ublication of the European Commission’s (EC) legislative proposal for the review of the general pharmaceutical legislation (GPL) at the end of April 2023 has been heralded as a “once in a generation” opportunity to make medicines more available, accessible, and affordable. The EC considers that the proposals will support innovation and boost the competitiveness and attractiveness of the EU pharmaceutical industry while promoting higher environmental standards. However, the published proposals introduce changes that would have a major impact on the global competitiveness of the EU market as well as erode incentives for investment in innovation.

This revision is the first major review of the EU’s pharmaceutical legislation since 2004. In contrast, the FDA’s drug statutes have been regularly updated at least every five years around the reauthorization and creation of the different user fee programs, as well as separate updates around pandemic preparedness. In Japan, the Pharmaceutical Affairs Law was last revised in 2014, when it was replaced by the Pharmaceuticals and Medical Devices Act (PMD Act).

The ambition of these EC proposals is welcomed. However, industry has expressed concerns that the objectives of the legislation may not be met by the published proposals, and that key provisions may have a detrimental impact on the attractiveness of the EU as a place for innovative medicines development. Some of these key provisions are described below.

Regulatory Data Protection: Undermining Essential Protection for the Development of New Medicinal Products?

The proposed directive suggests a reduction of regulatory data protection (RDP) from a standard period of eight years down to six years. In addition, RDP conditional extensions can be granted based on specific criteria. More specifically, an additional two-year period can be granted if the product is launched and continuously supplied in all 27 EU Member States (MS), an additional six months if an initial marketing authorization application (MAA) addresses an unmet medical need (UMN), an additional six months for new active substances including comparative trials in the initial MAA, and one additional year for a new therapeutic indication bringing a significant clinical benefit.

According to the proposals, a medicinal product is considered to address an UMN if:

• At least one of its therapeutic indications relates to a life-threatening or severely debilitating disease, and
• There is no medicinal product authorized in the Union for such disease, or, where despite medicinal products being authorized for such disease in the Union, the disease is associated with a remaining high morbidity or mortality, and
• The use of the MP results in a meaningful reduction in disease morbidity or mortality.

This modulated proposal generates uncertainty and unpredictability around obtaining these additional years/months of RDP. For example, the launch of a medicinal product in all MS within two years represents a difficult, if not impossible, target for many companies and is not only dependent on the Marketing Application Holder’s (MAH’s) willingness to do so but on the MS’s willingness to reimburse the product. This uncertainty introduces unnecessary complexity and risk.

Does the Definition of UMN Support Development of New Therapies?

The rather narrow definition of UMN and its connection to eligibility for incentives and regulatory pathways do not necessarily promote development of promising therapies. Incentives to enhance the development of such medicines include PRIME eligibility as well as longer market exclusivity. However, this type of development can take several years, and it is rarely possible to know in advance whether a particular R&D investment will result in a medicinal product that will address an UMN. Therefore, not knowing whether a medicine will be eligible for the above mentioned incentives makes it less attractive for companies to invest in them, which may ultimately impair the development of important therapies. The importance of incremental innovation and the development of therapies for these patients can be undermined by the proposed legislation. Patients suffering from a disease may have different individual needs and may value new treatments differently than society in general. The proposed definition of UMN does not adequately reflect this need or the patient’s perspective.

Are the Orphan Incentives of Genuine Value for Orphan Drug Manufacturers?

The Orphan Market Exclusivity period could be reduced to nine years from the current 10 years. One additional year of market exclusivity could be granted if the proposed definition of high unmet medical need (HUMN) is met; however, this conditional definition of HUMN would make it hard for orphan drug manufacturers to benefit from the one-year extension: The Commission is also proposing a one-year period of exclusivity per active substance if the product is launched in every EU market.

Less Flexibility around Pediatric Medicines?

While some changes regarding pediatric medicines seem to positively impact industry (such as the new simplified EMA structure (i.e., reducing the number of EMA Committees to two and organizing the remainder into working parties to eliminate duplicative work), the initial pediatric investigation plan [PIP], and the provision of an adapted PIP for products intended to be developed only for use in children), most of the changes suggest decreased flexibility and stricter obligations, some linked to financial penalties if not fulfilled.

First, the Commission’s proposed implementation of the “initial PIP” suggests an initial presentation of a high-level clinical development plan, which is expected to reduce the regulatory burden, that will be completed at precise timepoints in development. In addition, the obligation to place the pediatric product in the market within two years in all MS where the medicinal product has already been placed in the market is expected to prove burdensome for pharmaceutical companies and may not even help pediatric rare disease patients gain faster access.

Introduction of the Mechanism of Action (MoA) PIP could address unmet medical needs in pediatric populations and spur more research and development into underserved therapeutic areas. However, flexibility, transparency, and strong scientific foundations would be required to avoid increased complexity and burden from the MoA PIP, which could potentially undermine adult development. In addition, the proposed five-year cap on deferral as well as the possibility for EMA to request a PIP modification following PIP opinion suggest very little flexibility around the development of pediatric medicines.

Environmental Risk Assessment to Influence EU Drug Approvals

Industry recognizes that environmental risk assessment (ERA) is indispensable and is actively engaged in managing the impacts of pharmaceutical manufacturing on the environment. Pharmaceutical industry associations such as the European Federation of Pharmaceutical Industries and Associations (EFPIA), Medicines For Europe, and the Association of the European Self-Care Industry (AESGP) have endorsed the Technical Guidance on Responsible Manufacturing Effluent Management, and the AMR Industry Alliance has developed a third-party certification scheme for responsible manufacturing of antibiotics. EFPIA, Medicines For Europe, and AESGP have proposed an extended ERA concept, and prioritization approaches and new predictive models are being developed by the IMI Project PREMIER.

Nevertheless, the EC proposal suggests that a marketing authorization may be rejected solely on the grounds of adverse environmental impacts. This threatens the authorization system of medicinal products and would negatively impact patients’ access to medicines. In addition, the Proposal for a Directive on the Union code relating to medicinal products for human use has a strong focus on intrinsic substance hazardous properties rather than on environmental risks. This unnecessarily increases the testing burden for medicines expected to target small patient populations and reach the environment in very low amounts. Intrinsic hazardous substance properties are also proposed as grounds to consider medicines as prescription-only, again independent of the estimated environmental risk. That would increase the burden to healthcare systems and reduce patient access to medicines with no benefit to the environment.

Supply Security

The proposed legislation includes numerous measures to alleviate shortages and includes a list of EU-wide critical medicines, which creates the obligation to develop and regularly update a shortage prevention plan. However, the responsibilities of MAHs with regards to shortages should be examined on a product-by-product basis. Finally, a six-month shortage notification may be difficult to implement (and may not always be necessary) due to potential mitigation of issues behind the shortage.

Regulatory Provisions

The proposed legislation includes numerous revisions to the regulatory system. The reduction of the scientific evaluation period from 210 to 180 days, as well as the reduction of the EC decision from 67 to 46 days, are moves in the right direction. Similar adjustments to the timelines of acceleration tools such as PRIME and accelerated assessment would effectively speed up the approval timelines for much-needed innovative medicines. In addition, the proposed simplification of EMA structure (such as reducing the number of scientific committees which will be organized into working parties and/or advisory groups) suggests more streamlined processes and more efficient scientific dialogues, and perhaps even less burdensome procedures.

From a resources management perspective, the proposed unlimited validity of the marketing authorization (marketing authorizations will generally be valid for an unlimited period with no requirement for renewal after five years), as well as submission of variations via a database update, would have a significantly positive impact on internal regulatory resources. The proposed legislation aims to address the disconnect between EMA and Notified Bodies in the case of Drug-Device Combination products and introduces use of electronic Product Information (ePI). Another positive change from a regulatory point of view is the introduction of the Regulatory Sandbox, a framework that enables the development of innovative or adapted regulatory solutions in a controlled environment. Keeping this forward-looking provision in the proposed legislation is expected to promote innovation and support the testing of different regulatory approaches.

GPL Impact Overview

The overall impact of the changes in the proposed GPL is summarized below.

The proposal does include some positive changes for industry, such as the reduced MAA assessment timelines, the EMA structure simplification, and the introduction of the Regulatory Sandbox and ePI, in their interactions with the regulatory system. However, the large number of new obligations and regulatory reporting requirements it proposes will culminate in an increased mandate to regulators to control the R&D process, including the use of health data (including RWD) and repurposing data to force PI updates, and (most importantly) the reduction of RDP, which weakens incentives for investment in innovation and ultimately undermines the competitiveness of the EU pharmaceutical market.

All opinions expressed by the authors are personal perspectives and do not reflect the opinions of Novartis, its affiliates, or employees. The content herein is not intended to be a substitute for professional medical or legal advice and is for informational purposes only.