The guidance was released last week on the Federal Drug Adminsitration’s website, but has not yet been published in the Federal Register. The comment period will not begin until the Federal Register Notice is announced.

The United States paved the way for biosimilar approval in 2010 as part of the Patient Protection and Affordable Care Act. The Biologics Price Competition and Innovation Act provision of that bill said that biological products that are demonstrated to be highly similar (biosimilar) to or interchangeable with an FDA-licensed biological product may be approved under an abbreviated pathway similar to the process for small molecule generics.

The European Medicines Agency (EMA) approved its first biologic drug in 2006. About 14 biosimilars have been approved in the EU so far, but the market has not taken off as quickly as expected. This has been attributed to the considerable expense of developing biosimilars as well as the dearth of reference biologics that have gone off patent.

It is likely that companies that have already entered the biosimilar market in the EU will be the first applicants in the US, since they are familiar with the process. The guidelines also indicate that studies that have been prepared for other agencies may be submitted to the FDA.

Guidance in three parts

The FDA guidance documents consist of three main parts: 1) Q&As Regarding Implementation of the BPCI Act of 2009; 2) Scientific Considerations in Demonstrating Biosimilarity to a Reference Product; and 3) Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product.

Courtenay Brinckerhoff of Foley & Lardner said that she was somewhat surprised by the FDA’s definition of a protein in the document outlining scientific considerations. The document defines a protein as “any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size”. Brinckerhoff said: “That leaves a gap of shorter proteins that might not be synthetically made.”

Maria Zacharakis of McCarter & English noted that the guidelines are only an initial draft and that companies making smaller proteins will probably speak up in the notice and comment period.

Zacharakis said that the scientific considerations are helpful to both biologic companies and potential biosimilar applicants. For example, the FDA said that “minor modifications” such as truncations at either end of an amino acid sequence that do not affect safety and efficacy “may be justified”. This provides clarity to biosimilar applicants, but also clues for biologic companies who want to avoid patent challenges after the 12-year data exclusivity period for biologic products expires.

“Using that information, we can carefully craft patent claims covering biologic products broadly enough to also cover a biosimilar product or an interchangeable product that a generic competitor may want to bring to the market,” said Zacharakis.

“This guidance does drive home the importance of getting protection beyond the specific sequence that you have disclosed, but it still may be a challenge to find claim language that satisfies the PTO,” added Brinckerhoff.

Clarity needed on interchangeability

The guidelines provide little clarity with respect to the concept of interchangeability for biosimilar drugs. If a drug is considered interchangeable with a reference product, that means a pharmacist can offer it to a patient instead of the reference without consulting a health care provider. In the EU, rules on interchangeability for biosimilars vary from country to country.

The Q&A document indicates that the FDA is still considering how to determine that a biological product is interchangeable with the reference product.

“Being interchangeable is what people want,” said Brinckerhoff. “That’s really what a generic is.”

The lack of clarity on this point will probably be the subject of many comments once the Federal Register Notice is published.

Totality of the evidence

The FDA also emphasised that it will assess biosimilar applications on a case-by-case, or so-called totality-of-the-evidence, basis. Brinckerhoff said this will make it difficult for companies to decide whether to apply for a biosimilar or just start from scratch with a new biologic drug application. “It’s going to be hard for biosimilar companies to decide which route to go,” she said.

Both Brinckerhoff and Zacharakis agreed that the guidance indicates biosimilar development will be expensive. The FDA leaves open the possibility for requiring human clinical trials and other extensive data. Since the agency will consider each case individually, it will be hard for an applicant to guess what will be required, and such trials could add considerable time and expense.

“The lawmakers were hoping that opening the market to biosimilars would drive down prices for biologics by 40%, but I think that’s a very optimistic view,” said Zacharakis. She pointed to the example of the EU, where biosimilar products are only about 20% to 30% cheaper than their reference products so far.

But Brinckerhoff did not fault the FDA for its approach. “This is an unknown region, there will be lots of concerns. So I don’t criticise them, but it makes the cost-benefit analysis harder. Clearly it will be more expensive.”