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Biosimilars Law Blog

Posted in Biosimilar labeling, Biosimilars Patent Exchange, News & Events

Guide to Recent Biosimilar Activity by FDA and in the Supreme Court

The US Food and Drug Administration (FDA) recently completed a flurry of activity to help define the biosimilar pathway, including issuing final guidances on biosimilar clinical pharmacology and biologics non-proprietary naming, as well as a draft guidance on biosimilar interchangeability. In parallel, litigation that should clarify the BPCIA patent resolution process, including timing of the biosimilar applicant’s notice of commercial marketing is proceeding through the Supreme Court.

Guidance for Industry: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (December 2016): With this guidance, FDA finalizes the previous draft guidance of the same title. The final guidance largely tracks the previous draft. Of note, the final guidance removes categories of “similarity” (see previous post) in favor of describing certainty about similarity derived from analytical data on a development-phase continuum. This change is consistent with the statutory requirement that a biosimilar must be “highly similar” to the reference product.

Guidance for Industry: Nonproprietary Naming of Biological Products (January 2017): The final version of this guidance maintains the FDA position in the draft guidance that all biological products should carry distinguishable non-proprietary names. Specifically, related biologics and biosimilars should share a common core name, which should be followed by a dash and a four letter nonsense suffix. The core names are anticipated to be United State Adopted Names (USAN) for the biological substance. For example, the guidance provides a made-up example, replicamab-cznm and replicamab-hjxf, for two different products containing a version of the replicamab biological substance. Sponsors of new biological products should submit up to 10 proposed suffixes to the core name as early as the IND stage of development. Sponsors of marketed products should submit the suffix name change as a prior approval supplement.

Draft Guidance for Industry: Considerations in Demonstrating Interchangeability With a Reference Product (January 2017) (Draft Interchangeability Guidance): Perhaps the most anticipated biosimilars guidance since the enactment of the BPCIA, the Draft Interchangeability Guidance addresses general principles, product specific factors, the type and amount of data and other information, appropriate use of approved products in comparative studies, post-marketing studies, and product presentation (i.e., packaging and delivery devices) for demonstrating interchangeability to a reference biological product.

The Draft Interchangeability Guidance does not anticipate immediate situations where an interchangeable biologic may be approved without clinical studies. However, the clinical studies for products intended to be used more than once (i.e., switching studies) may use different endpoints than those used to demonstrate biosimilarity, and PK/PD endpoints rather than clinical endpoints are recommended. In general, the switching studies should be conducted in patients, not in healthy volunteers, and extrapolation of indications with appropriate scientific justification will be permitted for interchangeable biologics as it is for biosimilars. FDA recommends studies that evaluate changes in treatment involving two or more switches (alternating intervals) with the proposed interchangeable biologic and the reference product. The US-approved reference product should be used for studies to support interchangeability.

Because the interchangeable product may be substituted without the knowledge of the prescriber, FDA is concerned that patients and care-givers will be able to appropriately use the proposed product. Sponsors are instructed to conduct threshold analyses to determine if there are any minor or major differences in design between the reference and proposed interchangeable product, which will determine the need for additional data and information, such as human factors studies, to support a demonstration of interchangeability. Interoperability is not required, but differences should not negatively affect the end-user’s ability to deliver the biological product. In an appendix, FDA provides additional advice on comparative human factor study design and analysis.

Finally, the Supreme Court is preparing to hear arguments on April 26, 2017 regarding the BPCIA patent resolution process, including the notice of commercial marketing requirement. The case, Sandoz Inc. v. Amgen Inc., Docket no. 15-1039, involves the operation of two notification provisions in the BPCIA. Under the BPCIA, a biosimilar applicant is directed to provide a reference product sponsor (RPS) with a copy of its marketing application no later than 20 days after FDA notifies the applicant that its application has been accepted for review. 42 USC 262(l)(2). This provision is designed to permit the RPS to respond, within 60 days, with a statement asserting any patents that will be infringed by the application, and then a series of steps to resolve infringement disputes, culminating with a right to bring an infringement suit. 42 USC 262(l)(3)-(6). The Federal Circuit concluded that the biosimilar applicant may choose not to provide a copy of its application, and the only remedy available to the RPS is to seek a claim of patent infringement. The Supreme Court will now consider whether this notification is, in fact, optional. Second, the BPCIA directs that a biosimilar applicant “shall provide notice to the [RPS] not later than 180 days before the date of the first commercial marketing” of the licensed biosimilar product. 42 USC 262(l)(8). The Federal Circuit held that the biosimilar applicant cannot give the required notice until FDA has approved the biosimilar application. The Supreme Court will consider whether the biosimilar applicant may give the notice during the pendency of its application so that it may begin marketing at the time that its application is approved instead of having to wait for six months after approval. The US Solicitor General has weighed in and opined that the Federal Circuit was correct to view the only remedy for failure to disclose the marketing application to be declaratory relief, but that the Federal Circuit should be reversed on the timing of notice to the RPS, which may be given prior to approval of the application. A decision in the case is expected before the end of June, and the Supreme Court’s ruling on both issues is expected to have profound effects for biosimilar development.

Posted in Biosimilar labeling, News & Events

FDA Denies Three Petitions on Biosimilar Labeling: Refers Petitioners to Guidance Process

The U.S. Food and Drug Administration denied three pending petitions regarding biosimilar labeling without substantively addressing most of the issues raised in the petitions. FDA’s denial letter indicates that biosimilar labeling guidelines are still in flux while FDA works to finalize its March 2016 Draft Guidance for Industry: Labeling for Biosimilar Products. According to FDA,
“FDA has neither adopted nor abandoned a policy on biosimilar labeling.” Additionally, FDA notes that the labeling for the first biosimilar approvals, Zarxio (filgrastim-sndz) and Inflectra (infliximab-dyab), do not signal agency policy regarding biosimilar labeling. Rather, they reflect the agency’s actions on these specific products.

The petitions from AbbVie, Inc., the United Auto Workers (UAW) Retiree Medical Benefits and other investors, and the Pharmaceutical Research and Manufacturers of America (PhRMA) jointly with the Biotechnology Innovation Organization (BIO) were filed from June through December 2015. FDA notes the overlap between issues raised in the petitions and those addressed by its March 2016 Draft Guidance for Industry: Labeling for Biosimilar Products. The agency is developing a more broadly applicable policy toward biosimilar labeling through this guidance process.

Except for a few issues that were substantively addressed, FDA intends to review the issues raised in the petitions with the comments received in the docket for the Draft Guidance (FDA-2016-D-0643), which “will permit FDA to more efficiently finalize the biosimilar labeling guidance ….” The issues that were substantively denied include a request for a public hearing and an argument premised on the fact that FDA has unlawfully applied a “same labeling” approach. FDA denied that it has used a same labeling approach and reiterated that biosimilar labeling should include essential scientific information from the reference product labeling, with necessary product-specific modifications.

The formal comment period for the Labeling Guidance was extended to August 2, 2016.

Posted in Global Comparisons, News & Events

AIFA publishes “Second Concept Paper” on biosimilars

On June 15, 2016, AIFA (the Italian Medicines Agency) published a “Second Concept Paper” on the use of biosimilars within the National Health System (NHS). The document is intended to start a discussion that should eventually lead to an amended or new version of the agency’s Position Paper of 28 March 2013 on the same topic.

Relevance of AIFA Position Paper

The number and importance of biological medicinal products purchased by the National Health System (NHS) is constantly increasing. So it is their cost, in particular, for hospitals, which are often their ultimate purchasers. While in Italy territorial expenditure (i.e. for products distributed by territorial pharmacies to patients) seems to be under control, hospital expenditure is of concern, not least for the impact of highly innovative and expensive medicinal products made available by the Industry in the last years, while more are expected to come.

As patent protection on biological medicinal products expires, substitution of biological medicinal products with biosimilars may become a compelling need for hospitals to meet budgetary constraints. However, as physicians and experts know (and it is stipulated by EMA’s Guidelines), biosimilars are not identical to the original biological products of reference.

AIFA Position Paper 2013

This is acknowledged by AIFA’s Position Paper of 2013, which clearly states that biosimilars cannot be regarded as equivalent products and therefore no room is left for their automatic substitution by pharmacies. While “the choice to use a biological medicinal product or a biosimilar should be made by the physician prescribing the therapy“, AIFA noted that “biosimilars not only are a therapeutic option available to the treating physicians, but they should be preferred, if they are of economic advantage, in particular for the treatment of naive patients“.
In sum, biosimilars are not identical and are not interchangeable with the reference biological medicinal products (in the meaning of an automatic substitution in the therapy). For patients under treatment the use of biosimilars should be decided by the physician, provided that no safety and efficacy risks may derive to the patient.

AIFA Second Concept Paper

No material changes are proposed by AIFA as to the general principles. However, the agency seems to want to open the door for a more frequent use of biosimilars also for non-naive patients. The Second Concept Paper now proposes that the “biosimilar is a therapeutic option whereby the risk-benefit ratio is the same as for the corresponding original biological product of reference, as it is proved by the regulatory assessment procedure for the authorisation. Such considerations apply also to the patients under treatment, where the opportunity of the change is left to the clinical appreciation of the physician“.

That said, as biologicals and biosimilars are not identical (and this is still the opinion of AIFA), the risk-benefit ratio may be comparable but it is not necessarily the same. Moreover, the essential difference between biological and biosimilar products may still justify a different approach for naive patients and for those under treatment.

Since AIFA’s Second Concept Paper is intended for the discussion with the relevant stakeholders, we do not rule out that such aspects may be subject of additional considerations also on accounts of input from the Industry and the medical profession.

Comments on the Second Concept Paper are due by September 15, 2016.

Posted in Global Comparisons, News & Events

Biosimilar switching: Dutch MoH announces the set-up of a national system for biological medicinal products

The Dutch Minister of Health (MoH) announced the set-up of a national system to trace the safety of biological medicinal products. The MoH expects an increase in the number of biosimilar prescriptions. The national system should contribute to a responsible use of such cheaper alternatives and as such lead to a sustainable Dutch healthcare system. With that this initiative also fits in the vision of the MoH on medicinal products as published earlier this year.

The MoH asked the Netherlands Pharmacovigilance Centre Lareb to set-up the national system and made fundings available for this (EUR 300.000,-). Lareb will start this Fall with monitoring 5 hospitals and will monitor patients that are prescribed with a biological medicinal product (biosimilar and/or innovator biological). Based on these experiences, Lareb will work on a proposal for a national system that ensures safe switching between biological medicinal products. The system also aims to strengthen the faith in biological medicinal products, which essentially appears to aim at strengthening trust in biosimilars.

Posted in Biosimilars Patent Exchange, News & Events

FDA Guidance on Transition Biological Products: Implications for Exclusivity and Patent Listings

FDA issued a draft guidance on March 14, 2016 explaining how the agency proposes to implement the provisions under the Biologics Price Competition and Innovation Act of 2009 (BPCIA) for moving protein products currently approved under the drug statute (section 505 of the Food, Drug and Cosmetic Act) to the biologics system (section 351 of the Public Health Service Act). Essentially, the BPCIA requires that as of March 23, 2020, all new drug applications (NDAs) and abbreviated new drug applications (ANDAs) for protein products will be “deemed to be a license” under section 351 of the Public Health Service Act (PHS Act). The draft guidance is the first time FDA has issued an interpretation of the “deemed to be a license” provision. Continue Reading

Posted in Biosimilar Definitions, News & Events

FDA Announces Policy for Unique Nonproprietary Names for Biologics and Biosimilars

In a Federal Register notice, FDA announced its draft guidance, “Nonproprietary Naming of Biological Products,” in which the agency articulates the need “for biological products licensed under the Public Health Service Act (PHS Act) to bear a nonproprietary name that includes an FDA-designated suffix.”  Described in an accompanying proposed rule, the Agency proposes that the proper name of all biologics includes a core name and a designated suffix.  For originator products, the core name would be the name adopted by the United States Adopted Name (USAN) Council for the drug substance when available.  Related, biosimilar or interchangeable products would include the core name of the relevant, previously licensed product and a designated, 4-letter suffix attached by a hyphen.

Essentially, FDA is proposing a unique nonproprietary naming policy for all biologics approved under PHSA 351(a) or 351(k).  While ending some speculation on FDA’s policy toward naming of biosimilars, the guidance seeks extensive input from stakeholders regarding the application of a four-letter suffix to distinguish all biologics and biosimilars from one another and whether interchangeable biologics should similarly have unique suffixes or share the same four-letter suffix.   FDA summarized its intention with this policy:

“By differentiating biological products from one another that have not been determined by the FDA to be interchangeable, this naming convention is intended to help minimize inadvertent substitution. Inadvertent substitution may lead to unintended alternating or switching of biological products that have not been determined by FDA to be interchangeable. A naming convention that differentiates among biological products also could help facilitate pharmacovigilance for all biological products. By applying this naming convention to all biological products, this approach is intended to: (1) Encourage routine use of designated suffixes in ordering, prescribing, dispensing, and recordkeeping practices and (2) avoid inaccurate perceptions of the safety and effectiveness of biological products based on their licensure pathways.”

In the accompanying proposed rule, FDA provides additional details on its proposed naming policy and the application of this policy to six products.  Each of the six products is either a reference product for an approved or publicly disclosed biosimilar product application or a biological product that is either biosimilar to or related to one of these reference products.

Comments on the guidance, which has been assigned Docket No. FDA-2013-D-1543, are open through October 27, 2015.  (Although, per FDA regulation, comments on a guidance may be received at any time.)  Comments on the proposed rule, including  the assignment of proper names, should be sent to Docket No. FDA-2015-N-0648, which is open through November 12, 2015.


Posted in Biosimilar labeling

AbbVie Challenges FDA Biosimilar Labeling

In a citizen petition, AbbVie has challenged the Food and Drug Administration’s (FDA’s) approach to biosimilar labeling, as implemented in the agency’s recent approval for Zarxio (filgrastim-sndz) as a biosimilar to Neupoen (filgrastim).  As we previously blogged, the prescribing information FDA approved for Zarxio seems to follow a “generic drug” model; the Zarxio labeling is essentially the same as Neupogen’s, except for details regarding the administration of the product, which differ.  The labeling contains none of the substantial clinical or preclinical data submitted in the Zarxio application (see here), and which FDA presumably relied on in finding the product to be biosimilar and safe and effective; only Neupogen data are found in the Zarxio labeling.

The AbbVie petition requests that FDA require that the approved prescription drug labeling for biological products licensed under section 351(k) of the PHSA contain:

  • A clear statement that the product is a biosimilar, that the biosimilar is licensed for fewer than all the reference product’s conditions of use (if applicable), and that the biosimilar’s licensed conditions of use were based on extrapolation (if applicable);
  • A clear statement that FDA has not determined that the biosimilar product is interchangeable with the reference product (if applicable); and
  • A concise description of the pertinent data developed to support licensure of the biosimilar, along with information adequate to enable prescribers to distinguish data derived from studies of the biosimilar from data derived from studies of the reference product.

There is an open docket, FDA-2015-P-2000, while FDA considers the petition submitted June 2, 2015.

Posted in News & Events

FDA Updates U.S. Biosimilar Guidances

Five years after enactment of the BPCIA and following its first biosimilar approval, the U.S. Food and Drug Administration finalized its initial guidances describing the scientific and regulatory expectations for biosimilar approval under the 351(k) pathway.

A list of current versions of all biosimilars guidances is readily accessible on FDA’s web site.

Posted in News & Events

The First Biosimilar in the U.S. – Five Questions Left Open by FDA

Last month, the Food and Drug Administration (FDA) approved the first U.S. biosimilar, Zarxio (filgrastim-sndz). Since the positive vote of FDA’s Oncologic’s Drugs Advisory Committee at its January meeting, approval of Sandoz’s biosimilar to Amgen’s Neupogen for all 5 Neupogen indications was anticipated. This landmark event comes almost exactly 5 years after passage of the Biologics Price Competition and Innovation Act and demonstrates that the pathway created by Congress can be used to get biosimilars to the U.S. market and to patients with FDA’s full confidence in the underlying science for the safety and efficacy of biosimilars.

However, the Zarxio approval leaves key FDA regulatory questions about the pathway unanswered.

  1. Although Zarxio was approved with the non-proprietary name, filgrastim-sndz, FDA was quick to point out this was a “placeholder” name and that the agency has not yet decided on its policy for naming of biologics and biosimilars, though it plans to issue guidance “in the near future.”
  1. Contrary to FDA’s own draft biosimilars guidance, there is no statement in the Zarxio labeling that identifies the product as a biosimilar , a biosimilar to Neupogen or not interchangeable with Neupogen. Further, Zarxio’s labeling follows a “generic drug” model; the labeling includes ONLY data derived from studies with Neupogen and NONE of the data generated with Zarxio in support of its approval. Because FDA has not yet issued detailed labeling guidance any policy reasons behind the Zarxio labeling have not been articulated.
  1. Extrapolation of indications. FDA had earlier suggested that extrapolation could be acceptable; the Zarxio approval provides the sense that the “scientific justification” for extrapolation requires a relatively low threshold when there is a common molecular mechanism of action even across different disease states. Sandoz provided clinical non-inferiority data to Neupogen in treatment of neutropenia in breast cancer patients receiving chemotherapy; Zarxio was approved for 4 indications related to neutropenia and one indication related to mobilization of cd34 cells. In the ODAC meeting materials, FDA discussed the common mechanism of action at the cellular level.
  1. Reference product. FDA appears flexible in its use of a non-U.S. reference product with the appropriate “scientific bridge” between the three products—biosimilar, U.S. reference product and non-U.S. reference product. The bulk of the non-clinical and clinical data were generated in comparison to the European version of Neupogen; only 2 of the 12 referenced studies compared Zarxio to the U.S.-approved Neupogen.
  1. Sandoz did not request an interchangeability designation for Zarxio, and so this first biosimilar does not provide any additional insight on expectations for interchangeability of biologics and biosimilars.

Interestingly, the Center for Medicare and Medicaid Services appeared to have been ready for the event, issuing three policy statements on reimbursement for biosimilars on the heels of the approval. Although not the final word on biosimilar reimbursement, these releases on Medicaid, Medicare Part B and Part D establish the initial CMS policies.

Posted in Global Comparisons, News & Events

Netherlands MEB revises position on biosimilars and interchangeability

The Dutch Medicines Evaluation Board (MEB) published a new position on biosimilars, in which it accepts substitution or interchangeability of biosimilars under certain conditions.

The MEB’s revised position on biosimilars was published on 31 March 2015 and replaces its previous position of 2010. The 2010 position provided that patients should be kept at the same biological medicinal product if the patient responded well to such biological medicinal product. The MEB now considers that substitution of one biological medicinal product for the other – both for originator biological and biosimilar medicinal products – is possible, provided that the substitution is adequately clinically monitored and that the patient is well informed.

This results in the following new position of the MEB:

  • New patients can be prescribed with a biosimilar medicinal product without further ado.
  • Uncontrolled substitution between biological medicinal products – irrespective of whether it concerns an originator biological medicinal product or a biosimilar – should be avoided. This means that a patient should be informed about the substitution and that substitution should be adequately clinically monitored.
  • The patient file of a patient that is treated with a biological medicinal product should contain information regarding the biological medicinal product, including the batch number of such product in order to ensure that the product can be traced if problems should occur.

The MEB further informs that it is necessary that both the treating physician and the pharmacist are involved when one biological medicinal product is substituted for another in order to ensure that such decision is taken with due care. The MEB stresses that collaboration regarding pharmacovigilance is essential in this respect.