Regulatory and reimbursement approach to biosimilars
To best understand the rigor of the FDA process, it is helpful to have some context around the history of biosimilars in the U.S. Although the introduction of a biosimilar approval pathway became available through the Biologics Price Competition and Innovation Act (BPCIA) of 2009, the first biosimilar was not approved until 2015. This slow initial uptick in the biosimilar market was due to the fact that the Food and Drug Administration (FDA) did not initially have a defined process to approve biosimilars and payers did not have reimbursement policies in place.
In 2015, the FDA finalized their guidance documents for manufacturers outlining their approval process. Currently, several manufacturers have been active in the biosimilar marketplace with products in development or applications submitted to the FDA. The Centers for Medicare & Medicaid Services (CMS) has also issued its policy on reimbursement of biosimilars. CMS will assign all biosimilars to a single reference product with the same billing code under the Healthcare Common Procedure Coding System (HCPCS). CMS has interpreted the FDA approval process to be similar to that of small molecule generic drugs, and therefore are coding biosimilars as such. Private insurance payers have various policies but typically align with the policies developed by CMS. Based on these payment policies, payers are interpreting biosimilars to have the same clinical outcomes as branded biologics.
Currently, four biosimilars have been approved and one to three more products may be approved in the next 12-24 months. The four approved products include:
- Filgrastim-sndz (Zarxio®)—Approved in March 2015 and became available September 2015. This colony stimulating factor is a biosimilar for filgrastim (Neupogen) indicated for chemotherapy-induced neutropenia, acute myeloid leukemia following consolidation or induction chemotherapy, bone marrow transplant, peripheral blood progenitor cell collection, and severe chronic neutropenia.
- Infliximab-dyyb (Inflectra®)—Approved in April 2016 and became available in November 2016. This tumor necrosis factor (TNF) blocking agent is a biosimilar for infliximab (Remicade) indicated for ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn’s disease and ulcerative colitis.
- Two other TNF blocking agent biosimilars for arthritis and psoriasis have also been approved with no date of availability as of yet: etanercept-szzs (Erelzi®) and adalimumab-atto (Amjevita®).
All of these biosimilars were approved using a concept introduced by the FDA called indication extrapolation, through which one sensitive indication is studied in a Phase III efficacy trial; if the data is sufficient, it is extrapolated and the product is approved for all of the same indications as the reference product. Many physicians have voiced concern about the FDAs use of extrapolation to approve a biologic in settings where a Phase III clinical trial has not been conducted, stating that without clinical trial data, it is difficult to have confidence in the safety and efficacy of the biosimilar. Although conducting a Phase III trial for every indication would be ideal, it would be cost-prohibitive to providing lower cost biosimilars and take much longer for these products to hit the market. However, physicians should rest assured that the FDA uses the same (or similar) rigorous, well-established process for evaluating reference biologic products to review the scientific data used to develop biosimilars. The FDA’s strict manufacturing guidelines for biologics and biosimilars, as well as their emphasis on functional and structural testing in the approval process, provide evidence that approved biosimilars will meet appropriate safety standards as alternatives to reference biologics.
When reference biologic products were first introduced in the market, the FDA recognized that they are manufactured using complicated processes involving living cells, which would naturally result in variations in the manufacturing process. Due to technological advances, volume increases and manufacturing site changes, there needed to be a way to account for changes in the manufacturing processes to determine if the pre- and post-change product would have any clinical impact in terms of efficacy or safety on the patient.
With this in mind, the International Conference on Harmonisation (ICH) Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process Q5E guidelines were created in 2004. These guidelines outline that manufacturers may conduct functional and structural analyses on pre- and post-change products to establish similarity between products. The FDA would deem products similar and require no clinical trial or product labeling changes if functional testing showed the products were within certain bioequivalence limits (90 percent confidence intervals falling between 80-125 percent). Over the years, many biologics have undergone manufacturing changes and remain on the market solely based on functional testing that was conducted. These manufacturing changes are not publicized and no indications of a manufacturing change are made on the product labels.
Emphasis on structural and functional testing
The Q5E guidelines established by the ICH state that protein physiochemical and biological activity need to be considered with manufacturing changes. Specifically, the guidelines state that a “demonstration of comparability does not necessarily mean that the quality attributes of the pre-change and post-change products are identical, but that they are highly similar.” Keeping this in mind, biosimilars are approved with a heavy focus on these very same type of functional and structural testing established by the ICH Q5E guidelines. There are a host of tests that have been established to demonstrate biosimilarity between two products. As outlined in the ICH Q5E guidelines, data includes tests for molecular weight, impurities and higher order structure.
The FDA’s approval guidelines for biosimilars employ the same principles outlined in the ICH Q5E guidelines, but require supplemental data to establish biosimilarity, adding an additional level of rigor. Manufacturers are required to conduct numerous tests on products to ensure there is a finger-print like similarity between the biosimilar and the reference product. Manufacturers must perform the various tests listed above on both the reference product and their biosimilar and show identical results in the amino acid sequence and other structural and functional attributes of the products. More testing done at this foundational stage in biosimilar development may provide FDA confidence that the data submitted shows strong evidence of similarity. At this stage, the FDA may require additional or less data in subsequent data requirements. This is being termed as the FDA using a “step-wise approach” to approve biosimilars based on the totality of the evidence.
Additional studies for evaluation
Beyond structural testing, the required pharmacokinetic and pharmacodynamics animal and human studies, performed to establish equivalent mechanism of action between the biosimilar and reference product, demonstrate the FDA is evaluating that the biosimilar will have the same effect on the patient.
Again, products should show equal activity in terms of blood levels and mechanism based on the established bioequivalence limits of 80-125 percent. Immunogenicity testing should also be done in a parallel-arm study design so that the development of anti-drug antibodies can be attributed to one product.
Lastly, a clinical trial should be conducted in a sensitive indication. The sensitive indication could consist of a homogenous and sensitive patient population with the disease state in which the drug has the same mechanism of action as in the other indications. There is much debate around what would be considered a sensitive indication. For example, in the case of infliximab, Celltrion, the manufacturer, conducted clinical trials in inflammatory conditions and applied for approval in gastrointestinal indications as well. The FDA debated whether the medication acted through the same mechanism in these two different disease states. The advisory group to the FDA required Celltrion to submit further information that justified indication extrapolation. Ultimately, the FDA ruled 21 to 3 in favor of indication extrapolation to the gastrointestinal indications after review of supplementary data provided by Celltrion. This exemplifies the level of scrutiny that the FDA may use when analyzing the data dossier submitted by manufacturers.
Similar questions may arise for biosimilars used in oncology for varying indications, and the data may be reviewed in entirety to justify the use of indication extrapolation. The FDA, in the use of its judicious authority, may require further clinical trials or data to support use of a biosimilar in various indications not studied, or they may decide to only approve the biosimilar for a limited subset of indications of that of the reference.
Biosimilar efficacy and safety
Due to the FDA’s well-established, rigorous processes for reviewing biosimilar applications, physicians should be reassured that approved biosimilars will meet appropriate safety standards as alternatives to biologics. Although the issue of extrapolation still remains a concern to many, experience with the use of biosimilars will serve to reinforce physician confidence, as has been demonstrated in the European market.
Infliximab biosimilar was approved in Europe in 2013; at this time, approximately 60 percent of European physicians said they had little or no confidence in monoclonal biosimilars. Subsequently, a compilation of several studies involving more than 600 patients was presented at a European conference showing that patients who switched to the biosimilar had similar results in disease maintenance or progression as patients that were maintained on the reference. In 2016, only 20 percent of European physicians had little or no confidence in the use of biosimilars after first-hand experience with this product.
As more biosimilars are approved and become available in the U.S., physician use will enhance the biosimilar market. Other areas that may influence biosimilar acceptance include patent litigation which may impact availability, payer reimbursement reactions and market price adjustments upon entry of biosimilar products.