The Affordable Care Act was approved in 2010 with the goal of reducing healthcare costs. The Act’s main function was to clear the way for the Food and Drug Administration (FDA) to create an approval process for biosimilars. Biosimilars have been strongly advocated for by congress because they promise a 25-45% discount off the original product price. The Congressional Budget Office has estimated a savings to public health care programs, including Medicare, of $25 billion dollars over the next 10 years. In guidelines issued February 9th, FDA laid out an abbreviated licensure pathway for biosimilars and provided an open comment period that ended April 16^th. Public comments released on the 16^th expressed unhappiness on both sides of the debate, with calls for FDA to tighten safety conditions and clarify approval requirements. The primary issues raised during the open comment period involved defining what is “similar”, safety concerns, labeling requirements, and interchangeability in prescribing.

Citing concerns, drug developers including Genentech, Amgen and Novo Nordisk called for a tightening of what would constitute a “similar” product. Novo Nordisk suggested that FDA require biosimilars have the same amino acid sequence, without exception, as the reference product. “FDA should never permit biosimilar applications for products that cannot be adequately characterized,” Novo Nordisk stated in its letter, signed by James C. Shehan, Novo Nordisk’s corporate Vice President, legal, government, and quality affairs. Genentech also expressed concerns with FDA’s wording in a few places where it was stated that manufacturers “should” assess the analytical similarity of their products to the reference product and that they “should” perform in-depth chemical, physical and bioactivity comparisons to the reference product. Genentech argued that the use of the word “should” implies that it is not a requirement and recommended that FDA replace the “should” with “needs to” or “it is expected to”.

In the comments, another area of concern was in safety study requirements. Amgen requested that there be clear and convincing clinical data required for approval. The FDA needs to “make clear that clinical studies will be necessary for the foreseeable future due to the complexity and diversity of human biology and the limits of scientific knowledge today,” according to a report in PharmaTimes. Amgen is one of the companies most threatened by biosimilars, with two key products, Epogen and Neupogen, coming off patent in 2013. Novo Nordisk added a request for “at least one comparative clinical pharmacokinetic study” and some patient groups also called for more extensive clinical testing.

One patient group, Global Healthy Living Foundation (GHLF), expressed concerns about interchangeability. The concern is that if a biosimilar has been approved it would essentially be considered interchangeable with the original product. If the product is interchangeable, a pharmacist could provide the biosimilar as an alternative or insurers could choose to cover only the biosimilar. This substitution could happen even if the doctor has prescribed the original product, which is standard practice in small molecule drug generics. GHLF’s position is that biosimilars are not necessarily interchangeable and that products should be labeled as biosimilars so patients have a choice. “We believe that the choice of product should be decided only by patients and physicians, who are ultimately responsible for patient care and have the full spectrum of a patient’s medical history,” Seth Ginsberg, President GHLF stated in a letter to the FDA. Labeling would give patients and physicians a choice, but will they have sufficient information to make an informed decision?

On the other side of the debate biosimilar manufacturer, Biocon, took issue with FDA’s requirement that sponsors provide “sufficient scientific justification” for indication extrapolation. Indication extrapolation is the principal that if a biosimilar has been approved for one indication and performs similarly to the original product that the biosimilar should therefore be approved for all the same indications as the original product. For example, Enbrel has been approved for five indications, including rheumatoid arthritis and psoriatic arthritis and indication extrapolation would allow an Enbrel biosimilar approved for rheumatoid arthritis to subsequently be automatically approved for the other four indications. Normally, to receive those approvals for additional indications, a product would have to undergo additional clinical studies for each indication. This is a step that could be avoided by biosimilars if the principal of indication extrapolation is accepted. Biocon stated in their open comment letter “Once biosimilarity is established, and product is approved for one indication, no additional clinical studies should be expected for obtaining approval for other approved indications.”

An example where FDA permits indication extrapolation is for blood donor derived human serum albumin. Once a blood fractionation company shows similar specifications to the reference standard albumin product, the blood donor derived albumin is approved for all nine indications. Since blood products are biological origin and from an undefined and varied genetic, amino acid sequence and biophysical background, it seems to be in conflict with the biosimilar review process. Blood donor derived albumin is an interesting example where no additional clinical trials are required for a new manufacturer to enter the blood donor derived human serum albumin market. Even more interesting is the use of intravenous immunoglobulins, which are a cocktail of immunoglobulins of varying amounts and composition, that are also derived from blood donors. Using these examples, it is difficult to square the regulations for biosimilars with other types of biologics.

When issuing the guidelines in February, FDA stated that they did not want to take a standard cookie cutter approach, but preferred that each product be considered on a case-by-case basis. Their reasoning was that different products might require varying levels of studies to prove similarity, but based on these comments it seems that industry is pushing FDA to provide a more defined approach. FDA must balance drug developer and patient group concerns with the pressing need to reduce healthcare costs. While several biosimilars have been approved in Europe, waiting for an FDA pathway has prevented approvals in the United States.