FDA Lawyers Blog

The Pediatric Committee ("PDCO") of the European Medicines Agency ("EMA") is tasked with identifying the needs for children in a variety of therapeutic areas and aims to encourage the research and development of pediatric medicinal products. The first Inventory, which is now open for discussion and public consultation, covers medicines for cardiovascular diseases. The EMA points out that it will be releasing similar lists for other therapeutic areas for public consultation during 2012 and 2013.

According to the EMA, the Inventory aims to enable:

• Companies to identify opportunities for business development;

• The PDCO to judge the need for medicines and studies when assessing draft pediatric investigation plans, waivers and deferrals; and

• Healthcare professionals and patients to have an information source available to support their decisions as to which medicines.

The Inventory is based on a report on the survey of all pediatric uses of medicinal products in Europe completed by the PDCO in December 2010.

On August 27, FDA published a Federal Register notice announcing the availability of industry guidance for generic drug user fees entitled "Generic Drug User Fee Amendments of 2012: Questions and Answers" and "Self-Identification of Generic Drugs Facilities, Sites, and Organizations." Simultaneously with this notice, FDA also announced an upcoming public meeting on September 21, 2102 from 9 a.m. to 1 p.m. to discuss FDA's implementation of the Generic Drug User Fee Amendments of 2012 ("GDUFA"). Finally, on the same day, another related Federal Register Notice issued: "Notice of Opportunity to Withdraw Abbreviated New Drug Applications to Avoid Backlog Fee Obligations." Below is a snapshot of each of these items taken in turn.

GDUFA was signed into law on July 9, 2012 but the obligations arising therein begin on October 1, 2012. We have previously blogged on the genesis of GDUFA, when both the House and Senate passed GDUFA, for some background why and how we got here.

The GDUFA Q&A answers questions about the various types of fees (backlog fee, drug master file fee, generic drug submission fees (including a fee for active pharmaceutical ingredients ("APIs") not referenced in a drug master file), and facility fees for APIs and finished dosage forms ("FDFs")), self-identification of facilities, sites, and organizations, review of generic drug submissions, and inspections and compliance. For example, most immediately, backlog fees will be calculated based on the number of pending original abbreviated new drug applications ("ANDAs") at the start of October 1, 2012. As was mentioned in a recent conference discussing this topic, a recommendation was made for all generic applicants to "clean house" and make sure that they did not pay fees for any pending ANDAs that they were no longer pursuing. FDA explains in this Notice that in accordance with GDUFA, FDA will divide $50 million by the number of pending ANDAs pending on this day to arrive at an individual one-time backlog fee due for each pending ANDA. Applicants wishing to remove pending ANDAs from this list, however, must do so by written notification received by FDA on or before September 28, 2012. Failure to pay the backlog fee is further explained, including a public disclosure of the failure to pay, and FDA will not receive a new ANDA or supplement submitted by that applicant "or affiliate" until the fee is paid. The GDUFA Q&A also explains when the various fees will be collected and the effect of not paying those fees timely. For new ANDAs or supplements, feed need to be paid when due, e.g., for new ANDAs, within 20 calendar days of the date that FDA provides notification that failure to pay will result in the ANDA or supplement not being receive and, therefore, reviewed.

FDA Lawyers Blog is pleased to invite you to nominate FDA Lawyers Blog to the American Bar Association's ("ABA's") annual list of the best 100 legal blogs. The short ABA's Blawg 100 Amici Form may be found here.

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On August 10, 2012, FDA approved Intelliject's new drug application for Auvi-Q™ (epinephrine) Auto-injector, a device used for the emergency treatment of life-threatening allergic reactions, or anaphylaxis. Anaphylaxis is a severe whole-body reaction to an allergen, characterized by difficulty breathing/wheezing, reductions in blood pressure and pulse, hives/itchiness, swelling of the face, among other symptoms. Anaphylaxis occurs very rapidly, often within seconds or minutes of exposure, and can result in death without prompt medical attention. Epinephrine is the only first-line treatment for anaphylaxis, based on its ability to regulate heart rate, blood vessel and airway passage diameters, and metabolic shifts.

Currently, the EpiPen® Auto-injector is the most prescribed treatment for severe allergic reactions and anaphylaxis, with a market share of more than 95%. However, close to two thirds of patients and caregivers do not carry EpiPens® at all times as directed. Further, many patients have concerns that others will not know how to use EpiPens® in an emergency situation. Other epinephrine auto-injectors, similar in shape to EpiPen®, include Twinject®, Adrenaclick®, and Anapen®.

Unlike the currently-available auto-injectors, Auvi-Q™ is the size and shape of a credit card, and it is as thick as a smartphone, making it small enough to fit in a pocket or a small purse. In addition, Auvi-Q™ is the first epinephrine auto-injector to provide both audio and visual instructions to direct a user how to properly use the device. Intelliject's goal for AuviQ™ was to make it easy to carry and easy to use.

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On August 21, FLH Partner Brian J. Malkin was quoted in an FDAnews Article on a August 17 ruling refusing to stay a ruling regarding a settlement for K-Dur® 20 (potassium chloride) that was found to be presumptively anticompetitive. As part of the settlement in question, Upsher-Smith Laboratories ("Upsher-Smith") did not agree that the patent-at-issue was valid, infringed, and enforceable, but did agree to refrain from marketing its generic potassium chloride supplement or any similar product until September 1, 2001, when it would receive a non-royalty, non-exclusive license under the patent to make and sell its generic version. Upsher-Smith also granted the innovator, Schering-Plough Corporation ("Schering-Plough") a license to several Upsher-Smith products, including Niacor-SR, a sustained niacin product. Schering-Plough also agreed to pay Upsher-Smith $60 million over three years plus additional royalties depending on its sales of Niacor-SR. After the settlement, however, Schering-Plough abandoned its plans to market Niacor-SR.

The Third Circuit originally held:

Specifically, the finder of fact must treat any payment from a patent holder to a generic patent challenger who agrees to delay entry into the market as prima facie evidence of an unreasonable restraint of trade, which could be rebutted by showing that the payment (1) was for a purpose other than delayed entry or (2) offers some pro-competitive benefit.

For more background on this case, please see one of our blogs here.

Malkin was cited in the article in the following manner:

Both brand and generic-drug makers are likely to try to find more creative ways to craft settlements if pay-for-delay deals are ultimately found to violate antitrust law, Brian Malkin a partner at Frommer Lawrence & Haug, told DID. For example, such settlements could involve more than just the drug product at issue in the case, making it less clear whether there is a pay-for-delay element.

A high court ruling against pay-for-delay could also affect companies' willingness to litigate certain patent cases, Malkin added.

Meanwhile, Congress may be waiting to see if and how the Supreme Court rules on this issue, Malkin said. A representative from Sen. Orrin Hatch's (R-Utah) office told him earlier this year that legislation targeting pay-for-delay deals is "likely on the backburner."

Meanwhile, Defendants Merck & Co. Inc. (the successor-in-interest after Schering-Plough) and Upsher-Smith have asked the U.S. Supreme Court to look into the Third Circuit's pay-for-delay ruling. In particular, the K-Dur ruling differs from other circuits that have found such payments legal in the context of a patent that is presumptively valid and an agreement to market by the expiration date of the patents-at-issue in return for ending the litigation. The U.S. Federal Trade Commission ("FTC") Chairman, Jon Leibowitz, has reportedly commended the Third Circuit for having "gotten it just right" in K-Dur,as the FTC plant to expand the holding into other cases pending in the Third Circuit and possibly other circuits pending the Supreme Court's deliberation whether to hear the appeal.

On August 2, four members of the House of Representatives, led by Congressman Edward Markey, introduced, H.R. 6272, "The Trial and Experimental Studies Transparency (TEST) Act of 2012." The TEST Act will amend Section 402(j) of the Public Health Service Act, tightening the reporting requirements for the Internet site designed to better inform the public about ongoing and completed clinical trials in the United States, ClinicalTrials.gov. The main goal of the TEST Act is to prevent clinical-trial sponsors from withholding negative study data and safety concerns while emphasizing the positive results of their clinical trials.

Prior to the proposed TEST Act, under the Food and Drug Administration Amendments Act of 2007 ("FDAAA"), most United States-conducted interventional clinical trials were registered at ClinicalTrials.gov, and most of the results of those clinical studies were eventually published. However, loopholes in the requirements of the FDAAA resulted in clinical studies that were either not registered, that failed to report results, or both. There are a number of clinical trials, therefore, that are not registered in the publically-accessible database.

The TEST Act will require all interventional biomedical studies conducted on humans to be registered on ClinicalTrials.gov prior to enrolling any patients. In addition, sponsors of these clinical trials will be required to post the study results and other required information on ClinicalTrials.gov within one year of the completion date of the trial. According to the proposed legislation, interventional studies include all human studies where patients are assigned, via protocol, by an investigator to receive specific intervention where the effects of such intervention on biomedical or health-related outcomes are evaluated. For clinical trials involving drugs or medical devices that have never been approved for any use, the TEST Act permits a delayed results submission of up to two years from the date of completion of the clinical trial.

The U.S. Court of Appeals for the Federal Circuit recently rendered a follow-up ruling on remand from the Supreme Court's April 2012 decision regarding Orange Book use codes for method-of-use patents Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S. The Federal Circuit held, in a July 30 ruling, that: (i) a district court can issue a mandatory injunction requiring the owner of the NDA for the brand product to correct a use code which inaccurately describes the FDA-approved, patented use, but (ii) the court must first give the NDA holder the opportunity to correct the use code, rather than direct the company to use precise language for the code.

Nevertheless, the Circuit went on to state: (i) the NDA holder does not have "unbounded discretion" in proposing a new use code, and (ii) the district court has the power to construe the scope of the patent claims and provide limits on the appropriate scope of the corresponding use code. If the court determines that the new code is inaccurate and/or overbroad, the judge at that point can correct the error.

This latest development comes in the wake of the U.S. Supreme Court's decision arising from Caraco's proposed section (viii) labeling carve-out for use of the diabetes drug repaglinide (on which we have previously reported here, for example). The patent at issue claimed use of repaglinide in combination with the drug metformin. Caraco wanted to omit the combination therapy, and label its generic version to treat diabetes with repaglinide only. Novo Nordisk admitted that the patent did not cover the use of repaglanide alone, but then changed its use code in the Orange Book to wording that was broad enough to cover repagalanide alone.

On August 3, a jury in the U.S. District Court for the District of Massachusetts found Genzyme's U.S. Patent Number 7,931,030 ("the '030 patent) was both not infringed by Seikagaku Corp. and its U.S. distributor, Zimmer Inc., and invalid as obvious in light of the prior art.

Genzyme obtained FDA approval in February 2009 to market Synvisc-One®, an injectable hyaluronic acid gel to treat osteoarthritic pain in the knee. According to Genzyme, Synvisc-One® was an improvement over prior treatments since only one injection of Synvisc-One® was required at least every six months compared to existing drugs that require three injections one week apart for similar pain relief. Synvisc-One® was the only single injection treatment until the FDA approved Gel-One®, a similar treatment also containing hyaluronic acid produced by Seikagaku, in March 2011. One month later, Genzyme filed a complaint alleging that Gel-One® infringed U.S. Patent Number 5,399,351 ("the '351 patent"). Genzyme then amended its complaint to add the '030 patent to the suit in June 2011 and agreed to drop claims concerning the '351 patent in February 2012.

Following this jury verdict, U.S. District Judge Douglas Woodlock vacated a preliminary injunction issued on December 30, 2012 barring Zimmer from providing free samples of Gel-One® and from selling Gel-One® at less than $547.60 per injection. Judge Woodlock also refused to grant a judgment as a matter of law after the jury verdict.

The use of a jury in this case as opposed to a bench trial in front of a judge is consistent with the significant increase in the use of juries in patent cases since the 1980s according to a 2011 Patent Litigation Study by PricewaterhouseCoppers. However, the outcome in this trial, favoring in the alleged infringer, is contrary to the general trend demonstrating that patent holders are more likely to win in front of a jury instead of a judge according to the same study.

There has been an increased effort to increase pediatric testing for adult medications, due to the expense of pediatric clinical trials and parent concerns about participation. For example, an alarming 70 percent of medications prescribed for children have never been tested on them, the National Institute of Health ("NIH") estimates.

In an effort to address the issue, on July 9, 2012, President Barack Obama reauthorized the "Best Pharmaceuticals for Children Act" and "Pediatric Research Equity Act" providing drug companies with a six month period of "pediatric exclusivity" if they perform studies approved by the FDA. This approval is a main proponent in easing parents' minds when allowing their own children to participate in clinical trials. In addition, such initiatives have helped incentivize sponsors to conduct more pediatric research with NIH funding for pediatric research rising by 18% "from $2.77 billion in 2008 to $3.28 billion in 2011.

Still, while improvements are on the horizon, there is much to be done to fully address the lack of pediatric clinical trials. A July 23 study in Pediatrics found a scarcity in pediatric drug trials as well. Dr. Florence T. Bourgeois, lead researcher on the new study, expressed concern that doctors have long been known to "extrapolate" findings from adult studies to then apply them to children. Bourgeois said that "children are not small adults." Due to children's developing bodies, they metabolize drugs differently than adults do. In fact, children encounter disease just as frequently, or more so, than adults, according to Bourgeois, yet "[c]hildren continue to be underrepresented in clinical trials compared with their burden of disease." Overall, just 12 percent of all clinical trials focused on children and teenagers. Yet children accounted for 60 percent of those suffering the conditions studied. Bourgeois said that more may need to be done to encourage not only drug company trials, but studies funded by non-commercial sources as well.

"One of FDA's top priorities is giving pediatricians and parents the same level of tested and researched information on drugs used to treat children that is required for drugs used to treat adults," FDA spokesperson Sandy Walsh reportedly said. "Congress has helped increase studies for children by passing legislation that gives companies financial incentives to conduct pediatric studies and to require them to study a product they are developing for adults if the disease also occurs in children," Walsh added.

The impact and influence of the Best Pharmaceuticals for Children Act and Pediatric Research Equity Act will be discussed by FDA's Pediatric Advisory Committee this upcoming September. The meeting agenda includes the discussion of pediatric-focused safety reviews as mandated by both of the recently authorized Acts.

Yesterday, FLH Partner Brian J. Malkin was quoted in a MedPage Today article by Washington Correspondent David Pittman on a GPhA Study that also published yesterday entitled: "Savings $1 Trillion Over 10 Years: Generic Drug Savings in the U.S. (Fourth Annual Edition: 2012)". According to the Report, generic drug use has saved the U.S. health care system approximately $1.07 trillion over the past decade (2002 through 2011) with $198.8 billion in savings in 2011 alone. The GPhA Report in turn referenced a number of recent positive analyses of the generic industry, asking Congress not to change the innovator-generic incentives or restrict the use of generics, with a promise for delivering generic biologicals in the future.

Along these lines, MedPage Today attributed Malkin with the following statements:

Changing the 5-year exclusivity period for traditional small-molecule drugs or the 12-year exclusivity for biologics is unlikely, Brian Malkin, drug industry attorney and partner with Frommer Lawrence & Haug in Washington, told MedPage Today in an interview.

"It's an election year; maybe they're trying to position themselves for the future," Malkin said of Thursday's GPhA report. The savings analysis seemed to be mostly about creating awareness and generating good will for future policy decisions, he said.

For instance, seeking to dissuade a Health Affairs article in November 2011 that stated generic drug usage has increased at a rate that has discouraged the development of new drugs, the GPhA Report highlighted a recent IMS report in April 2012 that found: "...[A]though generic utilization has reached new levels, more new medicines were launched in 2011 that in any other year of the past decade ... since the implementation of Hatch-Waxman, there has been a multiple-fold increase in the innovation of new medicines." The GPhA Report observed: "By creating a fair balance between innovation of new medicines and accessibility to lower cost generic medicines, federal law has established a win-win for providers and American consumers."

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