In the Effort to Develop Global Comparator Products, Biosimilars Lead the Way

Biosimilars are often described as lagging behind generic drugs because there are fewer in the market and they have lower acceptance and uptake. However, according to stakeholders who spoke during the second day of the Medicines for Europe 18th Regulatory and Scientific Affairs Conference, held January 31 to February 1 in London, United Kingdom, biosimilars are leading the way in the effort to create global comparator products for use in drug development.

Suzette Kox, MPharm, of the International Generic and Biosimilar Medicines Association (IGBA), explained that there is an urgent need for an operating regulatory framework for global development for biosimilars, generics, and complex generics based on the concept of a global comparator product, and that, “for biosimilars, we have made some substantial inroads in the past couple of years” insofar as sourcing a foreign comparator is no longer a limiting factor for biosimilar development.

First, she said, it is important to understand the difference between reference products and comparators. A reference, she said, is the product legally authorized in the same territory as the biosimilar that is listed on a biosimilar’s application. However, a comparator may be of local of foreign origin, and is the molecule used in development. A global comparator, she proposed, would be one approved by a World Health Organization—listed authority that could be recognized as a suitable comparator by another jurisdiction.

According to 2014 EU guidelines, products licensed outside of the European Economic Area may be used as comparators in biosimilar development as long as bridging studies are provided, but the same is not the case for generics.

Bridging studies are widely used and have significant benefits, said Kox, but she added that they put the burden of proof to show similarity between products solely on the biosimilar applicant. “It is time today to share that burden of proof with the regulators, and [to ensure] that bridging studies are reduced … only done in exceptional cases,” she said.

Regulators can make that goal a reality by doing a better job of assessing information on foreign products. That information is available from public documents, public bodies, pharma companies, and information sharing between regulators on the basis of confidentiality agreements.

In terms of FDA and European Medicines Agency (EMA) data sharing, Kox said she believes the scope of the existing confidentiality agreement to be sufficient for sharing information, and she is encouraged by FDA policy steps, such as the advancement of new analytical tools and in vitro testing, that could help reduce time and cost in development. “This is extremely positive,” she said, “and we need to build on that.”

Alfredo García Arieta, PhD, of the Spanish agency for medicines and medical devices, provided a regulatory view of challenges facing development of global comparators for biosimilars and generics.

He posed the questions of why a foreign comparator would be deemed unacceptable, and how comparators could be different in each country if they were approved in all countries based on the same clinical development package.

The answer to both questions, he said, is that agencies are unaware if the product approved in other countries is the same as the product approved in their own country. The solution to that challenge is to share information, and to reduce legal restrictions on data sharing.

García Arieta went on to explain that, in some countries, like Australia, Canada, or Singapore, foreign comparators can be used if they are from the same company, or in some cases, if they can be demonstrated to have come from the same manufacturing plant. Additional criteria may include certain drug properties and the presence of some types of documentation (such as expiry dates or batch numbers).

Gerald Beuerle, PhD, senior director of pharmacokinetics for Europe at Teva, explained how the current burden of multiple bioequivalence studies impacts industry, further underscoring the need for a global comparator.

Currently, a company seeking to market a drug worldwide must perform bioequivalence studies comparing a generic with a US comparator, then conduct a similar study with an EU comparator, then conduct individual studies between the generic and local comparators in territories like Japan, Thailand, and Brazil. In some countries (including Japan, Thailand, Russia, and Mexico), they must also study the drug in local populations.

Even among EU nations, he said, it is not always easy to reach a consensus among nations about whether bioequivalence has been demonstrated with an EU comparator.

Given these challenges, said Kox, a global comparator “is no longer an option. It’s a must.” However, she said, this is a process that will require strong political will, and stakeholders will need to continue to make this issue a priority.