EMA’s Regulatory Impact: Not Yet in its PRIME

Editor’s Note: This article was published in Pharmaceutical Technology Europe’s September 2019 print issue.

The European Union’s medicines regulatory network, headed by the European Medicines Agency (EMA), is currently seeking ways to improve how it ensures that scientific innovations and new technologies lead to new medicines, particularly for patients with unmet needs. The agency is at present finalizing a report-EMA Regulatory Science to 2025-on the regulatory impact of emerging scientific and technological innovations (1). A six-month public consultation on the document, published in December 2018, was completed in June 2018.

Additionally, the agency is investigating ideas for raising the effectiveness of its three-year-old Priority Medicines (PRIME) scheme, which was developed to expedite the progression of new medicines for patients whose diseases cannot be treated or need better options for pharmaceutical treatments. Ideas were put forward at a joint EMA and US Food and Drug Administration (FDA) workshop, which was held in London during November 2018, for PRIME and FDA’s similar Breakthrough Therapy programme (2). EMA published a report on the workshop in July 2019 (3).

In fact, the objectives of PRIME and the aims behind EMA Regulatory Science to 2025 are closely linked. This is especially the case with the regulatory report’s number one goal of providing a basis for the integration of science and technology in medicines development. Among the core recommendations of the regulatory science report is increased investment in PRIME, shortening the time between scientific advice, clinical trials, and marketing authorization, and collaboration with stakeholders to ensure efficient post-approval oversight of medicines.

The main features of PRIME are an accelerated evaluation of a medicine’s development through close interaction between the sponsor and regulator, and support of a multi-discipline review team (4).

PRIME successes and challenges

In 2018, the first products developed under PRIME-two chimeric antigen receptor (CAR) T-cell immunotherapies for blood cancer treatment-were approved by EMA (5). PRIME’s main contribution to these successes was to identify at an early stage the data needed by the regulator for authorization. “Through PRIME, we offer early and enhanced dialogue to enable the generation of better data and more robust evidence on a medicine’s benefits and risks,” said Guido Rasi, EMA’s executive director (5).   

By the end of 2018, the agency had accepted 48 applications for medicines development support, equivalent to approximately a fifth of the total of applications, which predominantly consisted of small and medium-sized enterprises. Of the medicines admitted to the scheme, 42% were advanced therapy medicinal products (ATMPs), mainly gene and cell therapies. 

Encouraging development of ATMPs is a key aim of PRIME. An EMA report on the first two years of PRIME, issued in May 2018 (6), concluded that the scheme had been a success. Nonetheless in its implementation, regulators and sponsors of the medicines have been facing stiff challenges. These challenges mainly stem from the necessity of conducting evaluations, both of products and processes, and making risk/benefit analyses in less time than for the development of normal medicines.

The agency’s choice of ideas from the joint workshop for further investigation has been mainly dictated by the need to address these challenges, among the biggest of which is drawing up specifications and control strategies, and other quality assurance tools, on the basis of only relatively few batches compared to normal.

Lifecycle and stepwise approaches

EMA’s main preferred solution to scarcity of some evidence in PRIME projects appears to be to make greater use of regulatory actions through the lifecycle of new medicines so that knowledge gaps before authorizations can be filled by post-authorization decisions.

“We will often not understand the full clinical value of (new, life-changing) drugs at the time of approval,” Tomas Salmonson, who retired as chair of the EMA’s committee for medicinal products for human use (CHMP) in September 2018, said in an interview for EMA’s latest annual report (5). “Ensuring that we obtain answers to relevant questions from all stakeholders in the post-approval space is an increasing responsibility for the regulator,” he added.

The lifecycle approach will mean more use of concurrent validation, which is done simultaneously with a medicine’s commercialization. Usually it is performed only in exceptional circumstances and when the benefit-risk ratio is strongly in favour of the patient. As a result, some authorization applicants will be allowed to defer submission of process validation data until the post‑approval stage.

With control strategies, there will be more room for flexibility so that control parameters can be revised in the light of knowledge gained after commercialization. In this respect, biological molecules may have to be treated differently from small molecules, which have the advantage of back-up data from animal studies. Data for biological molecules may have to come from a combination of pre‑clinical data and prior knowledge derived from a company’s internal information, as well as external sources such as scientific and technical publications.

There could also be more use of post-approval change management protocols (PACMPs), in which submission of post-authorization data is linked to specific pre-arranged post‑approval product and/or process changes. It is a step‑wise approach that allows an early evaluation to be followed by a later, separate evaluation of the data produced, based on an agreed strategy. 

“Such a stepwise approach is expected to lead to faster and more predictable implementation of changes post-approval, since the (marketing authorization holder) will have obtained agreement from the regulatory authorities about the proposed strategy and tests to verify the effect of the change on product quality,” stated the EMA’s report (3).

Changes afoot

With PRIME products and ATMPs in general, there may have to be changes in regulators’ attitudes to timelines for PACMPs. With drugs under normal development, these timelines are quite flexible, whereas with priority and advanced medicines they may have to be made more time specific. There may have to be more guidance on the application of PACMPs with ATMPs, according to EMA (3).

The agency’s committee for advanced therapies (CAT) issued a question and answer guide on the use of out-of-specification batches of authorized cell/tissue-based advanced treatments in April 2019 (7). Forthcoming regulatory changes look likely to result in alterations to current practices but also standards and even legislation.

GMP guidelines may have to be modified to help inspectors deal with the issue of sites supplying both clinical trial investigational medicinal products (IMPs) but also commercial medicines. Increasingly hospitals, acting as centres of excellence for the development of ATMPs and other similar innovative drugs, are manufacturing small quantities of medicines for clinical and commercial use.

Matt Popkin, UK-based director chemistry, manufacturing, and controls strategy, product development, at GlaxoSmithKline (GSK) told the workshop that in accelerated access scenarios there was only limited time to develop long-term supply chain and complete commercial GMP‑certified activities, according to the EMA report. 

Instead, Popkin suggested alternative good manufacturing practice (GMP) tools may be appropriate for manufacturing facilities that are only supplying limited numbers of products to a small number of critically ill patients for a limited period (3).

Similar GMP rules for sites supplying clinical IMPs should be applied to those serving early stage commercial segments. Allowing commercial supply from clinical manufacturing facilities would enable patients to have accelerated access to medicines early in their commercial lifecycle, according to Popkin.

Further considerations

EMA listed in its workshop report, for further consideration, possible guidance on requirements for the use of IMP manufacturing sites for early commercial supply of innovative medicines (3). The agency also suggested using comparability as the basis for accepting clinical trial data from products manufactured in facilities not compliant with GMP. Furthermore, EMA indicated that the requirement for GMP certification could be waived for use of material from master or working cell banks in third countries, which are not compliant with GMP.

Difficulties with assessing the comparability of biological materials can also hold up accelerated product development. How, for example, could the comparability of materials from healthy donors and patients be validated when there may be significant differences between the two, asked the report. 

Demonstration of comparability was particularly important at different development phases of the manufacturing process. If an adequate risk assessment was to be performed on comparability, more knowledge of the impact, for example, of manufacturing changes on ATMPs was needed. 

“Most of the currently available knowledge is present in registration dossiers and not publicly available,” as stated in the EMA report (3). “It would be of great benefit if this information was published.”

There is a big gap in scientific knowledge about the differences between healthy donor and patient materials in relevant manufacturing processes, according to the EMA report. “It would be useful if all existing experience would be published,” EMA said (5). “That would be a good resource to assess new comparability cases.”

Greater global collaboration

Greater international collaboration, like that between EMA and FDA, could help to solve problems such as lack of accessible data. Agencies can cooperate to pool knowledge. They may even be able to distribute joint guidance on issues such as validation, control strategies, and specifications for innovative new medicines. 

One key area for international collaboration in the future will be the use of regulatory science to use big data and artificial intelligence to create models for validation and other quality controls. Global cooperation will be necessary to gain the most regulatory benefits out of digitalization.

References 

1. EMA, “EMA Regulatory Science to 2025-Strategic Reflection” (London, December 2018).
2. EMA, “Stakeholder Workshop on Support to Quality Development in Early Access Approaches, Such as PRIME and Breakthrough Therapies” (London, 26 November 2018). 
3. EMA, “Meeting Report: Workshop with stakeholders on Support to Quality Development in Early Access Approaches” (London, 26 November 2018). 
4. EMA, “PRIME: priority medicines” ema.europa.eu [accessed 22 August 2019].
5. EMA, “Annual Report 2018” (Amsterdam, May 2019).
6. EMA, “PRIME: a Two-Year Overview” (London, May 2018).
7. EMA, “Questions and Answers on the Use of Out-of-Specification Batches of Authorized Cell/Tissue-Based Advanced Therapy Medicinal Products” (Amsterdam, 24 April 2019). 

Article Details

Pharmaceutical Technology Europe
Vol. 31, No. 9
September 2019
Pages: 8–9

Citation 

When referring to this article, please cite it as S. Milmo, “EMA’s Regulatory Impact: Not Yet in its PRIME,” Pharmaceutical Technology Europe 31 (9) 2019.