BioRationality: The Adulthood of Biosimilars—Global Status and Future of Biosimilars

The European Union and United States’ experience of more than 18 years using biosimilars would make them adults, according to the NIH definition if it was a living being. An increasing number of follow-on products (a term used to describe copies of biologic drugs that have not been approved as biosimilars in the Stringent Regulatory Agency [SRA] countries) have been approved globally since the expiry of market exclusivity of many innovator biologics.

There are 304 unique follow-on biologics from many manufacturers for the 18 active substances included in this study. The FDA has approved 266 originator protein proteins. Of the 304 follow-on biologics, 67 (22%) are approved as biosimilars in at least 1 of the 5 major biosimilar markets (European Union, United States, Canada, Australia, and/or Japan). The remaining 237 (78%) follow-on biologics available in 1 or more of the 15 countries are not approved as biosimilars in the SRA countries. The most significant difference is in the ‘older’ biologics for which the first wave of biosimilars have been approved in the European Union before 2010, such as epoetin alfa, filgrastim, and somatropin, but also human insulin for which, yet, no biosimilars exist in any of the significant biosimilar markets, according to a recent study published in BioDrugs.

Of the 304, the majority are manufactured in India (n = 78; 25.7%) and China (n = 62; 20.4%), followed by Russia (n = 25; 8.2%), the Republic of Korea (n = 25; 8.2%), Iran (n = 23; 7.6%), and Argentina (n = 20; 6.6%).

Only 7 follow-on biologics from India and 1 from China are approved as biosimilars in any of the 5 major biosimilar countries. The manufacturing company that produced the most significant number of follow-on biologics is the Indian-based drug manufacturer Reliance Life Sciences, producing follow-on biologics for 12 of the 18 active substances, followed by Intas and Biocon, which are both Indian companies that manufacture follow-on biologics for 10 of the 18 active substances.

All follow-on biologics manufactured by Reliance Life Science are unavailable as biosimilars anywhere in the 5 major biosimilar markets. In contrast, 2 and 5 follow-on biologics produced by Intas and Biocon, respectively, are available as biosimilars in at least 1 of the 5 major biosimilar markets. Furthermore, the Russian-based manufacturer Biocad (producing 7 out of 18) and Iranian-based manufacturer Cinnagen (n = 6 out of 18) are the largest manufacturers of follow-on biologics for the 18 active substances outside India. None of their products are available as biosimilars in major biosimilar markets.

A few examples of a product being rejected by European Medicines Agency but widely marketed elsewhere. Some regulatory agencies treat biosimilars are chemical drugs and do not require extensive testing against the reference product, such as insulins approved by the FDA, and Admelog, which have been approved under the abbreviated 505(b)(2) pathway in the United States. In contrast, they have been approved under the biosimilar pathway in the European Union.

Clinicaltirals.gov reports 780 registered studies, of which 692 are interventional and 87 observational; there are 274 completed studies.

A PubMed analysis showed 5689 papers published on biosimilars over the past 20 years:

• Clinical trials: 500
• Meta-analysis: 78
• Randomized controlled trials: 444
• Reviews: 1368
• Systematic reviews: 145

These numbers are small compared to:

• Gene therapy: 479,651
• Recombinant protein: 461,932
• Biological drugs: 841,129.

But the topic of biosimilars was less related to scientific investigation and mainly reported the attributes, mostly in comparison with the reference product.

There are 3 factors to consider. First, when would the rest of the biological drugs appear as biosimilars from the list of over 260 molecules? Second, follow-on biologics have often not been “highly similar” with the reference product; when we would have data to show that such requirement for biosimilars may not be necessary. Third, is there a possibility of creating a universal development plan to enable follow-on biologics to gain the status of biosimilars, enhancing motivation for expanding biosimilars?

Reference

Klein K, Gencoglu M, Heisterberg J, Acha V, Stolk P. The global landscape of manufacturers of follow-on biologics: An overview of five major biosimilar markets and 15 countries. BioDrugs. 2023;37:235-245. Doi:10.1007/s40259-022-00568-0