A Comprehensive Resource on EU Regulatory Information for Investigators in Gene Therapy Clinical Research and Advanced Therapy Medicinal Products

Gene therapy medicinal product

A gene therapy medicinal product (GTMP) is defined as a biological medicinal product that has the following characteristics: (a) it has an active substance that contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, replacing, adding, or deleting a genetic sequence; (b) its therapeutic, prophylactic, or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains or to the product of genetic expression of this sequence. GTMPs do not include vaccines against infectious diseases.

Somatic cell therapy medicinal product

A somatic cell therapy medicinal product is defined as a biological medicinal product that has the following characteristics: (a) contains or consists of cells or tissues that have been subject to substantial manipulation so that the biological characteristics, physiological functions, or structural properties relevant for the intended clinical use have been altered, or of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor; (b) is presented or having properties for, or is used in or administered to human beings with a view to treating, preventing, or diagnosing a disease through the pharmacological, immunological, or metabolic action of its cells or tissues. For the purpose of point (a) the manipulation listed in Annex I to Regulation (EC) No. 1394/2007, in particular, shall not be considered as substantial manipulations (European Commission, [b]; Cohen-Haguenauer, 2012a).

Tissue engineered product

A tissue engineered product that (a) contains or consists of engineered cells or tissues, and (b) is presented as having properties for or is used in or administered to human beings with a view to regenerating, repairing, or replacing a human tissue. A tissue engineered product may contain cells or tissues of human or animal origin, or both. The cells or tissues may be viable or nonviable. The product may also contain additional substances, such as cellular products, biomolecules, biomaterials, chemical substances, scaffolds, or matrices. Products containing or consisting exclusively of nonviable human or animal cells and/or tissues, which do not contain any viable cells or tissues and do not act principally by either pharmacological, immunological, or metabolic action, shall be excluded from the definition. Cells or tissues shall be considered “engineered” if they fulfill at least one of the following conditions (defined in Article 2.1.c of Regulation EC 1394/2007): (i) the cells or tissues have been subject to substantial manipulation, so that biological characteristics, physiological functions, or structural properties relevant for the intended regeneration, repair, or replacement are achieved; the manipulations listed in Annex I to Regulation (EC) No. 1394/2007, in particular, shall not be considered as substantial manipulations; and (ii) the cells or tissues are not intended to be used for the same essential function or functions in the recipient as in the donor. Details on combined products and related hierarchy can be found in Cohen-Haguenauer (2012a).

The 2001 Clinical Trials Directive

The prominent goal of the directive was to simplify and harmonize clinical trial procedures across EU in order to (i) protect trial subjects; (ii) help and direct the process leading to authorization of trials; (iii) require and secure ethical approval of all protocols; (iv) scrutinize and define the quality of the study drug; (v) establish requirements for standards and inspections; (vi) frame and facilitate pharmacovigilance; (vii) encourage and streamline exchange of information between member states; (viii) reduce duplication of paperwork for submission; and (ix) improve the overall quality of research, standard operating procedures, training, monitoring, inspections, audit, and use of Good Manufacturing Practices and Good Laboratory Practices (GLP). Nevertheless, up until the marketing authorization phase, approval of clinical trials is being granted at the national level and each country has a slightly different interpretation of the directive and related guidelines.

The scope of the Clinical Trials Directive covers all trials of medicinal products except noninterventional trials (marketed products used for their licensed indication), includes all phase I studies and investigator-led studies (investigator does not need to be a medical doctor but patient care must be placed under the supervision of a medical doctor. In as far as the commencement of a clinical trial is concerned (Article 9), the clinical study can only start when (i) ad hoc ethics committee has issued “favorable opinion” and (ii) the member state “has not informed the Sponsor of any grounds for non-acceptance.” The submission to Regulatory Authority and Ethics Committee can be pursued in parallel.

Inconsistent implementation of the Clinical Trial Directive

Unfortunately, over 10 years later, many national procedures are still in place, a situation that may jeopardize the main objective of the Directive. EU countries lost almost 20% of global trials within the past 2 years. In order for EU countries to continue to play an important role in the clinical research arena, both procedures and standards of their studies need to be improved. The “Clinical Trials Facilitation Group” and the “Voluntary Harmonised Procedure” which involves concerted evaluation by up to three Member States Agencies have both been enforced which are meant to accelerate progress, with little evidence of practical success at present.

Multiple and divergent assessments of clinical trials

Few clinical trials are performed in one single member state. In theory, rules for clinical trial authorization should be identical, but theory and practice are divergent. Investigators and sponsors cannot prepare as many files as there are official bodies in each member state of the EU, in particular in the case of rare disorders and noncommercial clinical trials. A step forward towards EU-wide harmonization of first-in-man studies application dossier has long been a request from users under the form of a comprehensive dossier, which should encompass all requirements including genetically modified organism (GMO)-related aspects. With respect to gene- and cell-therapy clinical trials and in particular, those sponsored by academic or nonprofit organizations, the intention is not necessarily to generate data to support an application for the marketing authorization of a medicinal product. Therefore, the CliniGene-NoE proposed designing a specific track for the evaluation or approval of these studies, especially when they are not aimed at marketing authorization. While the model of Big Pharma driven multicenter large-scale study may be appropriate when considering the development of small molecules for common diseases, it is increasingly inappropriate when addressing a majority of rare disorders; indeed, the development model from phase I to phase IV does not seem accurate, given the reduced number of patients and the multinational accrual, within an academic setting in many cases at least in early phases of clinical studies. The legislation should be a Community legislation, to facilitate international cooperation in clinical research in this field. Because accurate expertise on ATMPs can be found at the EU-wide level only, the commission should take into consideration centralizing clinical trials authorization for these innovative products from the start.

From the Clinical Trials Directive to the Clinical Trials Regulation

The need to revise Directive 2001/20/EC was unanimously accepted during the course of year 2011 and the process is underway. It was decided that this revision would take an even more potent form than a Directive; i.e., as a EU Regulation. The new EU Clinical Trial Regulation, which is in advanced stage of finalization, will represent an important step forward. The proposal adopted on 17 July 2012 by the Commission has been submitted to the European Parliament and the Council, which engage in ordinary legislative procedure (follow-up at the “legislative observatory” of the European Parliament or PreLex, the EU-database on inter-institutional procedures) (PreLex, 2012).

Two other important regulations apply to clinical trials in the EU

EudraCT

EudraCT is a database of all clinical trials commencing in the Community from 1 May 2004 onwards (European Medicines Agency, [c]). The European database contains all ongoing or completed clinical trials falling within the scope of Directive 2001/20/EC; i.e., those with at least one investigator site in the EU (including the European Economic Area) and commencing after implementation of Directive 2001/20/EC by the Member States. This database gives the competent authorities of the Member States, the EMA, and the Commission the necessary information to communicate on clinical trials and to maintain oversight of clinical trials and investigational medicinal product (IMP) development. This provides for enhanced protection of clinical trial subjects and patients receiving IMPs. More information, including a user manual for EudraCT is available on the EudraCT Supporting Documentation web page (European Medicines Agency, [c]). Registration to EudraCT with a EudraCT number is mandatory when performing a clinical trial in the EU.

The Committee for Advanced Therapies

All across the EU, CAT is responsible for preparing a draft opinion on the quality, safety and efficacy of each advanced therapy medicinal product for final approval by the Committee for Medicinal Products for Human Use (CHMP) (European Medicines Agency, [a], [b]; Schneider et al., 2010). All ATMPs intended for marketing in more than one EU-member state benefit from a single centralized evaluation and be it the case, successful authorization via the EMA. According to the assessment procedure, the CAT prepares a draft opinion on the quality, safety, and efficacy of an ATMP, which is then forwarded to the CHMP. CHMP adopts in turn a recommendation for the European Commission, which may either grant or refuse a marketing authorization on the basis of the agency's recommendation. CAT thus plays a central role in the assessment of ATMPs and mobilizes the required expertise to do so at the EU level, through both case-by-case solicitation of ad hoc experts and the organization of stakeholder consultations such as Focus Groups of Interested Parties (FGIPs) occurred during 2011. In January 2012, a 1-day workshop was organized by the CAT at the EMA, as part of its effort to strengthen the dialogue with its stakeholders. The main aim of the workshop was to communicate the outcome of focus group meetings held in 2011. Attendees were given the opportunity to send questions to the organizing committee in advance. Intensive interaction proved extremely fruitful, and a report has been issued.

ATMP regulation: Directives and guidance documents

The regulatory framework currently enforced at the EU-centralized level has been detailed in Cohen-Haguenauer (2012a) in a table covering three different sections, the length of which reflect the maze of regulatory documents, which currently need to be referred to: (i) Main Legislation and guidelines concerning ATMPs in general: 14 directives, guidelines, and concept papers are listed; (ii) EMA-CAT Guidelines on ATMPs Classification, Evaluation and Certification: five guidelines, procedural advice documents, and reflection papers are referenced; and (iii) EMA Guideline on Pharmacovigilance applying to ATMPs.

EMA Scientific Guidelines on Gene and Cell Therapy

The guidelines are described in Kent et al. (2011) and Cohen-Haguenauer (2012a).

A prominent feature in ATMP evaluation: the risk-based approach

The risk-based approach is based on the identification of various risks associated with the clinical use of an ATMP and risk factors inherent to the ATMP with respect to quality, safety, and efficacy. The concept of a “risk-based approach” has been introduced to the legislation with the revision of Annex 1, part IV of Directive 2001/83/EC as amended by Directive 2009/120 EC. The aim of the risk-based approach in the development of ATMPs is to determine the extent of quality nonclinical and clinical data to be included in the Marketing Authorization Application (MAA), in accordance with the scientific guidelines relating to the quality, safety, and efficacy of medicinal products and to justify any deviation from the requirements of this Annex. The clinical use of ATMPs in humans may be associated with specific risks to the patient and to third parties. These risks are determined by various risk factors, which are related to the quality, biological activity, and application of the ATMP. Since ATMPs are very diverse in nature (i.e., GTMPs, somatic cell therapy medicinal products, and tissue engineering products), a flexible approach to address and evaluate potential risks associated with the clinical use of ATMPs is described in the risk-based approach guideline (European Medicines Agency, [d]). Risk factors associated with a specific risk (e.g., tumorigenicity, treatment failure) are likely to be product specific and multifactorial. Risk factors may for instance be related to either the biological characteristics, the manufacturing process, or the specific therapeutic use of the ATMP. With each risk factor, its contribution to a consolidated risk associated with the product under development will need to be evaluated. It is anticipated that a final specific profile will take shape as a result of the identified risks/risk factor in combination. Nevertheless, the application of the risk-based approach in the preparation of a MAA dossier, while recommended, is optional.

Structure and content of a Clinical Trial Application form and IMPD

The documentation to be provided to the National Competent Authority of the Member State are the Clinical Trial Application (CTA) and IMPD, the content of which is detailed in Table 1. The IMPD provides summary information (definition according to EC communication March 2010): the content of the dossier is adapted to the level of knowledge (and development phase). Why it is important to build the IMPD? This document is indeed essential because it will form the foundation for all future regulatory documents and be used for communications to regulators about the product as well as the basis of support for scientific advice, protocol assistance, orphan drug applications, etc. The IMPD gathers information generated from many sources, and all documents need to be consistent. In particular, it provides comprehensive information used to determine the risk/benefit profile of the IMP. Therefore, the establishment of the IMPD is a team effort that requires coordination and consolidation from many perspectives and complementary expertise.

IMPD requirements to the chemical and pharmaceutical documentation concerning IMPs in clinical trials: the eCTD does not fit the case of ATMPs

As it is, the guideline on the requirements for the chemical and pharmaceutical documentation concerning IMPs in clinical trials does not fit the case of ATMPs nor that of gene therapy vectors and products in particular (Cohen-Haguenauer, 2012b). As a first step, a frame could be established which addresses “Lentis for ex vivo GM-cells” on the one hand and “AAV in vivo” on the other. “Lentis in vivo” could be considered as the next target. The next step could consist in substantiating the IMPD with data that might be inferred from already acquired knowledge sourcing from both the literature and the clinical experience of the CliniGene investigators involved or others willing to participate in an endeavor likely to streamline the implementation of new clinical trials, especially when addressing rare disorders and academic-led initiatives.

IMPD nonclinical pharmacology and toxicology data

Data should be submitted in a logical structure, such as the headings of the current version of Module 4 of the Common Technical Document, or of the eCTD format. (Reference is made to the specific Community guidelines contained in Volume 3 of Eudralex; e.g., Nfg on nonclinical safety studies that include the need to proceed to a critical analysis of the data and implement GLP provisions in all experiments performed). However, where this preclinical toxicology/biodistribution and pharmacology data are concerned, the framework needs to be adapted to the case of ATMPs as already mentioned; in particular, gene transfer vectors and gene-manipulated cells deserve further consideration.

Towards an IMPD addressing ATMPs and gene therapy medicinal products in particular

Efforts were initiated within the CliniGene-NoE (www.clinigene.eu) to establish master files in parallel on lentivirus vectors and AAVs, as a first priority. The vector profile generic database should ideally consist of a compilation of safety and quality issues, biodistribution profiles, and pharmacotoxicology, building up “master files” that will need constant updating. Information gathered and access to it will vary according to the vector system. Lentivectors are being used for both ex vivo transduction of gene-manipulated cells and via direct in vivo administration routes while AAV-derived vectors are mostly used in vivo. The data set that needs to be assembled prior to clinical authorization follows rigorous common frames, as tentatively formulated (Cohen-Haguenauer, 2012b). Specifics to the gene and disease of concern remain a subject of case-by-case consideration and testing. Indeed, it should be discussed how processes that are customized to each patient individually could be described in a CTD. The idea that all processes can be described as a model is not relevant for individualized products like ATMPs.

A wonderful opportunity for improvement: the Revision of the Note For Guidance On The Quality, Pre-Clinical And Clinical Aspects Of The Gene Transfer Medicinal Products

Currently, the maze of EU regulatory documents that need to be referred to is counterproductive and works against the advancement of clinical implementation, as reflected by the density of references quoted in this article.

According to multiple comments communicated by the CliniGene-NoE and formerly by the Euregenethy network, the Note for Guidance on the Quality, Pre-Clinical and Clinical Aspects of the Gene Transfer Medicinal Products, (GT-NfG), the update of which is foreseen 10 years after coming into force, is the most mature and the best reference so far in the EU gene therapy field. While the Agency had to produce additional guidance documents according to companies' requests, the CliniGene-NoE has always viewed this so-called “mother” GT-NfG as a major one, user-friendly, adequately organized, comprehensive, and internationally recognized as a reference. So far, there has been no issue found to be missing in this document. The CliniGene-NoE anticipated that its revision should not be too complicated, given the quality of the existing document. Of course, the definition of gene therapy must be updated, which has been modified, according to Part IV of Annex I to Directive 2001/83/EC.

Scientific novelty should be covered by reflection papers

As mentioned on many occasions, the CliniGene-NoE recommended that scientific novelty will continue to be covered by excellent reflection papers, like in the case of AAV rather than with new redundant guidelines. The latter would require a revision only in the event that conceptual issues of concern had not been foreseen or deemed conceivable. For instance, there is no requirement for a specific change into the current NfG when considering transposon-related technology. Points to be considered and issues at stake are likely to have been covered already. The same rationale applies for genetically modified stem cell–based therapy and induced pluripotent stem cells: there is no essential scientific ground for guideline revision.