Life Science Compliance Update

April 06, 2016

FDA: Biosimilars Labeling Guidance

After several delays the FDA has finally released its draft guidance that says a biosimilar's label does not have to be identical to that of its reference product, adding that differences may be appropriate to inform safe and effective use of the product. FDA also says it may be appropriate to include information about reference product uses not approved for the biosimilar for safety reasons, and additionally calls for a "biosimilarity statement" as part of the prescribing information highlights. FDA did not resolve how interchangeable products should be labeled, but the agency said it is considering the types of information that would support a demonstration that a biosimilar is interchangeable with a reference product. FDA indicating that labeling recommendations will be included in a future guidance.

Comments to the draft guidance are due June 3. They can be submitted to using Docket Number FDA-2016-D-0643.

The Guidance

FDA's general principle is outlined in the guidance, recommending that, "in the biosimilar product labeling, applicants incorporate relevant data and information from the reference product labeling, with appropriate product-specific modifications." As a general matter, FDA believes the product should not include a description of these data because a clinical study supporting the licensure of the biosimilar product generally would not be designed to independently demonstrate the safety and efficacy of the product. However, labeling must meet the content and format requirements of the physician labeling rule and the pregnancy and lactation rule, regardless of the format of the reference product label.

The guidance outlines that relevant data and information from the reference product labeling that should be incorporated into the biosimilar product labeling depends on "whether the applicant is seeking approval for all conditions of use or fewer than all conditions of use of the reference product for the biosimilar product." FDA says that it anticipates "similar" text in biosimilar product labeling that is based on the reference product labeling, although it need not be identical and should reflect currently available information necessary for the safe and effective use of the biosimilar.

Furthermore, FDA outlines that the labeling for the biosimilar product should be "specific to the conditions of use sought for the biosimilar product and should be consistent with language previously approved for the reference product for those conditions of use." FDA explains circumstances where there may be a biosimilar licensed for fewer indications than the reference product. Additionally, FDA discusses inclusion of initial U.S. approval of the biosimilar and a biosimilarity statement which the FDA recommends including "on the line immediately beneath the initial U.S. approval date in highlights, that the product is biosimilar to the reference product."

The FDA also notes that in biosimilar product labeling, "the approach to product identification depends on the context of the information being presented." FDA recommends that the biosimilar product name be used in the labeling text that is "specific to that biosimilar product or refers solely to the biosimilar product." FDA further recommends that if the product has a proprietary name, "the proprietary name be used in these instances." If "a proprietary name is not available for the biosimilar product, the biosimilar product's proper name should be used". FDA outlines examples in the guidance, including when to use the biosimilar product name, the reference product name, core name, and more than one product name.

The guidance discusses FDA-approved patient labeling, including updated safety information and additional conditions of use. FDA also explains its thinking on the submission of initial and revised labeling. Regarding interchangeable biologics, FDA is still considering the issue and will make recommendations on the labeling of interchangeable products in future guidance.


According to a report, industry may not be too pleased with the guidance. Although Regulatory Focus quoted Duncan Emerton, senior director at FirstWord Pharma, as saying the guidance does not have any major surprises as it aligns with the way FDA labeled the first approved biosimilar in the US, Zarxio. Emerton says he's spoken to lots of physicians "and the general consensus has been a need for full disclosure (i.e. include all the relevant data for the biosimilar whenever possible)."

The details of the guidance are important, but it is also important that the document was released in the first place. "The big news about the draft guidance is that they got it out, and this alone will end some uncertainty for both the biosimilar applicant and the originator of the biologic, also known as the reference product sponsor," Siegmund Gutman, chair of Proskauer's life sciences patent practice told Bloomberg BNA.

Bloomberg BNA also reported that the Generic Pharmaceutical Association and its Biosimilars Council released a statement that it was a pleased with the guidance that "provides manufacturers with additional clarity needed to manufacture and distribute more affordable versions of biologic medicines for patients."

Meanwhile, Patients for Biologics Safety and Access and the American College of Rheumatology released statements indicating that the clinical trial data for the biosimilar should be included in the labeling and that the label should specify whether the supporting clinical data for each indication are derived from studies of the biosimilar or the reference biologic.

The guidance comes as an IMS Institute for Healthcare Informatics report highlights that the use of biosimilar drugs could save more than $100 billion in the United States and five European markets by 2020. The report reviewed markets in Britain, France, Germany, Italy, Spain, and the United States. It included eight commonly used brand-name medications that are scheduled to lose patent protection within the next five years and the projected savings that would result if corresponding biosimilars were introduced into the market. The report estimated that the United States and five European markets would save a combined $110 billion. However, the report noted the savings could not be realized unless health care providers are properly educated about biosimilars and drug makers adopt "smart market access strategies" to spur the drugs' use.

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).

March 04, 2016

FDA Offering Free Biosimilars CME Course

There is a ballooning interest in biosimilars and interchangeable products in the pharmaceutical industry, especially with the first biosimilar in the United States being approved in 2015. The Food and Drug Administration continues to review other marketing applications for proposed biosimilar products.

The FDA has announced that they have developed a free, Continuing Education Course for healthcare professionals, FDA Overview of Biosimilar Products. This course was created for healthcare professionals to strengthen their knowledge and understanding of biosimilars and interchangeable products. For example, biosimilars and interchangeable products are not generic products, and the course will help healthcare professionals fully appreciate and understand the distinction.

The course will help healthcare professionals understand how a biosimilar can be prescribed and dispensed, and how and when an interchangeable product can be substituted for another biological product. The course will also explain the development process and approval pathway for biosimilars and interchangeable products, and includes information about the FDA's general review process for these products.

The course is available to healthcare professionals on FDA's CDERLearn Website, and can also be completed on a tablet. At the end of the course, you will have the option to obtain CE credit by registering with your credentials. Once you have successfully completed the online assessment activity, your appropriate CE accrediting body will issue a certificate.

Course Overview

Healthcare professionals who complete the course will be able to: identify the changes to the law granting FDA authority to approve and regulate biosimilars products; understand biological products and biosimilar products; recognize the key terminology related to biosimilar products; and describe the FDA's general approach to the development and approval of biosimilar products.

Module Two of the course goes through the Biologics Price Competition and Innovation (BPCI) Act of 2009. It explains the way reference products and biosimilar products are evaluated by the FDA, and how the evaluation and approval process allows biosimilar products to be available at a potentially reduced cost, in comparison to the reference product. Module Two also includes a definition slide, which explains the difference between a generic drug, a biological product, a reference product, a biosimilar product, and an interchangeable product. Module Two closes out with a "Knowledge Check" of term definitions.

Module Three explains what a biological product is and the way they may be derived from natural sources such as human tissues, manufactured through biotechnology, or produced synthetically by other cutting-edge technologies. Module Three further explains that most biological products are complex molecules that are not characterized as easily as most small molecule drugs. The importance of tightly controlled manufacturing conditions for biologics is also explained in this module.

Module Four explains the complexity of biological product manufacturing. One such complexity is that many biological products are derived from natural sources, and therefore still show some variability. Therefore, the pure nature of biological products means that there can be variation within one single batch of product. Module Four continues, explaining lot-to-lot variability and how to assess and control it to ensure consistent product quality.

Module Five goes through what a biosimilar product is, and has a slide dedicated to the difference between a biosimilar product and a reference product. Module Five also explains that while biosimilar products may have some differences from the reference product, they must meet certain standards and the biosimilar sponsor must sometimes provide sufficient data and information demonstrating that the products are highly similar and that the differences are not clinically meaningful. This module also closes out with a Knowledge Check.

Module Six presents the abbreviated approval pathway for biosimilar products. It explains the general requirements for the abbreviated approval pathway and the importance of analytical studies.

Module Seven describes the standards for approval. The slides explain the "stepwise approach" that the FDA recommends sponsors use to develop the data and information needed to support a demonstration of biosimilarity. The FDA recommends that at each step, the sponsor evaluate the level of residual uncertainty about the biosimilarity of the proposed biosimilar product to the reference product and identify the steps they should take to address that uncertainty. The slides continue on with a step-by-step analysis of the five steps: analytical studies, animal studies, clinical PK/PD studies, clinical immunogenicity assessment, and additional clinical studies.

Module Eight is the conclusion, which provides contact information for relevant agency contacts and provides an opportunity for attendees to obtain either CE credit or a certificate of completion (for those not trying to obtain CE credit).


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