Like any new medical product, gene therapies must undergo rigorous approval processes. However, there are a number of additional regulations for gene therapies that don’t apply to conventional pharmaceuticals. This is especially true within the European Union.
(It’s important to note that while most gene therapy studies are based in the U.S. and Europe — which is why we focus on their regulations here — many countries and regions have their own unique laws guiding these trials. Consider speaking with a consultant, contract research organization [CRO], or other expert if you plan to market such products outside the U.S. and the EU.)
GMO Regulations and Processes
Although for the average person, “GMO” may bring to mind crops and agricultural products, the label of “genetically modified organism” also applies to all forms of gene therapy by definition.
A number of regulations and directives can be applied to gene therapy trials within the European Union, including:
- Regulation (EC) 1829/2003 on genetically modified food and feed
- Directive (EU) 2015/412 amending Directive 2001/18/EC regarding the possibility for the member states to individually restrict or prohibit the cultivation of GMOs in their territory
- Regulation (EC) 1830/2003 concerning the traceability and labeling of GMOs and the traceability of food and feed products produced from GMOs
- “Contained use” specifies that any activity involving GMOs is to be carried out under containment to limit contact with the environment and includes use, storage, transport, destruction and disposal
- Assessment is made in regard to the risks to human health and the environment. GMOs are placed into four classifications from lowest to greatest risk. Most investigational medicinal products tend to fall under Classes 1 and 2 (i.e., no or negligible and low risk)
- Directive 2001/18/EC on the deliberate release of GMOs into the environment, defined as intentional introduction 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
- Some countries — most notably Germany and Spain — always consider GMOs to be “deliberate release” and apply this directive to gene therapy trials by default. Uses a similar Class 1–4 system as Regulation 1830/2003
- Directive 2009/41/EC on contained use of genetically modified micro-organisms
- Regulation (EC) 1946/2003 on transboundary movements of GMOs
Although the ones discussed here are the main regulations within the EU, it’s important to remember that different localities within the region also have their own regulations that may be enforced. Because of these differences between EU member states, it is strongly recommended that sponsors work closely with CROs, vendors, and/or consultants who have gene therapy development experience in the country (or countries) of interest.
By contrast to heavy European regulations, the U.S. does not have any federal legislation that is specific to GMOs. However, GMOs are regulated under the Coordinated Framework for the Regulation of Biotechnology published in 1986.
Still, U.S. regulatory agencies have put forward a general guidance to focus on the nature of a specific product rather than the way in which it was produced. The road to market approval for treatments created through genetic engineering is the same process as any other therapeutic product, starting with a New Drug Application to the FDA.
When operationalizing a gene therapy trial, making sure each study site is able to comply with all relevant regulations is crucial. For example, some countries require extra certification for study sites participating in Phase I trials. Not all potential study sites may be able to comply with this regulation.
What extra documentation is needed for national regulatory bodies (e.g., submission to GMO authorities and/or the appropriate Competent Authorities)? Who is responsible for compiling this information? Although the sponsor is ultimately responsible for submission, our experience at Premier is that a coordinated effort between the sponsor and a CRO is essential here. On the other hand, some places require submission for GMOs to also be handled at the local level, often by a combination of site staff and CRO personnel.
Another detail each site must address is waste management. Some Competent Authorities will ask how GMO waste will be handled once the GMO has been moved offsite. Likewise, some of these authorities will require site-specific SOPs in such cases. Similarly, any GMO covered under “contained use” will need a specific storage room, and facilities must be checked during the site qualification visit.
Where is the drug being produced? Make sure to investigate any possible responsibilities for drug importation. Clear information from the sponsor and any necessary licensure should be obtained before the affected sites are initiated into the study. Make sure to avoid cases in which everything has been put into place and only in time it’s found that an import or export license is needed for the study drug.
Navigating the Regulatory Landscape
As you can see, gene therapy research comes with a host of complex regulatory considerations that must be successfully addressed for a trial to succeed. For sponsors new to the field — or even just the region — ensuring regulatory compliance is often best left in the hands of an experienced CRO or consultant.