The European Medicines Agency (EMA) on Thursday opened for consultation a new guideline on the structure and data requirements for a clinical trial application for exploratory and confirmatory trials with advanced therapy investigational medicinal products (ATIMPs).
The 53-page guideline addresses development, manufacturing and quality control, featuring sections on quality documentation (including parts on the active substance and the investigational medicinal product), non-clinical documentation and clinical documentation.
According to the guideline, advanced therapy medicinal products (ATMPs) include gene therapy, somatic cell therapy medicinal products and tissue engineered products.
“In general, the development of an ATMP should follow the same general principles as other medicinal products,” EMA says. “However, it is acknowledged that the distinctive characteristics and features of ATMPs are expected to have an impact on product development.”
EMA advocates for a risk-based approach in determining the content of an investigational medicinal product dossier (IMPD), with applicants performing an initial risk analysis based on existing knowledge on the type of product and its intended use.
“Aspects to be taken into consideration include the origin of the cells, the type of vector and/or the method used for the genetic modification, the manufacturing process, the non-cellular components and the specific therapeutic use as applicable,” the guideline says.
And EMA warns that an immature quality development “may compromise the use of the study in the context of a marketing authorisation application (e.g. if the product has not been adequately characterised). A weak quality system may also compromise the approval of the clinical trial if the safety of trial subjects is at risk.”
In explaining the development of such ATMP products, the guideline says that clinical trial phases “are usually not as clear-cut as they might be for other product types,” and exploratory trials, including first-in-human trials, are the main focus of the guidance.
For confirmatory trials, which are performed to obtain pivotal data for a marketing authorization application (MAA), the guidance says developers should also take into consideration existing relevant guidelines outlining MAA requirements.
Under quality documentation, the guideline notes that the IMPD should be divided into a drug substance (DS) and a drug product (DP) section. “For certain ATIMPs, the starting material, the active substance and the finished product can be closely related or nearly identical. The active substance, any intermediate and the final product should be identified, if possible. In those cases where the ATIMPs production is a continuous process, it is not necessary to repeat the information that was already provided in the DS part, into the DP section.”
Under the active substance section, the guideline says the proposed mechanism of action “should be presented and form the basis for the definition of the relevant properties of the active substance including biological activity (i.e. the specific ability or capacity of a product to achieve a defined biological effect).”
As far as the ATIMP manufacturing process and process controls, the guideline recommends careful design and concise, step-by-step descriptions. “The suitability of the controls for the intended purpose needs to be proven,” EMA says.
But it’s the non-clinical development that is really unique for ATMPs, especially as EMA says “potential flexibility can be applied."
“The non-clinical development pathway for ATMPs may be significantly different from the one for other medicinal products including the timing of studies. The sequential non-clinical development in which the amount of data required and the duration of dosing increase by the phase of clinical development and by the number of patients, is not generally applicable for ATMPs,” the guideline advises.
Instead, in many cases, the guideline says, most non-clinical data may need to be available before human exposure.
“In general, the non-clinical data supporting the safe use of an ATMP in humans should provide information for the estimation of the safe and biologically effective dose(s) to be used in clinical trials, support the feasibility of the administration route and the appropriate application procedure, identify safety concerns and target organs for potential toxicity and identify safety parameters to be followed in the clinical trials,” the guideline says.
As for clinical documentation, the guideline also notes that the distinctive characteristics and features of ATMPs are expected to have an impact on the trial design, specifically with regard to early phase trials and dose selection, pharmacodynamics and pharmacokinetics/biodistribution, while the general principles in late phase trials to demonstrate efficacy and safety in the specific therapeutic area are less affected and are essentially the same as for other products.
Comments on the consultation are due by 1 August.
Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials
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