Article 18 of Regulation (EC) No 1394/2007 on Advanced Therapy Medicinal Products (ATMP) provides that Small and Medium-sized Enterprises (SMEs) developing an ATMP may submit to the European Medicines Agency (EMEA) all relevant quality and, where available, non-clinical data required in accordance with modules 3 and 4 of Annex I to Directive 2001/83/EC on the Community code relating to medicinal products for human use, for scientific evaluation and certification.

Provisions for the evaluation and certification of such data have been laid down by the European Commission in its Regulation (EC) No 668/2009, published on 25 July 2009 in the Official Journal of the European Union.

The certification procedure aims at giving the SMEs an incentive to develop ATMPs regardless of any future application for marketing authorisation. It could, nevertheless, facilitate the evaluation of any future application for a clinical trial authorisation or a marketing authorisation application, provided that these applications are based on the same data.

Requirements

In order to be eligible for this new procedure, applicants must be (i) a micro, small or medium-sized enterprise, within the meaning of Recommendation 2003/361/EC, (ii) developing an ATMP and (iii) established in the Community.

To be valid, an application must contain:

(a)All information necessary to demonstrate the applicant meets all the requirements set out above;

(b)Indication as to the type and nature of the data submitted;

(c) Reference to any applications for certification previously submitted for the same product and related information;

(d)The relevant fee as provided for in Council Regulation (EC) No 297/95. According to the EMEA Rules for the implementation of Regulation (EC) No 297/95, the fees for this procedure will amount to €56,600 for the evaluation of an application relating to quality and non-clinical data and €37,700 for the evaluation of an application relating to quality data, respectively;

(e)The data referred to in module 3 of Part I of Annex I to Directive 2001/83/EC which is submitted for certification2; and

(f) Where the application relates to both quality data and non-clinical data, the data referred to in module 4 of Part I of Annex I to Directive 2001/83/EC which is submitted for certification3.

In case of applications for certification relating to combined ATMP4, additional requirements will apply in relation to the conformity of the medical device or active implantable medical device contained in the combined product with the essential requirements laid down in the relevant EU legislation5.

In the CAT6 Draft Procedural Advice (DPA) on the certification procedure, currently under consultation, further guidance on the procedure, timelines and dossier structure that SMEs should fulfill in order for the EMEA to issue its appropriate certificate are provided. According to this document, prior to the submission of the application for certification, the SME’s status shall have been obtained by the applicant and a letter of intent, stating the reasons for the product being classified as ATMP, shall have been sent to the EMEA (i.e. CAT Secretariat) at the latest four months prior to submission.

Scope

The CAT is responsible for evaluating applications for certification. Interaction between the EMEA and the relevant notified bodies may be necessary in cases of combined ATMPs, which in same cases may also lead to an “extension” of the ordinary timeframe for such a procedure (i.e. 90-days procedure to be possibly extended, via a clock-stop, in case additional information is needed). The possibility for the CAT to request site visits of the premises where the ATMP concerned is being developed has also been provided. If the applicant accepts the conduct of a site visit, it shall be carried out by inspectors from the Member States who hold the appropriate qualifications.

According to the DPA, the evaluation performed under Article 18 of the ATMP Regulation is intended to certify that each submitted study complies with the relevant scientific and technical requirement set out in the Annex I to Directive 2001/83/EC and adequately follows state-of-the-art scientific standards and guidelines.

For these reasons, the scientific and technical requirements followed by the CAT when assessing the data submitted for certification, will be the same applicable to the evaluation of a marketing authorisation. Not all sections as defined by part I of Annex I to Directive 2001/83/EC may however be completed for the application for certification.

Moreover, in order to distinguish between this new procedure and existing procedures (namely, scientific advice procedure), it is provided that the certification procedure will focus only on scientific evaluation of existing experimental data (quality/non-clinical). No advice as to further development of the product will be provided. In case the latter information is needed the appropriate procedure should have to be applied for (i.e. scientific advice).

In the same vein, a certificate is not intended to conclude either on the benefit/risk profile of the product or on the adequacy of the studies submitted for the product to be further developed in a clinical trial. The latter is the scope of a separate procedure, under the responsibility of the National Competent Authorities where the clinical trial will be conducted.

The Commission Regulation does not provide for any time limit for an application for certification to be submitted. An application for the certification can therefore legally be submitted at any time of the development of an ATMP. However, the DPA appears to be more restrictive in this regard when providing that a minimum quality and where available non-clinical data package will have to be submitted to allow for certification.

Outcome

If appropriate on the basis of the evaluation, the EMEA will issue a certificate identifying the quality and, where applicable, non-clinical data submitted and the corresponding testing methodologies followed by the applicant, which have been found acceptable in terms of regulatory compliance and scientific robustness. This certificate will not be binding with regard to any future regulatory procedure and all relevant data, even if already certified, and should be submitted again for the purpose of any future regulatory procedure.

In principle, the certificate should help EU SMEs to increase profits out of the R&D performed (e.g. by selling at a more profitable price their early-stage products or by attracting interested investors).

In practice, the actual value of the Certificate will mostly depend on: (i) the stage of development of the ATMP at the time when the Certificate was issued and (ii) any additional changes introduced to the ATMP after the Certificate was firstly issued.

In this regard, the DPA addresses a clear reminder to applicants that if a certificate is granted during early development its relevance/validity is likely to be limited.

Applicants may wish to follow the DPA of the CAT, according to which the optimum time point to apply for the certification procedure is when the ATMP has reached a level of sufficient development with respect to quality and non-clinical data.

Indeed, although from a legal point of view nothing prevents applicants from requesting certification of their data very early in the development of their products and to “update” their certificate as much as they might consider it necessary, the fee requested for each procedure as well as the “minimum” data requirements could act as serious deterrents to use this procedure too soon or too recurrently.

Furthermore, the fact that a list of “issues” as regards compliance with the above mentioned scientific and technical requirements for future consideration by the Applicant may be included in the evaluation report attached to the certificate as well as the possibility for the EMEA to issue a “refusal letter” whenever the opinion is negative, might also have an impact on the decision of a company as to if and when an application for certification should be submitted.

In a subsequent development relating to ATMPs, Commission Directive 2009/120/EC of 14 September 2009 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products, published in the Official Journal of 15 September 2009, and to be implemented no later than 5 April 2010, amends Annex I to Directive 2001/83/EC as regards ATMPs. It updates the definitions and detailed scientific and technical requirements for gene therapy medicinal products and somatic cell therapy medicinal products and establishes detailed scientific and technical requirements for tissue engineered products, as well as for advanced therapy medicinal products containing devices and combined advanced therapy medicinal products.