FDA Lawyers Blog

by Erin A. Lawrence

Eariler this month, three pharmacy chains and a wholesaler--CVS, Rite-Aid, Arthur's Pharmacy, and Louisiana Wholesale--petitioned the Supreme Court to review the legality of pay-for-delay settlements. Specifically, the petitioners cited a Second Circuit decision, from April, where the Court upheld the legality of a pay-for-delay deal, where Bayer Pharmaceuticals paid Barr Pharmaceuticals to drop its challenge to a patent covering the blockbuster antibiotic Cipro®. Pay-for-delay deals occur when a generic drug manufacturer agrees not to market its drug before the expiration of the branded drug's patent in exchange for money--thereby delaying the introduction of generic rivals onto the market.

The petitioners challenged the Supreme Court to answer the question: "whether, absent patent fraud or sham litigation, a brand drug maker's substantial payment to a competing generic drug maker to forgo judicial testing of the patent and restrict entry is per se lawful under the Sherman Act." The petitioners argued that such settlements are "antithetical" to the purpose of the Hatch-Waxman Act, that they violate fundamental antitrust principles, and that this issue is of "enormous public importance" and, therefore, should be considered by the Supreme Court.

The Federal Trade Commission ("FTC") has argued against pay-for-delay settlements for years stating that these deals are anti-competitive, because they delay the entry of lower-cost medicine into the market. The Chairman of the FTC, John Leibowitz, speculated, in a recent speech, that banning pay-for-delay settlements would save consumers $35 billion dollars in 10 years. However, the FTC has unsuccessfully lobbied Congress to enact legislation to restrict the pay-for-delay settlements. And further, appellate courts have not been aligned with the FTC. With the exception of a 2003 Sixth Circuit decision, other appellate courts have rejected the FTC's argument that pay-for-delay settlements are per se illegal. See Schering-Plough Corp. v. Federal Trade Commission, In re Tamoxifen Citrate Antitrust Litigation.

You can read more about developments in pay-for-delay in our blogs here (December 16), here (August 3), and here (May 10).

by Brian Malkin

On December 20, FDA announced an initiative to help curb the number of illegally-marketed animal drugs. Illegally-marketed animal drugs are not approved under approved new animal drug applications ("NADAs"), conditionally approved, or indexed. Animal drugs include injectable vitamins, topical solutions, shampoos. liniments, electrolyte and glucose solutions, anti-infectives, and antidotes. FDA's first steps were to publish a Notice in the Federal Register ("Notice") and launch a new FDA Internet page explaining the problems concerning unapproved animal drugs.

FDA's Notice requests public comments for how FDA can increase the number of legally-marketed animal drugs. FDA would prefer drug companies to legally-market animal drugs pursuant the Federal Food, Drug, and Cosmetic Act but is now open to new approaches to ensure more legally-marketed drugs are available to veterinarians, animal producers, and pet owners. For instance, FDA could exercise enforcement discretion for essential unapproved animal drugs, assuming that drug companies are working to obtain legal means to market these drugs. In the Notice, FDA suggests that it could establish a monograph process for some animal drugs, as it has done for over-the-counter drugs. Another proposal in the Notice is for FDA to proactively review the published literature and issue Federal Register notices containing FDA's review of the scientific literature and suggested data to include for NADAs. While FDA may consider human food safety standards, the agency may need to make more stringent standards for food-producing animals.

According to the Notice, comments are due by February 18, 2011. Comments are not limited to new approaches but may also include suggestions for which types of animal drugs may be appropriate for FDA's own suggested methods outlined in the Notice and described above.

by Howard E. Rosenberg, Ph.D.

On December 14, the European Commission presented a proposal opening the way for "enhanced cooperation" to create unitary patent protection in the European Union ("EU"). For many years the EU has been attempting to reach agreement for a single European patent. This proposal should not be confused with patents granted by European Patent Office ("EPO"), which cover all EU member countries as well as other countries not part of the EU. The sticking point has always been over languages and translations.

Despite various pressures for an EU patent, no agreement has been reached, but now several countries have banded together to try and circumvent the impasse. Under the EU Treaty, the "enhanced cooperation" mechanism allows nine or more countries to move forward in a particular area if no agreement can be reached by all EU members within a reasonable period. To date, the twelve countries that have requested the single EU patent are Denmark, Estonia, Finland, France, Germany, Lithuania, Luxembourg, the Netherlands, Poland, Slovenia, Sweden, and the United Kingdom. Member states can opt to join at any stage of the process.

The advantages of an EU patent are that it will provide just one patent covering this group of states, unlike the EPO patent, which results in separate patents in each contracting state, where the patent has to stand or fall in each state separately (no single EU judicial system). For example, if there were one EU patent, one court decision revoking this patent would revoke the patent in all the participating EU countries designated. It is also assumed that this one patent would reduce costs for small-to-medium sized firms in comparison to the current costs to obtain an EPO patent.

A lot of work needs to be done, however, to ensure the proposed "Enhanced Partnership" among the EU patent offices and the EPO results into a workable system. There is currently an attempt to set up a European court with jurisdiction over existing European patents (EPO). However, the Court of Justice of the European Union ("CJEU") first needs to decide on the legality of this proposal, and in July of this year, the CJEU Advocate General Juliane Kokott, whose job it is to advise the Court, opined that the court plans in their current form were incompatible with the European Treaties. While the CJEU does not always follow the advice of its Advocate General, the prospects for a European patent litigation system do not look rosy. It may be that these problems could be more readily overcome for a single EU patent, but what are the consequences if only part of the EU subscribe to the new EU patent?

At the end of the day will companies prefer to put all their eggs in one basket with an EU patent or stick with the EPO? And what transitional rules will there be to ensure there aren't two patent systems in force at the same time!

by Andrew S. Wasson

As the holiday season is upon us, it may be opportune to familiarize yourself with the medicinal or toxic effects of the flora characteristic of this time of year.

Mistletoe (Viscum album): It may not be surprising to learn that mistletoe, meaning "all-healer" in the Druid language, has long been reported have medicinal use. While mistletoe's true usefulness is controversial because of a lack of controlled clinical studies, mistletoe extract is marketed as Iscador and Helixor for the treatment of cancer in Europe (but not the United States). Others have reported that mistletoe can cure an entire range of ailments, from regulating blood pressure to reducing fatigue. Do not be tempted to try out the benefits of mistletoe by chewing a sprig or two because unrefined mistletoe is toxic to humans and pets.

Poinsettia (Euphorbia pulcherrima): Although poinsettia is commonly believed to be highly poisonous, its purported toxicity is nothing but a myth created by a case of mistaken identity in 1919. That being said, its taste has been described from "disgustingly bitter" to "indescribably awful." It is reportedly useful for pain relief, antibacterial, and emetic purposes, although it does not appear widely used.

American Holly (Ilex aquifolium): The red berries of the European Holly are said to have purgative, emetic, and diuretic properties. Holly teas made from holly leaves were apparently quite popular in the United States during the Civil War. The desired caffeine content can apparently vary depending on the type of holly used.

Fraser Fir (Abies fraseri): The Fraser Fir abounds with medicinal uses. For example, the Cherokee Indians were reported to use Fraser fir as a "panacea" employing it to treat lung pains, kidney trouble, internal ulcers, colds, venereal disease, and constipation. The resin itself was used externally on fresh wounds as well as adjunctively with other medicines.

With that, the writers of FDA Lawyers Blog warmly wish you and your family a very happy holiday season and a safe, healthy, and prosperous 2011!

by Elizabeth Murphy

On December 17, Representative Henry Waxman (D-CA), along with three other House Democrats, introduced H.R. 6543, the Drug Safety Enhancement Act of 2011. The proposed legislation would allow for increased FDA surveillance and regulation of the global drug market. In particular, H.R. 6543 would grant FDA mandatory recall authority, increase FDA funding to carry out inspections of overseas facilities, require parity between overseas and domestic facilities (FDA currently conducts far less inspections overseas than it does domestically.), create a registry of all facilities manufacturing drugs bound for the U.S., block entry of drugs into the U.S. that lack necessary safety documentation (or whose manufacturers refuse to comply with FDA standards), prohibit false reporting of information to FDA, and require manufacturers to document their own quality control procedures.

The bill's co-sponsors cite an increasingly globalized supply of drugs to the U.S. as well as a recent series of contamination issues stemming from foreign-manufactured drugs as compelling reasons for the proposed legislation. In remarks regarding a discussion draft of H.R. 6543 made in September, the bill's co-sponsors specifically referenced the heparin incident of 2008, whereby contaminated heparin from a Chinese facility resulted in 80 deaths. "We cannot continue to allow foreign manufacturers to produce drugs for the American people without granting the FDA strong regulation authority and enforcement tools over these entities," said Representative and co-sponsor Bart Stupak (D-MI).

HHS has already taken steps toward increasing FDA oversight of foreign manufacturers, establishing in 2008 a set of offices overseas. Despite the agency's efforts, however, the foreign FDA offices have exerted limited supervisory influence over the foreign entities thus far. A September 2010 GAO report discusses a host of challenges in regulating drug manufacturers abroad, particularly in China and India. For more information regarding the GAO report, see our blog here.

The fate of H.R. 6543 is unclear. The bill is currently sponsored by four House Democrats: Representatives Waxman, Dingell, Pallone and Stupak. With Republicans poised to take over the House next session, the absence of a Republican sponsor or Republican support may prove to be problematic for the bill. H.R. 6543 has been referred to the House Committee on Energy and Commerce.

by Brian Malkin

On December 9, FDA's Office of New Drugs Director John Jenkins, spoke out about FDA's view of the future of risk evaluation and mitigation strategies ("REMS") at an FDA-CMS Summit for Biopharma Executives sponsored by the publisher of The Pink Sheet (The Pink Sheet, December 9 and 20). Jenkins outlined FDA's vision of "plug-and-play" REMS elements that could be standardized for specific drugs. Jenkins reportedly said, "Plug-and-play doesn't mean that everything's the same, it means that it's compatible . . . its interoperable."

Based on these reports, Jenkins appears to believe that FDA currently does not have much control over what risk management elements are selected by new drug application ("NDA") holders, when a product is first approved. Following approval, moreover, FDA can ask a company to impose certain risk management elements but can only withdraw a product from the market, if an NDA holder does not want to comply with FDA's wishes.

Jenkins further said that FDA wants to be able to mandate a single, shared risk management program across a class of drugs, such as what FDA has been working towards for the opioid drug class, which is preferable to the other option of about 20-30 different REMS for the current opioid products on the market. Speaking to the audience, Jenkins indicated that there are pharmacy payment computer systems that may be helpful in the REMS standardization effort to facilitate payments and REMS program information for specific products. FDA also plans to reduce the number of Medication Guide-only REMS to reduce some of the REMS workload for pharmacists, who have a spotty record for distributing the mandated information.

by Mark P. Walters

On December 13, the U.S. Government, in a joint brief filed by the Solicitor General and the Department of Justice, and Teva, in a separate brief, urged the Supreme Court not to grant certiorari to Apotex's petition for writ of certiorari regarding 180-day, generic drug forfeiture under Federal Food, Drug, and Cosmetic Act ("FD&C Act") (21 U.S.C. § 355(j)(5)(D)). As reported in our previous blog, Apotex filed its petition, arguing that based on "unilateral" action by the holder of the challenged patent to delist a patent from the Orange Book, Teva had forfeited its 180-day exclusivity.

Apotex's petition followed a final decision by the D.C. Circuit, where the Circuit Court rejected Apotex's challenge to Teva's claim of market exclusivity, following a long-running battle over Merck's decision to delist U.S. Patent No. 5,608,075 ("the '075 patent") from Cozaar® ((losartan potassium)'s entry in the Orange Book. Merck's decision to delist the '075 patent led FDA in 2009 to take the position that market exclusivity had been forfeited under the plain language of the statute.

The Government agrees with Apotex that the D.C. Circuit erred, when it held that Merck's unilateral action, delisting a patent subject to a paragraph IV certification and allowing such a patent to expire for nonpayment of fees, may serve as basis for forfeiture of the first ANDA applicant's presumptive 180-day period of marketing exclusivity. Notwithstanding this error, the Government claims that "FDA has applied the MMA's forfeiture provisions on only a few occasions, and the D.C. Circuit is the only court of appeals to have construed those provisions." As a result, argues the Government, "[i]f future controversies materialize, they are likely to be heard by another court of appeals, giving the Court greater assurance that the question presented is of recurring significance and the legal issues have fully percolated in lower courts."

Taking a decidedly different approach from the Government, Teva argues that Apotex's petition should be denied because it is moot. According to Teva, Apotex's complaint sought only prospective relief challenging Teva's entitlement to 180-day marketing exclusivity. And since Teva's 180 days of exclusivity have come and gone, Teva claims that Apotex "can't turn back time," and there is thus no case or controversy left for the Court to resolve. Teva further argues that this case "would be a poor vehicle to address the question it purports to present, because it arises in the interlocutory context of a preliminary injunction proceeding." In any event, argues Teva, the D.C. Circuit got it right, "because Apotex's interpretation of the statute would allow brand companies to manipulate the exclusivity incentive despite the absence of any suggestion in the text, history, or structure of the statute that Congress intended to give brand companies that power."

by Elizabeth Murphy

On December 19, the Senate passed the Food Safety Modernization Act yet again, by unanimous consent. This marks the second time in a month the Senate has passed the bill: the Senate passed S.510 just a few weeks ago, on November 29. The bill passed last month, however, contained an unconstitutional glitch: a provision for levying fees preempted the House' exclusive tax-writing authority.

Congress is rushing to enact the Food Safety Modernization Act before the close of the lame duck session. The bill would increase FDA regulation of the food industry, with the exception of certain areas currently regulated by the U.S. Department of Agriculture. The legislation was drafted in response to a number of food contamination outbreaks in recent years.

The House is expected to approve the most recent incarnation of the Senate's version, having already passed the bill twice before (once in 2009 and again this month). Once it clears the House, President Obama will likely sign the bill into law. See our previous blogs outlining the saga here and here and here.

by Howard E. Rosenberg, Ph.D.

In a letter dated December 15, FDA warned makers of dietary supplements to police themselves and their suppliers and distributors, to ensure that drugs are not included in their products and to follow current Good Manufacturing Practices (cGMPs). The agency asked five trade organizations to do the same. FDA told the makers and distributors of dietary supplements that there are hundreds of products on the market that illegally contain drugs or compounds which act as drugs. Generally these supplements are labeled for weight-loss, bodybuilding and "sexual enhancers" and are illegal, because they contain known pharmaceuticals or similar chemicals, which effects on humans have not been studied or because they contain drug claims.

Although FDA actions have included recall of supplements and referral of companies for criminal prosecution, FDA believes the problem is still not being solved. The origin of the questionable supplements usually is not known, but many of the products come with Chinese writing, suggesting that they are made in China. Most of the questionable supplements are sold over the Internet. Federal law requires that supplement makers be responsible for marketing a safe product and for them to be manufactured to cGMP. The manufacturers don't have to prove the safety or effectiveness of their products.

Following the introduction of the Dietary Supplement Regulation Bill in 2007, the Indian SME segment has been finding it difficult to enter the U.S. market. Owing to this regulation, which requires the products are manufactured to cGMP, the U.S. dietary supplement market is dominated by the large players from India who have already invested in the high level of manufacturing and quality control that the regulation requires. cGMP compliance has up until now been viewed as cumbersome and an expensive exercise for these SMEs. Coincidentally, a recent article in Pharmabiz.com (Dec. 10, 2010) stated that the U.S. dietary supplement market is valued at $25 billion and that Indian Small and Medium Enterprises (SMEs), specializing in the manufacture of raw materials for dietary supplements, are eyeing this as a big opportunity. They are gearing up to obtain the mandatory certifications.

In view of latest FDA's concerns, it appears that self-policing will not be enough to ensure that dietary supplements are both free from illegal substances and routinely manufactured to cGMP.

by Erin A. Lawrence

On December 10, the U.S. Supreme Court granted certiorari in a case determining whether generic drug companies can be sued under state law over allegations of failure to provide adequate warning labels. The issue is whether the state law is preempted by federal law requiring that generic drugs include the same packaging insert as the brand company. The 8th Circuit Court of Appeals allowed the case to go through deciding that federal law did not preempt state failure-to-warn claims against generics. The Supreme Court ruled in 2009 that failure-to-warn claims were permitted against brand-name drug-makers.

The Supreme Court will likely hear arguments in March or April regarding whether failure-to-warn claims are permitted against generic drug-makers. The decision is expected before the end of June.

by Andrew M. Nason

The debate over the Transportation Security Authority's ("TSA's") new X-ray scanners has quieted somewhat since the Thanksgiving holiday, but with Christmas around the corner, it may heat up once again. Along with privacy concerns associated with government officials viewing essentially naked images of the traveling public during the screening process, concerns remain over the safety of TSA's new scanning technologies. TSA has remained steadfast in its position that both variations of its new machines--those using backscatter x-rays as well as those using millimeter wave technology--pose at most a miniscule risk. FDA says the X-ray machines emit a radiation dose roughly equivalent to the radiation people expose themselves to in 42 minutes of every day living, and that "no known adverse health effects" are associated with millimeter wave technology.

Most scientists and researchers agree in general with TSA's safety claims. Dr. Richard Morin, a radiation specialist at the Mayo Clinic in Jacksonville, Florida, called the levels of radiation emitted by both machines "pretty much insignificant." At least one scientist has questioned, however, the need to use technology that poses any risk at all when a risk-free alternative exists. David Brenner, director of Columbia University's center for radiological research, said despite the very low individual risk, factoring in the number of people exposed to that risk, a certain number of people likely will end up with a cancer from the radiation exposure. This might be an acceptable return for air security if an alternative with no known health risk--the millimeter wave machines--did not exist.

Other scientists have criticized TSA and FDA for not demonstrating adequately the machines' safety, and called into question comparisons between the scanners and other types of radiation. A group of doctors and scientists from the University of California, San Francisco ("UCSF") wrote a letter to President Obama's chief scientific advisor indicating that the machines may pose more danger than anticipated because of the different type of radiation involved. The X-rays in the TSA scanners, unlike other radiation, operate at low beam energies, which means they deliver most of their energy to the skin and underlying tissue, not to the entire body. Because the skin and adjacent tissue represent such a small fraction of body weight, the dose to the skin may be one to two orders of magnitude higher than expected from the total radiation emissions.

by Elizabeth Murphy

The Federal Trade Commission ("FTC") may soon exercise its rulemaking authority in its ongoing efforts to curb the anticompetitive effects of "pay-for-delay" patent settlements. "I think that you could see an attempt at the commission this next year . . . to promulgate a rule that essentially shifts the burden over to one who wants to justify a pay-for-delay settlement," stated FTC Commissioner Thomas Rosch at the World Generic Medicines Congress on November 17 (The Pink Sheet, Dec. 6, 2010).

FTC's resort to rulemaking is likely influenced by congressional inaction on the controversial pay-for-delay settlements, where a brand drug company will pay for or otherwise incentivize a generic's delay in bringing its competing product to market. As Rosch discussed in his speech, the House had included a provision in the war spending bill this past summer, which would have given FTC authority to challenge pay-for-delay settlements and made such settlements presumptively anticompetitive. However, the provision failed to make it past the Senate. The Senate had included the same provision in a financial services and government appropriations bill in July, but that bill is also likely to fail, given the recent passage of a continuing resolution to fund the government until September 30 by the House last week.

Additionally, a new Republican House in the next congressional session does not portend progress on the legislative front. "I just don't see the Republicans challenging pay-for-delay the same way that our chairman has wanted to challenge it, which is with every single weapon at our disposal," Rosch theorized in November (The Pink Sheet, Dec. 6, 2010).

by Erin A. Lawrence

On December 6, a three-judge panel of the Court of Appeals for the District of Columbia heard oral arguments on whether the federal government can fund human embryonic stem cell research. Beth Brinkman argued for the U.S. Department of Justice ("DOJ"). Thomas Hungar, of the firm Gibson, Dunn, argued for the plaintiffs. Each party's argument lasted about 45 minutes. The judges zeroed in on where stem cell derivation ends and where research begins, and if the two can actually be separated for legal purposes under the Dickey-Wicker Amendment, which banned the use of taxpayer money to derive stem cells from embryos. In August, Judge Royce Lamberth, of the District of Columbia District Court, held that they could not be separated and issued a preliminary injunction blocking funding of human embryonic stem cell research.

Plaintiffs argued that federal funding of human embryo research incentivizes the destruction of embryos and, therefore, violates the Dickey-Wicker Amendment. "Derivation links destruction to research," Hungar argued. The DOJ argued that the government's spending on research is legal, because the government is not paying for the destruction of embryos when the stem-cell lines were created outside of the government. Brinkman stated that embryos would not be destroyed or created for the express purpose of research. The DOJ also argued that without federal support of research, years of progress toward finding cures for diseases and disorders will be lost and scientists will look to other countries such as Singapore and China to continue their work.

For our previous blogs on this topic see here (December 1, 2010), here (September 13, 2010), and here (August 27, 2010).

by Andrew M. Nason

On December 13, President Barack Obama signed into law the Healthy Hunger-Free Kids Act of 2010, which reauthorizes many federal nutrition programs and represents a cornerstone of First Lady Michelle Obama's fight against childhood obesity. The law sets nutritional standards for all food sold in schools for the first time, and increases the meal reimbursement rate for the first time in three decades. Agriculture Secretary Tom Vilsack called it "a very significant day, if not one of the most significant days, in child nutrition perhaps since 1946 when [President Truman enacted] the School Lunch Act."

The Senate unanimously approved the landmark legislation in August, and the House voted 264 to 157 in favor in early December. See our previous blog on this, which includes a copy of the Healthy Hunger-Free Kids Act of 2010, here.

by Howard E. Rosenberg, Ph.D.

On November 30, the European Commission ("EC") carried out unannounced inspections at the premises of a limited number of companies active in the pharmaceutical sector in several Member States. While the EC did not mention what companies were inspected, news reports, such as Bloomberg, indicated that AstraZeneca and Nycomed were among those visited. The Commission apparently had reason to believe that the companies acted individually or jointly to delay generic entry for Nexium® (esomeprazole magnesium), AstraZeneca's product. If confirmed, it could be a potential violation of EU antitrust rules that prohibit restrictive business practices or the abuse of a dominant market position (Articles 101 and 102 of the EU Treaty). The Commission officials were accompanied by counterparts from relevant national competition authorities.

There is no legal deadline to complete inquiries into any anticompetitive conduct. The Commission completed its inquiry into the pharmaceutical sector in 2009. It had concerns that generic pharmaceuticals were being delayed entry to the market by various patent litigation strategies. Earlier this year it was also concerned that patent settlements, while being an effective means to end patent-related disputes and litigation, might prove to be anticompetitive.

AstraZeneca was involved in a previous landmark EU anti-trust case on omeprazole, the predecessor of the active ingredient in Nexium®. Here, AstraZeneca was ordered to pay 60 million euros ($79.5 million), although this was later reduced to 52.5 million euros ($69.6 million). At that time, however, omeprazole was considered to be dominant in the field. It may be that if this action is concerned with the market position of esomeprazole with respect to its dominance, it might not come out the same way in view of the presence now of generic omeprazole and other branded and generic proton pump inhibitors.

ACI Patent Term Adjustment and Patent Term Extension Conference 2011

ACI is pleased to announce its inaugural advanced forum on the "ins and outs" of Patent Term Adjustment and Patent Term Extensions. This conference will take place at the Downtown Conference Center in New York City on January 26-27, 2011. ACI has designed this conference on the "ins and outs" of Patent Term Adjustment and Patent Term Extensions to give you the winning edge on preventing drug patent losses related to these PTO and FDA procedures.

Brian J. Malkin will be on a panel with Mary Till from the PTO addressing the topic of Laying the Groundwork for Patent Term Restoration. The conference will help you:

• MASTER the essentials of PTA from questions of eligibility , calculation, application preparation and redress

• DECIPHER the mysteries of A, B and C-delays

• LEARN to solve the A and B-delay overlap dilemma and B-delay National Stage queries vis-à-vis Wyeth v. Dudas and Japan Tobacco

• AVOID applicant delays and circumvent "failure to engage" findings by the PTO

• NAVIGATE the complexities of PTE in terms of substance and procedure

• COMPREHEND how the key challenges in Wyeth Holdings, Photcure, Lupin and Angiomax will affect PTE determinations in the future

• APPRECIATE how second generation patents and regulatory exclusivities factor into patent term extensions

• EXAMINE the significance of Supplemental Protection Certificates (SPCs) in patent term restoration in the EU

ACI is pleased to offer a discount of $200 to FDA Lawyers Blog readers. Please visit here for further details.

by Brian Malkin

On December 7, the D.C. District Court of Appeals affirmed that Congress authorized FDA to regulate e-cigarettes not marketed for therapeutic uses as "tobacco products" under the Family Smoking Prevention and Tobacco Control Act of 2009 (the "Tobacco Act") rather than as "drug" or "device" products under the Federal Food Drug and Cosmetic Act ("FD&C Act"). FDA retains authority, however, to market all tobacco products--including e-cigarettes--as drugs/devices if marketed for therapeutic uses. See our related blog item on e-cigarettes marketed for therapeutic uses and FDA's related warning letters here.

E-cigarettes are designed to look and feel like conventional cigarettes but do not ignite tobacco leaf products. Instead, they include a vaporizer or atomizer, powered by a battery and controlled by a sensor and microcomputer chip, which heats and vaporizes fluid in a cartridge containing various chemicals. These chemicals often include liquid nicotine derived from natural tobacco plants.

Last year several e-cigarette manufacturers challenged FDA's jurisdiction over e-cigarettes by filing a lawsuit to lift FDA's import ban on e-cigarettes as drugs/devices or that FDA's action to detain e-cigarette imports without inspection was improper. On January 14, a federal district judge for the District of Columbia granted the e-cigarette manufacturer's motions for a preliminary injunction to prevent FDA from detaining or refusing admission of e-cigarette imports. FDA appealed and won a stay of that ruling with pending oral arguments that occurred on September 23. One of the original plaintiffs, Smoking Everywhere, Inc. later dismissed its claims against FDA, leaving only NJOY.

The D.C. Appeals Court agreed with the reasoning presented by Smoking Everywhere and NJOY in the lower court that the Supreme Court ruling in Brown & Williamson prevented FDA from regulating e-cigarettes as drugs/devices without claims of a therapeutic effect. The court decided that the regulatory gap identified in that case was solved by the Tobacco Act, which broadly defines tobacco products as "any product made or derived from tobacco." Because e-cigarettes often contain nicotine, which is derived from tobacco, and NJOY's products are not marketed for therapeutic uses, FDA has authority under the Tobacco Act to impose the necessary restrictions on the products to reduce public harm, such as advertising and manufacturing restrictions, the appellate court said.

While FDA's ban successfully prevented individuals from receiving e-cigarettes, FDA may have lost valuable time regulating e-cigarettes under the Tobacco Act. For example, tobacco product manufacturers have already provided FDA with information about their products and constituents. The Tobacco Act provides FDA with the authority to regulate but not ban tobacco products.

by Elizabeth Murphy

On December 8, the Food Safety Modernization Act moved a small step closer to enactment. In a 212-206 vote, the House passed the Senate's version of the bill (S. 510), folded into a year-end federal budget bill. This is the second time the House has passed a version of this legislation. The House originally passed H.R. 2749 in 2009, and the Senate passed its version, S. 510, last week (see our previous blog here). S. 510, however, unconstitutionally preempted the House's tax-writing authority. Rather than further jeopardize chances of the Act's passage by the end of the lame duck session, the House adopted the Senate's version without conference.

Although the version passed by the House on Wednesday does not allow for the same degree of FDA oversight as originally envisioned by H.R. 2749, at least some legislators took the view that the weaker version would nonetheless improve upon the current state of affairs. "Sometimes you have to accept a change you may not favor," stated Rep. Henry Waxman (D-CA), chair of the House Energy and Commerce Committee. "But, to go without this bill would be irresponsible." (as reported by Helena Bottemiller, for Food Safety News).

The bill would increase FDA oversight of food production facilities, increasing inspections and strengthening the agency's recall authority, among other things. The Senate is expected to vote on the bill in the next few days. See our other previous blogs on this topic here and here.

by Andrew S. Wasson

On December 8, in a Federal Register Notice FDA called for stakeholders to announce whether they intend to participate in "consultation meetings" to assist FDA in its implementation of user fees for biosimilar products submitted under the Biologics Price Competition and Innovation Act of 2009 ("the BCPI"). This action follows on the heels of FDA's two-day meeting on the implementation of the BCPI which took place in early November. See our previous blogs highlighting the two day meeting for day 1 and day 2. Thus, after several months of radio-silence following the BCPI's passage, FDA appears to be actively engaging the statute.

FDA's current meeting springs from a statutory call to action. In particular, Section 7002(f)(1) of the BCPI relates to the development of user fees for biosimilar biological products. This provision directs FDA to develop recommendations "with respect to the goals, and plans for meeting the goals, for the process for the review of biosimilar biological product applications" for the first five years after fiscal year 2012. The Act requires FDA to convene with the Senate (the Committee on Health, Education, Labor and Pensions), the House of Representatives (the Committee on Energy and Commerce), as well as scientific and academic experts, health care professionals, representatives of patient and consumer advocacy groups and the regulated industry. The BCPI directs FDA to submit its final recommendations to Congress no later than January 15, 2012.

In the Notice, FDA specifically called out its desire to speak with "other stakeholders, including patient and consumer advocacy groups, health care professionals, and scientific and academic experts" about its user fee plans. FDA stated that it had initiated the process of complying with the statutory directive by the November meetings. In addition, however, FDA asked the above stakeholders to "notify FDA of their intent to participate in consultation meetings related to the development of recommendations for a user fee program for biosimilar and interchangeable biological product applications." The Notice did not state when the "consultation meetings" would take place.

The Federal Register asks interested parties to notify FDA by e-mail at BiosimilarsUserFeeProgram@fda.hhs.gov by January 10, 2011.

by Dario A. Machleidt

On November 18, the Medical Device Manufacturers Association ("MDMA") announced a study led by Josh Makower, M.D. (Consulting Professor of Medicine, Stanford University; CEO, ExploraMed Development, LLC; Venture Partner, NEA) and assisted by other Stanford University researchers that paints a bleak picture of FDA's medical device regulatory procedures. The goal of the study, which consisted of survey responses from 204 medical technology ("medtech") companies, was to "address the need for data that could be used to evaluate the impact of U.S. medical device regulation on [United States] innovation and patients." According to the study, FDA's medtech regulatory process is "unpredictable, inefficient, and expensive," especially when compared to the systems used by similar European agencies.

FDA Impact U.S. Medical Technology Innovation

The study used average FDA review times as one way to quantify FDA's inefficiencies. The majority of survey respondents reported that, for low risk medical devices (510(k) process), it took their companies an average of 31 months from their first FDA communication until product approval. It took these same companies only 7 months from their first contact with the respective European agencies to receive regulatory approval for the same products that were introduced in the U.S. Respondents said that it took FDA longer to approve a product from the date of first U.S. filing, a period of 10 months, than the 7 months it took comparable European agencies to approve the same product from the date of first contact. For higher risk devices (premarket approval application ("PMA") process), it took companies 54 months from their first communication with FDA to get their product approved, compared to only 11 months in Europe. The study suggested that "untimely changes in key personnel" and the absence of appropriate FDA staff at important meetings could contribute to FDA's perceived inefficiency and longer regulatory review periods.

Long review times increase costs for medtech companies and, subsequently, the consumer. The survey revealed that companies spent an average of $24 million on FDA-related activities to bring a 510(k) product to clearance. The average total cost for such a product was $31 million. Companies spent $75 million of a $94 million total budget for a single product on FDA-dependent activities linked to PMA submissions. These high regulatory costs to medtech companies increase the prices for medical devices once they reach the market. As the study points out, this means that U.S. citizens are in fact paying higher prices than European patients for technologies that have been available in Europe for several years. Survey respondents reported that their products reached U.S. patients on average two years later than patients in European countries. This device-lag is due in part to direct FDA delays as well as indirect FDA delays, such as when companies pursue non-U.S. markets before spending time and resources on inefficient U.S. regulatory procedures. Thus, U.S. patients pay more for medical devices that are often conceived and created in the U.S. but introduced overseas years before officially entering the U.S. market.

by Elizabeth Murphy

On November 30, Synthes Inc. and its subsidiary Norian Corp. settled charges that they had tested their product for unapproved uses on approximately 200 patients from 2002 to 2004. Norian XR and Norian SRS, the products at issue, are cement bone void fillers approved for use in arm surgeries. According to the charges, the companies had promoted off-label use and conducted clinical trials for the treatment of vertebral compression fractures of the spine, a condition often suffered by elderly patients. At least three deaths have been linked to the illicit experimentation.

According to the U.S. Attorney's Office in Philadelphia, Synthes is guilty of one misdemeanor count for shipping misbranded products; Norian is guilty of one felony count for attempting to impede FDA efforts and 110 misdemeanor counts for shipping misbranded products. Under the terms of the settlement agreement, Synthes will pay $808,000 and Norian $23.5 million. Also pursuant to the agreement, Synthes must sell off its subsidiary, Norian, by May 2011.

The charges followed an FDA warning letter dated November 5, 2004. The warning letter outlined the alleged off-label uses and other deficiencies noting: "These serious violations of the law may result in the FDA taking regulatory action against you without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties." While the action may not seem swift in terms of years since the warning letter, it does follow FDA's new trend of following up on violations outlined in warning letters and also sends notice to other device manufacturers to market according to the FDA-approved labeling.

by Howard E. Rosenberg, Ph.D.

On November 29, FDA announced the availability of a guidance document on the use of active-controlled trials designed to show non-inferiority (NI) as a basis for approval of antimicrobial drug products. Although discussion initially focused on the indications acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and acute bacterial otitis media (ABOM) the science of active-controlled trials designed to show NI and the selection of appropriate NI margins could well prove useful as an appropriate trial design in other antimicrobial drug product indications and in other therapeutic areas too. A review of available data for ABS, ABECB and ABOM, has not found it possible to define an NI margin for active controlled NI trials in these three infectious disease therapeutic areas primarily, because a consistent and reliable estimate of the efficacy of active treatment relative to placebo has not been established.

However, public discussions have contributed to FDA's evolving understanding of the science of clinical trials and, in particular, the appropriate role of active-controlled trials designed to show NI in the development of antibacterial drug products. For some other infectious disease therapeutic indications (generally for more serious infections, such as hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, community-acquired bacterial pneumonia, and acute bacterial skin and skin structure infections), available data and deliberations have made it possible to define a consistent and reliable estimate of the efficacy of active treatment relative to placebo to serve as the basis for defining a new inferiority margin for an active-controlled NI trial.

Study plans will need to consider the basis for estimating the treatment effect of the potential active control as that will be a critical component of choosing the NI margin. NI trial designs need to show adequate evidence of a defined effect size for the control treatment, so that the proposed NI margin can be supported. ABS, ABECB and ABOM, for example, have a high rate of resolution without antibacterial drug therapy, and therefore other trial designs (i.e., superiority designs) will be needed to provide evidence of effectiveness. It may also be useful to compare time for clinical improvement in addition to overall cure rates (e.g., for a demonstration of superiority of the test drug to placebo, to an active control, or to delayed initiation of the test drug or an active control).

FDA clearly now feels that well designed NI studies could prove beneficial in these therapeutic areas, as long as well-thought-out and adequate scientific evidence is provided to support the proposed NI margin for the indication being studied.

by Brian Malkin

Yesterday, FDA posted transcripts for its initial Biosimilars Meeting held on November 2-3, 2010. FDA Lawyers Blog included blogs highlighting day 1 and day 2 of the conference and now has the transcripts linked to its Biosimilars Resources pages at FDA's Implementation of the Biosimilars Act. Comments regarding the hearing may be submitted to FDA's Docket No. FDA-2010-N-0477 until December 31, 2010.

by Mark P. Walters

On November 24, GlaxoSmithKline (GSK) and its partner Vivalis (France) announced that FDA will permit testing for a new influenza vaccine in a Phase I trial in humans. The vaccine will be the first of its kind to be produced using the Vivalis EB66® duck stem cell line. The EB66® platform derives avian-based stem cells for vaccine production. EB66® cells are non-genetically modified and represent the closest cell-based substrate for chicken egg substitution. The EB66® cell line does not require the use of viral genes to enable continuous and stable growth. This is the first trial for the line, which Vivalis and GSK hope will serve as an alternative to chicken eggs for producing vaccines. According to a Vivalis press release, the flu vaccine could be marketed as soon as 2015, if it progresses through its clinical trials according to plan.

Franck Grimaud, CEO, and Majid Mehtali, CSO, co-managers of VIVALIS, said, "[t]his achievement supports the regulatory review of the EB66® cell line by the US FDA and the corresponding Biologics Master File submitted to the agency in 2008. Evaluation or development programs for EB66® cells are being conducted by over 75% of the world's leading vaccine developers in human and animal health, with over 25 license and commercial agreements in place to date."

by Howard E. Rosenberg, Ph.D.

On November 29, FDA announced the availability of a guidance for industry entitled ''ANDAs: Impurities in Drug Products'', which updates and supersedes the December 1998 draft guidance ''ANDAs: Impurities in Drug Products." The guidance now brings abbreviated new drug applications (ANDAs) in line with new drug applications (NDAs) with respect to limiting impurities both in the drug substance and the drug product, i.e., those that arise from both the synthetic process and those due to product degradation. In 2009, FDA updated a related guidance for industry entitled "ANDAs: Impurities in Drug Substances".

ANDA Impurity Guidance 2010

The new drug product guidance has revised impurity limits and identification requirements due to degradation, making ANDAs conform to the current ICH ''Q3B(R2) Impurities in New Drug Products''. Effectively, it updates the required regulatory information on the listing of degradation products, the setting of acceptance criteria, and the qualifying of degradation products (thresholds and procedures) in ANDAs--information FDA would expect to see when assessing the dossier for approval. FDA had already brought drug substances for ANDAs into conformance with the guideline Q3A(R2)
in 2008. That guideline focused, in an analogous way, on setting limits, identification and procedures for impurities in new drug substances.

These two guidance documents now put ANDAs and NDAs on a par with regard to measuring, quantifying and identifying all impurities. The guidelines and Q3A(R2) and Q3B(R2) provide decision trees for acceptable levels of impurities and degradation products. Unusual cases are discussed and procedures clearly defined and guidance given as to what to do in these circumstances.

In Europe, for example, generic applications have already been required to comply with Q3A(R2) and Q3B(R2) by the Health authorities there. It is likely that ANDA filers will have already been following the guidelines too. So this new guidance document should not prove to be problematic.

by Andrew M. Nason

On December 2, the U.S. House of Representatives voted 264-157 in favor of the Healthy, Hunger-Free Kids Act--a $4.5 billion child nutrition bill that expands the National School Lunch Program ("NSLP") and sets new standards to improve the quality of school meals. First Lady Michelle Obama championed the bill as a "groundbreaking piece of bipartisan legislation that will significantly improve the quality of meals that children receive at school and will play an integral role in our efforts to combat childhood obesity." The legislation cleared the Senate in August through a process known as unanimous consent, where all 100 Senators agreed to pass the bill without a voice vote. It stalled in the House during the lead up to November's midterm elections, however, because some Democratic leaders and anti-hunger advocates denounced the $2 billion cuts to the federal food stamp program ("SNAP") that would partially fund the bill.

Following November's elections, two key Democrats relaxed their opposition to using SNAP funding to pay for the child nutrition bill, clearing the way for a House vote on the legislation. House Republicans, who decried the bill as another example of government overreach, attempted to derail the legislation with a last-minute procedural tactic: an amendment that would bar federal money from child-care institutions that hire workers who refuse background checks or lie about their past. The amendment would have sent the bill back to the Senate and effectively foreclosed the issue until after the Republican takeover of the House in January. Although some House Republicans supported the legislation, many objected to its cost, and the bill likely would not have fared as well in a Republican-controlled House. This political reality, combined with a post-election push from the White House, which pledged to help restore SNAP funding, led Reps. Rosa DeLauro (D-Conn.) and Jim McGovern (D-Mass.) to soften their opposition to using SNAP funding for the child nutrition bill.

The bill now heads to President Obama, who has committed to stating his support for SNAP during the White House signing ceremony. President Obama's signature will mark the first increase to NSLP's funding beyond general inflationary adjustments in three decades, providing the U.S. Department of Agriculture ("USDA") its first chance in as many years to make significant changes to school lunch programs. USDA Secretary Tom Vilsack praised the legislation, saying "[o]ur national security, economic competitiveness and health and wellness of our children will improve as a result of the action Congress took [December 2]."

by Elizabeth Murphy

On November 29, the Senate passed its version of the Food Safety Modernization Act (S. 510) by a vote of 73 to 25. The legislation would introduce sweeping changes to government regulation of food safety, providing FDA with increased power to inspect food processing facilities, implement stricter standards, and recall contaminated foods. Despite uncommon bipartisan support and pressure from the Obama Administration, however, the prospects of its passage before the end of the Congressional session are dim.

Before the bill is signed into law, the Senate and House first have to conference and agree upon a unified version of the bill. The House passed its version (H.R. 2749) over a year ago. The Senate version is considered the "softer" version of the proposed legislation: it does not provide as much money for inspections as the House version and generally contains more exceptions to the rules it proscribes.

The Obama Administration, increased food safety regulation being one of its priorities, has urged Congress to agree on a final version quickly before the end of the lame duck session. "With the Senate's passage of the Food Safety Modernization Act, we are one step closer to having critically important new tools to protect our nation's food supply and keep consumers safe," stated President Barack Obama.

Procedural delays aside, the Senate also appears to have overlooked a crucial detail that further stymies efforts in reaching a mutually-agreed upon version. Certain provisions of S. 510 levy fees, which are technically classified as revenue raisers, i.e., taxes. Under the Constitution, all tax bills must originate in the House. Therefore, the Senate's version of the bill preempts the House's tax-writing authority.

As such, the House is expected to "blue slip," or block the Senate's bill. Roll Call reports that this will result in one of two possible scenarios: (1) Senate Majority Leader Harry Reid (D-Nev.) may simply abandon the effort and allow the 112th Congress to take it up again next session; or (2) Reid may attempt to push the bill through the Senate after the House passes another version. The second scenario is somewhat unlikely, given the fact that such an expedited procedure would require unanimous consent in the Senate.

Whatever the outcome, FDA Lawyers Blog will update as more significant events related to the pending Food Safety and Modernization Act unfold.

by Elizabeth Murphy

On November 25, the Advisory Committee on Novel Foods and Processes (ACNFP), an independent body of experts who provide recommendations to the United Kingdom's Food Standards Agency, announced its findings that meat and milk produced from cloned animals and their descendants do not differ substantially from those produced from conventionally-raised farm animals. The Committee thus concluded that such meat and milk are "unlikely to present any food safety risk."

Currently, food produced from cloned animals must pass a safety evaluation before gaining approval in the European Union ("EU"). However, the European Commission recently announced in October its intention to legislate a ban on animal cloning for purposes of food production within the EU. The ban draws its support from ethical concerns relating to animal welfare and reduction in biodiversity, rather than merely food safety. The proposed ban would not, however, apply to food derived from cloned animals imported from outside the EU, e.g., from the U.S. or South America, where the cloning of animals for food production long has been common practice.

Opponents of the production of food from cloned animals are primarily concerned with the wellbeing of the cloned animals. Relying on a 2008 European Food Safety Authority opinion, they point to the fact that cloned animals suffer higher mortality rates and more developmental abnormalities than conventionally-reproduced animals. Additionally, the untimely death and generally poor health of Dolly the sheep, the world's first cloned mammal, lends credibility to their position.

The proposed ban on cloned food production in the EU is currently under debate in the European Parliament.

by Charles J. Raubicheck

On November 17, FDA sent four warning letters to sellers of certain alcohol-containing energy drinks that are spiked with caffeine, which has had their intended effect.

The Agency contends that caffeine added to these products is an unsafe food additive (not generally recognized as safe and lacking an approved food additive petition). Production and/or shipment of the drinks - Four Loko, Joose, Max, Core High Gravity HG, Lemon Lime Core Spiked and Moonshot '69 - has ceased, and products on retail shelves will be pulled by mid-December. FDA Commissioner Margaret Hamburg, M.D. told the Tan Sheet (November 29) that she expects the industry to heed the message and fall in line.

One dissenter, the small New England company New Century Brewing that created Moonshot '69, is perplexed. The product is a low-alcohol beer with much less caffeine than other malt energy drinks. In an interview reported by The New York Times reporter Katie Zezima, the company's president Rhonda Kallman said FDA should establish parameters for caffeine content, but not ban the products. She added: "This is prohibition in 2010."

For additional information, please see our previous blog on this topic here.

by Erin A. Lawrence

On November 11, embryonic stem cell research supporters announced the creation of a coalition--Stem Cell Action--to support attempts to enact comprehensive legislation for federal support and protection of stem cell research. The coalition is made up of 30 organizations and is led by the Genetics Policy Institute ("GPI"). The coalition was formed in response to Sherley v. Sebelius, where Judge Royce Lamberth issued a preliminary injunction that enjoined federal funding of embryonic stem cell research. In Sherley, Judge Lamberth held that embryonic research violated a 1996 law--the Dickey-Wicker Amendment--which banned the use of taxpayer money to derive stem cells from embryos. The Court of Appeals for the District of Columbia temporarily stayed Judge Lamberth's preliminary injunction until it could fully review the case. The Court of Appeals will hear oral argument on December 6. Judge Lamberth may issue a permanent injunction based on the merits at any time but will likely hold off until the Court of Appeals makes their decision.

Further, Boston Biomedical Research Institute ("BBRI") requested to join an amicus brief filed by the state of Wisconsin, GPI, and the Coalition for Advancement of Medical Research that directly opposed its employee--James Sherley--the named plaintiff and the man who initiated the lawsuit against the National Institutes of Health ("NIH"). In their statement of interest, BBRI stated that it is directly interested in the outcome of this case because BBRI has plans to expand their research to include the use of human embryonic stem cells.

Congress is also involved in the fight to maintain federal funding of stem cell research. Currently pending in Congress is the Stem Cell Research Advancement Act of 2010 (S. 3766). The legislation was introduced in September by Senator Arlen Specter (D-PA) and seeks to secure future federal money for stem cell research. The bill has already passed through Congress twice--in 2005 and 2007--but was vetoed by President Bush. The bill was also re-introduced in February 2009 but was stalled after President Obama expanded federal stem-cell funding via executive order. If Congress succeeds in passing this legislation, stem cell research will no longer be vulnerable to this legal challenge. However, some are skeptical that legislation will be a priority in the lame duck session and it is unknown how the Republican-heavy Congress will decide on the bill when it convenes in January 2011.