Update on Biosimilars US Regulation 1st Quarter 2016

 

Yesterday the FDA approved Inflectra the Pfizer/Celltrion version of Remicade, becoming the second biosimilar and the first monoclonal antibody to proceed through the the FDA 351 (k) pathway for biosimilars.   But given current resource allocations towards towards biosimilars at the FDA it may be a while before we see large numbers of approvals.

he biosimilars pathway will be significantly impacted by FDA guidance in the coming year. In 2015, FDA issued guidance documents but did not go so far as to settle fundamental questions related to the labeling of biosimilars, the requirements of interchangeability, and naming.

2015: Issues, guidances, and citizen petitions

In April 2015, FDA issued three relevant guidances, including “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product.” The guidance was criticized for eliminating labeling information to distinguish the biosimilar product from its reference product, such as identifying the product as a biosimilar. FDA also released “Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009.” This finalized a 2012 draft guidance but did not fully answer questions on the determination of interchangeability. In May 2015, a new draft guidance offered these questions and others, titled “Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (BPCIA).” FDA noted it would be difficult for a biosimilar applicant to establish interchangeability in an original 351(k) application given the statutory standard for interchangeability and the sequential nature of that assessment.

Citizen petitions from AbbVie and industry also raised industry concerns. AbbVie’s petition states the FDA’s approach to labeling was inconsistent with the Biologics Price Competition and Innovation Act of 2009. BIO and PhRMA also filed a petition urging the agency to require labeling distinguishing a biosimilar from its reference product. FDA intends to provide guidance on the requirements for interchangeability and labeling this year.

The naming of biosimilars is another important and unsettled issue. In August 2015, FDA released draft guidance for naming biosimilars. The agency proposed to add on distinguishable but meaningless suffixes to the nonproprietary name of the reference product for both biosimilars and reference products. Industry criticized this proposal. Those opposed, including representatives in the US Congress, argue that different names may create unnecessary confusion for doctors and patients. The confusion may possibly trigger medical errors and impede appropriate drug substitution, including drug substitution as a cost-saving measure.

New guidance

Now, in early March 2016, FDA released draft guidance on its interpretation of the “deemed to be a license” provision of the BPCIA. The Act states that an approved application for a biological product under the FD&C Act shall be deemed a license for the biological product on the date that is 10 years after the date of enactment of the BPCIA. In the guidance, FDA says it will not approve any pending or tentatively approved application for a biological product under the FD&C Act after March 23, 2020. On this date, biologics approved under section 505 of the FD&C Act will no longer exist as New Drug Applications (NDAs) (or Abbreviated New Drug Applications (ANDAs)) and will be replaced by approved Biologics License Applications (BLAs) under section 351(a) or 351(k) of the PHS Act.

Guidance’s Remaining

There are three guidance’s on the FDA guidance agenda for 2016 all of them were on the 2015 guidance agenda as FDA is running behind schedule on their biosimilars regulatory agenda.

They include:

• Considerations in Demonstrating Interchangeability with a Reference Product
• Labeling for Biosimilar Products
• Statistical Approaches to Evaluation of Analytical Similarity Data to Support a Demonstration of Biosimilarity

Interchangeability is especially important as several companies are weighing to file as an interchangeable but without draft guidance the goal is very difficult to achieve wanting for parameters.

FDA workload

In a February 2016 report, an analysis of the FDA’s workload around biosimilars illustrates how their development has progressed slowly. According to the report, 57 programs participating in the biosimilar product development program have been submitted under section 351(k). The report estimates that FDA has spent $87.1 million on biosimilars work in the first three years of the program, with the largest category of work coming in biosimilar development program activities. This includes meetings between industry and FDA. The most-frequently requested and scheduled meeting so far is the BPD Type 2 meeting, which is a meeting to discuss a specific issue (e.g., proposed study design or endpoints) or questions where the FDA will provide targeted advice regarding an ongoing BPD program. Only 7 type 4 meetings have taken place since 2013 this means that only seven products are close to registration and in the final stages of FDA approvals.

According to the report, in 2015 126 people worked on BioSimilars at the FDA. To put this in perspective there are 3,900 working at Centers for Drug Evaluation and Research at the FDA. Of those 126, 40 are working on guidance’s and administrative roles only 24 are working on biologic license application reviews for biosimilars this represents less than 0.6% of CDER staff.

In recent years, one of the most significant developments was the FDA’s approve of the first biosimilar—Zarxio. Congress passed the BPCIA in 2010 to create an abbreviated regulatory approval pathway for biosimilars – biologics demonstrating no clinically meaningful differences compared to a reference product. FDA approval of Zarxio is a step forward, but is dwarfed by progress in Europe, which has already more than 20 approvals for biosimilars and is reaping the benefits of significantly improved patient access and healthcare savings afforded by such prescience.

The FDA’s backlog in approving biosimilars can be related to several factors, including an insufficient number of qualified reviewers to meet the unanticipated demands previously forecasted. Moreover, critical guidances are absent, necessitating each FDA review team to move incrementally at best when working with biosimilar developers. Interchangeability guidance is eagerly awaited by the biosimilar industry, given the emerging state regulations around this concept. Interchangeability realizes the full potential of biosimilars by bolstering competition, lowering prices, and increasing availability for patients. Each day of delay of the issuance of guidance around achievable activities to create interchangeable biosimilars increases the time until these important therapeutic options can be made available to patients, with corresponding cost savings.

Physicians embracing biosimilars

Despite problems with FDA’s approval pathways, a survey shows that nearly half of all physicians in the United States are expected to prescribe more biosimilars over the next three years. “We believe the data show that physicians are beginning to understand the value of biosimilars, particularly those who are high prescribers of biologics and therefore familiar with biosimilars,” Diane Hayes, PhD, president and co-founder of InCrowd, told Drug Topics.

17% of respondents felt biosimilars would become the norm or replace biologics in the next three years. Questions concerning pharmacy-level substitutions offered mixed results with only two out of 10 stating they were likely to strictly prohibit pharmacy-level substitution of the originator biologic with biosimilars. This is compared to three out of 10 respondents who, conversely, said they would never prohibit substitutions, and four out of 10 that would treat substitutions on a case-by-case basis.

Additionally, efficacy (89%) and safety (81%) outranked patient costs (71%) among the top important factors in determining whether health care professionals would prescribe biosimilars. Furthermore, discounts drove anticipated prescribing patterns. Assuming physicians had the choice between an FDA approved biosimilar and its originator biologic, 83% would prescribe a biosimilar if it were 25% cheaper versus just 33% if it were 5% cheaper. Physicians also expect to prescribe biosimilars to a greater proportion of their treatment-naïve patients (49%)—those who have never tried any drug treatment—than to patients currently or previously treated with the originator biologics (30% and 38%, respectively).