On 20 May 2015, the European Medicines Agency (“EMA”) launched a three month consultation on a revised Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products. Once finalised, the draft Guideline will replace the 2001 Note for guidance on the quality, preclinical and clinical aspects of gene therapy medicinal products.

The draft Guideline is intended to offer advice on the development and evaluation of gene therapy medicinal products that are submitted for marketing authorisation in the European Union (“EU”). In accordance with Article 2(a) of Regulation (EC) No 1394/2007 it is recalled that an advanced therapy medicinal product may be based on a gene therapy medicinal product. The draft Guideline focuses on issues related to gene therapy medicinal products (“GTMP”) containing (i) recombinant nucleic acid sequences (e.g. DNA vectors); and (ii) genetically modified micro-organisms. GTMP containing genetically modified cells are excluded from the scope of the draft Guideline. However, vectors used in the modification of genetically modified cells are included. The below mentioned information contains certain pertinent requirements and recommendations, which, if the draft Guideline is adopted in its current form, must be taken into account by applicants.

1.  QUALITY

The draft Guideline identifies certain potential barriers to the development of successful gene therapies that could be encountered by applicants. This consideration must be taken into account in the context of the design of the GMTP:

  • The genetic material of the medicinal substance must be characterised as thoroughly as possible before analysis and use;
  • The potential likelihood of cross-contamination during construction and recombination with endogenous sequences in the cell substrate used during construction or in production must be evaluated;
  • Data on the control and stability of the vector and the therapeutic sequence(s) during development and in production must be provided;
  • Evidence must be supplied to demonstrate that the correct sequence has been made and that this has been stably maintained during amplification;
  • Cells used in the amplification of the genetic material must be characterised in accordance with the draft Guideline;
  • Details of the construction of any packaging/producer cell line or helper virus must be provided.

The draft Guideline also provides examples of tests that must be conducted on different types of starting material. The following elements must be provided:

  1. description (including source);
  2. characteristics; and
  3. testing of all the materials used during the manufacturing process.

Characterisation studies must be conducted throughout the development process. Characterisation of the vector must include all components, in particular, those present in the final product to be administered. The intended action and potential impurities must be demonstrated in the development phase. The specific properties to which the specification must reflect are also defined in the draft Guideline.

A clear description of the manufacturing process and the in-process controls which the medicinal product has gone through must be submitted in support of an application for marketing authorisation. This must be presented in the format of a flow diagram. Characterisation and specification of the excipients (i.e. the complexing material(s) for formulating the medicinal products) are considered to be critical aspects of the CTD.

If GTMP are combined with a medical device at the level of the medicinal product, characterisation of the medicinal product must be provided.

The draft Guideline identifies certain release specifications that the finished medicinal product is expected to demonstrate.

Process development and process validation for the medicinal substance and the medicinal product could require the support of in vivo studies. In vivo studies could be considered necessary to demonstrate that process changes incurred do not affect the safety and efficacy profile of the product.

Details of the tests used for batch release must be provided, including analytical methods. Each reference material used in control tests much be described and demonstrated to be suitable for the intended purpose.

The draft Guideline also outlines the relevant stability studies that must support the medicinal substance and the medicinal product.

2.  NON-CLINICAL STUDIES

Methods of analysis used in the non-clinical programme supporting an application for marketing authorisation must be technically validated with the test article in the appropriate tissue matrix. Applicants are required to justify the selection of assays used for these studies and their specificity and sensitivity. In view of the specific bioactivity of GTMP, non-clinical studies must be provided using appropriate pharmacologically relevant in vitro and in vivo models. The selection of a specific animal model must be considered and justified in accordance with the elements laid down in the draft Guideline.

The draft Guideline provides specific reference to the various pharmacology studies which must be supported. Proof of concept studies could be demonstrated by in vivo and/or in vitro studies. The draft Guideline recommends the use of homologous animal models to explore potential biological effects if this could be considered useful. A clear explanation of the investigational plan to address the objectives of safety pharmacology is required. This must include the effects of both the transgene product and the vector.

Pharmacokinetic studies must focus on the distribution, persistence, clearance and mobilisation of the GTMP and address the risk of germline transmission. Dosing used in biodistribution studies is required to reflect clinical use. In cases where the whole vector or part of it is intended for integration in the host genome, this feature of the vector must be supported by integration studies. The relevant issues to which integration studies must demonstrate are provided in the draft Guideline. The draft Guideline recommends integrating shedding studies into the design of biodistribution studies or other non-clinical studies where appropriate.

In terms of pharmacokinetic studies, the behaviour of any relevant part of the GTMP must be investigated. Assessment of toxicity must focus on the whole GTMP and the transgene product. Genotoxicity studies could be required subject to the nature of the GTMP.

3.  CLINICAL STUDIES

Clinical studies for GTMP are required to reflect the same principles as for any other medicinal product. A benefit-risk assessment of the approach of the GTMP must be submitted against existing treatments in the clinical overview as part of the application for marketing authorisation. It is recalled that long-term efficacy and safety follow-up of an advance therapy medicinal product is a requirement, which is provided in Regulation (EC) No 1394/2007. The draft Guideline emphasises the importance of long term monitoring of patients treated with a GTMP. Pharmacokinetic studies could be required in certain cases where the gene product is a product or another module affecting protein metabolism. In such a case, the following studies must be carried out:

  1. shedding studies;
  2. dissemination studies; and
  3. pharmacokinetic studies of the medicinal product and the gene expression moieties.

Efficacy studies must be designed to;

  1. demonstrate efficacy in the target population;
  2. support the proposed posology; and
  3. evaluate the duration of the therapeutic effect of the GTMP.

In certain cases, a validated surrogate parameter as a clinical endpoint could be considered as an acceptable alternative to endpoints. It is, however, required that a clinical endpoint is investigated in the long term. A safety database must be established to include adverse events, which are subsequently connected to the transgene product and/or to the vector or the transduction mechanism. Clinical safety precautions are also defined where medical devices are used for the delivery or implant of a combined GTMP.

Interested parties entitled to provide observations on the draft Guideline include the pharmaceutical industry, academia, and developers of GTMP. The consultation period will remain open until 31 August 2015. Comments may be submitted using the template form provided to advancedtherapies@ema.europa.eu.