Gene therapies represent one of the most advanced frontiers in medical sciences. The development of advanced therapies requires a parallel effort from the regulatory agencies in order to promptly make available all guidance to support the development of new treatments. The European Medicines Agency (EMA) is investing a lot of energy in this direction; the last couple of years has been the publication of several new guidelines discussing different aspects of the development of advanced therapies including gene and cellular therapies. In addition the EMA has issued the final version of its new Regulatory Strategy to 2025, together with a summary and analysis of the comments received during public consultation. The following is a summary of the most relevant documents to complement the proposals from other stakeholders on how to implement this emerging technology.

GCPs for advanced therapies

The EU’s guideline for good clinical practices (GCP) specific to advanced therapy medicinal products (C(2019) 7140 final) was published by the EU Commission in October 2019. The guideline introduces supplementary provisions specific to ATMP products, as required by art. 4 of Regulation (EC) No 1394/2007 on ATMPs, amending Directive 2001/83/CE and Regulation (EC) No 726/2004.

In addition, gene therapies, as well as all other ATMPs, are subject to ICH E6 (R2) Good Clinical Practice Guideline (EMA/CHMP/ICH/135/1995, current version Rev. 2). Similarly,  Regulation (EU) No 536/2014 on clinical trials also continues to apply to all ATMPs, in particular with reference to the specific content of the cover letter, Protocol, Investigators Brochure (IB), and Investigators Medicinal Product Dossier (IMPD).

A unique product cycle

The main feature that distinguishes gene therapy products from other types of medicines is the complex cycle used for their production. This cycle involves many different actors, including hospitals, and is made up by the sum of critical operations and not only strictly referred to the gene editing technologies used to prepare the therapeutic construct. Logistics, for example, plays an essential role, as this sort of therapy is often characterised by a limited shelf life and needs dedicated tools and pathways for transportation from/to the production and administration centres. The administration step itself requires a specific formation of healthcare professionals who are in charge and the long-term effects of the therapy need to be carefully monitored in order to assess its safety and efficacy. 

Special clinical trial designs

As for all ATMPs, the clinical study of a candidate gene therapy requires the development of a special design for clinical trials, in order to capture all the specificities of this category of medicinal product. According to the GCP guideline for ATMPs, this includes the choice of the study population (which should allow the correct assessment of the risk/benefit ratio vs existing alternative therapeutic approaches), the risk of long-term and/or irreversible exposure to the therapeutic agent, special safeguards in cases of paediatric population or in utero treatments on foetuses, the advancement of the disease, possible sensitisation compromising transplant success and the impact of the pre-existing immunity.

Part IB of the clinical dossier has to provide information on the potential impact of previous or concomitant treatments and on possible consequences for the patient in case further treatments for the targeted disease are required. Also the risk of treatment failure should be addressed as appropriate, and informed consent must always to be collected from patients.

The administration of gene therapies requires pre-treatment of patients with a pre-conditioning regime, a passage that may become critical for the survival of some patients. Administration of the therapy should be undertaken only by authorised centres possessing dedicated emergency units as very severe adverse effects may occur. Other features to be considered include the definition of the cohort size number and active comparator (that may be unavailable), how to blind the study and the scientifically and ethically justified use of a placebo. 

A particularly challenging step in early-phase trials is the definition of the dose range, because bias might occur (e.g. the type of cells that cause the ADRs or the presence of inactive particles which may impact transduction efficiency and potency, etc.). Also the guideline indicates that a dose escalation strategy may not be necessary or appropriate; in any case, the Protocol must always provide the description and justification of the chosen dosage, as well as a clear and unambiguous definition of the “end of the trial”, as a long-term follow-up is often required. 

The guideline also provides an indication of how to run non-clinical studies, which should be based on the most appropriate and relevant in vivo and in vitro models. With this regard, a current major limitation is represented by the often unreliable information coming from animal models, due to incompatibility between humans and animal species. Traditional non-clinical pharmacokinetic or dose finding studies may be difficult to perform. The dossier has to provide a discussion of the rationale for the non-clinical development including those cases where the sponsor considers non-clinical studies are not feasible.

The quality and GMP aspects 

As for all pharmaceutical products, ATMPs and gene therapies have to comply with GMPs governing manufacturing and final quality; a version of the GMP guideline specific for ATMPs was issued in 2017 (C(2017) 7694). Among the many aspects that may impact on the quality of the final gene therapy are the variability of donor or patient-based starting material, how the disease status affects the quality of the starting material and the potential variability of the final drug product.

As already mentioned, the limited stability of this sort of drug requires great attention to the definition of the storage, transport and handling conditions, that often require very low temperature and rapid, fast-track delivery. All steps and temperature conditions along the supply chain have to be traced and documented, with adequate training to be provided by the sponsor. This is also true for the reconstitution step often needed to prepare the final formulation to be administered to the patient. Detailed information on procedures and a full traceability of the entire supply chain is a fundamental pre-requisite. 

It is also important to consider the role of medical devices associated to the medical product, for example in the form of a “combined ATMP”. In such a case, the dossier has to provide information on the characteristics, performance and intended use of the device and on its compliance with the relevant general safety and performance requirements established by Regulation (EU) No 2017/745 on medical devices.

Exemption from batch controls on imported ATMPs

In July 2019 EMA published a Q&A document (EMA/354272/2019) providing guidance on when exemptions from batch controls are acceptable for ATMPs imported into the European Union from a third country. QPs have the sole responsibility for the verification and certification that these ATMPs are manufactured in accordance with GMP, and possess a quality corresponding to the marketing authorisation dossier. All imported batches have to be re-tested, as given in Article 51(1)(b) of Directive 2001/83/EC;however,  if the product has been manufactured and tested in a country having a relevant mutual recognition agreement (or equivalent) with the EU, then Article 51(2) applies and the QP can relay on controls conducted in the third country. 

The Q&A document specifies the cases of exemption from re-testing in the EU: when just limited amount of material is available or the product is characterised by a very short shelf-life, provided the testing run in the third country was carried out by a GMP-certified facility. EMA specifies that this “exceptional exemption is primarily foreseen for imported patient-specific ATMPs (e.g. autologous product)”.

All requests for exemptions have to be supported by justification and provision of scientific data, to be assessed by the Committee for Advanced Therapies of the CHMP during the evaluation of the marketing authorisation procedure. A pre-approval inspection of the extra-EU GMP facilities can arranged, should a GMP-certificate not have been provided. With this regard, data transmitted to the European regulatory authority includes the total batch size and number of units required for batch release testing, the available stability data and proposed shelf life, the  analytical sampling plan and a GMP certificate issued by an EEA Competent Authority relevant to the particular category of testing at the facility located in the third country.

Use of out-of-specification ATMPs’ batches

According to Section 11.5 of the Guidelines on GMP for ATMPs, the use of out-of-specification (OOS) batches is allowed in exceptional circumstances when there is need to avoid an immediate significant hazard to the patient. A specific Q&As document on the use of OOSs batches was published by EMA in April 2019.

To activate this procedure, the sponsor has to provide the physician with all information about the evaluation of risks; the physician him/herself has then to request the batch, on the bases of the specific condition of the patient and the evaluation of the risks provided by the manufacturer.

The manufacturer is also responsible for investigating the root causes for the OOS; agreements specifying the respective roles must put in place when the manufacturer differs from the marketing authorisation holder (MAH) and/or importer. Any OOS has to be promptly communicated to the treating physicians within 48 hours. The EMA and the regulatory authority responsible for granting the MA to the site manufacturing or importing the medicinal product in the EU have also to be informed by submitting a Quality Defect report, when a patient has been administered or an OOS batch has been supplied for administration. As ATMPs are centrally authorised, national competent authorities of the treating site(s) may be involved checking that appropriate others have been informed. The patient has to be informed in lay language, and documents provided to him/her can neither transfer any responsibilities to the patient nor discharge the responsibilities of the MAH or the manufacturer. 

QPs cannot certify the OOS batches, but they are responsible for ensuring that all verifications of the batch have been performed. Details about the manufacture, testing, transport and storage of the product, the request of the treating physician and the analysis of the risks provided by the MAH/manufacturer have to be  recorded and documented. No obligations can be waived either h by the MAHs or by the QPs

Comparability considerations for ATMPs

Another Q&A document on comparability considerations for ATMPs was issued by EMA in December 2019 (EMA/CAT/499821/2019), addressing the criticality of the changes in the manufacturing procedure and the estimation of their impact on the characteristics of the final product. Comparability is aimed to demonstrate that no adverse impact on the quality, efficacy and/or safety profile of an advanced medicinal product has occurred when a manufacturing process change/transfer is introduced.

EMA’s advice in order to determine the amount of comparability data needed is to apply the Variation Regulation (for authorised ATMPs) or the clinical trial framework (for investigational ATMPs). The final goal is to built a suitable comparability program able to follow all steps in the development of a new gene therapy product with the required degree of flexibility. As might be expected, non-clinical phases of development will be necessarily characterised by high uncertainty and flexibility, but the acceptable level of flexibility is reduced when reaching the stage of pivotal clinical use, and subsequent marketing authorisation. 

The EMA also specifies that “vector based gene therapy medicinal products can be considered products more closely related to biotechnology in terms of manufacturing process and process controls. In this regard, ICH guideline Q5E can be more extensively considered and the comparability exercise can be focused on the capacity to address the changes with a careful analytical strategy”.

The so-called “comparability exercise” should be conducted stepwise, starting with analytical testing to confirm the physico-chemical and biological properties of the product. A critical analysis of the manufacturing process to identify all critical steps and in-process controls/materials is also needed. 

An evaluation of the proposed changes with respects of the resulting possible risks to the quality and the efficacy and safety profile of the product should be provided, using the risk-based approach and selecting relevant critical quality attributes to be compared. The generation of new validation data should also be considered as appropriate.

Comparison of processes is particularly important when a new manufacturing site is added. There is not a binding indication of the number of batches to be evaluated, it has to be established case by case. All steps along the process should be fully evaluated, justified and tracked, starting from early phase development and laboratory scale batches. A full comparability exercise is required for pivotal clinical studies; EMA discourage the introduction of substantial changes in the product during this stage of development, as they may affect the regulatory acceptability of the clinical data. 

A deep understanding and explanation of analytical methods should always be provided as the basis for the comparability exercise. Bridging of methods used during development needs also to be considered to support the comparability claim. Two approaches can be used to run this type of study: side-by-side testing of products in the same analytical run or comparison of post-change data to historical data obtained from pre-change process (not recommended, but acceptable if the former is not feasible). 

The impact of storage should also be considered, as it may reflect on materials; full real time stability studies are in general not required, while dedicated stability studies under accelerated or stress conditions may be useful. The use of healthy donor material is acceptable only with reference to patient’s material scarcity and/or ethical concerns, and it needs to be justified. 

An appropriate pre-specified plan with justification must be provided for the statistical approach chosen to evaluate data, including comparability acceptance criteria for the relevant quality attribute. Solely meeting specifications is not considered sufficient evidence to conclude on comparability.

Pre-commercial procurement of NGS in oncology

Next Generation Sequencing (NGS) is an essential activity to support the Beating Cancer Plan, which will represent the focus of the van der Leyen EU Commission in the healthcare space. The Commission announced the activation of the oncNGS project, started on 1 January 2020, under which eight health procurers from five different countries (Belgium, France, Germany, Spain, and Italy) will launch a pre-commercial procurement to develop an NGS tumour-marker analysis kit applicable to all tumour types.

The activities aim to provide an efficient molecular DNA/RNA profiling of tumour-derived material in liquid biopsies by means of pan-cancer tumour marker analysis kit including NGS analysis integrated with an ICT decision support system including analytical test interpretation and reporting. It would be thus possible to dispose of a common tumour profiling strategy allowing to provide equal access to innovative medicines. Other expected results of the project relate to the outcome research analysis after treatments with targeted therapies, and to the application of this type of testing to all patients. 

How to improve access

At the end of January 2020, the Alliance for Regenerative Medicine (ARM), the international organisation representing the advanced therapies sector, published a position paper on how to improve timely and effective access to cross-border healthcare in Europe. The document assumes that not all approved ATMPs are expected to be available in all EU’s countries, with additional barriers represented by differential Health Technology Assessment/pricing assessment and constraints to health budgets. 

ARM’s recommendations include the creation of a ‘one-stop shop’ ATMP coordination body at EU/EEA level, that may act as a broker between the different stakeholders and facilitate cross-border patient treatment and funding. Similar bodies should be created in each  country with regional funding or with multiple payers/insurers, to ensure authorities in the regions of treatment are compensated for the costs of treating patients from other regions. HTA activities should be also more aligned in order to produce shared product value assessment measures. Further measures may include new opportunities for cross-country collaboration, removing duplicative processes at national level, and adopting policy principles to enhance cross-country collaboration.

As gene therapy continues to advance, so must the regulatory framework be established to oversee it.


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