Tag: FDA

FDA Issues Draft Guidance on Mandatory Food Recalls Under the Food Safety Modernization Act

The Food and Drug Administration (FDA) recently issued a draft guidance titled, “Questions and Answers Regarding Mandatory Food Recalls.” FDA was given general mandatory food recall authority by the Food Safety Modernization Act (FSMA). The guidance is notable for its brevity, coming in at a total of seven pages including the cover. Although much of the content will be familiar to those with experience in food recalls, the guidance does discuss the procedure for FDA to order a mandatory food recall and the assessment of user fees for those subject to such a recall.

With respect to the procedure, the guidance states after FDA finds that the criteria for a mandatory recall have been met, it must first provide the responsible party with an opportunity to perform a voluntary recall of the food. FDA will provide this opportunity in writing using an expeditious method. If the responsible party does not voluntarily cease distribution and recall the food within the time and manner prescribed by FDA, FDA may order the responsible party to cease distributing the article of food, order the responsible party to give notice to certain other persons to cease distributing the article of food, and give the responsible party an opportunity for an informal hearing. After these steps are completed, FDA may order a recall if it determines that the removal of the food from commerce is necessary. Only the FDA Commissioner has the authority to order a recall.

As to user fees, the guidance observes that the FDA has the authority to collect fees from a responsible party for a domestic facility and an importer who does not comply with a food recall order. The fees would cover time spent by FDA conducting food recall activities, including technical assistance, follow-up effectiveness checks, and public notifications. FDA defines noncompliance to include (1) not initiating a recall as ordered by FDA, (2) not conducting the recall in the manner specified by FDA in the recall order, or (3) not providing FDA with requested information regarding the recall, as ordered by FDA. FDA publishes a Federal Register notice of fees for non-compliance with a Recall Order no later than 60 days before the start of each fiscal year.

Given that most parties will voluntarily recall food when the statutory conditions are satisfied to avoid a public relations disaster and harsh FDA action, it seems unlikely that FDA will have to resort often to the exercise of its mandatory recall authority or assessment of fees. The fact that FDA has this authority, however, helps ensure FDA will not have to exercise it.

A copy of the draft guidance document can be found here.

ARTICLE BY Hae Park-Suk & Lynn C. Tyler, M.S. of Barnes & Thornburg LLP
© 2015 BARNES & THORNBURG LLP

Are Cosmetics Gaining Higher Congressional and FDA Scrutiny?

Currently, FDA regulates cosmetics to ensure they are not adulterated or misbranded, but does not have the authority to order cosmetic recalls or require adverse event reporting.  Senators Dianne Feinstein (D-CA) and Susan Collins (R-ME) seek to change that.

On April 20, 2015, they introduced the Personal Care Products Safety Act (S.1014). The Act, if passed, would modify Chapter VI of the Federal Food, Drug, and Cosmetic Act (FDCA) to strengthen FDA’s oversight of, and regulatory authority over, cosmetic products.

Title I of the Act (“Cosmetic Safety”) gives FDA authority to order cosmetic recalls, as well as require manufacturers to:

  1. Report adverse events,

  2. Label ingredients not appropriate for children,

  3. Post complete label information (including ingredients and product warnings) online, and

  4. Register their facilities with FDA.

In addition to this significant new authority over manufacturers, the Act also requires FDA to work with industry and consumer groups to annually select and review at least 5 ingredients or non-functional constituents.

The first 5 ingredients, if the law is passed, will be:

  1. Diazolidinyl urea

  2. Lead acetate

  3. Methylene glycol/methanediol/formaldehyde

  4. Propyl paraben

  5. Quaternium-15

Title II of the Act (“Fees Related to Cosmetic Safety”) outlines the costs associated with enforcement of the new standards. With an annual implementation cost estimated at $20.6 million, it is to be funded by annual fees from all registered owners or operators of cosmetic facilities engaged in manufacturing or processing in the United States.

The Act has wide industry support, including the Personal Care Products Council (a 600+ member company trade association), large cosmetics manufacturers, and consumer groups.  Since it was introduced, it has gained two co-sponsors, Senators Barbara Boxer (D-CA) and Amy Klobuchar (D-MN).

The Act is consistent with FDA’s current priorities related to cosmetics.  Two of these priorities have been reporting of adverse events (with the majority of issues seen in hair care products), and maintaining a distinct line between over-the-counter drugs and cosmetics, because cosmetics need not currently undergo the additional scrutiny that OTC drugs must.

More information on the Personal Care Products Safety Act can be found in Senator Feinstein’s statement upon its introduction.

ARTICLE BY Michelle Gillette & Katherine Fox of Mintz, Levin, Cohn, Ferris, Glovsky and Popeo, P.C.
©1994-2015 Mintz, Levin, Cohn, Ferris, Glovsky and Popeo, P.C. All Rights Reserved.

FDA Issues Final Guidance on Biosimilars

Shortly after approving the first biosimilar under the abbreviated approval pathway created by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), the FDA has recently issued 3 final guidances regarding biosimilars. Biological products, or “biologics,” are pharmaceutical products created from biological sources. Unlike chemically synthesized pharmaceuticals, biologics are isolated from natural sources, and are typically more complex than conventional pharmaceutical drugs.

The BPCIA provides abbreviated pathways for the FDA to approve two types of follow-on biologics: biosimilar and interchangeable biological products. Similar to the 1984 Hatch-Waxman Act’s abbreviated pathway for pharmaceuticals, the BPCIA allows a sponsor to seek approval of a “biosimilar” product under section 351(k) of the Public Health Service Act (“PHS Act”) by relying on certain existing scientific knowledge about the safety, purity, and potency of the reference product. The BPCIA defines “biosimilar” as (1) “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and (2) having “no clinically meaningful differences between the biosimilar product and the reference biological product in terms of the safety, purity, and potency of the product.” To meet the higher standard of “interchangeability,” the application must further show (1) the biosimilar is expected to produce the same clinical result as the reference product and (2) a patient can switch back and forth between the biosimilar and the reference product with no adverse effects.

The BPCIA provides abbreviated pathways for the FDA to approve two types of follow-on biologics

The FDA has been slow to accept and approve biosimilar applications, which has left open questions about how to establish biosimilarity and interchangeability under the statutory definitions. On April 28, 2015, the FDA finalized three draft guidances originally published in 2012:

  • Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

  • Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

  • Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product

The new guidances provide insight into the FDA requirements for establishing biosimilarity.

Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

This final guidance addresses three categories of commonly asked questions regarding FDA implementation of the BPCIA: (1) biosimilarity or interchangeability; (2) definitions relevant to the BPCIA; and (3) exclusivity. With regard to biosimilarity or interchangeability, the guidance states that a proposed biosimilar may have a different formulation, delivery device, or container closure than the reference product under certain circumstances. Additionally, the guidance discloses conditions permitting an applicant to obtain licensure for fewer than all routes of administration, presentations, and conditions of use for which the reference product is licensed. Further, the guidance describes conditions in which a sponsor may support biosimilarity using comparative data with a non-U.S.-licensed product or extrapolated clinical data designed to support a different condition of use. The guidance additionally instructs applicants how to describe the “strength” of a proposed injectable biosimilar. Finally, the guidance states that a biosimilar product that cites a reference product subject to the Pediatric Research Equity Act must include a pediatric assessment unless the applicant initially seeks approval as an interchangeable biological product.

With regard to the BPCIA’s definition of “biological product,” the guidance discloses the FDA’s regulatory definitions of “protein” and “chemically synthesized polypeptide.” Additionally, it defines when a proposed biological product is considered to be within the same “product class” as previously approved protein products.

With regard to exclusivity, the guidance instructs applicants and sponsor to search an online database to identify whether the reference product is subject to unexpired orphan exclusivity. The FDA will not approve a biosimilar during the 7-year exclusivity period.

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
This final guidance provides an overview of the FDA’s recommendations for establishing biosimilarity and discusses in detail relevant scientific principles for designing data and information to show biosimilarity. The FDA stresses that it will apply a totality-of-the-evidence approach in its assessment of biosimilarity and will use a risk-based approach to evaluate all data and information submitted. The FDA further emphasizes that the information sufficient to demonstrate biosimilarity will be determined on a product-specific basis.

The BPCIA requires an application to include analytical, animal, and clinical studies demonstrating that the biological product is “biosimilar” to a single reference product. As discussed above, the application must establish the product is “highly similar” to the reference product and has “no clinically meaningful differences.” Although the reference product must be U.S.-licensed, the application may rely on data from comparative studies with a non-U.S. licensed comparator product if the data is scientifically relevant. Because the FDA has discretion to determine what data is required to establish biosimilarity in a particular application, it encourages sponsors of the application to meet with the FDA early during product development to discuss adequate scientific justifications.

The FDA encourages sponsors to use a three step approach to develop evidence necessary to establish biosimilarity.

First, the sponsor should characterize the structural and functional aspects of both the proposed product and the reference product to identify potentially clinically relevant safety or efficacy risks. Structural analyses must use “state-of-the-art technology” to analyze multiple representative lots and show the proposed product will encode the same primary amino acid sequence as the reference product. Any minor modifications must be explained by the sponsor. The structural analyses for all relevant characteristics of the protein product (such as primary, secondary, tertiary, and quaternary structure; posttranslational modifications; and biological activities) must also be included. The FDA further recommends structural analysis of the finished dosage form to assess the effect of excipients or any other formulation effects. In vitro and/or in vivo functional assays must also be used to evaluate the pharmacologic activity of protein products.

Second, the sponsor should demonstrate safety and biosimilarity through animal studies. These studies generally do not establish safety, but are relevant to support the demonstration of biosimilarity through evidence of PK and PD measures. Nevertheless, animal toxicity and immunogenicity studies may be useful where uncertainty about safety remains after the initial structural and functional characterization.

Third, the sponsor should conduct comparative human PK and PD studies and a clinical immunogenicity assessment of the two products in an appropriate study population. The sponsor should discuss study proposals and overall clinical development plan with the FDA before initiating such studies. A sponsor should provide adequate scientific justification for choices in study design, population, endpoints, and other parameters. Human PK and PD measures comparing the proposed product to the reference product are typically fundamental to demonstrate biosimilarity. Even where relevant PD measures are not available, sensitive PD endpoints may be assessed. The FDA further expects at least one comparative clinical study regarding immunogenicity in order to assess the safety and effectiveness of the proposed product. The overall immunogenicity assessment should consider the nature of the immune response, the clinical relevance and severity of consequences, the incidence of immune responses, and the population being studied. Generally, the FDA expects studies to present statistical evidence that the proposed product is neither significantly inferior nor superior to the reference product. An applicant may provide sufficient scientific justification to extrapolate clinical data to support a determination of biosimilarity for various indications.

If there is uncertainty at each step, the sponsor should evaluate the uncertainty and consult with the FDA to adequately address it.

Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product

This guideline relates to the biosimilarity of therapeutic protein products and describes nine factors that are relevant in developing analytical studies to show a proposed product is “highly similar” to a reference product.

1. Expression System. The application should seek to minimize differences between the proposed and referenced expression systems. The FDA expects the expression construct for a proposed product encodes the same primary amino acid sequence as its reference product. However, minor modifications (such as N- or C- terminal truncations) that are not expected to change the product performance may be justified.

2. Manufacturing Process. The application should demonstrate its manufacturing process does not result in significant differences between the proposed product and its reference product.

3. Assessment of Physiochemical Properties. Physicochemical assessments are designed to maximize the potential for detecting differences between the proposed and reference products. The sponsor should consider all relevant characteristics of the protein product and design tests to account for the heterogeneity of the proposed product and the reference product as well as the ranges of variability for each.

4. Functional Activities. Functional assays are designed to complement physicochemical analyses and evaluate the function of the protein product. Sponsors should perform appropriate assays to evaluate the range of relevant functional activities for a product.

5. Receptor Binding and Immunochemical Properties. Sponsors should analyze specific binding or immunochemical properties when they are part of the activity attributed to the protein product.

6. Impurities. Sponsors should characterize, identify, and quantify impurities in the proposed product and reference product. Sponsors should further perform a risk-based assessment regarding any differences in process-related impurities between the proposed and reference products.

7. Reference Product and Reference Standards. Sponsors should provide a broad comparison of the proposed product to the reference product that is not strictly limited to analysis of each product in isolation. For example, the biosimilarity analysis may further consider applicable reference standards and relevant publicly available information.

8. Finished Drug Product. Product characterization studies should be performed on the most downstream intermediate best suited for each analytical procedure. Thus, sponsors should analyze the finished drug product if it is best suited for a particular analysis. If the analysis is performed on an earlier intermediate, sponsors should provide additional information. Additionally, sponsors should clearly identify excipients used in the proposed product that differ from those in the reference product.

9. Stability. Sponsors should include comparative studies conducted under multiple stress conditions to establish degradation profiles of the proposed and reference product.

Conclusion

The recently issued final guidances provide insight into how the FDA will evaluate biosimilarity and directions for sponsors throughout product development. However, many additional questions surrounding the BPCIA remain. For example, the currently issued guidances do not address how the FDA will determine “interchangeability.” Interchangeable drugs are likely to be more profitable than mere biosimilars because they can be sold in place of the reference drug without a prescribing doctor’s approval.

Upcoming draft guidances plan to provide additional information regarding the required scientific requirements for establishing biosimilarity and interchangeability as well as naming and labeling requirements for approved biosimilars. In January, the FDA’s Center for Drug Evaluation and Research (CDER) announced plans to publish five draft guidances on biosimilars in 2015:

  • Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

  • Considerations in Demonstrating Interchangeability to a Reference Product

  • Labeling for Biosimilar Biological Products

  • Nonproprietary Naming for Biological Products

  • Statistical Approaches to Evaluation of Analytical Similarity Data to Support a Demonstration of Biosimilarity

ARTICLE BY Imron T. Aly, Sailesh K. Patel, John K. Hsu and Helen H. Ji of  Schiff Hardin LLP
© 2015 Schiff Hardin LLP

FDA Finalizes Guidance Documents on Biosimilarity

On Tuesday, and over three years after the initial guidance documents were released, the US Food and Drug Administration released final versions of three guidance documents discussing how FDA will evaluate applications for regulatory approval of biosimilar products:

•Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

•Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein

•Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

Draft versions of the guidance documents were originally released by FDA for public comment in February 2012. In general, the final versions released Tuesday track the draft versions fairly closely, with a few noteworthy differences.

The guidance documents reiterate that the FDA will use a totality of the evidence approach to review applications for biosimilar products, and encourages a stepwise approach to demonstrating biosimilarity which with rare exceptions will include a comparison of the proposed biosimilar product with the reference product in terms of structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), clinical immunogenicity, and clinical safety and effectiveness. This stepwise approach is intended to better address residual uncertainty about biosimilarity that might remain at each step of the approval process.

The final guidance documents contain a few changes from the draft versions that are noteworthy:

•Most of the discussion of issues related to demonstrating the heightened standard for interchangeability was removed from the guidances with a note that it will be the subject of a separate guidance document that is forthcoming.

•The final guidances reiterate that, in most instances, a sponsor will need to provide information to demonstrate biosimilarity based on data directly comparing the proposed biosimilar product to FDA-approved reference product. However, they elaborate on the type of bridging data needed when a biosimilar applicant seeks to use a non-US licensed comparator product to support a demonstration of biosimilarity.

•Specific comments have been provided for biosimilar developers considering manufacturing/process changes after completing the initial analytical similarity assessment including a requirement to demonstrate comparability between the pre- and post-change proposed product.

•More detailed comments regarding animal toxicity studies were added.

•Previous Q and As relating to what constitutes the “publicly-available information” that should be included in a 351(k) application and whether an applicant can include a request for reference product exclusivity in its 351(a) application were deleted – an indication that the FDA is still considering its position on these points.

Authored by: Paul A. Calvo, Ph.D. and Timothy J. Shea, Jr., PhD. by Sterne Kessler

© 2015 Sterne Kessler

FDA Regulation of mHealth Updates

Covington & Burling LLP

At the Food Drug and Law Institute’s annual conference on April 21, 2015, Bakul Patel, Associate Director for Digital Health, Office of Center Director, Center for Devices and Radiological Health (CDRH), held a discussion of “FDA Regulation of Mobile Health/Medical Applications.”  There have already been several important developments in FDA regulation of mHealth products this year.  Patel stated that FDA recognizes the importance of digital health, and its potential to drive be

ARTICLE BY

Cassie Scherer
Covington & Burling LLP
Covington E-Health

tter health outcomes and promote patient engagement.  Patel discussed two recently released draft guidances that impact FDA regulation of mHealth, the draft General Wellness Guidance and the draft Accessories Guidance, and highlighted that FDA continues to work promote innovation while at the same time protecting patient safety.  The public comment period for these guidances ended on April 20th, and Patel noted that CDRH did not receive many comments.  Finally, Patel emphasized that industry can continue to reach out to FDA with questions about mobile health at mobilemedicalapps@fda.hhs.gov or digital health at digitalhealth@fda.hhs.gov.

The discussion draft of the 21st Century Cures Act includes sections that would exclude “health software” from regulation as a medical device, and would require FDA to promulgate regulations to establish standards and procedures for regulating “medical software.”  New 21st Century Cures language may be released by the end of this month.  We will be watching closely to see if there are any changes to the software language.

FDA Issues Final Guidance Documents on Medical Device Data Systems and Medical Mobile Apps

Barnes & Thornburg LLP Law Firm

The FDA recently issued two final guidance documents signaling its intention either not to regulate, or to give minimal oversight, to two categories of medical devices, medical device data systems and medical mobile apps. The guidance on medical device data systems bears the wordy title, “Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices.” The app guidance is titled simply, “Medical Mobile Applications.”

The data systems guidance defines “medical device data systems” as “a hardware or software product that transfers, stores, converts formats, and displays medical device data” and cites 21 CFR 880.6310 for a somewhat more elaborate definition. In perhaps record brevity, the substance of the guidance is expressed as follows:

The FDA does not intend to enforce compliance with the regulatory controls that apply to the following devices:

  • MDDS subject to 21 CFR 880.6310,

  • Medical image storage devices subject to 21 CFR 892.2010, and

  • Medical image communications devices subject to 21 CFR 892.2020.

The guidance notes that a medical device data system (MDDS) “does not modify the data, and it does not control the functions or parameters of any connected medical device. An MDDS does not include devices intended for active patient monitoring.”

The medical mobile app guidance states that it was changed from a prior final version only to be made consistent with the MDDS guidance. Our prior alert summarizing the medical mobile app guidance can be found here.

Copies of the final guidance documents can be found here and here.

ARTICLE BY

Lynn C. Tyler, M.S.
Hae Park-Suk
OF
Barnes & Thornburg LLP

FDA Requests Comments on WHO Recommendation to Classify Two Common Industrial Solvents as Psychotropic Substances

Beveridge & Diamond PC environmental and energy law firm

On January 27, 2015, the Food and Drug Administration (“FDA”) requested comments on a recommendation by the World Health Organization (“WHO”) to classify two common industrial solvents – gamma-butyrolactone (“GBL”) and 1,4-butanediol (“BDO”) – as psychotropic substances under Schedule I of the 1971 Convention on Psychotropic Substances (“Psychotropic Convention”). See 80 Fed. Reg. 4283.  The comments will be used by the Secretary of Health and Human Services (“HHS”) to prepare a recommendation on the WHO proposal to the Secretary of State, which will be binding on the U.S. representative to the upcoming 58th Session of the UN Commission on Narcotic Drugs (“CND”) in Vienna, Austria, on March 9-17, 2015.  At the Vienna meeting, CND may accept the WHO recommendations, reject the recommendations, or decide to control the chemicals in another way (i.e., under a different Schedule of the Convention).

FDA notes that if either chemical – or any of the other chemicals that are also recommended for listing, but are not addressed here because they have few, if any, legitimate industrial uses – are added by CND to Schedule I of the Psychotropic Convention, the U.S. will have to impose additional controls on the chemical(s) under the Controlled Substances Act (“CSA”) administered by the Drug Enforcement Administration (“DEA”).  Although FDA does not elaborate on what those controls might consist of, they would likely include additional restrictions on manufacture, distribution, import, and export of the chemicals, as well as enhanced recordkeeping and reporting requirements. For example, Article 2(7)(a)(i) of the Psychotropic Convention states that parties shall require licenses for manufacture, trade, and distribution of Schedule I substances.  Moreover, Article 7(a) provides that parties must “[p]rohibit all use [of Schedule I substances] except for scientific and very limited medical purposes by duly authorized persons,” although Article 2(7)(a) allows individual parties to notify the UN that they cannot do so as a result of “exceptional circumstances,” in which case the party need only “take into account” the prohibition “as far as possible.”

It is worth noting that GBL is already regulated under the CSA as a precursor to gamma-hydroxybutyric acid (“GHB”), which is a commonly abused central nervous system depressant drug that is currently regulated under Schedule II of the Psychotropic Convention and Schedule I of the CSA.  In particular, GBL is classified under the CSA as a “List I” precursor (not to be confused with a CSA Schedule I or other controlled substance), and thus is already subject to significant DEA controls.  In addition, some U.S. states and authorities in some other countries already regulate GBL directly as a controlled substance or its equivalent.  Nevertheless, the addition of GBL to Schedule I of the Convention would likely require new and more stringent controls in most jurisdictions.  Additional information on the basis for the WHO recommendation for GBL (including the chemistry of the chemical, abuse potential, legitimate uses, and current regulation around the world) can be found in the 2014 GBL Critical Review Report of the WHO Expert Committee on Drug Dependence.

BDO is also a precursor to GHB, but is not currently regulated under the CSA.  It is regulated in several U.S. states and other countries as a precursor or controlled substance equivalent.  Once again, however, if it is added to Schedule I of the Psychotropic Convention, it will likely become subject to substantial additional restrictions.  Additional information on the basis for the WHO recommendation for BDO can be found in 2014 BDO Critical Review Report of the WHO Expert Committee on Drug Dependence.

FDA will accept written comments on the WHO recommendations until February 26, 2015.  Requests for a public meeting will be accepted until February 6, 2015.

ARTICLE BY

Aaron H. Goldberg
OF
Beveridge & Diamond PC

Federal Circuit’s Sandoz Decision Increases Importance of Post-Grant Proceedings to Biosimilar Developers

Sterne Kessler Goldstein Fox

On Friday, December 5, the U.S. Court of Appeals for the Federal Circuit rendered its decision in Sandoz v. Amgen, No. 2014-1693, a case with major implications for the emerging U.S. biosimilars industry. The decision addresses when and how a party seeking to launch a biosimilar product in the U.S. can initiate litigation to challenge the brand company’s potential blocking patents. This is the first instance in which the Federal Circuit has had the opportunity to address the scope and applicability of the Biologics Price Competition and Innovation Act (BPCIA), which established a formal pathway for biosimilar approval in the US.

Background

At issue in Sandoz is a litigation Sandoz, Inc. initiated against Amgen, Inc. and Hoffman-La Roche Inc. on June 24, 2013. Sandoz’s complaint seeks a declaratory judgment (DJ) that two patents owned by Roche and exclusively licensed to Amgen are invalid, unenforceable, and would not be infringed by the commercial marketing of Sandoz’s biosimilar version of Amgen’s blockbuster biologic product Enbrel® (etanercept). The patents at issue extend Amgen’s protection around etanercept an additional 15 years past the original patents. Sandoz filed its complaint against Amgen prior to filing any application with the FDA for approval to market its biosimilar etanercept product, which is currently in Phase III clinical trials. Sandoz will not file with the FDA until the Phase III trial is complete, and of course will not be able to market its version of etanercept in the US without FDA approval. At the time of suit, Amgen had not alleged Sandoz was currently doing anything that exposes it to liability for infringing Amgen’s patents rights around Enbrel®.

The District Court Decision

Amgen moved to dismiss Sandoz’s complaint, asserting that the court lacked jurisdiction to hear the case because no immediate and real controversy between the parties exists. In a brief order, the court granted Amgen’s motion to dismiss on two separate grounds. First, the court ruled that its discretion to enter a DJ in the case is subject to the provisions of the BPCIA, which sets specific limitations on the timing and conduct of any litigation arising from the filing of an application for approval to market a biosimilar. The court concluded that “neither a reference product sponsor, such as Amgen, nor [a biosimilar applicant] such as Sandoz, may file a lawsuit unless and until they have engaged in a series of statutorily–mandated exchanges of information” related to patents potentially in dispute. In this case, Sandoz had not complied with the exchanges as it had not even started the process by filing its application with the FDA.

Second, the court found that Sandoz had not established jurisdiction under traditional grounds because it had not established a real and immediate injury or threat of future injury caused by Amgen. The court noted that Amgen had never advised Sandoz that it intended to sue Sandoz, and that the mere allegation by Sandoz that it intended to file an application for FDA approval in the future was not sufficient to create a case on controversy. Sandoz appealed the district court order dismissing the action.

The Federal Circuit Decision

On appeal, Sandoz argued that the litigation provisions of the BPCIA only govern the statutory patent infringement litigation authorized by the Act after a biosimilar application is filed with the FDA, and do not apply to DJ actions in general. Sandoz further argued that nothing in the BPCIA can be construed to bar or limit in any way the ability to bring DJ actions to resolve patent disputes prior to filing a biosimilar application. Finally, Sandoz argued that the district court erred in concluding that Sandoz had not adequately demonstrated a sufficient actual case or controversy sufficient to allow the DJ action to proceed.

The Federal Circuit panel affirmed the district court’s dismissal of Sandoz’s complaint, concluding that Sandoz had not alleged an injury of sufficient immediacy and reality to create subject matter jurisdiction. The Federal Circuit noted that “a case of actual controversy” is a prerequisite to exercising declaratory judgment jurisdiction. The test for determining whether a case or controversy exists is whether “ there is a substantial controversy . . . of sufficient immediacy and reality to warrant the issuance of a declaratory judgment.” The Federal Circuit, however, declined to address the lower court’s interpretation of the BPCIA as barring a lawsuit by either the reference product sponsor or the biosimilar applicant unless and until the parties have engaged in the statutorily-mandated patent information exchanges.

In concluding that Sandoz’s complaint does not present a case or controversy, the Federal Circuit panel noted that there was no prior decision in which the Federal Circuit had found a case or controversy to exist when the only activity that would create exposure to potential infringement liability was a future activity requiring FDA approval that had not yet been sought. The court found the immediacy requirement lacking where the conclusion of Sandoz’s Phase III trial, which was a prerequisite for filing for FDA approval, was still several years away when Sandoz filed suit. The court refused to assume that the Phase III trial would be successful, and noted that the trial could in fact uncover issues with Sandoz’s product that could push the application filing date back even further. Alternatively, the clinical trial could fail resulting in Sandoz never seeking FDA approval, or Sandoz could modify its proposed product and file for approval on the modified product. The court also noted that Sandoz’s complaint lacked specificity as to how Amgen’s patents read or don’t read on Sandoz’s product; and instead relies on prior general assertions by Amgen that the patents at issue cover Enbrel, that Amgen will assert the patents against products that compete with Enbrel, and that Sandoz intends to market a competing product at some point in the future. Ultimately, the court concluded that the events allegedly exposing Sandoz to infringement liability may not occur as anticipated or may not occur at all. The court found that Sandoz also had not shown that it would suffer any “immediate and substantial adverse impact” from not being able to seek or secure a patent adjudication before filing its application for FDA approval.

Unanswered Questions

The Federal Circuit specifically stated that its decision was limited to the particular facts before it, and does not address whether Sandoz would be able to seek declaratory judgment jurisdiction once it files its FDA application, or whether the BPCIA forecloses declaratory judgment actions outside of the statutorily-mandated patent information exchange once the application is accepted by the FDA. The decision also did not clarify the additional issue disputed by the parties concerning what constitutes sufficient “notice of commercial marketing,” which the BPCIA states must be provided by the biosimilar applicant prior to launch.

Increased Important of Post-Grant Proceedings before the USPTO

Although the Sandoz court made a point to limit the scope of its decision to the facts before it, the decision casts substantial doubt on the ability of any biosimilar developer to bring a district court action challenging the reference product sponsor’s patents prior to filing a biosimilar application with the FDA and triggering the patent information exchange provisions of the BPCIA. At the same time, the decision elevates the importance to biosimilar developers of post-grant challenges before the U.S. Patent and Trademark Office, such as inter partes review (IPR) and post-grant review (PGR), as means for obtaining some degree of early patent certainty before initiating the FDA approval process. IPRs in particular have proven to be a potent weapon for generic drug manufacturers in the context of ANDA litigation. The lower standard of proof required to show invalidity, the expedited pace of the proceedings, and the decreased cost in comparison to district court litigation coupled with the extremely high rate in which patent claims are being invalidated provide generic manufacturers with tremendous leverage to obtain favorable settlements with brand companies. We expect that the Sandoz decision should only increase the speed with which post-grant proceedings are adopted in the biosimilar arena.

ARTICLE BY

Timothy J. Shea, Jr., PhD.
Paul A. Calvo
OF
Sterne, Kessler, Goldstein & Fox P.L.L.C.

FDA Denies Citizen Petition’s Request to Ban Marketing of Non-Absorbable Surgical Mesh Products for Transvaginal Repair of Pelvic Organ Prolapse

Covington BUrling Law Firm

 

On July 14, 2014, FDA publicly posted its response denying Public Citizen’s August 2011 citizen petition concerning the marketing of non-absorbable surgical mesh products for transvaginal repair of pelvic organ prolapse (POP).  In its response, FDA took the position that a ban or recall of POP devices is not warranted at this time.

As background, in August 2011, Public Citizen filed a citizen petition asserting that POP devices “offer no clinically significant benefits in comparison to surgical repairs for POP performed without placement of surgical mesh” and “have high rates of serious complications.”  Public Citizen requested that the agency take the following actions: (1) ban the marketing of all available non-absorbable surgical mesh products for transvaginal repair of POP; (2) order all manufacturers to recall these products; and (3) classify all new non-absorbable surgical mesh products for transvaginal repair of POP as class III devices and approve the products only under a premarket approval application (PMA).

In its response, dated May 1, 2014, FDA denied the citizen petition.  While the agency rejected Public Citizen’s call for a ban or recall of POP devices, FDA noted that it shares some of the concerns outlined in the citizen petition and is taking actions to address these concerns.  In addition, the agency also determined that “a citizen petition is not the appropriate mechanism for requesting a reclassification of a device.”

FDA explained that in September 2011, the agency convened an advisory committee meeting of the Obstetrics and Gynecology Devices Panel to discuss the safety and efficacy of transvaginal surgical mesh products used for repair of POP.  The Panel determined that “a favorable benefit-risk profile” for these devices “had not been well-established” and that the devices should be reclassified from class II to class III.  The Panel also recommended that manufacturers conduct postmarket studies of currently marketed surgical mesh products for transvaginal repair of POP.  As of May 2014, FDA had issued 126 postmarket surveillance orders to 33 manufacturers of these devices.

FDA explained that it has evaluated information from the Panel’s recommendations and the published scientific literature and has tentatively determined that the device should be reclassified as a class III device.  On May 1, 2014, FDA published a proposed order in the Federal Register to reclassify surgical mesh for transvaginal repair of POP from class II to class III.  On the same day, FDA published another proposed order in the Federal Register to require the filing of a PMA following the reclassification of the device to class III.  Thus, although FDA did not grant Public Citizen’s third request, the agency “initiated the process that could ultimately result” in reclassification of the device and the requirement to submit a PMA for these devices.

Article By:

Colleen Kelly
Of:
Covington & Burling LLP

FDA Issues Guidance for Safety of Nanomaterials in Cosmetic Products (as well as in Food)

GT Law

For the last seven or so years, the U.S. federal government and some state governments have been collecting cradle-to-grave information regarding nanomaterials. The data collection call-ins were intended to create a collaborative, scientific dialogue with the goal of examining relevant information, and identifying information gaps and ways to address those gaps.

Last week, the FDA issued guidance documents for both cosmetic and food manufacturers. The guides are one more step intended to assist industry and other stakeholders in identifying the potential safety issues of nanomaterials in consumer products and in developing a framework for evaluating them. It also provides contact information for those who wish to discuss safety considerations regarding the use of specific nanomaterials in cosmetic products with the FDA.

If your company is considering the use of nanomaterials in its products, it is important to recognize that although nanotech cosmetics are still subject to the same legal requirements as other cosmetics, in that they do not require premarket approval, the products must be safe under customary usage conditions and properly labeled. Additionally, although the FDA has explained that the current safety framework used for conventional cosmetics is still appropriate for cosmetics using nanotech, companies should keep in mind the unique properties of nanomaterials when testing safety. Ultimately, as this guidance reminds, companies are legally liable for ensuring the safety of their products. As to food products, the FDA encourages manufacturers to contact the agency early in the development process to assist in assessing the safety and potential issues with using nanotechnology.

Read the complete press announcement from the FDA here.

Article By:

Angela Diesch
Of:
Greenberg Traurig, LLP