From Biosimilar to Interchangeable
Consider what happens when your bicycle breaks. You can easily go to the bike shop and get a replacement part, as long as you know the name of the part and all of the specifications to ensure that it will fit your two-wheeler. You walk into the shop and say, for example, “I need a 700 x 23 replacement tube with a Presta valve.”
Believe it or not, this example can help us understand a current issue in biologic medicine – interchangeable biosimilars. But before we dive in, it’s important to understand the basics about what biosimilars are.
Biosimilar medicines are versions of biologics that are very similar to the original medicine, but not identical. Unlike generic versions of chemical medicines, like statins or aspirin, it is impossible to make exact replicas of biologics.i This is because biologic medicines are made from living cells, and are extremely complex relative to chemical medicinesii – more like a 747 airplane than a bicycle.
To date, the four biosimilar medicines that have been approved by the U.S. Food and Drug Administration (FDA) have been deemed “highly similar,” meaning they have shown no clinically meaningful differences from the original medicine.iii However, they have not yet been deemed “interchangeable,” which would mean that in addition to being “highly similar” they can be expected to produce the same result for any given patient as the original medicine. The designation also requires that a person taking the medicine on an ongoing basis be able to switch from the original to the biosimilar, or vice versa, without any change in safety or effectiveness.
When dealing with complex biologic medicines, it’s not hard to imagine that determining interchangeability is going to be complicated.
These requirements may seem like nuances, but they are important because interchangeability allows pharmacists to substitute biosimilars without consulting the doctor or patient first. This practice, known as substitution, is covered by state laws, and is widely accepted for generic medicines but is still under consideration by some state legislatures for interchangeable biosimilars.iv
When dealing with complex biologic medicines, it’s not hard to imagine that determining interchangeability is going to be complicated. To this end, the FDA recently released initial guidance for companies wishing to demonstrate that their biosimilars meet the standard of interchangeability.v While this guidance is comprehensive, a couple of important questions remain.
First, how should biosimilars be tested to ensure they can be substituted for an original medicine and produce the same result as the original medicine for any given patient, particularly as multiple interchangeable biosimilars are approved? Though biosimilars share the target and mechanism of action of the medicine they are modeled after, they could interact with a patient’s body in a slightly different way from the original medicine when they are alternated or switched repeatedly with the original medicine.
Second, how should an interchangeable biosimilar be distinguished from the original medicine in terms of its name and label? People who are prescribed biologic medicines, and their doctors, have a right to know exactly which medicine the patient is receiving. Just like a bike mechanic should be able to tell the bike owner exactly what parts were used in a repair, someone with a serious disease such as cancer should know which medicine he or she is receiving.
The Reason for Vigilance
Biologics are extremely complex medicines. So while a biosimilar, by definition, must be deemed highly similar to the original medicine, the patient’s immune system may react differently due to the slight differences between the two medicines when they are alternated or switched multiple times.vi
This phenomenon, known as immunogenicity, is not a common occurrence. But there have been rare instances when very small differences between biologic medicines have caused immune system reactions that changed the way a medicine was metabolized or reduced its effectiveness.vii
In its draft guidance, the FDA recommended “switching” studies, which rotate patients between the biosimilar and the original medicine multiple times while monitoring for any differences in the patient’s response to the two medicines. The FDA has also carefully considered issues such as the container the medicine is stored in and the delivery method for the medicine. The goal is that when taken together, these measures will give patients and their doctors confidence in the safety and effectiveness of the interchangeable biosimilar.
What’s in a Name?
It’s also important for the FDA to provide specific recommendations about how interchangeable biosimilars should be named and what kind of information should be included on their labels. Last year, the FDA established a sound system of distinguishing an original biologic medicine from a biosimilar by appending different four-letter suffixes to the so-called “nonproprietary or generic names” for the medicines. For example, Inflectra, the biosimilar version of infliximab, is known as infliximab-dyyb.viii
It’s important for interchangeable medicines to have a distinct name that is different from the original medicine and from other biosimilars.
Regulators have not decided how interchangeable medicines should be named yet and are considering giving them the same name as the original medicine or keeping the suffix they were given when approved as a biosimilar. However, it’s important for interchangeable medicines to have a distinct name that is different from the original medicine and from other biosimilars. This will ensure they can be easily distinguished from each other if adverse events or manufacturing problems occur with one medicine but not the other versions.
The FDA should publish guidance on the need for distinct nonproprietary names and appropriate labeling for interchangeable biosimilars. This would protect patients from being switched between medicines that have not undergone the interchangeability assessment described in the draft guidance.
The Road Ahead
Based on the clinical testing program established in the FDA’s most recent draft guidance, appropriate measures are being taken to help protect patients, particularly from the risks of immunogenicity. But we’re not done yet. We still need to ensure that doctors and patients can easily distinguish different medicines, and that the unique properties of biosimilars have been addressed. I look forward to further discussions among all relevant stakeholders about this important topic.
i 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
ii Dorey, E. (2014). Forces Driving the Evolution of Biologics into Biosimilars and Biobetters. The Pharmaceutical Journal: Clinical Pharmacist, 6(9). Retrieved from http://www.pharmaceutical-journal.com/news-and-analysis/features/forces-driving-the-evolution-of-biologics-into-biosimilars-and-biobetters/20067091.article
iii 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
iv Cauchi, R. (2015). State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars. National Conference of State Legislatures (NCSL). Retrieved from http://bit.ly/1lvTIQM
v FDA Draft Guidance for Industry (2017). Considerations in Demonstrating Interchangeability With a Reference Product. Retrieved from https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf
vi Mirkov, S. and R. Hill. 2016. Immunogenicity of biosimilars. Drugs & Therapy Perspectives. 32:532-538. Retrieved from http://bit.ly/2nf0KSw
vii Louet, S. 2003. Lessons from Eprex for biogeneric firms. Nature Biotechnology. 21: 956-957. Retrieved from http://go.nature.com/2nfiNaZ
viii FDA Guidance for Industry (2017). Nonproprietary Naming of Biological Products. Retrieved from https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf