3699948229_d7732f8df0_o.jpgTowards the end of last year, FDA added two new final guidances related to the safety reporting requirements for investigational new drug exemptions (“INDs”) and bioavailability and bioequivalence (“BA/BE”) studies entitled: Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies and Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies-Small Entity Compliance Guide. These guidances are intended to explain final rules published on September 29, 2010 that amended the IND safety reporting requirements under 21 C.F.R. Part 312 and added safety reporting requirements for individuals conducting BA/BE studies under 21 C.F.R. Part 320. We blogged on that development then.

A key focus of the new regulations was to add clarifying definitions to certain terms, “adverse event”, “suspected adverse reaction”, “unexpected” adverse event or reaction, “serious” adverse event or reaction, and “life-threatening”, as well as further define reporting requirements. According to the main Guidance (not the one for small entities), sponsors frequently took a broad reading of the phrase “associated with the use of the drug” in the context of the former 21 C.F.R. § 312.32(a), which stated, “there is a reasonable possibility that the experience may have been caused by the drug.” With this broad reading, the Guidance continues, “sponsors frequently reported, as individual cases, serious adverse experiences for which there was little reason to believe that the drug caused the event.” The Guidance includes three examples of overzealous reporting, including reporting adverse experiences that were manifestations of the underlying disease, common occurrences in the study population independent of drug exposure, or study endpoints. FDA described these types of reporting as a drain on agency resources and “uninformative when reported as single events (i.e., without a comparison of the incidence of the event in treated and untreated subjects), they do not contribute meaningfully to the developing safety profile of an investigational drug or to human subject protection.”

Interestingly, this appears to be somewhat of a departure from how FDA had enforced its reporting regulations on clinical investigators. Shortly after I first joined FDA in the 1990s, I was involved in a clinical investigator disqualification proceeding that resulted in a clinical investor being disqualified from further clinical studies because, among other things, he had not timely or accurately reported certain adverse events. While the Presiding Officer took into account that many of the patients had underlying conditions prior to the experimental therapy, the Center for Drug Evaluation and Research (“CDER’s”) approach appeared to focus on the need for the investigator to report all adverse event associated with the therapy. In this case, the therapy had to do with infusing a drug with a catheter to help dissolve gall bladder and common bile duct stones, which the CDER described as a drug/device. The investigator admitted that he had not immediately reported certain events that occurred as a result of the catheter insertion (most likely not due to the drug) or the patient’s underlying conditions, because in his opinion, they were not associated with the drug therapy. At that time, CDER took the approach that the investigator’s opinion was irrelevant, because the adverse events were at least temporally associated with the drug/device and therefore had to be timely reported.
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drugs.jpgFDA Partner Brian J Malkin helped suggest key topics for and was quoted in an FDAnews article published on January 2, 2013, entitled “Landmark Year for Generics Cues Big Changes, Rulings in 2013”. First, Mr. Malkin was quoted in a section regarding risk evaluation mitigation strategies. Here, FDAnews wrote:

…But generic-makers failed to win a key provision that would have allowed access to hard-to-obtain products covered under risk evaluation and mitigation strategies (REMS).

… The loss of the REMS provision may be mitigated by the FDA’s move to more classwide REMS, a strategy that could keep brand drugmakers from using patents on the plans to block generic competition, Brian Malkin, a partner at Frommer Lawrence & Haug, said.

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Thumbnail image for supremecourt.pngThe Solicitor General has urged the U.S. Supreme Court to deny GlaxoSmithKline’s (“GSK’s”) pending certiorari petition in GlaxoSmithKline v. Classen Immunotherapies, Inc., case number 11-1078 The issue facing the Supreme Court should it grant GSK’s petition is whether the Federal Circuit correctly interpreted 35 U.S.C. § 271(e)(1)’s safe harbor as applying to only pre-market approval of generic counterparts. In its amicus brief submitted late last week, the Solicitor General explained that there is no need to clarify the safe harbor provision and voiced concerns that the Classen case would not be the proper vehicle to do so should the Supreme Court feel the need.

The dispute between GSK and Classen involves three patents, U.S. Patent Nos. 6,638,739, 6,420,139, and 5,723,283, which relate to methods of optimizing vaccine immunization schedules to decrease the risk of developing chronic immune-mediated disorders. Classen sued a number of defendants, including GSK, alleging infringement of its patents through various vaccination research projects. GSK’s allegedly infringing activities related to its participation in a government study that evaluated a suggested association between the timing of childhood vaccinations and the risk of developing type 1 diabetes. GSK argued, and the district court agreed, that such activity was within section 271(e)(1)’s safe harbor because the information was ultimately submitted to FDA. On appeal, the Federal Circuit reversed, holding that section 271(e)(1) “does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained.” Classen Immunotherapies, Inc. v. Biogen Idec at 1070. The Federal Circuit further explained, “§ 271(e)(1) is directed to premarketing approval of generic counterparts before patent expiration.” Id. at 1071.

In the amicus brief, United States Solicitor General Donald Verrilli expressed his belief that the Federal Circuit’s interpretation of § 271(e)(1) in Classen was incorrect. 35 U.S.C. 271(e)(1) reads:

It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention . . . solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.

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Thumbnail image for Thumbnail image for Thumbnail image for european commission.jpegThis Tuesday, the European Parliament approved European Union (“EU”) regulations creating a European patent with unitary effect (“unitary patent”) and setting forth related language translation requirements. The unitary patent, granted by the European Patent Office (“EPO”), will be offered in addition to already-existing national patents. It will be effective across the EU (except Spain and Italy) and enforceable with a single court ruling.

If ratified by at least thirteen states including France, Germany, and the United Kingdom, a Unified Patent Court (“UPC”) will exercise exclusive jurisdiction over unitary patents. The UPC Agreement will come to vote in February of next year. (Notably, the Court of Justice of the EU ruled last March that a proposed unified patents court would not be compatible with EU treaties.) The unitary patent is set to take effect beginning in 2014 or when the UPC is ratified, whichever is earlier.

European Commissioner Michel Barnier declared the “long-awaited agreement” a “decisive contribution to the implementation of the economic and growth agenda.” Barnier let the numbers speak for themselves: “In the United States, in 2011, 224 000 patents were granted, in China 172 000 while here in Europe only 62 000 European patents were delivered. One of the reasons for this difference is without a doubt the prohibitive cost and the complexity of obtaining patent protection throughout the single market.”
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Thumbnail image for Thumbnail image for Thumbnail image for FDA logo.jpgOn December 12, FDA held a meeting of its Drug Safety and Risk Management (“DSaRM”) Advisory Committee regarding development of a framework for addressing what risk evaluation and mitigation strategies (“REMS”) are appropriate for teratogenic drugs. Teratogenic drugs are drugs that may cause birth defects for developing fetuses. The Food and Drug Administration Amendments Act (“FDAAA”) requires FDA to bring to the DSaRM Advisory Committee for review at least one drug with Elements to Assure Safe Use (“ETASU”), and this was the topic chosen for 2012.

According to the opening remarks, FDA has recognized that over the years, its approach regarding the development of risk management programs for teratogenic drugs “appears to be inconsistent.” The DSaRM Advisory Committee began with FDA presentations, continued with stakeholder presentations from industry, prescribers, patients, and then ended with the full committee’s discussion of the questions to address:

FDA’s proposed framework would take as intrinsic factors: (1) scientific evidence of teratogenicity (biological plausibility, non-clinical data, and human data) and (2) drug-product related factors (characteristic of the drug product, efficacy, and safety profile). The proposed extrinsic factors to consider in the framework are (1) drug product-related factors (actual drug use), (2) clinical-use related factors (characteristics of medical condition, patient population profile, and context of care), (3) regulatory factors (regulatory precedent, previous REMS experience, availability of new REMS tools), and (4) anticipated consequences of REMS.
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Thumbnail image for supremecourt.pngOn December 7, 2012, the U.S. Supreme Court granted the Federal Trade Commission’s (“FTC’s”) certiorari petition and will address the question of whether settlements of Hatch-Waxman pharmaceutical patent litigation that include so-called “reverse-payments” are per se lawful unless the underlying patent litigation was a sham or the patent was obtained by fraud or, instead, are presumptively anticompetitive and unlawful.

As previously reported here, the FTC has repeatedly attacked reverse payment agreements between branded and generic pharmaceutical companies, alleging that such settlements–which the FTC also refers to as “pay-for-delay”–are a violation of antitrust laws. There is currently a split in the circuits regarding the legality of these agreements. In the decision now being reviewed by the Supreme Court, FTC v. Watson Pharmaceuticals, Inc. (involving the brand-name drug AndroGel), the Eleventh Circuit held that such settlements are legal so long as they fall within the “scope of the patent” and there is not evidence of sham litigation or fraud in obtaining the patent. Other courts have arrived at similar conclusions, including the Second Circuit (In re Tamoxifen Citrate Antitrust Litigation) and the Federal Circuit (In re Ciprofloxacin Hydrochloride Antitrust Litigation). In contrast, the Third Circuit’s recent In re K-Dur Antitrust Litigation decision held that these agreements create a rebuttable presumption that the settlement is anticompetitive. Both Merck and Upsher-Smith filed petitions to the Supreme Court to review the Third Circuit’s K-Dur decision; however, the Court has not yet announced whether it will grant those requests.

In AndroGel, the FTC asks the Supreme Court to adopt the Third Circuit’s approach. The FTC argues that the “scope-of-the-patent approach in general, and the decision of the [Eleventh Circuit] in particular, reflect a misapplication of federal competition law.” Thus, the FTC advocates for the Third Circuit’s “approach, [in which] the restraints embodied in reverse-payment agreements are presumed to be anticompetitive, and the antitrust defendants–who, after all, have settled litigation against each other by agreeing not to compete–bear the burden of advancing some countervailing procompetitive virtue.” (Internal quotation omitted).
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Thumbnail image for Thumbnail image for Thumbnail image for Thumbnail image for Thumbnail image for dna.jpgFLH Partner Brian J. Malkin’s chapter in the 2013 Edition of Recent Developments in Food and Drug Law published by Aspatore / Thomas Reuters entitled: “Challenges to the Development of a Biosimilars Industry in the United States” is now available as a PDF copy. The chapter takes a hard look at the new biosimilars pathway created by the Biologics Price Competition and Innovation Act of 2009 (“the Biosimilars Act”) and attempts to answer the question why no applicant appears to have filed a biosimilars application with FDA more than two and a half years after the Biosimilars Act was enacted. Some of the topics addressed include:

  • The Impact of the Biosimilars Act and Approval Issues for Biosimilars
  • Biological Innovator Challenges to Biosimilars
  • Interchangeability Issues
  • Biosimilar Manufacturing Issues
  • Patent Litigation and Confidentiality Issues
  • The FDA’s General Approach Based on Its New Guidances
  • The FDA’s Inverted Pyramid Approach
  • Enforcement/Pharmacovigilance Issues
  • Product Shortages, Liability, and Advertising Issues
  • Key Takeaways

Biosimilars are defined under the Biosimilars Act as “highly similar” to an innovator’s biological product already approved by FDA. Biosimilars are also known around the world as follow-on biologics or biogenerics. Biosimilars are already approved in Europe and other countries and are clearly feasible given current technology and analytical methods. Ultimately, as there are less small molecule targets for generic companies to pursue over time, innovator and generic drug companies alike will be drawn to design, test, and file applications for biosimilars. FDA appears to have hoped that the new biosimilars pathway would create partnerships to form standards for analytic testing of biosimilars. Instead, the high cost and technical skills to reverse engineer the innovator’s product and manufacture biosimilars has driven innovator and generic drug companies to form unique partnerships to develop proprietary analytical methods, including methods with either trade secret or patent protection.
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On November 19, 2012, FDA issued a draft Guidance entitled, “Electronic Source Data in Clinical Investigations.” The Guidance recommends various procedures relating to the electronic capture of source data in clinical investigations in an effort to reduce errors, to provide real-time data access, and to maintain accurate records for inspection by study investigators and FDA.

Clinical Data Guidance

Source data includes all information found in original clinical investigation documents (or certified copies of original documents) and this information is used for the reconstruction and evaluation of clinical trials. Accurate transcription of source data is extremely important, and the Guidance discusses methods of identifying source data, creating easy identification methods for auditing, capturing source data, and reviewing and retaining the data. The Guidance discusses the identification of source data originators, the capture of source data, the creation of data element identifiers, and the investigator’s duty to review and retain electronic data.

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Written by Julie E. Kurzrok

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The Guidance focuses on data entered into electronic case report forms (“eCRFs”). An eCRF is an electronic record, created for all clinical study subjects, that is reported to the study sponsor as per the study protocol. eCRFs contain data elements that are entered into the system by data originators such as investigators, medical devices, and clinical investigation subjects. Data elements are the smallest units of observation made during a clinical investigation and they include observations such as weight, birth date, race, or body temperature. The Guidance recommends that each sponsor and investigator maintain a list of data originators (e.g., people and devices) authorized to enter data elements for each study protocol. These lists limit access to data entry by creating unique user names, passwords, and identifications and by setting time periods for when each data originator can enter data.
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supremecourt.pngLast Friday, the Supreme Court decided to consider the question presented by generic drug manufacturer Mutual Pharmaceutical Co. (“Mutual”) whether federal law “preempt[s] state law design-defect claims targeting generic pharmaceutical products because the conceded conflict between such claims and the federal law governing generic pharmaceutical design allegedly can be avoided if the makers of generic pharmaceuticals simply stop making their products.” This issue emerges from the First Circuit’s affirmation of a $21 million verdict against Mutual in a state law products liability action.

This case originated in the District of New Hampshire, where Karen Bartlett filed suit against Mutual alleging that its anti-inflammatory drug sulindac (reference listed drug: Clinoril®) is “unreasonably dangerous” under New Hampshire products liability law. Bartlett had a severe allergic reaction to the product resulting in the loss of more than 60% of her outer skin layer. The New Hampshire Supreme Court has adopted § 402A of the Restatement (Second) of Torts (“RS (2nd) § 402A”), which imposes strict liability for selling “any product in a defective condition unreasonably dangerous to the user or consumer.” Under New Hampshire law, this requires a showing that “the magnitude of the danger outweighs the utility of the product,” regardless of whether there is a safer alternative design. Vautour v. Body Masters Sports Indus., Inc., 784 A.2d 1178, 1182-83 (N.H. 2001).

At issue is whether the Drug Price Competition and Patent Term Restoration Act of 1984 (“Hatch-Waxman Amendments”) and corresponding FDA regulations preempt design defect claims that are based in state tort law directed towards generic pharmaceutical products, such as Bartlett’s New Hampshire claim. The relevant sections of the Hatch-Waxman Amendments require a generic drug manufacturer to show that its product (1) has the same “route of administration,” “dosage form,” and “strength” as, and (2) is “bioequivalent” to, the brand name drug that its application references, in order to gain FDA approval. See 21 U.S.C. § 355(j)(2)(A). Mutual argues that these “sameness” requirements preclude generic manufacturers from materially altering the design of their products, and that a generic’s ability to comply with both federal and state law by withdrawing its product from the market (“the stop selling theory”) is not a valid rationale for finding non-preemption.
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Thumbnail image for Thumbnail image for FDA logo.jpgOn November 30, Endo Pharmaceuticals Inc. (“Endo”) sued FDA, seeking declaratory and injunctive relief for FDA to determine that Endo’s original Opana® ER (oxymorphone hydrochloride extended-release) was withdrawn from sale for safety reasons, because the product is inherently vulnerable to misuse and abuse. The current crush-resistant formulation of Opana® ER, which goes by the same name, was approved in December 2011, and Endo began marketing this formulation, which Endo called “Opana® ER CRF” in its Complaint to distinguish it from its earlier-marketed formulation. For consistency and clarity, this blog will use the same nomenclature. Endo’s complaint states that Opana® ER CRF is bioequivalent to Opana® ER but embeds the active ingredient in a polyethylene oxide matrix to make the pill harder and less crushable, as well as more difficult to liquefy and inject.

According to the Complaint, Endo discontinued Opana® ER on May 31, 2012, because it believed Opana® ER CRF to be less susceptible to misuse and abuse. Endo believes that FDA was required to make a determination whether Opana® ER was withdrawn from the market “promptly” (emphasis in original), because, by this time, FDA had already approved two generic versions to be marketed by Impax Laboratories, Inc. (“Impax”) and Actavis South Atlantic LLC (“Actavis”). Endo’s Complaint further explains that when FDA failed to make a prompt determination. it filed a Citizen Petition, requesting that FDA make the determination that Opana® ER was discontinued for reasons of safety and cannot be a reference listed drug and that only Opana® ER CRF can have generic versions, which must be similarly crush resistant. Endo further filed a second Citizen Petition and supplemented its original Citizen Petition. The second Citizen Petition sought to classify Opana® ER CRF as a separate dosage form to Opana® ER and require generic versions of Opana® ER CRF to be similarly crush-resistant. The supplement to its original petition included data suggesting that Opana® ER CRF resulted in less reports of abuse and diversion, among other things, which is also described in the Complaint.

Endo’s Complaint asserts that Opana® ER was safe and effective when used according to its FDA-approved labeling, but it became evident over time that it posed risks to humans. First, when crushed into a fine powder and inhaled or otherwise ingested, the active ingredient could be released very quickly, risking overdose. Opana® ER could also be chewed, either inadvertently or intentionally, also causing an accelerated release of its active ingredient. Approximately one year after introduction of Opana® ER into the market, Endo decided to develop a crush-resistant formulation with a German partner to reduce these potentials for abuse and misuse, the Complaint recounts..
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