EU on a Mission to Boost R&D

European Union regulators are stepping up their efforts to stimulate more research into new drugs, especially those for the treatment of life-threatening conditions and rare diseases. One priority is to help small- to medium-sized enterprises (SMEs) and academics to be more effective in taking newly developed medicines successfully through market authorization to commercial launch. Regulators are, therefore, offering scientific advice so that developers are able to sort out major efficacy, safety, and quality difficulties at an early stage. Nonetheless, there is the issue of how much this support should include advice on the development of manufacturing processes and quality issues covered by chemistry, manufacturing, and controls (CMC).

Drug development initiatives
In consultations on two of the most recent initiatives on new drug development, pharmaceutical trade and professional associations have stressed the need for more advice on production processes and CMC. One of the initiatives, launched by the European Medicines Agency (EMA), the London-based agency responsible for the centralized approval of new medicines, has been the introduction of a scientific advisory scheme targeting SMEs and the academia, called PRIority MEdicines (PRIME) (1). EMA’s guidance (2) accompanying the launch of PRIME, however, says little about help with CMC matters or process development.

The other initiative is a streamlining of guidance (3) by the European Commission (EC), the EU’s Brussels-based executive, on the implementation of the EU’s 15-year-old regulation on orphan medicinal products (OMP) in the hope of increasing the numbers of potential OMPs being authorized. But the EC is at the same time proposing to tighten up the EU’s regulation on orphan medicines, which could make the classification of a new treatment as a potential OMP more difficult to obtain, particularly if a key advantage of the product relates to quality issues such as the reliability of its manufacturing process.

EMA has tried to boost new drug research by issuing in February 2016 new guidance (4) on the operation of a 2004 regulation, which allows accelerated assessment of authorization applications for products of “major therapeutic interest.” It also published in March 2016 a new guideline (5) on a 2006 regulation allowing marketing approval of drugs with less than complete data on condition that comprehensive data on the product are provided post authorization.

Regulatory advice
In recent years, a growing number of companies, particularly the SMEs, have been seeking scientific advice from regulators, both at the EU and national levels. From 2011 to 2014, approximately two thirds of SMEs working on new medicines asked for scientific advice from EMA against 40% in the previous four years (i.e., 2007-2010), according to the agency’s latest annual report (6) on SMEs. SMEs have also been taking advantage of financial incentives, such as waiving of assistance and authorization fees and, in some EU countries, tax exemptions. Nonetheless, a lot of SMEs are still failing to gain authorizations for their new medicines. They account, for example, for only 20 percent of new OMP authorizations, which at the start of 2016 totalled 117 (7).

One reason for the failure of SMEs to gain authorization could be inadequate assistance on drug quality matters, particularly manufacturing problems. Among the objections raised by regulators to dossiers for market authorization application by SMEs in 2011-2013, 46% related to quality matters, one percentage point less than deficiencies with clinical efficacy and safety issues (6).

PRIME project
The objective of the PRIME project is to strengthen support for the development of medicines for dealing with unmet needs, especially those that offer major therapeutic advantage over existing treatments or benefit patients with no treatment options. The main aim of the project is to help researchers provide the necessary data for an application for a marketing authorization. These data will mostly come from adequately designed clinical trials but will also include information on quality and safety as well as efficacy. Eligibility for assistance from the scheme will require showing adequate non-clinical and exploratory clinical data about a therapeutically innovative medicinal product.

SMEs and academics will be targeted by PRIME advisory teams to help them progress from the stage of having demonstrated a convincing scientific concept to a point in the clinical stage where they can provide proof of the concept. “[This] is often a difficult step for these smaller actors with limited experience in regulatory aspects and medicine development,” says EMA in a response to comments in a public consultation on its PRIME proposals (8). Once the developers have achieved proof of concept, they will be allocated an EMA rapporteur to help them take their products through the clinical stage to application for marketing authorization.

Despite the relatively low profile given to quality problems in the EMA’s documentation on PRIME, the agency insists that SME, academics, and others will be able to seek advice on production processes under the scheme.
“There is no difference in the procedure and scope for scientific advice provided in the context of PRIME and (other advisory) schemes,” an EMA spokesman told Pharmaceutical Technology Europe. “Companies can ask questions on any aspect of the drug’s development (i.e., on quality, including CMC and manufacturing processes, and non-clinical, clinical efficacy, and safety issues).”

Representatives of pharmaceutical companies and R&D specialists point out that what matters the most is not so much the availability of advice on processes but the importance attached to manufacturing standards by the regulators.

In comments on a consultation document on the PRIME scheme, the International Society for Pharmaceutical Engineering (ISPE) pointed out that a study on the US Breakthrough Therapy scheme operated by the US Food and Drug Administration (FDA), which is similar to PRIME, showed the need for close interaction with regulators on CMC issues (9). This interaction was a necessity for larger companies as well as SMEs. “For exciting new therapies, companies not fitting the definition of SMEs may not have the previous experience of regulatory requirements for these new therapies,” said ISPE (9). “[They] would welcome regulatory advice to ensure the CMC programme is optimized alongside the proposed clinical programme.”

Also in comments on the consultation document (9), the European Federation of Pharmaceutical Industries and Associations (EFPIA), representing R&D-orientated companies, argued that PRIME would meet its objectives more successfully if its scientific advice covered both clinical development milestones and topics relating to production processes and CMC.

“We are confident that with PRIME, the advice will include CMC matters, were this to be requested by companies,” Paer Tellner, EFPIA’s regulatory affairs director told Pharmaceutical Technology Europe. “In fact, CMC could be very important, as not all CMC documentation might be available [when trying to achieve] earlier access to patients to innovative medicines.”

OMP designation
In the encouraging of research into unmet needs, the rules on development of OMPs overlap with those of PRIME, whose system can be used in R&D on orphan treatments for rare diseases. The EU feels that more could be done to close the gap between the number of estimated rare diseases at 5000-8000 and the number of authorized medicinal treatments, which amount to 1.5-2.5% of the conditions (7). Hence, the European Commission’s decision to issue new guidance on the designation of OMP status and granting of marketing authorizations to clear up uncertainties that may be acting as barriers to research.

By 2015, more than 1500 potential new drugs had been granted OMP status by EMA, which enabled developers to claim fee reductions and to gain 10-year market exclusivity in the event of a successful application for market authorization. However, as with the PRIME scheme, the issue of manufacturing standards has aroused controversy in the OMP sector.

Shortages of existing OMPs have become a fairly regular occurrence, often because of poor manufacturing standards of market authorization holders. Yet under the EC’s guidance, manufacturers with more reliable and efficient production processes will not be able to claim OMP status for alternatives to the products with scarcity problems because of the market exclusivity rule. Instead, they will only be granted an OMP designation for their replacements if they can provide evidence that shortages are causing patients harm.

On the other hand, the EC is planning to allow medicines to be made in hospital pharmacies for the assessment of products for OMP designation. This provision is despite the production units of hospital pharmacies being exempt from having to meet GMP standards.

The European Commission is also proposing that vaccines being developed to combat outbreaks of communicable diseases such as Ebola can be given an OMP status to speed up their development. Stakeholders, however, have been pointing out the dangers of going ahead with this plan without taking into account the ability of the potential OMP marketing authorization holders to make large quantities of vaccines at GMP standards in the event of an Ebola-type outbreak. Manufacturing capabilities seem likely to gain much more prominence when regulators are considering incentives to encourage more R&D into new medicines.

References
1. EMA, “Launch of PRIME-Paving the Way for Promising Medicines for Patients,” Press Release, 7 March 2016.
2. EMA, Enhanced Early Dialogue to Facilitate Accelerated Assessment of PRIority MEdicines (London, February 2016).
3. European Commission, Application of Articles 3, 5, and 7 of Regulation (EC) No 141/2000 on Orphan Medicinal Products-Consultation Document  (Brussels, 16 Nov. 2015).
4. EMA, Guideline on the Scientific Application and the Practical Arrangements Necessary to Implement The Procedure For Accelerated Assessment Pursuant to Article 14(9) of Regulation (EC) No. 726/2004 (London, 25 Feb. 2016).
5. EMA, Guideline on the Scientific Application and the Practical Arrangements Necessary To Implement Commission Regulation (EC) No 507/2006 on the Conditional Marketing Authorisation for Medicinal Products for Human Use Falling Within the Scope of Regulation (EC) No 726/2004  (London, 25 Feb. 2016).
6. EMA, Annual Report from SME Office-2014 (London, 3 Feb. 2015).
7. European Commission, “Orphan Medicinal Products-Major Developments,” Press Release, 29 Jan. 2016.
8. EMA, Outcome of the Public Consultation on the Reflection Paper on PRIME (London, 7 March 2016).  
9. EMA, Overview of the Comments Received on ‘Reflection Paper On A Proposal To Enhance Early Dialogue To Facilitate Accelerated Assessment of Priority Medicines (PRIME)’ (London, 7 March 2016).

Article DetailsPharmaceutical Technology Europe
Vol. 28, No. 5
Pages: 14–16

Citation: When referring to this article, please cite it as S. Milmo, "EU on a Mission to Boost R&D," Pharmaceutical Technology Europe 28 (5) (May 2016).