FDA Lawyers Blog

by Justine K. Donahue

On November 1, Gary Buehler, the longtime director of FDA's Office of Generic Drugs (OGD), is joining Teva Pharmaceutical Industries Ltd. as Vice President of Regulatory Strategic Operations.

Notably, as a former senior government employee at FDA, there are certain restrictions Mr. Buehler has to observe in his new position at Teva:

(1) He can never (i) appear before or communicate with FDA about matters in which he personally and substantially participated during his tenure at the Agency; (ii) use trade secret information that FDA obtained from businesses or individuals while he worked there, or (iii) share with industry non-public information he learned by virtue of his FDA employment.

(2) For a period of two years, he may not appear before or communicate with FDA on matters that were pending before OGD during the one-year period prior to his departure.

(3) For a period of one year, he may not appear before or communicate with FDA on any matter.

Nonetheless, these curbs do not prevent Mr. Buehler from providing internal advice to Teva management and Teva employees about current and future matters in which Teva has an interest at FDA. See here. This valuable assistance, coupled his wealth of experience at the Agency, are significant advantages Teva has gained by hiring him.

by Andrew S. Wasson

As promised, FDA will hold its public hearing on the implementation of the Biosimilars Act (referred to by the FDA as the "BPCI" (Biologics Price Competition and Innovation Act of 2009) on Tuesday and Wednesday of this coming week (November 2-3) at its White Oak campus in Maryland. In early October, FDA published a notice of public hearing and request for comments, asking for input on how to construe a number of centrally important yet roughly-outlined terms, such biosimilarity and interchangeability. FDA will also solicit input on the implementation of several critical provisions, such as the exclusivity provisions and the provisions covering follow-on biological products approved under Section 505 of the Federal Food, Drug, and Cosmetic Act.

Reviewing the Agenda for this week's meeting, it appears that FDA has met its goal of bringing a wide variety of interested parties together. Traditional brand and generic companies will share the stage with non-profit organizations and individuals from academia. Look for a particularly dramatic moment when Teva North America directly follows Pfizer, Inc.'s comments on the afternoon of the first day's presentation (keeping in mind, however, that the battle lines are not as clear in the biologics sector as with small-molecule drugs). It is a fair assumption that the order of speakers will generally mirror the order of questions put to the public in the Federal Register, the Agenda does not break down the sessions thematically.

Particularly interesting will be the responses to FDA's question about the range of structural differences consistent with the standard of "highly similar." Note that FDA is rarely forced to make true determinations of similarity based on structural characteristics: determinations of bioequivalence for small molecule drugs under the Hatch-Waxman Act are driven by quantifiable standards like serum blood levels. Not so in the Biosimilars Act, specifically calling for analytical studies to establish a high degree of similarity. A statutory term like "similarity" will present a serious problem of definition and application because of underlying disagreements about its fundamental meaning. If you don't believe me, look to the morass caused by the "doctrine of equivalents" in patent law, a morass conquered only after years of confusion and furor by the Federal Circuit's severe limitations placed on the usage of the doctrine. It is likely that the comments at this week's hearing will suggest that emerging analytical techniques will solve the problem of similarity, although query whether this actually addresses the underlying issues.

Click here for more information about the hearing and how to view the webcast.

by Brian Malkin and Christopher Gosselin

On October 19, FDA granted a citizen petition filed on behalf of Genzyme Corporation ("Genzyme") requesting FDA to confirm that a second 30-month stay would issue following a subsequent Paragraph IV notice sent for a reformulated generic version of Hectoral® injection (doxercalciferol). FDA recently granted the petition, despite language in a 2004 FDA guidance stating that the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 ("the MMA") "generally precludes multiple 30-month stays for those applications to which it applies."

In October 2007, Pentech Pharmaceuticals, Inc. (subsequently purchased by Cobrek; hereafter "Cobrek") submitted an application for a generic version of Hectoral® injection (ampules) containing a Paragraph IV certification for all of the Orange Book-listed patents. Within 45 days of receiving Cobrek's Paragraph IV notice letter, Genzyme asserted one of the patents against Cobrek, triggering a 30-month stay. Prior to approving Cobrek's application, Genzyme received approval for a new formulation of Hectorol® injection in stoppered vials. When FDA approved the supplement, Genzyme withdrew the ampule product from the market and submitted new patent information. Cobrek responded by amending its application to reflect the new patent information, but Genzyme did not sue on the new patent information.

FDA then required Cobrek to either file a suitability petition to determine whether the ampule Hectoral® injection had been withdrawn for reasons of safety or efficacy or reformulate to match the new Hectoral® injection formulation and provide Genzyme with a Paragraph IV notice letter for the new formulation. Cobrek chose-perhaps mistakenly-the latter route. Upon receiving Cobrek's notice letter, Genzyme sued Cobrek for infringement of the originally-asserted patent and the patent listed for the new stoppered vial formulation.

by Erin A. Lawrence

Four Loko is a caffeinated, malt beverage that is produced at City Brewing's Latrobe plant (the Rolling Rock brewery). It is a 23.5 ounce fruit-flavored beverage with 12 percent alcohol and has as much caffeine as a cup and a half of coffee. Four Loko is one of many caffeinated alcoholic beverages on the market today.

The only purpose of these caffeinated alcoholic beverages is to get the drinker intoxicated quickly. Therefore, (unfortunately) the primary consumers of these drinks are barely of age or underage drinkers.

The health concerns related to caffeinated alcoholic drinks are very significant. These drinks are dangerous because they send mixed signals to the body. The body's normal response to alcohol is to become fatigued. Fatigue is your body's way of saying it has consumed enough alcohol. The caffeine in the drink counteracts that feeling, leaving the drinker to believe that they can consume more alcohol--leading to a higher risk of alcohol poisoning. Also, mixing alcohol--a depressant--with caffeine--a stimulant--can cause cardiac problems. And, in addition, since alcohol causes dehydration and caffeine is a diuretic, the drinker's dehydration and possible subsequent hangover is aggravated.

Doctors and state attorneys general have gone to FDA for help. FDA approved the addition of caffeine to soft drinks, but has never approved the addition of caffeine to an alcoholic drink. In response, in November 2009 FDA began looking into the safety of caffeinated alcoholic beverages. FDA sent letters to almost 30 companies requesting that the companies submit documentation detailing the safety of combining alcohol with caffeine within 30 days. Almost a year later, only 19 companies have responded. Although FDA warned that it would take appropriate regulatory action, to date, that has not happened. However, FDA says they will try to evaluate the 19 responses as soon as possible and determine whether these drinks are safe and legal.

In July, Senators Charles Schumer (D-New York), Dianne Feinstein (D-California), Amy Klobuchar (D-Michigan), and Jeff Merkley (D-Oregon) wrote a letter to the FDA requesting that the agency make public its findings of the possible health risks of energy drinks that combine alcohol and caffeine. The senators stated that "alcoholic drinks appear to be marketed to underage teens, misleading parents and law enforcement by designing labels and containers so the products resemble non-alcoholic energy drinks."

by Elizabeth Murphy

On October 18, ReGen Biologics, Inc. ("ReGen") criticized FDA's decision to rescind clearance of its device, the Menaflex® Collagen Shield, a prosthetic knee implant. Gerald E. Bisbee, Jr., Ph.D., ReGen's Chairman and CEO, characterized FDA's decision as "totally unbelievable."

FDA had originally cleared the Menaflex® device, after a highly-contested and protracted review, under 510(k) procedures. The 510(k) review process permits accelerated approval of devices "substantially similar" to predicate devices already on the market. On October 14, FDA rescinded its market clearance of the device, relying on a September 2009 preliminary report that called attention to outside pressure on the agency in approving the Menaflex® device, as well as evidence that the device was technologically dissimilar to its corresponding predicate devices.

FDA's 2009 report outlined the "chaotic and contentious" review process that ultimately resulted in approval of the Menaflex® device. In addition to citing overt Congressional pressure to approve the device, the report also listed numerous internal departures from established agency practices and procedures that contributed to the agency's questionable approval of the Menaflex® device. According to the report, ReGen had obtained the assistance of Congressional members from New Jersey in advocating for a "fair" review process. Though the report acknowledge the fact that Congressional advocacy for constituent members is not entirely uncommon in the review process, the level of pressure exerted in this instance was "extreme" and the acquiescence by top level FDA officials "unprecedented." Overall, the report's findings supported FDA's conclusion that reevaluation of the approval was appropriate and warranted.

by Mark P. Walters

On October 8, FDA granted part of Abbott's citizen petition ("CP") concerning generic AndroGel®. Abbott's CP relied on FDA's response to Auxilium Pharmaceuticals's CP regarding generic Testim® testosterone gel. AndroGel® and Testim® both contain testosterone and are indicated for testosterone therapy in adult males with a deficiency or absence of endogenous testosterone. Both are designated in FDA's publication Approved Drug Products with Therapeutic Equivalence Evaluations ("the Orange Book") as reference listed drugs (RLDs) for potential generic transdermal testosterone gel (TTG) drug products.

Abbott's CP asked FDA to require any applicant for a product that does not contain the same penetration enhancers as AndroGel® to conduct skin transfer and hand-washing studies and to seek approval as a 505(b)(2) NDA (i.e., a new drug application submitted under section 505(b)(2) of the Food, Drug, and Cosmetic Act (FD&C Act)), not an abbreviated new drug application (ANDA) submitted under section 505(j) of the FD&C Act, unless the applicant obtains a right of reference Androgel® from Abbott. Abbott also requested that FDA require any NDA referencing AndroGel® to contain new certifications to all patents listed with AndroGel® in the Orange Book, and if any of those certifications assert that the patent is invalid, unenforceable, or will not be infringed, require the applicant to provide timely notification as provided for in section 505(b)(3) of the FD&C Act.

Beginning in early 2009, FDA apparently became aware of significant adverse effects in children from secondary exposure to TTG drug products occurring through inadvertent drug transfer from adult male users. FDA addressed this risk in April 2009 by requiring safety-related labeling changes for both AndroGel® and Testim®, including requiring a boxed warning cautioning about secondary exposure to testosterone, and a Medication Guide (a form of FDA-approved patient labeling) discussing these risks.

by Brian Malkin

On October 15, FDA approved Botox® (onabotulinumtoxinA) to prevent headaches in patient with chronic migraine. Chronic migraine means the patient has a history of migraines and experiences migraines on most days (15 or more days) of any given month with each migraine lasting 4 or more hours. Migraine headaches may be debilitating and often include intense pulsing or throbbing pain in one are of the head. These headaches may include nausea, vomiting, and sensitivity to light and sound.

To help prevent chronic migraines or dull their symptoms, Botox® is given as multiple (31) injections around the head and neck about every 12 weeks. Allergan submitted data from its Phase III Research Evaluating Migraine Prophlaxis Therapy Program (PREMPT), which it describes as the "largest" clinical trial in chronic migraine, including 1384 adults from 122 study sites in North America and Europe. The most frequent side effects reported were neck pain and headache. Botox®, however, has not been shown to work for treating migraine or other headaches that occur 14 days or less per month.

Botox was approved 21 years ago for the treatment of two eye muscle disorders, strabismus and blepharospasm. Since its approval, Botox® has gained expanded indications for upper limb spasticity, cervical dystonia, and primary axillary hyperhidrosis. Botox® Cosmetic (onabotulinumtoxinA) is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines (frown lines between the eyebrows) associated with corrugar or procerus muscle activity in adults up to 65 years old. As reported previously FDA and Allergan have been battling with the fight for how far Allergan can go with marketing Botox® for expanded uses prior to obtaining pre-market approval. In this instance, Allergan appears to have followed the more traditional route.

FLH Partner Brian Malkin will attend the Regulatory Affairs Professionals Conference in San Jose, California, from October 24-27. More than 2,000 fellow regulatory colleagues representing every facet of the global healthcare products community and more than 200 thought-leaders are expected to join Mr. Malkin at the 2010 RAPS Annual Conference & Exhibition to examine best practices and new strategies for success. More information about the conference may be found here.

by Andrew S. Wasson

On October 12, FDA sent a flurry of warning letters to eight companies marketing chelation therapies, asserting that the therapies were marketed as unapproved drugs. Proponents of chelation therapies assert that unbound metal ions wreck havoc on the body and cause a variety of ailments such as cardiovascular disease and autism. They maintain that chemical compounds with the ability to bind metal ions (known as chelators) can be used beneficially to treat these diseases. FDA has approved chelation therapy in a limited number of circumstances, such as to treat metal poisoning by reducing levels of lead in the blood.

In the warning letters, FDA found that the chelation therapies were marketed as "drugs" under the Federal Food Drug & Cosmetic Act ("the FD& C Act"). In particular, FDA pointed to the part of the definition of "drug" that covers "articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals." 21 U.S.C. § 321(g)(1)(B). FDA additionally argued that the targeted products were "new drugs" under 21 U.S.C. § 321(p), and could not be marketed without prior FDA approval, based on scientific data demonstrating their safety or efficacy. See 21 U.S.C. § 355(a).

Whether a particular therapy is a "drug" under the FD& C Act is not only significant to the targets of FDA enforcement actions, but it is also notable for its historical, sociological, and philosophical dimensions. In one law review, Professor Lewis Grossman examined the complex interaction between the legal and extralegal usage of the term "drug." Professor Grossman demonstrated that the definition of "drug" has changed over time as the synthesis of numerous factors. For example, legislative reaction over public health debacles, the attempt to avoid regulation by industry stakeholders, the growth of an industrialized synthetic pharmaceuticals industry, and colloquial usage generally, all played a role in creating the current definition. Regardless of the forces that have shaped the definition, it remains to be seen whether targeted manufacturers will challenge FDA's determination.

by Brian Malkin and Laura Fanelli

In just the past two weeks, FDA declared tighter controls on a popular anti-diabetes drug, admonished the makers of popular mouthwash products for misleading advertisements, commented on the debatable issue of genetically-engineered salmon, continued investigations into the biggest recalls in history of children's pediatric medications and contaminated eggs, cautioned consumers about the possibility that devices purportedly offering protection against Sudden Infant Death Syndrome could themselves be lethal, and announced that Meridia® (sibutramine), an anti-obesity drug, was being pulled from the market.

FDA's flurry of enforcement activity appears to be the result of a new regulatory activism that will likely continue as the Obama Administration attempts to advance its agenda through Executive Orders instead of through Congress. FDA's Center for Drug Evaluation and Research issued 103 warning letters in 2009 for misleading labeling and other violations. This number represents a drastic increase from the mere 21 warning letters issued in 2006. "I think the general approach has clearly been more warning letters, more regulatory activity, a much more rigorous approach to regulating products on the market," said Kenneth Kaitin, Director of the Tufts Center for the Study of Drug Development, a nonprofit research institute, as reported by Andrew Zajac, Tribune Washington Bureau, for the Los Angeles Tribune.

FDA's recent activism may also mean potential misdemeanor charges against pharmaceutical executives. FDA Deputy Chief for Litigation, Eric "Rick" Blumberg, announced that FDA is considering bringing a misdemeanor charge against industry executives whose companies promote unauthorized, or "off-label," uses of their medicines. "Unless the government shows more resolve to criminally charge individuals at all levels in the company, we cannot expect to make progress in deterring off-label promotion," said Blumberg, as reported by Anna Edney for Bloomberg.

Misdemeanor prosecutions of executives for violations of the federal Food, Drug, and Cosmetic Act fall under the Park Doctrine, which has not been widely used for drug industry cases in the past two decades. Executives could face as much as $100,000 fines and one year in prison. In addition, FDA can bar individuals from working in the drug industry. Blumberg said that industry executives should not wait until the first charges are brought to bring their marketing in compliance. He cautioned, "if you're a corporate executive or are advising a corporate executive, now is the time to comply."

by Elizabeth Murphy

On October 14, the FDA made available "Guidance for Industry: Early Clinical Trials with Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information." The draft guidance document provides content and format criteria for investigational new drug ("IND") applicants filing INDs for early clinical trials with live biotherapeutic products ("LBPs").

An LBP is defined broadly as "a biological product that: 1) contains live microorganisms, such as bacteria or yeast; 2) is applicable to the prevention, treatment, or cure of a disease or condition of human beings; and 3) is not a vaccine." The proposed guidance document requires the applicant submit specific information about the biological nature and manufacture of component organisms in the LBPs under review. Some examples of such specific information include detailed information regarding the source and history of the organism, flowcharts describing each step of the manufacturing process, and descriptions of each step of the cell growth, and harvesting process.

The guidance document covers all INDs of LBPs, whether submitted on behalf of commercial entities, academic institutions, or otherwise. Recombinant LBPs, those LBPs "composed of microorganisms that have been genetically modified through the purposeful addition, deletion, or modification of genetic material," are excluded from coverage. FDA notes that pre-IND meetings may be helpful, especially for sponsors new to working with the agency or for new products, technologies, or assays.

The FDA is accepting comments on the draft guidance document through December 13, 2010.

by Charles J. Raubicheck

FDA is imposing a new approval hurdle on makers of generic versions of the popular sleep medication Ambien CR® (zolpidem tartrate). In an October 13th decision on a Sanofi-Aventis citizen petition, the agency found that the standard criteria for a generic to prove bioequivalence to Ambien CR® (area under the curve (AUC) and maximum concentration (Cmax)) are not sufficient. The added pharmacokinetic parameter partial AUC must be satisfied as well.

Partial AUC is a measurement of the amount of the active ingredient in an extended-release tablet such as Ambien CR® that is absorbed into the bloodstream shortly after dosing. FDA says that generics must measure the level of the active ingredient zolpidem 1.5 hours after the drug is taken, because most people fall asleep at that point and must absorb enough zolpidem by then to maintain sleep over a 7-8 hour period.

However, this barrier does not appear to have slowed generic approvals. On the same day as FDA's decision, FDA approved a generic Ambien CR® 6.25 mg tablet (tentative approval for 12 mg tablet) filed by Actavis and tentative approvals for generic Ambien CR® 6.25 mg and 12 mg tablets filed by Synthon Pharmaceuticals, Inc.--evidently based on a partial AUC 1.5 hour analysis already conducted by the companies. More approvals are expected to follow.

by Christopher Gosselin

"Fields of Science" by Image Editor
In a speech at the National Press Club earlier this month, FDA commissioner Margaret Hamburg vowed to reform FDA's 20th-century methods to meet the demands of 21st-century science. Hamburg acknowledged that new drugs often find their way to patients too slowly, and hopes that greater investment in regulatory science will allow the agency to develop new tools, standards, and approaches for more quickly and effectively assessing FDA-regulated products. To that end, Hamburg announced a new Regulatory Science Initiative intended to bolster FDA's regulatory science capacity.

A key component in the new Regulatory Science Initiative is the establishment of an Office of Science and Innovation. Housed within the Office of the Chief Scientist, the Office of Science and Innovation will develop strategic plans, track the progress of the initiative, and organize scientific collaborations. FDA also has plans to accelerate the recruitment and training of in-house scientists.

The initiative coincides with President Obama's recent $25 million budget request for improvements in science. The money would be spent mainly on collaborations with other agencies, industry, and academia. Collaborative efforts at FDA first began in February, when FDA and National Institutes of Health (NIH) announced a $6.75 million joint request for research into regulatory science. A draft of FDA's Strategic Priorities over the next five years confirms a serious agency-wide effort to advance science and innovation. Other top strategic priorities include: (1) strengthening the safety and integrity of the global supply chain; (2) strengthening compliance and enforcement; and (3) meeting the needs of underrepresented populations.

The future of the initiative may be tied to the administration's proposed $4 billion budget for fiscal year 2011. Hamburg remains "guardedly optimistic" that funding will increase next year.

by Mark P. Walters

In early October, Apotex filed a writ of certiorari, asking the U.S. Supreme Court whether a generic drug manufacturer may forfeit marketing exclusivity under the forfeiture provisions of the Federal Food, Drug, and Cosmetic Act ("FD&C Act") (21 U.S.C. § 355(j)(5)(D)) based on "unilateral" action by the holder of the challenged patent to delist a patent from the Orange Book. At issue is generic Cozaar® (losartan potassium), Merck's blockbuster angiotensin II receptor antagonist.

Earlier this year, the D.C. Circuit finally 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®'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. Teva sued FDA in June 2009 to regain exclusivity, and, after losing at the district court level, Teva obtained a ruling from the D.C. Circuit in March 2010 that "FDA's interpretation [of the forfeiture provisions] is inconsistent with, and thus foreclosed by, the statutory scheme," and the case was remanded for further proceedings.

On remand, FDA informed the D.C. Circuit that it had learned that the '075 patent expired prior to Teva's lawsuit filing due to Merck's failure to pay maintenance fees for the '075 patent after it delisted the patent. Initially, FDA solicited comments on whether a brand name drug manufacturer could unilaterally cause its patent to expire and, thus, force a forfeiture of a first ANDA applicant's right to 180-day market exclusivity. Reluctantly relying on the D.C. Circuit's interpretation of the forfeiture provisions, FDA ultimately answered this question in the negative.

In its petition for certiorari, Apotex offers a spirited rebuke of the D.C. Circuit's interpretation of the forfeiture provisions in an attempt to invoke the High Court's discretionary jurisdiction in favor of consumers. This case would appear to be the first Hatch-Waxman case taken by the Supreme Court on issues arising from post MMA amendments to the statute. The last time the U.S. Supreme Court took a case relating to the Hatch-Waxman Act was Merck v. Integra, 545 U.S. 193 (2005), dealing with the safe harbor provisions for clinical research prior to applying for market approval under the FD&C Act.

by Elizabeth Murphy

On October 1, FDA's Principal Deputy Commissioner, Joshua M. Sharfstein, M.D., announced at the Council for Responsible Nutrition's Annual Conference in Lost Pines, Texas, that of the 90 Good Manufacturing Practices (GMP) dietary supplement inspections conducted by FDA in 2010, about one-third uncovered "serious problems." (The Tan Sheet, Oct. 11, 2010). Dietary supplement industry compliance is notably lower than in other FDA-regulated industries, where only about 5 to 10 percent of inspections uncover "serious problems."

Part of the problem may be due to the relatively recent implementation of FDA's guidelines. On June 22, 2007, the FDA issued regulations to require current GMPs (cGMPs) for dietary supplements. The regulations were meant to ensure the quality and consistency of dietary supplements, as well as accuracy in their labeling. The regulations were only gradually implemented, and although the final rule was effective in June 2008 for large companies, smaller companies received additional time to comply: June 2009 for companies with less than 500 employees and until June 2010 for companies with less than 20 employees.

FDA regulations concerning the manufacture and labeling of dietary supplements generally require some form of testing to verify the purity of the end-product, as well as oversight in the manufacturing and packaging processes. Among the "serious problems" uncovered by the 2010 inspections were: a lack of ingredient identity testing; absence of established manufacturing, recordkeeping, and quality-control plans; and a lack of end-product testing. Of utmost concern was the lack of ingredient identity testing, as the FDA is particularly concerned with illicit "pharmaceutical spiking" of supplements, especially in products marketed for "weight loss, sexual enhancement and bodybuilding." (The Tan Sheet, Oct. 11, 2010). Compliance with the GMP's ingredient identity testing procedures requires the entity selling the product to conduct its own analysis of ingredients, as opposed to relying on a supplier's certificate.

FDA had originally planned to conduct 250 inspections this year, with hopes of doubling that amount in 2011. (The Tan Sheet, Oct. 11, 2010).

by Andrew M. Nason

On September 23, the United States House of Representatives passed the Improving Access to Clinical Trials Act (I-ACT), clearing the way for President Barack Obama to sign it into law. The legislation aims to increase access to clinical drug trials for patients with rare diseases by excluding the compensation patients receive for participating in such trials from Supplemental Security Income (SSI) and Medicaid income threshold rules.

Currently, legislation categorizes compensation from clinical trials as income, which could increase a patient's earnings above the SSI eligibility threshold. As a result, some lower income patients with rare diseases are unwilling to enter potentially beneficial clinical trials because the increase in income would make them ineligible to receive government medical benefits. The I-ACT bill, introduced in the House by Representative Edward Markey, would allow patients with rare diseases to disregard up to $2,000 of compensation received for participating in clinical trials. "This bill will ensure that no patient will have to choose between their health benefits and the promise of a clinical trial," said Rep. Markey. The Congressional Budget Office determined the bill would come at no cost to the federal government.

The legislation only applies to rare disorders, or those affecting less than 200,000 people in the United States. There are currently more than 6,000 rare disorders that, taken together, affect approximately 25 million Americans. Examples include ALS, Crohn's Disease, Cystic Fibrosis, Huntington's Disease, and Parkinson's Disease. In a press statement by the Cystic Fibrosis Foundation in 2009, Senator Richard Shelby expressed confidence that the "legislation will open a pathway for more patients to receive life-saving treatments."

by Brian Malkin and Jennifer A. Hardy

On September 27, European Union (EU) heavyweights France, Spain, Germany, and the UK strongly criticized a proposal to grant member states more flexibility in genetically-modified ("GM") crop production. EU Health Commissioner John Dalli proposed the plan in July attempting to end the gridlock that has plagued GM crop production in the EU. The proposal is meant to replace the 2003 Commission Recommendation co-existence of GM crops with conventional and organic farms.

The new proposal would grant states the power to create "GM-free" areas and to adopt stricter isolation measures to avoid an unintended presence of genetically-modified organisms ("GMOs") in other products. EU Member States ("States") are also allowed to ban GM crop cultivation in their territories, but each State will need EU approval to act if its decision is not adequately based in science.

Dalli's proposal received criticism from both traditionally pro-GMO and anti-GMO States for several reasons. Many States fear that the production of GM crops would negatively affect the internal agriculture market and undermine farmer choices. States also fear that this proposal could create a multitude of legal disputes between farmers, corporations, and States, as well as breach World Trade Organization (WTO) rules.

Dalli answered these claims by stating that the plan would not way disrupt the internal agriculture market as each State is free to order their agriculture and economic sectors in whatever way they choose. A working group has been established to address the criticisms of the proposal.

The proposal needs the approval of both the European Commission and Parliament before it goes into effect. Further negotiations among States' environmental ministers will occur on Thursday, October 14, at the meeting of the Environmental Council. As reported previously, the U.S. is also taking a close look at the impact of GM crops.

by Brian Malkin

On September 30, Teva Pharmaceutical Industries Ltd. ("Teva") announced that FDA issued a complete response letter for its full Biologics License Application (BLA) for Neutroval® (filgrastim or recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF)) requesting additional data that did not include new clinical data. On December 1, Teva had previously announced that it had filed its first U.S. biologics application in lieu of the biosimilar pathway being considered by Congress (see related blog), and its full BLA was a "biosimilar" version of Amgen's Neupogen®. Neupogen® has a variety of indications related to the ability of filgrastim to stimulate the production of neutrophils, a certain type of white blood cell that serves as the body's primary defense against infections by destroying bacteria in the blood.

In Europe, Teva markets the same product as Tevagrastim®, which received approval in November 2008. Teva filed earlier in Europe, because the patents there expired in 2006 in contrast to the current U.S. patents that are expected to expire in 2013. In November 2009, Teva filed a complaint for declaratory judgment for patent non-infringement or invalidity of two key patents covering Neupogen® to help clear the way for its U.S. approval, in lieu of a formal pre-marketing litigation process such as for drugs. In January 2010, Amgen replied with counterclaims for infringement of the same two patents, seeking to block Teva from marketing Neutroval® prior to expiration of the two patents at issue. While the court has issued its claim construction, other motions are still pending, including a motion by Teva to file amended pleadings following the claim construction.

In addition to these snags, Teva will fight an uphill battle to obtain substitution of its product. Because Teva's product would be a separate BLA and not an interchangeable version, current Neupogen® patients would require a separate prescription to obtain Neutroval®. Unlike generic drugs, there is no automatic substitution for a separate BLA. Based on the labeling for TevaGrastim®, it does not appear that Teva would market Neutroval® as a biobetter, i.e., an improved version of Neupogen® with a better safety or efficacy profile, so Teva would likely rely on a lower cost to attract new prescriptions.

Despite Teva's decision to forego the biosimilar route in this instance, followers of FDA's developing biosimilar route will no doubt watch what happens with Teva's product closely. For background how the Biosimilars Act came about and how FDA has begun steps to implement, take a look at our new Biosimilars Resource pages.

Frommer Lawrence & Haug LLP Partner James K. Stronksi will speak on "Eye on the CAFC and District Courts: Life Cycle Lessons Derived from Paragraph IV Litigation" at ACI's Maximizing Patent Life Cycles Conference on October 7. The program is designed to help counsel and advisors understand Hatch-Waxman and the new biosimilars pathway and the impact on patent strategies and litigation. For more information for ACI's Conference, which will be held on October 6-7, 2010, click here.

by Erin A. Lawrence

On September 28, Senator Mark Begich (D-Alaska) and several other senators of coastal states sent a letter to FDA asking FDA not to approve the proposal from AquaBounty to produce a genetically-altered Atlantic Salmon. Senator Begich stated that if FDA certifies the hybrid salmon, they will introduce legislation to require such animal products on the market to be labeled as "genetically engineered."

Senator Begich asserts that approval of genetically-modified salmon is "unprecedented, risky and a threat to the survival of wild species." The biggest threats include potential new diseases and allergies for humans and the threat of escaped fish and their effect on the environment and the wild salmon population. Some research on the genetically-engineered fish raised in Canada found that some of the fish developed misshapen heads and bloated bodies. Deformed fish were not included in the studies that AquaBounty presented to FDA.

Senator Begich believes that FDA is using the wrong process to evaluate the safety of the modified fish. Senator Begich said that FDA incorrectly treats AquAdvantage salmon as if it were a new veterinary drug and not as a new animal that humans would consume. He argues that the public is missing critical information that AquaBounty's has classified as business information or "trade secrets." Therefore, the public cannot properly evaluate the health and environmental issues implicated.

Representative Rosa DeLauro (D-Connecticut), Chairwoman of the House committee that controls FDA's and the U.S. Department of Agriculture's budgets, introduced a bill on September 29 that would mandate labeling of genetically-altered fish. "If FDA approves the genetically modified salmon the American public deserves to know the truth about their food, and this legislation will ensure that they are provided with this critical information," DeLauro said. Additionally, House Representatives Peter Defazio (D-Oregon), Dennis Kucinich (D-Ohio), and Mike Thompson (D-California) also submitted a letter to the FDA on September 29 requesting FDA to halt the approval process of the genetically altered salmon.

by Rami Bardenstein

On September 29, FDA issued a final rule amending IND safety reporting requirements. The new rule, which is effective on March 28, 2011, is intended to increase the amount of meaningful information submitted to the FDA and bring FDA closer to the reporting standards of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use and the World Health Organization's Council for International Organizations of Medical Sciences.

Under the old rule, drug sponsors were obligated to report adverse reactions associated with the drug. Unfortunately, drug sponsors often supplied information that was greater than FDA needed. For example, drug sponsors often would report adverse experiences due to the underlying disease or that were common to the study population, independent of the drug's activity. FDA, therefore, received unnecessary information out of context.

The new rule is designed to clarify the reporting requirements and expedite FDA review of critical safety information. The new rule make clear that an individual adverse reaction that is not associated with the drug--such as those caused by the underlying disease--should not be reported. By clearly distinguishing between individual cases that should be reported and those that should not, the new rule will potentially increases FDA's ability to effectively evaluate new clinical safety data. For further information about the final rule, including FDA's draft guidance and question and answer document, please see here.

by Brian Malkin and Andrew S. Wasson

FDA Lawyers Blog is pleased to announce the creation of two new resource pages: (1) Biosimilars and (2) European Drug Law. To FDA Lawyers Blog knowledge, both pages represent firsts in the blogging community, which we are providing as an online clearinghouse for FDA lawyers and will continue to update.

The Biosimilars page represents a collection of primary and secondary sources assembled by FDA Lawyers Blog to help document the evolution and enactment of the Biologics Price Competition and Innovation Act ("Biosimilars Act"). The Biosimilars page provides links to key legislation, Congressional documents, FDA citizen petitions, and FDA's scientific considerations leading up to the Biosimilars Act. The Biosimilars page also provides links to new FDA developments implementing the Biosimilars Act and some related publications by FDA Lawyers Blog contributors.

The European Drug Law page includes three new European Drug Law Summaries designed by FDA Lawyers Blog to provide insight for FDA lawyers to understand how human drugs are regulated in the European Community and includes links to key regulatory documents referenced in the Summaries. The summaries include the topics: (1) Marketing Authorizations: Innovator Drugs and Biologics, (2) Generic and Hybrid Medicinal Drug Products, and (3) Regulatory Exclusivities, Patent Term Extensions, and Litigation Mechanism.