FDA Lawyers Blog

In a September 26 FDAnews article FLH Partner Brian J. Malkin was quoted regarding the latest decision. The article, "Jazz Appears to Win on Patent Claim Terms in Xyrem Fight." The article concerned a recent development in Jazz Pharmaceuticals' ("Jazz's") suit against generic competitor Roxane Laboratories ("Roxane"), where in an unpublished opinion, the District Court of New Jersey Judge Esther Salas Jazz appeared to side with virtually all of Jazz's claim constructions for the disputed terms in the patents-at-issue for Xyrem® (sodium oxybate), indicated for excessive daytime sleepiness and cataplexy in patients with narcolepsy.

Malkin was quoted in the article as reproduced in the following passage:

One major upside for Jazz is that it could make it harder for Roxane to negotiate more favorable terms if it chooses to settle, Brian Malkin, a partner at Frommer Lawrence & Haug, noted.

Meanwhile, Jazz was also issued another Xyrem patent Sept. 11, which the company is submitting for listing in the FDA's Orange Book. This move could prolong the case, Malkin said, as Roxane would have to amend its ANDA, likely by filing a Paragraph IV certification.

Finally, Jazz has outstanding citizen petitions related to Xyrem generics, including a July petition that demands the FDA rescind its acceptance of the Roxane ANDA because Roxane did not submit material related to a proposed risk management strategy for Xyrem when it originally filed the application (Generic Line, Aug. 1). FDA rulings on the citizen petitions are due on Nov. 18 for the earlier bioequivalence standards petition and on Dec. 10 for the July petition, Faerm said.

Malkin believes the FDA will deny Jazz's citizen petition, given that it already accepted Roxane's ANDA. However, the courts may be more apt to side with Jazz, given this latest opinion

Orphan Drugs and Rare Diseases
Maximizing Opportunities and Overcoming Stumbling Blocks in the Designation and Development Process
November 28-29, 2012
Hyatt Regency, Boston, MA

Developing drugs and investing in research and development can be risky business in general, and it can be even more so for small populations with unique disease states. Our faculty of leading experts from Pfizer, Shire, Medicis, GSK, Emergent BioSolutions and many more will give you strategies to offset potential risks inherent to orphan drug development including:

• Understanding and factoring in the unique incentives, including favorable exclusivity, pricing, and tax benefits, for companies who decide to pursue designation

• Replenishing product pipelines in the face of the patent cliff through novel therapies

• Preparing for eventual pharmacovigilance and labeling issues downstream as designation takes off

• Designing clinical trials end points and proving safety and efficacy in a smaller population

• Protecting orphan drug status and keeping competitors at bay post-Makena

For more information, please visit our website: www.americanconference.com/orphandrugs

FDA Lawyers blog readers are entitled to a discount when referencing the code: FDA 200

On September 19, ten top U.S. and European drugmakers announced that they have formed a new nonprofit organization called TransCelerate BioPharma Inc. ("TransCelerate") to help improve how experimental drugs are tested to get them to patients sooner. The New York Times broke the story, along with the Associated Press and Reuters getting the word out for this organization that has been in the works for about a year.

The ten companies are: (1) Abbott Laboratories Inc., (2) AstraZeneca Plc, (3) Boehringer Ingelheim, (4) Bristol-Myers Squibb Co., (5) Eli Lilly and Co., (6) GlaxoSmithKline Plc, (7) Johnson & Johnson, (8) Pfizer Inc., (9) Roche Holding's AG Genentech, and (10) Sanofi SA. TransCelerate's headquarters will be in Philadelphia, Pennsylvania, which it hopes to open later this year. All of the companies will contribute financial and other resources but for right now scientists and other staff are working from their corporate offices.

FDA's Director for the Center for Drug Evaluation and Research ("CDER"), Janet Woodcock, M.D., supported the move, said in a statement,

We applaud the companies in TransCelerate BioPharma for joining forces to address a series of longstanding challenges in new drug development.... This collaborative approach in the pre-competitive arena ... has the promise to lead to new paradigms and cost savings in drug development, all of which would strengthen the industry and its ability to develop innovative and much-needed therapies for patients.

The interim chief of the effort is Garry Neil, former Corporate Vice President for Science and Technology at Johnson& Johnson. "There's never been anything like this to take on these big challenges," Neil said, who has so far offered no details on how big this project will get other than the initial focus would be five projects to make clinical trials more efficient with a budget in the millions of dollars. "We want to simplify, standardize, and also raise quality. ... We worry about potentially promising drugs which might not get studies unless we can increase the overall efficiency of the system. I think it will make it easier for companies," Neil added.

On September 18, FDA approved the first medical device approved for ultrasound imaging for use in standard mammography screenings for women with dense breast tissue. Sunnyvale, California-based U-Systems manufactures the device called the somo-v® Platinum Automated Breast Ultrasound System ("ABUS"). The decision follows a unanimous recommendation to approve the device by an advisory panel.

Dense breasts have a high amount of connective and glandular tissue compared to breasts that have a higher percentage of fatty tissue. Physicians can determine whether a woman has dense breast tissue via a mammography exam. The National Cancer Institute currently estimates that about 40 percent of the women having mammography screening have dense breasts. These women appear to have a higher risk for breast cancer as well.

Mammography is a low-dose x-ray image of the breast. Until the ABUS, mammograms of breasts with dense tissue show both fibroglandular breast tissue and tumors as solid white areas on a mammogram, making results difficult to interpret. Often the dense breast tissue would obscure smaller breast tumors, which could delay breast cancer detection.

A research letter published online in the Journal of the American Medical Association ("JAMA") last Tuesday reports findings that pharmaceutical advertisements have a tendency to minimize potential adverse effects when the products they promote become available over-the-counter ("OTC"). The researchers attribute this shift in content to the differences in prescription drug advertising standards, governed by FDA, and those for OTC advertising, governed by the Federal Trade Commission ("FTC"). FDA requires that ads present a "fair balance" of the risks and benefits of a drug, a requirement that is absent from FTC's "reasonable consumer" standard. Commentators note that the FDA regulations are better equipped to ensure against "active deception."

The research endeavor, sponsored by CVS Caremark, considered four drugs that transitioned from prescription to OTC status within the last ten years: Claritin® (loratidine), Prilosec® (omeprazole), Xenical®/Alli® (orlistat), and Zyrtec® (cetirizine). It examined 133 total television and print advertising materials from twenty-four months prior to, through six months after, each transition, and found that the percentage of advertisements that referenced side effects plummeted from 70% while prescription only to 11% once available OTC. Conversely, the proportion describing drug benefits jumped from 83% to 97%. The study further reports that OTC advertisements frequently omit the generic names of drugs, "a powerful tool for the patient as a consumer in that it helps tie together scientific information on the drug from different places." Roughly 50% of the OTC ads mentioned the generic name, while over 95% had when the drugs were available by prescription only.

"In many, many cases information about risks simply disappeared from the ads once the drugs became [OTC]," remarked head researcher Dr. Jeremy Greene. This likely contributes to erroneous consumer beliefs that relocation out from behind the pharmacy counter automatically indicates a safer product. With 106 ingredients, indications, or dosage strengths having made the Rx-to-OTC switch since 1976, it is unlikely that this is always the case. Greene highlighted the danger of this situation given the frequency of overdoses on some of the most commonly used OTC drugs, such as acetaminophen (Tylenol®) and ibuprofen (Advil®). A 2006 study, for example, estimated over 450 acetaminophen overdose-related fatalities each year.

This research raises the question of where consumers can turn to obtain important information on potential side effects, if they are not receiving it from product ads or prescribers/suppliers. While some information is available online (such as at otcsafety.org or webmd.com), tracking it down requires active effort. Consumer Healthcare Products Association (CHPA) policy does note that the OTC label "is the most important element of a nonprescription drug," and "clearly lists a product's active ingredient, purpose, uses, warnings, directions, other information, and inactive ingredients." In an age dominated by electronic media, however, consumers are inevitably paying more attention to television and online/print advertising than drug labels. Also of note is that current OTC labeling requirements were promulgated by FDA, not FTC.

The Caremark study findings indicate that reform may be necessary to ensure transparency of consumer risks in the OTC pharmaceutical market, whether it be FDA oversight of OTC drugs or FTC adoption of stricter advertising criterion. With 240 million Americans currently using OTC medicines, according to a January 2012 CHPA report, it is a matter that deserves serious consideration.

FDA's various user fee acts ("UFAs") have not reached their implementation date in October 2012, yet FDA has already begun announcing staff changes to help with overseeing the new changes.

On the Commissioner level, Peter Lurie will be replacing David Dorsey as Acting Associate Commissioner for Policy and Planning. In a September 12 staff memorandum, FDA Commissioner Margaret A. Hamburg, M.D. announced the departure. Dorsey is leaving FDA to be a senior director in global regulatory policy and intelligence at Janssen Research & Development LLC in Rockville, Maryland. Hamburg wrote in the staff memorandum:

Throughout his long government tenure, David's colleagues repeatedly have sought him out for his extraordinary depth of knowledge, his vast experience on the Hill and at the agency, his thoughtfulness, and his patience under pressure. . . . David's departure will be a loss to the agency, and we will miss him.

(The Pink Sheet, September 13, 2012).

This changes follows a few earlier FDA staff changes at the Commissioner level and elsewhere last month. First, Associate Commissioner for Regulatory Affairs Dona Carrigan was announced as the new Director of FDA's Europe Office and Senior Advisor for Global Operations, stationed in Brussels, Belgium. Carrigan's new position is designed to help implement the Agency's strategic and risk-based global industry oversight and enforcement. Next, Melinda Plaisier will be Acting Associate Commissioner for Regulatory Affairs effective October 1. Plaisier was previously the Regional Food and Drug Director in the Office of Regulatory Affairs' central region, and before that she was Associate Commissioner for Legislation and Associate Commissioner for International Programs.

On September 12, FDA's Center for Drug Evaluation and Research ("CDER") Director Janet Woodcock, M.D. reported FDA's biosimilars program will be "under-resourced" until the biosimilars industry develops at a Drug Information Association ("DIA")/FDA Biosimilars Conference: Guidances, Science, and BsUFA. "This is going to be an under-resourced program for the next few years because that's how it is ... That'll cause, I think, some struggle, especially with allocation of resources amongst all the important activities that we do at FDA," Woodcock said. (The Pink Sheet, September 12, 2012.)

Once again, FDA reported that while FDA has the authority to approve biosimilars, FDA still has yet to receive a single biosimilars application, called 351(k) applications, based on their new statutory provision. FDA reported the same numbers that were discussed in two recent conferences discussing biosimilars that we reported on here and here: 11 investigational new drug applications ("INDs") and 30 pre-IND meetings with the Agency concerning biosimilars. FDA recently did approve Teva's biosimilar version of Amgen, Inc.'s Neupogen® (filgrastim), but Teva submitted this as a full biologics license application ("BLA") rather than a biosimilar, because reportedly Teva believed the biosimilar pathway was either infeasible or not ready for commercial approvals yet.

Woodcock speculated that annual product fee payments for sponsors with INDs will likely be the initial source of extra funding that FDA receives, with 351(k) fees to follow only after sponsors start submitting these applications. Under the Biosimilars User Fee Act ("BsUFA") that will become effective on October 1, 2012 along with other user fees, barring any possible derailment, which we reported here, the development fees are only 10% of the marketing application fees for each year, but the payments will be subtracted from the marketing application fee, once filed. For example, in Fiscal Year 2013, the product development fee for a 351(k) application is $195,880 with 351(k) application fees set at about $1.96 million per application.

On January 2, 2013, barely three months after FDA's new user fee programs go into effect, certain mandated spending reductions, called sequestration, also may go into effect that could prevent FDA from using the user fees it collects from industry. A Congressional Super Committee failed to find the required $1.2 trillion in cuts over ten years by a November 2011 deadline. The combined effect of lost taxpayer and user fees projected by Maryland-based Alliance for a Stronger FDA, would be an initial $294 million out of a $3.65 billion budget.

The catch comes from a component of FDA's user fee programs known as the "trigger" that requires a certain baseline of taxpayer funds to go to FDA, so industry user fees supplement rather than fund FDA's operations. FDA's projected funding for fiscal year 2013, set at $2.5 billion, would be cut by an across-the-board, 8% cut in federal government, coined as a "fiscal cliff", imposed to help curb the ever-increasing government debt. While FDA's cut of about $200 million would not normally hit the trigger to prevent FDA's use of user fees, Steven Grossman, Deputy Executive Director of the Alliance for a Stronger FDA, told Anna Edney from Bloomberg that the Obama Administration may still sequester FDA's user fee funds to help with federal spending reduction goals. The exact trigger levels, moreover, are based on formulas that include consumer inflation and past spending, which so far FDA has declined to comment on.

According to Grossman, if this occurs, about $68 million in drug and device user fees and $40 million in tobacco-company payments would be diverted to a U.S. Treasury Department account that would "reduce government because it would reduce what they can do." Faced with the sudden loss of these funds, drug industry experts have speculated that FDA would be forced to lay off personnel and take other measures to reduce costs.

Charles Raubicheck, head of our firm's FDA practice, will chair a panel and deliver an address at the "U.S. & Brazil Conference: Navigating New Frontiers in Pharmaceutical, Medical Device and Food Law and Regulation," to be held on September 10-11, 2012 in Sao Paolo, Brazil.

The conference, sponsored by The Food and Drug Law Institute ("FDLI"), will bring together representatives of companies, venture capital firms, government agencies, law firms and other groups involved in the drug, device and food industries. They will engage in high-level discussions about respective commercial, trade, legal and other aspects of doing business in this country and Brazil, the world's 6th largest economy.

Mr. Raubicheck's panel will focus on the interplay between regulatory and intellectual property issues pertinent to pharmaceuticals. His presentation is entitled "NDAs, ANDAs, FDA's Orange Book, and Patent Term Extensions."

On September 6, District of Columbia District Judge Amy Berman Jackson granted FDA's motion to dismiss claims brought by K-V Pharmaceutical Company ("K-V") either because the claims were unreviewable as discretionary FDA enforcement activities or failed to state a claim. Jackson's Memorandum Opinion helps solidify FDA's position that its discretion not to take an enforcement action is presumed to be immune from review unless Congress has otherwise provided "meaningful standards . .. for defining the limits of that discretion." (citing Heckler v. Chaney),

Makena™ is essentially a story about K-V's bid to take advantage of provisions under the Orphan Drug Act to obtain seven years of exclusivity to market the active ingredient in Makena™ (17-hydroxyprogesterone caproate) for women who have had a singleton pregnancy and a history of prior preterm delivery. Under the Orphan Drug Act, no other company can obtain approval to market the same active ingredient for this indication, which affects less than 200,000 patients per year in the United States, until this exclusivity would have expired. Prior to approval of Makena™, however, pharmacies had been compounding the same active ingredient for individual patients based on individual prescriptions--not a marketed product--at far less cost, around $10-20 per injection rather than the initial price of Makena™ at $1500 per injection, or up to $30,000 for the entire treatment. For more background, see, for example, an earlier blog here.

K-V had hoped that orphan drug approval would block competitors for seven years and its approval would make FDA take additional enforcement actions against pharmacies that had been routinely compounding the same active ingredient for the same indication. Indeed, many had feared, including a number of Congressmen, that FDA would take such actions, causing the cost of treatment to dramatically rise, under a general assumption that an approved drug product would be preferred, from a public health perspective, over a compounded product.

FLH Partner Charles J. Raubicheck, head of our firm's FDA/Regulatory practice, will moderate a panel and deliver an address at the upcoming Food and Drug Law Institute's Conference "U.S. & Brazil: Navigating New Frontiers in Pharmaceutical, Medical Device and Food Law and Regulation." The conference will be held on September 10-11, 2012 in São Paolo, Brazil.

Brazil has the world's 6th largest economy, and is becoming a leader in research and development in the drug, medical device and food industries. The Conference is a forum for representatives of companies, venture capital firms, government agencies, law firms and other interested groups to focus on business opportunities and regulatory hurdles in both Brazil and the U.S. Speakers will include officials of FDA and the Brazilian National Health Surveillance Agency ("ANVISA").

Mr. Raubicheck is moderating the "Medical Products: IP Issues" panel, which will discuss the interaction between regulatory and intellectual property issues applicable to pharmaceuticals and medical devices. Other panel members include Nuno Pires de Carvalho, Director, Intellectual Property and Competition Policy Division, World Intellectual Property Organization ("WIPO"), and Albert Keyack, Latin America Attaché, United States Patent and Trademark Office.

Mr. Raubicheck's presentation is entitled "NDAs, ANDAs, FDA's Orange Book, and Patent Term Extensions." Frommer Lawrence & Haug is a sponsor of the event.