The Biotechnology Industry Organization (BIO) thanks the European Medicines Agency (EMA) for the opportunity to submit comments on the "concept paper on the revision of the guideline on similar biological medicinal product."
BIO represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centersand related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment.
The decision to revise the overarching guidance document for biosimilars is welcome for the reasons given in the problem statement and further commented on below. We recognize that updating the annex guidance documents will require alignment with the overarching guidance.
A discussion of the general principles of trials to demonstrate clinical equivalence should be included in the overarching document:
A formal demonstration of clinical equivalence with the reference product would be preferred, except where there is a scientific rationale for a non-inferiority design in an indication approved for the reference product.
If the study is being used for extrapolation, demonstration of safety and effectiveness in a sensitive population is necessary to inform safety and efficacy relevant to other indications. The mechanism of action should be the same in the indication in which the clinical trials are conducted and in the indication applied for by extrapolation.
Clinical justification and pre-specification of equivalence margins for the primary endpoint are required.
For biological products that are administered over a short period, efficacy trials are typically conducted with a single primary endpoint.
For biological products that are administered over a long period where the dose is titrated to effect, trials are typically conducted with co-primary endpoints to measure efficacy and dose.
Clinical equivalence studies are generally designed to demonstrate similar efficacy, and thus are not always statistically powered to demonstrate equivalent safety. While equivalent safety should be concluded based on a valid scientific rationale at the time of approval, in some cases, establishing clinical equivalence for safety may require additional or post-marketing safety studies.
The biostatistical working party should consider writing a "Points to Consider" guidance on the design and analysis of trials with a clinical equivalence objective in a similar manner to the guidance that has been produced for the design and analysis of trials with a non-inferiority objective.