EMA Updates Clinical Requirements for Fixed-Dose Combinations

Sponsors seeking EU authorization to market fixed-dose drug combinations should conduct multiarm, randomized, controlled trials comparing the FDC with its individual components, the European Medicines Agency says.

If the FDC is intended for patients who didn’t respond to one or more of its components, for example, the trial should prove that the combination has superior efficacy. Sponsors will need this data to gain marketing approval for patients who already are responding well to optimal doses of the individual components and augment it with evidence of the FDC’s superiority from clinical trials, published literature or both, the EMA says in draft guidance released last week.

While many of the EMA’s recommendations for proving safety and efficacy mirror those in a 2009 draft guideline, the agency is no longer asking sponsors to conduct placebo-controlled trials or trials with active comparators.

For example, while the earlier draft recommended comparative pharmacodynamic data for FDCs, the agency now says this data can be dropped if safety and efficacy data are sufficient. The EMA still wants to see some pharmacokinetic data, such as drug-drug interaction studies and analyses of vulnerable patient subgroups like the elderly and patients with kidney damage.

The updated guideline also contains more specific recommendations for proving safety and efficacy in treatment-naïve patients. In this case, sponsors must prove that the safety and efficacy benefits of the FDC outweigh any disadvantages. They should also justify their target populations carefully, in line with clinical guidelines in the appropriate therapeutic area.

If the rationale for using the FDC in treatment-naïve patients is that it shows superior efficacy to any of its components, then sponsors should conduct a randomized, controlled trial showing superior efficacy of a clinical outcome and an acceptable safety profile in a three-arm study comparing the FDC against its components.

If superior safety is the rationale, then the trial should demonstrate similar efficacy at a specific point when patients have been given the optimal dose in both the FDC arm and the monotherapy arms. To prove safety in this trial, sponsors should define specific safety events as co-primary endpoints.

The EMA is accepting comments to FDCguideline@ema.europa.eu through Nov. 15. Read the guideline at www.fdanews.com/05-13-15-EMAFDCguideline.pdf. — Lena Freund