FDA Lawyers Blog

by Erin A. Lawrence

On November 16, FDA filed an amicus brief at the 6th Circuit's invitation in the consolidated appeals of Smith v. Wyeth, Inc. (Case No. 09-5460), Wilson v. Pliva, Inc. (Case No. 09-5466), and Morris v. Wyeth, Inc. (Case No. 09-5509). The issue on appeal is: "Whether federal law preempts a tort claim under state law that a generic drug approved by the Food and Drug Administration was inadequately labeled." FDA's position is that "failure-to-warn claims against manufacturers of generic drugs are not categorically preempted by federal law." Interestingly though, FDA filed a contrary amicus brief in 2006 for another case, Colacicco v. Apotex, advocating that state-law claims were preempted by federal law. However, FDA withdrew its opinion following the Supreme Court's decision in Wyeth v. Levine and after Obama's democratic administration took office.

The Wyeth cases concern the drug Reglan® (metoclopramide), which is indicated to relieve symptoms caused by slow stomach emptying in people who have diabetes. Plaintiffs assert that the drug was defective because the brand and generic drug manufacturers failed to adequately warn that long-term use of metaclopramide could result in tardive dyskinesia--a neurological disorder. The District Court dismissed the case, holding that plaintiffs' failure-to-warn claims were categorically preempted by federal law. The Court reasoned that generic drug manufacturers could not comply with Federal law--the Hatch-Waxman Amendments to the Federal Food, Drug, and Cosmetic Act in particular--if they were liable under state-law for failure-to-warn, because Federal law requires generic drugs to have identical labeling to the brand drugs.

FDA contends that the District Court's decision is therefore contrary to already-existing case law. For instance, the Supreme Court in Levine held that Federal Law does not pre-empt plaintiffs' claim that a drug or medical device manufacturer failed to give an adequate warning. However, the District Court distinguished Levine from the current case, because Levine involved a claim against a brand drug--not a generic drug--and, therefore, involved different regulatory provisions. Other court of appeals cases decided after Levine, held that Federal Law governing generic drugs does not preempt state law failure-to-warn cases against generic drugs. See Mensing v. Wyeth, 588 F.3d 603 (8th Cir. 2009); Demahy v. Actavis, 593 F.3d 428 (5th Cir. 2010). FDA also opined that although federal law may proscribe remedies in failure-to-warn cases, these cases are categorically preempted, because failure of a generic drug company to petition the FDA to change a warning label could be an actionable negligence.

by Howard E. Rosenberg, Ph.D.

On November 26, the European Union ("EU") decided to ban bispenol A ("BPA") in baby bottles starting March 2011 and ban sale from June 2011. A majority of EU governments backed this decision, despite the World Health Organization ("WHO") stating earlier this month that taking any public health measures to ban or control BPA would be premature since evidence of its alleged health risks is not strong enough. Canada, however, has already added BPA to its list of toxic substances.

An international panel of 30 experts was organized by WHO jointly with the Food and Agriculture Organization of the United Nations, with the support of the European Food Safety Authority, Health Canada, the U.S. National Institute of Environmental Health Sciences, and FDA. They reviewed the latest studies on the impact of BPA, which has been linked to serious health problems such as prostate and breast cancer, even though BPA is mostly eliminated through urine and doesn't accumulate in the body.

"There were areas of uncertainty, deriving from new studies, which showed that BPA might have an effect on development, immune response and tumour promotion," said John Dalli, EU commissioner in charge of health and consumer policy, in a statement. Dalli added that the decision was "the result of months of discussion and exchange of views between the Commission's services, the European Food Safety Agency (EFSA), the member states and the industry."

Consumer organizations welcomed the EU's decision to ban BPA from baby bottles. But manufacturers of the chemical pointed to a September opinion by the European Food Safety Authority (EFSA), in which the majority re-confirmed existing safe limits for BPA intake. Several U.S. states have banned BPA, and FDA's interim approach has been to recommend reducing exposure.

by Elizabeth Murphy

On November 18, the Senate failed to vote as planned to approve the Food Safety Modernization Act, despite speculation that passage of the legislation was imminent. Just one day prior, the Senate had agreed to limit debate on S. 510, the bill that would strengthen FDA oversight of food manufacturers across the country, in hopes of passing the legislation on to President Barack Obama before the end of the lame-duck Congressional session.

The House passed its version of the bill (H.R. 2749) over a year ago, largely in response to a Salmonella outbreak linked to contaminated peanuts. The Senate's version of the bill was introduced after a massive egg recall by the FDA this year. If the Senate were to pass its version, the two houses would normally still have to convene a conference committee in order to draft a unified version of the bill. In this instance, however, the House has agreed to approve the Senate's version of the bill for approval by President Obama.

The food safety bill has generally received wide support from the industry, as well as consumer safety advocates. In response to concerns that such sweeping regulations might put small-scale food manufacturers and producers at a disadvantage (see, for example, here), an amendment introduced by Sen. Jon Tester (D., Mont.) would exempt small, locally-distributing farms and food processors with annual sales under $500,000 from the new rules.

by Andrew M. Nason

The patent reform bills before Congress (S. 515 and H.R. 1260) seek in a number of ways to reduce patent litigation costs and improve the quality of issued patents. One such proposal involves implementing a post-grant review (PGR) proceeding to allow third parties to attack patents at the U.S. Patent and Trademark Office concurrently with, or instead of, litigation. As proposed, a challenger can bring a PGR proceeding on nearly any invalidity ground, obtain limited discovery and adjudication by an administrative patent judge, and obtain a relatively quick decision (the proceedings are designed to last no more than 12 to 18 months). While this may reduce patent litigation costs and improve patent quality in general by providing a less expensive alternative to litigation, as well as a mechanism for further review, litigants may not utilize widely such proceedings in the context of Hatch-Waxman litigations.

Primarily, the timeframe for post-grant review proceedings does not correspond to the timeframe for Hatch-Waxman litigation. FDA grants five years of market exclusivity to patent holders who list their patents in FDA's Orange Book. As proposed in H.R. 1260, a challenger must bring a PGR proceeding within 12 months of a patent's issuance. Generics producers, however, cannot file an ANDA until at least four years into the drug product's five-year period of FDA-granted market exclusivity. Additionally, the potential estoppel effects may discourage generics challengers from using PGR proceedings as a way to challenge a patent's validity.

In addition to the limited timeframe and the potential estoppel effects inherent in PGR proceedings, any successful post-grant challenger would have to share such success with other generics competitors. Generally, a generic-drug challenger would like to prevail on noninfringement, leaving the patent intact as an obstacle to later generic applicants. The same challenger may not want to invalidate the patent in a PGR proceeding and thereby open the door to any generics producer to compete freely in the open market. Thus, while the availability of PGR proceedings likely will have a substantial effect on the dynamics between patent holders and their competitors, it likely will play only a limited role in the context of litigations brought under the Hatch-Waxman Act.

This is the third and final (for now) part of a continuing series on proposed patent reforms and the potential effects on abbreviated new drug application (ANDA) litigants and litigation. Part 1 on the first-inventor-to-file system may be found here. Part 2 on supplemental examinations and inequitable conduct may be found here.

by Howard E. Rosenberg, Ph.D.

On November 9, the Government Accounting Office (GAO) released a report, "Food and Drug Administration: Response to Heparin Contamination Helped Protect Public Health: Controls that Were Needed for Working with External Entities Were Recently Added". The report was requested by House Energy and Commerce Committee Ranking Member Joe Barton (R-Texas). Among other things, GAO's report finds that FDA worked with several external scientists during the heparin crisis but failed to address certain risks to the agency for engaging two "volunteer" scientists that responded to oral requests for uncompensated services by FDA's Center for Drug Evaluation and Research ("CDER") staff.

According to FDA, it sought the advice of external scientists, because the agency felt it lacked the necessary instrumentation and expertise to identify and develop new testing methods to detect the specific contaminant issues. Both these volunteers, however, had professional and financial ties to heparin firms. They served as paid consultants to two of the primary firms associated with contaminated heparin. In addition, one of the scientists was a co-founder and member of the board of directors, as well as an equity interest holder, in a third firm, which, at the time of the crisis, had a pending application for a heparin product before FDA. This scientist obtained assistance from this third firm, which dedicated approximately 30 staff members for periods ranging from a few weeks to 3 months to assist in the effort to identify the contaminant in heparin. Although GAO's report does not identify any of the firms or individuals by name, it appears that the latter company is Momenta Pharmaceuticals ("Momenta"), whose co-founder and board member Ram Sasisekharan and co-founder and chief scientific officer Ganesh, Venkataraman co-authored several articles on heparin contamination with FDA officials in 2008, as reported by The Pink Sheet, on November 10.

FDA officials were aware of the scientists' ties to heparin manufacturers, but GAO's report pointed out that FDA did not take adequate steps to consider whether these relationships exposed the agency to the risks before engaging them, such as consulting with the Office of Chief Counsel, agency ethics officials, or following procedures described in FDA's The Leveraging Handbook. FDA believed that there was insufficient time to address these ties in the midst of the crisis and that the CDER staff could independently assess the input from these scientists through robust, detailed, and transparent discussions.

by Elizabeth Murphy

On November 9, the Department of Justice ("DOJ") announced that a former vice president and associate general counsel at GlaxoSmithKline ("GSK"), Lauren Stevens, had been indicted on charges stemming from an FDA investigation into GSK's drug marketing practices. The indictment charges Ms. Stevens with a total of six counts: one count of obstructing an official proceeding, one count of concealing and falsifying documents, and four counts of making false statements to FDA. The first two counts carry a maximum penalty of 20 years in prison, and the latter two five years for each false statement.

FDA's investigation began in 2002, when FDA became aware of GSK's marketing of Wellbutrin SR® (buproprion) for unapproved uses. Wellbutrin SR® had only been approved for the treatment of depression in patients over the age of 18, but GSK had allegedly been marketing the drug for, among other unapproved uses, weight loss and obesity. Ms. Stevens was in charge of cooperating with the FDA in its investigation and was less-than-forthcoming in her responses.

For instance, FDA requested presentation materials from a number of GSK-sponsored promotional events from 2001-2002. In response, Ms. Stevens contacted approximately 550 of the 2,700 speakers from these events. She received presentation materials from around 40 speakers, and informed 28 of them that their presentations were in violation of FDA policy, as they promoted off-label uses. Rather than forward the presentation materials to FDA, however, Ms. Stevens allegedly acted on the advice of a "nationally prominent law firm retained by her employer" (according to a statement by Ms. Stevens' lawyer) and failed to disclose the materials.

by Laura Fanelli

On November 8, Congressional investigators announced that they are conducting an investigation into the operations of FDA's Puerto Rican district office. A letter announced the investigation to FDA Commissioner Margaret Hamburg from Edolphus Towns and Darrell Issa on behalf of the House of Representatives Committee on Oversight and Government Reform.

The letter expressed the Committee's concern that "FDA's Puerto Rico district office may be having difficulty exercising oversight on the numerous pharmaceutical manufacturing facilities on the island." The letter indicates that these concerns stem from recent problems at manufacturing plants on the island. Recently, manufacturing problems at McNeil Consumer Healthcare, LLC's Puerto Rico facility led to an unusual "silent recall" of Motrin® (ibuprofen). Subsequently, GlaxoSmithKline signed a $750 million settlement with the Department of Justice following whistleblower allegations of good manufacturing violations at the firm's Cidra, Puerto Rico facility.

The Committee suggests in the letter that the Puerto Rico district office is not "adequately staffed to fulfill the agency's mission of securing the Nation's pharmaceutical supply." Additionally, in order to determine whether the office is fulfilling its regulatory responsibility, the Committee requested specific information from FDA, including all warning letters and inspection reports issued by the Puerto Rico office since 2000, an office organizational chart, and a status update on the investigation into the Motrin "silent recall." FDA must provide the Committee with this information by November 17, 2010.

FLH's Scientific Advisor Howard E. Rosenberg, Ph.D will present on Supplementary Protection Certificate (SPC) cases: Generics (UK) Ltd. v. Synaptech and Synthon v. Merz Pharma at the Royal Society of Chemistry Law Group, Seminar on Recent Chemistry Case Law - Patents. The Seminar will be held at the Royal Society of Chemistry, Burlington House, Picadilly, London. Event details may be found here.

by Erin A. Lawrence

On November 10, FDA released 36 proposed warning labels. The images are designed to cover half of the surface area of the front and back of packs and cartons of cigarettes and to cover a fifth of cigarette advertisements. The labels contain graphic pictures and text that says, for example, "Smoking can kill you" or "Cigarettes are addictive." FDA Commissioner, Margaret Hamburg, said, "We need to make sure that anyone who is considering smoking fully appreciates the consequences of cigarette use." According to the proposed rule, cigarette manufacturers will no longer be allowed to distribute cigarettes without the graphic warnings as of October 22, 2012.

Smoking is a grave concern with striking statistics. There are about 46 million smokers in the United States--20.6 percent of adults and 19.5 percent of high school students. Approximately 443,000 people die every year from smoking-related health problems. About 49,000 people die each year because of second hand smoke. It is estimated that 30 percent of all cancer deaths are related to tobacco use. Tobacco use is the leading cause of premature and preventable death nationwide. Smoking is also a fiscal burden on the United States. According to the Center for Disease Control, the United States spends around $193 billion a year on healthcare expenses and decreased productivity and an additional $10 billion on healthcare expenses related to second-hand smoke.

Canada, Europe, and other countries already require graphic warning labels on cigarette packs and cartons. Studies suggest that graphic warnings make smokers more likely to quit and adolescents less likely to start. In Canada, graphic warnings contributed to a five percent drop in the smoking population. Smokers now account for only 13 percent of the Canadian population--down from 18 percent of the population.

FDA hired a company to survey 18,000 smokers to determine which labels would be most effective. The 36 proposed labels will be narrowed to nine by June. The tobacco companies will not be allowed to pick their preferred label--they will be required to allocate all nine warnings evenly among products.

Some cigarette companies argue that the warning label requirement infringes the companies' Constitutional rights to free speech and due process. This issue was litigated and decided on January 4, 2010 in the Western District of Kentucky in a case called Commonwealth Brands, Inc. v. United States. The court held that a blanket ban on color and graphics in tobacco labeling and advertising was overly broad and that prohibiting tobacco companies from labeling products as FDA regulated was unconstitutional. However, the court also held that Congress and FDA could constitutionally ban tobacco companies from sponsoring events, require more conspicuous labeling, ban introduction of modified-risk tobacco products without FDA approval, and ban outdoor advertising, free samples, and gifts with purchases. The case is being appealed to the Sixth Circuit.

by Charles J. Raubicheck

The United States Department of Agriculture (USDA) wants to re-approve genetically-modified sugar beets on a short timetable, to allow seeds to be planted during the 2011 growing season. The new effort, published on November 2 with 30 days for comment, seeks to overcome a recent Federal court decision mandating an environmental impact statement (EIS) before this genetically-modified organism (GMO) crop can be planted next year (see our previous blog here). Industry voices concern that 60% of the nation's sugar beet supply will be affected by the ban.

GMO sugar beets are genetically engineered to withstand adverse effects of the weed killer Roundup, which is sold to farmers along with the beet seeds. Environmental groups argue that similar "Roundup Ready" crops have led to increased use of herbicides, proliferation of herbicide resistant weeds, and contamination of nearby conventional and organic crops.

USDA advocates a plan for a permit system with strict controls to minimize the possibility for the escape of plant pests that could contaminate non-GMO crops. The department announced that it has issued a draft environmental assessment, but it is not as comprehensive as the full EIS ordered by the court. Stay tuned.

by Howard E. Rosenberg, Ph.D.

FDA is charged with ensuring the safety of imported products, including food and medical products. FDA's oversight of imported products includes inspecting foreign manufacturing establishments and examining imported products at the U.S. border. FDA-regulated imported products arrive from more than 200 countries and territories, and the volume of these imports more than tripled from 1998 to 2008, according to a September 2010 Government Accountability Office (GAO) report. In 2009 there were 20 million line entries of FDA-regulated product that crossed U.S. borders whereas ten years ago, there were just 6 million. This is around 100,000 shipments each working day. These shipments include 40 percent of the finished drugs, 80 percent of the active pharmaceutical ingredients, the majority of the seafood, and large quantities of the fresh fruits and vegetables in U.S. supermarkets.

Incidents of illness and death caused by contaminated food and medical products highlight FDA's challenges in ensuring the safety of these imported goods. For example, in 2008, FDA began an investigation after receiving reports of serious adverse events in people receiving heparin sodium, a commonly used blood thinner. The agency later learned that an active pharmaceutical ingredient found in this drug contained a contaminant and had been manufactured at a Chinese establishment that had never been inspected by FDA. The Kansas City Star recently ran an article which stated that dietary supplements, without proper regulation, are pouring in from China and that consumers can not tell where imported drugs and dietary supplements are made, because country-of-origin labeling laws are not being enforced.

Back in November 2007, it was recommended that FDA establish a field presence in key foreign locations. FDA subsequently launched an initiative to establish five overseas offices covering particular countries or regions--China, Europe, India, Latin America, and the Middle East. FDA developed a proposal to establish these overseas offices in May 2008. As of July 2010, most of the offices had opened and each of these had posts in multiple locations. There was a total of 42 staff assigned to these overseas offices, of which 24 staff was posted in the countries and they had, in addition, 14 locally employed staff in India, China, and Latin America.

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By enacting the Prescription Drug User Fee Act (PDUFA) in 1992, Congress gave FDA authority to charge drugmakers fees to review and renew New Drug Applications (NDAs) or Biologics License Applications (BLAs). By statute, the money collected under PDUFA is used to speed up the review and renewal process.

A recent FDA proposal would expand agency review to include four phases. The proposed four-phase review includes an "administrative phase" for filing and validation activities before the review clock starts and an "information sharing phase" during the review where sponsors could meet with FDA to discuss the application and submit an amendment to address issues identified during FDA's review. According to FDA, "[t]his proposal is intended to increase mid-cycle communication between sponsors and the agency while reducing the need for multiple review cycles."

According to minutes released by FDA from a recent PDUFA reauthorization negotiation session held October 25, 2010, the idea of incorporating a four-phase review process has been dropped.
Four-phase review is widely believed by industry to be unworkable due to the time required for the additional phases of review. Industry representatives from Pfizer, Biotechnology Industry Organization, Johnson & Johnson, and the Pharmaceutical Research and Manufacturers of America, suggested that the information sharing phase may not be needed for applications with few matters requiring further discussion, or those likely to receive a complete response from the agency.

by: Erin A. Lawrence

On October 25, FDA announced that it has collected information and submitted it to the Office of Management and Budget to review and clear that is directed to minimizing food-safety hazards in fresh-cut fruit and vegetables. FDA was spurred to collect the information due to the increased consumption of fresh-cut fruits and vegetables and the heightened potential for foodborne illnesses and reported foodborne illnesses. Prior FDA recommendations for fresh-cut fruits and vegetables are found in the "Guide to Minimize Microbial Food Safety Hazards of Fresh-cut Fruits and Vegetables."

The recommendations are based on the "current state of science" and the application of Hazards Analysis and Critical Control Point (HACCP) principles or similar programs to the processing of fruits and vegetables A HACCP program indicates inherent risks and their occurrence to allow food processors to take steps at critical production points to control those risks. The recommendations are designed to minimize microbial food safety hazards common to the processing of most fresh-cut fruits and vegetables that are sold to customers in a ready-to-eat form. FDA pledged to work closely with state and local governments and operators of restaurants, grocery stores, and other food service establishments to help prevent illness from contaminated food.

FDA expects to issue a proposed rule on the safe production, harvesting, and packing of produce in 2011. To help develop training an educational materials related to the new agency requirements, Cornell University will house a public-private program aimed at providing growers and packers with the most current, science-based food risk and safety information. The new program is called the Produce Safety Alliance. It is a $1.15 million partnership that is funded by FDA and the U.S. Department of Agriculture's Agricultural Marketing Service.

by Andrew M. Nason

The patent reform bills before Congress (S. 515 and H.R. 1260) seek to reduce patent litigation costs and improve the quality of issued patents. For example, the new law would enable a patent owner to request supplemental examination of their patents prior to litigation. Proponents believe the supplemental examination provision would strengthen patents due to further examination and would also reduce the litigation costs, as patent owners surviving supplemental examination would gain immunity to later charges of inequitable conduct.

Currently, generic drug manufacturers commonly plead inequitable conduct--sometimes called fraud on the patent office--as an equitable defense in Hatch-Waxman litigations, especially those involving patents claiming a drug compound. The defense can render a patent unenforceable, if a judge determines that the patent owner intended to deceive the U.S. Patent and Trademark Office ("Patent Office"), or misrepresented or did not provide the Patent Office with material information. The judge then has discretion to balance these two factors to determine whether the court equitably should enforce the patent. The new law would allow patent owners to avoid this equitable defense entirely, if they have requested supplemental examination prior to litigation. Patent owners cannot, however, wait until a generic challenger points out the inequitable conduct; they must act first to avail themselves of the benefits of supplemental examination.

The Generic Pharmaceutical Association (GPhA) has acknowledged that this provision could significantly reduce the availability of inequitable conduct as a defense for generic challengers under the Hatch-Waxman Act. GPhA also believes that this provision could negatively impact the market for affordable generic medicines by increasing brand companies' "incentive[s] to be dishonest and cheat." After all, brand companies could exempt themselves from charges of inequitable conduct simply by deceiving the patent office twice instead of once.

This is part 2 of a continuing series on proposed patent reforms and the potential effects on abbreviated new drug application (ANDA) litigants and litigation. Part 1 on the first-inventor-to-file system may be found here.

by Howard E. Rosenberg, Ph.D.

A case in Estonia involving a Novo Nordisk advertisement in a medical journal for Levemir® (insulin detemir [rDNA origin] injection) may help to broaden the types of claims pharmaceutical manufacturers can make in the European Union ("EU"). Levemir® is a man-made long-acting insulin that is used to control high blood sugar in adults and children with diabetes mellitus. Novo Nordisk included three claims not present in its Summary of Product Characteristics (SPC): (1) Levemir® offered effective control of blood sugar with a low risk of hyperglycemia; (2) 68% of patients who took the drug did not gain, but rather lost weight; and (3) 82% of patients in clinical studies were given an injection of Levemir® each day.

The Estonian Medicines Agency Office of Drugs (Ravimiamet) objected to the advertisement as contradicting the SPC, which stated: (1) hyperglycemia was the most common side effect of Levemir®, (2) weight gain was insignificant or nonexistent in a comparative study with another type of insulin, and (3) Levemir® could be administered once or twice a day. The case (C-249/09) has been escalated to the Advocate General of the Court of Justice of the EU (CJEU, formerly the ECJ). Ravimiamet noted that this violated European Community (EC) DIrective 2001/83, which is very particular as to what can be written in advertisements both to the general public and to medical practitioners. A key requirement in Article 87 states...all parts of the advertising of a medicinal product must comply with the particulars listed in the summary of product characteristics...advertisements should encourage the rational use of the medicinal product, by presenting it objectively and without exaggerating its properties...and should not be misleading."

Advocate General Jaaskinen accepted that it should be illegal to quote in an advertisement new developments and scientific results going beyond the information included in the SPC, such as Novo Nordisk did, since there is a procedure specifically provided for updating this information to health authorities, i.e., by way of submitting variations to the product license. In such a case, it would be unjustified to allow such information to be included in advertising to professionals without the authorities having given their permission.

by Laura Fanelli

In 1976 when the Bioresearch Monitoring (BIMO) program first began, most FDA audits of clinical trials were real-time, occurring while the clinical investigation was in progress. However, "[o]ver time, inspections began to be application-focused" said Leslie Ball, Director of Scientific Investigations for FDA's Center for Drug Research and Evaluation (CDER), as reported by FDA News Clincal Trials Advisor (Oct. 28, 2010). Real-time audits were conducted only "for cause" in response to a reported problem.

Presently, FDA has decided to switch back to its original practice. The agency will once again conduct real-time audits of clinical trials, instead of waiting until after it receives an approval application for a drug or device. However, so far only a few real-time inspections have occurred that were not "for cause." FDA is searching for a suitable Phase III clinical trial to conduct a real-time audit, Ball said.

This change in practice will have a material impact on sites. Contract research organizations and sponsors will want to "partner with sites that have an infrastructure and commitment to meeting this new regulatory environment and process," said Christine Pierre, President and CEO of Rx-Trials, as reported by FDA News Clincal Trials Advisor (Oct. 28, 2010).

Although, a potential drawback is that sites may have less time to plan for an audit, according to FDA the real-time inspections are not meant to catch anyone by surprise. Rather, FDA is upholding its responsibility to ensure that the rights, welfare, and safety of human subjects are promoted, along with the caliber and integrity of research data.

by Brian Malkin and Andrew S. Wasson

FDA held round two of its public hearing on the implementation of the Biologics Price Competition and Innovation Act yesterday. Many of the debates spawned on the first day of the meeting bled into the second day, with FDA continuing to mull issues like the European biosimilar experience, the issue of product drift, and appropriate naming conventions. The speakers continued to raise a number of unique and novel viewpoints. The following are a few of the highlights:

1) The FDA panel queried many of the speakers on whether they had encountered problems in the European context. Indeed, most speakers were hard-pressed to specifically identify safety problems created by the European framework, although many pointed to a lack of quality data on the matter.

2) Nomenclature continued to occupy much of the conversation. During Day 1 of the meeting, some of the more biosimilar-friendly speakers maintained that the current system (based on National Drug Code (NDC) numbers and lot numbers) would be sufficient for pharmacovigilence purposes moving forward. The counter-position that took root on the first day but more fully blossomed on the second day was that NDC numbers were too foreign and unwieldy to be reliably referenced by patients in reporting adverse events.

3) iBio, Inc. provided another model of biosimilarity for FDA to consider: clinical data should supersede physiochemical differences between biosimilar products and the products that they reference. The speaker from iBio noted that biosimilars may use different manufacturing processes--some arguably better than the innovator's original process--that would introduce differences in physiochemical structure of the underlying molecule, which may not be clinically significant.

by Elizabeth Murphy

On October 26, the Department of Justice announced that GlaxoSmithKline ("GSK") had agreed to pay $750 million to settle civil and criminal claims stemming from adulterated drug products manufactured at their Cidra, Puerto Rico facility. Of the $750 million, $150 million constitutes a criminal fine for violation of the Federal Food, Drug, and Cosmetic Act. The remaining $600 million addresses the federal civil claims that originally gave rise to the action under the False Claims Act. The government will use the $600 million to settle healthcare fraud claims filed against government programs such as the TRICARE program, the Federal Employees Health Benefits Program, the Department of Veterans' Affairs, and state Medicaid programs.

The GSK action initially began as a qui tam, or whistleblower, action brought under the federal False Claims Act in 2004 by a former employee at the (now-closed) Puerto Rico facility. Cheryl Eckard, a former Quality Assurance Manager and plaintiff in the original action, claimed that the company had ignored her complaints regarding quality issues at the facility and fired her when she reported the issues to FDA. Under the qui tam provision of the Federal Claims Act, an individual (whistleblower) who discloses fraud on the government may share in the amount recovered. As a result, Ms. Eckard was awarded approximately $96 million of the $600 million in civil claims award.

The GSK settlement is noteworthy in that it is the first pharmaceutical healthcare fraud settlement to result from claims under the False Claims Act alleging current Good Manufacturing Practice (cGMP) violations. Additionally, the settlement is fourth largest amount ever paid by a pharmaceutical company to settle criminal and civil claims relating to the manufacture and distribution of contaminated drugs.

by Brian Malkin and Andrew S. Wasson

Day one of FDA's two-day public hearing to obtain input from interested stakeholders in FDA's implementation of the approval pathway under the Biologics Price Competition and Innovation Act ("Biosimilars Act") included a clash of viewpoints regarding whether FDA should create a pathway for interchangeable biosimilars and ended in a surprise announcement of new legislation. FDA's first day pitted patient treatment groups, academic-affiliated groups, pharmacies, and several heavy-hitters in biosimilars (Pfizer and Teva) against each other in an attempt to gather opinions a wide variety of opinions. The following comments include a few of the more thought-provoking elements from the meeting.

Beginning the day with patient treatment groups, representatives from the Immune Deficiency Foundation, Arthritis Foundation, offered opinions that while there may be cost savings in biosimilars, FDA should set high hurdles for biosimilars to be interchangeable and there should be no automatic substitution even for interchangeable biosimilars, given the complexity of biologics such as immunoglobulins. On the other hand, the American Academy for Pediatrics, presented a viewpoint that if the bar is set too high, then there will be less incentive for research with children, because the six-month pediatric exclusivity benefits would be negligible in light of the 12-year exclusivity.

Academic-affiliated groups presented several models for demonstrating biosimilarity, including both analytical methods such advanced spectroscopy methods as well as clinical models that involved surrogate pharmacodynamic endpoints, cross-over and parallel studies, and bridging data. While the new analytical technologies appeared impressive and may be valuable tools, it remains to be seen whether they can meaningful assay the structure of a biological product in the body. That being said, neither FDA nor any of the commenters addressed the more fundamental question about the nature of similarity--what does it mean for two products to be "similar" or "highly similar".

Others cautioned that it may be unethical to conduct duplicative clinical studies including bridging studies comparing the innovator to biosimilar, given the likely treatment groups for biologics that typically involves terminal patients or patients with serious diseases such as cancer. Because the European Medicines Agency (EMA) has already reviewed many of the likely first-time biosimilars in the U.S., some suggested that FDA should simply adopt the EMA's previous licensed biosimilar decisions to avoid duplicative studies. FDA appeared interested in maintaining its autonomy though recognizing manufacturers may want to design global studies that met both European and U.S. standards.

by Mark P. Walters

On October 25, Amphastar Pharmaceuticals, Inc. ("Amphastar") sued FDA over FDA's decision to detain imported raw material used to make a generic form of Lovenox® (enoxaparin sodium), the blockbuster, heparin-based blood thinner sold by Sanofi-Aventis SA. Heparin is an anticoagulant that prevents the formation (or growth) of blood clots. Heparin-based drugs are used to treat several conditions, including deep vein thrombosis, atrial fibrillation (abnormal heartbeat), and acute coronary syndrome (decreased blood flow to the heart).

Amphastar's complaint alleges that FDA wrongfully detained a required starting material for its production of generic Lovenox®, a "semi-purified heparin" produced in China by Amphastar's wholly owned subsidiary, Amphastar Nanjing Pharmaceuticals, Inc.

Since 2008, FDA has detained and seized heparin imports from China based on fears of contamination. China is the world's leading supplier of raw heparin, which is produced from pig intestines. According to a 2008 Associated Press article, "[t]iny family-run workshops near slaughterhouses send batches of raw ingredients to larger middlemen before they reach factories . . . FDA has not yet inspected those workshops, saying that was something under discussion with Chinese officials."

Amphastar's complaint is the latest in a long-running dispute with FDA concerning the drug maker's ANDA referencing Lovenox®. Amphastar filed its original application in 2003. Teva Pharmaceutical Industries Ltd. followed the same year. Two years later, Momenta Pharmaceuticals Inc. and its partner Sandoz, part of Novartis AG, filed. On July 23, 2010, FDA approved the Momenta-Sandoz generic. Amphastar has accused the FDA of bias toward Momenta. Amphastar also accuses FDA of scheduling more than a dozen inspections, specifically to harass the company.

Amphastar's lawsuit seeks declaratory relief that "FDA's actions . . . are contrary to federal law and regulations," and/or that FDA has "acted arbitrarily and capriciously in its application of federal law and regulations." Amphastar's complaint also seeks injunctive relief in the form of an order directing FDA to lift its ban on the import of heparin raw material.

by Andrew M. Nason

Both houses of Congress have proposed broad reform of the U.S. patent system (S. 515 and H.R. 1260) with the goals of reducing patent litigation costs and risks, improving overall patent quality, and harmonizing the U.S. patent system with those of foreign countries. On this last point, the U.S., in contrast with every other country in the world, operates under a first-to-invent system rather than a first-to-file. The suggested reforms would more closely align the U.S. with the rest of the world by adopting a first-inventor-to-file system.

Under current U.S. law, an inventor who files a patent application later than another inventor for the same invention may still win a priority contest by proving in an interference proceeding that he or she actually made the invention first. This invention date also determines the priority date for invalidating prior art under 35 U.S.C. § 102. Only prior art predating the priority date can invalidate an otherwise patentable invention. The proposed changes will eliminate the need for costly and time-consuming interference proceedings, but they will also limit the scope of certain prior art. Notably, § 102(g) prior invention art will no longer exist.

The shift to a first-to-file system incentivizes obtaining the earliest possible filing date, and thus will increase pressure on innovator companies quickly to obtain substantiating data and file patent applications for their inventions. Generic competitors will later seize on any opportunity to demonstrate that the innovator filed the application prematurely, i.e., without any credible utility for the claimed invention. Generic manufacturers will not welcome, however, the potential loss of § 102(g) prior art defenses. The Hatch-Waxman Act provides the generic industry with a route to accelerated market entry in exchange for taking the risk of challenging potentially invalid patents on brand-name pharmaceuticals. Any limitation on the defenses available for invalidation will limit the number of challenges brought by generic manufacturers, which could have a significant negative impact on the overall generic market.

by Howard E. Rosenberg, Ph.D.

The Italian Government, after having carried out a thorough revision of the current regulations, has amended the Italian IP Code ("IPC"). The new IPC was issued on August 13, 2010 and entered in force on September 2, 2010.

Italy's prior national Supplementary Protection Certificate ("SPC") law enacted before the European Union (EU) SPC law, included clause Art. 61(5) IPC. This clause provided that it "allowed" applicants to file a Marketing Authorization (MA) application, e.g., generic or hybrid applicaitons, up to one year before the expiry of the SPC--implying that an earlier filing would infringe the SPC and, by analogy, also the patent.

Recent case law in Italy had concluded, however, that the simple filing of a market authorization does not constitute evidence of an infringing activity (Court of Milan June 11, 2009, Eli Lilly v. Synthon and others). This decision complies with the Article 10(6) of the Directive 2004/27/EC of the EU.