A GTMP is an ATMP which has the following characteristics:

  1. it contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence.
  2. 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.

The EMA has published a guideline relating to the quality of GTMPs within multidisciplinary guidelines, multidisciplinary: gene therapy

The EMA’s scientific guidelines on gene therapy help medicine developers prepare marketing authorisation applications for human medicines.  As clinical trials provide a significant proportion of the information required for the marketing authorisation application and approval, these guidelines, where applicable, also lay the groundwork for planning and conducting clinical trials with gene therapy products.

Quality (including manufacturing)

Selected guidelines regarding GTMPs, focusing on quality:

For more specific applications, see the following documents:

Non-clinical (pre-clinical)

Non-clinical studies are designed to support the use of a specific product to treat a specific clinical indication.The non-clinical studies conducted are an important element of the overall development pathway for an IMP and significant for establishing feasibility and reasonable safety of the IMP´s proposed clinical route of administration. Non-clinical studies always should be performed in a relevant species. In the case of GTMP, this includes both the activity of the vector construct in animals and potential differences thereof to humans as well as potential differences in viral tropism between the species.

GTMPs usually comprise both a delivery system (vector, virus, cell) and a gene product. It is important to investigate both the delivery system and the therapeutic gene product, unless otherwise justified. Data obtained with other ‘similar’ products might be supportive but are, in general, not sufficient to warrant first clinical use.

Studies should be designed and carried out with the aim of establishing the following:

  • Pharmacodynamics

‘Proof of concept’ studies should generate non-clinical evidence supporting the potential clinical effect (i.e. potency assay) or at least the related biological effect/molecular mechanism of action [in vivo and/or in vitro studies to be performed – especially when in vivo relevant disease models are not available].

  • Bio-distribution

Studies should provide data on all organs, whether target or not, as recommended in Annex A to the Note for guidance on repeated dose toxicity (CPMP/SWP/1042/99) and include investigations into GTMP persistence, mobilisation and shedding.

  • Dose

The target dose and escalation scheme should be determined, considering the intended clinical dosing regimen and the toxicological/pharmacokinetic/pharmacodynamic profile of the GTMP.

  • Toxicity

Toxicity studies should be carried out for the whole GTMP construct (delivery system and gene product) using the same dose, route and method of administration as in the clinical protocol, unless otherwise justified. Target organs should be identified in terms of toxicity, safety, biological activity and mutagenesis.

Non-clinical studies required before first clinical use of gene therapy medicinal products



When the IMP is being tested for the first time in humans, it is useful to read the following guidelines from the EMA:


The main purpose of a Phase I/II trial is safety evaluation; this includes assessment of the nature and frequency of potential adverse reactions and an estimation of the relationship to dose, but also other issues, such as feasibility of administration and pharmacological activity.

Since the ATMP candidate may in fact have little or no toxicity, it may not be worthwhile using toxicity as an endpoint. Biological outcomes, such as engraftment, transgene expression, optimal biological dose or immune response to a vaccine are alternatives for primary endpoints. Secondary objectives for efficacy measures, either short-term response or longer-term outcomes, should be included for support in the design of later-phase trials.


Feasibility assessments are carried out if specialised devices or novel procedures are required for administration, customised preparation of products, special handling of products (e.g. very short expiration time) or adjunctive therapy. Consideration should be given to designing early-phase trials to identify and characterise any technical or logistical issues in the manufacturing or administration of the product. Such issues may need to be addressed before proceeding with further product development.


When using gene therapies for life-threatening diseases, some toxicities may be expected and acceptable. In these situations, the main objective might be to identify the maximum tolerated dose, i.e. the highest dose that can be given with acceptable toxicity using a dose-escalation protocol.

For some gene therapies, toxicity is not expected to be substantial in the predicted therapeutic range. In this situation, the objective of dose exploration may be to determine the range of biologically active or optimal effective doses.

In some cases, indicators of potential benefit may plateau above a certain dose such that further dose escalation to reach a maximum tolerated dose may be unnecessary.


Potential efficacy could be indicated by any of the following short-term responses and longer-term outcomes:

  • gene expression
  • cell engraftment
  • morphologic alterations
  • more common measures such as changes in immune function
  • tumour shrinkage
  • physiological responses to various assessments


Phase III usually is considered to begin with the initiation of studies in which the primary objective is to demonstrate or confirm therapeutic benefit. Studies in Phase III are designed to confirm the preliminary evidence accumulated in Phase II that a drug is safe and effective for use in the intended indication and recipient population. The investigational medical product must be in a final stage. These studies are intended to provide an adequate basis for marketing approval.


Follow-up of patients administered with gene therapy medicinal products: Guideline CHMP/GTWP/60436/07 (PDF)

Design modifications of gene therapy medicinal products during development: Reflection paper CAT/GTWP/44236/2009 (PDF)