Assessment of the Regulatory Dialogue Between Pharmaceutical Companies and the European Medicines Agency on the Choice of Noninferiority Margins.

Choosing a noninferiority margin is one of the main challenges when designing a noninferiority trial. The European Medicines Agency (EMA) published a guidance report on the choice of margins in 2005. Nonetheless, in 2008 and 2009 they did not accept 41% (35 of 86) of the noninferiority margins that were proposed by pharmaceutical companies in the context of scientific-advice letters. In this study, we focus on whether the EMA's recommendations were followed by pharmaceutical companies, and on a possible relationship with eventual drug approval. Five of the 35 unaccepted margins were equivalence margins; we considered only the 30 unaccepted noninferiority margins in our analysis. Twelve of these margins were defined based on clinical and statistical considerations (the approach recommended by the EMA) and were rejected due to unacceptable clinical considerations. The other 18 margins were rejected because they were considered too wide. The EMA's recommendations were followed in the cases of 10 of the 15 margins (67%) for which information on follow-through of recommendations was available. The main reason for ignoring the EMA's recommendation in the other 5 cases was that the margins had been accepted by the US Food and Drug Administration. The proportions of approved drugs for which recommendations were and were not followed were similar, yet numbers were too low for formal statistical testing. This study shows that the main concern of regulators with regard to noninferiority trials was the strictness of margins from a clinical perspective. Future studies using more recent data, including data on the US Food and Drug Administration, may help in assessing the impact of guideline recommendations on noninferiority margins used for drug approval and may assist in reaching consensus among regulators about the choice of margins.