Environmental stress and degradation, including the loss of biodiversity, contribute to the transmission of diseases between humans and animals as well as to the overall disease burden. In addition, pollution from active pharmaceutical ingredients negatively affects the quality of waters and ecosystems and rapidly increases antimicrobial resistance, posing risks to public health globally. Therefore, the Pharma Package tries to contribute to the implementation of the One Health Approach, stressing the well-established interconnectedness between human, animal and ecosystem health (Recital 46a of the new Regulation and Recital 65a of the new Directive). To this end, the Pharma Package provides for significant measures, including the extension and stricter enforcement of the ERA requirements in MA applications and for authorized medicinal products but also simplified procedures for clinical trials involving medicinal products containing or consisting of genetically modified organisms (GMOs).
1. ERA – current status
The current pharmaceutical legislation already requires companies to include an ERA in marketing authorization (MA) applications for all new medicinal products, whether through a centralized, mutual recognition, decentralized or national procedure (except for renewals or Type IA/IB variations).
However, the current ERA requirement has been considered insufficient to address environmental concerns, as (i) the ERA is a one-time snapshot at the time of the MA application without any follow-up mechanism and (ii) there are no practical consequences associated with the (lack of) quality of the ERA or (non-)compliance with the identified risk measures, apart from a non-binding recommendation issued by the competent authority.
2. ERA under the Pharma Package
Following the Pharma Package, the existing requirements on the ERA will be supplemented with additional information obligations and responsibilities for pharmaceutical companies, including extending the scope of the ERA to manufacturing and antimicrobial resistance. In addition, the ERA requirements will have more teeth, and non-compliance can lead to serious consequences with respect to a company’s MA (application) and its products already on the market.
2.1 Medicinal products in scope of the ERA requirement
Under the Pharma Package, all MA applications are still required to include an ERA (Article 22 of the new Directive). Generic, biosimilar or (bio-)hybrid MA applications, MA applications based on consent of the MA holder, and MA applications for fixed-dose combinations may rely on studies conducted for the reference medicinal product(s) or on ERA studies of any other medicinal product containing the same active substances, when preparing their ERA (Article 22(7) of the new Directive).
For products authorized before 30 October 2005, the European Medicines Agency (EMA) will set up a program for the ERA within 30 months after the entry into force of the new Directive to require an ERA for products that have not been subject to an ERA and that are identified by the EMA as potentially harmful to the environment. For this identification as “potentially harmful to the environment”, the EMA shall set scientific criteria using a risk-based approach (Article 23 of the new Directive).
2.2 Requirements of the ERA
MA applicants will be required to evaluate possible risks to the environment or public health due to the release of the medicinal product into the environment following the use and disposal of the medicinal product, and identify appropriate risk prevention, limitation and mitigation measures. The applicant shall provide a detailed explanation that the proposed mitigation measures are appropriate and sufficient to address the identified risks to the environment. The ERA should further take account of the scientific guidelines prepared by the EMA as well as risk mitigation measures under existing EU standards and ERAs performed under such legislation, for example, the Groundwater Directive (2006/118/EC) and the Industrial Emissions Directive (2010/75/EU) (Articles 4(33), 22(1) and 22(3) of the new Directive). The ERA shall indicate whether the medicinal product or any of its ingredients or other constituents is persistent, bioaccumulative and toxic (PBT); very persistent and very bioaccumulative (vPvB); persistent, mobile and toxic (PMT); very persistent and very mobile (vPvM); or an endocrine active agent. Furthermore, the applicant should make proposals for appropriate labelling provisions in the MA application based on the ERA (Annex II, Part I, Section 1.6. of the new Directive). More specific technical details on the content of an ERA are still to be established by the EMA in scientific guidelines.
In addition, specific ERA requirements will apply to medicinal products with an antimicrobial mode of action. The ERA will have to include an evaluation of the risk for antimicrobial resistance selection in the environment caused by the entire manufacturing supply chain both inside and outside the EU, as well as by the use and the disposal of the medicinal product (Articles 4(33) and Article 22(4) of the new Directive).
2.3 Post-authorization requirements
Once an MA has been granted, the MA holder must continuously update the ERA without undue delay if new information becomes available that could change the conclusions of the ERA. This includes information on environmental monitoring, new or updated risk assessment under other EU legislation, eco-toxicity studies and environmental exposure data. Moreover, for an ERA conducted at any time before the Pharma Package becomes applicable, competent authorities can request an update of the ERA if missing information has been identified for medicinal products that are potentially harmful to the environment (Article 22(6) of the new Directive).
Transparency increases: (i) the European public assessment report (EPAR) will include a summary of the ERA studies and their results as submitted by the MA holder and the assessment of the ERA by the EMA (Article 16(3) of the new Regulation) and (ii) the EMA shall set up a public register containing previously conducted ERA studies (Article 104a of the new Regulation). Furthermore, EMA shall in collaboration with the competent authorities of the Member States set up an active substance-based review system of ERA data, so-called “ERA monographs” for authorized medicinal products. The Commission can adopt delegated acts specifying inter alia the use of ERA monographs in the context of new MA applications (Article 24 of the new Directive).
2.4 Sanctions
The new Directive and new Regulation contain several far-reaching measures that competent authority can take when companies do not provide adequate evidence that environmental risks were evaluated or that risk mitigation measures were taken:
Withdrawal of MA application: where the competent authority considers the MA application to be incomplete – and that includes any matters that should be dealt with in the ERA – it will set a time limit for submitting the missing information. If the missing information is not provided within the time limit, the application will be considered to have been withdrawn (Article 29(3) of the new Directive and Article 5(6) of the new Regulation);
Refusal of the MA: an MA can be refused in its entirety if the competent authority considers that (i) the ERA is incomplete or insufficiently substantiated or (ii) if the identified risks have not been sufficiently addressed by appropriate mitigation measures such as the requirement of a medical prescription (Article 47(1)(d) of the new Directive and Article 15(1)(d) of the new Regulation). This is not the case, when the applicant has duly justified and substantiated the reasons for the incomplete or insufficiently substantiated ERA, and the competent authorities consider that the MA can be granted subject to the condition to conduct post- authorization ERA studies or to implement risk mitigation measures (Article 47(1)(d) of the new Directive and Article 15(1)(d) of the new Regulation);
MA subject to condition: an MA can be granted subject to the condition to conduct additional post-authorization ERA studies, collect monitoring data or information on use, or to implement appropriate risk mitigation measures, where concerns need to be further investigated or mitigated after the medicinal product is marketed (Article 44(1)(h) of the new Directive and Article 12(4)(j), 13(1) of the new Regulation).
Even after a national or centralized MA has already been granted, competent authorities may still impose obligations to conduct additional post-authorization ERA studies and collect further monitoring data or information on use. In this case, the MA will be modified to include the obligation(s) (Article 87(1)(c) of the new Directive and Article 20(1)(c) of the new Regulation). If such obligation applies to several medicinal products, the competent authority shall encourage the MA holders concerned to conduct a joint post-authorization ERA study;
Revocation, suspension or variation of the terms of the MA: a granted national or centralized MA may be suspended, revoked or varied if a serious environmental risk or public health risk has been identified and not sufficiently addressed by the MA holder (Article 195(2) of the new Directive); and
Prohibition of supply or withdrawal of products from the market: in addition to the sanctions mentioned in the previous bullet point, the competent authorities of the Member States and, in the case of centralized MAs, the Commission may take measures to prohibit the supply or withdraw the relevant medicinal products from the market if a serious environmental risk or public health risk has been identified and not sufficiently addressed by the MA holder (Article 196(1)(f) of the new Directive).
3. Special case: ERA for medicinal products containing or consisting of GMOs
3.1 Clinical trial applications for medicinal products containing or consisting of GMOs
The current pharmaceutical legislation already requires companies to include an ERA in clinical trial applications with investigational medicinal products containing or consisting of GMOs.
Currently, requirements and procedures for the ERA and required written consent by competent authorities vary greatly from one Member State to another. Accordingly, experience shows that the current ERA procedure is complex and can take a significant amount of time for multi-national clinical trials involving medicinal products containing or consisting of GMOs, since sponsors need to submit multiple ERAs to multiple competent authorities in different Member States in parallel.
The Pharma Package foresees a centralized assessment of the ERA and replaces multiple time-consuming requests to national competent authorities. Article 177 of the new Regulation will amend Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use (CTR) by introducing a new Article 5a in the CTR. In contrast to the current Regulation, an ERA involving medicinal products containing or consisting of GMOs will in future no longer be submitted to national competent authorities but centrally via the EU portal CTIS. The language for the ERA shall preferably be English. The ERA shall be conducted in accordance with the principles set out in Annex II to Directive 2001/18/EC and the scientific guidelines developed by the EMA in coordination with the competent authorities of the Member States. The CHMP shall assess the ERA in the form of a scientific opinion and submit this opinion to the competent authority of the Reporting Member State
(RMS) within 45 days from the validation date. Where appropriate, the opinion shall include risk mitigation measures. The sponsor shall provide evidence to the RMS and the Member States Concerned (MSCs) that these measures will be implemented (new Article 5a(4) of the CTR).
The Commission shall be empowered to adopt a delegated act to amend the Annexes of the CTR for specifying the submission and the harmonized assessment of the ERA for investigational medicinal products containing or consisting of GMOs (new Article 5a(8) of the CTR).
3.2 MA Applications for medicinal products containing or consisting of GMOs
Besides the general requirements mentioned above, further specific requirements apply to ERAs in the context of MA applications for medicinal products containing or consisting of GMOs. The ERA should identify and evaluate potential adverse effects of GMOs on human and animal health and the environment and shall therefore contain, inter alia, a description of the GMO and the modifications introduced, a characterization of the finished product, an identification and characterization of hazards for the environment, animals and for human health, an exposure characterization and a risk characterization taking into account the magnitude and probability of the identified hazards, risk minimization and mitigation strategies, as well as an overall evaluation and conclusion (Article 7, 8 of the new Regulation).
4. Next Steps
4.1 Legislative timeline for applicability of Pharma Package and new ERA rules
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).
By five years from the date of application of the Pharma Package, the Commission shall present a report to the European Parliament and the Council on the application of Article 22 of the new Directive and the impact of the ERA of medicinal products on the protection of human health and the environment (Article 216(3) of the new Directive).
4.2 How to prepare
Pharmaceutical companies should prepare for the expanded ERA requirements in MA applications, which will include continuous monitoring and updating the ERA if information emerges that could change the conclusions of the ERA. Based on the newly codified sanction options, the industry should also establish measures to provide adequate evidence that environmental risks were properly evaluated and that necessary risk mitigation measures were implemented.
In addition, pharmaceutical companies should also be prepared for requests to update the ERA of an already authorized medicinal product.
Furthermore, regarding medicinal products authorized without any ERA requirement before 30 October 2005, pharmaceutical companies should closely monitor the ERA requirements and the classification of their products as “potentially harmful to the environment” by EMA.
The centralized submission and evaluation of ERAs for clinical trials involving GMOs represents a welcome simplification for multi-national clinical trials.
