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.

On March 5, FDA issued a new draft guidance, "Types of Communication During the Review of Medical Device Submissions."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.

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.

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.

by Brian Malkin

On January 26, FDA's Acting Chief Counsel, Elizabeth H. Dickinson, Esq., and FDA's Deputy Center Director for Policy, Center for Devices and Radiological Health ("CDRH"), Nancy K. Stade, Esq., spoke at the Annual Meeting of the Food, Drug and Cosmetic Law Section of the New York State Bar Association. Dickinson provided an overview of the year's hot legal issues and Stade offered her views on FDA's efforts for improving its medical review process and plans for the future.

Stade spoke first in a spirited debate between former FDA and current consultant Philip J. Phillips, Esq., President, Phillips Consulting Group, LLC, Professor Ralph F. Hall, Professor of Practice, University of Minnesota Law School, and Partner, Lauren R. Silvis, Esq., Sidley Austin LLP. Section 513 of the Food, Drug, and Cosmetic Act ("FD&C Act") mandates that, prior to marketing, FDA must classify all medical devices into one of three classes depending on the intended use, indications for use, and level of control necessary to ensure the safety and effectiveness of the device. Class I requires the least control, followed by class II, and class III requires the most control. Section 513(i) of the FD&C Act essentially states that if a new device is substantially equivalent to an already-marketed device or "predicate" device, the new device is given the same classification as the device already in the market and may be submitted as a "510(k)" submission, which is based on section 510(k) of the FD&C Act. If the new device is not substantially equivalent to any such device, the new device is placed in class III and requires a premarket approval application ("PMA") under Section 515 of the FD&C Act.

Over the years, the 510(k) process has become the most common and controversial pathway for bringing medical devices to market. FDA's definition of medical device includes products ranging from simple tongue depressors to pacemakers to laser surgical devices. Under the current 510(k) process, device manufacturers must notify FDA of their intent to market a medical device at least 90 days prior to launch. If FDA determines that the device is substantially equivalent to an existing 510(k) cleared device or other device that was on the market when the Medical Device Amendments were enacted in 1976, then it may proceed to market. If not, it must undergo pre-market approval as a premarket approval application ("PMA").

by Brian Malkin

On January 18, FDA announced in the Federal Register the availability of a new final guidance, "Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage." Dated December 2011, the Guidance finalizes a draft guidance of the same title dated July 2007 and is a joint collaboration of the Center for Biologics Evaluation and Research ("CBER") and the Center for Devices and Radiological Health ("CDRH"), reflecting that products in this category typically are a biologic, medical device, or combination of the two. The guidance does not apply to prostheses such as unicondylar or total knee implants, or meniscus replacement products, nor does it apply to human cells, tissues, and cellular products and tissue-based products regulated solely under Section 361 of the Public Health Service.

According to FDA, it received "numerous" comments on its 2007 draft guidance, resulting in new sections and clinical study schedules with elaborations on nonclinical data considerations, as well as input from a public meeting of the Cellular, Tissue, and Gene Therapy Advisory Committee meeting on May 15, 2009.

The Guidance notes that FDA believes investigational devices for articular cartilage repair or replacement are significant risk devices requiring the submission of an investigational device exemption or investigational new drug exemption meeting there requisite requirements prior to initiating human research. In particular, FDA notes that approval of an Institutional Review Board ("IRB") alone is not sufficient to commence a clinical study for these types of products.

by Scot Pittman

FDA has put forth significant efforts in trying to tweak its 510(k) device approval pathway, which has created discontent among medical device companies for many years. In its most recent attempt to improve the medical device approval process, FDA released draft guidelines "De Novo Classification Process (Evaluation of Automatic Class III Designation)" last Monday.

De Novo Guidance

A typical low- to moderate-risk medical device approval requires either FDA clearance of a premarket notification or approval of a 510(k) submission. 510(k) submissions require a demonstration that the new device is substantially equivalent to an already legally-marketed device. The De Novo Classification Process attempts to streamline device approval for low- to moderate-risk devices that have been classified as Class III because they cannot be shown to be substantially equivalent to any legally market devices. In addition, the guidance also describes a mechanism for obtaining timely input on the type of data necessary to support de novo classification of a suitable device. When this guidance is final, it will replace "New Section 513(f)(2) - Evaluation of Automatic Class III Designation, Guidance for Industry and CDRH Staff" (February 19, 1998).

by Dario A. Machleidt

The medical device review procedures of FDA's Center for Devices and Radiological Health ("CDRH"), which have been the subject of significant industry criticism, may see improvement in the near future. As many commentators have noted, including in this blog, a frequent industry complaint regarding the 510(k) and Premarket Approval Application ("PMA") notification processes for medical devices centers on the high FDA reviewer turnover. The 510(k) process is the most common method used by companies to bring new medical devices to market, but has been plagued by problems and perceived inefficiencies. The PMA route takes longer to navigate and is reserved for higher risk devices that are not substantially similar to an existing 510(k) device. As with 510(k) applications, its effectiveness has been widely questioned. For both paths to medical device clearance, a change in key personnel in the middle of the process often resets the review clock, forcing a company seeking approval of an innovative medical device to start from scratch with a new reviewer. This situation leads to inconsistent FDA requirements in an already time intensive and costly process.

Reviewer turnover at the FDA's CDRH division is 8.6 percent, or twice the rate of the FDA's "sister drug and biologic arms." As Jeffrey E. Shuren, M.D., J.D., Director of the CDRH, admits, change is necessary to address this issue and that "[w]e need to find the means to handle the ever-increasing workload and reduce staff and manager turnover." Shuren has also stated that "the majority of my reviewers have less than four years of experience [and that] [m]y front-line managers generally have three years experience or less." To make matters worse, ratios of managers to reviewers range from 1 to 14 on the low side, to 1 to 27 at the higher end, which results in a small number of managers, let alone experienced ones, to train and oversee inexperienced reviewers. Further, the negative impact of the CDRH's high turnover is exacerbated by the fact that innovative medical technologies are becoming increasingly complex and therefore require longer review times even by experienced CDRH personnel.

A solution to the problem surrounding FDA reviewers may be on the horizon. In a recent meeting between the FDA and the Minnesota medical device community, Shuren announced that FDA medical device reviewers will undergo certification and training beginning September 2011. This program will be the first of its kind, and it is aimed at addressing concerns about the inexperience and frequent turnover of medical device application reviewers. Implicit in FDA's decision to implement the program is the hope that standardized training will reduce inconsistencies between individual reviewer decisions.

by Rachael P. McClure

On July 29, the Institute of Medicine ("IOM") released a report calling for FDA to revamp its 35-year-old approval process for medical devices. At issue is the 510(k) process (based on section 510(k) of the Federal Food, Drug, and Cosmetic Act ("FD&C Act"), which is the most common pathway for bringing medical devices to market. FDA's definition of medical device includes products ranging from simple tongue depressors to pacemakers to laser surgical devices. Under the current 510(k) process, device manufacturers must notify FDA of their intent to market a medical device at least 90 days prior to launch. If FDA determines that the device is substantially equivalent to an existing 510(k)-cleared device or other device that was on the market when the Medical Device Amendments were enacted in 1976, then it may proceed to market. If not, it must undergo pre-market approval as a premarket approval application ("PMA"). For example, FDA received approximately 4,000 501(k) submissions in 2009.

The Agency asked the IOM to review the 510(k) process, specifically requesting consideration of whether the current process best protects patients and promotes innovation in support of public health and, if not, recommendations as to what legislative, regulatory, or administrative changes might be implemented to better achieve those goals. The recently released report calls for a complete replacement of the medical device approval process. An accompanying press release criticizes the status quo as "lack[ing] the legal basis to be a reliable premarket screen of the safety and effectiveness of moderate-risk Class II devices," to the extent that an entire overhaul is needed.

The report suggests that, because a finding of substantial equivalence does not assure a finding of safety and effectiveness, Class II devices should not be granted 510(k) clearance. It recommends that FDA develop and initiate a new dual system of premarket clearance and post-market monitoring to guarantee safety and effectiveness of these moderate risk devices. The report further criticizes underreporting of device malfunctions and unfavorable reactions by device manufacturers under the current system as well as FDA's sluggish progress in reviewing reports of such adverse events.

by Julie E. Kurzrok

On May 31, ReGen Biologics, Inc. ("ReGen") filed suit against FDA for an alleged improper reclassification of ReGen's Collagen Meniscus Implant ("CMI") device. ReGen requests that this FDA action be set aside, and that such act is a nullity and without any legal effect. ReGen further requests an injunction enjoining FDA from rescinding CMI's class II classification and from challenging such classification except as authorized by law.

Section 513 of the Food, Drug, and Cosmetic Act ("FD&C Act") mandates that, prior to marketing, FDA must classify all medical devices into one of three classes depending on the intended use, indications for use, and level of control necessary to ensure the safety and effectiveness of the device. Class I requires the least control, followed by class II, and class III requires the most control. Section 513(i) of the FD&C Act essentially states that if a new device is substantially equivalent to an already-marketed device or "predicate" device, the new device is given the same classification as the device already in the market and may be submitted as a 510(k) submission. If the new device is not substantially equivalent to any such device, the new device is placed in class III and requires a premarket approval application ("PMA") under Section 515 of the FD&C Act.

According to ReGen, its CMI device is a collagen-based mesh used only to support damaged or weakened meniscus tissue in the knee. The CMI device has been marketed in Europe since 2000, and on July 22, 2008, ReGen applied to FDA as a 510(k) submission to market the CMI in the United States as the ReGen Menaflex® Collagen Scaffold ("CS") device. An FDA Orthopedic Advisory Panel met in November 2008 and agreed to classify the CMI device into class II, because it was substantially equivalent to a prior-marketed surgical mesh device with the same indication. ReGen then began preparing to market and sell the CMI device, and the device was first distributed on April 10, 2009.

by Dario A. Machleidt

On November 18, the Medical Device Manufacturers Association ("MDMA") announced a study led by Josh Makower, M.D. (Consulting Professor of Medicine, Stanford University; CEO, ExploraMed Development, LLC; Venture Partner, NEA) and assisted by other Stanford University researchers that paints a bleak picture of FDA's medical device regulatory procedures. The goal of the study, which consisted of survey responses from 204 medical technology ("medtech") companies, was to "address the need for data that could be used to evaluate the impact of U.S. medical device regulation on [United States] innovation and patients." According to the study, FDA's medtech regulatory process is "unpredictable, inefficient, and expensive," especially when compared to the systems used by similar European agencies.

FDA Impact U.S. Medical Technology Innovation

The study used average FDA review times as one way to quantify FDA's inefficiencies. The majority of survey respondents reported that, for low risk medical devices (510(k) process), it took their companies an average of 31 months from their first FDA communication until product approval. It took these same companies only 7 months from their first contact with the respective European agencies to receive regulatory approval for the same products that were introduced in the U.S. Respondents said that it took FDA longer to approve a product from the date of first U.S. filing, a period of 10 months, than the 7 months it took comparable European agencies to approve the same product from the date of first contact. For higher risk devices (premarket approval application ("PMA") process), it took companies 54 months from their first communication with FDA to get their product approved, compared to only 11 months in Europe. The study suggested that "untimely changes in key personnel" and the absence of appropriate FDA staff at important meetings could contribute to FDA's perceived inefficiency and longer regulatory review periods.

Long review times increase costs for medtech companies and, subsequently, the consumer. The survey revealed that companies spent an average of $24 million on FDA-related activities to bring a 510(k) product to clearance. The average total cost for such a product was $31 million. Companies spent $75 million of a $94 million total budget for a single product on FDA-dependent activities linked to PMA submissions. These high regulatory costs to medtech companies increase the prices for medical devices once they reach the market. As the study points out, this means that U.S. citizens are in fact paying higher prices than European patients for technologies that have been available in Europe for several years. Survey respondents reported that their products reached U.S. patients on average two years later than patients in European countries. This device-lag is due in part to direct FDA delays as well as indirect FDA delays, such as when companies pursue non-U.S. markets before spending time and resources on inefficient U.S. regulatory procedures. Thus, U.S. patients pay more for medical devices that are often conceived and created in the U.S. but introduced overseas years before officially entering the U.S. market.

by Elizabeth Murphy

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

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

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