Thumbnail image for Thumbnail image for Q1 ProductionisStreamlining Clearance & Approval Processes by Thoroughly Understanding Implications of New FDA Guidances Surrounding 510(K) Device Modifications & Refuse-to-Accept Policy while Successfully Addressing Inconsistency in Reviewer Feedback

The medical device regulatory landscape continues to evolve as new guidances are released by FDA, & global regulatory bodies are emerging or developing stricter guidelines for product approvals. Regulatory affairs executives in the device industry must stay abreast of these changing regulations in order to implement forward-thinking strategies for streamlining product approvals, & ultimately bring new & innovative products to market that will advance healthcare outcomes. The 3rd Annual Medical Device Regulatory Clearance & Approval Conference will build off the success from previous meetings by bringing together perspectives & insights from leading regulatory affairs professionals & innovative device manufacturers on how to ensure positive regulatory clearance & approval decisions in the US & internationally.

This two day conference will take place in Alexandria, Virginia on October 28-29, 2013. Attendees of this year’s program will have an exclusive opportunity to gather the latest insights into new & evolving FDA guidances & the implications for device manufacturers. Two key guidances of concern for regulatory affairs executives include the re-release of the 510(K) Device Modifications guidance along with the recent Refuse-to-Accept Policy. Presentations will also address internal strategies for tackling inconsistencies amongst FDA reviewer feedback & an increase in data requirements Continue reading

boywithflu.jpgOn June 28, 2013, FDA approved GlaxoSmithKline Biologicals’ (“GSK”) Flulaval® Quadrivalent (Influenza Virus Vaccine) for the 2013-2014 flu season. Flulaval® Quadrivalent protects against two influenza-A virus strains and two influenza-B virus strains and is approved for ages 3 and older. This season is the first time that vaccines protecting against more than three influenza strains will be commercially available. The other quadrivalent vaccines that are currently available include: Astrazeneca/Medimmune’s FluMist® Quadrivalent, GSK’s Fluarix Quadrivalent, and Sanofi’s Fluzone® Quadrivalent.

Seasonal flu is caused by either type-A influenza strains or type-B influenza strains. Each year, the World Health Organization recommends that vaccines address the two type-A strains that are most common in humans, and the type-B strain that is expected to be the most predominant in the upcoming flu season. Vaccines that protect against three influenza strains are referred to as trivalent vaccines. “Trivalent influenza vaccines have helped protect millions of people against flu, but in six of the last 11 flu seasons, the predominant circulating influenza B strain was not the strain that public health authorities selected,” said Dr. Leonard Friedland, V.P. and Head, GSK North America Vaccines Clinical Development and Medical Affairs. Dr. Friedland also noted that, “Trivalent vaccines do reduce influenza risk even in years when a vaccine strain-mismatch occurs, though quadrivalent influenza vaccines are the important next step in broadening strain coverage.” For the 2013-2014 flu season, the World Health Organization recommended protection against a second type-B influenza strain.

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Written by Julie E. Kurzrok

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Three other quadrivalent vaccines have been approved by FDA for the 2013-14 flu season. Fluarix Quadrivalent is an intramuscular vaccine that requires 1-2 doses depending on a person’s age and/or vaccination history. It is approved for ages 3 and older. FluMist® Quadrivalent is a live, attenuated vaccine that is administered via intra-nasal spray in 1-2 doses depending on a person’s age and/or vaccination history. It is approved for ages between 2 and 49 years. Fluzone® Quadrivalent is an intramuscular vaccine that requires 1-2 doses depending on a person’s age and/or vaccination history. It is approved for ages 6 months and older.
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Thumbnail image for DEA Badge.jpgOn August 19, Eisai Incorporated (“Eisai”) filed a Writ of Mandamus to Redress Unreasonable Delay by the Drug Enforcement Administration (“Writ”) to compel the Drug Enforcement Agency (“DEA”) to issue a Notice of Proposed Rulemaking (“NPRM”) within ten days of the Writ and otherwise expedite its drug scheduling for Fycompa® (perampanel). According to Eisai, DEA’s failure to initiate the scheduling of Fycompa® almost seven months after receiving a scheduling recommendation from the Assistant Secretary for Health (“ASH”) “constitutes unreasonable and egregious delay warranting mandamus.” In Eisai’s opinion, mandamus is warranted because: “(i) many thousands of patients who may benefit from the drug cannot obtain it, (ii) the drug’s sponsor is unable to benefit from FDA’s approval [of Fycompa®, and (iii) the burden on DEA of scheduling this drug is very small.”

Eisai’s Writ explained the process where FDA sends its drug scheduling recommendation through the ASH to DEA to initiate a scheduling proceeding “within a reasonable time” to permit the drug to be marketed with the appropriate scheduling safeguards. Under the Controlled Substances Act (“CSA”), if a drug has the potential for abuse, it must be subject to DEA scheduling, which considers “the eight-factor analysis” indicative of abuse potential and places the drug in one of five drug schedules. Schedule II is the most restrictive category where the drug is still accepted to have an accepted medical use, and Schedule V is the least restrictive schedule with an accepted medical use yet a low potential for abuse, physical dependence, or psychological dependence relative to other drugs or substances in Schedule IV.

The CSA permits DEA to add, change, or delete a substance’s schedule at any time by FDA/Health and Human Services or by petition from ay interested person or entity. The process that Eisai referred to, however, is the initial approval of a new chemical entity (“NCE”), where there was previously no schedule for the drug substance, and FDA recommends that a drug be scheduled prior to marketing. Although FDA lacks the direct authority to restrict marketing of products with pending DEA scheduling orders, FDA includes FDA Form 356h as a cover sheet for all new drug applications (“NDAs”) with a statement that the sponsor will not market until DEA makes a final scheduling decision. In the past, sponsors have honored these commitments to wait for a final scheduling decision before marketing their FDA-approved NDAs. Sponsors have waited despite FDA starting the clock for the five-year NCE exclusivity from the date of FDA’s approval letter rather than the final DEA scheduling, i.e., losing exclusive marketing time.
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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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