FDA Lawyers Blog

by Scot B. Pittman

As previously reported here, FDA and medical device industry reached a tentative user fee agreement earlier this month. The tentative agreement calls for $595 million to be paid to FDA in exchange for a number of performance goals and other measures meant to provide a faster, more streamlined review process. The proposed agreement has not yet been submitted to Congress (FDA expects to submit the proposal by mid-March.), but that did not stop the House Energy and Commerce Health Subcommittee from discussing the proposal at its February 15 device user fee reauthorization hearing.

A central concern with a number of the representatives was the magnitude of the increase in user fees. The proposed agreement calls for the medical device user fees to roughly double over the life of the five-year agreement. Jeffrey E. Shuren, M.D., J.D., Director of FDA's Center for Devices and Radiological Health ("CDRH"), defended the increased fees. According to Shuren, CDRH is in desperate need of additional funding to increase its review staff and improve the review process. Shuren also stressed that the increased user fees for small firms would not increase as significantly as the overall user fees. For example, a 510(k) submission fee for a small firm (those having annual revenues of $100 million or less) would start at $2000 in 2012 and top out at $2600 in 2017. A summary of some of the other fees include:

• Roughly $220,000 for a Pre-Market Application ("PMA") or Biologics License Application ("BLA") in 2012; small firms would pay roughly $55,000. These figures rise to roughly $268,000 and $67,000, respectively, in 2017.
• Larger firms would pay around $4,000 for a 510(k) submission in 2012 and around $5,400 in 2017.
• In 2012, the device registration fee (a fee paid by all registered device makers and reprocessors) will be a little over $2,000, but it will grow to almost $4,000 by 2017.

PIV Disputes 2012

American Conference Institute invites you to join your peers and colleagues at the 6th Anniversary Edition of its Paragraph IV Disputes conference. FLH Partner Barry S. White will be presenting at this timely and industry-leading forum where counsel and advisors for brand name and generic pharmaceutical companies will address every facet of Paragraph IV litigation, in addition to some of the most pressing and recent controversies surrounding these cases:

• Double patenting obviousness
• Inducement of infringement
• Section 8 carve-outs
• Inequitable conduct
• Damages
• Possible re-evaluation of the invalidity standard

This event -- which is widely recognized for setting the standards for Paragraph IV litigation and which also serves as the annual meeting place for the "who's who" of pharmaceutical patent litigation -- is now the single forum on which brand name and generic companies can rely for answers during this turbulent time in which the balance of power designed by the Hatch-Waxman Act may completely unravel. Come to this conference and get the up-to-the minute information that you need to prepare for the new litigation confrontations to come.

Do not miss your opportunity to enhance your learning and networking experience by attending one or both of our hands-on, informative and practical workshops:

• Hatch-Waxman and BPCIA 101 -- A Primer on IP Basics and Regulatory Fundamentals
• The Master Class on Settling Paragraph IV Disputes: Drafting and Negotiating Strategies
for Brand-Name and Generics

For more information and to register, click here. FDA Lawyers Blog readers can obtain a $200 discount with the code FDALB 200. Early bird pricing expires this Friday, March 2.

by Brian Malkin

This is part two of a two-part series covering the Generic Pharmaceutical Association's ("GPhA's") Annual Meeting in Orlando, Florida on February 22-24. Please see part one here for background information and information of public events on day two of the Conference.

On the third day, GPhA's new President and Chief Executive Officer, Ralph G. Neas discussed a number of key GPhA upcoming programs and initiatives. GPhA's has proposed an Accelerated Recovery Initiative ("ARI") to use independent third parties to collaborate with stakeholders to prevent drug shortages that are expected to last 90 days or more. ARI will be an open, voluntary program that will work with an FDA "SWAT"-like team to respond in a quick way to drug shortages. Hamburg has endorsed the program, and GPhA has engaged the Federal Trade Commission, the Drug Enforcement Agency, and others to make sure that ARI is not viewed as exclusionary, Neas added.

Neas summarized how GPhA has been involved in state-level advocacy preventing anti-drug-substitution laws in 22 states, as well as federal initiatives to prevent extending patents with no corresponding benefits to generics. GPhA established an affordable medicines research institute, Neas added. GPhA wants generic user fees to be added to FDA's budget and not be used as a substitute to adequate federal FDA funding for generic product review. GPhA hopes that FDA will build upon its biosimilar guidances to make interchangeable biosimilars a reality, not an insurmountable barrier. Neas also is concerned that innovators may open up Hatch-Waxman with suggestions to limit first time generic patent challengers to 90-days of exclusivity (instead of the current 180-day exclusivity) or extend new chemical entity exclusivity to match biologics (currently 5 years for small molecules and 12 years for biologics), which GPhA will continue to fight.

by Brian Malkin

On February 22-24, the Generic Pharmaceutical Association ("GPhA") held its Annual Meeting in Orlando, Florida to a first-time, sold-out crowd of approximately 625 attendees. During the public sessions to which this blog refers, representatives from the generic industry along with guest speakers such as FDA Commissioner Margaret A. Hamburg, M.D., addressed a variety of issues facing generic drug manufacturers in the upcoming year and years to come. Key topics throughout the conference included drug shortages, biosimilars, and challenges to survival of generic industry despite the promise of the user fees from the Generic Drug User Fee Act ("GDUFA") to shorten abbreviated new drug application ("ANDA") review times. This is part one of a two-part series.

Hamburg said that she had hoped to announce a new director for the Office of Generic Drugs ("OGD"). In the meantime, a big OGD focus will be gearing up to effectively utilize the $299 million per year user fees (to be adjusted by need and inflation) with the goal to shorten review times from a mean of 30+ months to 10 months. One of the challenges will be addressing the need to conduct overseas inspections now that approximately 40% U.S. generic drugs are imported and 80% U.S. generic drugs utilize imported active pharmaceutical ingredients. FDA also hopes to streamline the review process by issuing single response letters rather than multiple deficiencies, resulting in less review cycles.

According to Hamburg, the generic drug industry must continue to demonstrate therapeutic equivalence and equality to maintain that generics are as good as innovator products. Hamburg explained that the OGD will continue to address new scientific topics, such as bioequivalence for inhalation products, and hopes to tackle additional issues surrounding more complex dosage forms. In turn, Hamburg asked the generic industry to help support studies on generic drugs to address key patient concerns and to invest generally in high quality production to reduce drug shortages. Hamburg warned GPhA's members that currently there are more drug shortages attributed to generics, which could lead to a public misperception that generic drugs are not as good. Hamburg also discussed internal changes made within FDA to reduce drug shortages after President Barack Obama's Executive Order in October 2011, which has resulted in 195 shortages prevented in 2011. The generic drug industry can help, Hamburg said, by providing early notification of potential shortages. Hamburg also briefly discussed FDA's new biosimilar guidances and FDA's biosimilars statistics to date: 35 pre-investigational new drug ("IND") application meeting requests, 21 pre-IND meetings, and 9 in-house INDs.

by Andrew S. Wasson

FDA tied up several loose ends relating to biosimilars and trade secrets recently by denying a Citizen Petition filed by the Biotechnology Industry Organization (filed on April 23, 2003, now assigned Docket Number 2003-P-0003) and Genentech (filed on April 8, 2004, now assigned Docket Number 2004-P-0214). These petitions were filed during the long period of contentious debate about the legality and practicality of a biosimilars pathway that preceded the passage of the Biologics Price Competition and Innovation Act in 2010. Some of the early debate focused on whether any pathway contemplated by FDA, including approval of biological products under 21 U.S.C. § 355(b)(2), would constitute a violation of innovator property rights. In its recent decision, FDA denied both requests.

FDA responded to the majority of the issues set forth in the BIO and Genentech Citizen Petitions in responses from 2003 and 2006, however FDA still had not responded to two requests made by the petitioners:

(1) that FDA decline to publish a draft guidance regarding the 'similarity' or 'sameness' of a 'biotechnology-derived product' or 'therapeutic protein' that relies on confidential or trade secret information;

And (2) that FDA provide advance notice and a pre-deprivation hearing if FDA does decide to issue such a guidance using trade secret or confidential information

With the recent issuance of three draft guidance documents (Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product, and Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009), FDA found it appropriate to finally determine the remaining Citizen Petition issues.

FLH Partner Brian J. Malkin will attend the Generic Pharmaceutical Association's ("GPhA")'s Annual Conference in Orlando, Florida, from February 22-24. More than 500 attendees will join Mr. Malkin to hear from industry experts and other opinion leaders regarding insight into critical economic, regulatory, and legislative issues, particularly FDA's new proposed generic user fees, impacting the health care and generic pharmaceutical sector. Each year, GPhA's Annual Conference features presentations by leading industry CEOs, economists and financial analysts, FDA regulators, and state and federal officials. This year's conference features a keynote address by Margaret A. Hamburg, M.D., FDA Commissioner. More information about the conference may be found here.

by Richard F. Kurz

A February 17 news release announced that the California Supreme Court is considering whether a California state law may be used to challenge "reverse exclusionary payments" made in pharmaceutical patent litigation settlements. Sometimes referred to as "pay-for-delay" by detractors, this situation arises when a branded pharmaceutical manufacturer pays money to a generic manufacturer in the settlement of a patent infringement lawsuit. The question here is whether a suit under California's Cartwright Antitrust Act may be brought to challenge these settlements, which allegedly prolong the life of the patents at issue.

This case is particularly interesting because the dispute lies at the intersection between federal patent law (which gives patent owners the right to exclude others from making, using, or selling a patented good during the life of a patent) and California's antitrust law, which is intended promote competition. Preceding this petition, the California Court of Appeals held that these settlements do not violate the Cartwright Act if the settlement restrains competition only within the scope of the patent, unless the patent was procured by fraud or the enforcement suit was itself objectively baseless. In other words, such settlements are not violations of California's antitrust law, without more.

The petitioners, however, argue that these settlements are per se illegal under the Cartwright Act. In deciding otherwise, they allege that "the Court of Appeal accepted a misdirected line of recent federal authority that has no place in California jurisprudence" and "impose[d] a new standard on California, impairing the ability of the State and private citizens to vindicate their rights." This decision, they maintain, "offends the California public policy and public interest with respect to health care."

by Brian Malkin

On February 16, Leerink Swann's Global Healthcare Conference 2012 featured two presentations and several more private discussions featuring Center for Drug Evaluation and Research ("CDER") Director Janet Woodcock, M.D., as well as her colleagues, Steven Kozlowski, M.D., CDER's Director of Office of Biotechnology Products, and Keith Own Webber, Ph.D., CDER's Deputy Director, Office of Pharmaceutical Science, Acting Director, Office of Generic Drugs. The trio presented a discussion "Biosimilars Take the Stage" followed by Woodcock's Keynote Address on New Trends in Drug Regulation and Innovation, and several smaller question-and-answer-format meetings regarding these topics and more. This is part two of a two-part series and concerns the Keynote Address and followup presentations. Part one may be found here.

During Woodcock's Keynote Address, Woodcock addressed the swinging pendulum of new drug review, focusing on the impact of the various iterations of the Prescription Drug User Fee Acts ("PDUFAs") and FDA's road to shortening review cycles while providing increased transparency in the review process. Woodcock chronicled the shifting focus to drug safety to coincide with the shorter review cycles, stating that FDA now has better tools such as its Sentinel Initiative, providing "the same intensity as the pre-market review process."

Sentinel is a active network monitoring pharmaceutical use in over 100 million lives to date (about one-third the U.S. population), which provides FDA with important safety signals to investigate and respond to if an actual safety problem exists. Woodcock noted that a large part of FDA's post marketing review now includes monitoring for prescription drug abuse, which has become an "epidemic" problem that includes prescriber and end user failures, as well as ongoing problems of antibiotic resistance and improper offlabel use. Sentinel, for example, has already provided FDA with a very powerful finding that rare adverse events often reflect individuals with a particular genetic makeup that may permit previously-abandoned "bad" drugs to return, as long as there is a way to remove those individuals with genetic makeups that suggest the negative outcomes from using the products.

by Brian Malkin

On February 16, Leerink Swann's Global Healthcare Conference 2012 featured two presentations and several more private discussions featuring Center for Drug Evaluation and Research ("CDER") Director Janet Woodcock, M.D., as well as her colleagues, Steven Kozlowski, M.D., CDER's Director of Office of Biotechnology Products, and Keith Own Webber, Ph.D., CDER's Deputy Director, Office of Pharmaceutical Science, Acting Director, Office of Generic Drugs. The trio presented a discussion "Biosimilars Take the Stage" followed by Woodcock's Keynote Address on "New Trends in Drug Regulation and Innovation", and several smaller question-and-answer-format meetings regarding these topics and more. This is part one of a two-part series and concerns the biosimilars presentations. Part two will be posted on Tuesday.

Leerink's biosimilars session was moderated by Joshua Schimmer, M.D. and Jason Gerberg, J.D./M.B.A. with co-moderators Seamus Fernandez and Joseph Schwartz. Kozlowski provided some preliminary remarks followed by a question-and-answer format by the moderators. Kozlowski explained that the purpose of FDA's first set of biosimilars guidances, which we initially reported on here, was to set the scientific framework for approaching biosimilar product development and provide some interpretations of the new statutory terminology. Kozlowski explained that FDA decided to take a "totality of the evidence" and "stepwise approach", where the structural similarity of the biosimilar, as demonstrated by the sponsor, drives the development of the clinical program to support approval.

Woodock added that FDA has had a challenge to retrain their reviewers to think of biosimilar review as an "inverted pyramid." Typical drug review includes pre-clinical studies followed by increasingly large clinical studies, culminating in pivotal, larger-scale studies to demonstrate the safety and efficacy of the product that become the focus of the approval, i.e., the regular pyramid (pre-clinical on top, phase III clinical trials on the bottom). In contrast, biosimilar product development is envisioned to be characterized as spending a bulk of the resources up front, characterizing the innovator's product and the biosimilar (i.e., the top of the pyramid) to lead to smaller clinical studies to demonstrate similarity or test for immunogenicity or other elements that require testing, not duplicating the safety and efficacy testing that was already conducted by the innovator.

by Howard E. Rosenberg, Ph.D.

Late last year, the European Medicines Agency ("EMA") published a new guideline, "Guideline on the use of pharmacogenetic methodologies in the pharmacokinetic evaluation of medicinal products" to provide a framework for where it is recommended that pharmacogenetics should be implemented in the drug development process. At the same time, the guideline recognizes that pharmacogenetics may not be equally important for every drug.

Patients are not all identical and different individuals may well react to a particular medicine in diverse ways. For example the manner in which a patient absorbs and/or metabolizes a particular drug may well differ form one to another. In recent years there has been a rapid development in the understanding of the influence of genes on interindividual differences in drug action. Hence the pharmacokinetics of many medicinal products is prone to interindividual variability, caused by several factors such as gender, age, weight, impaired renal and hepatic function, and genetics.

In the field of pharmacogenetics, interindividual variability in genes influencing or predicting the outcome of drug treatment (e.g., genes encoding drug transporters, drug metabolizing enzymes, drug targets, biomarker genes) is studied in relation to efficacy of drug treatment and adverse drug reactions. A knowledge of genetic factors influencing absorption, distribution, metabolism and excretion ("ADME") is centered on drug metabolism. Genetic variations in metabolizing enzymes may lead to: (i) increased or decreased clearance of the parent drug or pharmacologically active or toxic metabolites, (ii) increased or decreased production of active metabolites of the respective prodrugs, or (iii) increased or decreased formation of toxic products.

by Brian Malkin

On February 9, FDA issued a Federal Register Notice announcing the availability of a new guidance, "Determining the Extent of Safety Data Collection Needed in Late Stage Premarket and Postapproval Clinical Investigations. FDA issued the guidance because it believes that more selective or targeted safety data may be possible for some late stage premarket trials and postmarket trials because certain aspects of a drug's safety profile may be well-established from previous studies or what is already known about the medical product's safety profile. While many general principles in this guidance apply to the clinical development of oncology drugs, FDA has developed a specific guidance for oncology drugs, Cancer Drug and Biological Products - Clinical Data in Marketing Applications. The guidance also does not modify general reporting of postmarketing adverse events.

Safety Data Collection Guidance

The guidance notes that while extensive safety-related data are collected through the course of drug development, in late stages or development or during a postmarket period, a selective and better targeted approach may be warranted, especially when certain safety aspects are already known. In the past, selective or specifically-targeted data collection and reporting during clinical trials has been implemented on a case-by-case basis, and there has been little public discussion of this practice. The more targeted approach reflects the view that less serious, less severe, and more common side effects are often characterized in earlier data collection, so little additional information would be gained by further collection of these events.

According to the guidance, the circumstances when targeting safety data is most appropriate are when the following conditions are present:

• The number of subjects exposed to the drug in previous studies in sufficient to characterize the safety profile for all but rare events;


• The occurrence of adverse events has been generally similar across multiple studies; and


• There is a reasonable basis to conclude that occurrence of adverse events in the population to be studied will be similar to previously observed rates.

On February 15-16, FLH Partner Brian J. Malkin will attend Leerink Swann's 2012 Global Healthcare Conference in New York City. This year's Conference features a Keynote Address by FDA's Director of the Center for Drug Evaluation and Research ("CDER") Janet Woodcock, M.D., entitled "New Trends in Drug Regulations and Innovation" as well as a panel presentation on biosimilars entitled "Biosimilars Take the Stage" featuring Dr. Woodcock as well as Steven Kozlowski, M.D., CDER's Director of Office of Biotechnology Products, and Keith Own Webber, Ph.D., CDER's Deputy Director, Office of Pharmaceutical Science, Acting Director, Office of Generic Drugs. Each year, Leerink Swann's Conference brings together nearly two hundred company presentations as well as specialty panels to provide a unique and productive forum to navigate the investing landscape.

Founded in 1995, Leerink Swann is recognized as a leading healthcare investment bank to a broad range of institutional, life sciences, corporate, and high-net-worth clients that are positioned to shape the future of healthcare. All of its services are enhanced by the expertise of its proprietary MEDACorp network of 35,000+ physicians, researchers, and healthcare professionals providing insights into cutting edge advances in healthcare.

by Brian Malkin

On February 7, a week before Valentine's Day, Janet Nudelman, representing the nonprofit coalition of environmental- and cancer-prevention groups, the Campaign for Safe Cosmetics ("CSC"), once again wrote to FDA, asking FDA to take follow California and Canadian health authorities and set safe limits of lead in lipstick. The letter notes that while FDA maintains certain information on its website about lead in lipstick, e.g., a "Is there lead in lipstick?" page and December 5, 2011 updated "Lipstick and Lead: Questions and Answers" page, FDA has not conducted a formal assessment of lead in lipstick nor determined safe limits.

FDA's Questions and Answers explains that while FDA sets specifications for lead in color additives used in cosmetics (currently no more than 20 parts per million ("ppm"), FDA does not set limits for lead in cosmetics nor conduct any pre-market approval of cosmetics that could lead to uncover total amounts of lead in lipsticks. FDA stated that since the 1990s it has been aware of traces of lead in lipsticks, which was highlighted again principally by CSC in 2007. As a result of CSC's report, FDA tested in 2007 some 400 lipstick brands, concluding none of them were unsafe, falling all below the more conservative 5 ppm limit recommended by the State of California and below the 10 ppm limit set by Health Canada, which has draft guidelines on impurities in cosmetics. The original study appeared in a July/August 2009 Journal of Cosmetic Science article.

FDA updated its data from a survey of lipsticks from February to July 2010, which will be published in the May/June 2012 issue of the Journal of Cosmetic Science, FDA's Questions and Answers states. What concerned CSC was that left without specific FDA guidelines or lead limits, lead levels in some lipsticks have more than doubled when compared to the maximum amounts found in 2007 (e.g., in 2007, Cover Girl/Procter & Gamble and Revlon sold lipsticks with just over 3 ppm lead, whereas in 2010, Maybelline/L'Oréal sold brands with 7 or more ppm (exceeding the California guideline but still less than Health Canada), despite a majority having levels below 5 ppm). Also, CSC pointed out that FDA's study demonstrated that it is possible to manufacture lipsticks with lead levels as low as 0.03 ppm, suggesting that FDA could limit lead levels to below Health Canada's limits, perhaps approaching the 0.03 ppm mark. CSC analogized this to maximum allowed lead limits in candy that is set to 0.1 ppm "not because that limit is considered safe but because FDA determined that level to be the lowest level candy manufacturers can feasibly achieve."

by Kyle Deighan

On February 9, the Federal Circuit held that AstraZeneca failed to state a claim for patent infringement under 35 U.S.C. §271(e)(2) against generic pharmaceutical manufacturers that filed abbreviated new drug applications ("ANDAs") seeking approval for uses of Crestor® (rosuvastatin calcium) not covered by AstraZeneca's patents. The case is AstraZeneca Pharms. LP v. Apotex Corp..

AstraZeneca alleged that ANDA filings by various generics infringed or would infringe several of its patents covering methods of using rosuvastatin calcium. These patents covered methods of using rosuvastatin compounds to treat heterozygous familial hypercholesterolemia ("HeFH") and elevated C-reactive protein ("CRP"). As per the Hatch-Waxman Act, AstraZeneca filed a New Drug Application ("NDA") and obtained approval from FDA to market the drug. FDA approved several indications for using rosuvastatin calcium, including those uses claimed in AstraZeneca's patents. Additionally, FDA approved the drug for treating homozygous familial hypercholesterolemia ("HoFH") and hypertriglyceridemia, uses not covered by AstraZeneca's patents-in-suit.

Defendants filed ANDAs seeking to market generic versions of the drug, but submitted so-called Section viii Statements under the Federal Food, Drug, and Cosmetic Act ("FD&C Act") indicating they sought approval for uses not covered by the patents. In other words, the ANDA filers requested approval to treat only HoFH and hypertriglyceridemia while "carving out" the indications covered by AstraZeneca's listed patents. The ANDA filers moved to dismiss AstraZeneca's complaint for several reasons, including that the complaints failed to state a claim for patent infringement under Section 271(e)(2) because the ANDA filers were not seeking approval for uses of rosuvastatin calcium claimed in AstraZeneca's patents.

by Brian Malkin and Andrew S. Wasson

Yesterday, hot on the heels of a federal court's affirmation of FDA's Generic Lovenox® (enoxaparin) bioequivalence determination, which we reported on here, and curiously missing a corresponding Federal Register announcement, FDA released a suite of highly-anticipated draft guidance documents relating to FDA's implementation of the Biologics Price Competition and Innovation Act of 2009 ("BPCIA"). The BPCIA authorizes FDA to approve biological products under the Public Health Services Act ("PHS Act") if FDA finds them biosimilar to or interchangeable with an already-approved biological product. These draft guidance documents are the first guidance documents issued by FDA on the standards of biosimilarity for applications submitted under 351(k) of the PHS Act ("351(k) application"). For the foreseeable future, these documents are likely to be the subject of intense scrutiny by industry stakeholders, lawyers, and academics as they present numerous complex and hotly-debated issues.

FDA appears to be trying to get across a few overarching concepts that they hope will generally guide the development of a biosimilars industry based on the BPCIA: (1) potential biosimilar applicants should use a "stepwise approach" to develop a biosimilar product while minimizing residual uncertainty as a touchstone; (2) robust analytical characterization (a "fingerprint-like analysis algorithm") up front may allow for a selective and targeted approach to animal or clinical trials, which should include an initial meeting with the agency to obtain input on a proposed biosimilar development program; (3) FDA will review applications using a risk-based, "totality-of-the-evidence" approach; and (4) interchangeability is a high standard unlikely to be met by an applicant at the present time and not in its initial 351(k) application. Innovator and potential biosimilar applicants will likely square off on the role of European data in the development of a biosimilar product, even though the referenced product will likely have to be a U.S. biological and bridging data will be required.

The guidance documents underscore a "stepwise approach." The foundation of this approach is the robust and exhaustive characterization of the proposed and reference products. The draft guidance titled "Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product" contains details about potential methods of characterization. FDA sets out the following as steps in development following analytical characterization:

• animal data (at base for toxicity assessment);


• comparative human PK and PD studies;


• comparative clinical immunogenicity; and


• comparative clinical safety and effectiveness data.

The draft guidance suggests, however, that the comparative clinical safety and effectiveness step should only be reached if "residual uncertainties about the biosimilarity of the two products" exist. The Agency also has the discretion to determine whether any element above is not required in a 351(k) application.

by Brian Malkin

On February 7, United States District Judge Amy Berman Jackson granted defendant FDA's motion for summary judgment and denied plaintiff Sanofi-Aventis's ("Sanofi's") cross-motions in Sanofi's challenge of FDA's decision of a citizen petition filed by Sanofi regarding generic versions of Lovenox® (enoxaparin sodium injection), a blood thinning drug. As we reported here in our coverage of FDA's response to Sanofi's citizen petition, Sanofi had requested that FDA withhold generic approvals until enoxaparin had been fully characterized, for any abbreviated new drug application ("ANDA") referencing Lovenox® that did not use an equivalent manufacturing process or did not show proof of equivalent safety and efficacy through clinical trials.

In that decision, FDA had concluded that enoxaparin had been adequately characterized to approve generic applications derived from natural sources and that five criteria would be sufficient to demonstrate "sameness" of enoxaparin in generic products compared to Lovenox®. In FDA's opinion, these elements would demonstrate sameness of enoxaparin, including its 1,6-anhydro ring structure, without (a) the need for a complete characterization of all of the different polysaccharides of exoxaparin, (b) using the same manufacturing processes by Sanofi, or (c) clinical trial data to demonstrate safety and efficacy. FDA's administrative record showed later, however, that while the Office of Generic Drugs ("OGD") supported this five-part test, the Office of New Drug Quality Assessment ("ONDQA") thought that the test was insufficient and the only way to demonstrate enoxaparin sameness was to fully characterize all of the different polysaccharides of enoxaparin.

Following FDA's decision on the citizen petition, FDA approved Novartis's/Sandoz's version and Sanofi filed a complaint that included a motion for a temporary retraining order ("TRO") and preliminary injunction ("PI") to prevent the sale of Sandoz's version and have FDA withdraw approval of Sandoz's version. Since then, the District Court consolidated and denied Sanofi's TRO/PI motion, based on the Court's finding that Sanofi was unlikely to success in its three claims. When these same claims were reviewed by the Court as part of FDA's motion for summary judgment, the Court concluded that all of Sanofi's contentions could be answered in terms of statutory construction:

1. the FDA acted within its statutory authority when it called for Sandoz to file immunogenicity data as part of its ANDA;


2. it did not unlawfully depart from agency precedent by approving a generic before the listed drug had been fully characterized; and


3. it reasonably found that the active in the generic drug was the same as the active ingredient in Lovenox.

by Scot B. Pittman

It's done--at least tentatively. Last week, FDA and the medical device industry reached a preliminary user fee agreement. The agreement, which must be approved by Congress, calls for medical device companies to pay $595 million over the next five years to have expedited FDA reviews. This will hopefully close the negotiations (see FDA Lawyers Blog previous post), on an agreement which have been over a year in the making. The nearly $600 million in user fees represents a fairly even split between FDA's highest demand of over $800 million and the industry's initial offer of $447 million. The current medical device user fee agreement, which was signed in 2007 and expires this September, only cost the medical device industry $295 million.

The agreement comes more than two weeks after a January 15 deadline, on which FDA submitted proposed user fee agreements for prescription drugs, generic drugs, and biosimilars for Congress' approval. While late, it appears that the proposed medical device user fee agreement will be submitted in time for the February 15 hearing before the health panel of the House Energy and Commerce Committee, where Congress is set to discuss the proposed user fee agreements. Once Congress grants its approval, the medical device user fee agreement must be drafted into law and enacted before October 1, 2012.

With the increased funds, FDA hopes to hire 200 new scientists to expedite the review of medical devices. These new reviewers will be instrumental in helping FDA uphold its end of the bargain. In exchange for the increased user fees, the agreement charges FDA with improving its device review process. Medical device companies want to see a more streamlined review process in hopes that FDA approval can match the speed of device approval in Europe and other foreign countries.

by Howard E. Rosenberg, Ph.D.

The European Medicines Agency ("EMA"), together with the European Member States and the European Commission, is preparing for the introduction of the new pharmacovigilance legislation in July this year. The new legislation (Directive 2010/84/EU and Regulation (EU) No. 1235/2010) amending existing legislation was adopted in the European Union ("EU") in December 2010. The legislation aims to promote and protect public health by strengthening the Europe-wide system for monitoring the safety and benefit-risk balance of medicines.

The new legislation is designed to strengthen the procedures for the submission of risk management plans and periodic safety update reports ("PSURs") to the EMA. Currently companies submit a risk management plan at the time of application for a marketing authorization. The plan includes information on how the medicine will be monitored for safety during its lifetime and describes risk minimization activities. PSURs provide an evaluation of the benefit-risk balance of a medicine and these are submitted at defined periods during the post-authorization phase. This month the EMA will be publishing draft good pharmacovigilance practice ("GVP") modules for both risk management plans and PSURs for consultation.

The legislation provides for a new approach to the use of post-authorization safety and efficacy studies ("PASS" / "PAES") and implementation will also begin in 2012. A PASS is a study of an authorized medicine which identifies, characterizes or quantifies a safety hazard, confirms the safety profile of the medicine, or gauges the effectiveness of risk management measures during its lifetime. A PAES aims to clarify the efficacy for a medicine on the market including efficacy in everyday medical practice. The information obtained in the studies is to support regulators in decision-making on the safety and benefit-risk profile of a medicine. Like the other GVP modules above a PASS module will also be published for public consultation in February 2012. The scientific guideline for public consultation on PAES will be published by the EMA during the year.

by Kyle Deighan

To say the Stop Online Piracy Act ("SOPA") and Protect IP Acts ("PIPA") has created a stir over the past few weeks is an understatement. The pair of anti-piracy bills have sparked widespread concern among millions over Internet censorship and First Amendment violations. Last week, protestors took to the streets to demonstrate their disapproval of the bills in cities such as New York and Washington, D.C., and popular websites such as Wikipedia and Google staged online black-outs to lobby against the measures. Wikipedia, for example, shut down its service for 24 hours to raise awareness about the legislation. The backlash caused lawmakers to officially postpone consideration of both bills.

While much of the focus on the bills has understandably centered on provisions dealing with piracy and copyright protection, one provision of SOPA has largely gone unnoticed--one that may have resulted in a crackdown on illegal online pharmacies. Section 105 of SOPA would have allowed entities such as "service provider[s]" and "payment network provider[s]" to take independent action against Internet websites that "endanger[] the public health." Conceivably, this could have allowed companies such as Visa and Discover to stop payments to dangerous websites such as illegal online pharmacies.

Currently, entities such as Visa have no incentive to refuse service or stop payments to dangerous websites, even those operating illegally, and in fact can suffer adverse legal consequences for doing so (e.g., breach of contract suits). However, SOPA would grant these entities immunity for revoking service if they believe the Internet site is endangering the public.

by Brian Malkin

Earlier this week, we included a post from FDAnews where FLH Partner Brian J. Malkin was quoted, reporting on FDA's secret e-mail monitoring of whistleblowers in FDA's Center for Devices and Radiological Health ("CDRH"). As a follow up, The Washington Post reporters Lisa Rein and Ellen Nakashima posted a letter released from Senator Charles E. Grassley, Ranking Member, Committee on the Judiciary, to FDA Commissioner Margaret A. Hamburg, M.D., dated January 31, 2012 about the issue.

Senator's Grassley's letter points out his concern how FDA handled the matter and implies that federal officials involved in the matter, including the Commissioner, should start changing their tune when it comes to whistleblowers. Grassley writes, "Whistleblowers point out fraud, waste, and abuse when no one else will, and while they do so while risking their professional careers, they are often treated like skunks at picnic. Whistleblowers have played a critical role in exposing harmful government actions and retaliation against whistleblowers should never be tolerated."

Grassley reminded Hamburg that during her Senate confirmation hearing in 2009 she stated," I think whistleblowers serve a very important role in government in surfacing critical issues and concerns and making sure they're addressed. As leader of FDA, I would very much want to create a culture that enables all voices to be heard." Yet despite Hamburg's remarks, the Agency went on to monitor nine FDA physicians and scientists who wrote a letter to the Presidential Transition Team in 2009 advising that, "Managers at CDRH have ignored the law and ordered physicians and scientists to assess medical devices employing unsound evaluation methods" and "ordered, intimidated, and coerced FDA experts to modify scientific evaluations, conclusions, and recommendations in violations of the laws, rules and regulation."

by Scot B. Pittman

According to an article in last week's The Washington Post, orphan drugs accounted for 11 of the 30 new drug approvals in 2011. This represents the highest percentage in the last thirty years. Specifically, last year saw new drug treatments for lupus and Hodgkin's lymphoma for the first time in 50 years and 30 years, respectively.

The Orphan Drug Act defines a "rare disease or condition" as one that affects less than 200,000 people in the United States, or one that affects more than 200,000 people in the United States but there is no reasonable expectation that the costs of developing and making available the drug will be recovered from its sale in the US. See 21 U.S.C. § 360bb. Applicants may petition FDA to give a particular drug orphan drug status. If FDA determines the drug meets the criteria required for orphan drug status, the applicant may enjoy the following benefits: (1) seven years of market exclusivity, (2) tax credits, (3) no user fees, (4) help on the costs of clinical testing, and (5) a shorter review period.

Another reason for the increase in orphan drug approvals appears to be the looming expiration of numerous patents covering more traditional ailments. EvaluatePharma Ltd., a London research firm, notes that the patents of drugs generating around $250 billion in annual sales are set to expire in 2016. With the expectation that generic versions of these drugs will flood the market, innovator drug companies are hoping the orphan drug market, where there are often fewer treatment options, can provide replacement revenue. Even with smaller numbers of patients taking these drugs, they often demand higher prices. Some drugs cost in the hundreds of thousands of dollars for a year's worth of treatment.