FDA Lawyers Blog

by Howard E. Rosenberg, Ph.D.

Up to three in four Americans say they don't take prescription medicine as directed, according to the National Community Pharmacists Association as reported in the Wall Street Journal. According to various reports, more than a third of the medication-related hospital admissions are linked to a lack of a real understanding of the patient information leaflet provided, resulting in poor adherence to the medication requirements. There was a 52% increase in people treated for illnesses and injuries from just from taking medicines between 2004 to 2008, rising to nearly 1.9 million people. A further 838,000 people were treated and released from emergency rooms due to harm from medications in 2008 alone.

With the growing complexity of medication regimens, especially for the elderly and those with multiple, chronic conditions, even highly educated consumers can fail to take their medications correctly, says Karen Weiss, program director of FDA's Safe Use Initiative. "We need to create better awareness about the gamut of harm that can occur."

Patients can receive up to three different types of drug leaflets, and recent studies by FDA have shown that the information offered is not consistently understandable, may sometimes appear to be conflicting or even inaccurate. A national awareness campaign has been arranged to highlight this problem, involving both industry and nonprofit groups, and will be launched in May by the National Consumers League.

by Brian Malkin

On April 25, FDA announced to the public and sent out a letter to stakeholders that it would regulate electronic cigarettes as "tobacco products". FDA's announcement follows a decision, the letter states, that FDA will comply and not appeal a decision by the U.S. Court of Appeals for the D.C. Circuit, Sottera, Inc. v. FDA. In this decision, the Court held that FDA should regulate e-cigarettes as "tobacco products", not drug/devices, as FDA had attempted previously, unless the products are marketed with therapeutic claims, such as a smoking cessation product. The letter was signed by FDA Center Directors for the Center for Tobacco Products and the Center for Drug Evaluation and Research.

According to the letter, FDA will propose a regulation to extend the "tobacco product" definition in the Family Smoking Prevention and Tobacco Control Act of 2009 ("Tobacco Control Act") that amended the Federal Food, Drug, and Cosmetic Act ("FD&C Act") to include not only e-cigarettes but other products "made or derived from tobacco". An exception to this classification would be for any product(s) that are "marketed for therapeutic purposes," where the product could be a drug, drug/device, or another type of FDA-regulated product. The Tobacco Act, however, prohibits tobacco products from being combined with other FDA-regulated products. FDA is taking this step, the letter explains, to ensure that "appropriate regulatory mechanisms" cover this extended class of products, which had previously been in limbo.

As part of the regulatory controls, all "tobacco products" must follow certain general controls, such as registration, product listing, ingredient listing, good manufacturing practice requirements, user fees for certain products and adulteration and misbranding provisions. In addition, as FDA's most recent draft guidance explains, "new tobacco product products" are any tobacco products marketed in the U.S. on February 15, 2007 or modified after February 15, 2007. "Modified-risk tobacco products" are products "sold or distributed for use to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products."

While e-cigarettes were first developed in 2003, many products only made their way into the U.S. market in more recent times, so it is likely that many e-cigarettes will require some form of premarket review or at least a finding of substantial equivalence. Time will tell whether this has been a victory or bane for the e-cigarette industry, but this appears to be a positive step for FDA to prevent certain tobacco-derived products from escaping regulatory oversight, along the lines suggested by several panel members at the Food and Drug Law Institute's Annual Conference earlier this month, as we reported here. For additional information about the Sottera case and FDA's previous attempts to regulate e-cigarettes as a drug/device, see our most recent blog here.

by Erin A. Lawrence

Republican legislators want to know exactly how Michigan's research universities are using stem cells. In order to do so, the a requirement of absolute transparency with stem cell projects was tied to the higher education funding bill passed last week. The same measurement was tried last year, but failed.

However, despite potential legislative set backs, Michigan recently reached a large milestone in its stem cell research. University of Michigan researchers created the state's first embryonic stem cell lines that carry the genes responsible for inherited disease. This achievement will enable scientists to work on the onset and progression of genetic disorders and to search for new treatments.

Oklahoma and Minnesota, on the other hand, are attempting a full-out ban on embryonic stem cell research, The Minnesota Senate and House of Representatives passed a bill that includes a ban on state or federal funds being used for certain types of stem cell research. This restricted research includes somatic cell nuclear transfer, which is a technique that can be used for the creation of stem cells. Similar to Michigan, Minnesota also added this amendment to the higher education funding bill in the House.

Oklahoma is moving forward to banning embryonic stem cell research. The House of Representatives Public Health Committee passed a bill banning all embryonic stem cell research by a narrow vote. The bill is now set to go to the full House of Representatives. The proposal would prohibit research which would result in the destruction of the embryo and would also make it illegal to "buy, sell, receive, or otherwise transfer" an embryo for such purposes. However transferring an embryo for in vitro fertilization would be excluded from the restrictions.

by Brian Malkin

On April 18, FDA published a Federal Register notice announcing a new final Guidance: How to Write a Request for Designation. This Guidance provides information that FDA's Office of Combination Products ("OCP") recommends that sponsors include in a Request for Designation ("RFD") to help designate a lead center for combination products, i.e., products comprised of one or more of the following: drug, device, or biological. RFDs should be submitted before any investigational or marketing application to avoid additional review delays and have relatively short review periods--5 days to review if complete, and 60 calendar days after filing to designate a lead center. This Guidance replaces an earlier Guidance issued on in August 2005.

Combination products are reported to be on the rise--up 24% when comparing fiscal year 2008 to 2009. John Weiner, Associate Director for Policy in FDA's OCP told The Pink Sheet (April 25, 2011), "We hear that combination products is the fastest growing segment of medical products . . . We've been sending them [RFDs] back more . . . One important issue is to explain how the product works. It may seem obvious, but very often an important question in deciding how to classify a product is, 'How does it achieve its effect, physically, chemically, mechanically?'"

While the Guidance goes in more detail, some chief considerations to include in the RFD include: (1) a sufficient description of the product and its intended marketing, (2) prior approvals and agreements for included components, (3) chemical, physical, or biological composition and manufacturing, (4) developmental work and testing, (5) proposed use or indications, (6) modes of action and primary mode of action and assignment algorithm, (7) schedule and duration of use, (8) dose and route of administration, (9) related products and other relevant information, and (10) sponsor's recommendations. RFD determinations may be contested via a request for redetermination that is reviewed and acted upon within 15 calendar days of receipt. FDA expects to issue final rules on good manufacturing practices and adverse event reporting for combination products sometime after this fall.

by Andrew S. Wasson

ViroPharma's suit against FDA was dismissed by the United States District Court for the District of Columbia due to a lack of standing on April 15, 2011. ViroPharma sued FDA in September 2010, seeking a declaratory judgment that FDA violated the Administrative Procedure Act ("APA") by allegedly adopting new bioequivalence standards without conducting notice-and-comment rulemaking (see previous blog here). FDA moved to dismiss under Sections 12(b)(1) and 12(b)(6) of the Federal Rules of Civil Procedure on the grounds that the court lacked subject matter jurisdiction because of "lack of standing and ripeness and that the plaintiff has failed to state a claim upon which relief can be granted."

ViroPharma Complaint Dismissed

At root, ViroPharma objected to what it perceived as FDA's emerging, less-stringent bioequivalence standards for locally-acting GI drugs. In FDA's response to Cobalt's Citizen Petition for Precose® (acarbose), FDA found that in its discretion it could accept in vitro studies under 21 C.F.R. § 320.24 to support bioequivalence (rather than requiring only in vivo studies). The implication, of course, was that FDA would take the same stance with regard to ViroPharma's own locally-acting gastrointestinal ("GI") product Vancocin® (vancomycin). Indeed, in 2006, FDA published draft bioequivalence guidelines (still not finalized) for Vancocin® which allowed generic applicants to submit in vitro data. Currently, eleven generic applicants have filed against Vancocin®, however, FDA has not approved any application to date.

The District Court for the District of Columbia determined that ViroPharma lacked standing despite alleged (1) future lost profits from generic competition and (2) current harms to ongoing business operations. With regard to the first alleged harm, the Court found that ViroPharma must show that it "substantially probable" that FDA's actions will cause harm in the form of lost profits due to generic competition. FDA countered, however, that ViroPharma would not suffer such an injury unless FDA actually approves a vancomycin ANDA or the approval was based on the disputed interpretation of the regulations. The Court agreed with FDA, finding that it could not assume that FDA would ultimately approve any of the filed ANDAs, and that even if it did, that such approval would be based on the challenged interpretation. Finally, the Court dismissed standing based on the alleged current harms as being "highly nebulous in both character and degree" and a "far cry" from the required "concrete and compartmentalized" injury required for standing. Therefore, the Court granted FDA's motion to dismiss.

It is interesting to note that in so ruling a number of core issues remain unaddressed. The court did not address the appropriate bioequivalence standard for vancomycin or other locally-active GI drugs (although it is unlikely that the Court would have gotten to this issue even if ViroPharma had standing). Also unaddressed, and more interesting from an administrative law perspective, was FDA's latitude in determining its standards of review. On the one hand, FDA needs the ability to update decisions based on new technology and circumstances. On the other hand, stakeholders need some amount of stability in order to act and to justify investment. It is a delicate balance. But whether that balance was reached in this situation will be a question put off for another day.

by Brian Malkin

On April 19, President Barack Obama announced a new action plan: Epidemic: Responding to America's Prescription Drug Abuse Crisis. The plan combines efforts from the White House Office of National Drug Control Policy ("ONDCP"), FDA, and the U.S. Drug Enforcement Agency ("DEA") to help educate the medical community about proper prescribing practices. The overall plan supports expanding state-based prescription drug monitoring programs, environmentally-responsible disposal methods to remove unused medications from the home, education for patients and healthcare providers, and reducing the number of "pill mills" and doctor shopping through greater enforcement.

FDA's component involved updates to FDA's website Opioid Drugs and Risk Evaluation and Mitigation Strategies (REMS) including a new list of long-acting and extended-release opioid drug products required to have a REMS, a Post-Approval REMS Notification Letter to holders of applications for innovator or generic drug products in the new list, a Questions and Answers document about the new requirements, and a consumer-friendly Consumer Health Information article describing how this fits into the new initiative. According to FDA Commissioner Margaret A. Hamburg, M.D., "Opioid drugs have benefit when used properly and are a necessary component of pain management for certain patients, but we know that they pose serious risks when used improperly--with serious negative consequences for individuals, families, and communities. The prescriber education component of this Opioid REMS balances the need for continued access to these medications with stronger measures to reduce their risks."

FDA's Letter states that FDA has determined that a REMS is necessary for certain long-acting and extended-release opioid drugs, and "[i]n the interest of public health and to minimize the burden on the healthcare delivery system of having multiple unique REMS programs," a single, shared system should be used by all members in the class to implement the REMS. Within 120 days of the date of the letter, each application holder must submit a proposed REMS including a "REMS supporting document" that must include: (1) training for prescribers to include successfully completing a knowledge assessment and proof of successful program, (2) educational materials for prescribers to use to educate patients in the safe use, storage, and disposal of opioids, (3) information to prescribers of the REMS and need to successfully complete the training, and (4) a timetable for submitting assessments that are no less frequent than 6 months, 12 months, an then annually after an initial REMS is approved.

by Elizabeth Murphy

On April 14, the Department of Justice ("DOJ") announced that prosecutors are re-indicting Lauren Stevens, a former GlaxoSmithKline ("GSK") attorney/executive on "essentially the same charges" originally brought in November 2010. In November 2010, the DOJ indicted Stevens on charges of obstructing an official proceeding, falsifying documents, and making false statements (see our blog post here regarding the original indictment). Judge Titus of the U.S. District Court for the District of Maryland dismissed the case last month, on the basis that prosecutors had incorrectly instructed the grand jury (see our blog here regarding the dismissal). Specifically, prosecutors provided incorrect instructions as to the bearing of Stevens' advice of counsel defense (a key component of her defense strategy) on the probable cause necessary for indictment. Judge Titus' dismissal was without prejudice to prosecution's right to seek re-indictment before another grand jury--an option they have apparently now chosen to pursue.

The charges include one count of obstructing an official proceeding, one count of falsifying documents, and four counts of making false statements. The charges stem from Stevens' role in an investigation commenced in 2002 by FDA into GSK's suspect marketing activities--namely the off-label promotion of GSK's Wellbutrin SR® (buproprion).

Judge Titus ordered a status hearing for April 15 and set a tentative trial date for later this month, on April 26. The outcome of the case may inform future application or success of the advice of counsel defense in these sorts of proceedings, and, correspondingly, the extent to which in-house lawyers may reasonably rely on the advice of outside counsel.

by Elizabeth Murphy

On April 1, FDA issued proposed regulations regarding the mandatory posting of calorie information by certain retail food establishments. The regulations would apply to establishments with 20 or more locations, including for instance chain restaurants, bakeries, coffee shops, snack shops, and some grocery stores. Movie theaters, airplanes, bowling alleys and other businesses primarily engaged in business besides the preparation and service of food would be exempt.

The regulations require covered establishments to prominently and conspicuously display calorie information on menus and menu boards (including menu boards for drive-through food establishments). Additional nutritional information is to be made available upon consumer request.

The regulations will eventually give effect to Section 4205 of the Patient Protection and Affordable Care Act, enacted last year, and aim to address the public health consequences of rising obesity rates in the United States. In a press announcement issued the same day, Department of Health and Human Services Secretary Kathleen Sebelius expressed optimism over the proposal, stating that "[g]iving consumers clear nutritional information makes it easier for them to choose healthier options that can help fight obesity and make us all healthier."

FDA is seeking public comment on the proposed regulations for the next sixty days, and hopes to issue final rules by the end of the year. See our previous coverage of the food labeling guidelines here and here.

by Brian Malkin

On April 13, FDA published a Federal Register notice announcing availability a new draft guidance entitled, "Safety Labeling Changes--Implementation of Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act." The draft notice provides guidance how FDA plans to implement new Section 505(o) to the Federal Food, Drug, and Cosmetic Act ("FD&C Act"), which was added by the Food and Drug Administration Amendments Act of 2007 ("FDAAA").

guidance

Section 505(o)(4) authorizes and permits FDA to order, in some cases, labeling changes, if FDA becomes aware of new safety information that FDA believes should be included in a drug's labeling. Section 505(o)(4) also imposes time frames for application holder to provide FDA with these changes and enabled FDA to use new enforcement tools to cause timely and appropriate labeling changes to occur.

Under 505(o), "new safety information" means "information derived from a clinical trial, an adverse event report, a postapproval study (including a study under section 505(o)(3)), peer-reviewed biomedical literature, data derived from the postmarket risk identification and analysis system under section 505(k); or other scientific deemed appropriate by [FDA]" about serious or unexpected drug risks since the drug was approved or a risk evaluation and mitigation strategy ("REMS") was required or following an assessment of the REMS. Typically, this safety information will be included in the following sections of the professional labeling: boxed warnings, contraindications, warnings and precautions, drug interactions, and adverse reactions.

In brief, once FDA learns about new safety information, FDA will first assemble a multidisciplinary team, which may include a representative from the Office of Generic Drugs, the Unapproved Drugs Coordinator, or the Office of Compliance, to evaluate whether the new information should be included in the drug's labeling. FDA will then send a safety labeling notification letter to the affected application holder(s), including generic (and presumably biosimilar, if relevant) applicants.

Once FDA sends its notification letter, the affected application holders have 30 calendar dates from the date the notification letter is issued to respond either with a labeling supplement to address the new safety information or a rebuttal statement, why a labeling change is not warranted based on the information. The guidance then explains the rebuttal process and time frames, a dispute resolution process, and FDA's enforcement mechanisms following a violation of section 505(o)(4) that include unapproved new drug charges, misbranding charges, civil monetary penalties, as well as additional enforcement actions such as seizures and injunctions.
How often and swiftly FDA begins to implement the guidance will be interesting to watch in light of the recent preemption cases that have recently included generics, as most recently reported here.

by Andrew M. Nason

On April 12, just two days prior to the bill's scheduled markup, House Judiciary Committee Chairman Lamar Smith (R-TX) offered a Manager's Amendment to H.R. 1249, the America Invents Act, that drew criticism from various industry groups as well as fellow lawmakers.

In a press release issued the day after Chairman Smith introduced the Amendment, the Generic Pharmaceutical Association ("GPhA") called on the House Judiciary Committee to alter or remove the bill's language with regard to the supplemental examination process. According to the GPhA, in its current state the bill "allows patent holders that knowingly falsify information in their original patent application . . . or intentionally omit material information in such filings, a mechanism to retroactively correct their filing without any consequences." In GPhA's opinion, lawmakers can only correct the process by striking the supplemental examination language from the bill entirely, or by amending it to prevent those that knowingly lie to the U.S. Patent and Trademark Office from using it. Until this happens, GPhA has indicated it will maintain its opposition to the bill.

Two Representatives, Mike Michaud (D-ME), and Tom Reed (R-NY), also issued a press release in response to the Manager's Amendment, requesting the incorporation of two provisions into the legislation prior to committee markup. Specifically, Michaud and Reed sought an increase in the threshold requirement for initiating an inter partes examination, and removal of provisions that would encourage stays of infringement lawsuits or U.S. International Trade Commission proceedings following initiation of a post-grant review or inter partes proceeding. According to the two legislators, their amendments would prevent the bill from providing "malicious organizations additional opportunities to misuse the patent system and discourage American innovators," noting that reexamination proceedings are already subject to abuse. The American Federation of Labor & Congress of Industrial Organizations ("AFL-CIO") sent a letter to Chairman Smith and Ranking Minority Member John Conyers (D-MI), expressing concern that the House version of the bill "weakens important safeguards concerning the time limits and standards for initiating administrative proceedings to review a granted patent," and imploring lawmakers to maintain those safeguards.

by Brian Malkin

On April 5, two panels at the Food and Drug Law Institute's ("FDLI's") Annual Conference in Washington, D.C. addressed the current status of FDA's regulation of tobacco products under the Family Smoking Prevention and Tobacco Control Act ("Tobacco Control Act" or "the Act") and ways FDA could improve its regulation and encouragement of new nicotine and modified-risk tobacco products.

The first panel featured FDA's Center for Tobacco Products ("CTP") Director, Lawrence R. Deyton, MSPH, M.D., as well as (1) David B. Abrams, Ph.D., Executive Director, The Schroeder Institute for Tobacco Research and Policy Studies, American Legacy Foundation, and Professor, Department of Health, Behavior and Society, The Johns Hopkins Bloomberg School of Public Health, (2) James E. Dillard, III, Senior Vice President, Regulatory Affairs, Altria Client Services, Inc. and (3) William A. McConagha, Fellow, Majority Staff, Committee on Health, Education, Labor and Pensions, U.S. Senate. The second panel included (1) Scott D. Ballin, Health Policy Consultant, (2) Jane Y. Lewis, Ph.D., Senior Vice President, Tobacco Regulatory and Health Sciences, Altria Client Services, Inc., (3) Brian J. Malkin, Partner, Frommer Lawrence & Haug LLP, (4) David Sweanor, Adjunct Professor, Faculty of Law, University of Ottawa, and Roseann B. Termini, J.D., Med, Professor, Widener University School of Law.

In the first panel, Deyton pronounced that CTP has met all statutory requirements of the Tobacco Control Act under its "forced march," but he admitted that CTP has had "less than ideal" communication with stakeholders, i.e., the tobacco industry, to continue to meet these requirements. Now, according to Deyton, CTP is aggressively reaching out to stakeholders to explain what requirements are in place to foster cooperation and trust. Upcoming CTP actions will include considering recommendations from the Tobacco Products Scientific Advisory Committee ("TPSAC") regarding menthol in cigarettes that we reported on here and here (CTP plans to issue a June update of its initial conclusions.), issuing final rules on graphic health warnings in June 2011, issuing final regulations on substantial equivalence exemptions in July 2011, and a TPSAC report submitted to FDA in March 2012. Deyton said CTP has issued about 100 warning letters and conducted about 2000 retail inspections but has yet to conduct a manufacturer inspection.

With regard to the latter, there was consensus between the first panel of speakers that FDA needs to provide good manufacturing practices ("GMPs") guidance based on the science for the tobacco industry to understand what it will take to comply. Dillard, for example, described the Tobacco Control Act as full of execution challenges for both FDA and industry, suggesting FDA could help by providing clarity, predictability, and transparency. Abrams described TPSAC's proposed menthol ban a human experiment that can be conducted, but Dillard cautioned that it will be difficult to predict what will happen to the market, because it is impossible to pretend that the menthol market (about 30% of the current cigarette market) never existed. A point where the speakers diverged was how FDA should define "tobacco products." Deyton said it was unclear whether certain products, such as dissolvable tobacco, are "tobacco products" under the Act, for example, because the term only appears as part of TPSAC's charge. Abrams, however, suggested that FDA should more broadly consider anything derived from tobacco, including naturally-derived nicotine, to be a "tobacco product," including e-cigarettes.

by Andrew S. Wasson

The Supreme Court is currently considering whether to grant Caraco's petition for certiorari with regard to the Federal Circuit's decision in Novo Nordisk A/S v. Caraco Pharm. Labs., Ltd. in April 2010. In fact, the Supreme Court recently asked the Solicitor General for its view on the matter. I reviewed use code narrative word counts to assay whether use code narrative practice has changed dramatically over the last years and since the Federal Circuit's decision.

The facts in Novo Nordisk A/S v. Caraco Pharm. Labs., Ltd. have been reiterated several times, so there is no need to rehash them here. Briefly though, the NDA holder submits a description of each method of use patent that it lists in the Orange Book (a "use code narrative"). The Hatch-Waxman amendments to the Federal Food, Drug, and Cosmetic Act allow a generic applicant to leave out subject matter from its prescribing information which is protected by patent or exclusivity by filing a statement under subsection viii of Hatch-Waxman. FDA will allow a generic applicant to use this pathway if there is no overlap between the use code narrative and the generic prescribing information. In Novo Nordisk, Caraco failed in its bid to compel Novo Nordisk to change the use code narrative for Prandin® back to its previous version by using 21 U.S.C. § 355(j)(5)(C)(ii). Because FDA does not review these narratives for accuracy, some in the generics industry are concerned that given this unchecked power, the brand could formulate a use code of unsurpassed breadth and could shut down the subsection viii pathway altogether. The Generic Pharmaceutical Association articulated this sentiment when in its amicus curiae brief supporting Caraco's request for en banc Federal Circuit review, stated: "If the panel's ruling stands, Novo's manipulative actions will become a playbook for all brands."

I sought to test this hypothesis by analyzing use code narrative word counts dating back to 2005. The underlying idea is that if brand actors were truly so emboldened by the Federal Circuit decision, it would somehow be reflected in the length of the use code narratives. For example, consider U-1078 ("treatment of acne") with U-917 ("treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris"). The broader use code (and thus more difficult to excise from a generic labeling) would clearly be the former. My results:
Use Code Chart

by Erin A. Lawrence

On March 30, the Supreme Court heard oral arguments, in consolidated cases Pliva, Inc. v. Mensing, Actavis Elizabeth LLC v. Mensing, and Actavis, Inc. v. Demahy, on whether federal drug labeling law preempts state tort claims against generic drug manufacturers for failure to warn of drug hazards. In 2009, the Supreme Court held in Wyeth v. Levine, a 6-3 decision, that federal law did not preempt state tort claims against brand manufacturers for failure to warn. The current case addresses whether generic manufacturers are similarly situated to brand manufacturers so that they are able comply with both federal drug labeling requirements and state tort standards of care.

Jay P. Leftkowitz, of Kirkland & Ellis, argued for the generic drug parties. Generic drugs are required by federal law to have labels that are identical to the brand drug. Generic companies argue that federal law preempts state tort actions because it would require generic companies to offer labeling that is different from the label of a brand name drug. Specifically, Leftkowitz argued his clients are obligated to report adverse events to FDA, but that there was no requirement or mechanism for them to seek label changes. Leftkowitz supported his argument with the Supreme Court's decision in Buckman Co. v. Plaintiff's Legal Committee, which held that injured plaintiffs cannot sue a medical device manufacturer for committing fraud on the FDA. During oral argument, several justices noted that the generic manufacturer's position appeared to conflict with their decision in Wyeth v. Levine.

Justice Sotomayer asked Leftkowitz that if Congress intended to "create a market in which consumers can only sue brand-name products" then "why would anybody ever take a generic [drug]?" Leftkowitz replied that Congress gave different obligations to brand and generic manufacturers. He also reiterated the fact that generic companies did not have a mechanism to change the label.

by Elizabeth Murphy

The European Fine Chemicals Group ("EFCG"), a sector of the European Chemical Industry Council ("CEFIC"), and the Society of Chemical Manufacturers and Affiliates ("SOCMA") have urged FDA to take a more active role in the regulation of foreign API manufacturers. Citing, among other reasons, "[t]he accelerating globalization of the industry," as well as "[t]he slow pace of adjustment by governmental bodies charged with oversight . . .," the comments submitted by EFCG and SOCMA advocate both improvements to the current compliance and oversight regime and a publicly-accessible database that would hold noncompliant entities accountable.

EFCG and SOCMA are lead trade associations in Europe and the United States, respectively. EFCG is a sector of CEFIC, which represents 29,000 companies and accounts for one third of the world's chemical production. SOCMA represents approximately 300 companies and encompasses over 2,000 manufacturing sites. Members of both trade groups manufacture APIs, excipients and intermediates.

FDA recently opened a second comment period in relation to its generic drug user fee plan, which aims to expedite review times for generic drug applicants through the collection of user fees. CEFIC and SOCMA posit that (along those same lines) all API manufacturers, particularly foreign manufacturers, whose products enter the U.S. market should submit to FDA inspections on a regular basis. In order to fund said inspections, FDA should impose registration and inspection fees for all relevant API manufacturers. The proposal further envisions a comprehensive online database that would make GMP certificates publicly available, similar to the EudraGMP database run by the European Medicines Agency.

The proposal aims to promote public safety, but also to level the playing field amongst API manufacturers. Due to the challenges inherent in increased inspections of foreign facilities (see our previous blog on the topic here), API manufacturers are thus incentivized to establish operations in areas where inspections are less frequent. EFCG and SOCMA submit that their proposal "would be a giant step forward in rebalancing the competitive environment." Both trade groups have expressed willingness to comply with the measures they propose.

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by Howard E. Rosenberg, Ph.D.

Guidance has now been provided by the Court of Justice of the European Union ("CJEU") on the first of the two European Supplementary Protection Certificates ("SPC") issues, which we discussed here.

Advocate General Mengozzi delivered his Opinion on the two closely related cases concerning the scope of Article 2 of Council Regulation (EC) No 1768/92 (the "SPC Regulation") and the types of marketing authorization, which could be considered to be "the first authorisation to place the product on the market in the Community" for the purposes of the SPC Regulation.
The opinions concerning memantine (C-195/09) and galantamine (Case C-427/09) can be found by inserting the case number here.

Both drugs had been marketed for many years in one or more member states prior to the later filing of dossiers, which included the full regulatory details and studies that are required under the European Economic Community Directive 65/65/EEC. Galantamine had been on sale in Europe as a medicine for more than 40 years. There were national marketing authorizations as Nivalin® in Austria (1960s) and West Germany (1978). Nivalin® continued to be marketed until its license was withdrawn once the 65/65/EEC compliant registration for Reminyl® was approved. Memantine was on the market in Germany before September 1976 (Akatinol®) and also authorized in Luxembourg. These licences were withdrawn, also, once a 65/65/EEC compliant registration for Ebixa® was obtained.

by Brian Malkin

On March 31, FDA's Food Advisory Committee concluded its two-day hearing with a 8-6 vote that foods that contain synthetic food dyes do not need special warning labels to suggest that the dyes may cause hyperactivity and behavioral problems in some children. FDA had not asked the Committee to consider a ban, reports Gardiner Harris from The New York Times.

During the hearing, commentary lined up as expected. Michael Jacobson, Ph.D., Executive Director of the Center for Science and the Public Interest ("CSPI") asked, "Why are these dyes in foods anyway? I would push for having them taken out completely. But if that can't be done, why not warn the public and parents that these dyes could have some effects?" reports CNN Medical Producer, Val Willingham. Harris reports that Dr. Jacobson, though disappointed by the outcome of the hearing, was encouraged that FDA was starting to acknowledge the debate still exists: "At least FDA is now acknowledging that dyes affect some children. That is a big change."

Industry representatives, however, rallied behind the conclusion, fearful that warnings might unduly alarm consumers without adequate data to substantiate the claims or create a market with less appealing food choices. For example, in a statement, David Schmidt, President and CEO of the International Food Information Council said, "Food colors add to our enjoyment of food by maintaining or improving their appearance. Without sufficient scientific evidence that a causal link truly exists between food colors and hyperactivity in children, communication that suggests a link could have unintended consequences, including unnecessarily frightening consumers about safe ingredients that are consumed every day," writes Health Day reporter Steven Reinberg.

The debate is probably not over, as the Committee said more research was needed in light of the evidence and suggestion by some researchers that hyperactivity may be triggered by artificial food dyes in combination with other factors, such as preservatives, and ongoing consumer concerns. During the public session, CNN reports, parents "from all over the United States" had stories to tell about how their children experienced hyperactivity or behavioral problems when exposed to artificial dyes that appeared to disappear when such dyes were eliminated from their diets.

by Andrew M. Nason

House Judiciary Chairman Lamar Smith, R-Texas, recently unveiled H.R. 1249, the America Invents Act, the long-awaited House companion to S.23. Despite overwhelming support for S.23, the Senate version of the U.S. Patent Reform bill that passed by a margin of 95-5 earlier this month, the House's companion bill could face significant opposition from both sides of the aisle. While the House version bears substantial similarity to its Senate companion--transitioning to a first-to-file system, establishing post-grant review procedures, and providing more fee-setting authority to the U.S. PTO--several key differences have led to early disagreements between lawmakers and industry groups.

For example, the House bill expands prior user rights, which provide a defense against claims of infringement in certain cases for products and processes in commercial use for at least a year. The current system limits the application of prior user rights to the context of business method patents, while the House version of the bill would make such rights applicable to essentially all technological inventions. Rep. Jim Sensenbrenner, R-Wis., worried that expansion of prior user rights could be tantamount to legalizing piracy, calling it a "get out of jail free card" for Chinese intellectual property pirates. Executive Vice President of the Association of American Universities John Vaughn claims such an expansion could severely damage universities' ability to protect their patents, and that companies should be free to choose to develop products via a trade secret route, but should be aware of the risks in doing so. Cisco Systems Inc. Senior Vice President and general counsel Mark Chandler provided the other side of the argument, saying a switch to first-to-file without an expansion of prior user rights would allow challengers to hold companies hostage with bogus claims on improvements to existing products.

Procter & Gamble Co. Vice President and general counsel for intellectual property Steven Miller cited the prior user rights issue among a number of provisions that could lead to stakeholders pulling their support for the legislation. Other provisions Miller said would contribute to discord included the higher threshold set in the bill for post-grant reviews, and provisions limiting venue and establishing a loser-pays regime in the transnational program handling business method patents. Among the squabbling, Chairman Smith called on lawmakers to "maintain a broader perspective if we want to enact a bipartisan, bicameral bill to modernize the patent system." Even if the House bill moves to a vote and passes, differences between the House and Senate versions will necessitate further negotiations regarding the final language in conference. Most experts, however, expect that the bill, in some form, will reach President Obama's desk sometime this year, perhaps within the next few months.

Frommer Lawrence & Haug LLP Partner Brian J. Malkin will speak on several hot topics regarding FDA's regulation of tobacco products--tobacco product classification and reduced risk on April 5 at the Food and Drug Law Institute's ("FDLI's") Annual Conference in Washington, D.C.

Update: FDLI has updated the session details as follows:

Title: Development and Regulation of Tobacco Products, Nicotine, and Alternative Tobacco Products under the Family Smoking Prevention and Tobacco Control Act and Beyond

Under the Family Smoking Prevention and Tobacco Control Act ("Tobacco Control Act"), FDA has broad authority to regulate tobacco products, but cannot ban tobacco products or nicotine. Rather than permit FDA to regulate all tobacco, nicotine, and alternative tobacco products in a single center or as its own group of products, the Tobacco Control Act created a regulatory scheme that fragmented these products into different FDA centers of responsibilities-tobacco products, drugs, foods, or combinations of these products. Recently, FDA has faced challenges determining how to classify and regulate e-cigarettes and will undoubtedly face more challenges with definitions created by the Tobacco Control Act such as "cigarette" or "tobacco product", as the tobacco industry creates hybrid products, such as cigarillos, or new products including noncombustible tobacco products, such as dissolvable tobacco. During this thought-provoking session, the panelists will create a dynamic forum for the audience to listen and react to concerns raised by the panelists about the Tobacco Control Act and its effect on the development and regulation of tobacco, nicotine, and alternative tobacco products and proposals for how FDA may address these issues in the coming months and years. In particular, the panel will raise issues about how FDA and Congress can better address the public health concern to develop more reduced risk tobacco, nicotine and alternative tobacco products, as well cope with the requirements set by the Tobacco Control Act to define limits for harmful constituents in tobacco products and ban or reduce the limit of substances used to make tobacco products more addictive or palatable and thereby encourage new or continued use.

Please check back here for additional updates regarding the agenda for this upcoming program.

by Andrew S. Wasson and Jennifer A. Hardy

On April 1, KV announced that it was slashing the price of Makena® from $1,500 to $690 per injection (54%). But will the price cuts be enough? While KV defended the new price, in a strongly-worded press release, the American College of Obstetricians and Gynecologists called the price cuts "inadequate."

The price cut comes on the heels of FDA's March 30 announcement that it will not pursue enforcement action against pharmacies that continue to compound hydroxyprogesterone caproate (recently approved as the branded product Makena®--see our previous story on this here) based on valid prescriptions as long as the compounds remain safe and are compounded in accordance with existing standards. In many cases, FDA will exercise "enforcement discretion" with respect to products made through traditional pharmacy compounding. Often, however, if a manufacturer reclaims an unapproved drug by completing clinical trials and obtaining FDA approval, FDA may signal that it will no longer refrain from enforcement, especially if there are marked differences between the FDA-approved product the compounded product. Indeed, renewed enforcement reinforces the motivation of manufacturers, because it allows them to more fully enjoy the benefits of exclusivity. If FDA announces that it will no longer exercise enforcement discretion, the FDA-approved product is the only game in town. Here, the extremely high price of Makena® seems to have put FDA in a difficult position.

FDA's announcement comes after weeks of public outcry regarding FDA's decision to grant KV Pharmaceuticals ("KV") a seven-year term of exclusivity under the Orphan Drug Act. The price of the injectable compound, which used to sell for $10 to $20 a dose, skyrocketed to $1,500 a dose, costing around $30,000 per pregnancy. KV justified the price by stating that they invested heavily in the development and efficacy studies. However, as FDA pointed out in their press release, the research KV relied upon to prove effectiveness was funded by the National Institutes of Health--not KV themselves.

FDA's decision has been praised by pregnancy advocates, women's groups and members of Congress such as Senator Sherrod Brown (D-OH). KV's price cut appears to be part of the promised reassessment it announced last week.

By Howard E. Rosenberg, Ph.D.

The Securities and Exchange Commission ("SEC") charged an FDA chemist with insider trading on confidential information that was privy only to the FDA. The trading consisted of using information about pending FDA approval decisions, which were not yet public, to deal in advance in 19 publicly-traded companies. This netted more than $3.6 million in illegal profits and avoided losses.

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Information obtained concerned announcements with respect to FDA's approval or negative decision for new drugs. In each instance, the trade was in the same direction as the ultimate announcement. The chemist, Cheng Yi Liang, went to great lengths to hide what he was doing by having several different trading accounts. Liang had been working this scheme since 2006.

"Liang victimized both the investors who were disadvantaged by his theft of inside information and the American citizens whose trust he violated by placing private gain above public good," said Robert Khuzami, Director of the SEC's Division of Enforcement. Daniel M. Hawke, Chief of the SEC's Market Abuse Unit, added, "The insider trading laws apply to employees of the federal government just as they do to Wall Street traders, corporate insiders, or hedge fund executives. Many government agencies like the FDA routinely possess and generate confidential market-moving information. Federal employees who misappropriate such information to engage in insider trading risk exposing themselves to potential civil and criminal charges for violating the federal securities laws."

Liam's focus was on biotech stocks, which are often dramatically affected by FDA decisions. The SEC alleges, in one example, that Liang traded in advance of an FDA announcement approving Clinical Data's application for the drug Vibryd®. Liang accessed a confidential FDA database that contained critical documents and information about the FDA's review of Clinical Data's application, and then used that information to purchase more than 46,000 shares of Clinical Data at a cost of more than $700,000. After the markets closed on Friday, January 21, 2011, FDA issued a press release approving Vibryd®. Clinical Data's stock price rose by more than 67 percent the following Monday, and Liang sold his entire Clinical Data position in less than 15 minutes for a profit of approximately $380,000.

The SEC's complaint alleges that Liang violated Section 17(a) of the Securities Act of 1933, and Section 10(b) of the Securities Exchange Act of 1934 and Rule 10b-5 hereunder, and seeks a permanent injunction against future violations, disgorgement of unlawful trading profits and losses avoided plus prejudgment interest, and a financial penalty.

Frommer Lawrence & Haug LLP Partner Brian J. Malkin will moderate a panel on a hotly-debated issue concerning biosimilars, "Ascertaining the Type and Volume of Clinical Data Necessary to Establish Biosimilarity" on June 8 at the American Conference Institute's Biosimilars Conference in New York City One of the key objectives of the Conference is to understand how FDA plans to implement the new biosimilar pathway, created by the Biologics Price Competition & Innovation Act ("BPCIA"). FDA Lawyers Blog maintains a Resources page on Biosimilars and has been following this issue from its inception and hopes that by the time of the Conference, FDA issues its anticipated guidance on biosimilars, as a follow up to its hearing on November 2 and 3, 2010.

ACIBiosimilars2011

by Brian Malkin

FDA's Tobacco Products Scientific Advisory Committee ("TPSAC") Report and Recommendations on the Public Health Impact on Menthol Cigarettes ("Menthol Report") is barely a week old (see our blog with the Menthol Report here), yet no one seems happy with TPSAC's conclusions. Below are some of the first set of comments that have surfaced.

FDA invited industry to comment or issue their own report on menthol in cigarettes. Two separate industry reports were prepared--one from the tobacco industry representing the non-voting industry members on the TPSAC and other tobacco industry stakeholders and a separate report from Altria. The main industry report requested that the TPSAC follow the Surgeon General's causality framework rather than the "speculative" framework adopted by the TPSAC, which, according to the report, would lead to conclusions that the evidence is inadequate to infer a causal relationship or suggestive of no causal relationship for all of the questions the TPSAC was asked to address with regard to menthol in cigarettes, which we previously reported on here. As a result, the industry report concludes that FDA should take no action regarding menthol in cigarettes. The report further concludes that if a ban were imposed on menthol cigarettes, there would be "severe negative impacts" on the public health, including increased exposure to contraband cigarettes, increased youth access to tobacco, increased criminal activity, reduced government revenues, and loss of jobs. Altria's report follows a similar framework with slightly different conclusions but the same overall conclusion that FDA should take no regulatory action or initiate restrictions on the use of menthol in cigarettes. Altria further recommends that FDA use its authority under the Tobacco Control Act ("Tobacco Control Act") to reduce harm from cigarettes, including menthol cigarettes.

In contrast, a TPSAC Shadow Panel formed by Drs. Michael Siegel and Adam Blum finds that TPSAC's Menthol Report "bends over backwards to acknowledge the input of the tobacco industry and the 'non-voting members of the committee'" and should have been more definitive that there is a causal relationship between menthol acting as an anesthetic agent to make smoking more appealing and masks the harshness of burning tobacco. The Shadow Panel, further, issued its own "report" calling for the "elimination of the use of menthol in cigarettes." The Shadow Panel calls the TPSAC Menthol Report "weak-willed" and a "disappointment" that should have added menthol to the other banned characterizing flavors used in cigarettes. The Shadow Panel criticized FDA's actions following the Tobacco Control Act to date, recommending that FDA direct resources to an aggressive anti-smoking campaign to help prevent youth smoking and encourage adult cessation, and that FDA determine whether "safer" tobacco products are even feasible by reducing harmful constituents or adding additional ingredients.

We previously reported that Lorillard Tobacco Company and R.J. Reynolds Tobacco Company had sued FDA and the Department of Health and Human Services, charging them with assembling a biased TPSAC in an attempt to block FDA "receiving or relying on" TPSAC's recommendations in the Menthol Report and otherwise. On March 21, Lorillard and Reynolds amended their complaint, providing exhibits allegedly supporting their charge that they had put FDA on notice that the TPSAC was biased and FDA's response to date.