Is it time to reform oversight of clinical gene therapy in the EU?

In their recent perspective published in the New England Journal of Medicine, Francis S. Collins, director of the US National Institutes of Health (NIH), and Scott Gottlieb, commissioner of the US Food and Drug Administration (FDA), propose reducing oversight regarding their organizations' regulatory redundancy by eliminating the NIH's Recombinant Advisory Committee's review and reporting of human gene therapy protocols 1. If these proposed changes come into effect, the future review of clinical gene therapy in the US will no longer be done by two separate organizations (i.e. NIH‐RAC and FDA) but will be done by one organization only (i.e. the FDA). The reviewing process will become both more efficient and consistent with current processes for reviewing other types of clinical research conducted in the US. In the new situation, it will be clear for all stakeholders which organization is responsible and accountable for the authorization of clinical gene therapy trials in the US. This is particularly important to keep the trust of the society in clinical gene therapy should incidents take place. This proposal for reform should be a wake‐up call for the European Committee (EC) to consider changing the current system for overseeing clinical gene therapy in the European Union (EU), which has largely failed to keep up with scientific progress regarding clinical gene therapy.

In the EU, several directives apply to clinical gene therapy. The process for reviewing the benefit‐to‐risk ratio for patients who participate in clinical trials using medicinal products, including gene therapy, is currently regulated by the 2001 EU directive entitled ‘Good Clinical Practice 2001/EC’. In this directive, the review period for ‘classic’ medicinal products is 60 days; for clinical gene therapies, the directive allows an additional 30 days for review. This additional review time was understandable at the start of the century, when the gene therapy field was still in its infancy and the process for assessing benefits and risks was hampered by several factors, including limited knowledge regarding the use of early‐generation gene therapy vectors. This is illustrated by the tragic death of a young Dutch patient with X‐SCID (X‐linked severe combined immunodeficiency) who participated in a gene therapy clinical trial designed to treat immune deficiency 2. Fortunately, lessons were learned from this case, and better and safer gene therapy vectors have been development and are now applied in gene therapy trials. Since the EU directive ‘Good Clinical Practice 2001/EC’ came into effect back in 2004, it has been widely criticized, and the scientific community has called upon the EC for reform 3. As a result, the EC will replace the 2001 directive with the new ‘Regulation 536/2014 on clinical trials on medical products for human use’, which is expected to come into effect in 2020 4. According to this new EU regulation, clinical gene therapy is still regarded as a special case, and the review period for gene therapy products can be extended by an additional 50 days.

On top of the above described directive covering the review on the benefits and risks for patients participating in clinical gene therapy trials, the EU has implemented legislation on the assessment of the environmental risks of genetically modified organisms (GMOs), which include genetically modified foods, as well as recombinant DNA laboratory studies and clinical gene therapy trials with GMOs. This system is based on two separate directives, the 2009 EU directive entitled ‘Contained use 2009/41/EC’ and the 2001 EU directive entitled ‘Deliberate release in the environment 2001/18/EC’; these directives apply to clinical gene therapy due to concerns originally raised in the early days of DNA recombinant techniques regarding the spread of gene therapy vectors into the environment. However, after more than 25 years of scientific progress in the development of safer gene therapy vectors and experience based on numerous clinical gene therapy trials worldwide, we can now conclude with confidence that the environmental risks associated with this therapy are negligible. Unfortunately, the two aforementioned environmental EU directives largely failed to keep up with the scientific progress and gene therapy vector development and still apply to clinical gene therapy trials, presenting an additional and separate assessment process which is not integrated in the aforementioned review on the benefits and risks for the patients.

The environmental risk assessment in the EU members states is generally done by governmental organizations associated with the departments covering environmental affairs. In the UK, for instance, the release of GMOs for research purposes is granted by the Secretary of State for the Environment and applications are processed by Department for Environment, Food and Rural Affairs (DEFRA). In the Netherlands, a permit is required from the Minster of Infrastructure and Water Management, and applications are processed by the GMO Office. The processes for these permits require even more extensive review periods and are poorly harmonized within the EU 5. In the UK, for instance, clinical gene therapy with GMOs is regulated under the contained use or the deliberate release frameworks depending on the biological characteristics and environmental risk assessment of the GMO (i.e. virus shedding). In the Netherlands however, the deliberate release framework always applies independent of a risk of virus shedding. This results in a lengthy assessment procedure on all gene therapy trials in the Netherlands 6.

Clinical gene therapy began in the 1990s as a promising new field, but the initial results were disappointing. Major mistakes – with severe consequences – have been made, which could have been prevented by better preparation and a more thorough understanding of the risks for the patients involved 7. However, lessons have been learned, the field is now considerably more mature, and new ex vivo gene therapy–based treatments are available for life‐threatening diseases 8. Indeed, several gene therapy products were recently approved by regulatory agencies in the EU, the US and elsewhere.

The original idea behind clinical gene therapy was to repair genetic diseases; however, the ability to specifically correct genetic defects was – until recently – not possible. New methodologies such as CRISPR/Cas9‐mediated genome editing become available to repair DNA mutations with high precision, thereby treating – or even preventing – devastating diseases such as sickle cell anaemia. Of course, proposals for clinical trials to test these novel interventions require a thorough review by multidisciplinary experts in order to safeguard patients, and such a review should ideally use a structured approach for assessing risk 9. This is essential, as identifying any possible adverse effects associated with these emerging technologies requires rational scrutiny and careful monitoring 10, 11; however, these concerns are not necessarily relevant with respect to environmental risks. It is therefore worrisome that the recent European Court of Justice's decision regarding the scope of the GMO directives may also affect new clinical gene therapy approaches 12; if so, this will undeniably hinder development of these novel medical interventions in the EU.

Given these considerations, it is time for the EU to consider following the example set by the US in which only one organization will be responsible and accountable for the review of clinical gene therapy trials. The EU Parliament and European Committee should consider proposals to change the current system for overseeing clinical gene therapy in the EU, particularly with respect to environmental legislation, thereby stimulating further scientific progress and ultimately benefiting the patient community.

One possible solution is to exempt clinical gene therapy research (and other clinical trials with GMOs) from the EU GMO legislation and integrate an environmental risk assessment in the EU clinical trial legislation framework and no longer consider gene therapy as a special case which require longer review timelines. If this proposal will be adapted, the future review of clinical gene therapy in the EU will no longer be done by separate organizations under disconnected legal frame works. It will lead to a more efficient review process and – importantly – appropriate safeguarding of patients and environment. In addition, this will increase the transparency on the approval process and will make it for all stakeholders crystal clear which organization is responsible and accountable for the approval of gene therapy studies in each EU members state.

Competing Interests

There are no competing interests to declare.

M.J.H.K. is the former director of the CCMO, the Dutch Competent Authority on drug trials and the assessment body for clinical gene therapy in the Netherlands. He is currently the director of the Paul Janssen Futurelab of the Leiden University Medical Center.

This work was supported by the Netherlands Organization for Health Research and Development (ZonMw), project number 80‐83600‐98‐13011.