EU pharma package: Environmental risk assessments for medicinal products

The EU pharma package is the European Union's effort to fundamentally reform environmental risk assessments for medicinal products. In future they will not simply be a formal requirement in the authorisation procedure to review these; instead they will be afforded substantive significance for the first time. This article reveals what changes the draft of the New Medicinal Products Directive entails related to how environmental risks are considered in the authorisation of medicinal products.

To date, the applicable law on medicinal products for human use has largely prioritised "furnishing the population with a proper supply of medicinal products" (see section 1 German Medicinal Products Act (AMG)) over environmental concerns. Under the latest drafts of the EU pharma package, this is now set to change in the procedure for authorisation. In the course of reforming the Directive on medicinal products for human use and the European Medicines Agency Regulation, the European Union identified the contamination of bodies of water and soils with residues of medicinal products in particular as a growing environmental problem and therefore declared that improving the environmental impact of medicinal products would be a goal of the reform.

Environmental risk assessment in applicable medicinal product authorisation law

Finished medicinal products may only be placed on the market within the purview of the German Medicinal Products Act (AMG) if they have been authorised either at the national level or through a centralised procedure by the Commission section 21 (1), sentence 1 German Medicinal Products Act (AMG)). Documents, in particular regarding the environmental risk assessment (ERA for short), must also be submitted with the application for authorisation. If storage of the medicinal product, its application or disposal of its waste requires particular precautionary or protective measures to avoid hazards for the environment or the health of humans, animals or plants, this must be stated. If the ERA documents are not submitted or are not submitted in full, authorisation can be refused on formal grounds. 

By contrast, refusal on substantive grounds is out of the question. The substantive grounds on which authorisation may be refused are ultimately derived from section 25 (2) German Medicinal Products Act (AMG). However, the environmental incompatibility of a medicinal product is not grounds for refusal under this provision, even if less environmentally damaging alternatives exist.

This demonstrates that under the current law on the authorisation of medicinal products for human use, environmental concerns are categorically subordinated to health-focused objectives. The significance of the ERA is limited to a purely procedural obligation to submit documentation. 

EU pharma package: The changes expected to apply to ERAs in the future

In adopting the EU pharma package, the European Union has set itself the goal of improving the environmental impact of medicinal products. The following changes are expected to apply to ERAs in the future:

New definition of and expanded requirements for the environmental risk assessment

Article 4 (1) No. 33 New Medicinal Products Directive establishes a legal definition of the ERA under the law on medicinal products for the first time. According to the directive, this includes assessing the risks to the environment or to public health posed by the release of the medicinal product into the environment following its use and disposal, as well as determining measures for risk prevention, limitation and mitigation.

Particular attention is paid to medicinal products with an antimicrobial effect: In this case, the ERA is also supposed to assess the risk of a selection of antimicrobial resistances in the environment over the entire life cycle of the medicinal product, including during the production stage.

Along with risks of unintended effects on the health of the patient or on public health and on the environment, at the same time the risk of undesired effects on public health caused by the release of the medicinal product into the environment, including antimicrobial resistances, is being made an explicitly mandatory component of every ERA (Article 4 (1) No. 35 (a) to (c) New Medicinal Products Directive).

The content of the specifications for the ERA is outlined in detail in Article 6 (2) in conjunction with Annexes I and II as well as in Article 22 New Medicinal Products Directive. These state that the ERA is generally to be conducted in compliance with the scientific guidelines from the European Medicines Agency (EMA). The applicant must indicate whether the medicinal product contains one of the substances listed in these guidelines, particularly one that is hazardous to the environment (e.g. endocrine active substances). In the case of antimicrobial medicinal products, the ERA must ultimately also include an assessment of the risk of the selection of antimicrobial resistances in the environment – a risk which follows from the entire industrial supply chain inside and outside the European Union and the application and disposal of antimicrobial agents. The authorisation application for an antimicrobial medicinal product must include additional information (see Article 17 New Medicinal Products Directive).

To date, submission of an ERA has not been required for medicinal products authorised before 30 October 2005. To close gaps in knowledge regarding the environmental risks of these "old medicinal products", Article 23 New Medicinal Products Directive establishes a requirement for an ERA to be submitted in arrears for these medicinal products if they have been classified as potentially environmentally damaging by the EMA. The EMA will publish the criteria for this 30 months after the Directive comes into effect.

ERA to be made a substantive criterion for authorisation of medicinal products

A significant amendment can be found in the catalogue of permissible grounds for refusal. According to this, authorisation can now be refused not just on formal grounds but also if the applicant has not given sufficient consideration to the identified risks, including in not taking measures to mitigate risks (Article 47 (1) (d) New Medicinal Products Directive and Article 15 (1) (d) New Medicinal Products Regulation).

However, when the medicinal product is authorised, if there are established or potential concerns arising from environmental risks that must be investigated further after the medicinal product has been placed on the market, the authorisation must not be refused if it can be granted under the condition that the applicant conduct post-authorisation environmental risk assessment studies, collect monitoring data or information on use or take certain appropriate mitigating measures (Article 44 (1) (h) New Medicinal Products Directive).

The proposed reform therefore upgrades the ERA from just a procedural duty to submit documentation to a genuine criterion for inspection. The authorisation is to be refused on formal grounds if the applicant simply records, illustrates and discusses the identified environmental risks in the documents. Another substantive criterion for authorisation is the quality of the data generated and of the risk assessment: The ERA must satisfy the requirements of the scientific guidelines of the EMA. Furthermore, the conclusions drawn must be reasonable, meaning they must not contradict the current state of scientific knowledge or be obviously disproportionate in how they weigh benefits and environmental risks. There is also now set to be the option to review the suitability and reasonableness of the mitigating measures provided for, meaning that the quality of these measures will potentially be relevant to the authorisation.

The result however remains that undesirable effects of the medicinal product on the environment cannot stop authorisation from being granted – even if they have been assessed as unreasonable in the ERA. This is because the risk/benefit assessment still only takes risks into account that are connected to the quality, safety or efficacy of the medicinal product as it relates to the health of the patient or to public health. Risks to public health that result indirectly from the release of the medicinal product into the environment are irrelevant to the assessment. 

Against this background, necessary measures to avoid or limit environmental risks are only to be provided for if they do not run contrary to the health-related goals to which the law around medicinal products is primarily committed. Just as before, the therapeutic benefit of a medicinal product for patients is still not weighed against its environmental risks.

ERA monographs from the EMA: Greater consistency in environmental assessments

Another addition to the authorisation system is the establishment of an active-substance-based review system of ERA data by the EMA (Article 24 New Medicinal Products Directive). These "ERA monographs" are intended to consolidate ERA data on active substances in various medicinal products into one standardised format. This is to increase consistency in regulatory decisions, improve data availability and facilitate compatibility with instruments under water law and chemical law.

This system is also expected to offer benefits for applicants and authorisation bodies (Article 25 (1) New Medicinal Products Directive): For one thing, they can make use of the scientific expertise stored in the monographs to conduct a new ERA. For another, instead of submitting the required relevant ERA data themselves, applicants may rely to this end on an equivalent certificate from the EMA confirming that the quality of the active substance in question is already suitably controlled by the relevant ERA monograph.

The active-substance-based monograph system thus recognisably follows the "one substance, one assessment" approach in the EU's Green Deal.

Conclusion

• The ERA is being made a key component of authorisation for medicinal products and its importance is being bolstered considerably by being upgraded from a formal duty to submit documents to a substantive criterion for authorisation.
• In future, applicants must perform more comprehensive assessments of environmental risks and prove they have taken suitable measures to mitigate risks.
• Pharmaceutical companies should integrate the new requirements into their authorisation strategy and documentation at the earliest opportunity.
• The new ERA monograph system at the EMA is intended to improve the quality, comparability and reusability of environmental data.
• Despite the greater consideration given to environmental concerns, the benefit to patients nonetheless remains the crucial criterion in the authorisation decision.
• Although the greater consideration given to environmental concerns in the authorisation procedure is to be commended in principle, this must not obscure the fact that the development of medicinal products is a laborious and costly process. Imposing a further administrative burden on the pharmaceutical companies due to new environmental investigation and documentation obligations carries the risk of slowing down the development of medicinal products and ultimately stifling innovations as a result.