Joint Press Release on ATMPs and GMOs in Europe

Possible solutions to improve the European regulatory procedures for clinical trials with Advanced Therapy Medicinal Products consisting of or containing Genetically Modified Organisms

Introduction

The objectives of this position paper are to:

- Summarize the issues faced by sponsors relating to Genetically Modified Organisms (GMOs)applications which are currently required in the European Union prior to conducting clinical trialswith Advanced Therapy Investigational Medicinal Products (ATIMPs) consisting of or containingGMOs;
- Describe how these issues will be further compounded by the introduction of the Clinical TrialsRegulation (EU) No 536/2014;
- Propose solutions to improve the application and assessment process in order to supportEuropean competitiveness with regard to biomedical innovation, including ATIMPs in both thenear term and long term and avoid unnecessary delays in patient access to these innovativemedicines.

Background

Advanced Therapy Medicinal Products (ATMPs) such as Gene Therapy medicinal products (GTMPs) are innovative medicinal products which have the potential to bring high transformative value to patients, including potential cures, by either correcting the underlying cause of their disease (e.g. a genetic defect) or by modifying a function in the body to cure or significantly ameliorate their disease.

The European Union (EU) created the Advanced Therapy Medicinal Product (ATMP) Regulation in 20071 to detail specific registration considerations for ATMPs that comprise somatic cell therapy medicinal products, tissue engineered products, and gene therapy medicinal products. The European Medicines Agency (EMA) has now approved 8 ATMPs, four of which are either gene therapy or cell therapy products containing genetically modified cells (Glybera®, Strimvelis®, Zalmoxis® and Imlygic®). This number is higher than in other regions of the world and thereby, a relatively positive environment for further development of new gene therapies or other types of ATMPs consisting of and/or containing GMOs has been created in Europe. Examples of approved gene therapy products include hematopoietic stem cells or T cells that are genetically modified ex-vivo with a lentiviral vector or a gamma retroviral vector, and in-vivo gene therapies with adeno-associated viral vectors administered via local or systemic administration.

As for any new medicine, well-designed and adequately controlled clinical trials to demonstrate the safety and efficacy of ATMPs consisting of or containing GMOs must be conducted prior to their approval. However, due to their GMO status, these products require additional steps in the clinical trial authorisation procedure as outlined below.

For each clinical trial application, there are three levels of review, which are often performed by separate national agencies:

1. Standard review of a Clinical Trial Authorisation (CTA) application, regulated under Directive 2001/20/EC, which in the EU is a national Member State responsibility (although this will change with the revised Clinical Trials Regulation2 expected to come into force in 2019).
2. Ethics review, through which specific issues relating to the use of the GMO are commonly assessed. EU Member States normally assign this review to national or regional agencies with specialist expertise in gene therapies.
3. Additionally, and specifically for products consisting of or containing a GMO, a review of the environmental and biosafety aspects of the use/release of the GMO.

The latter requirement is a complicating factor since these assessments are based on GMO legislation (detailed below) which is designed mainly to cover crops and animal genetic modification rather than medicinal products.

In addition, and most importantly, the recent adoption of the Clinical Trials Regulation2 aiming at facilitating the conduct of clinical trials in the European Union and which sets out to harmonize clinical trial requirements across the EU, does not cover the additional requirements associated with GMO assessments. Therefore, concern is now being raised as to how it will be possible to obtain these national approvals once the new legislation is fully adopted.

The issues relating to the cumbersome and lengthy processes for completing GMO application were discussed in May 2016 during an EMA workshop to explore solutions to foster development of ATMPs3. This workshop included participation of multiple stakeholders, including national competent authorities, the European Commission, small and large companies, as well as leading academics and researchers, patients and healthcare professionals’ organizations, etc.

The topic of GMO applications was also discussed during a dedicated meeting at the European Commission on 8 November 2016 and a conference co-sponsored by EMA and the European Biopharmaceutical Enterprises (EBE) on 16 December 2016 (ref: EMA/853948/2016).

Existing regulations for the GMO review process

The main pieces of legislation applying to ATIMPs consisting of or containing GMOs4 are:

• Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms;
• Directive 2009/41/EC on the contained use of genetically modified micro-organisms;
• Regulation (EC) 1946/2003 on transboundary movements of genetically modified organisms.

The two Directives have been implemented in the national legislation in each Member State with significant differences between Member States. This has the effect of different documentation request and different review and approval frameworks between the Member States.

For example, according to Article 2 of Directive 2001/18/EC, a genetically modified organism (GMO) is defined as follows: ”an organism, with the exception of human beings, in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination.”

And in accordance with the same Directive, an “organism” is defined as: “any biological entity capable of replication or of transferring genetic material”.

Thus, while some gene therapies are by definition GMOs, the applicability of this definition to other gene therapy products, such as genetically modified cells, is not obvious. However, without a clear derogation from the GMO Directives, all such products need to follow both the medicinal products and GMO legislations.

The legislation leaves some room for interpretation and for multi-state trials, there can be dissimilarities in classification by Member States as ‘contained use’ or ‘deliberate release’ regulations or in the definition of GMO. This creates some difficulties for applicants in the authorization of multinational clinical trials as outlined in the document.

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Conclusions

Currently there is no harmonized framework for the assessment and approval of ATIMPs consisting of or containing GMOs. The disparity between authorities and requirements at Member State level make applying for clinical trials for such ATIMPs a lengthy and cumbersome exercise. However, the application and approval process will become even more challenging upon the introduction and full implementation of the Clinical Trials Regulation (EU) No 536/2014.

ARM, EFPIA, EBE and EuropaBio would welcome any initiative aiming at facilitating the dialogue among the different GMO authorities in the EU Member States to improve the currently fragmented system and ultimately aiming at developing a framework compatible with the requirements of the Clinical Trials Regulation.

Without the suggested harmonisation and simplifying of the GMO registration process for clinical trials with ATIMPs consisting of or containing GMOs, it will be difficult for developers to leverage the advantages of the improved Clinical Trials Regulation and on the contrary, it may act as a disincentive for companies to conduct clinical trials with ATIMPs consisting of or containing GMOs in the European Union.

The access by patients to new medicinal products, in particular when these are potentially curative or transformative, should be facilitated and the review time for clinical trials applications optimized without compromising the patient and environmental safety. The proposed solutions would help to ensure that development of such innovative medicines is facilitated and unnecessary delays are avoided.

Download the file below to read the full Letter.