Decades of painstaking research have recently begun to yield gene therapy products that are delivering meaningful benefits to human health. The approvals of voretigene neparvovec-rzyl (Luxturna) for inherited vision loss, tisagenlecleucel (Kymriah) for lymphoblastic leukemia, and axicabtagene ciloleucel (Yescarta) for lymphoma have ushered in a new era of therapeutics.
With the rapid evolution of the gene therapy field, regulatory agencies have been working to keep pace with these scientific and clinical breakthroughs.
Oversight in the U.S.
Over the past 45 years, gene therapy oversight by the National Institutes of Health (NIH) and the U.S. Food and Drug Administration (FDA) has evolved significantly. In 1974, the NIH established its Recombinant DNA Advisory Committee (RAC) to oversee the protocols of gene therapy trials. The FDA began to regulate gene therapy products in 1984 and issued its first guidance document in 1991.
Since then, there have been a number of changes in the oversight of gene therapy, most notably the elimination of the need for NIH director approval of gene therapy protocols in 1997, the implementation of closer scrutiny following the death of a clinical trial participant in 1999, and the limitation of RAC review to studies posing special risks in 2016.
The FDA has issued numerous draft guidance documents reflective of its current thinking and relevant to gene therapy. In August 2018, the NIH and the FDA jointly proposed to streamline gene therapy oversight by eliminating unnecessary duplicative reporting requirements to both agencies, reflecting significant expansion in FDA’s technical manufacturing, non-clinical pharmacology and toxicology and medical expertise. Prior to this, sponsors of gene therapies were required to register gene therapy protocols and provide trial updates to both agencies. This duplication in paperwork and reviews did not necessarily result in a commensurate increase in protecting participant safety.
The joint NIH-FDA proposal eliminates RAC review and reporting requirements, removing that secondary layer of oversight. While this reduces the burden of duplicate protocol registration, review, and reporting requirements, it represents a procedural change and does not alter the underlying regulatory pathway for gene therapy approval.
Oversight in the EU
In the EU, gene therapies fall under the regulations and processes for genetically modified organisms (GMOs), which include:
- Directive 2001/18/EC on the deliberate release of GMOs into the environment. Deliberate release refers to any intentional introduction into the environment of a GMO or a combination of GMOs for which no specific containment measures are used to limit their contact with and to provide a high level of safety for the general population and the environment. This directive includes risk classifications from no or negligible risk to high risk. Of note, some countries, such as Spain and Germany, consider GMOs to be “deliberate release” by default, even in the context of a clinical trial.
- Directive 2009/41/EC on contained use of genetically modified micro-organisms. Contained use is defined as any activity involving GMOs that is carried out under containment to limit contact with the environment, including use, storage, transport, destruction, and disposal. This activity must also include an assessment of the risks to human health and the environment. This directive includes four risk classifications, ranging from Class 1 (covers activities of no or negligible risk) to Class 4 (covers activities of high risk). Investigational medicinal products (IMPs) tend to fall under Class 1 or 2.
- Regulation (EC) 1829/2003 on genetically modified food and feed.
- Directive (EU) 2015/412 amending Directive 2001/18/EC as regards the possibility for the Member States to restrict or prohibit the cultivation of GMOs in their territory.
- Regulation (EC) 1830/2003 concerning the traceability and labelling of genetically modified organisms and the traceability of food and feed products produced from genetically modified organisms.
- Regulation (EC) 1946/2003 on transboundary movements of GMOs.
In the EU, gene therapies are generally classified as advanced therapy medicinal product (ATMPs), which are governed under the ATMP Regulation (Directive 2001/83/EC, as amended by Regulation [EC] 1394/2007). The EMA’s Committee for Advanced Therapies (CAT) is responsible for delivering scientific recommendations on ATMP classification after consultation with the European Commission. ATMP classification qualifies sponsors for substantial fee reductions for scientific advice as well as access to innovation offices where they can solicit informal advice.
SMEs can also obtain certification of quality and non-clinical data to provide scientific certainty that they are on the right track for a future MAA. ATMPs must comply with EU pharmaceutical regulations and marketing authorizations for ATMPs are through the centralized procedure, so one license is valid for the entire EU. Procedural and guidance documents related to the marketing authorization for ATMPs can be found here.
The European Medicines Agency (EMA) has developed a number of scientific guidelines specific to gene therapy products, which are available here. Currently, the EMA is accepting comments on its Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells [PDF].
As gene therapy continues to change, the regulatory frameworks that oversee the development of these novel treatments will continue to be modified in response to our understanding of these scientific advances and their associated risks. According to a recent joint statement by FDA Commissioner Scott Gottlieb and Center for Biologics Evaluation and Research (CBER) Director Peter Marks, the FDA plans to add about 50 additional clinical reviewers to the review group charged with evaluating cell and gene therapies in the near future.
An understanding of the regulations and guidance documents reflecting regulator current thinking surrounding gene therapies is essential to success, and consideration of the regulatory expectations and requirements at the earliest possible stage of development will increase the likelihood that these products will ultimately enter clinical trials that will result in approved marketing applications and improvement in human health and welfare.
 Collins FS, Gottlieb S. The next phase of human gene-therapy oversight. N Engl J Med 2018;379:1393-1395.
 National Institutes of Health. Statement on modernizing human gene therapy oversight, August 16, 2018. Available at https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-modernizing-human-gene-therapy-oversight.
 EUR-Lex. Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC – Commission Declaration. Available at https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A32001L0018.
 EUR-Lex. Directive 2009/41/EC of the European Parliament and of the Council of 6 May 2009 on the contained use of genetically modified micro-organisms (Recast) (Text with EEA relevance). Available at https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A32009L0041.
 EUR-Lex. Regulation (EC) No 1829/2003 of the European Parliament and of the Council of 22 September 2003 on genetically modified food and feed (Text with EEA relevance). Available at http://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX:32003R1829.
 EUR-Lex. Directive (EU) 2015/412 of the European Parliament and of the Council of 11 March 2015 amending Directive 2001/18/EC as regards the possibility for the Member States to restrict or prohibit the cultivation of genetically modified organisms (GMOs) in their territory Text with EEA relevance. Available at http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=OJ:JOL_2015_068_R_0001.
 EUR-Lex. Regulation (EC) No 1830/2003 on the traceability and labelling of genetically modified organisms (GMOs) and the traceability of food and feed products produced from GMOs. Available at
 Official Journal of the European Union. Regulation (EC) No 1946/2003 of the European Parliament and of the Council of 15 July 2003 on transboundary movements of genetically modified organisms. Available at http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2003:287:0001:0010:EN:PDF.