globalmap.pngEarlier this month, FDA released the transcript of its July 12, 2013 Public Meeting on Implementation of Drug Supply Chain Provisions of Title VII of the Food and Drug Administration Safety and Innovation Act (“FDASIA”). The day-long public meeting concerned the drug supply chain provisions and was meant to discuss how the Agency means to implement those provisions, and for FDA to hear public comment about those provisions that specifically address imported drugs and importers.

The morning session opened with Margaret A. Hamburg, M.D., Commissioner of Food and Drugs, who spoke on “The Challenges of Globalization.” Hamburg praised the passage of FDASIA and recognized FDA’s expanded authorities under the legislation. In a theme that was repeated throughout the morning session, Hamburg stressed that the drug supply was becoming “progressively more complex and more global” and that while FDA’s mission and focus remain domestic, the reality is that the agency rapidly becoming a global agency. In fact, nearly 40% of all U.S. drugs are made elsewhere, 80% of the sites that manufacture active pharmaceutical ingredients (“APIs”) are located outside the U.S, and imports are now coming in from over 150 countries. This global expansion has forced FDA to increase its collaboration with its international regulatory counterparts. The Commissioner highlighted the higher penalties for counterfeit drugs, the proposed rule for the administrative detention of drugs, and the draft guidance on penalties for manufacturers that refuse, delay, limit, or deny FDA inspections as key new developments that should help FDA secure the safety and integrity of the supply chain.

John M Taylor III, Counselor to the Commissioner and Acting Deputy Commissioner for Global Regulatory Operations and Policy, spoke next on “FDA’s Globalization Strategy.” Echoing the comments of the Commissioner, Taylor noted the increase in U.S. imports that has “eliminated the distinction between domestic and imported products” and recognized the trouble FDA has had keeping up with a more complex drug supply chain that involves more ingredients and more players. Threats to that supply chain include: (1) adulteration of products, (2) counterfeit products, and (3) cargo theft. In particular, Taylor noted how FDA was not prepared–both technologically and statutorily–for the alarming rise in Internet pharmacies and drug products being shipped through the mail and air courier systems.
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Thumbnail image for Thumbnail image for Q1 ProductionisKeeping Current on Domestic and International Compliance Regulations, Exploring Best Practices and Lessons Learned in Implementing Sunshine Reporting while Encouraging and Creating a Culture of Compliance

The 4th Annual Medical Device and Diagnostic Ethics and Compliance Conference will take place in Chicago, Illinois on October 21-22, 2013. This annual program will bring together prominent compliance executives as well as representatives from government agencies to discuss current challenges and forward thinking solutions to some of the industry’s major hurdles. Through keynote presentations providing high-level perspectives, to roundtable peer-to-peer discussions where attendees will have the opportunity for close-knit conversations, this program will provide compliance teams with the information needed to remain at the forefront of good compliance practices. With Sunshine reporting starting August 2013, the conference will provide attendees with a unique experience; the opportunity to discuss best practices and challenges exposed within the first few months of implementation and execution.

Sessions will explore cutting-edge topics focusing specifically on the top concerns of device and diagnostic compliance professionals. Due to increased scrutiny on international compliance and a growing effort to expand into emerging markets, the conference will focus not only on U.S. compliance regulations but will concentrate on specific international statutes as well. From communicating transparency to health care professionals to fostering a culture of compliance within an organization, attendees will leave with a well-rounded understanding of lessons learned and best practices for compliance in the Device and Diagnostic Industry.
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shareball.jpgOn August 7, FDA issued a response to a Citizen Petition filed by Dr. Reddy’s Laboratories, Inc. regarding generic versions of products subject to certain risk evaluation and mitigation strategies (“REMS”). As with many of FDA’s responses to citizen petitions in general, FDA granted in part and denied in part the Petition.

According to Dr. Reddy’s Petition, certain REMS with elements to assure safe use (“ETASU”) may have restricted distribution programs that “significantly limit drug product availability and prevent a prospective generic applicant from obtaining a sufficient quantity of a drug product to conduct required bioequivalence testing and for retained samples.” As a result, Dr. Reddy’s requested in its Petition, among other things, that: (1) FDA issue guidance for how generic applicants can obtain samples from the reference listed drug (“RLD”) for its generic version in these situations, (2) certain statements to be included into REMS that restricted distribution systems will not be used to delay or block generic competition, (3) enforce the Federal Food, Drug, and Cosmetic Act (“FD&C Act”) against RLD sponsors who refuse to sell sufficient quantities of the RLD to generic applicants for bioequivalence testing, and (4) refer to the U.S. Federal Trade Commission (“FTC”) any complaints that REMS have been used in an anticompetitive manner.

In the Petition, Dr. Reddy’s listed as an example where obtaining samples has been problematic Celgene Corporation’s (“Celgene’s”) REMS for Thalomid® (thalidomide) and Revlimid® (lenalidomide). Dr. Reddy’s explained how Celgene either ignored Dr. Reddy’s requests for samples or said that it had no obligations to provide samples and declined to do so. Dr. Reddy’s further cited to statements from a patent litigation between Celgene and Barr Labs., Inc. (“Barr”), now part of Teva, where, according to Barr, Celgene not only refused to supply Barr with samples but also interfered with Barr’s ability to obtain the active pharmaceutical ingredient. Celgene, in turn, asserted that Barr engaged in illegal or inequitable conduct by “improperly purchasing the drug from a pharmacy” that was not in accordance with the REMS for Thalomid®.
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redbloodcells.jpgAMAG Pharmaceuticals (“AMAG”) recently filed a Citizen Petition requesting that FDA apply more stringent bioequivalence standards to potential generic versions of its Feraheme® (ferumoxytol) Injection. Feraheme® is a non-biologic complex drug (“NBCD”) indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease. Specifically, AMAG requested that FDA: (1) refrain from approving any generic products referencing Feraheme® until post-marketing studies evaluating the therapeutic equivalence another IV iron replacement product to its reference listed drug (“RLD”) are complete (Nulecit™ to its RLD Ferrlecit®); (2) require sponsors of generic Feraheme® to show bioequivalence using a comparative study in patients with clinical endpoints; and (3) require generic Feraheme® sponsors to demonstrate bioequivalence using the additional assays being evaluated in the Nulecit™ post-marketing studies.

Ferumoxytol is a colloidal crystal of polynuclear ferric oxyhydroxide encased within a carbohydrate. It is a large, complex chemical entity (approximately 750 kDa) and its chemical structure has not been fully characterized. The carbohydrate serves to encase and sequester the iron moiety until it is taken up by its site of action, the macrophages of the reticular endothelial system (“RES”). In other words, the iron becomes bioavailable only inside the macrophage vesicles. This sequestration function is important because free iron is toxic and causes oxidative stress. Indeed, iron is normally sequestered in the body (e.g. hemoglobin, ferritin) because of this toxicity.

AMAG requests that FDA refrain from approving any generic Feraheme® products until the Nulecit™ post-marketing studies demonstrate that the standards currently established for generic IV iron replacement products are sufficient to therapeutic equivalence. FDA approved Nulecit™ as a generic version of Ferrlecit® in 2011. However, FDA issued a “Sources Sought” notice in April 2013 to determine the availability of third-party businesses to evaluate the therapeutic equivalence of Nulecit™ to Ferrlecit®. In particular, FDA proposed studies of: (1) in vitro phagocytosis to compare RES uptake of generic and RLD; (2) the time-dependent iron content in the major target organs and a comparison of biodistribution in animal models; (3) a prospective, randomized, 2-way crossover study to compare non-transferrin bound iron levels in hemodialysis patients treated with generic and RLD products. AMAG argues that a moratorium on generic approvals of IV iron products is reasonable pending the outcome of these studies. In addition, AMAG requests that FDA require prospective generic applicants perform these studies.
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soda.jpgNew York City has been attempting to take on various health problems by thinking locally by banning or discouraging unhealthy activities such as banning smoking in public places or by disclosing information about trans fats or high calorie foods to discourage their consumption. More recently, New York City proposed a prohibition on certain sugary beverages over 16 ounces in establishments regulated by the city’s health department, including food chains such as Subway and Dunkin’ Donuts (but not establishments not regulated by the city’s health department, such as 7-Eleven and grocery stores). The New York State Supreme Court Appellate Division Panel agreed with a lower court decision from March 2013 finding the ban unconstitutional.

Associate Justice Dianne T. Renwick wrote in an unanimous four-judge panel decision:

The regulatory scheme is not an all-encompassing regulation . . . It does not apply to all sugary beverages. The Board of Health’s explanations for these exemptions do not convince us that the limitations are based solely on health-related concerns.”

Renwick’s sentiments echoed what was said in the lower court by Judge Milton Tingling who wrote in his decision that the proposed regulation was “fraught with arbitrary and capricious consequences” and “loopholes in this rule effectively defeat the state purpose of the rule.”
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Thumbnail image for Q1 ProductionisAdvocating for Diagnostic Innovation through Examination of Key Stakeholder Insight Regarding Regulation of Lab Developed Tests, Open and Frank Dialog with FDA Reviewers to Ensure Precise & Compliant Data Collection during Diagnostic Clinical Trials Resulting in Timely Approvals

Diagnostic testing has reached monumental heights providing physicians and patients with lifesaving information and healthcare opportunities. As innovation continues to evolve and tests advance in their complexity, the challenges in assuring regulatory approval increases in tandem. Manufacturers face numerous hurdles in defining clinical evidence to support and secure timely regulatory approval in an increasingly competitive marketplace.

This conference will take place in Alexandria, Virginia on October 21-22, 2013. This comprehensive two-day program will bring together prominent diagnostic clinical and regulatory thought leaders from a variety of leading organizations to share lessons learned as well as expert practices and forward thinking solutions. This dynamic meeting will provide attendees speakers and sponsors with an ideal opportunity to network, knowledge share, and openly discuss challenges and opportunities surrounding clinical affairs and regulatory approvals for diagnostic tests.
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gift.pngStarting today, the reporting of all gifts or payments to physicians or teaching hospitals that total over $100 in a year will be required for drug and medical device companies per the new reporting requirements for the Affordable Care Act. These donations will be posted on a publically-accessible, Centers for Medicare and Medicaid Services (“CMS”) Internet site starting in September 2014. By decreasing the reporting threshold, this new law will likely make it harder for ethically-suspect activities to slip under public perception, at a cost of greater reporting requirements and an increase in the possible number of false accusations of unethical behavior. Because the reporting is based on the activity of the companies, physicians need not take any affirmative action or even be aware of the activity for their name to be posted.

The detection and prevention of ethics violations presents a trade off between under- and over-diagnosis. As a society, we want a system where ethical lapses are identified and resolved. However, due to the powerful stigma of accusation, it is no surprise that many physicians would prefer to avoid situations that later could be misconstrued as ethically suspect. For example, no physician wants their attendance at an educational conference to result in a random charge of violation of professional responsibilities to patients. This concern may cause physicians to avoid certain educational or other activities rather than worry about the impact of reporting on their reputation. CMS has addressed some of these issues and provided guidelines on what activities are not required to be disclosed, however, there will continue to be uncertainty until the regulation has been practiced for a while and appropriate norms and procedures are developed and agreed upon.

Gifts or payments to physicians fall into a number of different categories with varying levels of public utility. On one side, the sponsorship of medical conferences, continuing education seminars, and research grants are examples of gifts that provide significant public benefit as well as significant personal benefit to physicians. Reducing corporate sponsorship of such events will increase the cost to participants, resulting in a reduced participation in such activities. Physicians are already giving up their time and incurring the opportunity costs to improve their skills and knowledge by attending such events. The reporting aspect may further reduce attendance and learning.
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UDIdevice.bmpFDA continues to be late in issuing its final rules to implement the unique device identifier (“UDI”) system authorized in 2007. Congress had requested that FDA finalize the rule by June 19, 2013, but FDA’s latest action has been its proposed rules published in the Federal Register on July 10, 2012.

A UDI is a unique numeric or alphanumeric code that includes a device identifier, which is specific to a device model, and a production identifier, which includes the current production information for that specific device, such as the lot or batch number, the serial number and/or expiration date. A UDI system has the potential to improve the quality of information in medical device adverse event reports, which will help FDA identify product problems more quickly, better target recalls and improve patient safety.

FDA is also reportedly creating a database that will include a standard set of basic identifying elements for each UDI, which it plans to make generally available to the public so that medical device users can easily find more information about specific devices. The UDI does not indicate and FDA’s database will not contain any information about who uses a device, including any personal privacy information.
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RISK.jpgThis is part two of a summary of an FDA public meeting on Standardizing and Evaluating Risk Evaluation and Mitigation Strategies (“REMS”) held in FDA’s White Oak campus on July 25-26, 2013. On both days, public speakers offered their views on how to standardize REMS and better evaluate whether individual REMS elements are working to reduce the risks intended. FDA requested speakers to post their slide decks on the docket for this meeting, Docket No. FDA-2013-N-0502, as well as additional comments prior to September 16, 2013 to be considered for the REMS Integration Initiative Report.

While a variety of comments were made by speakers, many of the comments circled back to similar themes. Below is an attempt to capture a flavor of many of the comments, but more details will be made available in the coming month or so in FDA’s Docket. None of the speakers knew who was going to speak or on what topics/viewpoints, and many of the comments reflected company speeches that had been approved in advance of the meeting. Therefore, there was a certain amount of repetition of topics, which I have tried to reduce where possible, which resulted in a somewhat skewed summary leaning towards earlier speakers. For example, multiple speakers, including pharmacy chains such as CVS Caremark, recommended a single REMS portal to process claims in a more efficient workflow rather than multiple websites and portals that put an increased burden on the healthcare system.

  • On the first day, the Pharmaceutical Research and Manufacturers of America (“PhRMA”) (Sarah A. Spurgeon) kicked off the public session with a request for using the same REMS elements for the same risks, a “one-stop-shop” for all REMS systems on the Internet with a link to all REMS websites with less paperwork, an FDA logo for REMS-official programs, and templates for risk communication. Another PhRMA speaker on the second day (Sarah A. Spurgeon) supported research to determine the most effective REMS elements and asked FDA to consider selectively removing elements from REMS after proper assessment tools are validated. Also on the second day, FDA asked PhRMA to go its members and try to gather data concerning assessment tools and data whether those REMS tools are working, as well as whether post approval REMS are being streamlined or additional elements are being added in the interest of further risk management that may be increasing the burden on the healthcare system.
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RISK.jpgOn July 25 and 25, 2013, FDA held a public meeting on Standardizing and Evaluating Risk Evaluation and Mitigation Strategies (“REMS”), which we previously announced here. During the two days, FDA heard from a variety of public speakers from the healthcare and regulated industry, trade associations, the risk management support community, and law, which was interspersed with FDA’s observations and activities to date.

FDA’s Chair for the meeting, Theresa Toigo, R.Ph., M.B.A., Associate Director for Drug Safety Operations, Center for Drug Evaluation and Research (“CDER”) provided opening remarks and managed the diverse group of speakers. Toigo explained that the most recent Prescription Drug User Fee Act (“PDUFA”) V provided FDA with the authority and mandate to take a closer look at REMS under its REMS Integration Initiative and determine ways to reduce the burden on the healthcare system to administer the myriad of REMS programs. One thing FDA has already done, Toigo explained, was reduce the number of REMS from about 200 REMS in the beginning of 2013 to 72 REMS as of July 2013–many of these being MedGuide-only REMS. Of these 72 REMS, there are 66 individual drugs with 6 shared REMS programs included in approximately 84 applications, she explained.

According to Toigo, FDA has been hearing that some physicians have been avoiding REMS products because of the extra paperwork and other requirements, whereas the intent for REMS is to better control the risk factors for a particular therapy. In FDA’s view, Toigo explained, REMS are more than just filling out paperwork or providing repetitious messages, and FDA continues to hear in the standardization meetings that “one size does not fit all.” FDA’s requirements for and review of REMS has been facilitated by industry’s view point, in particular the business processes and assessments, which FDA hoped to hear more of during the two-day meeting.
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