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Early access to medicines: EMA’s regulatory tools and support pathways

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Lini Subin, director — regulatory affairs, ELC Group, highlights EMA’s regulatory tools and support pathways that are available during development.

Lini Subin, director — regulatory affairs, ELC Group

In recent years, the pharmaceutical world has been witnessing huge demand to serve unmet health needs and deliver early access to medications. Many companies are focusing on R&D innovation to meet these needs, however, the regulatory pathway for early access to medicines is always a challenge globally.

With significant developments in regulatory tools, and in approaches towards regulatory routes and access of medicines, the EMA plays a central role in the global development of medicines. The EMA approval system is based chiefly on benefit-risk assessment. Early access to medicines and assessment are particularly challenging because of the limited clinical evidence available.

Within the EMA there are different regulatory tools and support available for the earlier access of medicines for unmet medical needs, or where there is a major public health interest. The main regulatory tools and pathways include accelerated assessment procedure, conditional marketing authorisation, compassionate use, PRIME scheme and adaptive medicines pathway.

Accelerated assessment procedure

This regulatory tool reduces the overall timeframe for the assessment of a marketing authorisation of a centralised procedure (CP) from 210 days to 150 days (excluding the clock stops for products with major interest for public health and therapeutic innovation). Marketing authorisation holders have to submit the request for accelerated assessment to the Committee for Medicinal Products for Human Use (CHMP) two to three months before the planned submission of the application, justifying the major public health interest of the product.

Though the overall timeframe would be reduced, standard requirements for the marketing authorisation application are still applicable. A pre-submission meeting could be requested six to seven months in advance of the submission date. Early confirmation of the possibility of accelerated assessment is now feasible during the clinical development phase, since the EMA’s launch of the PRIME scheme in 2016.

Conditional marketing authorisation (CMA)

The EMA grants the conditional marketing authorisation in the interest of public health, providing early EU access to medicines based on some conditions before completed data are available. It is granted for medicines which fulfil unmet medical needs and where the benefit of immediate availability for patients is greater than the risk of less comprehensive data than is normally required. Pending data is generated based on the agreed timeframe post-authorisation.

A product is eligible for CMA if it belongs to one of the following categories:

CMAs are granted for a one year period and can be renewed annually.

Stricter post-authorisation monitoring and fulfilment of obligations from the side of the applicant are applicable. Upon availability of the data, the authorisation converts to a standard MA with a validity of five years.

In the absence of comprehensive data, under exceptional circumstances the agency may grant an MA if the applicant cannot obtain comprehensive data in the agreed timeline.

Similarly to standard marketing authorisation applications, applicants can seek early stage advice and assistance in the clinical development stage. The intention to acquire conditional marketing approval could be discussed in the early stage advice meeting. However, the request for the application is submitted along with marketing authorisation application. Under the conditional marketing authorisation route, it is also possible to obtain the privileges of the accelerated assessment scheme under the provision of applicable legislation.

On 23 January 2017, the EMA published a 10-year evaluation report based on data collected from 2006 – the start of CMAs – to 2016, and the EMA’s experience gained during the period on the success rate of conditional marketing authorisation applications. According to this report, the EMA recognises conditional marketing authorisations as an important tool for ensuring timely access to medicines in the areas of unmet medical need, and provides an in-depth analysis of the positive impact of this regulatory approach.

Based on the statistical results for which the obligations were fulfilled by companies, it was shown that the regulatory approval granted by CMA was, on average, four years earlier than standard marketing authorisation procedures. In the last decade, the EMA granted 30 CMAs, of which 24 are targeting debilitating or life-threatening conditions, 14 are rare medicines and three address the medicines for emergency situations. Seventeen of these medicines were oncology medicines. With respect to fulfilment of obligations and success rate, the report shows that 90% of the holders fulfilled the obligation without changing the scope and 70% did not request for extension.

Engaging in early stage dialogues with different stake holders [the EMA and other key parties such as health technology assessment (HTA) bodies] plus careful planning is required to deliver early stage approvals and access to medicines for patients.

Compassionate use

This regulatory tool allows access to an unauthorised medicine, which is under development or entered into a marketing authorisation process. Patient groups with life-threatening, long-lasting or seriously debilitating illnesses, which cannot be treated satisfactorily with currently available drugs and who cannot enter in clinical trials, can benefit from this process.

On the request of national competent authorities, the EMA provides recommendations through CHMP on the use of such medicines, whereby the national patient access programmes can consider this opinion before making a decision. This opinion cannot be requested by applicants themselves. The benefits of this programme are co-ordinated and implemented by national competent authorities.

PRIME scheme (priority medicines scheme)

PRIME is a new voluntary scheme launched by the EMA in 2016, and based on the existing regulatory framework fostering the early dialogue and accelerated assessment of medicines with unmet medical needs. Products that demonstrate significant medical benefit over existing therapies and patients with no treatment options can benefit here. Products that are eligible for this scheme can also gain an advantage from the accelerated assessment tool. The scheme promotes efficient development and robust data generation.

Based on preliminary clinical evidence, applicants can request PRIME eligibility, which is open to all companies. The agency will respond within 40 days. Once selected, applicants will have access to:

Other emerging initiatives

Adaptive medicines licensing

Adaptive licensing is an emerging scientific concept from the EMA which enables early and progressive patient access to medicines that are expected to have a significant therapeutic effect. This concept is based on these core principles:

The concept is based on the existing regulatory framework of scientific advice, conditional marketing authorisation, patient registries and pharmacovigilance tools for collection of real-world data, compassionate use and so on. Though this is an emerging concept, there are lot of uncertainties — particularly on the real-world data, early access timeline and reimbursement process, stakeholder involvement and so on.

The European Commission and EMA organised a workshop on adaptive pathways in December 2016. Post-workshop reports show that the EMA addressed the challenging areas of adaptive licensing and discussed the limitations and strengths of the observational studies. The EMA and EC will further assess the different views expressed at the workshop, and we may expect the action plan in the coming months. Early collaboration between industry, regulators and HTA is essential to achieve the objective of the adaptive licensing pathway.

Parallel consultation – EMA and HTA bodies

To overcome the complexity of market access issues, the EMA also offers scientific advice and protocol assistance in parallel with HTA bodies.

Are these early access tools exclusive?

Early access tools are not mutually exclusive. It is possible to use these in combination within the scope of defined criteria. As an example, products which are benefiting from PRIME can have conditional marketing authorisation granted before comprehensive data are available.

Conclusion

Although the EMA has introduced many regulatory tools since 2005 to support early access of medicines, significant improvement and transparency is needed to help foster effective development and to ensure early access of these medicines to patient groups. In particular, greater clarity is required with respect to the disease condition and criteria for each regulatory category. Early stage dialogue with regulators and other stake holders is therefore strongly recommended to avoid any gaps in the development.

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