INTRODUCTION

Accelerated assessment procedures in the European Union (EU) have been initiated to foster the development of medicines for which there is a clear unmet medical need. The PRIority Medicines (PRIME) and Accelerated Assessment programmes were developed with the intention of enabling earlier patient access to critical medicines in therapeutic areas of major interest to public health. The criteria to be met for designation are discussed in the below section. Regulation (EC) No 726/2004 (Article 14(9)) provides the legislation for the Accelerated Assessment procedure, whilst the PRIME scheme aims to maximise the potential of the existing regulatory framework and procedures.

The PRIME initiative was established as a means to aid Sponsors through the regulatory landscape during the development of such medicines, by initiating an early and continued dialogue with the European Medicines Agency (EMA), to support the generation of a robust application for EU marketing authorisation. Conversely, Accelerated Assessment is applicable during the latter stages of product development, leading to marketing authorisation application (MAA).

UNMET MEDICAL NEED OF MAJOR
PUBLIC HEALTH INTEREST

The eligibility criteria for both PRIME and Accelerated Assessment are identical. Applicants should justify that the medicinal product is of major interest to public health, particularly in the context of therapeutic innovation, and should justify their expectation that the product will, to a significant extent, fulfil an unmet medical need. 

Unmet medical needs are conditions for which there exists no satisfactory method of diagnosis, prevention or treatment in the European Community. Alternatively, if such a method exists, the medicinal product concerned must offer a major therapeutic advantage to affected patients. Where possible, the justification for unmet medical need should be supported by substantiated epidemiological data including life expectancy, symptoms and duration, and health-related quality of life. The Applicant should provide a comprehensive overview of the available treatment options/standard of care (SoC), including medicinal products used in clinical practice (approved or off label use), devices, surgery and radiotherapy.

Additionally the Applicant is expected to justify how the unmet medical need is not fulfilled by any current diagnostic, prophylactic or therapeutic approaches. 

EMA recognise that there is no single definition of what constitutes major public health interest; each individual situation should be justified by the Applicant and will be assessed by the CHMP on a case by case basis. Arguments should support the claim that the product addresses, to a significant extent, the unmet medical need for maintaining and improving the health of the Community. Examples include introduction of new methods of therapy or improvement to existing ones, however new mechanisms of action or technical innovations may not necessarily represent a valid argument.

PRIORITY MEDICINES (PRIME)

The PRIME initiative was introduced in 2016 to support the development of medicines to target unmet medical needs. The intention of PRIME is to instigate an early dialogue between Sponsors and the EMA and to provide scientific advice at critical stages of development, with the objective of improving clinical design and generating robust scientific data. PRIME designation also provides the opportunity for the Agency to identify products fulfilling the criteria for accelerated review early in development, rather than at the stage of MAA filing.

As of June 2020, 68 products had been granted PRIME designation (22% of PRIME applications received a positive outcome), approximately 50% of which are being developed by small to medium sizes enterprises (SMEs). The therapeutic area with the highest number of applications is oncology
(85 applications, 18 successful (21.2%)); however, the area which has shown the most success in achieving PRIME designation is haematology/haemostaseology. In a two-year review of the PRIME scheme, the majority of requests received at proof of concept stage were for products in Phase 21. 

The scheme has received high numbers of requests for advanced therapy medicinal products (ATMPs), and of the 46 products holding PRIME designation as of June 2020, just under 50% of these were ATMPs, despite representing only 25% of designation requests.

Given the complex developmental nature of such products, it is not altogether surprising that Sponsors of ATMPs are seeking heightened levels of support and advice from the Agency.

Eligibility to PRIME

To achieve PRIME designation, medical products must target conditions of an unmet medical need of major public health interest, particularly from the viewpoint of therapeutic innovation. Critically, Sponsors must provide evidence to support the claim that the product has the ‘potential to address to a significant extent the unmet medical need’ and to bring a major therapeutic advantage to patients in a given indication. This can be demonstrated through a clinically meaningful improvement in efficacy, such as an impact on the prevention, onset and duration of the condition, or improving the morbidity or mortality of the disease. The magnitude of the treatment effect, and relevance of the observed clinical outcome (for example, an endpoint that predicts an effect on associated morbidity, mortality or progression of the underlying disease) will be considered. The Sponsor should include a description of the medicinal product’s observed and predicted effects, their clinical relevance, the added value of the medicinal product over and above any authorised treatments or established methods, should they exist, and the potential impact on medical practice within the therapeutic space.

Key Benefits for Sponsors

The following benefits are provided to recipients of PRIME designation.

Early development (SMEs and Academic Sector):

• Scientific and regulatory advice on the overall development plan and at major development milestones, with the option to involve multiple stakeholders (e.g. Health Technology Assessment (HTA) bodies and patients).

• Exemption from the payment of fees for scientific advice and follow-up requests. 

• Advice on data to be generated to support proof of concept. 

Clinical Development:

• Appointment of a Rapporteur from the Committee for Medicinal Products for Human Use (CHMP) or the Committee for Advanced Therapies (CAT) based on relevant expertise of the therapeutic area or product type. The assignment of a Rapporteur promises ongoing familiarity with the product, continuity in a life-cycle approach and provision of support throughout development. The Rapporteur will also ensure that critical aspects of the development programme are discussed at CHMP through Scientific Advice or Protocol Assistance at appropriate stages in development.

• Kick-off meeting with multidisciplinary participation from the EU network (SAWP, CAT, COMP, PDCO, PRAC and experts, as relevant), including the CHMP Rapporteur, to discuss the proposed development programme. This meeting provides the optimal setting for Sponsors to garner the Agency’s input on the overall development plan and regulatory strategy and receive preliminary guidance on requirements for MAA. A proposed schedule for regulatory and scientific advice and for submissions of applications to fulfil legislative requirements (e.g. paediatric investigation plan) may also be discussed. 

• Scientific advice on key decision points/issues at critical development milestones, leading to the preparation of MAA, with the option to involve multiple stakeholders (e.g. HTA bodies and patients), when relevant. Scientific advice regarding the risk management plan and post-authorisation activities may also be discussed.

• Appointment of a dedicated contact point at EMA.

• Confirmation of potential for accelerated assessment, to be formally confirmed 2 - 3 months prior to MAA submission.

Timing and Level of Data Required for Application

In most cases it is anticipated that entry to the PRIME scheme will be supported by data from exploratory clinical studies, demonstrating a significant clinical response in patients (proof of concept). Products should not be authorised in the European Union and should be intended for MAA via the Centralised Procedure.

As SME applicants, or those from academic backgrounds, frequently have less experience and insight into the regulatory framework, it is understood that such Sponsors would benefit from earlier scientific and regulatory advice. Therefore, in exceptional cases, applications will be considered during early development for SMEs and academic applicants. Often, the term ‘early development’ is interpreted as products in the pre-clinical stage; although PRIME applications for such products are predominantly supported by a convincing scientific rationale and compelling non-clinical efficacy data (proof of principle), tolerability data from initial clinical trials is required.

Assessment Procedure

Applicants should submit a request for PRIME electronically to EMA, in accordance with the EMA published timetable for assessment. Submission deadlines occur monthly.

Given the extensive regulatory incentives offered, the bar for PRIME designation is exceptionally high. Sponsors should present a consolidated overview of their product (no more than 30 pages), including the available nonclinical and clinical data, with a view to demonstrating that the product addresses the criteria for designation.

PRIME eligibility requests are reviewed through the Scientific Advice Working Party (SAWP) and recommendations are forwarded to the CHMP for final adoption. In the case of ATMPs, CAT will additionally review the request and provide their recommendation to CHMP. Applicants will receive the outcome following the monthly CHMP plenary meeting, at Day 40 of the procedure. 

Although an appeals process is not available, Applicants may submit a new request should new evidence or data be considered to support eligibility. In such situations, a different SAWP reviewer will be appointed to assess the subsequent request.

It should be noted that for products entering the scheme in early development, justification of progress to proof of concept will be required. The same assessment procedure will apply and where possible, the request will be reviewed by the SAWP reviewer appointed at the time of the initial request.

ACCELERATED ASSESSMENT

Accelerated Assessment is an attractive regulatory incentive which permits a reduction in MAA assessment timeline from 210 to 150 days for medicinal products assessed via the Centralised Procedure.

Agency experience with the Accelerated Assessment process in 2017 reported an increase in the volume of requests for Accelerated Assessment over the years 2012 to 2017, with a parallel increase in acceptance rate by the Committees3.  Between the period of January 2015 to June 2017, the highest number of requests were for oncology products, followed by infectious diseases. In 2016, 67% (4 of 6) requests received Accelerated Assessment designation.

Between September 2016 and June 2017, nine applications were submitted for MAA under Accelerated Assessment, five of which were recommended for approval4.  Three of the applications were still ongoing at time of the published data cut, whilst one had switched to the standard timeline for assessment. 

Eligibility for Accelerated Assessment

As described for the PRIME scheme, Applicants requesting Accelerated Assessment must justify their expectation that the medicinal product is of major interest to public health, particularly from the perspective of therapeutic innovation. The request should outline the expected major benefits and demonstrate that the product introduces new methods, or improves on existing methods of therapy, thereby addressing an unmet need. In the context of the request, the unmet medical need could be described separately for different indications or subpopulations.

The safety and efficacy data to support the notion that the medicinal product is expected to fulfil an unmet medical need should be supplemented by an overview of the significance of the effect, the added value of the medicinal product and the potential impact on medical practice.

The strength of evidence to support justifying major interest from the perspective of public health will be dependent on the nature of the product, indication and application type.

Timing of Application

Applicants are recommended to discuss their proposal for Accelerated Assessment during the MAA pre-submission meeting, typically held six to seven months ahead of the scheduled submission date. The meeting will provide the opportunity for the Applicant to receive feedback from CHMP Rapporteurs and any other concerned parties. 

The formal request for Accelerated Assessment should be submitted at least two to three months prior to the intended submission date for MAA. 

To prevent delays as a result of GMP and GCP inspections, Applicants are requested to provide information concerning GMP and GCP compliance at the time of request for Accelerated Assessment, in order that inspections can be integrated into the assessment procedure. 

Assessment Procedure

Applications are submitted electronically to EMA, including a justification and summary of the available data in a 5 – 10 page document. Details of the manufacturers and pivotal clinical studies should be appended to the request.

The timetable for request evaluation will be set by the EMA Project Manager assigned to the MAA, and will be dependent on the proposed submission date. 

The request will be reviewed by the Rapporteurs appointed to the product, who make a recommendation to CHMP. CHMP will then consider this recommendation alongside the Sponsor’s request and justification to arrive at a final conclusion. It should be noted that the granting of Accelerated Assessment does not necessarily lead to a positive opinion for MAA.

Figure 1 illustrates the timeline for Accelerated Assessment (including presubmission activities).

Deferral to Standard Timeline for Assessment

At the request of either CHMP, or the Applicant, the assessment may be deferred to the standard Centralised Procedure assessment timeline. This may arise should CHMP consider that it is no longer appropriate to conduct an accelerated assessment, in situations such as:

1. Identification of major objections that cannot be resolved under an accelerated timetable.

2. If a longer clock-stop is requested by the Applicant.

3. When the need for GMP or GCP inspection(s) becomes apparent during the assessment.

4. If an oral explanation results in a negative outcome or trend.

Applicants also have the option to submit a request for a deferral to a standard assessment procedure, if the request can be justified (i.e. if the Applicant requires additional time to provide information requested by the CHMP). Such requests are reviewed on a case by case basis.

CONCLUSIONS

The PRIME and Accelerated Assessment programmes have a primary focus on the development of products for unmet medical needs of major public health interest within the European Community and offer attractive regulatory incentives for Sponsors developing such products. 

Given the highly competitive landscape, the strength of evidence required to support a successful application is exceptionally high and a well-positioned application is critical. It is imperative that Sponsors consider the relevance of their product in the context of current EU medical practice in the given indication and should establish this unmet medical need as the foundation on which to construct their respective applications.