This event drew over 1,000 people from both the Chinese and U.S. pharmaceutical industry. Link to the event is available here.

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As this blog has reported before, Amgen markets Neupogen (filgrastim), a biologic. Sandoz submitted a biosimilar application for Zarxio (filgrastim-sndz) referencing Neupogen on May 8, 2014. (Zarxio received FDA approval on March 6, 2015.) Although Sandoz notified Amgen that Sandoz had submitted an application and that it intended to market Zarxio immediately upon approval, Sandoz did not provide a copy of the application as described under the patent resolution process, or “patent dance,” in 42 USC 262(l)(2)(A). Previously, the Federal Circuit held that Sandoz did not violate the BPCIA in failing to disclose its application and that the BPCIA provides, as the exclusive remedy for failure to disclose, that the innovator may seek an injunction for artificial infringement under 35 USC 271(e). The Federal Circuit also held that the biosimilar applicant may not provide its mandatory 180-day notice of commercial marketing until after FDA has granted approval of the application.

The Supreme Court reversed the Federal Circuit on the timing of the commercial marketing notice. The Supreme Court held that while notice must be given at least 180 days before marketing, the notice may come either before or after FDA approval of the application. Accordingly, the biosimilar applicant may choose to provide notice while the application is still pending and will not be required to wait 180 days after approval to begin marketing its biosimilar product.

Regarding the application disclosure issue, the Supreme Court agreed with the Federal Circuit that disclosure was not enforceable by injunction under the BPCIA, but for different reasons than those provided by the Federal Circuit. The Court found that disclosing an application was not part of the act of artificial infringement under 35 USC 271(e), and thus failure to disclose the application was not remediable under section 271(e). Instead, the sole remedy under BPCIA for failure to disclose an application is supplied by section 262(l)(9)(C), which authorizes the innovator, but not the applicant, to bring an immediate declaratory-judgment action for infringement regarding any relevant patent. Thus, the innovator gains the control over the scope and timing of the patent litigation that the applicant would otherwise have if it disclosed its application as described in BPCIA. This declaratory-judgment remedy, the Court found, “excludes all other federal remedies, including injunctive relief.”

However, the Court held that the Federal Circuit improperly dismissed the possibility of state law remedies including, in this case, remedies for violation of California’s unfair competition law. The parties framed the issue as whether the disclosure provision under section 262(l)(2)(A) is mandatory, in which case a biosimilar applicant that fails to disclose its application acts unlawfully and violates state unfair competition law. The Court refused to address that issue because it did not present a question of federal law. Rather, the Court directed the Federal Circuit to determine on remand whether noncompliance with the application disclosure provision would be unlawful as a matter of California law, and whether BPCIA preempts any additional state law remedy.

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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.

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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.

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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.

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The most significant aspect of the draft guidance is the position FDA takes on exclusivity and patents for this group of products (which we refer to as “transition products”). The draft guidance also addresses the situation in which a drug application for a transition product may be pending at FDA as of the March 23, 2020, “deemed to be a license” date. Examples of protein products that FDA notes as being subject to the transition provisions are: insulin, hyaluronidase, human growth hormone or somatropin, desirudin, pancrelipase, pegvisomant and thyrotropin alfa products.

The key to FDA’s interpretation of the provision is that as of the March 23, 2020, transition date, any approved drug applications for products that meet the definition of a biological product “will no longer exist” as NDAs or ANDAs. Draft Guidance at 5. Instead, they will immediately be replaced by approved biologics license applications (BLAs). Importantly, FDA does not take a position in the draft guidance on how it will determine whether an approved NDA will be deemed to be a 351(a) biologic or a 351(k) biosimilar, which has significant implications for protein products approved under 505(b)(2) NDAs. Similarly, it might be presumed that ANDA products would be deemed to be 351(k) biosimilars, but the draft guidance is silent on that issue as well.

Second, FDA emphasizes that the statutory transition provision only accounts for approved drug applications. FDA reads this to mean that any NDA or ANDA for a biological product that is either pending or tentatively approved as of March 23, 2020, will effectively be deemed withdrawn. Draft Guidance at 5-6. The sponsor would have to resubmit the application under 351(a) or 351(k), potentially imposing a disruption for the sponsor. Draft Guidance at 8-9. Again, this may be quite significant for 505(b)(2) NDAs or ANDAs that are submitted about one to two years before the transition date, and which do not receive final approval before the March 23, 2020, deadline (e.g., because the review is still pending or because final approval is blocked by another sponsor’s exclusivity or by a 30-month litigation stay).

FDA notes that one way around this problem for 505(b)(2) sponsors is to submit an application for a product as a 351(a) application during the transition period, which is permitted under the statute. However, it would require a 505(b)(2) applicant to modify its development program to meet the requirements of a full BLA, something which FDA suggests in the draft guidance but which may in fact not be practical for most sponsors. See Draft Guidance at 8. Alternatively, the 505(b)(2) applicant could defer its application until after the transition date, and file it as a 351(k) application, provided it includes the data FDA would expect to see in a 351(k) application. Draft Guidance at 9 Note that unlike a 351(a) application, a 351(k) application could not be submitted prior to the transition date because such applications must reference an approved BLA.

With respect to Orange Book listings – including patents and exclusivities for these products – the listings and the exclusivities will be terminated as of the transition date, except for orphan drug exclusivity. Draft Guidance at 6. This means that any existing Hatch-Waxman exclusivity (3 year new use exclusivity or 5 year new chemical entity exclusivity), and any remaining 30-month stay time, will immediately be extinguished and, in FDA’s view, forever lost. The only exclusivity that will survive is 7-year orphan drug exclusivity (plus any pediatric exclusivity that attaches to the orphan exclusivity), because that exclusivity is by law capable of blocking approval of BLAs as well as NDAs and ANDAs.

Even more, FDA makes clear in the draft guidance that it does not believe a “deemed licensed” transition product is entitled to receive any amount of the 12-year exclusivity period allowed under section 351 for reference biological products. Draft Guidance at 6. FDA bases this conclusion on two points. First, the agency notes that 12-year exclusivity is only available for a product that is “first licensed” under section 351(a). The agency states – as if it were self-evident – that an application “deemed” to be licensed under section 351(a) for the first time is not “first licensed” under 351(a). Second, the agency claims that there is nothing in the BPCIA to suggest that Congress intended to award 12-year exclusivity to biological products previously approved as drugs, “some of which were approved decades ago.” Draft Guidance at 7. However, there is also nothing apparent in the statute indicating that Congress intended to deny exclusivity to such products. Moreover, if a new sponsor of a previously approved transition product were to obtain approval of its own version of the product under section 351(a), that product would be protected by 12-year exclusivity, even if a prior version of the product had been approved “decades ago.”

Comments to draft guidances are generally submitted within 60 days of publication of the guidance, or May 13, 2016, in this instance. See Docket FDA-2015-D-4750.

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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.

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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.

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• Scientific Considerations Demonstrating Biosimilarity to a Reference Product. Final 4/28/15.

• Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product. Final 4/28/15.

• Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. Final 4/28/15.

• Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. Draft 5/12/15.

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

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