6. Optimal designs and analysis methods for the development of Biosimilars

Team: Prof Byron Jones (Novartis), Dr Franz König (Medical University Vienna)
Clinical Advisor: Prof. Dr. Bernd Jilma, an expert in early phase trials including first-in-human and biosimilar trials.

Location: Novartis Pharma AG (Basel, Switzerland)

Biosimilars are generic copies of biotechnologically produced medicinal products, whose active drug substance is made by or derived from a living organism by means of recombinant DNA or controlled gene expression methods. Such copies are produced with the aim of being lower priced alternatives to the innovator products that have lost their patent. Biosimilarity of a generic product, as compared to a reference product, may be interpreted as meaning “that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product”¹⁰ . Interchangeability, stating that for a new biological product to be accepted as interchangeable with a reference product, the sponsor has to demonstrate that: “(i) the biological product is biosimilar to the reference product; and (ii) can be expected to produce the same clinical result as the reference product in any given patient, and that the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switching”.

To date, there are no established statistical methods for showing biosimilarity, or “switchability” and the aim of this project is to develop clinical trial designs and analysis methods that will maximize the probability of successfully demonstrating that the original or reference product (R) is biosimilar/switchable to the new product (T). It is anticipated that the class of designs under consideration will be of the cross-over type where patients receive both R and T in sequence over a period of time. Because of the high variability in the responses measured in biosimilar trials, the designs will include sequences that repeat either R or T or both, e.g., RRTT, TTRR. Such designs will also provide increased confidence in any conclusion reached regarding that T and R are biosimilar, by showing the trial is also able to confirm that T and R are biosimilar to themselves.

Also, due to the high variability in response in biosimilarity trials, the properties of different adaptive designs will be investigated. Such designs will be especially attractive when there are two or more alternative biosimilars in development and a choice needs to be made to take one into full development. Adaptations will include sample size re-estimation and the dropping or adding of a biosimilar at one or more interim analyses. A particular feature of adaptations in such designs is that they need to take account of the correlation structure of the repeated measurements taken on each patient.

Meet our Early Stage Researcher: Johanna Mielke, Novartis Pharma AG

I was born in Herdecke (Germany) and received a Bachelor’s and Master’s degree in statistics from TU Dortmund University (Germany). My Master’s thesis focused on the development of an asymptotic and robust test for location shifts in time series (change points). During my studies, I spent a semester abroad at University of Warwick (Coventry, UK) and completed an internship at Monash University (Melbourne, Australia) and at Novartis (Basel, Switzerland). In my free time, I enjoy travelling, swimming and reading.

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