By Kurt R. Karst –      

A new report released by the Government Accountability Office (“GAO”), titled “Antibiotics: FDA Needs to Do More to Ensure That Drug Labels Contain Up-to-Date Information,” says that since the September 27, 2007 enactment of the FDA Amendments Act (“FDAAA”) FDA has not taken sufficient steps to ensure that antibiotic labels contain up-to-date information, and that certain FDAAA provisions relating to antiobotic innovation have not resulted in the submission of marketing applications for antibiotics. 

The GAO report focuses on three FDAAA provisions:

(1) Section 1111, titled “Identification of clinically susceptible concentrations of antimicrobials,” which required FDA to identify “antibiotic breakpoints” “where such information is reasonably available,” to periodically update them, and to make these up-to-date breakpoints publicly available within 30 days of identifying or updating them.  (A “breakpoint” included on an antibiotic’s label reflects the concentrations at which bacteria are categorized as susceptible to treatment with a given antibiotic drug and can change over time.  An outdated breakpoint can result in the unknowing selecting ineffective treatments, which can also contribute to antibiotic resistance.);

(2) Section 1112, titled “Orphan antibiotic drugs,” which authorized funding for grants and contracts under the Orphan Drug Act and required FDA to convene a public meeting to discuss incentives, such as those included in the Orphan Drug Act, to develop or otherwise obtain marketing exclusivity for antibiotics that treat serious and life-threatening infectious diseases; and

(3) Section 1113, titled “Exclusivity of certain drugs containing single enantiomers,” which is not specific to antibiotic drug development, allows a sponsor of an enantiomer of a previously aproved racemate to elect to have its drug considered a New Chemical Entity (“NCE”) eligible for a period of 5-year NCE exclusivity (instead of 3-year exclusivity for enantiomers of previously approved racemates) provided certain statutory conditions are met.

Antibiotic Labeling Breakpoint Updates.  In 2008, FDA sent letters to application holders requesting that they inform the Agency as to whether or not their product included up-to-date breakpoints.  In June 2009, FDA issued final guidance on compliance with FDAAA § 1111 and discussing a sponsor’s responsibility to maintain up-to-date breakpoints on their antibiotics drug labels.  According to the GAO report, although FDA has taken these initial steps to update breakpoint information on antibiotic labels, the Agency “has not confirmed that the information is up to date for most reference-listed antibiotics.”  Indeed, as of November 2011:

over 3.5 years after FDA sent its letters, 146, or 70 percent, of the 210 antibiotics are still labeled with breakpoints that have not been updated or confirmed to be up to date. For 78 of the 146 antibiotics, FDA has not yet received a submission regarding the currency of the breakpoints; for 12 of the antibiotics, the sponsors’ submissions are pending FDA review; and for 56 of the antibiotics, FDA determined that the sponsors’ submission was inaccurate or incomplete and therefore requested a revision or additional information. Thus far, FDA has determined that 64, or 30 percent, of the 210 antibiotics have up-to-date breakpoints.

There are two reasons so many antibiotics still have breakpoints that FDA has not confirmed to be up to date, according to the GAO: (1) “many sponsors have not fulfilled the responsibilities outlined in FDA’s 2008 letters;” and (2) “FDA faced difficulty in keeping up with the workload that resulted from sponsors’ breakpoint submissions.”

The GAO recommends that FDA Commissioner Hamburg take several actions to help ensure the accurate labeling of antibiotics, including “expeditiously review sponsors’ submissions regarding the breakpoints on their antibiotics’ labels,” taking “steps to obtain breakpoint information from sponsors that have not yet submitted breakpoint information in response to the 2008 letters sent by the agency;” and establishing “a process to track sponsors’ submissions of breakpoint information included in their annual reports to ensure that such information is submitted to FDA and reviewed by the agency in a timely manner,”

Enhanced Incentives.  The two FDAAA provisions (Sections 1112 and 1113) applicable to antiobotic drug sponsors (although only generally in the case of FDAAA § 1113) that provide for enhanced incentives have apparently not encouraged the development or approval of new antibiotics.  According to the GAO:

To date, drug sponsors, including those we received comments from, have not submitted any NDAs for antibiotics as a result of the FDAAA provision granting additional market exclusivity for new drugs containing single enantiomers of previously approved racemic drugs.  According to FDA officials, they have received very few inquiries regarding this provision and as of November 2011, no NDAs for antibiotics have been submitted that would qualify for this exclusivity. . . .

The lack of NDAs for antibiotics submitted in response to this FDAAA provision is consistent with the overall trend in the approval of innovative antibiotic NDAs.  The number of annual approvals of antibiotic NMEs from 2001 through 2010 has not changed significantly since the passage of FDAAA. Specifically, the annual number of antibiotic NME approvals was two or less for the years prior to, and one or less for the years following, the enactment of FDAAA. 

FDAAA § 1113 amended the FDC Act to add § 505(u), which is scheduled to sunset this year unless reauthorized by Congress.  Although there are public reports of companies that have expressed interest in developing drug products that might qualify for the 5-year NCE exclusivity election, we are not aware of any NDA (antibiotic or otherwise) that has been approved and granted exclusivity under this provision.  Another exclusivity provision originally included in FDAAA, but removed and later enacted as part of the QI Act, that is targeted to so-called “old” antibiotics (i.e., FDC Act § 505(v)) is not discussed in the GAO’s report, presumably because of the limited scope of the GAO report.

On the orphan drug front (FDAAA § 1112), FDA held a public meeting on April 28, 2008 (Docket No. FDA-2008-N-0225) to, among other things, explore whether and how existing incentives and potential new incentives could be applied to promote the development of antibiotics as well as to discuss whether infectious diseases may qualify for grants or other incentives that may promote innovation.  While potential new incentives and tinkering with current ones were suggested at the public meeting, the GAO says that “many of these suggestions – such as tax incentives and extended market exclusivities – would require a statutory change.”

The GAO also examined orphan drug designation data and found that it is relatively uncommon for FDA’s Office of Orphan Products Development to designate an antibiotic an as orphan drug.  According to the GAO, its examination of odphan drug designations showed:

that the annual number of antibiotics that received an orphan drug designation from 2001 to 2007 – when FDAAA was enacted – was three drugs or fewer each year.  The number of antibiotics that received orphan drug designation following FDAAA’s enactment in 2007 has remained constant at this rate through 2010.  Additionally, not all antibiotics that have been awarded orphan drug designation have been or will apply to be approved for marketing.  Of the 15 antibiotics that received an orphan drug designation from 2001 through 2010, only 1 was approved for marketing as of November 2011.

To give you a sense of how small the figure 15 is, we tallied the number of orphan drug designation between 2001 and 2010 and came up with 1,262.  So, a mere 1.19% of those designations represent antibiotics.  

By Kurt R. Karst –      

The U.S. Patent and Trademark Office (“PTO”) has been sued once again after denying a Patent Term Extension (“PTE”) request.  The latest case in a long line of lawsuits concerns U.S. Patent No. 5,206,248 (“the ‘248 patent”), which is listed in FDA’s Orange Book as a method-of-use patent covering Avanir Pharmaceuticals Inc.’s (“Avanir’s”) NUEDEXTA (dextromethorphan hydrobromide and quinidine sulfate) Capsules, and that is scheduled to expire on March 27, 2012.  The Complaint, filed last week by Avanir and the Center for Neurologic Study in the U.S. District Court for the Eastern District of Virginia (Alexandria Division), alleges that the PTO’s December 20, 2011 decision denying Plaintiffs’ PTE application for the ‘248 patent (Docket No. FDA-2011-E-0269) violated the Administrative Procedure Act (“APA”).  Plaintiffs request that the court vacate and set aside the PTO’s decision and order the PTO to extend the term of the ‘248 patent for the full period required under the PTE statute at 35 U.S.C. § 156. 

FDA approved NUEDEXTA on October 29, 2010 under NDA No. 021879 for the treatment of pseudobulbar affect (“PBA”).  NUEDEXTA is the first and only FDA-approved treatment for PBA.  PBA is a neurological condition sometimes referred to as “emotional incontinence” that is characterized by sudden outbursts of involuntary crying and/or laughing in patients with underlying neurological disease or injury.  In addition to the ‘248 patent, NUEDEXTA is listed in the Orange Book as covered by two additional patents – U.S. Patent Nos. 7,659,282, which expires on August 13, 2026, and RE 38,115 (“the ‘115 patent”), which expires on January 26, 2016 – and a period of 3-year exclusivity (new combination) that expires on October 29, 2013.  (Plaintiffs submitted a second PTE application to the PTO with respect to the ‘115 patent – Docket No. FDA-2011-E-0268.  The PTO also denied that PTE application on December 20, 2011; however, the ‘115 patent is not identified in the Complaint.)

Under the PTE statute at 35 U.S.C. § 156, the term of a patent claiming a drug shall be extended from the original expiration date of the patent if, among other things, “the permission for the commercial marketing or use of the product . . . is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred.”   While Plaintiffs acknowledge in their PTE application that “dextromethorphan-containing products have previously been sold in the United States,” they contend that “the approval of dextromethorphan hydrobromide in NUEDEXTA™” meets the “first permitted commercial marketing or use” prong of the PTE statute.  Specifically, according to the Plaintiffs in their PTE application:

The provision of law under which the dextromethorphan hydro bromide active ingredient in NUEDEXT A™ was subject to a regulatory review period is section 505 of the FFDCA as amended by the [1984 Hatch-Waxman Amendments].  To the best of Applicant's knowledge, dextromethorphan-containing products sold prior to 1962 were not subject to a “regulatory review period” as defined under section 156(g), and were permitted to be marketed under a provision of law different from the provision of law under which NUEDEXTA™ was studied, reviewed, and approved.  To the best of Applicant’s knowledge, dextromethorphan-containing products sold after 1962 have been marketed under the [FDA’s] Over-the-Counter Drug Review, and not under the provision of law under which NUEDEXTA ™ was studied, reviewed, and approved (35 U.S.C. § 156(a)(5)(A)).

Plaintiffs also proactively address in their PTE application the 1989 decision in Westwood v. Quigg, 13 U.S.P.Q.2d 2067 (D.D.C. 1989), which affirmed a PTE denial by the PTO for a drug that first came to market before 1962.  Plaintiffs maintain, however, “that Westwood was wrongly decided, is distinguishable, and would not withstand scrutiny today.  Among other reasons, the court erred in failing to apply the FFDCA as it existed at the time it was amended by the [1984 Hatch-Waxman Amendments].”

Not convinced by Plaintiffs’ arguments, the PTO denied the ‘248 patent PTE application after receiving notification from FDA that both the dextromethorphan hydrobromide and quinidine sulfate components in NUEDEXTA had each been approved for commercial marketing or use prior to the approval of NDA No. 021879.  Among other things, the PTO cites in its denial the Federal Circuit’s decision in Arnold P'ship v. Dudas, 362 F.3d 1338, 1341 (Fed. Cir. 2004), concerning a PTE denial for VICOPROFEN (ibuprofen and hydrocodone bitartrate), the Westwood decision, and a 2007 decision from FDA concerning PTE ineligibility for a patent concerning BiDil (isosorbide dinitrate and hydralazine hydrochloride) Tablets (a copy of which is attached to the PTO’s ‘248 patent PTE decision).  Referencing the BiDil case, the PTO states:

Applicant is mistaken in its reading of § 156(a)(5)(A).  As previously explained by FDA in a similar situation, FDA maintains that the phrase “provision of law” refers “to the statutory provision under which the regulatory review occurs for a particular class of products that is eligible for patent term restoration, regardless of whether that statutory provision is amended.”  The FDA stated there, and the USPTO concurs, that the phrase is unambiguous on its face.  However, as explained in the 2007 FDA letter, even if the phrase is ambiguous, this interpretation is permissible in light of legislative intent, public policy concerns, and applicable case law.  There is no suggestion in the legislative history that the phrase “first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred” as used in § 156(a)(5)(A) is intended to treat amended versions of section 505 as different provisions of law.  Rather, as explained by the FDA at page 6 of the 2007 FDA letter, to treat each different amended version of section 505 as a different provision of law would contravene the legislative intent of Congress by allowing the term of more than one patent to be extended if a product received more than one approval as a member of a particular class of products.

(Interestingly, a somewhat similar dispute arose a few years ago after the enactment of the QI Act concerning so-called “old” antibiotics.  In that case, Citizen Petitions were submitted to FDA arguing, among other things, that the plain language of the QI Act directs FDA to apply the relevant statutory provisions of the Hatch-Waxman Amendments as they were enacted in 1984, not as subsequently amended by Congress.  FDA ruled otherwise.  See our previous post here.)

In their Complaint, Plaintiffs first argue that “the PTO erroneously defined the relevant ‘product’ for purposes of 35 U.S.C. § 156 as either dextromethorphan alone or quinidine alone.”  “Taken by themselves,” contend Plaintiffs, “dextromethorphan is a cough suppressant and quinidine treats heart arrhythmias and neither dextromethorphan nor quinidine alone has any effect on PBA.  However, together in Nuedexta®, the dextromethorphan/quinidine is a wholly new active ingredient that treats PBA.  The ‘248 patent covers this use of dextromethorphan/quinidine.”  Second, Plaintiffs argue that “the PTO erroneously determined that dextromethorphan has previously been the subject of a ‘regulatory review period’ under the same ‘provision of law’ under which Nuedexta® was approved.”  Not only is the conclusion misplaced based on the dextromethorphan/quinidine argument, contend Plaintiffs, but the PTO’s denial violates the APA “even if dextromethorphan alone is considered the active ingredient in Nuedexta®.”  According to the Plaintiffs:

[I]t is undisputed that Nuedexta® was approved for commercial marketing under the version of [FDC Act § 505] in effect on October 29. 2010, which requires proof of efficacy as well as safety. . . .  It is also undisputed that all other dextromethorphan products were approved by FDA under the pre-1962 version of [FDC Act § 505], which required no proof of efficacy, and no “regulatory review period.”  Despite these undisputed facts, FDA arbitrarily and capriciously found that the pre-1962 dextromethorphan products have been the subject of a “regulatory review period” and denied Avanir’s request for a PTE.

After all, write Plaintiffs, for NDAs submitted prior to the enactment of the 1962 Drug Efficacy Amendments, “FDA neither ‘reviewed’ nor ‘approved’ these NDAs before the products could be marketed. Instead, by operation of the statute, NDAs became automatically effective 60 days after they were filed, unless the FDA determined that it needed more time to ‘study and investigate the application’” (citing FDC Act § 505(c) (1938)).

Strap yourself in for another exciting ride on the PTE litigation train.

By Jennifer D. Newberger –

On Tuesday, January 24, FDA’s Center for Devices and Radiological Health (“CDRH”) released its strategic priorities for 2012:  (1) fully implement a total life cycle approach; (2) enhance communication and transparency; (3) strengthen the CDRH workforce and workplace; and (4) proactively facilitate innovation to address unmet public health needs.  Though the priorities have remained consistent over the last three years, the strategies and goals (sometimes) differ.  This blog post addresses some of the highlights.

Total life cycle approach.  This is the most comprehensive and aggressive of the four priorities.  Perhaps most ambitious is CDRH’s goal to finalize all guidance documents issued as part of the plan to improve premarket programs.  Given the number of draft guidance documents issued in 2011 for this purpose (approximately 11), it is unlikely CDRH will achieve this goal, nor, perhaps would it be advisable to do so.  While final guidance is helpful to industry, in this case, rapid finalization would likely mean that CDRH did not take the time necessary to consider and address all the comments submitted by stakeholders or consider the relationship between the various documents.  Rather than striving to finalize all guidances, CDRH should focus on those likely to have the biggest impact:  those regarding benefit-risk determinations, the 510(k) paradigm, appeals, and when to submit a 510(k) for modifications to currently marketed products.

This priority also proposes implementing a knowledge management strategic plan and a Center-wide quality assurance program.  It is not clear what role these proposals will play in day-to-day operations of the Center, or what issues they are intended to address.

A repeat goal is to enhance compliance capability by implementing its “business-case-for-quality” (in 2011 this was referred to as “Case for Quality”), though the sub-goals are different.  In 2011, this goal was to be completed by September 30, 2011.  In the 2012 priorities, CDRH will begin to implement the program by December 31, 2012.  Precisely what this initiative will entail is not clear from either the 2011 or 2012 language.

Enhance communication and transparency.  Given the importance of improving communication and transparency with industry, it is surprising that this priority has only two rather thin strategies and goals.  One goal (a repeat from 2011) is to continue taking “steps to strengthen information exchange and improve gathering feedback” from external constituencies.  It seems that industry’s concern is less about CDRH’s ability to gather feedback, and more its failure to adequately respond to the feedback it receives and its shortcomings in communicating with companies. 

Strengthen the workforce and workplace.  This priority emphasizes employee training and education, and enhancing effective leadership, all of great importance to industry.  Hopefully, training “to enhance premarket reviewer knowledge of how medical devices are designed, manufactured, and utilized” will allow for a better, more realistic understanding of devices by reviewers. 

The proposal “to provide CDRH managers and supervisors information and tools to assure effective leadership” has the potential to, for instance, encourage supervisors to work with reviewers to understand the boundaries of requests for additional information and to provide better guidance to staff.  Hopefully, it will also empower supervisors to overturn a subordinate’s decision when appropriate.

Proactively facilitate innovation to address unmet public health needs.  Innovation, and FDA’s role in its facilitation, is a “hot topic” in medical device regulation and reform.  Though the first strategy within this priority is the same as 2011—to foster the development of innovative medical devices—there are far fewer goals to implement this strategy in 2012 than there were in 2011.  The only goal in 2012 is to “create processes and tools that will improve the pipeline for innovative medical devices and transform the way CDRH works with medical device innovators.”  While this is a laudable goal, it lacks any specifics.  Until the review processes are more transparent and predictable, and review times are shortened, it is likely also an unrealistic one.

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By Riëtte van Laack –

On Monday, January 23, 2012, the U.S. Supreme Court ruled that a California state law prohibiting the slaughter, processing, and sale of any non-ambulatory animals is preempted by the Federal Meat Inspection Act (“FMIA”).

As we previously reported, under California's Downed Animal Law, section 599f of the California state penal code, prohibits the slaughter of any non-ambulatory livestock.  This law was adopted in 2008 as a reaction to the publication of an undercover video in 2008, showing workers at the California Westland/Hallmark Meat Co. cattle slaughterhouse dragging sick and disabled cows.  This video resulted in the largest beef recall in U.S. history, and federal regulations prohibiting slaughter of non-ambulatory cattle but not of other non-ambulatory livestock.  California’s law, section 599f, expanded the federal protections provided to non-ambulatory cattle to all non-ambulatory livestock, requiring that these animals must be returned to the farm or immediately euthanized, without examination by a veterinarian. 

Shortly after passing of the California law, the National Meat Association ("NMA") filed a request for an injunction on the grounds that the California law was preempted by the FMIA.  The U.S. District Court granted the injunction. However, the Court of Appeals of the Ninth Circuit upheld California’s right to prohibit slaughter of non-ambulatory pigs, reasoning that a non-ambulatory pig is a different kind of animal and that regulating what kind of animal may be slaughtered fell within the type of regulatory activity typically reserved for states.  According to the Ninth Circuit, just as California had the right to prohibit slaughter of horses, it had a right to prohibit slaughter of non-ambulatory pigs.  NMA petitioned the U.S. Supreme Court.

In the Supreme Court's unanimous decision (Docket No. 10-224), Justice Kagan writes that the FMIA regulates a broad range of activities to ensure the safety as well as human handling of animals.  The FMIA contains an express preemption provision in section 678 of the FMIA, which was added in 1967.  Section 678 provides, in relevant part, that “Requirements within the scope of this [Act]  . . . which are in addition to, or different than those made under this [Act] may not be imposed by any State.”  As Justice Kagan explained, this section “prevents a State from imposing any additional or different-even if non-conflicting-requirements that fall within . . . the scope [of the act] and concern slaughterhouse facilities or operations.”  According to the Court, the California law effectively tried to ban slaughterhouse activities that the FMIA and FSIS implementing regulations expressly allow.  As the Court explained, under federal law, non-ambulatory pigs can be slaughtered, processed and sold, subject to FSIS inspection and monitoring requirements.  Thus, the Court concluded, California’s section 599f is preempted by the FMIA. 

Although this case focused on pigs, the ruling applies equally to non-ambulatory sheep, goats and veal calves.

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By John A. Gilbert, Jr. & Larry K. Houck –

The Government Accountability Office (“GAO”) has issued a report focusing on federal agency efforts to educate prescribers and the public about prescription pain reliever abuse and misuse.  The report’s title, “Prescription Pain Reliever Abuse: Agencies have Begun Coordinating Education Efforts, but Need to Assess Effectiveness” telegraphs the report’s conclusion.  The report evaluates the nine programs to educate current and future prescribers and nine programs to educate target groups within the general public about prescription pain reliever abuse and misuse, noting duplicative efforts and recommending coordination between the multiple agencies and measuring their effectiveness.

The GAO conducted the performance audit of federal efforts to educate prescribers and the public about prescription pain reliever abuse and misuse from December 2010 to December 2011.  The report notes at the outset that key measures of prescription pain reliever abuse and misuse increased from 2003 to 2009.  “Abuse” and “misuse” refer to using a prescription pain reliever to get high, using a prescription pain reliever for pain relief without a prescription or using a prescription pain reliever but in ways other than as prescribed.  

The report summarized the increased problem of prescription pain reliever abuse and misuse through several key measures.  The estimated number of emergency visits annually related to prescription pain reliever abuse and misuse increased by 288,000 visits, (142 percent), from 2004 to 2009; annual admissions to substance abuse treatment facilities for prescription pain reliever abuse and misuse increased by 133,000 admissions, (131 percent), from 2003 to 2009; and the annual number of deaths from unintentional overdoses of prescription pain relievers increased by more than 5,000, (83 percent), from 2003 to 2008.  Lastly, the estimated number of persons who abused or misused prescription pain relievers increased from an estimated 11.7 million in 2003 to 12.4 million in 2009, an increase of 6 percent.

The report notes that agency officials have suggested that the increase in adverse health consequences that are key measures of prescription pain reliever abuse and misuse are due to the increasing availability of prescription pain relievers, especially higher potency extended-release and long-acting pain relievers.  Another factor is the increase in high-risk behavior.  High-risk behaviors include combining the prescription pain relievers with other prescription drugs and alcohol as well as inhaling or injecting the pain relievers instead of taking them orally as prescribed.

The report notes that officials from each of the responsible federal agencies opined that more prescriber education about prescription pain reliever abuse and misuse is required.  The Food and Drug Administration (“FDA”), National Institutes of Health (“NIH”), and Substance Abuse and Mental Health Services Administration (“SAMHSA”) have implemented different voluntary CME programs to educate prescribers about issues related to prescription pain reliever abuse and misuse.  FDA requires manufacturers to develop a CME or CE course for prescribers as part of a Risk Evaluation and Mitigation Strategy (“REMS”) for extended-release and long-acting pain relievers.  NIH communicates with prescribers at medical conferences while SAMHSA developed a CME course on prescribing opioids for chronic pain, partnering with local organizations such medical organizations.  FDA requires prescribers of certain transmucosal immediate-release fentanyl products to be trained and certified, then re-certified every two years.  NIH and SAMHSA are pursuing funding to develop physician clinical support systems that provide educational resources and free mentoring services related to prescribing prescription pain relievers.  Lastly, NIH and SAMHSA are developing curricula for medical students.
 
The report further notes that the Office of National Drug Control Policy (“ONDCP”) with Drug Enforcement Administration (“DEA”), FDA and SAMHSA assistance, “are working to develop a legislative proposal to require all prescribers who request DEA registration to prescribe controlled substances be trained on the appropriate and safe use, proper storage, and disposal of prescription pain relievers as a precondition of registration.”  HPM will monitor and report on this legislative proposal.

The report also discusses the various efforts of DEA, FDA, NIH, ONDCP and SAMHSA to educate teenagers, parents, college students and the general public about prescription pain reliever abuse and misuse.  The report notes that several of the public education efforts are duplicative of those of other agencies though concedes that the agencies have different constituencies and approaches to the issue.
  
The report concludes that the agencies have established or plan to establish metrics to assess the impact of only two of the educational efforts, which leaves the agencies “with limited knowledge as to whether such efforts are effective.”  The GAO states the agencies should establish metrics to measure the effectiveness of their education efforts.  The GAO also believes that the agencies have missed opportunities to share feedback about their efforts, leveraging their resources and coordinating similar efforts.  The report concludes that “there is much to be gained from continued and robust coordination among similar education efforts” and that ONDCP occupies a unique position to coordinate similar agency efforts and ensure that agencies do not duplicate efforts.  While duplicative educational efforts can reinforce messages, given the limited resources available to government, it is reasonable for agencies to coordinate education efforts aimed at similar constituencies.   

The report’s appendices also contain several informative discussions relevant to the prescription pain reliever abuse and misuse issue in the appendices.  One section discusses the various abuse-deterrent formulations of prescription pain relievers.  A second summarizes DEA’s controlled substance aggregate production, bulk manufacturing and procurement quota system.  We would like to see GAO investigate and issue a full report on DEA’s quota process and its impact on these issues.       

By Kurt R. Karst –      

In a recent Hatch-Waxman decision from the U.S. District Court for the Northern District of Illinois (Eastern Division), the court denied Plaintiffs’ Seattle Children’s Hospital, Novartis Vaccines and Diagnostics, Inc., and Novartis Pharmaceuticals Corporation (collectively “Novartis”) Motion to Dismiss the lawsuit that they brought against Akorn, Inc. (“Akorn”) for lack of subject matter jurisdiction and granted Akorn’s Motion to Amend its Answer to include a claim for a declaratory judgment of noninfringement of U.S. Patent No. 5,508,269 (“the ‘269 patent”).  The ‘269 patent, which expires on October 19, 2014, is the only patent listed in the Orange Book for TOBI (tobramycin solution for inhalation), 300 mg/5 mL (NDA No. 050753).  The court’s decision sets up the possibility of a subsequent ANDA sponsor causing a 180-day exclusivity forfeiture event for a first applicant under the failure-to-market provisions at FDC Act § 505(j)(5)(D)(i)(I).

Akorn appears to have submitted ANDA No. 201422 to FDA back in 2010 seeking approval for a generic version of TOBI.  Akorn’s ANDA, which FDA has not yet tentatively approved, contains a Paragraph IV certification to the ‘269 patent; however, according to the court, non-party Teva Pharmaceuticals USA, Inc. (“Teva”) submitted the first ANDA containing a Paragraph IV certification to the ‘269 patent, making Teva a first applicant eligible for 180-day exclusivity.  (FDA’s Paragraph IV Certification List shows June 29, 2009 as the date of the first ANDA submission.)  In June 2011, Novartis granted Akorn a covenant not to sue with respect to infringement of the ‘269 patent, and subsequently argued that the court lost subject matter jurisdiction since the covenant not to sue moots the patent infringement lawsuit.  Although Akorn admitted that the covenant not to sue “resolves the infringement issue,” the company has maintained that the covenant does not resolve the “regulatory issue;” namely, approval of ANDA No. 201422.

Enter the now familiar Federal Circuit decisions in Caraco Pharm. Labs. v. Forest Labs., 527 F.3d 1278 (Fed. Cir. 2008) and Janssen Pharmaceutica, N.V. v. Apotex, Inc., 540 F.3d 1353 (Fed. Cir. 2008) which analyzed whether an Article III controversy exists in a declaratory judgment action arising under the Hatch-Waxman Amendments.  As the Illinois District Court notes, “Caraco holds that the exclusion of non-infringing generic drugs from the market can be a judicially cognizable injury-in-fact,” and “Janssen reaffirms Caraco’s holding that the injury-in-fact must stem from the actions of the company that listed the patents in the Orange Book, not the inherent framework of the Hatch-Waxman Act.”

Holding that the TOBI case presents an actual controversy, and that as in Caraco, a favorable judgment for Akorn “would eliminate the potential for the [‘269 patent] to exclude [Akorn] from the drug market,” the court stated:

Notwithstanding Plaintiffs’ unilateral covenant not to sue, the case or controversy between the parties here endures because of the continued listing of the ‘269 Patent in the FDA’s Orange Book in connection with NDA No. 50-753 for Novartis’ TOBI drug product, which bears on Akorn’s efforts to obtain FDA approval to market a generic version of Novartis’ TOBI.  In these circumstances, guidance from the Federal Circuit, admittedly decided under the pre-2003 version of the Hatch-Waxman Act, suggests that Akorn may pursue a court judgment in order to advance the regulatory issues surrounding Akorn’s efforts to obtain FDA approval to market a generic version of Novartis’ TOBI in light of Akorn’s status as a subsequent filer.

Moreover, the court made its decision notwithstanding the fact that FDA had not yet tentatively approved Akorn’s ANDA No. 201422:

Notably, such a [civil action to obtain patent certainty] would have been authorized by statute even though Akorn had not received tentative approval for its ANDA at that time and even if Plaintiffs had not threatened suit.  The case law and the expression of congressional intent . . . , as well as the realities and time commitments associated with complex litigation, support Akorn’s attempt to pursue tentative approval of its ANDA with the FDA while simultaneously seeking “a favorable judgment in this action [to] eliminate the potential for the [listed] patent to exclude [Akorn] from the drug market.”  See Caraco, 527 F.3d at 1293; see also Pfizer, 726 F. Supp. 2d at 930 (denying motion to dismiss even though applicant’s ANDA had not yet been approved and its Paragraph III certification independently precluded approval at the time it filed its claims).

Undeterred by the district court’s decision, Novartis promptly filed a Renewed Motion to Dismiss the case and Akorn’s counterclaim for lack of subject matter jurisdction.  According to Novartis, since the court issued its decision “any possible remaining case or controversy has been mooted by the statutorily mandated forfeiture of any 180-day exclusivity” available with respect to Teva’s ANDA. 

Novartis points to the faiure to obtain tentative ANDA approval forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV) and alleges that Teva’s failure to obtain tentative approval by December 29, 2011 (“30 months after the June 29, 2009 submission of its ANDA”) means that exclusivity was forfeited and that there is no barrier to FDA approving Akorn’s ANDA No. 201422, and therefore, no Article III controversy supporting subject matter jurisdiction in the case.  (Novartis says in a footnote that this is the same issue recently raised in another Illinois District Court Hatch-Waxman case involving generic FOSRENOL (lanthanum carbonate) 500 mg, 750 mg, and 1000 mg Chewable Tablets – Shire Canada Inc. v. Alkem Laboratories, Ltd., Case No. 11-cv-00206 (N.D. Ill.).) 

Interestingly, Novartis asserts that the exception provision under the tentative approval forfeiture provision – that failure to obtain timely tentative approval results in forfeiture unless such failure “is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed” – “is inapplicable here as there is no evidence that there was any change in the requirements for ANDA approval that resulted in Teva’s failure to obtain tentative approval by December 29, 2011.”  Of course, only FDA really knows the answer to the question of whether there has been a change in or review of ANDA approval requirements.  In our experience, it is a fact-intensive and case-specific analysis.  Whether the court will effectively step into FDA’s shoes on the matter remains to be seen. 

By Kurt R. Karst –      

It’s absolutely amazing how, after nearly 28 years, the 1984 Hatch-Waxman Amendments continue to provide surprises.  Consider the latest example we came upon recently (with a little help) involving PRISTIQ (desvenlafaxine) Extended-Release Tablets.

FDA approved PRISTIQ under NDA No. 021992 in a leap year, on February 29, 2008 at 3:15 PM Eastern Time (within business hours).  PRISTIQ is listed in the Orange Book with a single patent – U.S. Patent No. 6,673,838 (“the ‘838 patent”) expiring on February 11, 2022.  PRISTIQ is also identified in the Orange Book as a New Chemical Entity (“NCE”) with a period of 5-year exclusivity that expires in a non-leap year, on March 1, 2013.  The combination of an Orange Book patent listing and the 5-year NCE period granted to NDA No. 021992 sets up the possibility under the FDC Act that an ANDA (or a 505(b)(2) application) containing a Paragraph IV certification to the ‘838 patent could be submitted on the so-called “NCE-1 date.”  But is the correct 2012 (also a leap year) submission date March 1st or February 29th?

Let’s turn to the FDC Act’s ANDA provision at FDC Act § 505(j)(5)(F)(ii) under which 5-year NCE exclusivity is discussed.  (The provision applicable to 505(b)(2) applications – FDC Act § 505(c)(3)(E)(ii) – is substantially identical.)  FDC Act § 505(j)(5)(F)(ii) states, in relevant part (emphasis added):

If an application submitted under [FDC Act § 505(b)] for a drug, no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application under [FDC Act § 505(b)], is approved after September 24, 1984, no application may be submitted under [FDC § 505(j)] which refers to the drug for which the [FDC Act § 505(b)] application was submitted before the expiration of five years from the date of the approval of the application under [FDC Act § 505(b)], except that such an application may be submitted under this subsection after the expiration of four years from the date of the approval of the [FDC Act § 505(b)] application if it contains a [Paragraph IV] certification . . . .

In the case of PRISTIQ, “four years from the date of the approval” of NDA No. 021992 is February 29, 2012, not March 1, 2012.  If one were to use the often-referred-to “NCE-1 date” in this case, which calculates the submission date backwards beginning on the date of NCE exclusivity expiration, it would yield March 1, 2012, not February 29, 2012. 

So what’s the lesson here?  Beware of Hatch-Waxman shorthand and do the math under the statute.  After all, we all know how dates count and how counting can lead to controversy (and even changes in the law) – think ANGIOMAX (for which a settlement was just announced); also, see our previous post on counting here. 

UPDATE: A new note was added to the Orange Book stating: "Applications referencing NDA 021992 Pristiq (Desvenlafaxine Succinate) and challenging the listed patent may be received by the Agency beginning on Feb 29, 2012, four years from the NDA approval date."

By Ricardo Carvajal –

In tandem with the release of a House Energy and Commerce Committee staff report on last year’s outbreak of Listeria monocytogenes in cantaloupe, members of that committee sent Commissioner Hamburg a letter calling for reforms in the conduct and oversight of third-party audits.  Based on the findings of the Committee report, the letter calls for FDA to develop regulations and guidance to address the following issues noted with the third party audit of Jensen Farms (the producer of the cantaloupe implicated in the outbreak):

• The audit was geared only toward assessing compliance with FDA regulations, and not FDA guidance or best industry practices.
• Jensen Farms was not required to correct any deficiencies noted in the audit.
• The auditing firm does not report findings to federal, state, or local officials, even when there is an egregious deficiency that prompts immediate termination of the audit and results in failure of the audit.  
• Jensen Farms had ample advance notice of the audit, and the audit was relatively brief. 
• Jensen Farms had final say over the selection of auditors, thereby giving rise to a potential conflict of interest.  In addition, the auditing firm had recommended processing equipment that was faulted in FDA’s subsequent investigation.

The letter asserts that these issues are similar to those identified in prior committee investigations of outbreaks of Salmonella in which third party audits were faulted. 

As we noted in a recent posting, FDA’s oversight of food facility inspections conducted by state agencies has already come under scrutiny by the HHS Office of Inspector General.  Thus, food companies can expect the reliability of non-FDA inspections and audits to remain a hot topic – one doubtless fueled by the naming of third-party auditors in follow-on litigation.

Pharmaceutical and medical device applicants faced with an adverse decision from FDA (e.g., regarding data requirements, study design, or regulatory pathway) may dispute that decision through multiple routes.  The appeal processes in both CDER and CDRH offer numerous strategic and procedural advantages that, when used effectively, can maximize success.  On March 21, 2012 (12:30 – 2:00 PM ET), Hyman, Phelps & McNamara, P.C. will host a free webinar, titled “FDA Appeals – Improving Your Odds of Success; Trends, Expectations, Strategies.”  You can register for HP&M’s March 21st FDA Appeals Process webinar here.

The webinar will provide a brief overview of the appeal processes in the drug and device centers, followed by a focused, in-depth discussion of various case studies and trends.  Participants will gain an understanding of how to use appeal timing, content, meeting strategy, and potential outcomes to their full advantage. 

The webinar will feature HP&M attorneys Josephine Torrente and Jeffrey Shapiro, who have years of experience helping drug and device companies to navigate the appeals processes.  (Mr. Shapiro recently posted on FDA’s draft guidance on medical device appeals. During the webinar, Ms. Torrente and Mr. Shapiro will:

• Describe the appeals processes within CDRH and CDER, including appropriate appeal content and timeframes for agency response; 
• Share their insights on potential outcomes of an appeal, including risks and benefits; 
• Analyze publicly disclosed case studies and evaluate appeal trends; 
• Provide strategies for success and recommendations on how to effectively appeal within the agency; and 
• Answer participants’ questions submitted during or before the webinar.

The FDA appeals process is a hot topic these days.  We anticipate a robust turnout for the webinar, so register early. 

The American Conference Institute will be holding its FDA Boot Camp conference in New York City from Tuesday, March 20 to Wednesday, March 21, 2012.  A copy of the conference program can be obtained here.  Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will be presenting at the conference in a session on the Hatch-Waxman Amendments and the Biologics Price Competition and Innovation Act of 2009.

The conference will include presentations from a virtual “who’s who list” of FDA regulatory experts on myriad topics, including the approval process, pre-approval concerns, product labeling, clinical trials, adverse events reporting, and patent and non-patent marketing exclusivity issues. 

FDA Law Blog is a conference media partner.  As such, we can offer FDA Law Blog readers a special $200 discount off the current price tier.  The discount code is: FDA 200.  We look forward to seeing you at the conference.

By Kurt R. Karst –      

Last week, FDA Commissioner Margaret A. Hamburg, M.D. announced that the Agency sent to Congress packages for three user fee programs, including proposed statutory language for the fifth iteration of the Prescription Drug User Fee Act (“PDUFA V”), and two new user fee statutes – the Generic Drug User Fee Amendments of 2012 (“GDUFA”) and the Biosimilars User Fee Act of 2012 (“BSUFA”).  FDA previously announced the proposed performance goals and procedures (Fiscal Years 2013 through 2017) for PDUFA V, GDUFA, and BSUFA (here, here, and here), which we reported on here, here, and here.  Noticeably absent from FDA’s submission is proposed statutory language and performance goals and procedures for the next iteration of the Medical Device User Fee and Modernization Act (“MDUFMA”). According to press reports (see here), FDA and industry are still haggling over some issues.  The House Energy and Commerce Committee has scheduled three hearings for February 2012 to consider each of the four user fee programs (see here, here, and here).

Of the various “UFAs” (User Fee Acts) up for consideration by Congress, GDUFA will likely have the most wide-ranging and immediate effects (both on industry and on FDA and the Office of Generic Drugs).  (Biosimilar are still in their infancy.  Earlier this week it was reported that the highly-anticipated and seemingly always “shortly forthcoming” draft guidance from FDA on the Biologics Price Competition and Innovation Act may be further delayed.)  We thought we would take a few minutes to point out a couple of the interesting and unique provisions in the proposed statutory language (as compared to other UFAs), which we alluded to in a previous post after GDUFA negotiations were completed.

User Fee Types and Amounts.  People have already been asking: “What will the GDUFA user fees rates be set at?”  The fact is that nobody (not even FDA) really knows yet exactly what all of the user fee rates will be set at for Fiscal Year (“FY”) 2013 or thereafter, because some of the rates depend on information that still needs to be collected.  That being said, the user fee rates for FYs 2014-2017 will likely be higher than what will be set for FY 2013 given that in FY 2013, $50 million of the total user fee revenue amount of $299 million (adjusted each FY) will come from a one-time ANDA backlog fee.

There are proposed to be four types of fees in two categories – application fees and facility fees.  Application fees, which account for 30% of total fee revenue each FY, include an original ANDA fee and Prior Approval Supplement (“PAS”) fee (one half of the ANDA fee) (both accounting for 24% of the total revenue amount), and a Type II Drug Master File (“DMF”) “first reference fee” (6% of total revenue amount).  There is also a one-time (FY 2013) ANDA backlog fee for ANDAs pending on October 1, 2012.  That fee will be calculated by dividing $50 million by the number of ANDAs in the backlog, which as of January 1, 2012, was at 2,696 ANDAs.  (There was a record 210 original ANDA submissions to FDA in December alone, historically the highest volume month of submission.  A total of 946 original ANDAs were submitted to FDA in 2011.)  The number of ANDAs in the backlog on October 1, 2012 may increase or decrease from the current backlog number as companies decide whether or not to withdraw applications (or perhaps play a game of chicken with other ANDA sponsors). 

A facility fee, which accounts for 70% of total fee revenue each FY, must be paid by both Finished Dosage Form (“FDF”) and Active Pharmaceutical Ingredient (“API”) manufacturers.  FDF facility fees account for 80% of facility fee revenue (56% of the total revenue amount), and API facilities account for 20% of facility fee revenue (14% of the total revenue amount).  There is “a modest fee differential” of not less than $15,000 and not more than $30,000 for foreign FDF and API facilities “reflecting the added costs of overseas inspection.”

For FY 2013, FDA is supposed to set the application fees and ANDA backlog fee by October 31, 2012.  The FY 2013 facility fee rates must be set “within 45 days after the date to comply with the requirement for identification of facilities in [proposed FDC Act § 744G(f)(1)].”  Proposed FDC Act § 744G(f)(1) states in relevant part that “[b]y October 1, 2012, the Secretary shall cause to be published in the Federal Register a notice requiring each person that owns a facility as identified in [proposed FDC Act § 744G(a)(4)(A)] or a site identified in [proposed FDC Act § 744G(f)(3)] to identify each such facility or site.  Each such person shall comply with that requirement within 60 calendar days of the publication of such notice.”

Failure to Pay User Fees.  The penalties for failing to pay GDUFA fees are particularly harsh under the proposed statutory language. 

Failure to pay the ANDA backlog fee will result in placing the ANDA sponsor on an arrears list, “such that no new ANDAs or supplement submitted on or after October 1, 2012 from that person, or any affiliate of that person, will be received within the meaning of [FDC Act § 505(j)(5)(A)] as implemented in [FDA] regulations, until such outstanding fee is paid.”  Proposed FDC Act § 744G(g)(1) (emphasis added). 

Failure to pay the required application fee within 20 calendar days of the due date will result in the application not being received (FDC Act § 505(j)(5)(A)) until the fee is paid.  ANDA receipt date is, of course, particularly important when 180-day exclusivity is at stake.  And the proposed statute recognizes this at § 744G(o), which states:

An [ANDA] that is not considered to be received within the meaning of [FDC Act § 505(j)(5)(A)] because of failure to pay an applicable fee under this provision within the time period specified in [FDC Act § 744G(g)] shall be deemed not to have been “substantially complete” on the date of its submission within the meaning of section 505(j)(5)(B)(iv)(II)(cc).  An [ANDA] that is not substantially complete on the date of its submission solely because of failure to pay an applicable fee under the preceding sentence shall be deemed substantially complete and received within the meaning of section 505(j)(5)(A) as of the date such applicable fee is received.

Failure to pay the DMF fee within 20 calendar days of the due date “will result in the Type II [API DMF] not being deemed available for reference.”  An affected ANDA “shall not be received within the meaning of [FDC Act § 505(j)(5)(A)]” unless the fee “has been paid within 20 calendar days of the Secretary providing the notification to the sponsor of the [ANDA] or supplement of the failure of the owner of the Type II [API DMF] to pay the [DMF] fee . . . .”  Proposed FDC act § 744G(g)(2).

Failure to pay a facility fee within 20 calendar days of the due date will result in several penalties, included what might be the harshest penalty of all – misbranding.  Specifically, proposed FDC Act § 744G(g)(4) (emphasis added below) states that failure to pay a fee will result in:

(A) identification of the facility on a publicly available arrears list, such that no new [ANDAs] or supplement submitted on or after October 1, 2012 from that person, or any affiliate of that person, will be received within the meaning of [FDC Act § 505(j)(5)(A)] as implemented in [FDA] regulations;

(B) any new generic drug submission submitted on or after October 1, 2012 that references such a facility shall not be received, within the meaning of FDC Act § 505(j)(5)(A)] as implemented in [FDA] regulations if the outstanding facility fee is not paid within 20 calendar days of the Secretary providing the notification to the sponsor of the failure of the owner of the facility to pay the facility fee as specified in [proposed FDC Act § 744G(a)(4)(C)]; and

(C) all drugs or [APIs] manufactured in such a facility or containing an ingredient manufactured in such a facility being deemed misbranded under [proposed FDC Act § 502(aa)].

The penalties in [proposed FDC Act § 744G(g)(4)] shall apply until the [facility] fee . . .  is paid or the facility is removed from all generic drug submissions that refer to the facility. 

Proposed FDC Act § 502(aa) (Section 106 of GDUFA) would amend the statute to state that a drug shall be deemed to be misbranded:

If it is a drug, or an [API], and it was manufactured, prepared, propagated, compounded, or processed in a facility for which fees have not been paid as required by [proposed FDC Act § 744G(a)(4)] or for which identifying information required by [proposed FDC Act § 744G(f)] has not been submitted, or it contains an [API] that was manufactured,  prepared, propagated, compounded, or processed in such a facility.

The misbranding provision, which was a point of controversy during GDUFA negotiations, appears to be intended to add some teeth to the proposed user fee statute.

User Fee Refunds.  Although other UFAs, like PDUFA and BSUFA, include user fee waiver/refund provisions (e.g., small business waiver), as well as strict waiver/refund request timelines (i.e., requests must be submitted within 180 days after a fee is due), the proposed GDUFA statute does not.  There is a 75% refund of the application (original ANDA and PAS) fee if an application is not received, see Proposed FDC Act § 744G(a)(3)(D); however, such an application will be subject to a new fee upon resubmission.  See id.  § 744G(a)(3)(E).  It is unclear whether an ANDA sponsor must specifically request in writing a 75% refund of the application fee, or whether such refund is automatic.  Proposed FDC Act § 744G(n) (emphasis added), titled “Disputes concerning fees,” states that “[t]o qualify for the return of a fee claimed to have been paid in error under this section, a person shall submit to the Secretary a written request justifying such return within 180 calendar days after such fee was paid.”  Is a fee subject to the 75% refund provision a fee that can be claimed to have been paid in error, thereby requiring a written refund request?

By JP Ellison –

An important issue relating to when an action by an administrative agency can be challenged in court was argued before the Supreme Court last week.  The case involved administrative enforcement activities of the U.S. Environmental Protection Agency (“EPA”). The case, Sackett v. EPA (Docket No. 10-1062), involved a dispute between EPA and an Idaho couple and has recently received widespread press for the Justice’s sharp questioning of the government (see more here).  Buried within the intricacies of the Clean Water Act and this land use battle was the issue that may be of interest to our readers.

As we have explained in previous posts (here and here), the Administrative Procedure Act (“APA”) is the commonly used vehicle for challenging federal government action.  The APA requires final agency action for a lawsuit to be filed, and it is not uncommon for a case to be dismissed on the grounds that whatever else it represented, what the agency did was not final agency action. 

In the Sackett case, the government argued that EPA compliance orders were not final agency action, and therefore not subject to court review.  “‘The compliance order is not ‘final agency action.’  See 5 U.S.C. 704. A[n] . . . order marks only a step in EPA’s decision-making process, not its consummation.”  At oral argument, the Justices seemed unconvinced.   Justice Scalia asked “when you have something as formal as this which shows that the agency does intend to prosecute, why wouldn't you be able to bring a declaratory judgment action,”? and Justice Breyer observed, “of course a warning isn't reviewable. But this seems to meet the test where that [argument] fails.”

The government acknowledged during the argument that the issue before the Court had potentially wide-reaching ramifications, noting, that “it would cause a huge upheaval in the practices of many agencies to say that declaratory relief is typically available when the agency issued an informal warning.”

A prediction on when and how the Court will address this issue is beyond the scope of this post, but we will be watching for the decision later this year to see whether it sets forth a standard for judicial review of agency enforcement activities that upsets traditional notions of the types of agency action subject to challenge.

By Riëtte van Laack –

USDA’s National Organic Program ("NOP") published a proposed rule that would amend the listing of vitamins and minerals in the National List of Allowed and Prohibited Substances (National List).  The National List identifies non-agricultural synthetic ingredients that may be used in or on “organic” and “made with organic” food.  See 7 C.F.R. § 205.605(b).  Since 2000, the National List has included “Nutrient vitamins and minerals, in accordance with 21 C.F.R. § 101.20, Nutritional Qualify Guidelines for Foods.”  The annotation referring to FDA’s fortification policy at § 101.20 has created confusion and controversy about which nutrients are permitted.  Specifically, it led to questions about whether “accessory nutrients” are permitted (NOP defines “accessory nutrients” as nutrients not specifically classified as a vitamin or mineral but found to promote health, such as DHA, ARA, lutein ester, and taurine).  It also led to questions about whether certain nutrients are permitted for use in or on organic infant formula.  Based on communications with FDA, the NOP learned that FDA’s fortification policy does not apply to infant formula.  Moreover, FDA clarified that so-called “accessory nutrients” are not within the scope of FDA’s fortification policy.   

To provide clarity as to which nutrients may be added to organic food and organic infant formula, NOP now proposes to amend the National List to state:  “Vitamins and minerals.  For food – vitamins and minerals identified as essential in 21 C.F.R. § 101.9.  For infant formula – vitamins and minerals as required by 21 C.F.R. § 107.100 or § 107.10.”  Thus, the proposed rule would permit use in organic food and infant formula of the essential vitamins A, C, K, D, E, thiamin, riboflavin, niacin, B6, B12, biotin, folic acid, and pantothenic acid, and the essential minerals calcium, iron, phosphorus, magnesium, zinc, iodine, copper, potassium, selenium, manganese, and chloride.  In addition, the essential minerals chromium and molybdenum would be permitted in organic food but not in organic infant formula, and the essential nutrients choline, inositol, and sodium would be permitted in organic infant formula but not in organic food.  Nutrients that do not fall within the identified categories of vitamins and minerals, e.g., EPA and DHA, would no longer be permitted in organic food and infant formula, unless these nutrients are specifically included in the National List.  To allow industry time to submit petitions for inclusion of these nutrients in the National List, NOP proposes a compliance date of two years after the rule is finalized.

The NOP is specifically seeking comments regarding the delayed compliance date and on the actual economic impacts of the proposed action on industry, including small entities.  Comments may be submitted until March 12, 2012. 

By Kurt R. Karst –      

FDA recently denied a 2008 citizen petition (Docket No. FDA-2008-P-0291) requesting that the Agency amend its drug label regulations to require that product labels include the Orange Book-listed NDA number under which the product is approved.  According to the petition, “[i]ncreasingly, it has become more difficult for pharmacists to determine the status of the prescription drug products on his or her shelf.  Due, in part, to the accelerated pace of corporate mergers and acquisitions, the labels on many drug products no longer contain the information necessary for identification of that product in the Orange Book.”  Two examples used in the petition are authorized generics (defined at FDC Act § 505(t)(3)) and distributirs that relabel or repackage drug products.  In both cases, such products are not specifically identified in the Orange Book, but can be traced back to an approved drug product.  According to the petitioner, PRN Publishing, requiring the application number on drug product labels would allow pharmacists “to quickly and easily determine the equivalence status of any drug product by simply comparing the [application] number on the bottle to the [application] numbers listed in the Orange Book under the heading of the particular drug in question.”

FDA, in its petition denial, says that the Agency does not agree that a requirement to add the application number to product labels (both products approved under NDAs and ANDAs) would address the issues identified by PRN Publishing.  Tackling each of the petitioner’s examples, FDA says with respect to authorized generics that:

because an authorized generic drug shares the same NDA number as the branded innovator product, the authorized generic would not be identified separately from the branded drug in the Orange Book.  Pharmacists could be confused when they look up an NDA number in the Orange Book and find only a listing for the innovator product (which would not match in certain respects the label of the authorized generic drug in hand). 

And with respect to distributors, FDA comments that:

because distributors that relabel or repackage drug products do not separately identify their products for listing in the Orange Book, such marketed drugs would not be traceable by searching the Orange Book.  Pharmacists could be confused when they look up the application number in the Orange Book and find only a listing for the approved application holder (which would not match the label of the product in hand).

Finally, FDA notes that there are also several factors that need be taken into account when considering whether or not to amend the Agency’s drug label requirements, including “the Agency’s statutory mandate, space limitations, alternatives, potential for confusion, and potential safety risk.”  “Weighing these and other considerations in deciding how to use agency resources to efficiently and effectively promote and protect the public health,” FDA concluded that it is not necessary at this time to amend its drug label regulations to require companies to identify the application number under which the product is approved and marketed.

Curiously, neither the citizen petition nor FDA’s response discusses now-repealed FDC Act § 301(l).  Prior to the enactment of the 1997 FDA Modernization Act (“FDAMA”), FDC Act § 301(l) prohibited the use in labeling of any representation or suggestion that “approval of an application with respect to such drug . . . is in effect under section 505 . . . .”  FDAMA § 421 removed this vestigial remnant of the 1938 FDC Act.  Although the legislative history surrounding the repeal of FDC Act § 301(l) is a bit sketchy, it appears to be related to legislation introduced as far back as 1985 by Representative Henry Waxman (D-CA) – H.R. 2244, The FDA Approval Labeling Act – that proposed to amend the FDC Act to permit use of the statement “FDA Approved” in drug product labeling and advertising.  Subsequent to the repeal of FDC Act § 301(l), FDA has stated, in the context of the promotion and advertising of a drug, that companies can use the statement “FDA Approved” in labeling pieces and advertisements for prescription drugs, provided the company has approval for the drug product with respect to which the statement is made. 

We also note that in December 1998, FDA stated in a draft guidance document, titled “Placing the Therapeutic Equivalence Code on Prescription Drug Labels and Labeling” (FDA Docket No. 1998D-1266), that the Agency “believes it is legally permissible to allow the therapeutic equivalence code [identified in the Orange Book] linked to the proprietary name of the reference listed drug product to be placed on container labels and/or drug product labeling,” and that with the repeal of FDA Act § 301(l), “any legal arguments that therapeutic equivalence ratings should not be used in the labeling are moot.”  FDA never finalized the draft guidance, and, in fact, removed the draft guidance from its website after receiving adverse comments.  We understand that FDA currently has no public position on the issue of including in generic drug labeling a therapeutic equivalence code or similar information. 

While we’re on the topic of application numbers, we thought it would be helpful to provide folks with a Rosetta Stone of sorts with respect to FDA’s application numbering system, which changed not too long ago with FDA’s implementation of the Document Archiving, Reporting and Regulatory Tracking System (“DARRTS”).

• Application Nos. 00001 to 13000 (approximately): Pre-1962 NDA approvals (evaluated under DESI)
• Application Nos. 13000 (approximately) through 20,000 series applications: Post-1962 NDA approvals
• 40,000 Series Applications: ANDAs for generic versions of pre-1962 NDA approvals (A continuation of the 80,000 series applications.)
• 50,000 Series Applications: Old antibiotic NDAs approved under now-repealed FDC Act § 507
• 60,000 Series Applications: Old antibiotic ANDAs approved under now-repealed FDC Act § 507 (Some of the early 60,000 numbers could be considered innovator products.  For example, early in this numbering system when the NDA sponsor wanted a new manufacturing site, we understand that FDA assigned a 60,000 series application number. So the early 60,000's were probably NDAs in disguise. The 50,000 and 60,000 series numbers were the identification system used because of Form 5's and Form 6's.)
• 70,000 Series Applications: Contemporary, post-Hatch-Waxman ANDAs (The pre-/post-MMA ANDA No. cutoff – December 8, 2003 - is approximately ANDA No. 076925.)
• 80,000 Series Applications: ANDAs for generic versions of pre-1962 NDA approvals
• 90,000 Series Applications: Contemporary, post-Hatch-Waxman ANDAs (A continuation of the 70,000 series applications.  Beginning around October 2007, it is believed that the 90,000 series combined all ANDAs, such that the 40,000, 60,000, and 80,000 series numbers were no longer used.)
• 200,000 Series Applications: Post-DARRTS applications; numbers are assigned sequentially to NDAs and ANDAs

By Riëtte van Laack –

The Animal Medicinal Drug Use Clarification Act of 1994 (“AMDUCA”) amended the FDC Act § 512(a) allowing veterinarians to prescribe extralabel use of certain approved animal and human drugs for animals.  (Extralabel use includes use in species not listed in the labeling, use for other indications than listed in the labeling, use of drugs approved for humans in animals, and deviation from the labeled withdrawal time).  Such extralabel use is permitted provided the use is prescribed by a veterinarian, the drug has been approved by FDA, a veterinarian-client relationship exists, the extralabel use is for therapeutic use (i.e., not for production use), and the use does not result in a violative food residue.  Special rules apply for drugs administered in water and extralabel use in feed is not permitted.  If, however, FDA determines that the extralabel use of an approved drug “presents a risk to the public health [the Agency] may, by order, prohibit [the extralabel] use.”  FDC Act § 512(a)(4)(D).

On January 6, 2012, FDA issued an order prohibiting the extralabel use of certain Cephalosporins in food-producing major species.  As explained in the order, FDA believes that the specified extralabel uses present a risk to public health because these uses in animals have not been evaluated for safety to animals and humans.  Specifically, FDA is concerned about the possible effect of certain extralabel uses in animals on antimicrobial resistance of microorganisms that have been associated with diseases in humans, including pneumonia, skin and tissue infections, pelvic inflammatory disease, and serious gastrointestinal infections in children.  As a result, treatment of these infections in humans with human cephalosporin drugs may be ineffective or require drugs with more serious side effects.

More than three years ago, FDA issued a similar order prohibiting the extralabel use of cephalosporin antimicrobial drugs in animals.  See 73 Fed. Reg. 38110 (July 3, 2008).  However, after extending the comment period, and receiving numerous substantive comments, only few of which supported the order, FDA decided to revoke the 2008 order.  See 73 Fed. Reg. 71923 (Nov. 26, 2008).   The majority of the comments felt that the 2008 order was too broad in scope, would have negative consequences for animal health, and was not based on sound scientific evidence.  In response, the current order is more narrowly tailored to prohibit only certain extralabel uses of certain cephalosporins.

FDA’s current order prohibits the extralabel use of cephalosporin antimicrobial drugs (except cephapirin) in the food-producing major animals, i.e., cattle, swine, chicken, and turkeys, 1) for disease prevention purposes, 2) at unapproved doses, frequencies, durations, or routes of administration, and 3) for use in a species and production class for which the drug has not been approved.  Extralabel use of cephalosporins in food-producing minor species, such as rabbits, is not affected by the order.

The order has been applauded by various advocates for control of antimicrobial drugs in food-producing animals – see here, here, and here. 

Unless revoked or modified by FDA, the order becomes effective April 5, 2012.  Comments may be submitted until March 6, 2012.