The EMA’s incentive mechanisms aiming at facilitating access to market

A regulatory study by Regnstrom et al. indicates that company size may be an independent predictor of success of a marketing authorisation application to the EMA:

the smaller the company, the more probable a negative outcome.⁷²² Their study also suggests that smaller companies are developing a larger proportion of orphan (and ultra orphan) medicines than larger ones. Whilst Macuilaitis et al. point out that regulators are well aware of idiosyncrasies of the ATMP field and there are a number of ways the EMA may provide guidance to developers of ATMPs.⁷²³ The particular needs of SMEs, hospitals and academia have been acknowledged by the EMA. The EMA provides pursuant to the ATMP Regulation incentives for product development tailored to them.

The incentives, which focus on the main financial and administrative entry obstacles for SMEs in pre-marketing authorisation procedures are presented in Table 6 below. In addition, SMEs, academia and non-profit actors may take advantage of the EMA’s existing early access incentives and initiatives (such as PRIME scheme, adaptive pathways, Innovation Task Force meetings, health technology parallel scientific assessment and the certification procedure) to facilitate market entry of ATMPs.

Despite the incentives, SMEs still have had historically a lower success rate in the marketing authorisation procedure than larger companies.⁷²⁴ As possible explanations for this the EMA has acknowledged that the main problems relate to quality issues and clinical efficacy, in particular. Therefore, it is especially advisable for SMEs to seek scientific advice from the EMA early in development to ensure that the adequate trials are conducted to avoid that any major objections regarding the trial design are raised when the marketing authorisation application is assessed.⁷²⁵ Interestingly, a study by Regnstrom et al. indicates a strong association between a positive outcome of a marketing authorisation procedure and requests for and compliance with regulatory scientific advice. According to Regnstrom et al. direct interaction with regulators

722 Regnstrom, J., Koenig, F., Aronsson, B., Reimer, T., Svendsen, K., Tsigkos, S., et al. Factors associated with success of market authorisation applications for pharmaceutical drugs submitted to the European Medicines Agency. Eur J Clin Pharmacol. 2010; 66: 39–48.

723 Maciulaitis, supra note 559, 481-482.

724 Maciulaitis, ibid.

725 Maciulaitis, op.cit., 482.

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seems to be a key predictor of success.⁷²⁶ Therefore, to facilitate translation of research into authorised ATMPs and to deal with the regulatory and scientific challenges of ATMPs, the EMA recognises the need for increased and early interactions and open dialogue with the developers and producers of these innovative medicines. Figure 6. in Appendix 4 illustrates the EMA’s regulatory procedures for ATMPs. Figure 7. in Appendix 5 describes possibilities for interaction with the EMA during different stages of product development and the role of incentives in the regulatory path for ATMPs. As presented in Figure 7. certification system may facilitate early dialogue with the regulators. The certificate could support SMEs who wish to license out their technology or it could be used to attract venture capital allowing them to further develop their products.⁷²⁷ Yet, certification procedure is used very seldom as it relates to the pre-clinical data and it is not linked with the marketing authorisation procedure.⁷²⁸ The certification procedure would be more useful if it had a clear link with the marketing authorisation procedure.

Table 6. The EMA’s pre-authorisation incentives for SMEs⁷²⁹: Scientific advice

90% fee reduction for non-orphan products 100% fee reduction for designated orphan products 100% fee reduction for products granted eligibility to PRIME

Inspection (pre-authorisation) 90% fee reduction and deferral

100% fee reduction for designated orphan products Application for marketing authorisation

Fee deferral until the outcome of marketing authorisation application

Conditional fee exemption, where EMA scientific advice is followed and a marketing authorisation application is not successful

100% fee reduction for designated orphan products Scientific services (e.g. certification) 90% fee reduction for non-orphan products

100% fee reduction for designated orphan products Translations Assistance with translations of product information

into all official European Union (EU) languages Reference: The European Medicines Agency, supra note 729. PRIME= piority access medicine.

726 Regnstrom, et al., supra note 722.

727Jekerle, V., Schröder C., Pedone, E. Legal basis of the Advanced Therapies Regulation.Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2010;Jan;53(1):48.

728 European Commission, supra note 6, 12.

729 European Medicines Agency. SME Office. Addressing the needs of small and medicum size

enterprises. Available at:

http://www.ema.europa.eu/docs/en_GB/document_library/Brochure/2011/03/WC500104237.pdf.

Accessed 21 June 2016. See also European Medicines Agency. Explanatory note on general fees payable

to the European Medicines Agency. Available at:

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/06/WC500208145.pdf. Accessed 12 August 2016.

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Developers of ATMPs are also encouraged to take advantage of informal briefing meetings with the EMA’s Innovation Task Force that promotes early dialogue and interaction with the EMA experts on administrative and scientific issues, as well as interactions with the CAT in its stakeholder meetings, training sessions and workshops for industry, academia, and hospitals developing ATMPs.⁷³⁰ In 2015, 34 briefing meetings with Innovation Task Force took place, almost two-thirds of which were on methods, for instance to facilitate the development of medicines (e.g. biomarkers), or to improve the manufacturing of medicines, particularly in the context of certain advanced therapies that need to be produced at the patient’s bedside. According to the EMA nearly 40 percent of requests came from SMEs and 31 percent originated from academia.⁷³¹

The EMA has recently lauched new incentives for developers of medicines for unmet medical need. Fee reductions on the EMA’s scientific advice have been recently extented to cover non-profit organisations, such as academic research establishments if they qualify for the EMA’s PRIME Scheme.⁷³² This voluntary scheme is relies on improved interaction and early dialogue with developers of promising medicines for an unmet medical need, to optimise development plans and speed up evaluation so these medicines can reach patients earlier.⁷³³ The recently launched PRIME scheme focuses on ‘priority medicines‘ that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options. To be accepted for PRIME, a medicine must show its potential to benefit patients with unmet medical needs based on early clinical data. By means of this new initiative the EMA aims at offering early and proactive support to developers of medicine so that they can to optimise the generation of robust data on a medicine’s benefits and risks and enable accelerated assessment of medicines applications. According to the EMA special benefits (beyond financial ones) for developers of priority access ATMPs include:

 appointment of a rapporteur from the CAT to provide constant support and assistance to generate knowledge before marketing-authorisation application;

 organisation of a kick-off meeting with the CAT rapporteur and a multidisciplinary group of experts, so that they provide guidance on the overall development plan and regulatory strategy;

 assignment of a dedicated contact point;

730 Klug, B. Celis, P., Carr, M., Reinhardt, J. Regulatory structures for gene therapy medicinal products in the European Union. Methods Enzymol. 2012;507:337-54, 345.

731 European Medicines Agency, supra note 70, 50.

732 European Medicines Agency. Decision of the Executive Director on fee reductions for scientific advice requests on PRIME products for SMEs and applicants from the academic sector, 27 May 2015. Available at:http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/06/WC500208143.pdf Accessed 12 August 2016.

733European Medicines Agency. PRIME: Priority Medicines Available at:

http://www.ema.europa.eu/ema/index.jsp%3Fcurl%3Dpages/regulation/general/general_content_000660.j sp%26mid%3DWC0b01ac058096f643. Accessed 12 August 2016.

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 provision of scientific advice at main development milestones, involving additional stakeholders such as health-technology-assessment bodies, to facilitate accelerated access for patients to the new product;

 confirm potential for accelerated assessment at the time of an application for marketing authorisation (it may in some cases be reduced from 210 days to 150 days).⁷³⁴

The EMA has also quite recently launched a pilot project on adaptive pathways that aims at accelerating the market entry of medicines in areas of high medical need where it is difficult to gather data through traditional means and where large clinical trials would unreasonably expose patients who are unlikely to benefit from the treatment. Benefits and limitations of this approach for developers of ATMPs will be discussed in further detail in Section 8.3.of this study.

7.8 Cost of ATMPs and reimbursement issues affecting access