23/24 November 2021
The European Medicines Agency (EMA) published the final version of the so-called reflection paper on "Similarity". The paper discusses the appropriate use of statistics during drug development when a comparative assessment of quality attributes (QAs) is needed (e.g. in case of pre- and post-manufacturing changes, biosimilar & generics´ development).
In 2017, the EMA released a draft Reflection Paper (RP) on statistical methodology for the comparative assessment of QAs. This was followed by a 1-year public consultation phase ending on 31 March 2018. The EMA considered the comments received during the public consultation period and from a workshop conducted in 2018 when finalizing the RP. In total, about 300 general and 1000 specific comments were received by the time the consultation period ended. According to the EMA, examples, where the comparative evaluation of QAs plays a major role in regulatory decision-making, are:
According to the agency, one of the most relevant comments received during the consultation period was that the draft RP did not answer the question: "What is similarity?". Thus a new concept, the "similarity condition", is introduced in the revised RP. Thereby, it is pointed out that a definition is first required on when the two data distributions (e.g., data taken from two manufacturing processes) to be compared would allow the conclusion of "similarity". In addition, it is important to differentiate the "similarity condition" from the "similarity criterion": The former corresponds to a consensus between stakeholders involved in regulatory decision-making (applicants as well as regulators). The latter is a concrete instruction on how data should be analyzed to check whether the a priori agreed "similarity condition" can be assumed to hold or not.
The following definition is provided for the RP in the Procedure for European Union Guidelines and Related Documents within the Pharmaceutical Legislative Framework:
"A reflection paper may be developed to communicate the current status of discussions or to invite comment on a selected area of medicinal product development or a specific topic. It can provide a framework for discussion or clarification particularly in areas where scientific knowledge is fast evolving or experience is limited. A reflection paper does not provide scientific, technical or regulatory guidance, but may contribute to future development of such guidelines, or related documents."
The U.S. Food and Drug Administration, FDA, previously withdrew their draft guidance on “Statistical Approaches to Evaluate Analytical Similarity" issued in September 2017. According to the FDA, the draft guidance was intended to provide advice for sponsors developing biosimilar products regarding the evaluation of analytical similarity between a proposed biosimilar product and a reference product. After considering public comments, the FDA determined to withdraw the draft guidance. The comments addressed a range of issues that could impact the cost and efficiency of biosimilar development, including the number of reference product lots the draft guidance recommended to sample.
For more information please see the final "Reflection paper on statistical methodology for the comparative assessment of quality attributes in drug development" published together with the comments received on the draft RP on the EMA website.