EMA Drafts New Clinical Development Guideline for Fixed Dose Combination Drugs

Regulatory NewsRegulatory News | 13 May 2015 |  By 

In response to a rise in the use of fixed dose combination (FDC) drugs, the European Medicines Agency (EMA) has revised its guideline addressing the clinical development requirements for FDCs.


FDCs—or drugs containing multiple active ingredients—are used to treat a variety of medical issues, ranging from the common cold to tuberculosis and HIV.

For many treatments, combining multiple active ingredients can result in a simpler, more effective treatment regimen. However, combining active ingredients can also have negative consequences, such as increased toxicity.

Evidence Base and Therapeutic Scenarios

EMA says this guideline is applicable to FDCs regardless of the marketing authorization procedure a company intends to use (centralized, decentralized or national procedure). Additionally, the scientific principles contained within the guideline can be applied to products with a single active ingredient that "dissociates in vivo into two or more active substances."

To justify the use of an FDC, EMA says companies must establish an evidence base that demonstrates the need for a given combination. To do so, the agency calls on companies to clearly define the population in need of a particular combination and gather data for "each situation/intended claim."

Companies must also demonstrate that an FDC is "pharmacologically plausible and based on valid therapeutic principles," and take into account dosage and frequency. When there are multiple possible dosages of the different ingredients in an FDC, EMA says, “Dosages that have shown benefit on hard clinical outcomes may be preferable [compared to] dosages effective on surrogate endpoints only."

Additionally, companies must be able to demonstrate that the FDC improves efficacy and/or safety compared to a single active ingredient, and must show that all active ingredients contribute to the product's therapeutic effect.

EMA describes three therapeutic scenarios that can be used to establish an evidence base supporting the use of FDCs:

  • "add-on treatment of patients insufficiently responding to an existing therapy with one or more (mono-) components;"
  • "substitution in patients adequately controlled with two or more mono-components used in combination;"
  • "initial combination therapy for patients receiving previously neither of the substances."

The first scenario describes a situation where an FDC will substitute for an existing therapy in patients who are not responding to one or more mono-component treatments. In this scenario, companies should either conduct drug-drug interaction (DDI) studies for all active ingredients in the FDC, or be able to justify not conducting such studies. Companies are required to prove the "superiority" of an FDC in this scenario through a randomized controlled trial (RCT) comparing the FDC to the respective mono-components.

The second scenario describes a situation where an FDC is substituted for an "optimal dose of the mono-components," in patients who are responsive to the mono-components. In the third scenario, patients are immediately treated with an FDC. This scenario should only be used in situations where "the benefits of starting two drugs at the same time outweigh its disadvantages (unnecessary treatment, safety issues)."


EMA Draft Guideline


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