On 27 June 2015, the Committee for Medicinal Products for Human Use (“CHMP”) launched a two month public consultation process on a draft revised Guideline governing the implementation of Regulation (EC) No 507/2006 on the conditional marketing authorisation for medicinal products falling within the scope of Regulation (EC) No 726/2004.

The draft revised Guideline provides guidance on the early grant of a marketing authorisation where less comprehensive clinical data is supplied than is required in a normal application for marketing authorisation. It is intended to provide updated procedural information for applications that are submitted on the basis of Article 14(7) of Regulation (EC) No 726/2004. In accordance with this provision, the European Commission could grant a marketing authorisation to a medicinal product that is subject to specific conditions and annual review by the European Medicines Agency (“EMA”).

It is recalled that in order to fulfil the requirements for the grant of a conditional marketing authorisation the applicant must demonstrate the following points in the application for marketing authorisation: (i) the benefit-risk balance of the candidate medicinal product is positive and such benefit could outweigh the risk that additional data is required; (ii) evidence that it is likely that comprehensive clinical data can be provided after the marketing authorisation; (iii) the candidate medicinal product has the promise to fulfil unmet medical needs; and (iv) the candidate medicinal product targets a seriously debilitating disease, a life-threatening disease, a rare disease or could be used in an emergency situation. These requirements are reflected in Article 2 and Article 4 of Regulation (EC) No 507/2006.

Demonstrating a positive risk-benefit balance

The draft revised Guideline provides greater clarity concerning how a positive risk-benefit balance of the candidate medicinal product can be supported in the absence of less comprehensive clinical data than is required in a normal applicable for marketing authorisation. Available scientific data from clinical trials must be sufficient to demonstrate that the benefit of the candidate medicinal product can be assessed against the risks.

A request for conditional marketing authorisation in an emergency situation will be considered on a case-by-case basis by the CHMP. Such an assessment would take into account the relevant health threats and the effects of the candidate medicinal product.

Where certain elements of the data are not available at the time of the marketing authorisation this should be discussed by the applicant in the application for marketing authorisation and the available data. The draft revised Guideline recommends that the following elements be included in the application for marketing authorisation:

  • Data on the prospective, most relevant efficacy endpoint in clinical trials;
  • Safety and efficacy data from a larger database or for a longer timeframe which have the same endpoint and population in clinical trials;
  • Additional data concerning endpoints in clinical trials and identification of specific issues;
  • Additional data concerning further patient populations; and/or
  • Additional data demonstrating the impact of other medication.

The draft revised Guideline also discusses the establishment of intermediate endpoints in clinical trials that are likely to translate into clinical benefit. In this case, a conditional marketing authorisation could be granted where it can be demonstrated that the intermediate endpoint in a clinical trial shows benefits that outweighs any uncertainties of the clinical benefit.

Evidence of future comprehensive clinical data

As a specific obligation to the grant of a conditional marketing authorisation, the applicant is required to provide comprehensive clinical data that there is a positive risk-benefit balance through ongoing or new studies. An outline of the information which must accompany an ongoing or new clinical study is provided for applicants in the draft revised Guideline. Prior to the submission of an application for marketing authorisation, it is recommended that the applicant discusses the development plan and the design of studies of the candidate medicinal product with the EMA. This could be done through the scientific advice procedure, for example. Joint scientific advice may also be requested in coordination with health technology assessment bodies.

In the case of the submission of an application for marketing authorisation for an orphan medicinal product, the applicant is recommended to take into account the suitability of future data for confirmation of the orphan designation.

Demonstrating that the medicinal product fulfils unmet medical needs

The draft revised Guideline provides updated information concerning major therapeutic advantages. A conditional marketing authorisation could be granted to a candidate medicinal product that provides a significant improvement to patient care over an existing therapy in exceptional circumstances. The applicant will be required to demonstrate the following requirements in an application for marketing authorisation:

  • A critical review of the existing available methods of prevention and medical diagnosis of treatment which indicates an unmet medical need;
  • Quantification of the unmet medical need which discusses technical arguments; and
  • Justification of the extent to which the medicinal product could address the unmet medical need.

Seriously debilitating diseases or life-threatening diseases

The draft revised Guideline provides updated guidance on circumstances in which a condition could be considered as seriously debilitating or life-threatening. It is highlighted that a condition could be considered as seriously debilitating if it can be shown that it has a well-established major impact on the daily life of patients. A seriously debilitating disease must have long term effect. It is also outlined that the target disease and therapeutic indication of the candidate medicinal product must demonstrate serious debilitation or a fatal outcome.

Renewal of a conditional marketing authorisation

The draft revised Guideline also provides updated information concerning the renewal of the conditional marketing authorisation. In accordance with Article 6(1) of Regulation (EC) No 507/2006, a renewal of the marketing authorisation must be conducted on an annual basis. The CHMP will assess the renewal request in light of a positive risk-benefit balance in order to determine whether the marketing authorisation may be maintained, varied, suspended or indeed revoked. The specific obligations of the marketing authorisation holder and the relevant timeframes will also be taken into account.

Certain documentation must be submitted by the marketing authorisation holder in the application for renewal of the marketing authorisation. This includes the following information:

  • A chronological list of specific obligations and other conditions of the marketing authorisation;
  • Summary of the Product Characteristics, Annex II to the Commission Decision, labelling and package leaflet;
  • An interim report on the fulfilment of specific obligations, including details for each specific obligation;
  • A clinical expert statement addressing the current benefit-risk of the medicinal product on the basis of data generated in the specific obligations and other relevant safety or efficacy data generated since the authorisation of the marketing authorisation; and
  • Clinical data related to the specific obligations of the marketing authorisation holder where the due date for submission is due to coincide with the renewal of the marketing authorisation.

The draft revised Guideline recommends that where data included in an application for renewal of the marketing authorisation requires an update of the product information or risk management plan these changes could be included in the application.

It is also recommended that in cases where data which is included in other submissions (for example, an application for a variation to an existing marketing authorisation) and is relevant to the benefit-risk assessment of the medicinal product, this information could be included in the application. Nevertheless, this data must not serve to replace other required submissions nor be postponed until the following renewal of the marketing authorisation.

Once the draft revised Guideline is adopted in its final form it will replace the current Guideline on the procedure necessary to implement Commission Regulation (EC) No 507/2006 on the conditional marketing authorisation for medicinal products falling within the scope of Regulation (EC) No 726/2004.

The consultation process will remain open until 30 September 2015. Comments may be submitted by interested companies and individuals using the template form indicated on the draft revised Guideline to cma_guideline@ema.europa.eu.