FDA Lawyers Blog

This blog is a second part to a blog here, describing Annual Conference for the Food and Drug Law Institute ("FDLI") held on April 23 and 24, 2013, its in Washington, D.C.

On the first day, FLH Partner Brian J. Malkin spoke on a panel discussing the priorities for the Center for Biologics Evaluation and Research ("CBER"). The two key CBER presentations came from Diane Maloney, J.D.., Associate Director for Policy, and Mary Malarkey, Director, Office of Compliance and Biologics Quality. The panel also included Michael S. Reilly, Executive Director, Alliance for Safe Biologic Medicines, and Mark S. Robbins, Ph.D., Vice President, Clinical Regulatory Affairs, DiaMedica USA, Inc. and was moderated by Scott Cunningham, Partner, Covington & Burling LLP. A key issue raised by panel was the status of biosimilars. Reilly, for example, was concerned that there may be misinformation about biosimilars, especially because there is no public information concerning biosimilars applications being considered in the United States. Malkin asked when FDA planned to issue additional guidance, because FDA's guidance has so far been very general and concerns pre-investigational or pre-biosimilars application stages, not the key issues of interchangeability and naming that have been debated. Maloney explained that CBER and the Center for Drug Evaluation and Research ("CDER") have been discussing strategy, even though there still have been no filed biosimilar applications, and would issue additional guidances. At the same time, Malkin and others acknowledged that at the state level, legislators have been passing bills that specifically prohibit substitution of biosimilars for their referenced counterpart, unless FDA deems the biosimilar "interchangeable" and naming issues and more persist.

A question was raised about a pending Citizen Petition that includes an argument that it was a taking for biosimilar applicants to file applications referencing biologic products before the passage of the Biologics Price Competition and Innovation Act ("BPCIA") (March 23, 2010). In this Petition, Abbott argued that before this date, when biologics license applications ("BLAs") were submitted, their sponsors had "reasonable, investment-backed expectations that the trade secrets in their applications would not be used to approve competing products." Abbott asserts, therefore, that FDA's use of trade secrets in these BLAs to support biosimilar approvals "would constitute a taking under the Fifth Amendment to the U.S. Constitution. FDA should not implement the BPCIA in any manner that would raise constitutional issue." While most panel members declined to respond, Malkin hazarded a guess that based on comments FDA has made (see for example here) and in the context of FDA's Citizen Petition response for a similar issue concerning 505(b)(2) new drug applications (where a similar takings argument has been made), FDA wanted to decide that there was no "taking," but FDA has not answered the petition in part because no biosimilar application has been filed to date.

Over the past months, there has been a lot of speculation (see recent blogs here , here, and here) whether the White House's proposed budget would cause a sequester situation for FDA, resulting in potential layoffs or program cuts, in an era of new user fees for generic drugs and biosimilar biological products. While initial reports and temporary budget fixes (called continuing resolutions) appeared to keep FDA's user fees intact and available for use, FDA's Commissioner, Margaret A. Hamburg, M.D., recently reported to members of a biotechnology trade association, the Massachusetts Biotechnology Council ("MassBio"), that it was not clear what would happen with user fees in the new federal budget.

Released on April 10, the White House's proposed fiscal year 2014 budget is a mixed bag that has been called a "political document rather than a serious piece of legislation" with a "series of bargaining positions" that "would bleed pharma." On the one hand, the plan would appear to confirm that FDA's user fees would not be sequestered, given that it supported the $4.7 billion in total program budget requested by FDA, which included user fees that would help fund over 90 percent of the requested increases. On the other hand, the budget includes a myriad of proposals that would change the way the government pays for medical care and products. For example, Medicare (senior citizens' drug coverage) Part D manufacturer discounts for branded drugs would be increased from 50% to 75% in 2015 (rather than 2020) and low-income individuals would be pushed more to generic drugs by increasing certain copayments for branded drugs and lowering certain copayments for generic drugs.

Many of the more controversial proposals were nestled in a document called "Reducing the Deficit in a Smart and Balanced Way". Here, the White House proposes, among other things, several items to purportedly lower drug costs, including: 1) authorizing the Federal Trade Commission to stop companies from entering into certain "pay-for-delay" agreements (see below) and 2) beginning in 2014, to reduce biologic product exclusivity from 12 years to 7 years and prohibit additional periods of exclusivity for minor changes to product formulations. These two items could open up some unanticipated debate regarding the White House's budget.

On April 1, FDA issued a Federal Register Notice announcing a new draft biosimilars guidance, "Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants". This is the latest in FDA's new biosimilar guidances for 2013, which FDA has announced in earlier meetings this year would be coming to help spur the filing of a biosimilars application, which FDA has called 351(k) applications based on the section in the Public Health Service Act ("PHS Act"). As of a few weeks ago at the Massachusetts Biotechnology Association's ("MassBio's") Annual Meeting, which we blogged on here, FDA's Commissioner, Margaret A. Hamburg, M.D., continued to report that FDA has not received a single 351(k) application to date.

The Guidance focuses on formal meetings for 351(k) applications and the associated requirements or performance goals from the Biosimilar User Fee Act of 2012 ("BsUFA"), which was enacted as part of the Food and Drug Administration Safety and Innovation Act ("FDASIA"). In particular, the Guidance discusses the principles of good meeting management practices ("GMMPs") and describes standardized procedures for requesting, preparing, scheduling, conducting, and documenting such formal meetings.

On March 14-15, the Massachusetts Biotechnology Council ("MassBio") held its Annual Meeting in Cambridge, Massachusetts. The Meeting also featured a Keynote from FDA Commissioner Margaret A. Hamburg, M.D. (see related blog here). Key themes at the Meeting were the importance of the Cambridge/Boston biotechnology community for advancing new therapies and the unique resources available in the area that have made it an industry leader. Some of the Cambridge/Boston advantages discussed were the intellectual research capital (local universities such as Harvard and Massachusetts Institute of Technology), venture capital, and local biotechnology businesses, such as Biogen Idec and Genzyme, as well as other biotechnology companies that now have offices in the Cambridge/Boston area and are seeking partnerships to develop new products, such as AstraZeneca, Pfizer, Merck, Novo Nordisk, and Sanofi.

On the second day, Hamburg described here "special affection" for the Cambridge/Boston region dating back to her days at Harvard, saying that she hopes D.C. "would be as efficient and congenial as here." Hamburg said that the Cambridge/Boston region is a life sciences enterprise fueled by top notch research and medical care with the top five NIH-funded hospitals and a "biotech supercluster second to none" with "a remarkable 500 biotech and pharma companies here, and some thirty venture capital firms."

Hamburg described FDA as striving for true collaboration and regulatory flexibility with industry, including MassBio, and has been hearing that industry wants more clarity, certainty, transparency with decisions. Hamburg said that FDA is trying to have creative approaches--not a one size-fits-all approach. To this end, Hamburg described approaches that FDA has taken with four new products from the Massachusetts area: 1) Inclusig® for two rare forms of leukemia, 2) Juxtapid® (an orphan drug), 3) Linzess® for irritable bowl syndrome, and 4) Kalydeco® for cystic fibrosis. In addition, Hamburg highlighted new provisions in the Food and Drug Administration Safety and Innovation Act ("FDASIA") for expedited approvals, citing 31 breakthrough therapy designation requests, of which 9 have been granted, 10 denied, 11 pending, and 1 withdrawn. To help with more companies taking advantage of this new process, FDA will be publishing a new guidance shortly, Hamburg announced.

On March 14-15, the Massachusetts Biotechnology Council ("MassBio") held its Annual Meeting in Cambridge, Massachusetts. The Meeting featured key topics such as biosimilars and a Keynote from John Crowley, Chairman and CEO of Amicus Therapeutics.

On the first day of the conference, Crowley exemplified many of the speakers' entry in biotechnology, which originated with a family member or friend with a disease requiring development of a biotechnology product. For Crowley, it was his two children Megan and Patrick, were diagnosed with a severe neuromuscular disorder, Glycogen storage disease type II, known as Pompe's disease. Rather that sitting still to wait for a cure, Crowley became involved in the process, first moving to Princeton, New Jersey, to be close to doctors specializing in the disease and leaving his job with Bristol-Myers Squibb. He later took a position as CEO of Novazyme Pharmaceuticals, a biotechnology research company located in Oklahoma City founded by Dr. William Canfield, which was conducting research on a new experimental treatment for the disease. Novazyme was acquired by Genzyme Corporation, which was then the world's third largest biotechnology company. Crowley was put in charge of Genzyme's global Pompe program, becoming the largest research and development effort in the company's history.

Through these efforts, an experimental enzyme replacement therapy was developed, and Megan and Patrick Crowley received the therapy, which Crowley credits with saving his children's lives. Crowley went on to become President and CEO of Orexigen Therapeutics and was named the President and CEO of Amicus Therapeutics, based in Cranbury, New Jersey, which he helped take public in 2007. Crowley's efforts were documented in a Wall Street Journal article and other publications, which ultimately resulted in Harrison Ford working to bring the story to life in a major motion picture, Extraordinary Measures.

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.

The last day of the Generic Pharmaceutical Association ("GPhA") 2013 Annual Meeting also featured an FDA Keynote Address by FDA Commissioner Margaret A. Hamburg, M.D. For a summary of public sessions from Day Two, please see the previous blog here; a summary of the CEOs Unplugged session may be found here.

Video streaming by Ustream

Following the CEOs Unplugged session on day three, Hamburg delivered her Keynote Address. Hamburg said that GPhA was one of the few organizations that she has chosen to address each year since becoming Commissioner, "because of the dynamic character of this group, your prominent role in the nation's health care system and the importance of the work you do." Celebrating GDUFA and the FDA Safety and Innovation Act ("FDASIA"), Hamburg emphasized that FDA is making "quality one of the highest priorities this year," hoping that GPhA's members do the same. Despite generic drug companies providing 85 percent of all prescriptions filled, some studies have suggested that many physicians still have "negative perceptions about the quality of generic medicines," which Hamburg said was "troublesome - and assuredly not fair."

Hamburg reported "impressive strides in implementing GDUFA," explaining that FDA got the word out of new requirements and fees early, resulting in the collection of almost $125 million in fiscal year 2013 user fees to help brining in staff and other resources to help reduce the backlog of ANDAs above 2,500 applications with median review times at about 31 months. FDA has assembled a list of about 2,000 facilities supplying generic drugs to the U.S. following self-identification procedures.

This Thursday, FLH Partner Brian J. Malkin will host Legal Office Hours at The Venture Café in Cambridge, Massachusetts. Mr. Malkin's Legal Office Hours description reads:

Learn how you can protect your start-up with patent and trademark protection from intellectual property Partner Brian J. Malkin, Frommer Lawrence & Haug LLP. Mr. Malkin is an expert on FDA-regulated products, in particular pharmaceutical/biotechnology products and biosimilars, and can discuss pathways for FDA approval, as well as life cycle management and due diligence investigations. Mr. Malkin recently published a chapter on biosimilars, has a primer on the drug and biologics approval process, frequently speaks on a variety of IP- and FDA-oriented topics, and is the editor of FDA Lawyers Blog, a blog that focuses on legal and scientific developments for FDA-regulated products.

Mr. Malkin welcomes members of The Venture Café community to stop by his Legal Office Hours to help discuss ways to develop and protect your innovative ideas. According to The Venture Café's website:

The Venture Café was created to provide a resource for the Boston entrepreneurial and innovation communities. Our mission is to enable fresh and useful conversations.

Cambridge is a fountain of innovative spirit, spirit that needs a framework to reach its full potential. The Venture Café serves as a nexus for helping innovators and entrepreneurs find one another and collaborate to bring their dreams to reality.

Even in this digital world, it's important to have a physical space. Shared physical spaces provide common meeting ground and a forum for semi-serendipitous encounters that often foster brainstorming and drive creativity. Meeting in person establishes the trust that's so crucial to working together, particularly on risky, underfunded projects. The Venture Café can provide the framework upon which numerous experimental "applications" can be nurtured and launched.

***This event occurs at The Venture Café located at the Cambridge Innovation Center, One Broadway, 4th Floor. Visitors must comply with The Venture Café attendance policies.***

On January 28, The New York Times reported that biotechnology companies are actively lobbying state legislatures to limit access to biosimilar versions, i.e., "highly similar" versions of previously-approved, innovator biological products ("biologics"). According to the author, Andrew Pollack, Amgen and Genentech are proposing bills that would make it more difficult for pharmacists to substitute biosimilar versions for the innovator's products, unless FDA determines that a particular biosimilar version is "interchangeable" with the innovator's product.

For instance, the Virginia House of Delegates reportedly already passed such a bill last week by a 91-to-6 vote. Other bills in the works require patient consent for substitution, pharmacist notification of the patient's physician if a switch is made, and for both the pharmacist and patient's physician to maintain records of any such substitutions for years.

The Generic Pharmaceutical Association ("GPhA") and insurers generally accept that biosimilar substitution for a biologic should follow similar methods as with drugs only if deemed interchangeable by FDA but find that many of the bills go further to discourage use of biosimilars. "All of these things are put in there for a chilling effect on these biosimilars," commented Brynna M. Clark, Director of State Affairs for GPhA, adding that many of the limits "don't sound too onerous but undermine confidence in these drugs and are burdensome." GPhA and insurers would prefer that legislatures leave biosimilar regulation to FDA, which has been entrusted with using its regulatory prowess to determine the necessary requirements for biosimilars and "interchangeable" biosimilars, as well as when to waive those requirements based on what is know about a particular biosimilar product.

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.

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.

FDA Partner Brian J Malkin helped suggest key topics for and was quoted in an FDAnews article published on January 2, 2013, entitled "Landmark Year for Generics Cues Big Changes, Rulings in 2013". First, Mr. Malkin was quoted in a section regarding risk evaluation mitigation strategies. Here, FDAnews wrote:

...But generic-makers failed to win a key provision that would have allowed access to hard-to-obtain products covered under risk evaluation and mitigation strategies (REMS).

... The loss of the REMS provision may be mitigated by the FDA's move to more classwide REMS, a strategy that could keep brand drugmakers from using patents on the plans to block generic competition, Brian Malkin, a partner at Frommer Lawrence & Haug, said.

FLH Partner Brian J. Malkin's chapter in the 2013 Edition of Recent Developments in Food and Drug Law published by Aspatore / Thomas Reuters entitled: "Challenges to the Development of a Biosimilars Industry in the United States" is now available as a PDF copy. The chapter takes a hard look at the new biosimilars pathway created by the Biologics Price Competition and Innovation Act of 2009 ("the Biosimilars Act") and attempts to answer the question why no applicant appears to have filed a biosimilars application with FDA more than two and a half years after the Biosimilars Act was enacted. Some of the topics addressed include:

• The Impact of the Biosimilars Act and Approval Issues for Biosimilars


• Biological Innovator Challenges to Biosimilars


• Interchangeability Issues


• Biosimilar Manufacturing Issues


• Patent Litigation and Confidentiality Issues


• The FDA's General Approach Based on Its New Guidances


• The FDA's Inverted Pyramid Approach


• Enforcement/Pharmacovigilance Issues


• Product Shortages, Liability, and Advertising Issues


• Key Takeaways

Biosimilars are defined under the Biosimilars Act as "highly similar" to an innovator's biological product already approved by FDA. Biosimilars are also known around the world as follow-on biologics or biogenerics. Biosimilars are already approved in Europe and other countries and are clearly feasible given current technology and analytical methods. Ultimately, as there are less small molecule targets for generic companies to pursue over time, innovator and generic drug companies alike will be drawn to design, test, and file applications for biosimilars. FDA appears to have hoped that the new biosimilars pathway would create partnerships to form standards for analytic testing of biosimilars. Instead, the high cost and technical skills to reverse engineer the innovator's product and manufacture biosimilars has driven innovator and generic drug companies to form unique partnerships to develop proprietary analytical methods, including methods with either trade secret or patent protection.

Whenever an applicant wishes to register their follow-on medicinal product, be it a generic product or a biosimilar, the applicant has to include in their dossier a comparison between the newly-developed product with a previously-approved and registered medicine. For "standard" generic products evidence, such as the approved product's dosage form, strength, excipient and content can be obtained from published information and further "proof" is generated by such things as dissolution profiling and bioequivalence studies. However, there is always a question as to whether the comparison product (usually the originator's product) is the same internationally. For example, it is possible that the same active ingredient in the same dosage form could have been formulated differently from country to country, either as a result of differing timing of the drug's development and launch or on purpose to create artificial barriers, such that the follow on products will be more complex to develop. Of course, the difficulty of having what outwardly appears to be the same product, but inwardly is significantly different, creates potentially dangerous problems for both doctors and patients. Clearly, if a patient travels across borders and needs to refill their prescription, it could result in real problems, if the apparent same drug and dosage form act differently biologically.

Health authorities around the world now work much more closely together and confidential information about their registered and approved products can be passed between them, such that differences in formulations that affect bioavailability would be available to them and thus will be alert to possible issues. For a company making a follow-on product, however, this information is not available. As a result, companies wishing to make a generic product have to carry out extra studies as outlined above to investigate the differences from country to country and carry out bioequivalence studies against a local reference product.

Biological medicines are medicines that are made by or derived from a biological source. They can consist of relatively small molecules, such as human insulin or erythropoietin, or complex molecules, such as monoclonal antibodies. Biosimilar products are, thus, far more complex and need far more studies to show similarity, requiring a large number of clinical trials, as opposed to the bioequivalence studies that generic products undergo. Given the difficulty in developing, testing and registering new biological, it may well be that, unlike non-biological medicines, biological products may well be the same product internationally.

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

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

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

On July 17, 2012, FLH Partner Brian J. Malkin joined other experts in the field of clinical trials to discuss methods for ensuring safe and compliant domestic and international clinical trials. New to the ACI's Clinical Trials Conference running for more than seven years was Malkin's presentation "Safely Conducting Biosimilars Clinical Trials: Understanding FDA's Requirements for Biosimilar Clinical Trials". The audience was comprised of many individuals seasoned in traditional clinical trials, who came to the conference in Boston to learn about the newest trends in clinical trials.

Some of the featured government speakers included Karena Cooper, J.S., M.S.W., Acting Associate Director of Policy and Communications and Regulatory Counsel, Office of Scientific Investigations ("OSI"), Center for Drug Evaluation and Research, FDA, and Mary E. Crawley, Assistant U.S. Attorney, Eastern District of Pennsylvania. Other featured speakers included former government enforcers and top in-house counsel from sponsor biopharmaceutical and medical device companies, contract research organizations ("CROs"), hospitals, universities, and research institutions.

Cooper described FDA's new inspection platform, where FDA does not need to inspect a facility to issue a warning letter, and the reorganization of the Office of Compliance. In terms of postmarket studies, sponsors are now provided with milestone timetables where failure to complete a milestone by a certain time will result in a violation. While a sponsor may show "good cause" for failure to meet a milestone, FDA has a very limited high bar, essentially for items completely outside the sponsor's control. Examples where FDA did not find good cause included difficult recruitment, costly studies, or development of data in lieu of the data that the sponsor agreed to provide. Regarding postmarket studies, however, FDA has already issued its first warning letter dated February 17, 2012 that utilized the no-inspection format. In this letter, FDA provided the sponsor with 30 calendar days to respond. FDA's Office of Compliance also has new civil money penalties to enforce its provisions that Cooper said FDA is "actively considering" but has not utilized yet. Cooper also described how FDA is working with the European Medicines Agency ("EMA") for joint and observed inspections, where there is a "robust" confidentiality agreement in place.