From expanded approaches to scientific advice and a shift away from animal testing to new frameworks for platform technologies, faster marketing authorization pathways and the use of regulatory sandboxes, these developments will shape regulatory practice in the years to come.
Developing a new medicinal product is a time-consuming and resource-intensive process which usually takes more than ten years from initial concept until a product can be placed on the EU market. Against this background, the Pharma Package aims to promote innovation, in particular for unmet medical needs, by reducing regulatory burden and accelerating authorization procedures for medicinal products.
1. Extension of scientific advice
Status quo—current scientific advice and protocol assistance
Under the current regulatory framework, one of the tasks of the European Medicines Agency (EMA) is to advise companies “on the conduct of the various tests and trials necessary to demonstrate the quality, safety and efficacy of medicinal products.” As such, scientific advice may currently be requested for all medicinal products for human use, irrespective of the eligibility of the medicinal product for the centralized procedure, and relate to aspects of the design of studies, trials, and programs to support quality, safety, and efficacy of a medicinal product. This advice can also be given in the form of parallel joint scientific consultations with the Member State Coordination Group on HTA or in parallel with the U.S. Food and Drug Administration (FDA).
Pharma Package—extension of future scientific advice
In future, scientific advice for applicants seeking a marketing authorization should be provided more generally and in greater depth and should be adapted to the specificities of the medicinal product concerned. The increased importance of future scientific advice is also reflected in the context of regulatory exclusivities (Article 81 of the new Directive). A prolongation of the regulatory market protection period can be granted if comparative clinical trials have been conducted using a comparator based on scientific advice provided by EMA (see also our first article in the EU Pharma Package series for further details).
In the preparation of scientific advice, EMA should in future be able to consult other authorities or other public bodies within the EU. Such consultees may include experts from the member states with relevant expertise, for example in clinical trials, medical devices or any other field necessary for the specific scientific advice concerned. In duly justified cases, this may also include public bodies established in non-EU countries. Furthermore, the new Regulation clarifies that scientific advice by EMA can also take place in parallel to scientific advice provided by other bodies, e.g., in cases of medicinal products involving a medical device, in parallel with the consultation of the expert panels as described in Article 106 of the MDR.
Practical implications
A crucial question in the development of new medicinal products is the selection, planning and conduct of adequate (non-) clinical studies that are able to demonstrate the quality, safety and efficacy as well as the advantages of the new medicinal products. The extended options of scientific advice by EMA offer pharmaceutical companies further potential to gather relevant information for designing their study plan most efficiently.
2. Replacement of animal testing in pre-clinical development
Status quo—factual and legal background
Animal testing remains an integral part of the pre-clinical development of human medicinal products. Nevertheless, the importance of New Approach Methodologies (NAMs), such as organoids and organs-on-chips, which allow relevant data to be generated without the use of animals, has grown rapidly in recent years. However, based on the current legal framework in Directive 2001/83/EC, animal testing is generally required before clinical trials, while replacement by other methods is also permitted.
Pharma Package
The Pharma Package continues the shift away from animal testing. While Annex II of the new Directive continues to refer to the requirement of animal testing prior to clinical trials, other provisions introduce a fundamentally different regulatory approach. In particular, Article 6(5) of the new Regulation and Article 6(7) of the new Directive explicitly reverse the traditional hierarchy by establishing an obligation not to conduct animal testing where scientifically satisfactory non animal testing methods, such as NAMs, are available. Under this revised framework, animal testing is no longer considered the norm, but rather a backup option.
Practical implications
The coexistence of different references to animal testing within the new legislative package gives rise to legal and practical uncertainties. In particular, the requirement of animal testing under Annex II of the new Directive must be reconciled with the strengthened obligation elsewhere in the legislation to rely on non animal methods wherever scientifically possible. This raises questions as to how competent authorities will interpret and apply these provisions in practice, especially during early scientific advice procedures and marketing authorization assessments.
The practical application of the new rules will depend heavily on the interpretation of the notion of “scientifically satisfactory non animal testing methods” and the assessment of when such alternatives can be considered to be “available.” Further regulatory guidance will therefore be essential to clarify expectations for applicants, ensure legal certainty, and promote consistent implementation across member states.
Replacing animal testing will largely depend on the availability and validation of corresponding NAMs. Nevertheless, the new regulatory framework continues to align the EU with developments in the U.S., where animal testing should be significantly reduced and phased out in pre-clinical safety/toxicity studies by 2030. Pharmaceutical companies should therefore prepare for further reductions in animal testing and increased integration of NAMs to meet the EU and U.S. requirements. This might require the development of own NAMs or the collaboration with/ acquisition of companies developing specific NAMs.
3. Implementation of platform technology master files for human medicinal products
Article 26a of the new Directive codifies the concept of platform technology master files for human medicinal products in the EU for the first time. This mechanism allows pharmaceutical companies to rely on certain pre-evaluated quality, non-clinical, and clinical information, within their marketing authorization application. The approach avoids duplication of assessments and minimizes repetition of studies, thereby streamlining and accelerating both development and regulatory evaluation processes of medicinal products.
Status quo—current EU master files
The concept of master files is not entirely new to EU pharmaceutical legislation. For example, Directive 2001/83/EC describes active substance master files, which provide detailed confidential information on the manufacturing of active substances and Regulation (EU) 2019/6 describes vaccine platform technology master files for veterinary medicinal products. However, for human medicinal products, no similar concept exists so far.
Pharma Package—new platform technology master files
Platform technologies include, for example, viral and bacterial vector systems, recombinant protein-based methods, and synthetic biology technologies. Their defining feature is a common dataset that can be used unchanged across all medicinal products based on the same technology (Article 4(1)(30a) of the new Directive). To rely on a platform technology master file, marketing authorization applicants must demonstrate that this common dataset is applicable to their product, adequately describe the underlying development and manufacturing platform and provide a scientific justification confirming the relevance of the platform data for the specific medicinal product.
If these conditions are met, applicants may refer to EMA pre-certified platform technology master files instead of submitting the relevant data themselves (Article 26a(1) and Recital 93a of the new Directive). Even where the certified platform technology master file is owned by a third party, full responsibility and liability for the authorized medicinal product, including the use of the platform technology, remain solely with the marketing authorization holder (Article 26a(2) of the new Directive).
Practical implications
The new Directive contains no provisions regarding the ability of marketing authorization applicants to access platform technology master files owned by other companies. The EMA guidelines according to Article 26a(1) of the new Directive need to further specify mechanisms of granting rights of reference or letters of access to other marketing authorization applicants.
In any case, the newly introduced platform technology master files for human medicinal products can significantly accelerate pharmaceutical development. Therefore, owners of platform technologies should familiarize themselves with the duties and certification procedures for these new master files, while marketing authorization applicants should engage with platform owners to leverage relevant master files.
4. Options of accelerating marketing authorization procedures
Reduced evaluation period for marketing authorizations
Under the current pharmaceutical legal framework, marketing authorization procedures for centrally authorized medicinal products can take between 10 and 20 months (depending on clock stop periods). The scientific evaluation of the dossier by the Committee for Medicinal Products for Human Use (CHMP) as part of the centralized marketing authorization procedure currently requires 210 days. The Pharma Package seeks to enhance the competitiveness of the EU regulatory framework by reducing this evaluation timeframe to 180 days (Article 6(6) of the new Regulation).
Furthermore, the timeframe within which the European Commission has to take a final decision on a centralized marketing authorization should be reduced from the current 67 days to no longer than 46 days. To further reduce bureaucracy, the default renewal requirement for marketing authorizations after five years will also be removed, and marketing authorizations will generally be granted for an unlimited period.
Codification of further acceleration measures
In certain circumstances, such as when addressing an unmet medical need or responding to a public health emergency, further acceleration of the marketing authorization procedure may be required. So far, accelerated pathways, such as the PRIority MEdicines (PRIME) scheme and rolling review, have been largely based on EMA guidance. Currently, PRIME represents a voluntary scheme designed to support the development of medicines for unmet medical needs based on early dialogues of EMA with companies to optimize development plans and speed up regulatory assessment. The mechanism of rolling review allows the CHMP to assess data as they become available even while development is still ongoing and was widely used during the COVID-19 pandemic.
Article 60 of the new Regulation now codifies the PRIME scheme, which provides enhanced scientific and regulatory support together with accelerated assessment mechanisms for:
(i) medicinal products that are likely to address an unmet medical need and are expected to be of major interest from the point of view of public health
(ii) specific antimicrobials, or
(iii) medicinal products likely to target a neglected tropical disease, leading to an increase in legal certainty.
Article 6(2) of the new Regulation codifies the concept of rolling review, permitting a phased review of complete data packages for:
(i) medicinal products that are likely to address an unmet medical need and are expected to be of major interest from the point of view of public health
(ii) specific antimicrobials, or
(iii) medicinal products intended for use in relation to a potential or recognized public health emergency. Besides increasing legal certainty, the new codification extends the scope of rolling review beyond its previous use, which was generally limited to public health emergencies such as the H1N1 and COVID-19 pandemics.
Practical implications
Pharmaceutical companies should familiarize themselves with the new timelines and the newly codified acceleration options during the authorization process in order to fully benefit from them.
5. Introduction of regulatory sandboxes
The new Regulation establishes the concept of regulatory sandboxes in Article 113 et seq. to facilitate the development and authorization of innovative products and thus enable patients’ early access to groundbreaking new therapies.
Necessity of regulatory sandboxes
The development and authorization of several innovative medicinal products would not be achievable under full compliance with the requirements of the ordinary regulatory framework due to methods related to those products or their inherent scientific or technical characteristics, e.g., in the context of digitalization or the use of artificial intelligence and machine learning during the life cycle of medicinal products. However, these characteristics or methods are likely to positively and distinctively contribute to the quality, safety or efficacy of medicinal products or provide a major contribution to patient access to prevention, diagnosis, treatment or patient care.
With the help of a regulatory sandbox, a framework, adapting respective requirements, is established during which it is possible to develop, validate, and test medicinal products for a limited time in a controlled environment under the supervision of the EMA and national authorities. The adaptations shall not compromise the standards of quality, safety, and efficacy and can be terminated at any time based on public health considerations.
Process of establishing a regulatory sandbox
EMA will determine whether establishing a regulatory sandbox might be appropriate based on market monitoring and input from various stakeholders, in particular developers of innovative and emerging medicinal products. Where EMA considers it appropriate to set up a regulatory sandbox for medicinal products, it shall provide a recommendation to the European Commission, listing the products or category of products covered by the sandbox and including a sandbox plan based on data submitted by the developers.
The sandbox plan should include inter alia clinical, scientific, and regulatory justification for the necessity to establish a sandbox and outline further particularities of the sandbox, including its duration. Following this recommendation by EMA, a regulatory sandbox is established based on a Commission Implementing Decision.
Medicinal products developed under a regulatory sandbox
The supervisory and corrective power of the competent authorities as well as the liability of participants, such as sponsors, marketing authorization applicants and holders, are not affected by regulatory sandboxes. The initial validity of a marketing authorization of a medicinal product developed based on a regulatory sandbox shall not exceed the duration of the regulatory sandbox but may be renewed. Furthermore, the development as part of a regulatory sandbox shall be indicated in the summary of product characteristics and the package leaflet.
Results of a regulatory sandbox
Regulatory sandboxes can play an important role in the development and authorization of new innovative medicinal products and groundbreaking therapies, which do not fit under the current regulatory framework. As a long-term aim, the learnings and insights gained from a regulatory sandbox might lead to particular innovative aspects being integrated into the future legal framework. (Recital 135 of the new Regulation).
Practical implications
In the case of new methods and inherent scientific or technical characteristics of medicinal products, regulatory sandboxes can present a valuable option for facilitating development and authorization of innovative medicinal products, so that marketing authorization applicants and developers should closely monitor the opportunities arising from this new option.
6. Next steps
The provisional agreement must now be endorsed by both the Council of the European Union and the European Parliament before being formally adopted. The new Directive and Regulation will enter into force upon publication in the EU's Official Journal. The Regulation will become applicable in 2028, two years after publication in the EU's Official Journal (Article 181 of the new Regulation), the new Directive needs to be transposed into national law of the member states at the same time (Article 219 of the new Directive). The provisions on regulatory sandboxes will apply from entry into force of the new Regulation, estimated to take place by the end of 2026.
In the meantime, pharmaceutical companies should prepare for the new provisions to take full advantage of these newly introduced concepts and opportunities.
