Life Science Compliance Update

February 10, 2017

FDA Finalizes Guidance on Assigning Non-Proprietary Names to Biologics and Biosimilars

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Recently, the Food and Drug Administration (FDA) finalized guidance detailing its approach to assigning non-proprietary names to biologics and biosimilars. The guidance, titled “Nonproprietary Naming of Biological Products,” finalizes an August 2015 draft of the same title. In the final guidance, the FDA says a biologic product’s nonproprietary name (“proper” name) will consist of two components: a “core name” and a distinguishing suffix (with no specific meaning) composed of four letters. The FDA, however, did not finalize an approach to the suffix format for interchangeable products.

Scope

The FDA intends to apply the naming convention to both newly licensed and previously licensed biological products. The FDA is also continuing to consider the process for implementation of the naming convention for previously licensed products but, for right now, intends to assign distinguishing suffixes to a limited group of these products and will accept submissions of prior approval labeling supplements that include proposed suffixes.

Core Name

FDA says the core name will be the name designated by the USAN Council for the originator biologic product, and that any related biological product, biosimilar product, or interchangeable product will have the same core name. The FDA notes in the guidance that “use of a shared core name will indicate a relationship among products.”

Distinguishing Suffix

For the second component of a product’s proper name, the FDA says “a distinguishing suffix that is devoid of meaning and composed of four lowercase letters will be attached with a hyphen to the core name of each originator biological product, related biological product, or biosimilar product.” The agency notes that its choice of using a suffix rather than a prefix will help products with the same core name being grouped “together in electronic databases to help health care providers locate and identify these products.”

Inadvertent Substitution

The finalized naming approach “should help prevent inadvertent substitution” which can lead to “unintended alternating or switching of biological products that are not determined by FDA to be interchangeable with each other,” the agency says. The FDA notes the distinguishing suffix should clear up potential confusion when related biological products are licensed for different indications, different routes of administration, or fewer than all indications for which the reference product is licensed.

The FDA also says the unique suffix should also prevent confusion among health care providers who, “based on their experience with small-molecule drugs and generic versions of those drugs, may incorrectly assume that FDA has determined biological products with the same proper name to be interchangeable.”

Interchangeability

In the guidance, the FDA says that it is continuing to consider the appropriate suffix format for interchangeable products. The FDA says it intends to apply a naming convention to interchangeable products that will feature a core name and a suffix included in the proper name; however, FDA is continuing to consider the appropriate format of the suffix for these products.

In addition, FDA requests that biologic and biosimilar applicants and application holders propose a suffix composed of four lowercase letters for use as the suffix included in the proper name.

February 08, 2017

2017 Biosimilar Update

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We have taken an interest in the growing biosimilars market in the United States. Recently, we covered the Friends of Cancer Research event, “The Future of the U.S. Biosimilars Market: Development, Education, and Utilization,” a half-day forum that brought together clinicians, originator and biosimilar drug sponsors, advocates, regulators, and payers in an attempt to tackle uncertainty surrounding the future of the United States biosimilars market. With now several biosimilars approved in the United States, there is an ever-growing interest in their approvals and further development. But heading into a new year, uncertainties remain. After several years of interest, there is not a whole lot to show for the interest of drug makers and regulators, although that could change in 2017.

Approvals and regulations

In April 2016, we saw the FDA approve Inflectra, a biosimilar to infliximab (Remicade), which was the first monoclonal antibody biosimilar. Since April, two other biosimilars have received approval: Erelzi, a biosimilar to etanercept (Enbrel), and Amjevita, a biosimilar to adalimumab (Humira).

Regulatory authorities grant approval to biosimilars based on a totality of evidence: whether the product has demonstrated similarity in terms of physiochemical properties, efficacy, and safety after extensive comparability studies. Because of the complexities involved in developing biopharmaceutical products in general compared with small molecules, a tailored approach to safety may be necessary. Biosimilar developers are required to demonstrate understanding of the characteristics of innovator products and to design thorough studies involving analytic and biological assessments performed by way of nonclinical and clinical trials. Differences between biosimilars and originators are most likely to emerge during production, such as the use of different cell lines and different growth conditions.

United States vs. International Approval: FDA moving slow on guidance

Bloomberg BNA recently reported that a panel of regulators at the DIA 2016 Biosimilar Conference in Washington highlighted the differences among biosimilar regulations internationally and the ongoing changes as countries revise their biosimilar guidances. As we have previously noted, in Canada, biosimilars are regulated as new biologics as opposed to the U.S.’s abbreviated pathways under the BPCIA.

Bloomberg also reported that the FDA’s representative said the FDA “cannot commit” to issuing draft interchangeability guidance in 2016. This stands in contrast to reports only a few weeks old that the FDA would indeed release the long-awaited draft guidance this year.

Also in contrast to the United States, the European Medicines Agency (EMA) announced it will launch a tailored scientific advice pilot project in February 2017 to support the development of new biosimilars. The pilot will be open to all types of biosimilars and includes a pre-submission meeting to review the suitability of the data package. EMA also says that applicants should note that the agency’s Scientific Advice Working Party will need an extra month in addition to normal scientific advice timelines to review applications for the pilot. More than 20 biosimilars have been granted central marketing authorization by the European Medicines Agency (EMA) in the past 10 years—many of them for multiple indications

Investors, noting the difference between American and international regulators, have sounded upbeat headed into 2017. As reported by Pharmexec, a growing number of companies are targeting and developing biosimilars as the regulatory authorities become more adept and comfortable with these products. For example, Samsung’s biosimilar version of Remicade (infliximab) is under review, representing an important step in the electronic giant’s endeavor to enter the US drug market. Almost 50 distinct biosimilars are currently in development and will likely generate a highly competitive marketplace in the next five years, according to the IMS.

In its report, the IMS Institute for Healthcare Informatics said regulatory bodies, payers, and product manufacturers will have to reassure physicians about the science behind the data on biosimilar safety and efficacy. “Doctors need to trust that by driving the uptake of biosimilars, they are helping deliver savings for the health system as a whole and are helping improve patients’ access to much-needed treatments,” the report’s authors state.

Different under President Trump?

An interesting report points out that the onerous regulatory and legal landscapes in the United States have essentially kept biosimilars from replacing many costly biologic drugs that have lost patent protection. After all, the FDA has approved only four biosimilars to date, despite the regulatory framework being in place for nearly five years. Many brand-name drug makers also believe that they can successfully keep biosimilar versions of their top drugs from entering the market for years through various legal challenges.

The report suggests in keeping with President Trump's mandate to dramatically lower costs firmly in mind, it only seems logical that clearing these enormous legal and regulatory hurdles for biosimilars would become a prime objective for the new administration. A Trump administration promises to usher in a new era of fewer regulations at the FDA and perhaps innovative ways to bring cheaper medicines to patients.

Hope in Generic User Fee Agreement?

The new generic user fee agreement, which will be taken up by Congress next year, mostly focuses on setting expectations for these meetings between the FDA and industry, with the goal of increasing the number of applications that FDA can approve on their first try. In exchange for these more predictable review cycles, the generic industry will pay FDA around $493 million annually for the next five years, a substantial increase over the approximately $330 million FDA received in previous years. The total fees the makers of biosimilars will pay to FDA has not yet been determined, but during the first five years of the program FDA collected around $20 million per year. Similar to the generic agreement, the biosimilar agreement focuses on timelines for review, which will be 10 to 12 months, and the kinds of meetings that will be held during the review process.

Impact on drug pricing?

Medpage Today quotes Douglas White, MD, PhD of the American College of Rheumatology (ACR), stating the group is “hopeful that biosimilars will help reduce the cost of biologics and thus improve patient access to these complex and lifesaving drugs.”

However, Dr. White continues, "I've not seen any reason to believe that the availability of biosimilars in the U.S. will reduce the out-of-pocket expenses to patients who rely on biologic therapies”.

"Nor have I seen any evidence that the availability of biosimilars will reduce costs to these patients by reducing their insurance premiums. Indeed, early pricing information that I've seen indicates that discounts will be modest at best. Hopefully that will change as more biosimilars enter the market and competition increases."

Major development in Sandoz case from Solicitor General

As reported, the Solicitor General of the United States has filed an amicus brief in Sandoz Inc. v. Amgen Inc., asking the Supreme Court to grant certiorari and reverse the Federal Circuit’s interpretation of one of the “patent dance” provisions of the biosimilar statute. In particular, the Solicitor General does not agree that the pre-marketing notice required by 21 USC § 262(l)(8)(A) cannot be given until the biosimilar product has been approved by the FDA. While not dispositive, this filing increases the odds that the Court will weigh in on this issue, and may increase the odds that the Supreme Court also will side with Sandoz.

The case has been reported to be one of the top legal developments in the biosimilar world as Amgen v. Sandoz works its way toward the Supreme Court.  If the Supreme Court decides to hear the case, it could clarify important provisions of the BPCIA related to resolving patent disputes regarding biosimilar products. In July 2015, the Federal Circuit held that a) that the disclosure procedures set forth in subsection (l)(2)(A) of the BPCIA (the “patent dance”) are not mandatory and a biosimilar applicant can choose between either disclosing application and manufacturing information or not disclosing such information and instead facing an immediate infringement action from the reference product sponsor; and (b) that a notice of commercial marketing pursuant to subsection (l)(9)(A) of the BPCIA can be given only after FDA approval of the biosimilar product, effectively extending the reference drug’s exclusivity by 180 days. 

In February 2016, Sandoz filed a petition for a writ of certiorari, asking the Supreme Court to review the Federal Circuit’s interpretation of the BPCIA’s “notice of commercial marketing” provision.  In March, Amgen opposed Sandoz’s petition and also filed a conditional cross-petition for certiorari, challenging the Federal Circuit’s ruling that the patent dance is optional. Several entities filed amicus briefs supporting Sandoz’s petition. 

On December 7, the Solicitor General filed a brief recommending that the Supreme Court grant both Sandoz’s cert petition and Amgen’s conditional cross-cert petition regarding how to interpret the BPCIA, and also siding with Sandoz on the merits of the questions. The Solicitor General’s recommendation that the Court grant cert is a very strong indicator that the Court will grant the petition and cross-petition. We will continue to follow this important case as it makes its way to the Court.

January 24, 2017

FDA Releases Draft Guidance for Industry on Biosimilar Interchangeability

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On January 17, 2017, the Food and Drug Administration (FDA) released a draft guidance intended to assist sponsors in demonstrating that a biosimilar is interchangeable with a reference product. This guidance specifically focuses on therapeutic protein products and gives an overview of FDA’s thinking on what FDA expects to be included in the data package that sponsors would submit to demonstrate interchangeability. Remarkably, the guidance does not address how interchangeable products will be named by FDA, an issue left open in final guidance on biosimilar naming that was previously released. Some takeaways from the draft guidance are as follows.

Interchangeability Standard

By law, a biosimilar is interchangeable with the reference product if FDA determines that the information submitted in the application is sufficient to show that the biological product “can be expected to produce the same clinical result as the reference product in any given patient” and that for products administered more than once, the risk of switching between the biological product and the reference product is “not greater than the risk of using the reference product without such alternation or switch.” Once interchangeability is demonstrated, “the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

FDA’s Process for Review

The FDA recommends that sponsors use a stepwise approach in “generating data and information to address residual uncertainty about demonstrating interchangeability during product development.” FDA says it intends to consider the totality of the evidence, noting that “the product’s degree of structural and functional complexity may also influence the data and information needed to support a demonstration of interchangeability.” FDA continues, “the data and information to support a [finding of interchangeability] may vary depending on the nature of the proposed interchangeable product.” While seeking licensure for only one reference product condition is permissible, FDA recommends that sponsors seek licensure for all of a reference product’s conditions of use when possible.

Switching Studies

FDA expects that applications will include data from a switching study or studies in one or more appropriate conditions of use. In doing so, FDA is addressing the legal standard that “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.” FDA says the main purpose of a switching study or studies “is to demonstrate that the risk in terms of safety or diminished efficacy of alternating or switching between use of the proposed interchangeable product and the reference product is not greater than the risk of using the reference product without such alternation or switch.”

Post-Marketing Data

FDA believes that postmarketing data from a licensed biosimilar product may be “helpful as a factor when considering what data is necessary to support a demonstration of interchangeability.” FDA notes, however, that “our current thinking is that postmarketing data collected from products first licensed and marketed as a biosimilar, without corresponding data derived from an appropriately designed, prospective, controlled switching study or studies, generally would not be sufficient to support a demonstration of interchangeability.”

Reaction from the American College of Rheumatology

Dr. Angus Worthing, MD, FACP, chair of the ACR’s Government Affairs Committee notes, “The ACR is pleased to see the FDA issue draft guidance on biosimilar interchangeability. This guidance brings us one step closer to the shared goal of lowering prices in the biologics marketplace. While the ACR is still reviewing the document and will provide detailed comments to the FDA in the coming weeks, our initial reaction is that the draft guidance strikes a good balance between ensuring safety and efficacy while also getting biosimilar products to market as efficiently as possible.”

Dr. Worthing continued, staying, “We also applaud the FDA for suggesting clinical studies which switch back and forth, not just one-way from the reference drug to the biosimilar. The use of at least two exposure periods to each drug will mimic to some extent what our patients are likely to experience with changing formularies in a multi-payer, multi-state, ever-changing market."

Conclusion

Comments on the guidance should be submitted within 60 days (by March 20, 2017) to ensure FDA consideration before it begins working on a final version. FDA also poses questions for stakeholder feedback related to (1) considerations behind regulating post-approval manufacturing changes of interchangeable products, and (2) how the FDA should approach a situation when a reference product is approved for a new condition after an interchangeability determination has been made for a related product.

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