Biosimilars raise complex questions for patients, doctors and regulators. Unlike generics, which are exact copies of the chemical medicines they are modeled after, biosimilars retain slight differences from the original biologic medicines.¹ These differences exist because biologics and biosimilars are made with distinct strains of living cells resulting in medicines that can’t be identically copied.¹

There are specific considerations involved in the approval process for biosimilars. The U.S. Food and Drug Administration (FDA) requires the maker of a biosimilar to show that its medicine, when compared to the original biologic, functions the same and is made up of similar components. More specifically, biosimilars must react the same way in the body — a concept known as pharmacokinetics and pharmacodynamics (PK/PD) — and have equivalent effectiveness and safety as the original biologic.²

One specific consideration relevant to the FDA and important for doctors and patients to understand is extrapolation. This concept allows the maker of a biosimilar to perform clinical trials in one appropriate disease and then potentially use the data to support the approvals for all of the original medicine’s approved indications. For example, the immunosuppressant medicine infliximab has been studied in and received approval to treat six conditions, including rheumatoid arthritis, Crohn’s disease and plaque psoriasis. The FDA has approved two biosimilar versions of infliximab for all six, even though they only underwent testing for a few of those conditions.^3,4

There are potential benefits to extrapolation, including shortening the amount of time it takes to study a biosimilar before it’s approved. This can help give patients and their doctors more choices for treating serious or life-threatening diseases. However, there are a number of scientific questions surrounding extrapolation that the FDA considers during the approval process.

A fundamental question about extrapolation is how biosimilar makers choose an adequately sensitive disease in which to study a biosimilar. It’s important to select a disease that will help the FDA determine whether any clinical differences exist between the biosimilar and the original product, and the applicability of those data to other diseases for which the original medicine was approved.

To achieve this, the FDA requires that biosimilar makers perform studies for a condition of use that is adequately sensitive to detect clinically meaningful differences in therapeutic effectiveness and potential negative effects such as toxicity and immunogenicity.² Efficacy testing, for example, should be done in a disease where clinically meaningful differences between the original and the biosimilar will be detectable. Toxicity testing is focused on patients who are likely to experience negative reactions to the medicine.

Immunogenicity can be an important safety concern with biologic medicines. In rare cases, due to the complexities of biologic medicines, small differences in therapeutic proteins can trigger harmful immune reactions in patients, known as immunogenicity.⁵ To identify potential immunogenicity, the FDA recommends biosimilar manufacturers test their medicine with people who are able to have an immune reaction.² Most tests are conducted in people who have the disease being studied, but immunogenicity may need to be evaluated in healthy people since those with serious diseases may already have a weakened immune system due to immunosuppressants, which are often prescribed as a part of treatment, and can impact results.⁶

Once all of these important tests are completed, if a biosimilar is shown to be highly similar to the original medicine and clinical tests for PK/PD, immunogenicity, efficacy and safety show no meaningful differences, the FDA may extrapolate the results to the other diseases for which the original medicine was approved.²

It’s important that doctors and patients are aware of this context because a biosimilar’s label (a regulatory document that gives detailed information about a medicine and summarizes the clinical trials that support its safety and efficacy) lists the results of key clinical trials for the original medicine, not the results of any studies conducted with the biosimilar.⁷

Where do we go from here? As with any biologic, we must monitor for signs of immunogenicity as biosimilars enter the market. Most importantly, we need to heed the FDA’s guidelines and ensure doctors and patients have the information they need to make informed decisions.

^{1. Office of the Commissioner. (2015). Biosimilars: More Treatment Options Are on the Way. U.S. Food and Drug Administration’s Consumer Updates. Retrieved from http://1.usa.gov/1CNyPIg}

^{2. FDA Guidance for Industry (2015). Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Retrieved from https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf}

^{3. Pahon, E. (2016). FDA approves Inflectra, a biosimilar to Remicade. U.S. Food & Drug Administration. Washington DC: Office of the Commissioner. Retrieved from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm}

^{4. Samsung Bioepsis (2017). Renflexis: Highlights of Prescribing Information. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761054Orig1s000lbledt.pdf}

^{5. Mirkov, S. and R. Hill. 2016. Immunogenicity of biosimilars. Drugs & Therapy Perspectives. 32:532-538. Retrieved from http://bit.ly/2nf0KSw}

^{6. Schimizzi, G. (2017) Biosimilar Indication Extrapolation. Examine Biosimilars. Retrieved from https://www.examinebiosimilars.com/biosimilar-indication-extrapolation.html. Accessed October 5, 2017.}

^{7. FDA Draft Guidance for Industry (2016). Labeling for Biosimilar Products. Retrieved from https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM493439.pdf}