Focus: Clinical trials and Advanced Therapies
Authors: Janneke Westra – de Vlieger, Janssen; Carol McConnell, AstraZeneca, together with the following members of the TOPRA Biotech SPIN group and TOPRA Clinical Trial SPIN group: Susan Bhatti, Merck, Sharpe and Dohme; Shaila Choi, KKSC solutions Ltd.; Pierre Omnes, Syneos Health; Kathryn Parsley, Boyd Consultants; Sean Russell, Achilles Therapeutics Ltd.
Keywords: Genetically Modified Organism (GMO); Advanced Therapy Medicinal Product (ATMP); Contained use (CU); Deliberate Release (DR); Clinical trial; Clinical trial application (CTA); Investigational Medicinal Product (IMP).
Innovative biotechnological medicinal products may contain or consist of a Genetically Modified Organism (GMO). These GMO-containing medicinal products constitute a special regulatory case, often involving a designated GMO-national competent authority. In this article, the authors provide a comparative overview of the GMO regulatory framework in the context of clinical trial start-up in Europe, including the application processes and documents, for several EU member states. Major developments from the European Commission, include GMO requirements for novel IMPs.
In recent years, an increasing number of IMPs either consist of, or contain, a Genetically Modified Organism (GMO). GMOs are defined in accordance with the legal basis provided in Directive 2001/18/EC (Article 2)1. IMPs containing a GMO constitute a special regulatory case, as these IMPs are subject to a separate assessment and approval process, to ensure protection of persons (including non-patients inadvertently exposed), as well as to permit the release of the GMO-containing IMP into the environment. Successfully navigating the GMO legislative framework in Europe can facilitate clinical trial start-up for these IMPs.
The EU definition of a GMO is based on the technology used to modify the actual organism. It should be noted that EU Pharmaceutical legislation is not consistent with the GMO definition (see Figure 1). Therefore, GMO-containing IMPs may range from genetically modified viral or bacterial vectors, administered directly to patients (in vivo gene therapy and vaccines), to cells prepared in vitro prior to re-administration to patients (ex vivo gene therapy), such as the recently authorised chimeric antigen receptor (CAR) T-cell medicinal products.
Centralised Marketing Authorisation Decisions for GMO-containing medicinal products are issued by the European Commission, with environmental aspects being addressed during an integrated (combined) review of the marketing authorisation by the European Medicines Agency (EMA). In contrast, the EU Clinical Trial Directive (EU CTD, 2001/20/EC)2 as well as the future Clinical Trial Regulation (EU CTR, Regulation (EU) No 536/2014)3 do not cover biosafety or environmental aspects, and this is therefore legislated at country level. Consequently, application requirements and administrative procedures for GMO-containing IMPs differ significantly between member states.
Figure 1: Schematic showing overlap between GMO Legislation and Pharmaceutical Legislation
The overarching Directives relevant to products consisting of, or containing, GMOs are:
- Directive 2001/18/EC on the deliberate release (DR) into the environment of genetically modified organisms;
- Directive 2009/41/EC4 on the contained use (CU) of genetically modified micro-organisms.
It is important to note that the GMO legislation was not developed specifically for medicinal products. The scope of the GMO legislation includes micro-organisms, animals or plants, when used for research or agriculture, therefore, terminology and administrative information may not appear appropriate for medicinal products.
- Genetically Modified Organism (GMO): “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. […]”. A similar definition exists for genetically modified micro-organisms (GMM);
- Contained Use (CU): “any activity in which microorganisms are genetically modified or in which such GMMs are cultured, stored, transported, destroyed, disposed of or used in any other way, and for which 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”;
- Deliberate Release (DR): “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”.
As shown in Table 1 below, the CU Directive includes defined risk categories. The CU risk categories may also be classified in line with human exposure risks provided in Directive 2000/54/EC5. These risk categories are used to determine the level of containment required as well as influence the documentation, timelines for review, and the fees associated with the GMO applications, whether for research, industrial or clinical use.
Table 1: Risk Categories applicable to Contained Use
|CU Risk Category||Directive 2009/41/EC4||Directive 2000/54/EC5|
|Class 1||No or negligible risk||
|Class 2||Low risk||
|Class 3||Moderate Risk||
|Class 4||High Risk||
CU classification (biosafety level) of the GMO IMP should be proposed and justified by the sponsor. This should take into account the source components and the use of the GMO, whether it is intended for research use, or for manufacturing use and/or clinical use. The content of the dossier should then be customised with a description of the relevant containment and monitoring measures to be implemented. CU classes for GMO containing IMPs in a clinical trial setting are in most cases restricted to risk level 1 or 2 (e.g. in vivo administration of a modified virus or bacteria). In certain cases, higher levels may need to be considered for GMO authorisation of manufacturing sites, depending on the donor organisms and genetic sequences used.
Challenges for Clinical Trial Authorisations of GMO Containing IMPs
Clinical Trial Applications (CTA) for GMO IMPs are more complex than the process applying to non-GMO CTAs, as there can be multiple submissions and several rounds of review, sometimes involving different competent authorities depending on local legislation and individual member state requirements:
- Standard review of the CTA under Directive 2001/20/EC (Competent Authority – CA- and Ethics Committee(s) – EC);
- A GMO application covering the review of either biosafety/ CU and/or DR aspects (and corresponding legislation).
The biosafety rules in the EU are described in Directive 2000/54/EC5 on the protection of workers from risks related to exposure of biological agents at work, which will also need to be considered from a submission and clinical trial set up standpoint. This can include clinical site-specific submissions and site biosafety standard operating procedures, i.e. spillage and waste management and infrastructures (workers’ protection, eventual containment measures for the patient, etc.). A thorough assessment and confirmation of the regulatory pathway (down to site requirements) in each of the countries is therefore critical, to ensure compliance with applicable Member State legislation. These challenges were reviewed and discussed as part of a workshop on ATMPs organized in 2016 by EMA6, which became the starting point of further work by the EU Commission and stakeholders to address some of those clinical development hurdles.
As mentioned previously, the Clinical Trials Regulation (EU) No 536/2014 (EU CTR) does not include any provisions on GMOs. In fact, it excludes GMOs from its scope, triggering several questions from industry stakeholders and competent authorities, as to how the submission and assessment of GMO CTAs can be processed in the future EU CTR environment. Indeed, no GMO-specific functionality is currently foreseen for the EU Portal that will support the EU CTR due to the absence of a legal basis for GMOs. Implementation of the EU CTR is foreseen no earlier than end 2020 due to EU Portal development timelines, so we can but hope that ongoing discussions will lead to a solution in that area by the time the EU CTR goes live.
Sponsors are suggested to discuss the potential for an integrated approach with the relevant national competent authority and the GMO competent authority. A decision will be taken by the on a case-by-case basis. Furthermore, some GMO competent authorities can offer flexibility and efficiencies for multiple clinical trials with the same medicinal product. Use of Voluntary Harmonization Procedure (VHP) for the assessment of multinational clinical trial applications for GMO-containing IMPs is problematic and should not be used due to the dependencies between CTA and the differing GMO national processes.
Practical aspects and recommendations for the preparation of GMO-applications
The annexes to the GMO Directives provide information on the content of the technical dossiers and assessment methodologies to be considered when planning for any GMO application:
- 2009/41/EC, Annex III: content of the CU notifications regarding risks to human health and to the environment (GMO technical dossier);
- 2001/18/EC, Annexes II and III: principles for the Environmental Risk Assessment (ERA) and content of the corresponding DR notification and ERA dossier (Annex III);
- Summary Notification Information Format (SNIF) template, derived from Article 11 of Dir. 2001/18/EC, for the transfer by Member States of key information regarding DR notifications to the European Commission for the GMO Register.
Understanding the legal basis for national regulatory pathways (national transposition of the GMO Directives) will guide the country CTA submission strategy and define which document requirements will apply. When required, Environmental Risk Assessments need only provide enough detail to draw conclusions about the hazards present. For a GMO that presents no hazard to humans and would be unable to survive in the receiving environment, a detailed assessment would not be expected. Conversely, GMOs that do present harm to humans (e.g. by acting as a disease vector or by being toxic when consumed), to the environment (risk of recombination with wild type organism, or granting new characteristics to those) and that could survive in the receiving environment would require more detailed consideration and careful application of control measures. Some GMO competent authorities offer pre-submission meetings to discuss and agree the content of the GMO dossier to be submitted to obtain the necessary environmental approvals to conduct a clinical trial, such as the Gene Therapy Office in the Netherlands7.
A proposed approach for a multinational GMO clinical trial should take into account EU GMO-requirements first and create a set of EU core GMO-documents and information. This can be adjusted to any country-specific adjustments and support application activities in non-EU countries (as discussed in previous TOPRA-articles7,8). A schematic overview of risks and regulatory requirements of GMO-containing IMPs is included below (see Figure 2).
Figure 2: Schematic overview of risks and regulatory requirements for GMO containing IMPs.
This strategy can of course be focused on a reduced set of country requirements for early stage trials involving few countries. The following outlines an example of main GMO documents and information to be compiled:
- Information supporting CU (or GMO technical dossier): source and history of the genetic constructs and all constituents of the GMO. Annexes of both Directives 2009/41/EC and 2001/18/EC should be considered;
- Information supporting DR
- Environmental risk assessment: Information relating to the release, interactions of the GMO with the environment and potential impact on the environment. This is particularly important if there are significant differences from the recipient or parent organism. Information should be included relating to monitoring, post-release and waste treatment, and emergency response plans. Identification of hazards, including risks of GMO reverting to its wildtype form and shedding data are considered important to ensure appropriate containment measures are implemented. Patient management after administration of the GMO IMP is another important aspect to consider in the management of the study (see e.g. ICH considerations on vector shedding and EMA guidelines for gene therapy medicinal products for further details);
- Conditions of the release and the recipient (this includes in-depth discussion of the facility where administration of the GMO will take place, and the patient that will be receiving the medicinal product);
- Summary Notification Information Format (SNIF). The SNIF is a publicly accessible document through the EU Register on DR. The SNIF includes summary information on the GMO constituents and on the planned DR. The SNIF should be completed bearing in mind that it will become publicly available, excluding confidential information when preparing it.
- Instructions for staff / pharmacy manual: summarizes the risks and provides guidance in handling, administration disposal and incidents related to the GMO IMP, as well as management of the patient (as applicable).
Not all documents and information are required in each individual member state, hence the importance to liaise early on with authorities, as well as clinical sites, to ensure that all requirements and documents are identified upfront.
Overview of regulatory GMO requirements for key EU countries
The GMO review procedure can prove challenging, since unlike the maximum review timelines for CTAs that are embedded in the clinical trial legislation, this is not aligned for GMOs: this review includes multiple stakeholders, parallel or sequential assessments, several rounds of questions and publication obligations. Lack of harmonization between the GMO application and CTA regulatory requirements often results in overlapping questions from environmental agencies and competent authorities in different countries, particularly related to quality of the IMP and the capacity for shedding of the GMO containing medicinal product from the patient into the environment. The GMO technical dossier needs to include details on the donor organism(s) and subsequent manipulations, particularly related to the modifications (cloning steps) performed to generate the GMO from its wildtype form and the origin of regulatory elements, such as promoters. This can often be challenging if the GMO has originated from an academic institute. In addition, details regarding product specific training for staff who may inadvertently contact the GMO, in relation to transport, storage, preparation for administration and disposal of the GMO, the management of study subjects, and the collection of biological samples from subjects that may contain the GMO. Review may include aspects of viral shedding and the risk of transmission to healthcare workers in contact with the patient, highlighting the importance of providing robust nonclinical biodistribution data to support the proposed monitoring regimen and safety measures in the clinical setting.
Table 2 provides an overview of a select number of current national processes for GMO applications associated with clinical trial applications, looking at some of the key regulatory aspects. The country list included in the overview is based on available practical experience from the authors. Industry experiences -although limited- regarding actual documentation requirements, questions and timelines have been included, but should only be considered for illustration purposes and be reconfirmed at the time of new GMO applications. A great disparity remains, including basic aspects such as the GMO classification and corresponding documentation requirements and application processes. Encouragingly, several European countries, including Germany and Sweden (also Estonia, Greece and Lithuania), have implemented a single coordinated submission procedure, which permits the applicant to obtain authorisation under both GMO and clinical trials framework in a single decision. However, as of June 2018, most of the Eastern European countries (e.g. Bulgaria, Poland, Romania, Slovenia and Slovakia, based on historic experience from the authors), require sponsors to obtain authorisation under the GMO framework before the CTA can be submitted.
Table 2 – EU overview of current regulatory GMO-requirements.
|EU Member State||Authorities involved for GMO applications||Submission details||Industry experience timelines (months)*||Classification (CU**/DR***)||Documentation requirements and comments|
|Belgium||Biosafety Advisory Council (SBB) for CU and regional competent authorities for DR. In addition, classification via FAMHP/Belgian Biosafety Advisory Council||Parallel or in advance of CTA||3-4||CU or DR||Classification via FAMHP STA procedure. For DR, 90 days assessment and public consultation of 30 days required, in local language (either in Dutch or French) For CU typically shorter review times (30–70 days).|
|Bulgaria||Ministry of Environment and Water (MoEW)||Not parallel; prior GMO authorisation required||3||DR, but sites should comply with CU requirements||Application in Bulgarian; technical documents in English acceptable, except for information related to the safety of personnel conducting the trials. No public consultation. Plan of site training and CV of PI required. Technical questions expected.|
|France||Ministry of Research (MESRI)
for CU: GMO classification/
CU agreement per clinical site. Ministry of Environment (MTES) for DR. High Council of Biotechnology (HCB) for opinion and assessment involved.
|Parallel or in advance of CTA||Up to 6||CU or DR (DR upon determination by HCB||Class 1 is notification only. Via HCB for DR determination. If DR applies, an additional submission is required to MTES. Public consultation of 15-30 days may apply, in French. Electronic submission via a portal in French.#|
|Germany||Paul-Ehrlich-Institut (PEI) with consultation of Federal Office of Consumer Protection and Food Safety (BVL), plus local GMO/ Federal office of consumer protection and food safety||Single submission via PEI parallel, or separately in advance of CTA||4-9||DR only||Single application includes CTA and GMO aspects. DR limits the GMO storage time to 3 days at site, any longer requires CU application.|
|Italy||Ministry of Health (ISS) for CU Ministry of Environment for DR||Parallel or in advance of CTA||4||CU or DR||CU: form specific by class (1 and 2–4) Complex public consultation in case of DR (30 days), in Italian. Application forms in Italian.#|
|Netherlands||Gene therapy office: GMO office as single point of contact. Ministry of infrastructure, Environment and Water management (IenW) for permit application||Parallel or in advance of CTA||Up to 12||DR only||Pre-submission meeting recommended. IenW requires 120 days assessment for environmental risk. Extensive dossier required, multiple question rounds typically required.# Public consultation applies (12 weeks); included in 120 days assessment period.|
|Poland||Ministry of the Environment – GMO unit||Not parallel; prior GMO authorisation required||More than 3||CU||Public consultation required (30 days via GMOs register); layman summary of technical information required in dossier. Application forms in Polish.#|
|Spain||Consejo Interministerial de OMG (CIOMG) and Comisión Nacional de Bioseguridad (CNB)||Parallel or in advance of CTA||3-4||DR only||Questions focus on local site operations. GMO review and approval times may be extended if public consultation is sought. Application forms in Spanish.#|
|Sweden||Medical Products Agency (MPA)||Single submission via MPA parallel, or separately in advance of CTA||3-4||DR only||Single application to MPA for
CTA and GMO aspects; no GMO application forms; add SNIF and
ERA as required according to Directive 2001/18 (English language acceptable). A short – non- confidential – summary is posted for public consultation on MPA webpage (30 days within 90 days assessment period).
|UK||Health and Safety Executive for CU (HSE in England; 4 regional authorities can be involved in UK). Department for Environment Food and Rural Affairs (DEFRA) for DR||Parallel or in advance of CTA||3-4||CU or DR (DR seldom used, almost always CU)||CU review timelines are shorter than DR; also dependent on CU classification and if site is already authorised for use of GMO. Case- by-case assessment if DR should be applied (DR for, eg, replication- competent products).|
* Standard 90-day review may be extended by a further 90 days, in accordance with CT Directive 2001/20/EC; multiple question rounds are feasible.
** CU often requires clinical site-specific notifications and/or submissions to authorities.
*** ERA requirements plus a dossier in the summary notification information format (SNIF), for publication on EU register.
# Technical documents in English are acceptable.
New developments facilitating GMO Clinical trial start up
Following the EMA ATMP Workshop dated 26 May 2018, an action plan was developed. The action plan has already been partially implemented, such as the creation of a repository containing details of each member state GMO competent authorities and national procedures that must be followed for the conduct of clinical trials with GMO containing medicinal products. These documents are published on the EU Commission’s website9.
As described below, three new GMO documents, focusing mainly on transduced human cells (such as CAR T-cells), have been published on the European Commission website:
- Questions and Answers (Q&A) document10. For the purposes of the Q&A document, the term “GMO framework” is used to refer to the DR and/or the CU framework, as appropriate. The answers provided in the Q&A document reflect the evolving field of GMO containing medicinal products and aims to facilitate GMO requirements for IMPs, with a focus on transduced cells (CAR T-cells). The Q&A covers post-authorisation clinical trial use (i.e. new indications) for GMO containing medicinal products previously reviewed and approved. It also provides mutually agreed interpretations of GMO classifications for genetically modified human cells, to provide clarification to applicants whether or not a GMO application is required.
- Good Practice document11 on the assessment of GMO-related aspects in the context of clinical trials with human cells genetically modified by means of retro/lentiviral vectors. The content of this document (including the specific environmental risk assessment (ERA)) cannot be extrapolated to products other than human cells genetically modified by means of retro/lentiviral vectors, in cases where the applicant demonstrates absence of formation of replication competent virus and absence of residual infectious viral vector particles in the transduced cells.
- Common Application Form12 for Clinical Research (relevant to genetically modified human cells, such as CAR T-cells) has been endorsed by the competent authorities in Austria, Belgium, Cyprus, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Italy, Luxembourg, Malta, Portugal, Romania, Spain and Norway; and when required, to be accompanied by SNIF documentation. The publicly available SNIF document may require a redacted version to be made available by the study sponsor intended for public release.
Additional developments covering GMO aspects of IMPs are anticipated to provide an increased level of support for companies developing GMO-containing medicinal products. Future harmonisation of the EU national GMO requirements is anticipated based on the joint action plans of the European Commission and EMA to improve the regulatory framework for Advanced Therapies. Though the action plans are encouraging, it would be important to also extend these plans to include all innovative GMO-containing medicinal products.
- Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms. Available at: https://pdfs.semanticscholar.org/0ffb/732a08f81718ff5aec3bed774b7ddfb3fcf9.pdf (accessed at 31 January 2019).
- Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Available at: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02001L0020-20090807&from=SL (accessed 31 January 2019)
- Regulation (EC) No 536/2014 on clinical trials on medicinal products for human use.https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32014R0536&rid=6 (accessed 31 January 2019).
- Directive 2009/41/EC on the contained use of genetically modified micro-organisms. Available at: https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:125:0075:0097:EN:PDF (accessed at 31 January 2019).
- Directive 2000/54/EC of the European Parliament and of the Council of 18 September 2000 on the protection of workers from risks related to exposure to biological agents at work. Available at: http://www.asset-scienceinsociety.eu/pages/directive-200054ec-european-parliament-and-council (accessed 31 January 2019).
- Multi-stakeholder advanced therapy medicinal products (ATMPs) expert meeting: exploring solutions to foster ATMPs’ development and patient access in Europe. Available at: https://www.ema.europa.eu/en/events/multi-stakeholder-advanced-therapy-medicinal-products-atmps-expert-meeting-exploring-solutions (accessed at 31 January 2019).
- Regulatory Rapporteur – Vol 14, No 6, June 2017: S. Jurmeister and K. Parsley. Global regulatory challenges during early stage development of gene therapy medicinal products.
- Regulatory Rapporteur – Vol 14, No 1, January 2017: S. Russell. Specific European challenges for clinical trials with advanced therapy medicinal products.
- European Commission’s website, section Advanced Therapies, subsection GMO – requirements for investigational products, including a link to the repository of national regulatory requirements. Available at: https://ec.europa.eu/health/human-use/advanced-therapies_en (accessed 31 January 2019).
- GMO – requirements for investigational products – EU Commission Q&A entitled “Interplay between EU Legislation on medicinal products and GMOs”. Available at: https://ec.europa.eu/health/sites/health/files/files/advtherapies/2018_gmcells_qa_en.pdf (accessed 31 January 2019).
- GMO – requirements for investigational products – Good practice document (EU Commission website). Available at: https://ec.europa.eu/health/sites/health/files/files/advtherapies/2018_gmcells_gp_en.pdf (accessed 31 January 2019).
- GMO – requirements for investigational products – Common Application Form (EU Commission website). Available at: https://ec.europa.eu/health/sites/health/files/files/advtherapies/2018_gmcells_caf_en.pdf (accessed 31 January 2019).
This was published in Regulatory Rapporteur, Volume 16, Issue 4, April 2019.