The European Medicines Agency (EMA) has recently published for public consultation its draft guideline on clinical development of fixed combination medicinal products (Draft Guideline), which is intended to replace CHMP/EWP/240/95 Rev. 1 (Existing Guideline).  The Draft Guideline applies to fixed combination medicinal products containing two or more active substances within a single pharmaceutical form.  The active substances may be known active substances or substances that have yet to be authorised in the EU.

An EMA concept paper on the Existing Guideline suggested that it be revised in order to suppress regulatory aspects and restrict it to the scientific requirements for clinical development of fixed combination products.  The Draft Guideline therefore contains a number of changes from the Existing Guideline, including:

  • It no longer describes the applicable legal basis for approving marketing authorisation applications for fixed combination products. The Existing Guideline places a strong link between Article 10b of Directive 2001/83/EC and the development of fixed combination products.  However, the Draft Guideline provides that “The legal basis for applications concerning fixed combination medicinal products may vary depending on the particularities of the active substances in combination and the development undertaken.  The choice of legal basis lies with the applicant…”  The Draft Guideline, as is the case with the Existing Guideline, does not discuss data exclusivity in respect of fixed combination products.  The European Commission’s guidance contained in its Notice to Applicants, Volume 2 A continues to apply in this regard.  It is worth noting that Teva has recently withdrawn its application and has discontinued proceedings in litigation before the General Court of the European Union (Case T-547/12) concerning regulatory data exclusivity for fixed combination products.
  • The Draft Guideline no longer addresses requirements for combination packs (i.e., where active substances are included in separate pharmaceutical forms marketed in the same package). The Existing Guideline states that scientific principles applicable to fixed combination products will also be applied in the assessment of combination pack medicinal products.  However, the EMA has subsequently recognised that from a regulatory point of view combination packs are not the same as fixed-dose combinations.  As such, reference to combination packs has been removed from the Draft Guideline.
  • The Draft Guideline contains more detail on the scientific aspects relevant for approval of fixed combination products. In summary, it provides that the basic requirements for a marketing authorisation application for a fixed combination product are: (1) justification of the pharmacological and medical rationale for the combination, (2) establishment of the evidence base for the: (a) relevant contribution of all active components to the desired therapeutic effect; and (b) positive risk-benefit for the combination, and (3) verification that the evidence base presented is relevant to the product applied for.

The deadline for submitting comments on the Draft Guideline is 15 November 2015.  Comments should be sent to FDCguideline@ema.europa.eu, and should be submitted using this template.