To address challenges faced in Europe’s pharmaceutical sector, the European Commission (EC) has proposed a new pharmaceutical strategy for Europe¹. This patient-centred strategy aims at creating a future-proof regulatory framework to ensure that patients have access to high-quality, effective and safe medicines, while boosting the sector’s global competitiveness.
On 26 April 2023, the EC adopted a proposal to revise and replace the existing general pharmaceutical legislation2. The proposed changes were drawn up with the objective to ensure a future-proof and crisis-resistant medicines regulatory system3.
One aspect of the package’s revisions addresses medicines consisting of, or containing, genetically modified organisms (GMOs), or for short, ‘GMO medicines’. These medicines include many viral vector-based vaccines and advanced therapy medicinal products (ATMPs) such as gene therapies. The current European legislative framework governing GMOs is not specific to medicines but applies to all organisms in which the genetic material has been altered in a way which does not occur naturally (as defined in Directive 2001/18/EC). As a direct result, initiating clinical trials for GMO medicines can be complex, and time and resource consuming.
The current regulatory framework governing GMOs in the EU contains two Directives, the Deliberate Release Directive 2001/18/EC (DR Directive) and the Contained Use Directive 2009/41/EC (CU Directive). As EU Directives are implemented into local law by each EU member state, this provides flexibility for national interpretation. Consequently, application requirements and administrative procedures differ significantly between EU member states, both in terms of classification of the clinical study (which Directive applies – CU, DR or both), the application process, responsible agencies, submission requirements, review timelines and potential publication obligations.
A similar problem of country-specific variability due to national interpretation of EU Directives previously existed for clinical trial applications. The proposed solution to this was the introduction of the Clinical Trial Regulation (EU) No 536/2014 (CTR) which came into effect on 31st January 2022 (replacing the Clinical Trials Directive 2001/20/EC (CTD)). The main aim of the CTR was, and is, to harmonise the clinical trial application submission and assessment procedure for trials in multiple EU countries and provide a single outcome without the need for multiple national applications and associated variable assessment timelines. Unfortunately, the CTR excludes the GMO Directives from its scope and GMO medicines still require separate GMO applications in each EU country in which the clinical trial is planned to take place. The net result is that there is still an extra layer of complexity to gain approvals for GMO medicines, especially in multi-national EU clinical trials. The challenge of managing the complex interplay between these requirements has been flagged by many stakeholders and acknowledged by the EC to be addressed as part of the proposed changes to the Pharmaceutical Legislation4.
The reform of the pharmaceutical legislation aims at harmonising submission and review of the risk assessment for GMO medicines with the clinical trial application procedure, resulting in aligned assessment timelines. Under the adopted proposal, separate national applications under the GMO Directives would no longer be required. Instead, a single application in the form of a GMO risk assessment would be submitted alongside the clinical trial application using the same portal, as an independent part of the application. The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) would review the GMO risk assessment and provide a scientific opinion. If gaps in the risk assessment are identified, further information can then be requested, using a process that is harmonised with the timeline for questions arising from review of the clinical trial application. EMA would only consult with the national GMO competent authorities when an application contains a first-in-class product, or novel questions arise during the assessment. The proposal also details the content requirements of the GMO risk assessment, taking existing streamlining approaches such as common application forms and published risk assessments for more common GMO medicine product types5 into account. It also clarifies that local language translations should not be required. Furthermore, the current need to publicly communicate any GMO application under the DR framework to the EC (in the form of a ‘summary notification information format’ – SNIF6) would be removed for clinical trial applications for GMO medicines, and harmonised labelling requirements for GMO medicines are proposed.
The proposed updates, aimed at removing the fragmented national requirements and at streamlining inclusion of the GMO risk assessment into the harmonised clinical trial applications, are a welcome step towards an improved clinical trial framework for GMO medicines in the EU. The hope is that no additional national requirements would be required in future, and that the updates will allow a risk-proportionate approach especially for product categories with negligible environmental risks for which a lot of experience has been collected over the recent years.
While the revised proposals still provide assurances that novel, innovative medicines in clinical trials are safe from an environmental risk perspective, a well-implemented harmonised approach could reduce unnecessary complexity and administrative burden, making clinical trial start-up timelines more competitive, and ultimately expedite patient access.
(1) European Commission. A pharmaceutical strategy for Europe. 25 November 2020. Link: https://health.ec.europa.eu/medicinal-products/pharmaceutical-strategy-europe_en Last accessed 19 October 2023.
(2) European Commission. Reform of the EU pharmaceutical legislation. 26 April 2023. Link: https://health.ec.europa.eu/medicinal-products/pharmaceutical-strategy-europe/reform-eu-pharmaceutical-legislation_en Last accessed 11 October 2023.
(3) European Commission. Have your say: Revision of the EU general pharmaceuticals legislation. Link: https://ec.europa.eu/info/law/better-regulation/have-your-say/initiatives/12963-Revision-of-the-EU-general-pharmaceuticals-legislation_en Last accessed 9 November 2023.
(4) Ruehle S, Omnes P, Parsley K, et al. Evolution of GMO requirements for innovative investigational medicinal products upon transition to the EU CTR. Regulatory Rapporteur, 2023;20(5).
(5) European Commission. Advanced Therapies. Link: https://health.ec.europa.eu/medicinal-products/advanced-therapies_en Last accessed 19 October 2023.
(6) Pursuant to article 11 of Directive 2001/18/EC6 and published on the Council Decision 2002/813/EC. Link: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex:32002D0813 Last accessed 19 October 2023.