First published in our Biotech Review of the year – issue 9.

There aren’t enough viruses. At least, there are not enough engineered ones, the viral vectors used in gene therapies such as Novartis’ CAR-T based Kymriah, to whack a nucleic acid into a cell. It’s not hard to see where the demand is coming from. At over 700, the number of trials of gene therapy medicinal products (GTMPs) taking place across the globe has more than doubled in five years, with between 10 to 20 cell and gene therapy medicinal products expected to be approved by 2025 in the US alone. Most of these GTMPs are vectored. But the appetite of GTMPs for vectors is nothing compared to that of vaccines. Although the vaccines in the limelight, the mRNA products of Pfizer-BioNTech and Moderna, use lipid nanoparticles instead of viral vectors, they have their own component supply issues and are more expensive and difficult to produce and transport than vectored vaccines, which comprise about 22% of all the COVID-19 vaccines needed by the world’s population. The Oxford-AstraZeneca  COVID-19 vaccine is an example: it uses a modified chimpanzee common cold viral vector to deliver DNA coding for the SARS[1]CoV-2 spike protein into cells. The net effect is that vector demand now far outpaces production capacity, significantly impacting manufacturers and contractors, who are concertedly recruiting experts in vector manufacture and scale-up, building facilities, acquiring niche businesses and developing technologies for improving efficiency.

Don’t be misled by a nostalgia for the growth pains of monoclonal antibody production. Vector manufacturing is not only harder, but demands higher biosafety levels, wandering as it does into a territory notorious for impeding the availability of products: GMO regulation. If we can unblock the manufacturing logjam, we’ll also have to fix the regulations.

As a “biological entity capable of transferring genetic material”, a viral vector is an “organism” in EU and UK law. As its “genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination” it is a “genetically modified” organism, or “GMO”. Consequently, most GTMPs and all vectored vaccines are GMOs. Unfortunately, however, neither of the two core GMO Directives[1], one on contained use and the other on deliberate release, contemplate the use of GMOs in medicines. This has some unfortunate effects.

With no common EU approach for assessing the risk to the environment and human health of GMO investigational medicinal products (IMPs), different Member States take different approaches. Faced with a proposed trial for an GMO-IMP vaccine, some states apply the deliberate release Directive, others the contained use Directive, while still others decide on a case-by-case basis, or apply both Directives simultaneously to different operations within the same clinical trial, with a single request for authorisation to conduct a clinical trial being submitted to a single national competent authority along with the GMO aspects, unlike those states in which parallel requests need to be submitted to different competent authorities. On top of this, national requirements about matters such as the content of the technical dossier, the procedures for the environmental risk assessment, and authorisation for deliberate release, vary greatly across Europe. Take the UK (which has implemented the pre-existing EU legislation). If you obtain authorisation to carry out a clinical trial in the UK of an IMP that uses an adeno-associated viral vector to express a human heart calcium transporter gene, the approval letter may well carry a scene of haystacks in rolling countryside, being the logo of ACRE, the non-departmental public body advising the Department for the Environment and Rural Affairs on the deliberate release of GMOs. Even allowing for the UK going its own way, it feels rather odd.

Multi-centre trials may be crucial when the target indication is a rare disease, as it often is with a gene therapy, and it’s here that the lack of harmonisation of GM medicines presents the most serious impediment to GTMP developers. To have to submit multiple requests for authorisations to multiple competent authorities in different Member States in parallel is a considerable burden for trial sponsors. Attempts to streamline the process through informal coordination between Member States’ competent authorities have been unsuccessful, and the UK has erected its own barriers. As gene therapies begin to appear in the clinic, regulatory failure presents at least as serious an impediment to the roll out of therapies using viral vectors as the manufacturing bottleneck.

When the coronavirus pandemic struck Europe, the regulatory stranglehold on viral vectors hit home with a vengeance. Burdening trials of  COVID-19 vaccines with environmental risk assessments and applications for GMO release was hardly likely to bring a public health benefit, but in the absence of clear law, Member States were unsure as to whether such products could even be made available for emergency use[2], to meet a patient’s special needs[3], or on a compassionate basis[4]. without prior environmental risk assessment and authorisation by national authorities such as departments of agriculture. As the crisis deepened through the Spring of 2020, the need to clarify and streamline the regulation became truly urgent. Responding with a draft regulation on the conduct of clinical trials and the supply of medicines containing or consisting of GMOs intended to treat or prevent COVID-19, the Commission noted that to obstruct the exemptions for emergency and compassionate use and special needs would be “incoherent and contrary to the very purpose” of those exemptions to require GMO authorisation. That July, the Covid-GMO Medicines Regulation was passed[5].

The net effect of the Covid-GMO Medicines Regulation is two-fold. First, it exempts all operations relating to the conduct of clinical trials of IMPs containing or consisting of GMOs (e.g. attenuated viruses and live vectors) from the requirements of packaging and labelling, storage, transport, destruction, disposal, distribution, supply, administration and use that would otherwise apply under the GMO Directives, as well as the need for consent to release. Second, it applies the same exemption to the supply and use of such products, including where supplied for special needs and compassionate use, and, most pertinently, to their temporary release by Member States in response to the suspected or confirmed spread of  COVID-19. The manufacturing of such products must still comply with contained use requirements, with specific measures to limit exposure to the environment. The appropriate biosafety level must also be assessed so as to determine applicable procedures. However, as viral vectors are likely to be low risk, compliance is likely to be manageable.

Notably, the Covid-GMO Medicines Regulation is not restricted to vaccines: if a non[1]vaccine GTMP were produced for treating or preventing  COVID-19, it would also benefit from its exemptions. But of course this highlights the most obvious limitation of the rule change. If your target is SARS-CoV-2, the exemptions apply. But if you’re a cancer patient, you are going to have to wait until the developers of the gene therapy product that might treat you succeed in getting it through a patchwork of GMO-specific departments, procedures, documentary requirements and languages across a range of European governments in order to run a satisfactory trial. Nor is it clear that the exemption applicable to the compassionate use of a GM medicine for  COVID-19 is also applicable to cancer GTMPs. Indeed, once the World Health Organisation declares the COVID-19 pandemic over, the only thing keeping the 2020 Regulation alive will be the Commission’s recognition of a  COVID-19 public health emergency. Once that ceases, it’s back to square one.

From the point of view of those developing gene therapies, the temporary and limited exemption of certain GMO products from the Kafkaesque machinery of the GMO Directives has provided a tantalising example of a better world. They certainly need one. Their own had fallen under a cloud in 2018, when the CJEU determined that, contrary to advice of its own Advocate General, products of precision editing technologies such as CRISPR should be regulated as GMOs, even though GMOs produced by random means with mutations of unknown effect would be exempted (sic)[6]. At a stroke, the court hobbled the European gene therapy sector, including those engineering viral vectors, just as it was embracing the most powerful new genetic technology in decades. Could the pandemic help to change regulation for the better? Organisations such as the Alliance for Regenerative Medicine (ARM), European Federation of Pharmaceutical Industries and Associations (EFPIA), and European Association for Bioindustries (EuropaBio), as well as patient groups, certainly hoped so.

Contrary to news reports and political claims, the Commission has effectively endorsed the view of its scientific advisory panel that EU GMO laws are not fit for purpose across the board[7]. But while media and politics dwells on crops and livestock, they have largely ignored the plight of GM medicines. Yet forcing potentially life-saving treatments for cancer and cardiovascular disease through the same regulatory mill as blight-resistant potatoes is simply deterring product development in the face of patient need. Last November, the Commission expressly acknowledged the problem, declaring that the field of GM medicine development is “hindered by the fragmentation of national requirements” and not “fit for purpose when it comes to addressing the specificities of medicines and the conduct of clinical trials”. With the CJEU’s devastating response to CRISPR clearly in mind, it proposed that, “In general, consideration should be given to mechanisms for the continuous and timely adaptation of its technical requirements in light of emerging science and technologies with a view to enhance effectiveness to protect human health whilst minimising harmful impacts on the environment[8].”

But, at last, the train of legislative change may be lumbering out of the station. The Commission proposes to distinguish the position of new genetic technologies in medicinal products from that of other GM products, placing each in a different regulatory framework. Under the Commission’s new Pharmaceutical Strategy[9], the regulation of GM medicines, including those using viral vectors, would fall within the body of a new medicinal products regime, updated to reflect technological change and health priority[10]. MEPs approved this new strategy in November[11], and legislative details will emerge in due course. In the same month, the Commission published guidance agreed by all but five EU states (and endorsed by Norway) on good practice when assessing GMO-related aspects of clinical trials involving genetically modified human cells. Without dictating the specific regime to be followed, contained or deliberate release, the guidance sets risk assessment standards of relevance to each with a view to expediting the processes.

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[1] Directive 2001/18 (Deliberate Release); Directive 2009/41 (Contained Use).
[2] Article 5(2) Directive 2001/83.
[3] Article 5(1).
[4] Article 83, Regulation 726/2004.
[5] Regulation 2020/1043.
[6] Case C-528/16, Confédération paysanne, 25 July 2018
[7] For example in a statement to the World Trade Organisation in July 2021.
[8] An allusion, perhaps, to Article 191 of the Treaty on the European Union.
[9] Case C-528/16, Confédération paysanne, 25 July 2018.
[10] https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:52020DC0761
[11] See https://www.europarl.europa.eu/doceo/document/A-9-2021-0317 EN.html#title1 (paras 97, 98 & 103)
https://www.europarl.europa.eu/doceo/document/ENVI-PR-681109_EN.pdf
GM regulation may also change: https://ec.europa.eu/info/law/better-regulation/have-your-say/initiatives/13119-Legislation-for-plants-produced-by-certain-new-genomic-techniques_en