FDA Lawyers Blog

FLH Partner Brian J. Malkin will attend the Massachusett's Biotechnology Council's ("MassBio's") Annual Meeting in Cambridge, Massachusetts on March 14-15, 2013. FLH is a member of MassBio, reflecting FLH's commitment to the development and promotion of new biological and related products. Each year, the MassBio Annual Meeting focuses on the most timely and critical challenges facing the Massachusetts biotechnology industry. The meeting program is pulled together by a Steering Committee of leaders in the industry and the agenda encompasses keynote presentations, panel discussions, interactive working sessions, and extensive networking opportunities for all MassBio members. This year, keynote presentations feature John Crowley, Chairman & CEO of Amicus Therapeutics, Inc. and FDA Commissioner Margaret A. Hamburg, M.D. Key topics of interest include personalized medicine and companion diagnostics, biosimilars, RNA therapeutics, healthcare reimbursement strategies, research resource sharing opportunities and a variety of orphan drug candidate topics. Mr. Malkin looks forward to seeing you and catching up on the latest biotechnology developments with some of the best biotechnology leaders in the Massachusetts area and beyond.

Written by Dario A. Machleidt

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On January 28, 2013, consumer-advocacy group Public Citizen filed a letter "in response" for FDA to reconsider its August 8, 2012 denial of the group's petition that asked FDA to withdraw its approval for a medical device directed to stent technology. Public Citizen's original petition urged the withdrawal of approval for and recall of Stryker Corporation's ("Stryker's") Wingspan Stent System with Gateway PTA Balloon Catheter ("Wingspan Stent"), which is used to treat narrowing of the blood vessels in the brain.

In its January 28 letter, Public Citizen claimed that FDA denied the petition based on flawed reasoning. Specifically, Public Citizen argued that FDA's decision minimized the importance of crucial scientific evidence indicating that the Wingspan Stent is ineffective and, furthermore, that it is more harmful to patients experiencing intracranial narrowing of the blood vessels when compared to alternative forms of treatment. Public Citizen also criticized FDA's attempt at comprise by narrowing the proposed indication of the stent in response to the scientific data outlined in the petition. Public Citizen argued that such attempts fell far short of being sufficient to ensure the safety of patients that might consider using Stryker's medical device.

The Wingspan Stent is a class III medical device that comprises a stent with a balloon catheter and, until recently, was indicated for use "in improving cerebral artery lumen diameter in patients with intracranial atherosclerotic disease, refractory to medical therapy, in intracranial vessels with ≥ 50% stenosis [(a narrowing of the blood vessels that supply blood to the brain)] that are accessible to the system." In simple terms, the device uses a self-expanding tube that is inserted into a blocked artery in the brain with the "goal of increasing blood flow and preventing strokes in patients who have experienced repeat strokes, even after taking medication to prevent blood clotting."

On March 5, FDA issued a new draft guidance, "Types of Communication During the Review of Medical Device Submissions." During the development of the various medical device user fee amendments ("MDUFA"), the discussion of improving communications between device applicants and FDA was suggested, described as an Interactive Review. The collection of additional funds from MDUFA-related activities will enable FDA to improve the device review process and help meet certain performance goals incorporated into MDUFA. Some of the suggested communications included Acceptance Review, Substantive Interactions, Interactive Review, and, where applicable, Missed MDUFA Goals.

The purpose of Acceptance Review communications are to: (1) identify the lead reviewer or Regulatory Project Manager assigned to the submission and (2) confirm acceptance of the submission or notify the submitter that the submission was not accepted based upon the review of objective acceptance criteria. FDA aims to make these communications within 15 days of receipt of a 510(k), original premarket approval application ("PMA"), or a Panel-Track PMA Supplement, with such confirmation by fax, e-mail, or other written communication.

Written by Brian J. Malkin

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Substantive Interactions tell applicants that FDA either: (1) intends to continue working with the applicant to resolve any outstanding deficiencies (no hold), or (2) FDA has identified deficiencies sufficient to place the submission on hold. Substantive Interactions should occur following acceptance of the submission and only after FDA has performed a complete review with targets of within 60 days of receipt of a complete 510(k) or within 90 days of the filing date of an original PMA, Panel-Track PMA Supplement, or 180-Day PMA Supplement.

On February 13 and 14, 2013, Leerink Swann ("Leerink") held its annual Global Healthcare Conference at the Waldorf-Astoria Hotel in New York, New York. Each year the Conference highlights emerging themes and controversies in healthcare, where Leerink's equity analysts present surveys and moderate discussions with MEDACorp Key Opinion Leaders and industry specialists to provide unique and timely insights. MEDACorp is Leerink's network of 30,000 healthcare professionals including key opinion leaders, practitioners, clinicians, and hospital administrators. In between the main panels, senior management from some of the companies identified by Leerink as the most prominent and promising deliver "fireside chats" and presentations with company updates, including discussions of new products in their pipeline under review. This year the sole sponsor of Leerink's Global Healthcare Conference was Latham & Watkins LLP.

Headlining the Conference was a Keynote Address entitled "Innovating Medical Product Development - FDA and Other Forward Looking Trends" delivered by Vicki L. Seyfert-Margolis, Ph.D. Seyfert-Margolis just recently was the Senior Advisor for Science Innovation and Policy in FDA's Office of the Commissioner. Seyfert-Margolis is currently Chief Science and Strategy Officer for Precision Health, which provides services, infrastructure, and technologies to companies developing personalized medicines.

Written by Brian J. Malkin

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Seyfert-Margolis worked for about three and a half years in FDA's Office of the Commissioner, where she led the effort to help develop a more coherent policy for companion diagnostic and personalized medicine, including developing guidances for personalized medicine such as "In Vitro Companion Diagnostic Devices" and "Qualification Process for
Drug Development Tools". While at FDA, Seyfert-Margolis looked at why companies were not seeing as many returns from their investments in research and development, noting that it was not FDA's "fault" for less new chemical entity filings, because FDA can only review or approve products that are filed in new applications.

Yesterday, FDA issued two new items to help clarify combination products: 1) a Final Rule published in the Federal Register entitled, "Current Good Manufacturing Practice Requirements for Combination Products" and 2) a Draft Guidance entitled, "Guidance for Industry and FDA Staff:
Submissions for Postapproval Modifications to a Combination Product Approved Under a BLA, NDA, or PMA", also announced in the Federal Register.

The Final Rule is intended to clarify which good manufacturing practice ("CGMP") requirements apply when drugs, devices, and biological products are combined to create combination products. The Rule also provides a mechanism that FDA describes as "transparent and streamlined regulatory framework" for companies to use when demonstrating compliance with CGMP requirements for "single-entity" and "co-packaged" combination products. "Single-entity" combination products are two or more regulated components, e.g., drug/device, biologic/device, drug/biologic/device, which are physically, chemically, or otherwise combined or mixed and produced as a single-entity. Two or more separate products packaged together in a single package or as a unit and comprised of two or more regulated products is a "co-packaged" combination product. The Final Rules started as a Draft Guidance announced on October 4, 2004 (69 FR 59239), entitled "Current Good Manufacturing Practices for Combination Products." Based on comments and FDA's own internal review, FDA decided that "rulemaking was warranted" and issued Proposed Rules on September 23, 2009 (74 FR 48423).

Written by Brian J. Malkin

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The concept behind the CGMP Rule is simple for parts that are separately manufactured and marketed: each of the constituent parts of a combination product are subject only to the CGMP regulations applicable to that part, e.g., drug, biologic, or device. The two categories of combination products mentioned above, however, "single-entity" and "co-packaged" are slightly different due to the possibility for overlapping CGMP requirements for the different regulated components. Companies have two basic options for these types of products: 1) demonstrate compliance with the specifics of all CGMPs to each of the parts, or 2) demonstrate compliance with the specifics of either the drug CGMPs at 21 C.F.R. Parts 210 and 211 or the quality system ("QS") regulation at 21 C.F.R. Part 820 rather than both, for drug/devices under certain conditions. For combination products including biologics, the specific regulations are 21 C.F.R. parts 600 through 680, and for product including any human cell, tissue, and cellular tissue-based products, the regulations are 21 C.F.R. Part 1271.

Today, FDA Center Officials from the Center for Drug Evaluation and Research ("CDER"), the Center for Biologics Evaluation and Research ("CBER"), and the Center for Devices and Radiologic Health ("CDRH") provided an overview of upcoming biotechnology issues to the TechCouncil of Maryland, MdBio / MdTech at a full house in Bethesda, Maryland.

Representing CDER, Steven Kozlowski, M.D., Director of the Office of Biotechnology Products, Office of Pharmaceutical Science, said that his Office, which regulates monoclonal antibodies and therapeutic proteins, has been primarily concerned with the mechanism of action and potential for immunogenicity for these products. Describing a triad of research and development, application review, and inspections, Kozlowksi described his Office's challenges as often concerning "too many notes" for biologics--discerning which notes matter, given that technology has come up with ways to further characterize products and reveal more notes.

Written by Brian J. Malkin

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Kozlowski said that through the life cycle continuum of a biotechnology product, it is the applicant's responsibility to make sure that biotechnology products are manufactured using the best available science to prevent issues such as viral contamination that can cause plant shut downs and shortages. To help prevent such issues, FDA is further integrating its review and compliance functions, in part with the use of new user fee authorizations. For biosimilars, FDA recognizes the studies necessary for approval will depend on the analytics and results from those analytics, comparing the innovator's product to the proposed biosimilar product.

Earlier this week, the U.S. Supreme Court denied GlaxoSmithKline's certiorari petition in a case that would have helped clarify the scope of 35 U.S.C. § 271(e)'s safe-harbor provision. The issue facing the Court was whether section 271(e)(1) applies to postmarketing activity as well as premarketing activity.

Section 271(e), which states that it is not an act of infringement to make, use, offer to sell, or sell a patented invention "solely for uses reasonably related to the development and submission of information under [federal drug laws]," does not include a time limitation. The question about timing was highlighted in two recent Federal Circuit cases. In Classen Immunotherapies, Inc. v. Biogen Idec, 659 F.3d 1057 (Fed. Cir. 2011), the Federal Circuit explained that "§ 271(e)(1) is directed to premarketing approval of generic counterparts before patent expiration." Last year, however, a different panel of judges in Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc., 686 F.3d 1348 (Fed. Cir. 2012) held that post-approval studies performed for the FDA fall within § 271(e)(1)'s safe harbor and explained that Classen held that 271(e)(1) "does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained."

Written by Scot B. Pittman

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As previously blogged on here, the Solicitor General had urged the Supreme Court to deny GSK's petition in the Classen case. Despite a belief that the Federal Circuit erred in Classen, United States Solicitor General Donald Verrilli offered the following reasons why the Supreme Court should deny certiorari: (1) the Federal Circuit's Momenta decision sufficiently clarified and narrowed the Classen holding; (2) it was unclear whether the safe harbor applied to the types of patents at issue in the Classen case; and (3) the petitioners were not entitled to the safe harbor protection regardless of the Supreme Court's interpretation of the provision.

Written by Brian Malkin

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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.

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.

Written by Brian Malkin

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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.

Now in its second year, ACI's FDA Boot Camp - Devices Edition has been designed to give products liability litigators, as well as industry in-house counsel, federal and regulatory affairs professionals, and life sciences investment and securities experts, a strong working knowledge of core FDA competencies. Learn from an experienced faculty of FDA regulatory attorneys whose sole purpose is to provide you with the information you need to remain compliant and in command. Don't wait until 2013 to hone your practice and to hear from a stellar faculty, led by a "who's who" of the nation's leading medical device regulatory lawyers, who will help you understand:

• The basics of the application and approval processes, including 510(k) clearance and PMAs
• The complexities of device regulations
• The structure of the FDA and the roles of the three major agency centers: CDER, CBER, and CDRH
• A practical working knowledge of clinical trials and IDEs
• How devices are classified, monitored, and regulated
• The pivotal role of labeling and learn how to avoid misbranding and off label promotion
• The importance of cGMPs and QSRs to the post-approval regulatory process
• The protocols of adverse events monitoring, product withdrawals, and recalls

Attend the pre-conference workshop to seamlessly join the FDA regulatory law discussions at the main conference. The perfect primer to accompany FDA Boot Camp, the pre-conference workshop: Fundamentals of FDA Device Regulatory Law, provides the FDA law refresher course essential to getting the most benefit from the main conference program.

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.

Written by Julie E. Kurzrok

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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.

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.

Written by Shelly Fujikawa, Ph.D.

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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.

Over the past 8 years, thousands of your fellow legal professionals - from Associates to Partners to GCs have relied on ACI's FDA Boot Camp Conference to provide them with both a comprehensive overview of the basics of FDA law and current information on the status of regulatory law in the pharmaceutical, biotechnology, and medical device industries. We hope that this time you will be able to join your peers as this unique event returns to Boston in September.

Learn FDA regulatory basics from the experts--a veritable Who's Who of the FDA Regulatory Bar--and save the calls to regulatory counsel for the really complicated questions. Come, hear, and learn from a stellar faculty of the nation's leading food and drug lawyers, who will explain:

• The application and approval processes for drugs, biologics, and devices
• The regulatory balance between brand name and generic products
• The complexities of the patent and IP landscape, including Hatch-Waxman, Orange Book, 180-day exclusivity, 30-month stay, Paragraph IV, NDA, ANDA and 505(b)(2)
• The pivotal role of labeling in the drug and biologics approval process
• The importance of cGMPs to the post-approval regulatory process
• Advertising and Promotion, DTC Advertising, & Off-Label
• The protocols of adverse events monitoring, pharmacovigilance, and REMS
• Non-patent exclusivity, bioequivalency, and Follow-On Biologics
• Recalls, product withdrawals, and FDA oversight authority

Save the phone calls to your colleagues or other regulatory counsel for the truly complicated issues; attend ACI's FDA Boot Camp to boost your regulatory IQ
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Seating at this event is extremely limited and previous versions of this event SOLD OUT.

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

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On July 25, Corindus Vascular Robotics announced that FDA has granted a 510(k) premarket clearance for its CorPath® 200 System for use in performing percutaneous coronary interventions ("PCI"), otherwise known as angioplasty. David M. Handler, President and CEO of Corindus, calls it "the world's first system designed for robotic assisted PCI procedures." The newly-approved system is designed to assist interventional cardiologists in performing PCI more accurately and with reduced health concerns for surgeons.

PCI procedures are relatively common, but they pose risks to the operating cardiologists. The procedure involves a surgical technique in which blood flow is restored to a blocked coronary artery by inserting a balloon catheter into the artery, inflating it, and then implanting a stent to keep the artery open. While undergoing the procedure, the patients are x-rayed, and the surgeon is also exposed to the radiation. Generally surgeons wear a protective lead apron to minimize exposure to the radiation, but recent data has demonstrated that daily exposure can lead to health risks such as cancer and cataracts. The aprons are often heavy and the procedure can last for several hours. Over time, this can lead to orthopedic problems. Additionally, Corindus points to data published in the American Journal of Cardiology in 2008 showing that nearly 47% of stents are not optimally placed due to difficulties in visualization, measurement, and imprecise stent deployment.

The CorPath® 200 System offers a solution to these problems by robotically-assisting the cardiologist in the controlled placement of coronary guidewires and stent/balloon catheters while the physician resides safely inside lead-lined cockpit. The cockpit protects the cardiologist from radiation exposure and allows the procedure to be done in a seated position in front of monitors which provide an enhanced view of the angiography screen. The system includes a robotic drive and a single-use cassette, which contains the guidewire, balloon, and stent, mounted to an arm on the cathether lab table. The cardiologist controls the robotic drive from the cockpit by using two joysticks and a touch screen monitor, which allow the surgeon to be incredibly precise while minimizing radiation exposure and fatigue. The CorPath PRECISE trial, a study involving 164 patients at nine locations, which served as the basis for the 510(k) application, showed a reduced radiation exposure rate of 95% for physicians. The cockpit is located at the foot of the cathether lab table and the operator can easily switch from a remote procedure to a manual procedure if necessary.

In February 2012, FDA Lawyers Blog wrote regarding FDA's secret e-mail monitoring of whistle-blowers in the Center for Devices and Radiological Health ("CDRH"). Now it appears that FDA's surveillance program, which began as an effort to determine whether five FDA scientists were leaking trade secret information, may have been much broader than previously known. According to a New York Times article published on July 15, an FDA contractor inadvertently posted a database containing more than 80,000 surveillance-related documents onto a public website. These documents revealed the extent of the surveillance program that tracked communications between the scientists and Congressional officials, journalists, and others. The surveillance software utilized by FDA allegedly tracked keystrokes, intercepted personal e-mails, and took screen shots of letters being drafted to members of Congress, the Office of the President, and the Office of Special Counsel ("OSC"), an independent federal agency which investigates whistle-blower retaliation claims.

Federal agencies have broad power to monitor employees' computer usage. In fact, FDA computers warn employees when logging on that they have "no reasonable expectation of privacy," and that the Agency may intercept data for any lawful government purposes. However, it is still possible that FDA acted unlawfully when intercepting certain legally protected communications, such as, attorney-client communications, whistle-blower complaints, and workplace grievance filings. The OSC sent a memorandum to all government agencies in June identifying the legal restrictions and guidelines that agencies should consider with regard to monitoring employee communications. Members of Congress have demanded an investigation into the legality of the FDA's program.

FDA defended the program, saying it restricted surveillance to the five scientists suspected of leaking trade secret information. The Agency established the operation after the Inspector General at the Department of Health and Human Services refused to launch a criminal investigation into the scientists' alleged wrongdoing. FDA officials acknowledge that the operation intercepted communications that the scientists had with Congressional officials, journalists, and others, but FDA maintained that the e-mails "were collected without regard to the identity of the individuals with whom the user may have been corresponding." Additionally, FDA claimed that they did not intend to prevent employees from making these communications, and that individuals outside of the agency were not targets of the operation.