Global Biosimilars Require Regional Development Approaches

While much attention is paid to the US and European biosimilars markets and the benefits that biosimilars could accrue for patient access and cost reduction, other large regulatory jurisdictions, including those with limited healthcare resources, could also benefit from these products. However, bringing biosimilars to countries outside of European Medicines Agency (EMA) or FDA authority has its unique challenges.

During the BioTech Pharma third annual Biosimilars and Biologics Summit, held March 21 to 22 in Porto, Portugal, Roman Ivanov, MD, PhD, vice president of research and development for the Russian biosimilar developer Biocad, described the variable requirements for biosimilar approval in several emerging markets.

First, Ivanov explained that while EU or US approval of a biosimilar would go a long way toward facilitating authorization of a biosimilar in emerging markets, such a foreign authorization is no guarantee that a product will be approved for marketing.

In China, he said, the government has issued a technical guideline for the development and evaluation of biosimilars, and has so far issued specific product development guidelines for bevacizumab and trastuzumab biosimilars. These guidelines specify the design of clinical studies for biosimilar of these products. Additionally, China requires in vivo nonclinical studies, which is not common in other jurisdictions. Local pharmacokinetic (PK) studies and phase 3 studies that enroll at least 15% to 20% of patients from the local area are also required.

India released regulatory requirements for marketing authorizations in 2016 that largely mirror the World Health Organization’s approach to biosimilars. However, unlike other countries, India also requires minimum-enrollment, local phase 3 studies. India pays close attention to adverse events (AEs), and requires postmarketing clinical studies in approximately 200 patients to assess long-term safety and immunogenicity.

In Russia, prior to 2010, there were no clinical trials required for “copy biologics,” and therefore there are a number of such products in the market that have never been subject to a clinical program. In 2016, Russia adopted guidelines similar to those of the EMA for all biologics, including biosimilars, and gave manufacturers of previously approved copy products 10 years to provide information about how their products show compliance with those standards.

In Russia, a clinical program needs local sites in the phase 3 trial, and it is mandatory to include local patients. While EU-licensed reference products are allowed for use in theory, it is not permissible to import EU products into Russia, so all Russian clinical activities use local products.

A learning from these markets, said Ivanov, is that “The only way to develop a biosimilar for a global market is to develop it locally.”

Ivanov also gave practical advice for developers: in some developing markets, regulators may ask to see data for a phase 3 study in the most commonly used indication of a biologic. In such cases, it may be necessary to provide education to the regulators that explains that the most sensitive indication may not be the most commonly used one; psoriasis is the indication in which the effect of adalimumab is often the greatest, for example, though adalimumab is more often used to treat rheumatoid arthritis.

Developers should also discuss the choice of end points with regulators; end points such as a 75% reduction in the Psoriasis Area and Severity Index (PASI75) are no longer considered the most sensitive, as PASI75 is a binary end point: patients either have 75% improvement or they do not. Continuous end points, like improvement in PASI over time, are preferable.

The time point of evaluation should also be a subject of discussion; because adalimumab, for example, typically generates a rapid response, an assessment by week 8, rather than the usual week 16, would provide a better opportunity to identify any potential difference in the effect of the biosimilar versus the reference.

Finally, he explained, the EMA and the FDA do allow—but do not encourage—use of a noninferiority hypothesis, and nearly all regulatory jurisdictions require 1-year comparative immunogenicity data.

While the additional hurdles of developing a drug for multiple markets make the development of a biosimilar more complicated, Ivanov ended with case studies that show how great an impact on emerging markets biosimilars can have for individuals and for the healthcare system. Two years after biosimilar bevacizumab entered Russia, bevacizumab experienced a 75% price erosion and a 2-fold increase in the number of patients treated with the drug. Similarly, trastuzumab’s price fell by 63% in 2 years, and twice as many patients with breast cancer now have access to the therapy.