Regulators Look Back on 15 Years of Biosimilars in Europe

This year is the 15th anniversary of biosimilar availability in the European Union, and in an overview sponsored by the generics and biosimilar trade association Medicines for Europe, experts from regulatory and business venues discussed some of the major achievements and hurdles yet to be crossed.

One of the biggest advances in biosimilars has been the improvement in the consistency of manufacturing, said Elena Wolff-Holz, medical assessor for the Paul Erlich Institute in Germany and chair of the European Medicines Association Biosimilar Medicinal Products Working Party. Whether biologics are sourced in the United States or Europe, they are dependably similar in quality, and that applies also when you compare products over a span of time, she said. “Humira [adalimumab] manufactured 5 years ago is the same as Humira today.”

The same holds true for Humira and biosimilar versions of adalimumab. “We can exchange one medicine for another, and it will have the same clinical effect in a given clinical setting and any patient,” she said.

Methods of assessing whether biosimilar candidates are equivalent to reference drugs have improved a great deal from 10 or 15 years ago. For example, the growing confidence in analytical tests for functional and structural characterization of biosimilars has enabled regulators to lower requirements for comparative clinical efficacy trials, which are not as sensitive.

Exponential Biosimilar Use

“We continue to accrue so much experience and knowledge and across certain classes of biologics, like monoclonal antibodies, and that’s been really foundational in enabling confidence and reliance on analytical results for demonstrating products are biosimilar or interchangeable with their reference products,” said Sarah Yim, director of the Office of Therapeutic Biologics and Biosimilars at the FDA. “I think the experience is going to be exponential. A lot more people are going to start being comfortable with biosimilars,” she said.

According to Hye-Na Kang, a scientist on the Norms and Standards for Biological Products team in Health Products Policy and Standards at World Health Organization (WHO), countries these days are much more consistent with one another in how they define biosimilars. “This trend is welcome because it avoids confusion with other products that are not biosimilars,” she said. “Not all products called ‘biosimilar’ are at the same level of quality.”

Also positive is that there are many more biosimilars by low-cost producers on the market in countries that used to be dominated by large originator companies. However, problems remain in WHO countries that Kang monitors. Some of these have insufficient supplies of even originator biologics and lack resources to conduct evaluations of biosimilar candidates.

Early biosimilars (epoetins, bone marrow growth factors, somatotrophins) were simpler molecules compared with monoclonal antibodies (manmade proteins that behave like antibodies), but it took a while before tools emerged for adequate analysis of these second-generation agents, said Anne Cook, an expert quality assessor for the UK Medicines and Healthcare products Regulatory Agency.

“It was the advances in technological areas that made it possible to analyze some of these bigger molecules, because before that it hadn’t been possible. This has really led to an explosion in the number of monoclonal antibodies and fusion proteins that have been approved,” she said.

Greater Detail Than Before

These new technologies allow analysis in much greater detail than before, although for that detail to be of practical value “the next step is to work out what is important and whether that’s going to have a clinical impact,” Cook said. “It’s understanding how these products work within patients and how best to examine the differences, because you’ll always see some differences. You’ll see batch-to-batch variation.”

“There was an awful lot of discussion in the early days as to what was acceptable and what we needed to do in order to approve these products, and there was some unease about whether this was going to be OK, but I think the last 10 years have proved that we have the analytical tools,” Cook said.

Ana Hidalgo-Simon, head of Advanced therapies for the European Medicines Agency, said biosimilars have proved themselves in Europe over 15 years. “For me, the weight of history has shown how good they are; how, if we are careful and approve them with the highest standards that we have, we can be very comfortable with them.” The challenge going forward is to transmit this confidence to decision makers and patients. “Biosimilars are very complex, and a lot of doctors are comfortable with part of it, but they will always want to learn more.”

When biosimilars were introduced, stakeholders were reluctant to embrace them, recalled Martin Schiestl, global head of Regulatory Affairs and Policy at Sandoz. “There was a lot of controversy and anxiety around this class of drugs. I remember in 2009 when there were leading experts in academia who said you will never see biosimilar antibodies, so this is reflecting how fast things can move. The idea of physicians inferring that biosimilars approved for one indication of a reference product could be used for other indications of that product—known as extrapolation—was anathema, he said. “Even for the very simple biosimilars, there was a very huge resistance initially from prescribers to extrapolate.”

Another major advance was the realization that comparative clinical efficacy trials (using study populations and efficacy end points) were neither essential nor even very useful for biosimilar equivalency assessment.

“This was, I think, a huge finding, and this opens up the door to more efficiency in the future. Specifically, for each data element in the biosimilar assessment, we should ask, ‘What is the purpose? What is the scientific question?’” Schiestl said.