By Larry K. Houck –
 
The Drug Enforcement Administration (“DEA”) recently amended its regulations to allow practitioners to issue electronic prescriptions for controlled substances (“EPCS”) in lieu of hardcopy paper prescriptions.  See 75 Fed. Reg. 16,236 (March 31, 2010).  DEA requires that any electronic prescription application or pharmacy application used for EPCS must be reviewed, tested and determined by a third party to meet all of the required technical specifications.  21 C.F.R. § 1311.300(a).  As an alternative to the third party audit requirements of 21 C.F.R. §§ 1311(b)-(d), an electronic prescription or pharmacy application may be verified and certified as meeting DEA requirements by a certifying organization whose certification process has been approved by DEA.  21 C.F.R. § 1311.300(e).  DEA stated that it would notify registrants of any approved third party certifications on its website.  75 Fed. Reg. 16,243.

DEA announced on August 1, 2012 that it has approved the certification processes developed by two certifying organizations (77 Fed. Reg. 45,688 (Aug. 1, 2012)) and has posted relevant information about those approvals, and about an earlier approval, on the DEA Diversion Control website.   

By Kurt R. Karst –      

There’s a first time for everything!  And on August 8th, 2012, FDA decided, for the first time since the enactment of the Orphan Drug Act, to rescind a period of 7-year orphan drug exclusivity.  The decision came in the form of a response granting in part and denying in part a citizen petition (Docket No. FDA-2011-P-0213) CSL Behring (“CSL”) submitted to FDA in March 2011 requesting that the Agency: (1) revoke the orphan drug designation and the period of orphan drug exclusivity FDA subsequently granted to Octapharma USA, Inc. (“Octapharma”) for the December 4, 2009 approval of WILATE (von Willebrand Factor/Coagulation Factor VIII Complex (Human)) under BLA No. 125251 “for the treatment of spontaneous or trauma-induced bleeding episodes in patients with severe von Willebrand disease (VWD) as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated;” and (2) “refrain from making any orphan drug designations and approval decisions based on hypothetical claims of superiority.”  FDA decided not to revoke orphan drug designation for WILATE, and also denied CSL’s request regarding “hypothetical claims of superiority.”

WILATE is the “same drug” as HUMATE-P (Antihemophilic Factor/von Willebrand Factor Complex (Human)) for orphan drug purposes.  That is, FDA considers them to be “chemically the same drug” and for the same orphan indication.  FDA approved HUMATE-P on April 1, 1999 for the same orphan disease as WILATE.  Because WILATE is the “same drug” as HUMATE-P, the issue of “clinical superiority” comes into play – for obtaining orphan drug designation and for obtaining orphan drug exclusivity.

FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “a sponsor of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain orphan-drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug.”  FDA’s orphan drug regulations define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways: (1) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials; (2) greater safety in a substantial portion of the target population; or (3) demonstration that the drug makes a major contribution to patient care.

As FDA explains in the petition response (as well in the Agency’s 2011 proposed rule – see our previous post here):

Though the sponsor of a subsequent orphan drug must set forth a plausible hypothesis of clinical superiority over the previously approved drug at the designation stage, such a sponsor faces a higher standard at the time of approval.  At approval, the sponsor of a drug which was designated on the basis of a plausible hypothesis of clinical superiority must demonstrate that its drug is clinically superior to the previously approved drug.  Should the sponsor fail to do so, then the subsequent drug will be considered to be the same drug as the previously approved drug, and will not be able to gain marketing approval if the previously approved drug’s orphan-drug exclusive approval period is still running.  Once this exclusivity has expired, the subsequent drug may be approved . . . , but it will not be eligible for orphan-drug exclusivity because the same drug has already been approved for the same orphan indication.

In the case of WILATE, FDA designated the drug as an orphan drug in April 2007 after determining that there was a plausible hypothesis of clinical superiority.  Specifically, FDA determined that WILATE “may be safer than [HUMATE-P] in a substantial portion of the target population due to its two dedicated viral inactivation steps compared to a single dedicated viral inactivation step for [HUMATE-P].”  After approving WILATE, FDA allowed Octapharma to make its case for a demonstration of clinical superiority, and on June 24, 2010, FDA determined that WILATE “appeared to be clinically superior to [HUMATE-P] because of greater viral safety,” and, in fact, “had been shown to be clinically superior to [HUMATE-P] within the meaning of the FDA’s orphan drug regulations . . . .”  As such, FDA granted a period of 7-year orphan drug exclusivity retroactive to December 4, 2009 when FDA approved WILATE.

CSL subsequently contacted FDA and questioned the evidentiary support for FDA’s exclusivity decision.  FDA requested that CSL raise its concerns in a citizen petition, which CSL submitted in March 2011.  CSL’s main premise is that the evidence Octapharma presented to FDA to support clinical superiority of WILATE over HUMATE-P does not meet the applicable regulatory standards. 

After reanalyzing available evidence, FDA concluded that WILATE had not, in fact, been demonstrated to be clinically superior to HUMATE-P due to greater safety.  According to FDA, “the record does not contain sufficient evidence to support a finding that Wilate is clinically superior to Humate due to its ‘[g]reater safety in a substantial portion of the target population.’”  Accordingly, FDA withdrew its clinical superiority determination, and, as a result, rescinded the orphan drug exclusivity for WILATE. 

FDA decided not to rescind orphan drug designation for WILATE, however.  FDA’s orphan drug regulations provide three independent bases under which orphan drug designation can be revoked – if FDA finds that: 

(1)  The request for designation contained an untrue statement of material fact; or

(2)  The request for designation omitted material information required by [21 C.F.R. Part 316]; or

(3)  FDA subsequently finds that the drug in fact had not been eligible for orphan drug designation at the time of submission of the request therefor. [(21 C.F.R. § 316.29(a))] 

FDA rarely rescinds orphan drug designation.  We are aware of only three instances:

(1) Papaverine – On February 6, 1992, OOPD designated Pharmedic Co.’s papaverine topical gel for the “treatment of sexual dysfunction in spinal cord injured patients.”  FDA revoked the designation on September 16, 1993 after additional information showed that the potential target population of the drug could be significantly larger than originally stated.

(2) Methylnaltrexone – On June 17, 1996, FDA designated the University of Chicago’s methylnaltrexone for the “treatment of chronic opioid-induced constipation unresponsive to conventional therapy.”  FDA revoked the designation on January 9, 1998 after new information indicated that the drug could be used in a significantly larger patient population.

(3) Pancreatic Enzymes – On January 23, 2002, FDA designated Altus Biologics Inc.’s TheraCLEC-Total, a microbially-derived pancreatic enzyme product containing amylase, lipase, and protease, as an orphan drug for the “treatment of exocrine pancreatic insufficiency.”  FDA revoked the designation on June 28, 2007 based on information showing that the drug could be used in a significantly larger patient population – specifically HIV/AIDS patients who suffer from fat malabsorbtion (see our previous post here).

In each of these cases, orphan drug designation was revoked because FDA determined (see 21 C.F.R. § 316.29(a)(3)) that the drug “had not been eligible for orphan drug designation at the time of submission of the request.”  In 2011, FDA denied a petition seeking the revocation of orphan drug designation for MAKENA (then known as GESTIVA), which is another orphan drug the orphan drug exclusivity of which has been in the news as of late (see here).

With respect to the orphan drug designation for WILATE, FDA concluded that although WILATE’s “hypothesis of clinical superiority has not been demonstrated to be true,” that does not mean that the plausible hypothesis of clinical superiority “was implausible ‘at the time the [designation] request was submitted.’  The salient fact is that, at the time Octapharma advanced it, the designation request presented a plausible hypothesis.”  As such, according to FDA, none of the grounds in FDA’s regulation to rescind designation apply.

FDA also denied CSL’s second request concerning “hypothetical claims of superiority,” because “‘hypothetically plausible’ is the very standard that the Agency applies to designation requests under its orphan drug regulations.”

Octapharma submitted comments to the petition docket advancing several arguments.  Among other things, Octapharma claimed that the company has “a Constituionally-protected interest” in the orphan drug exclusivity FDA granted for WILATE, and that FDA may not rescind exclusivity without providing the company an opportunity to defend its exclusivity interest at a formal hearing.  FDA reiterated the Agency’s position that “a manufacturer has no property right in its orphan-drug exclusivity that would entitle it to the sort of process to which Octapharma claims it is entitled.” 

By Carmelina G. Allis –

On August 2, 2012, the FDA published a final rule amending its regulations in 21 C.F.R. Part 807 to reflect the 2007 statutory amendments to the device registration and listing provisions of the Federal Food, Drug, and Cosmetic Act ("FDC Act").  This final rule also facilitates the FDA’s collection of additional registration information in order to comply with the 2002 Bioterrorism Act.

The most significant change is that all contract manufacturers and contract sterilizers must now register and list.  This change eliminates the long standing exemption for contract manufacturers and sterilizers who performed these activities for another party who both initiated the specifications and commercially distributed the device.  77 Fed. Reg. 45,927, 45,941 (Aug. 2, 2012) (amending 21 C.F.R §§ 807.20(a)(3) and (c)(1) to remove this exemption).

The usual registration user fee will apply.  The FY 2012 establishment registration fee is $2,020.  In FY 2013, the fee will be $2,575 (see our previous post here).

There also are new requirements for foreign establishments to identify all known importers and to register/list even when their devices enter a foreign trade zone.  According to FDA, these requirements will comply with the Bioterrorism Act, and help increase the Nation’s ability to prepare for an respond to acts of bioterrorism and other public health emergencies.

The regulation also has been revised to require that all registration and listing information be submitted electronically to FDA (absent a waiver).  This formally implements the 2007 statutory amendments, although FDA in fact has been requiring electronic regulation for several years now.

The effective date of the final rule is October 1, 2012.

Hyman, Phelps & McNamara, P.C. is pleased to announce that Anne Walsh will moderate a panel on “Trends and Priorities in Enforcement” at this year’s Food and Drug Law Institute’s (“FDLI”) Advertising and Promotion Conference.  The conference will be held in Washington, DC on October 1-2, 2012.  Panelists will include speakers from the HHS OIG, DOJ, and the states, and will complement Ms. Walsh’s former experience at FDA.  They will discuss what can be learned from recent settlements involving medical product advertising and promotion. 

FDLI’s annual Advertising & Promotion conference brings together regulated industry and the regulators responsible for overseeing the advertising and promotion of prescription drugs, medical devices, biologics, and animal drugs. Top-level officials from FDA’s four medical product-related Centers (CBER, CDER, CDRH, and CVM), and speakers from GlaxoSmithKline, Abbott, Pfizer, Merck and Medtronic (a full list of speakers is online) will provide helpful insight and be available to answer your questions during panel discussions and networking opportunities.

This conference is attended by experienced professionals in the fields of regulatory, legal, public relations, marketing and management who work in the pharmaceutical, medical device, diagnostic, biologics and veterinary medicine industries. The conference is also beneficial for consultants in the areas of advertising, public relations, law and marketing communications.

FDA Law Blog readers can receive a 15% discount off the conference registration price.  To receive the discount, use the following promotional code: AP2012.  For more information and to register, visit the program website.

By Kurt R. Karst –      

We were eager to delve into the Federal Circuit’s recent 2-1 decision in Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc. (Docket Nos. 2012-1062, -1103, -1104) concernng the scope of the Hatch-Waxman “safe harbor” provision at 35 U.S.C. § 271(e)(1), particularly in light of the Court’s prior decision in Classen Immunotherapies v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir. 2011), which is on appeal to the U.S. Supreme Court (Docket No. 11-1078).  Although the 2012 London Olympics captured most of our attention over the weekend, we did find some time to look over the decision.  And we weren’t disappointed – at least insofar as the decision, and Chief Judge Randall Rader’s dissent, provided some legal entertainment.

The case involves a generic version of LOVENOX (enoxaparin), which FDA approved after addressing active ingredient sameness criteria (i.e., “standards for identity”) in a citizen petition response (see our previous post here), U.S. Patent No. 7,575,866 (“the ‘866 patent”) assigned to Momenta that generally relates “to methods for analyzing heterogeneous populations of sulfated polysaccharides” such as enoxaparin, and 35 U.S.C. § 271(e)(1), which states: 

It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention (other than a new animal drug or veterinary biological product (as those terms are used in the Federal Food, Drug, and Cosmetic Act and the Act of March 4, 1913) which is primarily manufactured using recombinant DNA, recombinant RNA, hybridoma technology, or other processes involving site specific genetic manipulation techniques) solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.

Momenta sued Amphastar for patent infringement alleging that Amphastar infringed the ‘886 patent by manufacturing for commercial sale enoxaparin using the patented method.  Ultimately, the U.S. District Court for the District of Massachusetts granted Momenta a preliminary injunction and denied two emergency motions filed by Amphastar for relief from the preliminary injunction.  (Copies of those decisions are available here, here, and here.)  Among other things, the District Court ruled that Amphastar’s activity fell outside of the “safe harbor” provision at 35 U.S.C. § 271(e)(1), because:

although the safe harbor provision permits otherwise infringing activity that is conducted to obtain regulatory approval of a product, it does not permit a generic manufacturer to continue in that otherwise infringing activity after obtaining such approval. . . .  Here, the alleged infringing activity involves use of plaintiffs’ patented quality control testing methods on each commercial batch of enoxaparin that will be sold after FDA approval.  Thus, it is not exempted under § 271(e)(1).

In coming to its decision, the District Court relied on the U.S. Supreme Court’s decision in Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005), and on the Hatch-Waxman legislative history of 35 U.S.C. § 271(e)(1) quoted by the Federal Circuit in Classen; namely that:

[T]he only activity which will be permitted by the bill is a limited amount of testing so that generic manufacturers can establish the bioequivalency of a generic substitute . . . .  [T]he generic manufacturer is not permitted to market the patented drug during the life of the patent; all that the generic can do is test the drug for purposes of submitting data to the FDA for approval.  [H.R. Rep. No. 98–857, at 8 (1984)]

In Integra, the Supreme Court stated that the text of 35 U.S.C. § 271(e)(1) “makes clear that it provides a wide berth for the use of patented drugs in activities related to the federal regulatory process,” and that there is “no room in the statute for excluding certain information from the exemption on the basis of the phase of research in which it is developed or the particular submission in which it could be included.”  In Classen, which concerned whether a vaccine license holder was required to report to FDA certain adverse event information, the Federal Circuit held that 35 U.S.C. § 271(e)(1) “does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained.”

Amphastar appealed each of the District Court’s preliminary injunction decisions to the Federal Circuit and argued that the District Court improperly took a restrictive view of the “safe harbor” provision.  Momenta argued that the District Court’s decisions were correct and that, among other things, the Federal Circuit in its Classen decision previously ruled that 35 U.S.C. § 271(e)(1) does not apply to routine reports to FDA post-approval, such as the batch testing Amphastar carried out as a condition to ANDA approval of its generic LOVENOX.  (Copies of the Amphastar and Momenta Federal Circuit briefs are available here, here, and here.)

The Federal Circuit first sought to ascertain the scope of 35 U.S.C. § 271(e)(1) and focused on the the passage in the “safe harbor” provision stating “solely for uses reasonably related to the development and submission of information under a federal law.”  According to the Court:

Congress could not have been clearer in its choice of words: as long as the use of the patented invention is solely for uses “reasonably related” to developing and submitting information pursuant to “a Federal law” regulating the manufacture, use, or sale of drugs, it is not “an act of infringement.” . . .  Limiting the scope of 35 U.S.C. § 271(e)(1) to just the submission of information pursuant to the [FDC Act] generally, or to the ANDA provision of the [FDC Act] in specific, would read words into the statute in violation of the express language chosen by Congress.

Moreover, while the statute does include a limitation – that the use must be “for uses reasonably related to the development and submission” – the term “reasonably related,” says the Court, citing and quoting Integra, “does not mean that the use of the patented invention must necessarily result in submission of information to the FDA.”   Rather, “[a]s long as the accused infringer has a reasonable basis for believing that use of the patented invention might yield information that would be appropriate to include in a submission to the FDA, that use is ‘reasonably related’ to the ‘development and submission of information’ . . . .”  (internal quotations omitted).

(Although this question is perhaps best reserved for another day, given the Federal Circuit’s broad reading of the “safe harbor” provision, would the Court perhaps include in its interpretation of 35 U.S.C. § 271(e)(1) information related to a biosimilar application under PHS Act § 351(k)?)  

Noting that the information Amphastar produced was not actually submitted to FDA, but rather is retained by the company, the Federal Circuit next addressed whether such information can nevertheless be “submitted” for purposes of 35 U.S.C. § 271(e)(1).  And the court said “yes,” stating:

We think that the requirement to maintain records for FDA inspection satisfies the requirement that the uses be reasonably related to the development and submission of information to the FDA. . . .  The fact that the FDA does not in most cases actually inspect the records does not change the fact that they are for the “development and submission of information under a Federal law.”

Then came the big issue: whether Amphastar’s submissions are within the 35 U.S.C. § 271(e)(1) “safe harbor.”  Here again, the Federal Circuit said “yes” (because they are required “submissions”), and in doing so addressed the Classen decision:

This case . . . fits well within Classen because the information submitted is necessary both to the continued approval of the ANDA and to the ability to market the generic drug.  Here, the submissions are not “routine submissions” to the FDA, but instead are submissions that are required to maintain FDA approval. . . .

Under a proper construction of 35 U.S.C. § 271(e)(1), the fact that Amphastar’s testing is carried out to “satisfy the FDA’s requirements” means it falls within the scope of the safe harbor, even though the activity is carried out after approval.  Unlike Classen, where the allegedly infringing activity “may” have eventually led to an FDA submission, there is no dispute in this case that Amphastar’s allegedly infringing activities are carried out to “satisfy the FDA’s requirements.”  The district court’s interpretation of § 271(e)(1) was erroneous.  Under the correct construction, Momenta cannot establish a likelihood of success on infringement and the preliminary injunction must be vacated.

The Federal Circuit also disagreed with Momenta’s argument that Amphastar’s testing is not protected under 35 U.S.C. § 271(e)(1) because there are non-infringing alternatives available that are endorsed by FDA. 

Chief Judge Rader, who hesitantly noted that he was present through the Hatch-Waxman legislative process (see here), lodged a blistering 29-page dissent that begins and ends with the conclusion that Amphastar is a trespasser.  In between, Chief Judge Rader provides a history of 35 U.S.C. § 271(e)(1), saying that the provision “won approval because it was limited in time, quantity, and type,” and that the majority opinion runs counter to legislative intent and significantly expands the scope of the provision.  According to Chief Judge Rader:

This new interpretation would allow almost all activity by pharmaceutical companies to constitute “submission” and therefore justify a free license to trespass.  The FDA can inspect records of any drug manufacturer and seller.  See 21 U.S.C. § 374.  Thus, the drug manufacturer need only make a record, which could potentially be inspected by the FDA, and then any activity could satisfy this new meaning of “submission.”

Moreover, says Chief Judge Rader, the majority decision cannot be reconciled with the Federal Circuit’s Classen decision, and the “decision should instead request the entire court to resolve the issue en banc.”  Although we’ve made such predictions before and they did not pan out (to our surprise), this Federal Circuit decision seems destined to further appeal.

By Kurt R. Karst –      

There’s a lot of parlance (legal and scientific) bandied about in the food and drug world, and perhaps nowhere more so than in the world of Hatch-Waxman.  Things can get confusing.  Take, for example, the term “Reference Listed Drug,” or “RLD.” 

FDA’s regulation at 21 C.F.R. § 314.3(b) defines the term “reference listed drug” to mean “the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its abbreviated application.”  (A “listed drug” is defined in the same regulation to mean, in part, “a new drug product that has an effective approval under section 505(c) of the act for safety and effectiveness or under section 505(j) of the act. . . .”). 

Fast forward through the Code of Federal Regulations to FDA’s ANDA content and format regulations, which require, among other things, that an ANDA sponsor identify a basis for submission.  Specifically, 21 C.F.R. § 314.94(a)(3) says that an ANDA “must refer to a listed drug.  Ordinarily, that listed drug will be the drug product selected by the agency as the reference standard for conducting bioequivalence testing” (emphasis added).  That “reference standard” is identified in the paper version of the Orange Book with a “+”.  (The electronic version of the Orange Book does not use “+”.  Instead, it has a column titled “RLD” where each drug product listing is set to either “Yes” or “No.”) 

Now on to the Preface to the Orange Book, which states the following in a section titled “Reference Listed Drug (RLD)”:

A reference listed drug (21 CFR 314.94(a)(3)) means the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its ANDA.

FDA has identified in the Prescription Drug Product and OTC Drug Product Lists those reference listed drugs to which the in vivo bioequivalence (reference standard) and, in some instances, the in vitro bioequivalence of the applicant's product is compared.  By designating a single reference listed drug as the standard to which all generic versions must be shown to be bioequivalent, FDA hopes to avoid possible significant variations among generic drugs and their brand name counterpart.  Such variations could result if generic drugs were compared to different reference listed drugs. 

Unfortunately, none of these references clearly delineate what we’ll call the “big RLD” and the “little rld.”  Instead, they tend to mosh them together. 

So . . . . When someone uses the term “reference listed drug,” is that person referring, generally, to a drug approved under an NDA (i.e., the “big RLD”), or to the particular reference standard identified in FDA’s Orange Book with a “+” (i.e., the “little rld”)?  Not understanding the difference between the “big RLD” and the “little rld” can lead to faulty decisions and costly mistakes – at least insofar as decisions to submit ANDAs are concerned.  

Here’s an example to illustrate this point . . . .  FDA approves an NDA for a drug with multiple strengths but delays making a decision on which particular strength is the reference standard (i.e., which strength should get the “+” in the Orange Book).  Generic Company No. 1 takes a “big RLD” approach.  It believes that all that is needed as a basis for ANDA submission is a drug approved under an NDA.  It does not wait for FDA to identify a reference standard and instead conducts bioequivalence testing on all of the approved strengths and submits its ANDA with a Paragraph IV certification to an Orange Book-listed patent.  Generic Company No. 2 takes a “little RLD” approach.  It thinks that FDA must first add the “+” in the Orange Book for a particular strength, becuase without it there is not a basis for ANDA submission.  As such, it waits for FDA to identify a specific reference standard, then conducts bioequivalence testing and submits an ANDA with a Paragraph IV certification to an Orange Book-listed patent. 

Which company, Company No. 1 or Company No. 2, was smarter?  Answer: Company No. 1, which in this scenario would have submitted the first ANDA to FDA containing a Paragraph IV certification making that company eligible for a period of 180-day marketing exclusivity.  Why?  Because Company No. 1 correctly understood that all that is needed as a basis for ANDA submission is an approved NDA drug to reference (along with, of course, bioequivalence data and information).  FDA does not need to identify a particular reference standard before accepting an application. 

REMINDER:  You can follow us on Twitter @fdalawblog

By Riëtte van Laack –

The U.S. Government Accountability Office ("GAO") released a report on FDA’s  food recall process prepared in response to a congressional directive in the Food Safety Modernization Act ("FSMA"), which provided FDA with mandatory recall authority for foods.  In evaluating FDA’s implementation, the GAO considered how other government entities with recall authority, such as the Consumer Product Safety Commission, handle recalls and advise the public.

Since FSMA was enacted in 2011 and therefore FDA’s mandatory recall authority is relatively new, there is no information about an actual mandatory recall of food.  Moreover, although FDA has had mandatory recall authority for other product categories such as medical devices, the Agency has rarely used that authority.  Nevertheless, GAO developed some recommendations for FDA to more effectively implement and strengthen its new mandatory recall authority.  Specifically, GAO recommends that FDA:

• publish its currently internal document describing the steps it takes to order a food recall;
• document its process for ordering food recalls in regulations or guidance, including the process of weighing whether a recall is warranted and whether the standard of proof for a mandatory recall is met;
• define categories of ordered recalls in FDA’s central recall database;
• determine and implement ways to improve the sharing of information among databases that contain recall information.

GAO also examined the challenges FDA faces in advising the public about food recalls or outbreaks of foodborne illness.  GAO acknowledged that FDA faces a number of communication challenges when advising the public about food recalls or outbreaks of foodborne illness, ranging from balancing technical accuracy with timeliness of communications, to coordinating messages with other agencies and meeting the needs of diverse public audiences.   For example, a delay in communication can result in more illnesses and deaths, but a premature communication can trigger major financial losses for the food industry and deter the consumption of certain healthful foods.  GAO further recognized that FDA has taken steps to begin meeting these challenges, but concluded that FDA has yet to fully address recommendations from the GAO and others to fashion a comprehensive food recall communication policy and related implementation plans.  

GAO recommends that FDA implement recommendations from others to address FDA communication challenges when advising the public about food recalls and outbreaks. Specifically, GAO recommends that FDA:

• develop a policy for communications during emerging events;
• implement a coordinated plan for crisis communication; and
• consult with USDA on USDA’s experiences in advising consumers about recalls and determine whether those experiences may be helpful for FDA.

Although a significant part of the report is devoted to a discussion of possible options to compensate the food industry for erroneously ordered recalls, the report does not include a specific recommendation for a mechanism.

By Ricardo Carvajal –

According to an informal policy, FDA considers the use of the term “natural” in food labeling to mean that nothing artificial or synthetic (including colors regardless of source) is included in, or has been added to, the product that would not normally be expected to be there.  Cases dealing with this policy typically focus only on whether the food contains an artificial or synthetic substance, and do not address the italicized element.  So we couldn’t help but notice when a California district court delved into the issue in a recent opinion that keeps alive a class action against Dreyer’s Grand Ice Cream (“DGIC”).

In relevant part, the court refused to dismiss state law claims essentially alleging that Haagen-Dazs ice cream was falsely advertised as “All Natural Ice Cream” despite the fact that it contained cocoa alkalized with potassium carbonate, a substance alleged to be artificial or synthetic.  Among other things, DGIC argued that, “because potassium carbonate is commonly used as an alkanizing agent. . . nothing artificial or synthetic has been used in its ice cream.”  The court found this argument problematic:

[E]ven if potassium carbonate is commonly used, that does not necessarily imply normally expected; a reasonable consumer may not have the same knowledge as, e.g., a commercial manufacturer.

Thus, at least in this court’s eyes, the presence of an artificial or synthetic substance is compatible with a “natural” claim only if one can demonstrate that consumers normally expect the substance to be present.  Awareness of the presence of the substance among manufacturers is irrelevant. 

By Jamie K. Wolszon –

FDA published in the July 31, 2012 Federal Register a notice announcing the Fiscal Year (“FY”) 2013 rates pursuant to the third iteration of the Medical Device User Fee Act (“MDUFA III”), which was recently enacted as part of the FDA Safety and Innovation Act (“FDASIA”), Pub. L. No. 112-144, 126 Stat. 993 (2012) (see our summary).  The notice includes the fee for establishment registrations, which FDASIA broadened to include many more establishments than in the past.

The device user fee schedule establishes the Premarket Approval (“PMA”) Application fee as the baseline fee, with other fees tied to that fee.  For instance, MDUFA III sets 510(k) fee amounts at 2% of PMA fees.  The fee for a PMA in FY 2013 will be $248,000.  This baseline also applies to BLAs (for devices regulated by CBER), Product Development Protocols (“PDPs”) (which are essentially never submitted), a premarket report (seeking permission from FDA to market a reprocessed version of a class III single-use device) and a BLA efficacy supplement.

The notice also sets out the fees for PMA supplements, notices, and reporting.  The fee for a panel-track supplement will be $186,000.  The fee for a 180-day supplement will be $37,200.  The fee for a real-time supplement will be $17,360.  The fee for a 30-day notice will be $3,968.  The annual fee for periodic reporting on a class III device will be $8,680.

The fee for a 510(k) premarket notification submission will be $4,960, while the fee for a 513(g) request for classification information will be $3,348.

The fee for annual establishment registration is $2,575.  FDASIA significantly expanded the scope of establishments subject to the annual establishment registration.  Prior to enactment of MDUFMA III, only three types of establishments were subject to registration fees: (1) manufacturers; (2) single-use device reprocessors; and (3) specifications developers. MDUFA III broadened the fee to apply to any establishment that is “engaged in the manufacture, preparation, propagation, compounding, or processing of a device.”

The fees are outlined in Table 1 of the Federal Register notice, and go into effect on October 1, 2012.  They are generally modest increases to the fees for FY 2012.

MDUFA III also includes a provision permitting FDA to waive medical device fees, or reduce applicable fees, if it is in the interest of public health.  The Federal Register notice does not discuss how FDA intends to apply that new discretion. On the drug side, FDA has published a guidance that discusses, among other waivers and reductions, waivers and reductions to prescription human drug user fees necessary to protect the public health. 

By Kurt R. Karst –      

Ever since the U.S. Court of Appeals for the First Circuit issued its opinion in May 2012 in Bartlett v. Mutual Pharmaceutical Co., ___ F.3d ___, 2012 WL 1522004 (1st Cir. May 2, 2012) denying Mutual Pharmaceutical Company’s (“Mutual’s”) appeal of a decision from the U.S. District Court for the District of New Hampshire in which the district court denied Mutual’s Motion for Judgment as a Matter of Law – see Bartlett v. Mutual Pharm. Co., 760 F. Supp. 2d 220 (D.N.H. 2011) – concerning design defect and generic drug preemption, there’s been a lot of speculation that Mutual would petition the U.S. Supreme Court to review the case.  That day has come with Mutual’s July 31st Petition for Writ of Certiorari.

The Bartlett case has a long history in federal court beginning with a September 2009 pre-Mensing decision (see our previous post here), and then, after a couple of additional district court decisions, ending (until now) with the First Circuit’s post-Mensing decision.  Our Mensing reference, of course, refers to the U.S. Supreme Court’s June 23, 2011, 5-4 landmark decision in PLIVA Inc. v. Mensing, 131 S.Ct. 2567 (2011), in which the Court ruled that FDA’s regulations preventing generic drug manufacturers from changing their labeling except to mirror the label of the brand-name manufacturer (whose drug product is approved under an NDA) preempt state-law failure-to-warn claims against generic drug manufacturers, because generic drug manufacturers are unable to comply with both federal and state duties to warn.  This is in contrast to the Court’s March 4, 2009 decision in Wyeth v. Levine, 555 U.S. 555 (2009), holding that a state-law tort action against a brand-name drug manufacturer for failure-to-warn is not preempted.  Since the Supreme Court issued its Mensing decision, scores of court decisions have dismissed litigation against generic drug manufacturers on Mensing grounds, including some Circuit Court decisions.  The Drug and Device Law Blog maintains a Generic Drug Preemption Scorecard of the decisions.

The drug at issue in Bartlett is Sulindac Tablets, a non-steroidal anti-inflammatory drug. Mutual markets the drug under an ANDA FDA approved in 1991 (ANDA No. 072051).  (Mutual’s product is an AB-rated version of Merck’s CLINORIL (sulindac) Tablets, which FDA approved in September 1978 under NDA No. 017911.)  The Bartletts (Respondents) claim that Mrs. Bartlett suffered serious injuries after taking Mutual’s Sulindac Tablets and raised myriad state-law tort claims.  Those claims were ultimately winnowed down to a state-law design defect claim that proceeded to trial.  (Specfically, the claim that “sulindac’s risks outweighed its benefits making it unreasonably dangerous to consumers, despite the [FDA] having never withdrawn its statutory ‘safe and effective’ designation that the original manufacturer had secured and on which Mutual was entitled to piggyback,” which goes to the very core of the generic drug system established under the Hatch-Waxman Amendments.)  A jury eventually awarded Respondent over $21 million in damages, and the district court denied various post-trial motions filed by Mutual, including Mutual’s renewed preemption defense based on the Supreme Court’s Mensing decision. 

Mutual appealed to the First Circuit, which affirmed the district court in a decision that our friends over at the Drug and Device Law Blog characterized as an “essentially absurd result.”  In reaching its decision, the First Circuit first turned not to Mensing, but to Wyeth, saying that although Wyeth, which did not involve a design defect claim, “was technically limited to failure-to-warn claims, its logic applies to design defect claims as well.”  Moreover, according to the Court, Mensing merely “carved out an exception to Wyeth, finding that the FDCA preempts failure-to-warn claims against generic drug manufacturers . . . [because] the generic maker cannot alter the labeling.”  That is, the Supreme Court “adopted a general no-preemption rule in Wyeth. . . .”  Based on this thinking, the First Circuit concluded that to avoid state tort law liability a company could simply stop making its generic drug product. 

Setting the case up for a request for Supreme Court review, the First Circuit commented that “it is up to the Supreme Court to decide whether [Mensing’s] exception is to be enlarged to include design defect claims. . . .  Given the widespread use of generic drugs and the developing split in the lower courts . . . , this issue needs a decisive answer from the only court that can supply it.”  And maybe that will happen with Mutual’s Petition for Writ of Certiorari, which presents the following question for the Supreme Court: 

Whether the First Circuit erred when it created a circuit split and held—in clear conflict with this Court’s decisions in PLIVA, Inc. v. Mensing, 131 S. Ct. 2567 (2011); Riegel v. Medtronic, Inc., 552 U.S. 312 (2008); and Cipollone v. Liggett Group, Inc., 505 U.S. 504 (1992)—that federal law does not preempt state law design-defect claims targeting generic pharmaceutical products because the conceded conflict between such claims and the federal laws governing generic pharmaceutical design allegedly can be avoided if the makers of generic pharmaceuticals simply stop making their products.

By Riëtte van Laack –

The Animal Drug User Fee Amendments of 2008 (“ADUFA”) directs FDA to prepare and publish annual summaries of antimicrobial animal drugs sold or distributed for use in food-producing animals.  The data are derived from information submitted by sponsors of antimicrobial new animal drugs who each year must submit to FDA a report regarding, among other things, their distribution data for antimicrobial animal drugs distributed domestically and exported for use in food-producing animals. 

A 2011 GAO report suggests that this information is insufficient to support a meaningful analysis of the possible relationship between antimicrobial resistance and the use of medically important antibiotics in food-producing animals, however.

On July 27, 2012, FDA published an Advance Notice of Proposed Rulemaking requesting comments as to how the Agency might be able to obtain more detailed information about the use of antimicrobial animal drugs when the drugs are used in numerous species, including non-food producing animals.  Specifically, the Agency invites comments on:

• Whether and how it should amend its regulations to obtain additional accurate sales and distribution information for each food producing species on the label; 
• How it can best compile and present the annual summary information, while still protecting confidential business information as directed by the law; and
• Options, within FDA’s authority, for obtaining additional data and information about the extent of antimicrobial drug use in food-producing animals to further support the analysis of the relationship between antimicrobial resistance and the use of medically important antibiotics in food-producing animals.

Comments are due September 25, 2012.

By Riëtte van Laack –

The Patient Protection and Affordable Care Act of 2010, in part, amended the FDC Act by adding Section 403(q)(H) requiring restaurants and similar retail food establishments (“SRFEs”) that are part of a chain with 20 or more locations to provide calorie and other nutrition information for standard menu items. 

Last year, FDA issued proposed rules (here and here) implementing the new legal requirements.  The new law and FDA’s proposed regulations have generated many comments and questions.  Major issues with the proposed regulation include the meaning of “menu” and the related requirement to provide nutritional information in establishments where consumers are not usually physically present when ordering items, the application of the law to grocery stores which may sell store-prepared food items, and the listing of calories for multi-serving foods, e.g., for an entire pizza rather than per slice (see our previous post here).

On July 24, Rep. John Carter (R-TX) introduced the Common Sense Nutrition Disclosure Act of 2012 (H.R. 6174) to amend the menu labeling provisions.  The amendment would allow delivery and take-out restaurants to post calorie (and other nutritional) information on the establishment's website rather than in their establishments and allow the listing of calories for multi-serving foods per serving or per common unit in which the food is usually divided.  In addition, the Bill includes a provision that providing various alternatives for disclosing nutrient content of standard menu items that come in different flavors, varieties or combinations.  As amended, the FDC Act would allow presentation of nutritional information for such products in ranges, averages, individual labeling of flavors or components, labeling of one preset standard build, or other methods as determined by FDA. 

H.R. 6174 also redefines the “reasonable basis” for a restaurant’s or SRFE’s nutrient disclosures to allow for variation in nutrient content related to variations in serving size, inadvertent human error in formulation of menu items, and variation in ingredients.  The bill further defines “restaurant or SRFE” as a retail food establishment that derives more than 50 percent of its total revenue from the sale of food, thereby resolving the uncertainty about what establishments are subject to the new requirements.

By Jennifer D. Newberger –

The Medical Device User Fee Amendments of 2012 ("MDUFA III") require FDA to “publish guidance outlining electronic copy of submissions ("e-Copy") and objective criteria for revised ‘refuse to accept/refuse to file’ checklists.”  On July 30, 2012, FDA issued a draft guidance in response to this commitment, titled “Acceptance and Filing Review for Premarket Approval Applications (PMAs).” 

The draft guidance is intended to provide FDA staff with a “clear, consistent approach to making acceptance and filing decisions on original PMA applications and panel-track PMA supplements.”  Though similar to the PMA filing checklist and guidance document issued in 2003, the draft guidance makes three modifications:  1) it divides the filing criteria into two distinct sets of criteria, acceptance criteria and filing criteria; 2) it encourages applicants to provide one electronic copy of the PMA in place of one of the six hard copies of the PMA application, and; 3) it includes manufacturing information as one of the sections required for a PMA to be considered complete.

Dividing the filing criteria into two checklists allows reviewers to reach an earlier decision about whether the PMA is sufficiently complete to allow the review to proceed.  Within 15 calendar days of receipt of the PMA, the reviewer must consider the preliminary questions (e.g., is the product a device, is appropriately reviewed under the PMA pathway) and determine whether the acceptance criteria have been met.  These criteria include all organizational and administrative elements, or a rationale for why certain elements are not included.  If the application contains all required elements, FDA should inform the applicant in writing that the application has been accepted.  If FDA fails to complete the acceptance review within 15 days, the application is considered accepted.

If the reviewer determines certain elements are missing, he should obtain concurrence from his supervisor, and then issue a letter to the applicant identifying the missing elements.  If the applicant provides the missing information, FDA will again have 15 days to review the acceptance elements.

Once FDA accepts the application, it reviews the application for the elements contained in the filing checklist to “determine the basic adequacy of the technical elements of the PMA.”  To be filed, the application must be “sufficiently complete to permit a substantive review.”  FDA has 45 calendar days from date of receipt of the PMA within which to complete the filing review.

The draft guidance includes two checklists, one for acceptance criteria and one for filing criteria.  When compiling a PMA, these checklists can assist sponsors in assuring that the PMA includes all the information required by FDA, which in turn can help FDA accept and file the PMA in a more timely manner. 

By Kurt R. Karst –      

In two Federal Register notices (here and here) scheduled for publication on August 1st, FDA will announce the Fiscal Year (“FY”) 2013 user fee rates pursuant to the fifth iteration of the Prescription Drug User Fee Act (“PDUFA”) and pursuant to the first iteration of the Biosimilar User Fee Act (“BsUFA”).  (In separate notices, FDA will announce – or has already announced – the FY 2013 user fee rates for animal drugs, animal generic drugs, medical devices, and fees under the Food Safety Modernization Act domestic for foreign facility reinspections, recall, and importer reinspection.)  Later this year, FDA should announce the FY 2013 user fee rates established pursuant to the Generic Drug User Fee Amendments (“GDUFA”).  Among other things, the FDA Safety and Innovation Act (“FDASIA”), Pub. L. No. 112-144, 126 Stat. 993 (2012) (see our summary here), reauthorized and amended several several existing user fee statutes that were scheduled to sunset and established new user fee statutes for generic drugs (GDUFA) and biosimilars (BsUFA).

The FY 2013 PDUFA application user fee rate is set at $1,958,800 for an application requiring “clinical data,” and one-half of a full application fee ($979,400) for an application not requiring “clinical data” and a supplement requiring “clinical data.”  (The term “clinical data” for PDUFA user fee purposes is explained in an FDA guidance document available here.)  These figures reflect FDA’s estimate of 122.3 fee-paying full application equivalents – an average of the number of full applications that paid fees over the lateset 3 years.  Annual establishment and product fees have been set at $526,500 and $98,380, respectively, and are based on estimates of 455 establishments and 2,435 products. 

The FY 2013 fees go into effect on October 1, 2012 and represent a modest change vis-à-vis FY 2012 user fee rates.  All BsUFA user fees – i.e., the initial and annual biosimilar biological product development fees, the reactivation fee, and the biosimilar biological product application, establishment, and product fees – are keyed to PDUFA user fees.

As we have done in past years, we provide tables (below) showing the increase/decrease in PDUFA user fee rates since the previous FY for each fee type (and in this case for each of the five FYs under PDUFA IV).  The first set of tables should be used with the table from our previous post, which tracks user fees rates since the inception of PDUFA.  The next set of tables illustrate the historical trend for each PDUFA user fee.

By Karla L. Palmer & Larry K. Houck –

The Drug Enforcement Administration (“DEA”) published a Final Rule on July 30th (77 Fed. Reg. 44,456 (July 30, 2012) placing prostanozol and methasterone into Schedule III of the federal Controlled Substances Act (“CSA”) as anabolic steroids.  DEA’s administrative scheduling of prostanozol and methasterone, along with their salts, esters and ethers, becomes effective August 29, 2012.

According to the CSA, DEA schedules drugs according to statutory procedures set forth in 21 U.S.C. § 811, which mandates a detailed, eight factor scheduling analysis set forth in 21 U.S.C. § 811(b).  In the case of anabolic steroids, however, the DEA uses another, simpler process drawn from the Anabolic Steroid Control Act of 1990.  The 1990 act establishes and regulates anabolic steroids as Schedule III controlled substances.  It also provides that any “new” anabolic steroids are not scheduled according to the multi-step procedures set forth in 21 U.S.C. § 811.  Instead, new anabolic steroids are classified through the administrative rulemaking process if the product meets the “regulatory definition of an anabolic steroid” set forth in 21 C.F.R. § 1300.01.  Congress defined “anabolic steroid” in the Anabolic Steroid Control Act of 2004, which classifies a drug or a hormonal substance as an anabolic steroid if that substance meets four criteria: (A) The substance is chemically related to testosterone; (B) the substance is pharmacologically related to testosterone; (C) the substance is not an estrogen, progestin, or corticosteroid; and, (D) the substance is not dehydroepiandrosterone ("DHEA").  Any substance that meets the foregoing criteria “is considered an anabolic steroid and must be listed as a Schedule III controlled substance.” 

DEA concluded that prostanozol and methasterone are chemically-and pharmacologically-related to testosterone; are not an estrogen, progestin or a corticosteroid; and are not DHEA.  Because DEA determined that prostanozol and methasterone met the criteria for anabolic steroids under 21 U.S.C. § 802(41)(A), DEA had no discretion other than to place the substances in Schedule III of the CSA. 

DEA stated that the U.S. Food and Drug Administration (“FDA”) issued a Warning Letter in response to adverse health effects associated with methasterone in March 2006.  DEA further noted that FDA later issued a warning in July 2009 concerning bodybuilding products containing steroid or steroid-like substances including a product containing the THP ether derivative of prostanozol.  DEA also stated that there are no approved medical uses at present for the two substances, and no one can dispense them pursuant to a prescription until such time as a manufacturer applies to FDA and obtains appropriate approvals for products containing such substances.  DEA published its Notice of Proposed Rulemaking for classification of these anabolic steroids on November 23, 2011 (76 Fed. Reg. 72355 (Nov. 23, 2011). 

DEA’s placement of prostanozol and methasterone in Schedule III subjects manufacturers, distributors, dispensers such as pharmacies and physicians, importers, exporters, and anyone in possession to the applicable provisions of the CSA and its implementing regulations, including administrative, civil and criminal sanctions.  DEA registration, recordkeeping and reporting, labeling and packaging, importation and exportation, security and disposal requirements for handlers of prostanozol and methasterone take effect on August 29, 2012.

The scheduling of prostanozol and methasterone is the second major action involving the federal control of anabolic steroids in less than a week.  On July 25, 2012, the Designer Anabolic Steroid Control Act of 2012 (S. 3431) was introduced in the Senate and reported here on July 26, 2012.  The Act would significantly increase DEA control over anabolic steroids as well as expressly adding twenty-seven additional anabolic steroids to schedule III.