“Delays in clinical trials result in delays of potentially life-saving treatments”
The European Commission is streamlining the rules for clinical trials of medicines consisting of, or containing genetically modified organisms (“GMOs”). Under the current EU GMO framework, getting authorization for clinical trials of GMO medicines is a long and costly process. Industry groups have vocally criticized it; and the Commission itself has voiced the need for change.
The Commission proposes a single, centralized application for clinical trials of GMO medicines. The sponsor will include a detailed environmental risk assessment with the application. In turn, the Commission will exempt clinical trials from the scope of many GMO rules. The new system will be leaner, greener and will get potentially life-saving treatments to patients with less administrative delay.
The changes are part of the EU’s new package of revisions to the bloc’s common pharmaceutical regime, set out in a draft Regulation and a draft Directive, published by the Commission on 26 April 2023. The new GMO medicines rules are just one part of a range of environment‑focused reforms to EU pharmaceutical law set out in the proposals — for more information, see our post here.
What are GMOs? Why are they regulated? Why do medicinal rules regulate them separately?
The term “genetically modified organisms” covers a broad range of animals, plants and products. The distinguishing feature, according to EU legislation, is that a GMO is an organism in which the genetic material has been altered in a way which does not occur naturally through mating and/or natural recombination (i.e. spontaneous mutation). Researchers and industry use genetic modification to create an organism with some useful trait e.g. a crop modified to be more resistant to disease or drought.
GMOs play an exciting — and increasing — role in modern medicine. Pharmaceutical companies can modify yeast or bacteria, so that they produce complicated medicinal compounds (e.g. vaccines or insulin). Many ATMPs, such as cell therapies and gene therapies, involve the supply of GMOs. Some COVID-19 vaccines used genetically modified viruses to carry COVID-19 genetic information into the human body (i.e. a viral vector).
However, genetic modification is complicated, and human understanding of genes and DNA is imperfect. Attempts to perform a particular modification can go wrong, or can have unintended side-effects. When GMOs are used in a lab, or research setting, scientists can put containment measures in place to ensure that the GMOs do not “escape” into the broader environment. Legally, this is known as “contained use” of the GMO. Containment measures can include using protective clothing, sterilizing equipment and treating contaminated waste.
However, in many cases, the end-goal of research to actually using the new technologies in the broader environment, often in a marketable product, such as a gene or cell therapy. Legally, this is known as “deliberate release” of the GMO. Deliberate release increases the risk. Once a GMO gets “into the wild”, it might undergo more genetic or phenotypic change; infect other organisms; compete with other species; reproduce; or transfer genetic material to other micro‑organisms, animals, plants or humans.
Using GMOs in medicines makes the inherent risks harder to control. After administration to a patient, the patient hosts and may excrete the medicine. Manufacturers will typically design medicines to be stable, meaning that the excreted GMOs may be — in some way — still active or functional.
Summary of existing GMO rules for human medicinal products
A. Clinical Trials
To address the risks associated with developing and using GMOs, the EU has created a framework of rules: the Contained Use Directive 2009/41/EC (“Contained Use Directive”) and the Deliberate Release Directive 2001/18/EC (“Deliberate Release Directive”), respectively (together, the “GMO framework”).
- The Contained Use Directive requires a site‑specific risk assessment (taking into account the site’s planned use of GMOs, and its containment measures), and a notification to the national competent authority for GMOs (“NCA”). For high‑risk uses of GMOs, the NCA must grant consent before the use begins.
- The Deliberate Release Directive requires a persons that deliberately releases GMOs into the environment — whether by using GMOs in a way that is not contained use, or by placing GMO‑containing products on the market — to submit a detailed environmental risk assessment (“ERA”) to the NCA, and to get an authorization before releasing any GMOs.
- The GMO framework does not exempt investigational medicinal products. This creates two, related problems for clinical trials of human medicines.
- First, it means that a sponsor often has to make two separate applications before commencing the trial: one application for permission to conduct the clinical trial itself (via the Clinical Trails Information System, CTIS, under the Clinical Trials Regulation (EU) 536/2014 (“Clinical Trials Regulation”)); and another to use GMOs, under the national implementation of either the Contained Use Directive or Deliberate Release Directive.
- Second, because the GMO framework is set out in EU Directives, its provisions are not directly applicable and each EU Member State has to implement the rules into national law. Inevitably, different Member States take slightly different approaches. Some Member States require all trials to be authorized under the Contained Use Directive; other Member States regulate all trials under the Deliberate Release Directive; still others apply one or the other Directive, depending on the structure of the clinical trial.
Industry position papers have suggested that the additional requirement for sponsors to make a GMO application may delay the start of a clinical trial by up to 12 months. Aside from the potential for a time-consuming and duplicative application process, national GMO authorities may not have the expertise required to assess a GMO medicine (see here and here).
The current reality is that GMO clinical trial applications are difficult, and GMO clinical trial applications for trials that take place in multiple EU Member States are even more difficult. EFPIA recently put the issue into sharp language, stating that “[d]elays in clinical trials result in delays of potentially life-saving treatments” (EFPIA, Call for more effective EU regulation of clinical trials with Advanced Therapy Medicinal Products consisting of or containing Genetically Modified Organisms, 2020). The problem came into particular focus in 2020, when — faced with urgent need for GMO‑based vaccines on the one hand, and the bottleneck created by the GMO framework on the other — the EU temporarily exempted investigational COVID-19 treatments and vaccines from many provisions of the GMO regime (Regulation (EU) 2020/1043).
The GMO framework does not contain any exemption for manufacturing GMO medicines. In most cases, manufacturing is likely to take place within the scope of the Contained Use Directive. This means that manufacturers may need to notify the NCA and obtain consent under local GMO legislation.
C. Marketing Application Authorization
Under the Clinical Trials Regulation, applications for a marketing authorization (“MA”) of a human medicine must include an ERA, drawn up according to the requirements set out in Annex II of the Deliberate Release Directive.
In most circumstances, before placing a GMO product on the market, a company must submit an ERA to, and get authorization from, the NCA. However, because pharmaceutical manufacturers need to submit an ERA along with the MA application for a GMO medicine, the GMO framework provides a carve-out for human medicines. Once a medicine is authorized, manufactures can place it on the market, without any GMO-specific notification or consent.
New framework under the proposed revisions to EU pharmaceutical legislation
The proposals address GMOs in two respects. First, and most importantly, the proposals exempt clinical trials of GMO medicines from the scope of the Deliberate Release Directive. Second, the proposals harmonize, and add detail to the requirement to submit an ERA along with a MA application.
A. Clinical Trial Applications
The proposed Regulation modifies the Clinical Trials Regulation, and provides that investigational medicinal products will be exempt from the requirement, contained in the Deliberate Release Directive, to apply and secure authorization for deliberate release of GMOs.
The proposed Regulation also provides that a sponsor must submit an ERA with any clinical trial application for a GMO medicine. The sponsor must draw up the ERA in accordance with the requirements set out in Annex II of the Deliberate Release Directive, and the EMA’s scientific guidelines. The Committee for Medicinal Products for Human Use (“CHMP”) will assess the ERA and issue a scientific opinion. CHMP can also ask the sponsor for more information to assist its assessment.
In Member States where sponsors are currently required to make applications for authorization under both the Clinical Trials Regulation and the local implementation of the Deliberate Release Directive, this proposal should dramatically streamline the application process. Further, since the ERA will be assessed by CHMP, instead of GMO NCAs, the ERA will be assessed by experts in human medicines, with the particular issues and standards relevant to human medicines in mind. In addition, since the proposed change is set out in a Regulation rather than a Directive, it will apply directly across Member States, ensuring a harmonized approach across the EU.
That said, the proposals do not completely exempt clinical trials from the GMO framework. The proposals do not change the application of the Contained Use Directive. Therefore, in some jurisdictions, trial sites may still be required to notify, and get consent from NCAs before engaging in contained use of GMOs.
B. MA Application
The proposals also update and harmonize the rules around the authorization and placing on the market of GMO medicines. The proposed Regulation provides that the MA Application of a medicinal product containing or consisting of GMOs must be accompanied by an ERA, drafting in accordance with Art. 8 of the proposed Regulation and Annex II of the proposed Directive, and based on the principles set out in Annex II to the Deliberate Release Directive. CHMP will assess the ERA, and may consult with NCAs or other EU bodies.
C. Placing on the market in exceptional cases
The proposed Regulation also provides that Member States can allow manufacturers to place unauthorized GMO medicines on the market, in response to: (i) individual patient needs; (ii) a public health emergency; and under (iii) a compassionate use programme (Reg. Art. 7). In those cases, an ERA is not a prerequisite. However, Member States need to implement measures to “minimise foreseeable negative environmental impacts”.
Conclusions and takeaways
It is an exciting time for GMO medicines. Researchers are constantly developing and refining new applications for GMOs. The new EU GMO medicines rules may help to get those applications to patients sooner.
The new rules will not eliminate the regulatory burden: sponsors will have to include a comprehensive ERA in MA applications, which the EMA will scrutinize in detail. Sponsors of clinical trials may also have to notify and secure consent for site‑specific contained use. Manufacturers of GMO medicines may still need to notify the local competent authorities and obtain consent for manufacturing activities. In addition, sponsors and manufacturers may still need to consider transport of dangerous goods rules. Authoriz ed medicines are generally exempt from transport of dangerous goods rules, but genetically modified microorganisms (GMMs), GMOs and medical/clinical waste may still be covered. Therefore, biological material, including the GMO product, and patient tissue samples, may need to be assessed against the criteria set out in the transport of dangerous goods regime, to determine whether there is sufficient risk to humans or animals such that the packaging, labelling and transport rules apply.
However, the cross-EU harmonization, and the new, single application should cure quite a few regulatory headaches. This blog is based on the wording of the EU’s proposal published on 26 April 2023. This wording could significantly change during the legislative process. Our Dublin, Brussels, Frankfurt and London teams will continue to monitor this legislation. We will be hosting a webinar to discuss the impact on 9 May. To sign up for the webinar please click here.
 Directive 2001/18/EC, Art. 1.