The approval process for biosimilars, similar to most other medicines, is quite rigorous and extensive. This process can also be, at times, confusing without proper explanation. Two concepts that are essential to understanding the process are the "totality of evidence" examined by the FDA, and the "stepwise approach" used to develop this evidence.
The stepwise approach refers to a set of tests carried out by organizations wishing to submit a new biosimilar to the FDA for approval. The information that is gained through this approach aims to show the FDA that there are no significant differences between the biosimilar and the reference biologic medicine. The tests typically consist of comparing an aspect of the reference product to the same aspect in the biosimilar and gathering data to show that any differences between the two are not meaningful to patients.
The earliest tests in this process are analytical and are used to find physical and functional similarities between the reference and biosimilar medications. This is followed by comparative tests in animals, and then small groups of humans. These tests are done in healthy humans and come in two forms: PK and PD. The PK (pharmacokinetic) tests compare how the human body handles the reference and biosimilar products, while the PD (pharmacodynamic) tests compare how the body responds to the medications.
The final part of this process consists of studying the effects of the biosimilar, compared to the reference, in patients who have the target disease. "Confirmatory clinical studies" are used to confirm that the biosimilar acts the same as the reference product in patients. Certain attributes that biosimilar manufacturers identify as extra important to the effectiveness or safety of the product can be focused on in these tests, and often must fit within an acceptable range.
Once all of these tests have been completed, the data and conclusions from each one are compiled to form what is referred to as the "totality of evidence". This is presented to the FDA, which scours the information for evidence of biosimilarity between the new product and the reference. If the FDA is convinced that the biosimilar product comes with no clinically significant differences from the reference, the biosimilar is approved.
Extrapolation & Prescription
After a biosimilar has been approved through the process above, it can still be approved for use in other conditions through extrapolation approval. In extrapolation approval, the biosimilar is approved for conditions that the reference product is used in, but for which there wasn’t a direct clinical trial comparing the two products. So, if a biosimilar is compared to a reference and approved for one condition, but the reference is also approved for another condition, the biosimilar can then also be approved for the second condition without another round of direct comparisons. This is because the idea of biosimilarity suggests that the two compounds are so similar in all relevant ways, that the biosimilar will produce the same result as the reference in any condition.
The FDA provides extrapolation approval on a case-by-case basis using existing scientific evidence; eliminating the need for extra and unnecessary clinical studies and bringing biosimilars to market in a safe but expedited manner. Similar to the concept of extrapolation is interchangeability. Interchangeability plays off the idea that biosimilars produce the exact same clinical outcomes as the reference biologic. In the U.S., biosimilars must be approved by the FDA as interchangeable through evidence that shows that switching between the reference and the biosimilar is no different that starting and sticking with the reference.
Once approved as interchangeable, a prescribed reference biologic can be switched with the biosimilar without doctor intervention. This means, at a pharmacist’s discretion, if (for example) an interchangeable version of the prescribed biologic is better covered by a patient’s insurance, the patient may elect to receive the biosimilar over the prescribed medication. While the FDA assembles and publishes the list of interchangeable medicines, in the U.S., individual state governments oversee the regulation of pharmacy. Because of this, each state must update their pharmacy substitution laws to account for interchangeability in biosimilars.