Walking the Biosimilar Guideline

Biosimilars have been available in Europe for more than a decade and during this time the European Medicines Agency’s (EMA’s) original 2005 biosimilars guidelines have been regularly updated. Although many papers have been published describing how the regulations have changed over time, few have focused on how these regulations are applied in practice. For example, do all successful applications follow the guidelines exactly or are there instances where regulators are more flexible?

Bernd Jilma, Professor of Clinical Pharmacology, and his colleagues at the Medical University of Vienna, carried out a systematic comparison of all clinical development programs that were approved by the EMA (1). The research was part of an IDEAS project – a European training network for early-stage researchers working on statistical methods for early drug development – and funded by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement. The researchers found that companies go about demonstrating biosimilarity in many different ways, with some even deviating from the guidelines but still receiving approval. We asked Jilma to tell us more.

What were the main findings of your study?

We found that there is a large variability between the clinical development programs submitted to the EMA for getting biosimilar approval. Clearly, there will always be variability in applications because of the differences in the characteristics of the reference product. However, even for biosimilars with the same reference product, the development strategies could not always be considered comparable; for example, some companies conducted more studies that focused on whether the pharmacokinetics were comparable to the reference product, whereas others put a greater emphasis on clinical trials in patients with the target disease. Our study shows that the details of the development programs are negotiable with the EMA and there are many ways in which companies can show biosimilarity.

Do some applications deviate from the guidelines?

There seem to be some negotiations between companies and health authorities on this matter; for example, by seeking Scientific Advice from EMA when planning a biosimilar drug development program. Our study relied on publicly available information, we have no insights into these. Sometimes, the relevant product-specific guidelines may not have been available at the time the study was planned. In addition, the overarching guideline only gives general advice for biosimilars to all biologics, which might not be applicable to all active substances due to the great diversity between biologics. For example, guidelines ask applicants to add pharmacodynamic markers to the pharmacokinetic studies, but this was not done in three applications we studied. Perhaps the reason for this is that there was no established pharmacodynamic marker.

Where there was no pharmacodynamic assessment, the companies conducted large Phase III trials – and this seemed to compensate for the lack of pharmacodynamic comparison. A very interesting aspect is that some products were approved even though not all primary pharmacokinetic/ pharmacodynamic endpoints met the equivalence margins. In these cases, the sponsor provided additional studies, explanations or modeling results that were convincing enough to make the development program successful. It is important to keep in mind that biosimilars are still fairly new drugs and the process might become more standardized and regulated within the next few years as the industry gains more experience.

Although deviations from the guidelines seem to be possible if justified, not all applications for biosimilars were successful, which shows that companies have to provide convincing evidence to receive approval. We definitely don’t recommend companies to embark on developmental programs that contradict guidelines without seeking scientific advice from the regulators.

Do you have any recommendations for the regulators, based on your findings?

The European public assessment reports (EPAR) for human medicines published by the EMA are a great source for gaining insight into the most important factors in the scientific assessment of a new drug. However, to better inform the public, a more standardized format for the scientific discussion section of the EPAR would be desirable. Due to the recent data transparency initiative of the EMA we assume that in the (near) future, even more information will become publically available.

In order to link the results reported in the EPARs to other sources more easily, it would be valuable to also report the registration number in relevant clinical trial registries (such as the EudraCT number) by default for all trials referred to in an EPAR. Furthermore, to understand the rationale of the design, it would be valuable if the underlying assumptions for the sample size calculations would be made publically available in the future – an important example is the choice of equivalence margins in Phase III trials for biosimilars. These margins are crucial for trial success so it would be beneficial to understand the reasons for them.