PRIME annual update for any products that have not yet been discussed in a Kick-off meeting. Contents of both the roadmap and development tracker are detailed in the updated guidance.
Submission readiness meetings are the third new measure introduced by EMA. The meetings will serve as the final checking point to assess the status of development, with respect to the implementation of the regulatory advice previously provided by the Agency, and the resulting data package intended to support the MA application. Mature plans for post-marketing evidence generation should also be presented, as needed. Applicants are expected to start organise the submission readiness meeting approx. 15 months prior to the intended MAA submission date; the meetings should occur approx. 9-12 months prior the same date. Confirmation of eligibility to accelerated assessment should be checked 2-3 months before submission of the MA application.
Key features of PRIME scheme
At the end of 2022, the PRIME scheme supported the development and final recommendation for approval for 26 medicines. Sponsor can voluntarily file an application to access the scheme, providing evidence the eligibility criteria are met, in particular with reference to a potential major public health interest. These include conditions for which there is an unmet medical need in prevention, diagnosis or treatment, a new therapeutic method is introduced providing significant benefit over the existing ones or bringing a major therapeutic advantage to patients in a given indication.
The PRIME scheme articulates its support through different actions along the planned pathway. Depending on the type of medicinal product under development, the early appointment of a Rapporteur from the Committee for Medicinal Products for Human Use (CHMP) or the Committee for Advanced Therapies (CAT) allows for the discussion of all preparatory aspects of the ap-plication from both a technical and scientific perspective. Opinions may be also provided by other relevant EMA’s Committees and Working Parties, as needed.
Sponsors can also benefit from an initial Kick-off meeting with all the above-mentioned regulators and experts, to obtain preliminary guidance on the overall development plan. Key development steps subject to future scientific advice and the recommended regulatory strategy should be addressed during this meeting.
Special provisions are set forth to facilitate access to the PRIME scheme for SMEs and academic applicants. Upon demonstration of proof of principle, these may be granted Early Entry PRIME status, allowing for introductory meetings to raise awareness on regulatory requirements, and provide early advice on the overall development plan and relevant milestones. The requested proof of principle should be based on compelling non-clinical data in a relevant model providing early evidence of promising activity, and first-in-human studies indicating adequate exposure for the desired pharmacotherapeutic effects and tolerability.
Advice on the generation of proof of concept data is also provided at this stage by the EMA pro-duct team, and it must be fulfilled in order to confirm transition to full PRIME eligibility. In this instance, appointment of the CHMP/CAT Rapporteur is also activated.
The main steps of the procedure
Upon a first checking of acceptability of the application and related documentation, a Scientific Advice Working Party (SAWP) reviewer and a EMA scientific officer are appointed (plus a CAT reviewer in case of advanced-therapy products), and sponsors are informed of the start of the procedure and expected timelines. The SAWP committee should provide its comments to the reports by day 30, followed by final adoption by CHMP by day 40. A flowchart describing the criteria to determine eligibility is reported in Annex 1 of the guideline. The opinion of the CHMP is followed by the issuing of a letter detailing the reasons for the positive/negative decision. The outcomes of the CHMP meetings including discussions of PRIME developments are published as part of the highlights on the monthly adopted recommendations.
The confirmation of eligibility to the centralised procedure triggers the appointment of the CHMP Rapporteur, according to the specific procedure. A letter of intent to submit an MAA (approximately 6-7 months prior to submission of the MAA) is also requested.
In the case of SMEs accessing Early Entry PRIME, the appointment of the Rapporteur follows the generation of data confirming eligibility at proof of concept stage. SMEs or academic applicants also benefit from a full fee waiver for scientific advice or follow-up requests.
The Kick-off meeting is usually scheduled around 3-4 months after granting of the PRIME eligibility; submission of relevant background information and a detailed regulatory roadmap is requested to applicants in order to prepare the meeting.