By Kurt R. Karst –      

Bayer HealthCare, LLC’s (“Bayer’s”) court challenge to FDA’s approval of Abbreviated New Animal Drug Application (“ANADA”) No. 200-495 submitted by Norbrook Laboratories, Ltd. (“Norbrook”) for Enroflox™ 100, a generic version of Bayer’s fluroquinolone animal drug Baytril® 100 (enrofloxacin) Injectable Solution, has paid off.  FDA, following an April 12, 2013 Order from the U.S. District Court for the District of Columbia suspending the ANADA approval (and its associated labeling) for use in cattle (but not in swine), administratively suspended the cattle approval pending completion of the Agency’s consideration of issues raised by Bayer in a June 2006 Citizen Petition (Docket No. FDA-2006-P-0010, formerly FDA Docket No. 2006P-0249).  That stay was memorialized in a Stipulated Stay and Preliminary Injunction agreed to by the court, but opposed by Norbrook, and cited in an April 24, 2013 Order remanding the case to FDA for reconsideration.

As we previously reported, Bayer sued FDA on April 10th alleging that the Agency’s approval of ANADA No. 200-495 for use in cattle violates the Administrative Procedure Act (“APA”) and FDC Act § 512(c)(2)(A)(ii) – as added by the Generic Animal Drug and Patent Term Restoration Act of 1988 (“GADPTRA”), Pub. Law No. 98-417, 98 Stat. 1585 (1988), the Hatch-Waxman equivalent in the animal drug world – and served as a constructive denial of Bayer’s 2006 Citizen Petition in violation of the APA.  Baytril® 100 is approved for two different dosing regimens: (1) Single-Dose Therapy (7.5 to 12.5 mg/kg of body weight (3.4 to 5.7 mL/100 lb)); and (2) Multiple-Day Therapy (2.5 to 5.0 mg/kg of body weight (1.1 to 2.3 mL/100 lb)).  The Single-Dose Therapy use is covered by U.S. Patent No. 5,756,506 (“the ‘506 patent”), which expires on June 27, 2015, and claims the use of enrofloxacin in a single high dose to replace multiple lower doses in bovine respiratory disease and swine pneumonia.  FDC Act § 512(c)(2)(A)(ii), as amended by GADPTRA, states that FDA will approve an ANADA unless, among other things, the Agency finds that “the conditions of use prescribed, recommended, or suggested in the proposed labeling are not reasonably certain to be followed in practice . . . .”  FDA’s regulations prohibit the extralabel use of fluoroquinolones in food-producing animals (21 C.F.R. § 530.41(a)(10)), and, in particular, extralabel use of enrofloxacin in food-producing animals (21 C.F.R. §522.812(d)(2)(iii)).

Bayer’s 2006 Citizen Petition requested that FDA refrain from approving ANADAs for generic Baytril® 100 for Multiple-Day Therapy in cattle with labeling that omits information on Single-Dose Therapy protected by the ‘506 patent.  According to Bayer, any generic approved for Multiple-Day Therapy only will be promoted and used extralabel for the protected Single-Dose Therapy, which would directly conflict with the provisions of the GADPTRA and FDA regulations and undermine the incentives for discovery and innovation that GADPTRA and patent laws were intended to protect. 

Other than a boilerplate tentative response from FDA in December 2006 saying that the Agency “is currently considering the issues raised by your citizen petition,” and that “the agency will require additional time to issue a final response because of the complexity and the number of issues raised in your petition,” the petition docket has remained dormant.  In an April 17th Opinion made public last week granting in part and denying in part Bayer’s Motion for a Temporary Restraining Order, the DC District Court (Judge Rosemary Collyer), which has previously been critical of FDA Citizen Petition decisions (see, e.g., here at pages 21-24) criticized FDA’s failure to respond to Bayer’s petition.  Judge Collyer commented in her decision:

FDA recognizes that it erred by failing to respond to Bayer’s Citizen Petition before approving Enroflox but argues that the Court cannot conclude that FDA “knew” when making its decision that off-label use was reasonably certain to occur.  The Court rejects FDA’s formulation of the issue: resolution does not turn here on what FDA “knew” in a vacuum, but whether, based on all the facts before it, FDA had found that the conditions of use specified in the proposed labeling were not reasonably certain to be followed in practice.  Since FDA offers no evidence that it considered the full record before it or made the necessary finding, FDA presents an exceptionally weak position despite the excellence of its lawyering. . . .

The facts set forth in the Petition stand unchallenged and bereft of reasoned agency response.  Although counsel for FDA claimed that someone within FDA had prepared a tentative draft response denying the Citizen Petition, neither a “tentative draft” nor the prediction that a response is forthcoming can substitute for reasoned decisionmaking at the time FDA approved the Norbrook application for Enroflox.

At this juncture, FDA presents only legal argument that the Court should presume regularity and defer to its expertise.  But, while agency action may generally be “entitled to a presumption of regularity,” here FDA itself acknowledges that its action has not been regular: it failed to respond to the Citizen Petition for years and failed to provide a reasoned basis for rejecting it before approving Enroflox.  Further, the present record is devoid of any explanation at all for the basis for FDA’s decision to approve Enroflox. [(Emphasis in original; internal citations omitted)]

FDA’s failure to timely respond to citizen petitions (or to provide a substanstantive response and not just a denial without comment) before taking an action has been a sticking point with the FDA-regulated industry for years.  See, e.g., Warner-Lambert Co. v. Shalala, 202 F.3d 326 (D.C. Cir. 2000).  Indeed, Purdue Pharma L.P. (“Purdue”) recently submitted a Petition for Reconsideration (Docket No. FDA-2012-P-0939) after FDA denied without comment an August 2012 Citizen Petition concerning the approval of generic versions of reformulated OxyContin® (oxycodone HCl controlled-release tablets) approved under NDA No. 022272.  According to Purdue, FDA’s denial of the petition on non-substantive grounds was improper and based on a flawed interpretation of FDC Act § 505(q), which requires FDA to respond to certain petitions within 150 days of receipt.  Will companies now argue, in light of the Baytril® decision, that this kind of response is inadequate?  Will FDA have to change the way the Agency handles Citizen Petitions?  Something tells us that Judge Collyer’s Baytril® decision will show up again in litigation with FDA. 

Hyman, Phelps & McNamara, P.C. is pleased to announce that Joseph (“Jay”) W. Cormier, J.D., Ph.D. has joined the firm as an Associate.  Prior to joining the firm, Dr. Cormier served as a pharmacologist in the Animal Biotechnology Interdisciplinary Group in FDA’s Center for Veterinary Medicine.  While at FDA, Dr. Cormier evaluated the manufacturing of new animal drugs and helped develop policies regarding the regulation of genetically engineered animals.  He is the recipient of several awards, including the FDA Scientific Achievement Award and the Center for Biologics Evaluation and Research Scientific Achievement Award.  Dr. Cormier has extensive knowledge of issues concerning genetic engineering, drug and medical device manufacturing and product promotion, medical device data systems, and mobile medical apps.  He also has experience advising on matters involving general FDA-regulatory compliance policies, product development and FDA-submission strategies, oversight of clinical trials, tobacco product manufacturing, and organic food labeling.

Dr. Cormier graduated from Dartmouth College in 2000 with a Bachelor of Arts in Genetics, Cell, and Developmental Biology modified with Computer Science.  He earned a Master of Arts in Pharmacology in 2001, a Master of Philosophy in Pharmacology in 2003, and a Doctor of Philosophy in Pharmacology in 2005 – all from Columbia University.  Dr. Cormier graduated from Georgetown University Law Center in 2010 with a Juris Doctor, where he served as a Notes Editor for the American Criminal Law Review.  He is admitted to practice law in the District of Columbia, New York, and Massachusetts.  Since leaving FDA, Dr. Cormier has worked as an attorney in private practice representing major pharmaceutical and medical device clients.

By Karla L. Palmer –

The Senate’s Health, Education, Labor and Pensions (“HELP”) Committee released draft legislation on Friday, April 26, 2013, that would replace section 503A of the Federal Food, Drug & Cosmetic Act (“FDCA”), amend other sections, and clarify FDA’s authority to regulate pharmaceutical compounders and compounded pharmaceutical products.  Interested persons, industry and other stakeholders are asked to submit written comments concerning the draft legislation to compounding@help.senate.gov by 6:00 PM on May 3, 2013.  The draft legislation is available here, along with a summary, and an easily digestible section-by-section analysis of the draft bill.  

Set forth below is a summary of the draft legislation: 

Compounded Drugs Would Be Considered “New Drugs.”  In a section titled, “Clarification of New Drug Status” the proposed legislation explicitly clarifies that compounded drugs are “new drugs” subject to regulation under the FDCA. This clarification would put to rest decades of ambiguity concerning whether the FDCA’s provisions relating to new drug approval requirements apply to compounded drug products.

The Proposed Legislation Seeks to Establish Clear Regulatory Boundaries By Defining “Traditional Compounder” and “Compounding Manufacturer.”  The legislation would create two categories of compounding pharmacies: “traditional compounders” and “compounding manufacturers.”

Compounding Manufacturer.  The draft defines “compounding manufacturer” as an entity that: (1) makes sterile drug products without receiving or in advance of a prescription and introduces those drugs in interstate commerce; or (2) “repackage[s] a drug using sterile preservative-free single-dose vials or by pooling sterile drugs.”  Compounding manufacturers would be required to pay FDA annual registration fees, follow statutory restrictions on drugs they can compound (both for humans and animals), submit to FDA inspections similar to those conducted of drug manufacturers, and make regular reports to FDA pursuant to a national, uniform set of rules.  Drugs compounded by newly defined compounding manufacturers that meet the requirements set forth in the new section 503A would be exempt from the Act’s requirements regarding adequate directions for use (Sec. 502(f)(1)) and the new drug approval provisions (Sec. 505 for human drugs and Sec. 512 for animal drugs), but are subject to current Good Manufacturing Practices (“cGMP”) applicable to drug manufacturers.  In order for the exemptions to apply, the compounding manufacturer would have to comply with the other provisions of the legislation, and cannot be licensed as a pharmacy in any state.

More specifically, under the legislation, compounding manufacturers would have to:

• Ensure that a pharmacist, licensed in the state where the compounding manufacturer is located, exercises direct supervision over the operations of the compounding manufacturer.

• File with FDA every six months a list of drugs compounded during the previous six month period (including active ingredients, NDC numbers, the strength of active ingredients per unit, dosage form and route of administration, number of individual units produced, the NDC of the final product, and other requirements as established by FDA pursuant to regulation).

• Report to FDA any serious adverse drug experience not later than 15 days after receipt of information about the adverse event and maintain records of serious adverse drug experiences for 10 years.

• Label compounded drugs with the following statement: “This is a compounded drug,” or a reasonable comparable alternative statement (as specified by FDA).  The label also would include the name, address, and phone number of the compounding manufacturer; the lot or batch number; established name of the medication; strength; statement of quantity; directions for use; date the product was compounded; the “beyond use date;” storage instructions; and other information that the FDA determines is necessary.

• Pay registration fees.  For compounding manufacturer establishments with more than 25 employees, the annual fee would be $15,000 (subject to inflation); those with less than 25 employees would pay roughly one-third of that fee.  To the extent that FDA must reinspect a compounding manufacturer, that entity would be responsible for 100% of the reinspection-related costs.  All fees collected will be used by FDA solely to pay costs associated with inspections.

Traditional Compounders.  As defined by the legislation, a “traditional compounder” requires a licensed pharmacist in a state-licensed pharmacy, a licensed physician or licensed veterinarian, to the extent permitted under state law, to compound a drug, but only (1) upon receipt of a prescription for an individual patient; or (2) in limited quantities before receipt of a prescription for an individual patient if such compounding is based on an “established history” of such prescriptions.  Compounded drugs meeting the requirements set forth in the new 503A would be exempt from FDA’s cGMP (Sec. 501(a)(2)(B)), adequate directions for use requirements (Sec. 502(f) (1)), and the new drug provisions of the FDCA (Sec. 505 for human drugs and Sec. 512 for animal drugs).

The Proposed Legislation Contains An Exemption for Hospital Pharmacies.  A pharmacy located within a “health system” that compounds and ships drugs for dispensing within that health system (which may include interstate shipment) is considered a traditional compounder, subject to specified conditions, if it otherwise meets the definition of a traditional compounder.

Prohibitions on Compounding Certain Drugs.  The draft legislation states that certain drugs may not be compounded except under limited circumstances.  Those drugs include complex dosage forms and biologics as designated by FDA pursuant to regulation (this may include “extended release products, metered dose inhalers, transdermal patches, and liposomal products”). 

Copies of marketed animal or human drugs, including variations of such drugs compounded from bulk substances also could not be compounded, with a few exceptions.  These exemptions include: (1) if the compounder receives a prescription order for an identified individual patient indicating that the compounded variation produces for that patient a significant difference, as determined by the prescribing practitioner; (2) for copies of marketed FDA-approved drugs, if the drug at the time of compounding and its distribution is on FDA-maintained drug shortage lists, and the compounder notifies FDA prior to compounding.

Other Provisions.  The draft legislation also contains restrictions on the bulk chemicals that can be used in compounding, prohibits compounding manufacturers from selling to middlemen or wholesalers.  Lastly, references in the draft legislation to a prescription order for an “identified individual patient” would, in the case of animals, include a prescription order for a specific herd or flock of animals.

By Kurt R. Karst –      

In a brief opinion handed down last week by the U.S. Court of Appeals for the District of Columbia Circuit, the Court affirmed a July 5, 2012 decision from the U.S. District Court for the District of Columbia granting summary judgment for FDA in a case brought by AstraZeneca Pharmaceuticals LP’s (“AstraZeneca’s”) over the approval of generic versions of the company’s blockbuster antipsychotic drug SEROQUEL (quetiapine fumarate) Tablets.  As we previously reported, the case concerns the applicability and scope of 3-year exclusivity under FDC Act § 505(j)(5)(F)(iv) based on FDA’s simultaneous approval of supplemental NDAs (“sNDAs”) that contained information on pediatric uses of quetiapine and that made changes to the drug’s labeling to add “Table 2” of the Warnings section regarding “general safety information that is not indication-specific.” 

AstraZeneca’s legal attempts to stave off FDA approval of generic SEROQUEL started in March 2012 when the company sought to enjoin FDA from granting final ANDA approvals for generic SEROQUEL after FDA denied without comment two citizen petitions (Docket Nos. FDA-2011-P-0662 and FDA-2011-P-0663) AstraZeneca submitted to FDA concerning labeling carve-out issues (see our previous post here).  The DC District Court dismissed the action without prejudice, saying that it was premature (see our previous post here).  Just days later, however, FDA approved several ANDAs for generic SEROQUEL.  AstraZeneca filed a second lawsuit seeking to vacate FDA’s ANDA approvals and to enjoin FDA from granting any further final ANDA approvals.  The DC District Court denied AstraZeneca’s Motion for Temporary Restraining Order (see our previous post here). 

The case progressed to the summary judgment stage, where the AstraZeneca argued that under the plain language of FDC Act § 505(j)(5)(F)(iv), the company is entitled to a period of 3-year marketing exclusivity for the Table 2 information until December 2, 2012, plus 6 months of pediatric exclusivity (until June 2, 2013).  FDA, following the explanation provided in the Agency’s March 27, 2012 Letter Decision, [http://www.hpm.com/pdf/blog/SEROQUEL%20-%20FDA%20Letter%20Decision%203-27-2012.pdf] primarily argued that the scope of 3-year exclusivity relates to the scope of new clinical investigations conducted by the NDA sponsor and approved in an sNDA, but that “AstraZeneca reads the statute to provide for exclusivity for any labeling change, even if the change was initially submitted through general correspondence (and not a supplement), and it was unrelated to the purpose for which the supplement was submitted, and the change occurred only coincidentally and contemporaneously with the changes relating to the new clinical investigations that were the subject of the supplements.”  Finding FDC Act § 505(j)(5)(F)(iv) ambiguous, the DC District Court ruled that under Chevron Step Two,  FDA’s interpretation of the statute – i.e., “that a substantive relationship between new clinical studies and changes in the supplement, not the format of a submission, dictates what changes receive exclusivity” – is reasonable and granted summary judgment in favor of FDA.

On appeal, FDA argued the case was moot because the period of 3-year exclusivity at issue expired on December 2, 2012.  The DC Circuit disagreed, citing the possibility of pediatric exclusivity expiring on June 2, 2013.  Moving on to the merits of the D.C. District Court’s summary judgment decision, the Court examined the core of the dispute: the reasonableness of FDA’s interpretation of FDC Act § 505(j)(5)(F)(iv), which limits exclusivity to “a change approved in the supplement” and requires that “the supplement contain[] reports of new clinical investigations . . . essential to the approval of the supplement,” to deny exclusivity in this case.  As the Court pointed out, the statutory language “is permeated by ambiguities that, under Chevron, leave discretion in the FDA to adopt reasonable interpretations of the application process outlined by the statute.”

AstraZeneca argued that FDC Act § 505(j)(5)(F)(iv) clearly entitles Table 2 to exclusivity on two grounds, thereby making FDA’s approval of ANDAs incorporating Table 2 prior to June 2, 2013 contrary to the statute.  First, AstraZeneca argued that Table 2 was “a change approved in” the pediatric supplements the company submitted to FDA, and that the supplements included “reports of new clinical investigations . . . essential to the approval of the supplement[s].”  Second, AstraZeneca argued that the labeling changes independently warrant exclusivity because some of the clinical studies that provided the data for Table 2 were “new clinical investigations” “essential to the approval” of the labeling changes.  FDA maintained that that Table 2 was not “a change approved” in any supplement, and that only changes approved in an sNDA are entitled to marketing exclusivity.  (Briefs in the case are available here, here, and here.)

Noting that FDA “has exhaustive regulations detailing the parameters of the application process, including how to amend pending supplements and applications,” the Court said that “AstraZeneca makes no attempt to show that these procedures are contrary to the statute,” and that AstraZeneca did not show “that the FDA’s application of the law to the relevant facts was arbitrary or capricious.”  As such, the Court found “nothing arbitrary or capricious about the FDA’s reasoned explanation for its actions.”  AstraZeneca’s  attempts to establish that FDA was arbitrary or capricious in its exclusivity an ANDA approval decisions by directing the Court to prior grants of exclusivity to label changes approved in supplements similarly fell flat. “FDA’s explanation that it considered Table 2 independently of a supplemental application sufficiently distinguishes this case to defeat that claim,” wrote the panel of Judges Rogers, Tatel, and Sentelle.  “The consistency of the FDA’s denial of exclusivity in this case with prior FDA actions is strikingly underscored by the fact that the agency did not extend exclusivity in seven other recent labeling changes for drugs in Seroquel’s class.”

By Carmelina G. Allis –

As we previously reported, ReGen Biologics, Inc. ("ReGen"), which has been acquired by Ivy Sports Medicine, LLC ("Ivy"), filed suit in 2011 challenging FDA’s authority to rescind the 2008 510(k) substantial equivalence determination for the company’s “Menaflex” product, a collagen meniscus implant intended to reinforce damaged meniscal soft tissue.  ReGen Biologics, Inc. v. Sebelius, No. 1:11-cv-01006 (D.D.C. filed May 31, 2011). 

The 510(k) clearance for Menaflex classified the device into Class II.  In October 2011, FDA rescinded the 510(k) substantial equivalence determination alleging that the device does not have the same intended use as the predicate devices.  By rescinding that classification, pursuant to Section 513(f)(1) of the Federal Food, Drug, and Cosmetic Act ("FDC Act"), the product is now classified as a Class III device subject to the more stringent premarket approval ("PMA") requirements.

The company argued in the U.S. District Court for the District of Columbia that FDA lacks legal authority under the FDC Act to rescind a 510(k) substantial equivalence determination.  Because the rescission resulted in a reclassification of the device from Class II to Class III, ReGen argued that FDA should have complied with the reclassification procedures in 21 U.S.C. § 360c(e).  The procedures in § 360c(e) require that the agency secure an advisory panel recommendation and a publication in the Federal Register of a recommendation regarding the device’s classification prior to reclassifying the device.

Instead, FDA administratively rescinded the 510(k) substantial equivalence determination after conducting a review of the agency’s records in the matter.  The agency concluded that the record shows that FDA decision-makers departed from administrative processes, procedures, and practices, which resulted in a failure to document and explain the bases for the substantial equivalence determination, and also resulted in misconduct that affected the integrity of the administrative process.

FDA argued in court that it acted properly within its inherent administrative authority.  And the court agreed.  District Judge Robert L. Wilkins ruled that FDA has the inherent administrative authority to reconsider and change a 510(k) substantial equivalence determination in these circumstances if it does so within a reasonable period of time, even if the agency could have invoked a statutory provision to achieve the same result.  Ivy Sports Med., LLC v. Sebelius, No. 11-cv-1006 (D.D.C. Apr. 10, 2013).

In this case, the court agreed with FDA that the administrative record was “tainted.”  Examples given by the court of procedural irregularities and misconduct include:

• The agency’s failure to respond appropriately to external pressure on decision-makers – for example, FDA allowed Ivy to meet with agency officials without members of the review team present, and allowed members of Congress to speak directly to the Commissioner and Principal Deputy in violation of agency usual procedures.
• The exclusion of individuals, if not viewpoints, from parts of the scientific debate – for example, the court found that the company was successful in excluding the review team from speaking at the panel meeting.  The court explained that such exclusion could have skewed the panel meeting discussion in Ivy’s favor, and also did not allow the panel members to consider the reviewers’ concerns.
• The excessive reliance on advisory panel deliberations – for example, the court found inappropriate that the agency based its decision “entirely or almost entirely on the views of an outside Panel,” even though those views were in conflict with those of the FDA reviewers and the decision-making documents did not address the reviewers’ concerns.  Moreover, the panel meeting was convened with such “haste” that there was little time for panel members to properly prepare on the substantial equivalence standard or FDA’s panel procedures, and key panel members could not participate.

See id. at 17.

The court also found that FDA acted within a reasonable period of time when only eight to ten months passed between the initial agency determination of substantial equivalence to when the “affected party received notice that the determination was ‘actively under reconsideration,’ not when the agency made its final decision.”  Id. at 26-27.  In this case, FDA classified the device via the 510(k) substantial equivalence determination in December 2008.  The agency then began its review of the record in April 2009, published a preliminary report in September 2009, and met with the company in October 2009 to inform them of the administrative review.  The court ruled that this time period of eight to ten months “falls comfortably within the reasonableness standard.”  Id. at 27.

Ivy also argued that the FDA acted arbitrarily and capriciously because it did not limit its review of the substantial equivalence determination on the intended use statement of the device as set forth in the proposed labeling submitted in the 510(k).  According to the court’s opinion, FDA reviewed the indications for use and instructions for use of the Menaflex and predicate devices, and the directions for preparation of the surgical site of the Menaflex and predicate devices.  The agency also considered comments from panel members on the use of the Menaflex – such as statements that they were “‘having trouble with comparing’” the Ivy device with predicate devices because they “‘really aren’t used in the same way,’” and they “‘expressed uncertainty about what the [Ivy] device is intended to do.’”  Id. at 29.  The court ruled that “there is nothing improper about” “looking beyond the Indications for Use Statement” submitted in the 510(k) even though that is not “‘[t]ypically’ what is done.”  Id.

The court also found that FDA’s determination to rescind the 510(k) is based on a “review of the relevant material, including an examination of both panels, meetings with the review team, and the overall record,” and further concluded that the agency “properly based [its] conclusion on the [Ivy] device’s proposed labeling.” Id. at 31.

In sum, FDA has always asserted that it has the inherent authority to rescind 510(k)s.  It would be a mistake to infer from this decision support for the proposition that FDA may administratively rescind a 510(k) clearance simply because new or different agency officials arrive at a different scientific or policy judgment than their predecessors.  However, this decision does appear to affirm FDA’s rescission authority if the agency gives notice of reconsideration in a reasonable time frame and if there is evidence in the record of fraud and/or other misconduct affecting the integrity of the original decision. 

By Jessica A. Ritsick & William T. Koustas –

Within the last week, members of health committees in the House and Senate unveiled draft bills addressing prescription pharmaceutical supply chain security.  The House Energy & Commerce Committee is set to hold a hearing on the House bill on April 25, 2013.  Dr. Janet Woodcock, Director of FDA’s Center for Drug Evaluation and Research, will be a witness (witness list available here).  Witness’ prepared statements have been released prior to the hearing, and are available here.  The Senate Health, Education, Labor and Pensions Committee has not scheduled a hearing, but is accepting comments on its draft bill until April 26, 2013. 

In late 2012, we blogged about earlier Congressional efforts to create uniform, national standards for supply chain security.  The current drafts are not radically different from earlier proposals, but some provisions are worth mentioning.  Both draft bills endeavor to create uniform licensing standards for wholesale distributors and third-party logistics providers ("3PLs"), and a uniform standard for pharmaceutical pedigrees.

Each bill also requires the Secretary of Health and Human Services to establish though new regulations standards for the licensing of wholesale distributors and 3PLs, and describes in some detail what requirements these licensing standards must contain.  The licensing standards under both bills would include: recordkeeping requirements;  mandatory background checks and fingerprinting for facility managers or designated representatives; and a requirement that wholesalers and 3PLs to submit to FDA annual reports regarding licensure.  Under both bills, the annual reports from wholesalers and 3PLs must include the licensed entity’s name, address, and state licensure information.  The House bill, however, adds that annual reports must include information regarding any disciplinary actions taken against the entity by state or federal regulators; for wholesalers, this reporting requirement would extend to foreign governments.  The Senate bill would require FDA to maintain a public database of the reports, while the House bill would require FDA to make licensure information available via its website. 

Both bills include preemption provisions, although those provisions differ from each other.  The Senate bill provides that the federal licensing standards would be minimum requirements and that states could enact more stringent requirements.  In addition, the Senate bill calls for wholesalers and 3PLs to be licensed by the Secretary in the event the state does not have a licensure requirement.  The House bill would expressly preempt state licensing requirements, although states would continue to license drug wholesalers and 3PLs and collect associated fees.  However, the House bill later states that upon enactment, no state may establish or continue wholesaler or 3PL licensure requirements that are “inconsistent with, less stringent than, in addition to, or more stringent than, the standards and requirements under this Act,” which sounds like full-fledged preemption of state licensure of wholesalers and 3PLs.

The House and Senate bills differ regarding implementation and timing of the legislation.  For example, the Senate bill requires manufacturers to provide serialized products within four years of enactment; repackagers within five years; and wholesalers and 3PLs within six years.  Dispensers, under the Senate bill, must be able to accept serialized product within seven years after enactment.  The House serialization implementation requirements add an additional year  on to the Senate’s proposal for each type of entity.  The prescription drug product tracing requirements – such as the provision of a transaction history to downstream members in the supply chain – for manufacturers in the Senate bill are to begin “not later than 270 days after the date of enactment” of the bill, as compared to “5 years after the date of enactment” in the House bill.  Similar disparities exist for wholesalers, dispensers, and repackers, as well.  Interestingly, the Senate bill would require that an interoperable electronic unit level tracing system be in place 10 years after the date of enactment (pursuant to guidance by FDA).  The House bill does not have a firm timeline, but instead calls for studies to inform the implementation of a track-and-trace system, and requires a report from the GAO not later than 10 years after the bill’s enactment.

We are waiting to see what happens during the House hearing on the bill this week –  particularly what FDA has to say in terms of suggested timelines and the many new requirements the bills would place on the Agency.  It will also be interesting to see if states have any response to this legislation.  We have previously reported that the California Board of Pharmacy may be open to a national track-and-trace standard, but only if that system is “sufficient.”  In addition, FDA has for years advocated a uniform, national track-and-trace system, and perhaps this year the Agency will finally get its wish. 

The Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School is is holding its annual conference on Friday and Saturday, May 3-4, 2013, at Harvard Law School in Cambridge, Massachusetts.  This year, the conference will focus on FDA and is titled “The Food and Drug Administration in the 21st Century.”  The conference boasts an impressive cast of speakers, with a keynote address from Deborah Autor, FDA’s Deputy Commissioner for Global Regulatory Operations and Policy.

Conference topics include:

• Major Issues in Device Regulation
• Major Issues in Drug Regulation
• Balancing Access and Uncertainty
• The FDA in a Changing World
• Preserving Public Trust and Demanding Accountability
• Protecting the Public Within Constitutional Limits
• Regulatory Exclusivities and the Regulation of Generic Drugs and Biosimilars

Hyman, Phelps & McNamara, P.C.’s Jeffrey K. Shapiro will be speaking about his paper, “Substantial Equivalence Review of Medical Devices” during the conference session on Major Issues in Device Regulation. The paper argues that the 510(k) program has proven its worth as a premarket pathway for medium risk devices, and has little-recognized strengths, including a proven ability to successfully balance patient safety with fostering innovation.

Attendance at the conference is free and open to the public; however, registration is required and space is limited.  A copy of the conference agenda is available here.  Additional information on registration is available here.  Any questions about the conference can be sent to petrie-flom@law.harvard.edu or by calling 617.496.4662.

By Delia A. Stubbs –
 
The U.S. District Court for the Central District of California issued a ruling last week in an unusual, if not unprecedented, case arising from alleged federal False Claims Act (“FCA”) violations where one drug manufacture has sued its competitor.  In Amphastar Pharm., Inc. v. Aventis Pharma SA, No. 09-0023 (C.D. Cal., Apr. 19,2013), Amphastar, on behalf of the United States, alleged in its amended qui tam complaint that Aventis had “fraudulently inflated the price of enoxaparin” thus overcharging the federal and various state governments in violation of the FCA.  Interestingly, Amphastar’s claims are predicated on allegations that Aventis fraudulently sold Lovenox®, that was “in essence, non-patented enoxaparin,” thereby charging inflated prices.  Id. at 7, n. 9.  In an earlier decision, the U.S. Court of Appeals for the Federal Circuit affirmed the district court’s ruling that Aventis engaged in “inequitable conduct” and thus held its patents regarding Lovenox® unenforceable.  Id. at 2, n. 4.

This case garnered our attention due to the fact that the FCA case was brought by Aventis’s competitor.  While qui tam actions against drug manufacturers are by no means rare, those cases are usually brought on behalf of the government by a former employee of the defendant.  This is because plaintiffs in FCA cases are required to plead their complaints “with particularity,” a standard that is difficult to meet in any FCA case, and especially difficult to meet without access to inside information.  See Fed. R. Civ. P. 9(b).  In fact, some jurisdictions require the plaintiff to plead the specific amounts and dates of the alleged fraudulent claims.  See, e.g., United States ex rel. Roop v. Hypoguard USA, Inc., 559 F.3d 818, 821 (8th Cir. 2009).

However, the District Court in Amphastar ruled last week that in the 9th Circuit, “pleading representative examples of false claims is one way, but not the only way to meet the Rule 9(b) pleading requirement.”  Amphastar, slip Op. at 6.  It explained that Amphastar met its pleading obligations by alleging:

(1) Aventis held the exclusive right to sell enoxaparin in the United States through its fraudulently obtained patent;

(2) Aventis submitted or caused to be submitted to the United States false claims based upon inflated price due to its falsely obtained market exclusivity;

(3) The Government paid claims submitted by Aventis for enoxaparin at illegally high prices and reimbursed Medicare or Medicare providers for dispensing Defendants’ enoxaparin; and

(4) An identified reliable source of data indicated that between 1993 and 2002, the government purchased 6,298,000 units of Lovenox® from Aventis or its distributor for use at federal facilitates totaling $102,655,000 and that between 2003 until the third quarter of 2012, the government purchased 22,497,000 units of Lovenox® from Aventis or its distributors for use at federal facilities totaling $470,559,000.

Id. at 7.

By Ricardo Carvajal –

The U.S. District Court for the Northern District of California granted summary judgment to the Center for Food Safety and Center for Environmental Health in their lawsuit (see our previous post here) alleging that FDA’s delay in issuing regulations to implement the Food Safety Modernization Act ("FSMA") constitutes action unlawfully delayed or unreasonably withheld, in violation of the Administrative Procedure Act ("APA").  Because FSMA provides specific deadlines for the issuance of implementing regulations, the court concluded that “the failure to comply with those deadlines constitutes a ‘failure to act’ under the APA,” and therefore the court need not analyze whether FDA’s delay is unreasonable.  (Briefs in the case are available here, here, here, and here.)

In deciding what relief to grant, the court recognized that Congress did not intend for FDA to have “total discretion in deciding when to finalize the regulations,” but also noted that “the purpose of ensuring food safety will not be served by the issuance of regulations that are insufficiently considered, based on a timetable that is unconnected to the magnitude of the task set by Congress.”  The court therefore ordered the parties to confer “in the hope that [they] will themselves arrive at a mutually acceptable schedule.”  Curiously, the court admonished that it would “behoove the parties to attempt to cooperate in this endeavor, as any decision by the court will necessarily be arbitrary.”  The parties are to submit a “joint written statement setting forth proposed deadlines” by May 20, 2013.

It may prove challenging for the parties to reach agreement on proposed deadlines for issuing the regulations that isn’t arbitrary, given the intricate relationship between several of the major regulations, the likelihood of extended review by OMB/OIRA, and the near certainty of industry insistence on comment periods commensurate with the complexity of the task at hand. 

By Jennifer D. Newberger –

FDA is proposing to amend the medical device labeling requirements to allow for use of internationally recognized stand-alone symbols explained in an accompanying symbols glossary.  The symbols glossary would include a list of each symbol used in the device labeling and an explanation of the symbol’s meaning.  The permitted symbols would be those recognized by a standards development organization (“SDO”) such as the American National Standards Institute (“ANSI”) and the International Organization for Standardization (“ISO”).  FDA will retain a list on its website of the standardized symbols it recognizes.

Allowing use of these symbols is intended to harmonize medical device labeling with European Union requirements.  Currently, stand-alone symbols are generally not permitted on medical device labeling in the United States; any symbols used must be accompanied by text directly on the label.  In Europe, however, stand-alone symbols are widely used.  According to FDA, the inconsistent requirements result in manufacturers having to revise their label for the U.S. market, which has “created confusion and generated industry complaints that manufacturers have to develop different labels for each market.”

The proposed rule provides the option to continue labeling devices as they have been—symbols with accompanying text—or to use stand-alone symbols explained in an accompanying symbols glossary.  In other words, FDA will not require manufacturers to use stand-alone symbols for devices in the U.S. market if they do not wish to do so.  For global manufacturers, however, the ability to create one label for worldwide distribution (not taking into account necessary language differences) will likely be a welcome relief.

By Ricardo Carvajal –

FDA reportedly intends to extend the comment period on the preventive controls and produce safety proposed rules by an additional 120 days (the comment period was scheduled to expire on May 16).  The extension was requested in a letter by the United Fresh Produce Association and other stakeholders, which noted that the two rules are voluminous and “intersect at many different points.”  Further, the letter notes that FDA “requested comments on over 100 questions,” some of which “require scientific and economic analysis that could take months if not years to synthesize comments around.”  The letter requested an extension of at least 180 days after the issuance of the proposed rules on foreign supplier verification, preventive controls for animal feed, and accreditation of third-party certifiers so that industry has an opportunity to evaluate and comment on all of the proposed rules at the same time.  The three latter rules continue to be under review at OMB, which suggests that their issuance is not imminent.

Earlier in April, FDA requested comment on a draft compliance policy guide ("CPG") on food facility registration.  The CPG states FDA’s policy with respect to initial and biennial registration, as well as suspension of registration.  Comments are due by May 6.

By Riëtte van Laack –

As previously discussed, in 2011, the FTC filed an action against Garden of Life and its owner (collectively “GOL”) asking the District Court to order GOL to show cause why it should not be held in civil contempt.

The case stems from a 2006 settlement the FTC reached with GOL.  The consent decree prohibits disease claims unless such claims are substantiated by competent and reliable scientific evidence.  The FTC alleged that certain advertising claims subsequently made by GOL were not supported by “competent and reliable evidence.”

GOL retained a consulting firm to evaluate scientific evidence for potential advertising claims.  Nevertheless, the FTC’s expert opined that the claims were not substantiated by competent and reliable scientific evidence.  GOL’s expert opined that they were.  The lower court refused to find that GOL violated the consent decree because the dispute was based on a “battle of the experts.”

The Eleventh Circuit on Monday refused to revive most of the FTC’s claims.  Except for one claim concerning certain allegedly false statements GOL had made, the Court affirmed the lower court decision.

The Eleventh Circuit Court of Appeals upheld the lower court's finding that the FTC failed to meet its burden based on conflicting expert testimony.  The consent decree defines “competent and reliable scientific evidence” to mean “tests, analyses, . . . and other evidence based on the expertise of professionals in the relevant area, that has been conducted and evaluated in an objective manner by persons qualified to do so, using procedure generally accepted in the profession to yield accurate and reliable results.”  In its appeal, the FTC argued that the FTC’s expert was the only one qualified to speak to the substantiation of the claims because the FTC’s expert was an expert in the relevant subspecialty whereas GOL’s expert was an expert in pharmacology and medicine in general.  In other words, the FTC sought to narrowly construe the meaning of “professionals in the relevant area.”  The Court, however, was unpersuaded by the FTC’s assertion that GOL's consultant expert was  not qualified to interpret the results of medical studies and held that the lower court’s interpretation that “professionals in the relevant area” means experts in medicine or pharmacology in general rather than specialists in the given medical subspecialty was reasonable.

Although the Court affirmed the lower court’s denial of the FTC’s contempt motion as to the substantiation issue, it remanded the issue of how to handle GOL’s alleged misstatement in its now-withdrawn ads for Grow Bone System.  Apparently, due to a mistake by its consultants, these ads stated that a bone density study had shown double the average increase in density than it actually did.  Because the lower court's order did not address that misstatement, the Court lacked a sufficient record to review the issue, and sent the claim back so the lower court could address it in the first instance.

The FTC’s loss in a contempt proceeding against Lane Labs caused FTC to insert more specific substantiation provisions into its consent decrees.  The current case could have similar consequences.  To reduce the likelihood of similar losses, the FTC could further refine the definition of “competent and reliable evidence” in future consent decrees by seeking to narrow the meaning of “professionals in the relevant area.”

By Jeffrey K. Shapiro & Jennifer D. Newberger –

The medical device appeals process has long been in need of improvement.  See our previous posts here and here.  There are several ways an entity can appeal a decision of the Center for Devices and Radiological Health (“CDRH”), but the most common of these is by “supervisory review,” described in 21 C.F.R. § 10.75.  This allows an appeal to the next level supervisor above the individual who signed the decision.  FDA historically has taken a long time to make its appeal decision, and industry also has had to appeal from cryptic written decisions that made it difficult to understand the basis for the adverse decision.  In December 2011, FDA issued a draft medical device appeals guidance with voluntarily adopted target deadlines for an appeal decision to be communicated within six weeks of submission of the written appeal or appeal meeting.

A few months later, Congress included a device appeals provision, Section 603, in the recently enacted Food and Drug Administration Safety and Innovation Act (“FDASIA”).  This provision imposed a 45 day deadline for FDA to decide an appeal (or 30 days from a requested appeal meeting).  Section 603 also requires FDA to issue a “substantive summary” explaining the basis for the adverse decision.  The latter requirement is intended to assist industry in understanding the basis for adverse decisions. 

We recently contacted knowledgeable officials at CDRH to help us better understand interpretational issues that have arisen around Section 603.  We were also curious as to how FDASIA would affect the draft guidance.  We were told that CDRH intends to issue final updated guidance, which will address FDASIA, perhaps as early as July 2013.  We summarize below what we learned.

1.    FDASIA § 603, enacted as section 517A of the Federal Food, Drug, and Cosmetic Act (“FDC Act”), applies only to appeals of “significant decisions,” but does not define that phrase.  CDRH is currently working on a definition of this term to be provided in the forthcoming updated guidance.  It is our understanding that CDRH’s interpretation may be published in draft, either as a draft addendum to the final guidance or a separate document, providing stakeholders with an opportunity to comment prior to final issuance.

2.    FDC Act § 517A(b)(2) states that a person requesting supervisory review of a significant decision must submit the request for review within 30 days after the date of the decision in dispute.  The guidance will likely reflect CDRH’s interpretation that this provision means a firm that fails to appeal within 30 days loses all right to a supervisory appeal.  The firm could not fall back to the old non FDASIA request for supervisory review under 21 C.F.R. § 10.75, which does not impose a deadline for filing.  Also, CDRH apparently interprets the FDASIA language as not allowing for waivers, placeholders, or “partial submissions.”  They view the 30 day time limit as a “hard cap.”  The bottom line is that a request for supervisory review must be filed in 30 days, in full, or that option will likely be lost forever.  (A disappointed applicant could still invoke other appeal procedures.  For instance, a citizen petition could be filed under 21 C.F.R. § 10.30.  But that is a public proceeding and FDA could take years to respond, making it unrealistic in most cases.)

3.    One might think that the hard 30 day deadline applies only to appeals of significant decisions, which are the focus of the new FDASIA appeal procedure deadlines.  However, CDRH is considering whether to apply it to non significant decisions as well.  (It is unclear to us what the legal basis would be.)  If CDRH does apply the 30 day appeal deadline to non significant decisions, they would probably also honor the response deadlines in FDASIA as a sweetener.  It is also possible that CDRH will allow an appeal of a non significant decision to be submitted within a longer time frame and, unlike the appeal of a significant decision, may allow a stakeholder to request an extension.

4.    FDC Act § 517A(a)(1) requires FDA to provide to the submitter a “substantive summary of the scientific and regulatory rationale” underlying the significant decision.  The summary must include “documentation of significant controversies or differences of opinion and the resolution of such controversies or differences of opinion.”  Presumably, an applicant would seek this information to assist in preparing an appeal of the “significant decision.”  The law, however, does not set a time frame within which a request for a substantive summary must be submitted and does not impose a deadline on FDA as to when it must issue the substantive summary.  CDRH is trying to determine when the substantive summary will be provided, what it will include, and if there is a way to work development of the summary into the reviewers’ workflow to make it easier to provide in a timely manner.  These issues will be addressed in the updated appeals guidance.  We were told, however, that there is no guarantee that the guidance will require CDRH to provide these summaries before the 30 day deadline to appeal the decision.

We will follow up with any additional information as it becomes available.

By Ricardo Carvajal –

Our colleagues at the Drug and Device Law Blog recently blogged on the decision in Wilson v. Frito-Lay North America, Inc., a false advertising case out of the Northern District of California in which the court held that statements on a food company’s website did not constitute labeling even though the labels of some products included a reference to the website.  That piqued our interest because FDA has repeatedly asserted in warning letters (see here, here, and here) and other communications that a website referenced on a product’s label constitutes labeling, on the theory that the website “accompanies” the product within the meaning of FFDCA § 201(m).

The court acknowledged that “statements not actually printed on a label itself can constitute ‘labeling’ for FDCA purposes.”  However, because the website did not explain or supplement the individual products, the court found that the website did not “accompany” the products.  In the court’s view, the mere inclusion of the website address on the products’ label was insufficient to render the website labeling, absent some connection between the products and the language on the website.

Intriguing though this analysis may be, it must be noted that the plaintiffs failed to cite any authority for their assertion that websites constitute labeling.  Query whether the court would have viewed the issue differently if presented with FDA’s perspective.  We may yet find out, as plaintiffs were given leave to amend – if they can point to website language that constitutes labeling.

By Kurt R. Karst –      

The cherry blossoms are finally in full bloom in Washington, D.C., and so too is FDA’s thinking on one non-abuse-deterrent drug.  In a prepublication version of a notice that will be published in the Federal Register on April 18, 2013, FDA has determined that OXYCONTIN (oxycodone hydrochloride controlled-release) Tablets, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, and 160 mg, approved under NDA No. 020553, have been discontinued for reasons of safety or effectiveness.  The highly anticipated decision was made on the same day that U.S. Patent No. 5,508,042 was set to expire, potentially paving the way for ANDA approvals, and on the same day FDA announced the approval of abuse-deterrent labeling for a reformulated version of OXYCONTIN approved under NDA No. 022272 (presumably in accordance with FDA’s draft guidance on the topic – see here).  The move also comes just a day after resolutions were introduced in the U.S. Senate (S. Res. 97) and House of Representatives (H. Res. 161) expressing the sense that FDA should encourage the use of abuse-deterrent formulations of drugs.  (Congress is currently considering legislation – the Stop Tampering of Prescription Pills Act of 2013 (H.R. 486) (see our previous post here) that would establish new requirements for tamper-resistant drugs.  In addition, several Members of Congress and the National Association of Attorneys General recently urged FDA to adopt standards requiring manufacturers and marketers of generic prescription opioids to develop tamper-resistant versions of such products (see here and here).)

FDA’s decision was made in response to several Citizen Petitions submitted to the Agency over the past 12 years (Docket Nos. FDA-2001-P-0238, FDA-2010-P-0526, FDA-2010-P-0540, and FDA-2011-P-0473), but primarily after FDA approved NDA No. 022272 on April 5, 2010 for a reformulated version of OXYCONTIN with physicochemical properties that are intended to make the drug product more difficult to manipulate for purposes of abuse or misuse.  Just days later, Purdue Pharma, L.P. (“Purdue”), the sponsor of both OXYCONTIN drug products, notified FDA that the company ceased shipment all of the strengths of the original version of OXYCONTIN, and FDA then moved the drug products to the “Discontinued Drug Product List” section of the Orange Book.  Under FDA’s regulations at 21 C.F.R. § 314.161, the Agency must determine whether a listed drug that has been voluntarily withdrawn from sale was withdrawn for safety or effectiveness reasons before approving an ANDA for a generic version of the drug.

According to FDA’s notice concerning original OXYCONTIN:

FDA has conducted an extensive review of data available to the Agency regarding reformulated OxyContin, including in vitro, pharmacokinetic, clinical abuse potential, and postmarketing study data.  The data show that, when compared to original OxyContin, reformulated OxyContin has an increased ability to resist crushing, breaking, and dissolution using a variety of tools and solvents. . . .

FDA has long considered the abuse potential of a drug in numerous regulatory contexts.  Where appropriate, FDA may take into account abuse potential as part of the safety profile of a drug when weighing its benefits and risks.  In this case, FDA has considered the abuse potential as part of the Agency’s determination of whether the original formulation of OxyContin was withdrawn from sale for reasons of safety or effectiveness.  This approach is particularly appropriate here in light of the extensive and well-documented history of OxyContin abuse.

Original OxyContin has the same therapeutic benefits as reformulated OxyContin.  Original OxyContin, however, poses an increased potential for abuse by certain routes of administration, when compared to reformulated OxyContin.  Based on the totality of the data and information available to the Agency at this time, FDA concludes that the benefits of original OxyContin no longer outweigh its risks.

As a result, original OXYCONTIN will be removed from the Orange Book entirely and FDA will not approve any ANDA for a generic version of the drug product. 

FDA’s decision might have been foreshadowed by an April 15th approval of a supplement to NDA No. 022272 for reformulated OXYCONTIN concerning modifications to the approved Risk Evaluation and Mitigation Strategy (“REMS”) for the drug (among other drugs identified in Appendix 1 to the approval letter).  According to the approval letter, FDA approved REMS modifications, including “[r]evision to the REMS document to remove ANDA holders from the Timetable for Submission of Assessments.”  (Additional information on FDA’s REMS for extended-release and long-acting opioids is available here.)

Still pending at FDA is a Citizen Petition (Docket No. FDA-2012-P-0895) Endo Pharmaceuticals Inc. (“Endo”) submitted to FDA last August requesting that the Agency determine that the company’s non-crush-resistant formulation of OPANA ER (oxymorphone HCI) Extended-release Tablets approved under NDA No. 021610 was discontinued for reasons of safety and can no longer serve as the basis of approval for an ANDA, that FDA refuse to approve any pending ANDA for a generic version of Original Formulation OPANA ER, and that FDA suspend and withdraw the approval of any ANDA referencing original formulation OPANA ER as its basis for approval.  An FDA decision on that petition is expected in May.  Last November, Endo sued FDA seeking a preliminary injunction ordering FDA to make a decision on the Citizen Petition by December 31, 2012 (see our previous post here).  On December 19, 2012, the D.C. District Court denied the motion and dismissed the case.

A natural question raised by FDA's decision on original OXYCONTIN is whether it has any read-through to the upcoming FDA decision on Endo's OPANA ER Citizen Petition.  Whether it does (and the extent to which it does) or not will likely be debated at length over the next few weeks.  Within hours of FDA releasing its OXYCONTIN decision, RBC Capital Markets was already commenting that “FDA is likely taking a 'case by case' approach and the risk/benefit for generics of OxyContin may not be the same as for Opana.”

It is unclear whether any ANDA sponsor will challenge FDA’s determination on original OXYCONTIN in court.  If someone does, however, rest assured that we will be on the case.