By Riëtte van Laack –

The U.S. Court of Appeals for the District of Columbia Circuit recently declined to stop USDA/AMS implementation of the amended Country of Origin Labeling ("COOL") regulations for beef, pork, and poultry products requiring identification of the country where the animals are born, raised and slaughtered and preventing commingling. The amended COOL regulations were issued in May 2013 (see our previous post here).   USDA gave industry until November 2013 to comply.  The American Meat Institute ("AMI") and others filed a complaint and request for preliminary injunction, which was denied by the district court. On appeal, AMI claimed that USDA’s amended regulations were outside the Agency’s authority under the COOL statute and violated the First Amendment.  They further claimed that the rule merely satisfied consumers’ curiosity.  The Court of Appeals affirmed the district court's decision that “AMI [was] unlikely to succeed on the merits of its claims.”

Even if there is no appeal, the appellate decision is not the end of the road for controversy over COOL.  The World Trade Organization ("WTO") already found that an earlier version of COOL was a trade barrier.  The new COOL requirements allegedly are more onerous than the first, and Canada and Mexico are back at the WTO (see here).  A WTO decision is expected in summer 2014.

By Ricardo Carvajal –

A putative class action targeting certain food products that declare “evaporated cane juice” (ECJ) as an ingredient was recently stayed based on the doctrine of primary jurisdiction.  As noted by the Court, prior decisions have gone both ways on the question of whether deferral under the primary jurisdiction doctrine is appropriate in cases alleging that the use of “evaporated cane juice” as an ingredient name is false and misleading.  What makes this decision noteworthy is its reliance on the fact that FDA recently reopened the comment period on its 2009 Draft Guidance, titled Ingredients Declared as Evaporated Cane Juice. The Court explained:

Leaving aside the question of whether the Court can properly determine, in the first instance, if ECJ is or is not the “common or usual name” of this ingredient, the FDA’s action clearly indicates that the agency is exercising its authority in this area. In light of the fact that FDA has revived its review of the ECJ issue, the Court finds that the FDA’s position on the lawfulness of the use of that term is not only. . . “not settled,” it is also under active consideration by the FDA. Any final pronouncement by the FDA in connection with that process almost certainly would have an effect on the issues in litigation here.

The Court stayed the action until August 1, at which time it expects an update from the parties on the status of FDA’s action.  It remains to be seen whether other courts presiding over similar lawsuits will follow the Court’s lead.

GMA Science Forum 2014 kicks off on April 6 in Washington, DC.  The Forum will feature numerous sessions addressing scientific and regulatory issues of interest to the packaged food industry.  A complete agenda is available here.  HPM attorneys will help present a half-day introduction to food law using a case-study approach that will cover (1) evaluating the regulatory status of ingredients and products, (2) securing supply chains and adhering to manufacturing requirements, (3) developing product labeling and advertising, (4) anticipating and responding to crises, and (5) managing relationships with regulators.  We’re also participating in a half-day session on administration of the GRAS exception.  Registration is available here.

By Allyson B. Mullen –

On March 25, 2014, FDA issued a proposed rule amending the regulations for classification and reclassification to conform to the changes to the Federal Food, Drug, and Cosmetic Act (the Act) made by the Food and Drug Administrative Safety and Innovation Act (FDASIA).  79 Fed. Reg. 16252 (Mar. 25, 2014).  Under Section 513(e)(1)(A)(i) of the Act, FDA may, based on new information, reclassify a device by administrative order (as opposed to the pre-FDASIA requirement of reclassification by regulation) and revoke any related regulation or requirement in effect under a PMA approval order.  FDA may undertake such reclassification on its own initiative or upon request from an interested person.  21 U.S.C. § 360c(e)(1)(A)(i).  The post-FDASIA statutory procedures have made it easier to reclassify medical devices (see our prior post here).  

The proposed rule seeks to implement the statutory changes from FDASIA in the regulations and to bring clarity to the classification and reclassification process for devices.  The changes that FDA proposes making to Part 860 include removing repetitive language from the regulations, using definitions that are consistent with the statute, and clarifying the class III device definition.  By modifying the class III device definition, FDA intends to make it clearer which devices that are currently classified as class III are not suitable for down-classification.

Specifically, FDA has proposed making the following material changes to the 21 C.F.R. Part 860:

• In 21 C.F.R. § 860.3
• Changing the term “life-supporting or life-sustaining device” to “supporting or sustaining human life.”
• Making minor clarifying changes and removing repetitive language from the definitions of class I and class II devices.
• Clarifying the definition of “generic type of device” to address the inter-relationship between a device product code, generic type and classification regulation.
• Removing definitions for “classification questionnaire” and “supplemental data sheet” because FDA has proposed removing the use of these forms.
• Adding definitions of “general controls” and “special controls.”  The definition of general controls is consistent with the definition in Section 513(a)(1)(A) of the Act.  The definition of special controls identifying such controls as necessary to provide a reasonable assurance of safety and effectiveness for a class II device.
• Changing the defined term “implant” to “implantable device.”  This change has been incorporated throughout Part 860.
• Adding a definition of a “special controls guideline” as a means for providing reasonable assurance of safety and effectiveness pursuant to Section 513(a) of the Act.
• In 21 C.F.R. § 860.3, substantially rewriting the definition of class III.  The proposed rule defines a class III device as one that is classified as such under section 513(f)(1) or 520(l)(1) of the Act, or a device for which there is insufficient information to determine if general or special controls are sufficient to provide a reasonable assurance of safety and effectiveness and the device (1) is intended for use in supporting or sustaining life; (2) is intended for “a use that is of substantial importance in preventing impairment of human health;” or (3) presents a potential unreasonable risk of illness or injury.  The proposed definition seeks to clarify when the Commissioner can find that there is insufficient information to determine if general or special controls are sufficient to provide a reasonable assurance of safety and effectiveness by listing five examples:
• Devices that have a favorable risk-benefit profile, but present “significant risks that cannot be adequately controlled through general or special controls.”
• Devices that have an unknown or unfavorable risk-benefit profile.
• Devices that have a favorable risk-benefit profile but require more stringent controls, including a full review of manufacturing information.
• Devices that require premarket review of any changes that may affect safety or effectiveness of the device.
• Combination products with a device primary mode of action, which include a drug or biologic constituent part that require a finding of safety and effectiveness, and such a finding has not been made.
• In 21 C.F.R. § 860.7, updating the class II classification or reclassification requirements for safety and effectiveness.  The proposed changes include establishment of special controls for class II devices, thereby replacing the term “performance standard” because special controls include performance standards.  This change has been adopted through the remainder of Part 860 as well.
• In 21 C.F.R. §§ 860.84 and 860.123, removing the requirement to utilize classification questionnaire and supplemental data sheet as part of the classification process.  FDA now requests that practitioners focus on providing information regarding “review of available valid scientific evidence, appropriate regulatory controls give the risks presented by the device, and regulatory standards to understand whether general controls are sufficient to provide [reasonable assurance of safety and effectiveness] or whether general controls and special controls are sufficient to provide [reasonable assurance of safety and effectiveness].”
• Adding new 21 C.F.R. § 860.90 and amending 21 C.F.R. § 860.125 to explain how and when FDA will consult with panels regarding classification of preamendment devices.
• In 21 C.F.R. § 860.93, adding a provision requiring that any panel recommendation for classification or reclassification into class II for any implantable device or any device intended for use in sustaining or supporting human life must describe the special controls necessary for providing reasonable assurance of safety and effectiveness. 
• In 21 C.F.R. § 860.120, clarifying that a reclassification can pertain to all of the devices within a classification or only one generic type, and that the Commissioner can reclassify class I, II or III devices into any of the other classes and under what conditions a reclassification may be initiated.
• In 21 C.F.R. § 860.130, amending the language to reflect the new reclassification procedures from FDASIA and requiring that a proposed reclassification order must include “(1) A substantive summary of valid scientific evidence, including the public health benefits and risks of the device; (2) when reclassifying from class II to class III, an explanation that general and special controls are insufficient to reasonably assure safety and effectiveness; and (3) when reclassifying from class III to class II an explanation that general and special controls are sufficient to reasonably assure safety and effectiveness.”
• In 21 C.F.R. § 860.132, making the process to initiate reclassification of a device after FDA has initiated the establishment of a performance standard or requirement for a PMA consistent with FDASIA.
• In 21 C.F.R. § 860.133, revising the procedures for requiring the filing of a PMA for a class III preamendment device to be consistent with FDASIA, including issuance of the final rule in the Federal Register and holding a classification panel meeting.  A proposed order must include the same information discussed above in 21 C.F.R. § 860.130.  Given the dwindling number of class III preamendment devices, this will affect only a few devices.
• In 21 C.F.R. § 860.134, clarifying the process for reclassifying postamendment devices and including a reference to the de novo classification process.  Also, the proposed rule adds the process for reclassification of a postamendment device when such reclassification is initiated by FDA.
• In 21 C.F.R. § 860.136, revising the procedures for reclassification of a transitional device when initiated by FDA or by the manufacturer or importer. 

The most interesting of the proposed changes is the new definition of class III.  The portion of the definition defining a class III device is relatively unchanged, although we find the proposed definition easier to read.  The addition of the five categories of devices for which there is insufficient information to determine if general or special controls are sufficient to provide a reasonable assurance of safety and effectiveness are likely to elicit the most comments from industry.  While the amendments to the reclassification procedures in FDASIA have made it easier for FDA to reclassify devices, the proposed substantive changes to the class III definition shows that FDA wants industry to know which devices the Agency believes are class III.  This change not only affects requests for reclassification of current class III devices to class I or II, but will also likely impact new devices seeking classification through the de novo pathway.  Thus, the change to the class III definition could result in a great number of new devices requiring approval of a PMA rather than clearance through a de novo petition. 

Comments to the proposed rule may be submitted through now and June 23, 2014. 

Earlier this week we gave a “Coming Soon” announcement about a forthcoming posting of an FDA-related crossword puzzle written by Jeffrey N. Gibbs and Etan J. Yeshua as part of a celebration of Hyman, Phelps & McNamara, P.C.’s 34th anniversary earlier this month.  Well, it’s here – game on folks!

Below is the crossword puzzle, followed by the clues to completing it.  You can also download a PDF copy of the puzzle here (see the Note below).  We’re posting this at Noon (Eastern Time) on Wednesday, March 26th.  Contestants have 48 hours to complete the crossword puzzle – until Noon (Eastern Time) on Friday, March 28th – and submit their results to us.  Completed puzzles can be emailed to Mr. Gibbs at jgibbs@hpm.com.  Good luck!  And have fun!

We’ll update this post later on Friday with the crossword puzzle answers.  Everyone who submits a correct set of answers will be congratulated with a coveted HP&M Crossword Puzzle certificate.  The first one to submit a correct set of answers will receive a special HP&M Crossword Puzzle certificate commemorating the accomplishment.

 Across
1. Cartoon explorer
5. Beat handily
9. Tally at the end of an Advisory Committee
14. _____ Pharmaceuticals (recently acquired Dublin-based company)
15. Year: Lat. (NOTE: Mea culpa. This clue was changed from "Years: Lat." to "Year: Lat.")
16. What a 19-Across does with photons
17. Sought-after agency designation
19. A Part 1040 product
20. Sought-after agency designation
21. Animal regulated as a medical device
23. More festive, as apparel
24. Invokes section 302
28. Some preclinical subjects
30. ___ Mack (long-serving manager)
31. Sec. 502(g) compendium
34. Boy band started in 1995
37. Popular OTC IVDs
38. Confirmed Agency official?
42. Attorney William who signed the Articles of Confederation in 1778
43. Like some dealings or figures
44. Also
45. Demand
48. Hoppers down under
50. Atlanta and Boston District Offices, e.g.
53. _____ Harbor
57. First line of a letter from President McKinley, maybe
58. Former Director of DDMAC and FDLI Chair ________ Baylor Henry
59. Offer before “Buckle up.”
62. Like an FDA-approved drug
64. Blender setting
65. Reviewer of an academic paper
66. With 63-Down, ever-increasing Agency cost
67. Hon. title of honor for some priests
68. Arbor Day honoree
69. Destinations of individuals under section 333?

Down
1. Remove condensation, as on a windshield
2. Ugandan attorney and political leader Otunnu
3. Hoarse
4. National_____
5. Sew
6. Chemical consisting of A, C, G and U
7. “Let me go!”
8. Some Sec. 890.5370 devices
9. Sphygmomanometer feature, often
10. FDA regional office located on John Galt Blvd.
11. “___ healthy to be sick sometimes.” – Henry David Thoreau
12. Summer in Paris
13. Ukr., formerly
18.  Designer Tarantino
22. List ender
24. Syndrome on a bottle of aspirin
25. Comment, as to a proposal
26. FDA-approved angina treatment, for short
27. Directive to a top FDA official to depart?
29. Sponsor’s post-trial document: Abbr.
31. 1921 Fritz Lang film, “Vier ___ Frau”
32. Steam room
33. The Gray Sheet and FDA News, for example, with “the”
35. High degree
36. Organization ______
39. Containing more particulate matter
40. Hoopla
41. Like some people treated by 19 across
46. Scottish treats
47. FDA summary of physical/functional result, e.g., QOL
49. Parodied
51. Expert
52. Like a drug with fewer side effects
54. Plant listed in Part 182
55. In two
56. Gawks naughtily
58. Just
59. Largest FDA specialty firm
60. Sold in the UK and Aus., e.g.
61. Czech dest.
63. See 66-Across

Friday, March 28, 2014

Thank you to all of our contestants.  We received many entries – several with the puzzle solution.  The first person to submit a correct puzzle solution, and the recipient of the special HP&M Crossword Puzzle certificate, is: Steven Lawrie, MS, MA.  The puzzle solkution is below.

By Anne K. Walsh –

The Supreme Court of Arkansas recently overturned (here and here) a lower court’s $1.2 billion award to the State of Arkansas, and also reversed and remanded the decision granting over $200 million in attorney’s fees and costs to the state.  Putting aside the huge dollar figures at stake for Johnson & Johnson, the defendant, what makes this decision interesting for FDA Law Blog followers is the court’s opinion limiting the use of FDA’s Warning Letter as evidence.  While this litigation involved allegations specific to the state’s false claims act and consumer fraud statute, the implications potentially reach beyond the State of Arkansas or these legal theories.

At trial against J&J, the State of Arkansas relied heavily on a 2004 Warning Letter issued to Janssen Pharmaceutica, Inc., the J&J unit responsible for marketing Risperdal, an antipsychotic drug.  FDA objected to a “Dear Healthcare Provider” letter that Janssen had sent in 2003, claiming Janssen failed to disclose certain information contained in the product labeling, minimized the risk of certain adverse events, failed to recommend regular monitoring to identify adverse events, and misleadingly claimed that Risperdal is safer than other atypical antipsychotics.  Janssen attempted to convince FDA to the contrary, but ultimately sent a corrective letter to the recipients of the “Dear Healthcare Provider” letter.  FDA closed the matter six months after the Warning Letter was issued.

At trial, the State of Arkansas claimed the Warning Letter supported its position that Janssen had violated the Arkansas Medicaid Fraud False Claims Act and the Arkansas Deceptive Trade Practices Act.  Indeed, the State referred to the Warning Letter repeatedly throughout the trial, and mentioned it at least 15 times during closing arguments alone. 

On appeal, Janssen argued that the circuit court wrongly allowed Arkansas to use the Warning Letter as evidence, claiming it was inadmissible hearsay under the state’s rules of evidence.  Hearsay is generally inadmissible unless subject to a specified exception.  Here, the issue for the court was whether the Warning Letter was a public record containing factual findings resulting from an investigation made “pursuant to authority granted by law,” (admissible), or whether the factual findings resulted from a “special investigation of a particular complaint, case, or incident,” (inadmissible).  Primarily relying on FDA’s language in the Warning Letter itself and the closeout letter it issued, the supreme court found that the Warning Letter stemmed from a special investigation of the Dear Healthcare Provider letter, and was not part of FDA’s routine recordkeeping authority.  Therefore, the court concluded that the Warning Letter was inadmissible hearsay.

The dissent disagreed that FDA conducts a “special investigation” every time it issues a Warning Letter, focusing on the stated mission of FDA’s Division of Drug Marketing, Advertising and Communication’s (“DDMAC”), the predecessor to FDA’s Office of Prescription Drug Promotion.  Because the office was created to monitor and surveil prescription drug advertising, the dissent stated that “it appears that the warning letter was merely the result of the agency’s routine duties of reviewing and regulating the information on, and advertising of, drugs such as Risperdal.”  Slip op. at 29.  

The majority also discussed the unfair prejudice resulting from the Warning Letter:  “Reports issued by governmental agencies, because of their ‘official’ nature, may well carry inordinate weight in the minds of jurors.”  Slip op. at 26 (quoting Boude v. Union Pac. R. Co., 277 P.3d 1221, 1225 (Mont. 2012)).   The court concluded that the Warning Letter was more prejudicial than probative, and thus inadmissible even if it met the public records exception for hearsay evidence.

For jurisdictions that have rules of evidence excluding “special investigations” like Arkansas (for example, Delaware, Indiana, Louisiana, and Montana, to name a few), the Arkansas Supreme Court’s analysis may be persuasive.  For those states without similar exceptions, however, the ruling still may be helpful in its findings related to the prejudicial nature of FDA’s Warning Letters.  Because the court’s analysis was wholly independent of the underlying statutory basis for the litigation, it also could impact other types of cases involving FDA-regulated products.  Several amicus briefs were filed by interested parties, including Washington Legal Foundation and Allied Educational Foundation, Pharmaceutical Research and Manufacturers of America, Public Citizen, AARP, the Arkansas Chamber of Commerce, a former FDA Commissioner, and 34 states.  

By Kurt R. Karst –      

Earlier this week, Senator Richard Blumenthal (D-CT) and Representatives Joaquin Castro Joaquin Castro (D-TX) and Randy Forbes (R-VA) introduced the “Independent Innovator and Repurposing Act” in their respective houses of Congress (S. 2150; H.R. 4287).  Styled as a bill “[t]o advance the public health by encouraging independent innovators to pursue drug repurposing research and develop new treatments and cures by providing appropriate intellectual property protections for those innovations,” the Independent Innovator and Repurposing Act, if enacted, would allow the sponsor of a BLA for a biological product approved pursuant to Section 351(a) of the Public Health Service Act (“PHS Act”) to obtain a Patent Term Extension (“PTE”) of 5 years (or an interim extension for successive 1-year periods as appropriate) for a patent claiming a method of using that approved biological product because of “regulatory delay.” 

The bill does not amend the PTE statute at 35 U.S.C. § 156.  Rather, the bill allows the owner of record of an applicable patent to submit to the Director of the Patent and Trademark Office (“PTO”) an application requesting the extension.  Such an application must contain: (1) the identify of the biological product; (2) information on the patent for which an extension is being sought (and the identity of each claim of such patent that claims the method of using the biological product); (3) a brief description of the activities undertaken by the patent owner (or the agent of such owner) during a specified regulatory review period period; and (4) information demonstrating that the patent was issued to an “independent innovator,” that the owner of record is the “independent innovator” or a “qualified small business” in which the “independent innovator” has an ownership interest, that a Section 351(a) BLA was submitted to FDA for the claimed method of use, and that a period of not less than 10 years elapsed between the original date of submission of an IND for investigating the patented method of use and the date on which FDA approved the Section 351(a) BLA.

An “independent innovator” is defined in the bill to mean: “any person or entity that (i) obtains a method of use patent for a biological product; and (ii) is not, at the time of invention or patent filing, affiliated with the holder of a marketing application approved under [PHS Act § 351(a)] for the commercial marketing of such biological product.”  Affiliation includes “any relationship of employment, control, or common ownership, whether direct or indirect, including through one or more intermediaries.”  A “qualified small business” is defined in the bill to mean “any entity with fewer than 500 employees, including employees of affiliates, and which is not affiliated with the holder of the marketing application approved under [PHS Act § 351(a)] for the commercial marketing of such biological product.”

Any determination that an applicable patent is eligible for a PTE must be made by the PTO Director “solely on the basis of the representations contained in the application for the extension.”  And if the PTO Director determines that a patent is eligible for extension and that the application requirements have been complied with, then the PTO Director “shall issue to the applicant for the extension of the term of the patent a certificate of extension, under seal, for 5 years” (emphasis added).  The PTE certificate must be recorded in the official file of the patent and is considered as part of the original patent.  Interim PTEs of 1-year in length may be granted if the the term of an applicable patent for which an application has been submitted would expire before a PTE certificate is issued or denied.

Of particular interest to us is the “Effective Date” provision of the bill.  It says: “This section shall take effect on the date of the enactment of this Act and shall apply to any unexpired patent issued before, on, or after that effective date.”  That got us thinking . . . .  This bill certainly did not materialize out of thin air.  There’s a particular interest behind the bill (as there is with many pieces of legislation).  And while there may be several patents out there for approved Section 351(a) BLAs claiming a method of using an old product for a new use that might benefit if the Independent Innovator and Repurposing Act is enacted, we suspect the bill is intended to address a particular patent for a particular biological product.  While we’re not sure which patent, we think the product is BOTOX (onabotulinumtoxinA) Injection, which FDA approved under BLA No. 103000/S-5215 on October 15, 2010 “for a new indication for the prophylaxis of headaches in adults with chronic migraine.” 

By Ricardo Carvajal –

FDA announced that it has implemented a new electronic reporting tool for livestock animal food problems, which the agency refers to as the Livestock Food Reporting Portal.  Essentially, the portal expands the categories of reports that can be submitted through the Safety Reporting Portal, which is used for reporting a range of potential safety issues to FDA and NIH.  That portal will now accept reports about foods made for livestock from veterinarians, livestock producers, and other consumers. 
Expansion of electronic reporting should help FDA better detect and respond to potential safety issues associated with food for livestock.  In its instructions for submission of such reports, FDA asks for a description of the problem (e.g., “foul odor, off color, inconsistent texture”), information on any clinical signs of illness, and contact information for the treating veterinarian. 

Below is a list of the types of reports currently accepted through the Safety Reporting Portal:

• Reportable Food Registry Report (mandatory): A food facility or responsible party that manufactures, processes, packs, or holds foods who is submitting a reportable food report.
• Reportable Food Registry Report (voluntary): A federal, state, or local public health official who is submitting a reportable food report involving human and/or animal food. 
• Pet Food Report: A veterinarian or veterinary staff member who is submitting a product problem and/or adverse event report involving pet food. 
• Pet Food Report: A consumer or concerned citizen who is submitting a product problem and/or adverse event report involving pet food. 
• Livestock Food Report: A veterinarian or other professional who is submitting a product problem and/or adverse event report involving livestock food. 
• Livestock Food Report: A consumer or concerned citizen who is submitting a product problem and/or adverse event report involving livestock food. 
• Animal Drug Report: A marketing authorization holder (manufacturer) for an animal drug who is submitting a report on a product problem and/or an adverse event.
• Tobacco Product Report: A healthcare professional submitting a product problem and/or health-related problem report involving a tobacco product. 
• Tobacco Product Report: A consumer or concerned citizen who is submitting a product problem and/or health-related problem report involving a tobacco product.
• Dietary Supplement Report(mandatory): A dietary supplement manufacturer, packer, or distributor who is submitting a mandatory serious adverse event report. 
• Dietary Supplement Report (voluntary): A consumer, concerned citizen, or healthcare professional who is submitting a report about an illness, injury, or product problem associated with dietary supplement(s), or a manufacturer, packer, or distributor who is submitting a dietary supplement voluntary adverse event and/or product problem report.
• Gene Research Study Report: A clinical trial primary investigator or researcher who needs to report an adverse event involving a gene research study.

By Kurt R. Karst –       

In a Complaint filed last Friday in the U.S. District Court for the District of Columbia, Perrigo Israel Pharmaceuticals Ltd. and Perrigo Company (collectively “Perrigo”) (represented by Hyman, Phelps & McNamara, P.C.) allege that FDA has shirked a duty under the Federal Food, Drug, and Cosmetic Act (“FDC Act”) by failing to timely act to update the Orange Book to add a Therapeutic Equivalence (“TE”) rating for Perrigo’s Testosterone Gel, 1%, drug product approved under NDA No. 203098.  FDA approved NDA No. 203098, submitted pursuant to FDC Act § 505(b)(2), well over a year ago on January 31, 2013.  According to Perrigo, FDA “had an obligation at that time to update the Orange Book with a TE rating for Perrigo’s Product,” but “despite repeated requests by Perrigo to FDA asking the Agency to publish a TE rating for Perrigo’s Product, and despite publishing TE ratings for numerous other drugs approved after Perrigo’s Product, FDA has not fulfilled its statutory obligation.”  FDA determined Perrigo’s drug product to be bioequivalent to the listed drug relied on for approval, namely ANDROGEL (testosterone gel) 1%, based on data and information contained in Perrigo’s NDA.  Perrigo’s drug product is also pharmaceutically equivalent to ANDROGEL.

Under FDC Act § 505(j)(7)(A)(i), FDA is required to publish in the Orange Book three distinct pieces of information:

(I) a list in alphabetical order of the official and proprietary name of each drug which has been approved for safety and effectiveness under subsection (c) of this section before September 24, 1984;

(II) the date of approval if the drug is approved after 1981 and the number of the application which was approved; and

(III) whether in vitro or in vivo bioequivalence studies, or both such studies, are required for applications filed under this subsection which will refer to the drug published.

While each subsection of FDC Act § 505(j)(7)(A)(i) imposes a discrete nondiscretionary statutory duty on FDA, only the latter two subsections – and specifically the third subsection – are at issue in Perrigo’s Complaint.

FDA has stated on several occasions that the Agency fulfills the statutory duty at FDC Act § 505(j)(7)(A)(i)(III) through the use of TE codes in the Orange Book.  See, e.g., 54 Fed. Reg. 28,872, 28,911 (July 10, 1989); 21 C.F.R. § 320.24(a); FDA Petition Response, Docket No. FDA-2012-P-0499, at 7-10 (Nov. 13, 2012); FDA Petition Response, Docket No. FDA-2006-P-0346, at 36-40 (Aug. 22, 2012).   Under FDC Act § 505(j)(7)(A)(ii), “[e]very thirty days after the publication of the first list under clause (i),” FDA is required to “revise the list to include each drug which has been approved.”  The obligation to revise the Orange Book “under clause (i)” (i.e., under FDC Act § 505(j)(7)(A)(i)) includes Subsection (i)(III), which FDA has said it meets through the publication of TE codes in the Orange Book. 

As an aside, two Citizen Petitions (Docket Nos. FDA-2011-P-0610 and FDA-2013-P-0371) challenge FDA’s authority to assign TE ratings to 505(b)(2)-approved drug products, and, in particular, 505(b)(2) applications approved for testosterone gel, absent rulemaking under the Administrative Procedure Act (“APA”) (see our previous post here).  Nevertheless, as Upsher-Smith Laboratories recently noted in comments to FDA, the Agency has continued to assign TE ratings to 505(b)(2)-approved drug products despite the petitions.

Perrigo alleges that FDA has violated the FDC Act and the APA by failing to publish a TE rating with respect to Perrigo’s NDA No. 203098.  The company asks the court for both injunctive and declaratory relief.  Specifically, Perrigo asks the court to enter a mandatory preliminary injunction compelling FDA to publish a TE rating for Perrigo’s NDA No. 203098 as soon as possible (and in any event no later than 14 days from the date a preliminary injunction is entered and throughout the pendency of the case), and a declaratory judgment that FDA’s failure to provide the non-discretionary statutorily-required published TE rating constitutes agency action unlawfully withheld and unreasonably delayed.  In addition, Perrigo asks for a permanent injunction upon the completion of a trial on the merits.

(In our best Don LaFontaine voice) IN A WORLD where food and drug attorneys and regulatory professionals are all work and no play, there’s something coming to relieve the monotony and to spice up your work life. 

That’s right, after a very, very long hiatus, our “Lighter Side of Food and Drug Law” is back.  But as opposed to providing an entertaining story (see, e.g., here and here), this time we’re going to help exercise your brain. 

Later this week, we’ll be posting an FDA-related crossword puzzle written by Jeffrey N. Gibbs and Etan J. Yeshua as part of a celebration of Hyman, Phelps & McNamara, P.C.’s 34th anniversary earlier this month.  Be prepared!  While it may not be The New York Times Crossword Puzzle, it’s difficult! 

We’ll give FDA Law Blog readers about 48 hours to submit to us completed puzzles, then we will post the answers.  A special autographed certificate will be awarded to the first person to submit a correct response, and a different certificate will be awarded for all other correct submissions.  Our decision on the winner will be final, and not subject to reversal unless shown to be arbitrary and capricious.  (But we’ll be the judge of that!)  Stay tuned! 

By Kurt R. Karst –      

Since we started this blogging gig seven years ago (March 6th was our anniversary) we’ve strived to cover topics of interest to FDA-regulated companies, fellow food and drug and healthcare lawyers and regulatory personnel, as well as people just generally interested in FDA law.  Among other things, this has meant compiling and providing information on topics and happenings not usually reported on by other media outlets.  FDA’s activities with respect to orphan drugs is one such area.  But we’re not talking about reporting on your regular orpan drug approval, such as FDA’s recent approval of IMPAVIDO (miltefosine) to treat leishmaniasis (resulting in the third Tropical Disease Priority Review Voucher) (see here).  No, we’ve tended to look at things in the orphan drug space more broadly.

Over the years we’ve kept track of the success of the Orphan Drug Act (“ODA”), which President Ronald Reagan signed into law on January 4, 1983.  We have measured that success by the number of orphan drug designations submitted to and granted by FDA, and the number of orphan drug approvals resulting from those designations.  The ODA turned 30 last year, and we celebrated that anniversary – as did FDA (see here) – with a February post titled “The Orphan Drug Act: 30 Years and Still Going Strong!”  Although we looked at some new orphan drug metrics in that previous post, we didn’t have any records to report; just some near-records showing that interest in orphan drugs remains quite high.  Well, our 2013 numbers are in . . . . and it was an across-the-board record breaking year for orphan drugs.  That’s quite appropriate for the 30th anniversary year of the ODA. 

In 2013, FDA approved 31 orphan drugs – 5 more than the previous record year (2011) – pushing the total number of orphan drugs approved past the 450 mark.  Both orphan drug designations and orphan drug designation requests skyrocketed in 2013.  There were an astounding 260 orphan drug designations and a similarly astounding 346 orphan drug designation requests submitted to FDA’s Office of Orphan Products Development (“OOPD”) in 2013.  Previously, records for those metrics were set in 2011 with 203 orphan drug designations and in 2010 with 325 orphan drug designation requests, as shown in the tables below.  FDA’s grant rate for orphan drug designation requests has remained steady at about 70% of the requests submitted to the Agency since 1983 (2,989 requests granted of 4,271 submitted to OOPD).

Just as astounding as the 2013 numbers is the fact that the funding for (and the number of personnel in) FDA’s OOPD has reportedly remained relatively steady over the past several years.  Presumably, at some point an infusion of new funding and personnel will need to be made.  Indeed, FDA continues to push orphan drug development and, in addition to OOPD, has a Rare Diseases Program.  In January 2014, FDA held a two-day public workshop on “Complex Issues in Developing Drug and Biological Products for Rare Diseases” (Docket No. FDA-2013-N-0985).  In March 2014, there was an internal FDA all-day training session in which about 100 FDA reviewers participated, titled “Meeting the Challenges of Rare Disease Drug Review: Thinking Outside the Regulatory Box.”  In addition to presentations from FDA officials, Hyman, Phelps & McNamara. P.C.’s Frank J. Sasinowski presented on “Cataloguing FDA’s Flexibility in Regulating Therapies for Persons with Rare Disorders.”  Mr. Sasinowski previously authored a landmark report on flexibility in FDA’s review of potential treatments for orphan diseases (see our previous post here).  He also authored an analysis of FDA's Accelerated Approval/Subpart H/Fast Track approvals (see ourprevious post here).  The growing interest in orphan drug development likely means that many record breaking years are ahead. 

The Food and Drug Law Institute (“FDLI”) recently announced that President and Chief Executive Officer Susan C. Winckler will step down from that position effective May 23, 2014.  Ms Winckler, a pharmacist and attorney, was named to the position in November 2009.  She previously served as Chief of Staff at FDA.

“Susan has done a tremendous job leading FDLI over the past 4½ years, and it has been a pleasure working with her.  Her presence will be missed,” said Jeffrey N. Gibbs, a Director at Hyman, Phelps & McNamara, P.C. and member of the FDLI Board of Directors and the organization’s General Counsel. 

Founded in 1949, FDLI is a non-profit organization that provides a marketplace for discussing food and drug law issues through conferences, publications and member interaction.  FDLI is accepting applications for the position of President and CEO (see here).  The President and CEO is responsible for developing and managing FDLI’s programs, publications and other services, and is also responsible for membership development, assuring the financial stability of the organization, and leading, motivating and managing FDLI’s staff.

By Allyson B. Mullen –

On March 12, 2014, FDA issues a revised version of the Guidance Document “Administrative Procedures for CLIA Categorization” (the “2014 Guidance”).  FDA, Guidance for Industry and FDA Staff, Administrative Procedures for CLIA Categorization (March 2014).  The 2014 Guidance replaces the final guidance with the same name originally issued on May 7, 2008.  73 Fed. Reg. 25752 (May 7, 2008).  The 2014 Guidance has been revised to include information regarding FDA’s current administrative processes, including CDRH’s eCopy and the 510(k) Refuse to Accept policies.  2014 Guidance at 5.  In addition, the 2014 Guidance breaks down the procedures for determination of CLIA Categorization by in vitro diagnostic (IVD) devices under premarket review and other legally marketed IVD devices (e.g., tests exempt from premarket notification).  Id. at 5-6.  Perhaps most importantly, the 2014 Guidance provides timelines for FDA.  In the past, CLIA categorization tended to languish. 

For IVD devices undergoing premarket review (e.g., 510(k) or PMA), FDA will automatically create a CLIA tracking number (a CLIA Record “CR” number), which is separate from the premarket application number (e.g., 510(k) “K” or PMA “P” number).  Id. at 5. FDA will notify the sponsor of both the CLIA Record number and the premarket submission number.  The process by which FDA will determine test complexity will not change.  FDA aims to notify applicants of the CLIA categorization of the IVD device within two weeks following a positive marketing application decision (e.g., a substantial equivalence letter for a 510(k) or a PMA approval decision).  Id. at 5-6. 

For IVD devices that do not undergo premarket review, applicants should submit a request for CLIA categorization to the CDRH Document Control Center.  Id. at 6.  Although not required, FDA strongly encourages that applicants provide an eCopy of such CLIA categorization requests to expedite the review.  FDA will assign CLIA categorization requests a CLIA record number for tracking purposes.  FDA will attempt to notify sponsors of the CLIA categorization within thirty (30) days of the request.  Id. 

FDA maintains a searchable database of CLIA categorizations.  If an applicant changes the name of its tests or if the manufacturer or distributor changes, FDA recommends that a new request for CLIA categorization be submitted with the revised labeling to ensure that the record of the test in the public database is accurate.  Id.  Companies should be aware that this seemingly innocuous step could prompt a more substantive review.

If an applicant is submitting an application for a CLIA Waiver for a moderate complexity test, FDA strongly encourages providing an eCopy of such CLIA Waiver application to expedite the review.  CLIA Waiver applications are not accepted for devices that are under premarket review at the time of the submission, unless the application references a Pre-Submission during which agreement was reached for a Dual 510(k) and CLIA Waiver application strategy.  Such Dual submission should contain the full 510(k) and CLIA Waiver application in a single submission.  The Dual submissions will be subject to the 510(k) Refuse to Accept Policy.  The 2014 Guidance also sets forth current performance goals for CLIA Waiver applications:

    1 This performance goal applies to both the CLIA Waiver application and the 510(k).

Per the 2014 Guidance, a Substantive Interaction may include “a request for Additional Information (via letter or email), a notification that review will Proceed Interactively (via email), or notification of Waiver Granted (via formal letter).”  A MDUFA Decision may include “a notification of Waiver Granted (via formal letter), notification of Waiver Denial (via formal letter), or withdrawal by the sponsor.”  Id. at 7-8.

Lastly, for additional information regarding CLIA Waiver applications, the 2014 Guidance suggests referring to the Guidance Document “Recommendations for Clinical Laboratory Improvement Amendments of 1998 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices.”  Further, applicants can seek feedback from FDA prior to submitting a CLIA Waiver application or conducting studies in support of such an application through the Pre-Submission program (see our earlier post on the Pre-Submission program).  Overall, we think this updated guidance document will be a useful reference for understanding the administrative process for seeking CLIA Categorization or Waiver, and understanding the new, more predictable timeframes.
   

By Kurt R. Karst –      

It was just a little more than three months ago that we blogged on the topic of “premature notice” in the context of a Complaint filed by Otsuka Pharmaceutical Co., Ltd. (“Otsuka”) against Par Pharmaceutical, Inc. (“Par”) concerning Par’s notice of a Paragraph IV certification contained in an ANDA Par submitted to FDA for a generic version of SAMSCA (tolvaptan) Tablets.  Since then, we’ve noticed an uptick in the number of premature notices being sent out by ANDA applicants.  (We neither take any credit, nor any blame for any increase in premature notices.)  Different notice recipients – i.e., NDA holders and patent owners – have chosen different ways to deal with those premature notices . . . unless, of course, the recipient is not even aware that it has received premature notice.     

By way of background, an ANDA applicant (or 505(b)(2) applicant) that certifies Paragraph IV to a patent listed in the Orange Book for the listed drug relied on, or RLD, must provide notice of that certification to the NDA sponsor and patent owner.  FDC Act § 505(j)(2)(B)(ii) governs the timing of sending that notice.  It states:

(ii) TIMING OF NOTICE.—An applicant that makes a [Paragraph IV] certification . . . shall give notice as required under this subparagraph—

(I) if the certification is in the application, not later than 20 days after the date of the postmark on the notice with which the Secretary informs the applicant that the application has been filed; or

(II) if the certification is in an amendment or supplement to the application, at the time at which the applicant submits the amendment or supplement, regardless of whether the applicant has already given notice with respect to another such certification contained in the application or in an amendment or supplement to the application.

Notice sent prior to FDA’s acceptance of an original ANDA is considered premature and ineffective.  Some NDA holders/patent owners have decided not to act on premature notice, as seems to be the case with VASCEPA (icosapent ethyl) Capsules, as recently reported by Amarin here on page 31 (and here as well).  Others, however, have sued for infringement after receiving premature notice, perhaps out of an abundence of caution.  Such an action, although without any regulatory significance insofar as FDA is concerned, could result in ANDA approval earlier than if notice was timely sent.  As the court in SB Pharmco Puerto Rico, Inc. v. Mutual Pharm. Co, Inc., 552 F. Supp. 2d 500 (E.D. Pa. 2008), pointed out: premature certification could lead to manipulation of the Hatch-Waxman scheme by “accelerat[ing] the timing provisions and litigation process well beyond the framework that Congress intended.”  

Of course, if patent infringement litigation initiated as a result of premature notice is nipped in the bud – i.e., if a case is dismissed before litigation arising from later and valid notice is initiated and made a part of the first case – then it all may be water under the bridge.  That seems to be the case with SAMSCA.  After Otsuka filed a Motion for Judgment on the Pleadings and the motion was briefed (see here and here), the district court issued an Order granting Otsuka’s request that Par’s notice be considered improper, null, void, and without legal effect, among other things.  In the meantime, FDA’s Paragraph IV Certifications List still does not indicate that the Agency has received (i.e., filed) and ANDA with a Paragraph IV certification for a generic version of SAMSCA.

A similar fact pattern is playing out in the U.S. District Court for the Eastern District of Texas, where Allergan, Inc. (“Allergan”) recently filed a Complaint against Watson Laboratories and Actavis Pharma alleging premature notice concerning generic RESTASIS (cyclosporine ophthalmic emulsion) 0.05%.  Allergan is seeking, among other things, a “Declaratory Judgment of False Paragraph IV Notification.”  Allergan filed suit notwithstanding receiving confirmation from FDA in a letter that Watson’s ANDA was not yet received.

Another interesting case is generic EFFIENT (prasugrel HCL) Tablets, 5 mg and 10 mg.  In that case, Par sent notice to Eli Lilly and Company (“Lilly”) in December 2013 “stating that Par had included within its ANDA” a Paragraph IV certification to certain patents listed in the Orange Book for EFFIENT.  At that time, FDA’s Paragraph IV Certifications List did not identify that FDA had received a Paragraph IV ANDA for generic EFFIENT.  Indeed, the list was not updated with such information until February 4, 2012, despited having been updated on January 6 and January 23, 2014 with information on other drugs.  Lilly filed a Complaint on January 23, 2014 alleging infringement; however, Lilly’s Complaint is silent with respect to premature notice.  Apparently Lilly was unaware that Par’s notice was prematurely sent. 

That apparent oversight seems to have been subsequently realized when Lilly filed a Complaint against Par and several other ANDA applicants on March 12, 2014.  According to the Complaint:

377. On or about December 9, 2013, Par sent Lilly, Daiichi Sankyo, and Ube a letter, dated December 9, 2013, and an attached memorandum (collectively, the “December Par Notification”) stating that Par had included within its ANDA a certification pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV) that the ’703 and ’325 patents are invalid, unenforceable, and/or will not be infringed by the manufacture, use, importation, sale or offer for sale of the Par Products in the United States (“Paragraph IV Certification”).

378. Plaintiffs filed suit against Par Pharmaceutical in this judicial district on January 23, 2014, 1:14-cv-00109-SEB-TAB, and Par Pharmaceutical filed its Answer on February 28, 2014.

379. On or about January 31, 2014, Par sent Lilly, Daiichi Sankyo, and Ube a second letter, dated January 31, 2014, and an attached memorandum (collectively, the “January Par Notification”) repeating that Par had included a Paragraph IV Certification within the Par ANDA.

380. Unlike the December Par Notification, the January Par Notification represented that the FDA received the Par ANDA for substantive review.

381. Plaintiffs are therefore filing the instant Complaint against Par Pharmaceutical to preserve its right for a 30-month stay under 21 U.S.C. 355(j)(5)(B)(iii) and 21 U.S.C. 355(c)(3)(E)(ii) in response to the January Par Notification.

So what is FDA doing to halt the practice of a company sending out premature notice?  We’re not exactly sure yet . . . . but we think that some action is afoot. 

By John A. Gilbert –

The 57th session of the Commission on Narcotic Drugs (“CND”) recently convened in Vienna, Austria.  A prominent issue on the first day of the general session included concern over the increased use of cannabis, especially for recreational purposes.  The International Narcotics Control Board (“INCB”), which serves as the secretariat for the CND, has expressed a “long-standing concern” about the Netherlands’ policy that authorizes the use and abuse of cannabis in “coffee shops.”  In its latest annual report and at the meeting, the INCB identified a new target for this issue: the United States.  INCB, Report of the International Narcotics Control Board for 2013 (Mar. 4, 2014).  In the report, the INCB provides a detailed summary of the marijuana initiatives in the 21 states and the District of Columbia, while acknowledging that cannabis is still illegal under the Federal Controlled Substances Act.  Id. ¶ 374-375, at 49.  The INCB also noted the guidance issued by the Attorney General in addressing how the Drug Enforcement Administration (“DEA”) and other federal agencies should react to these state laws.  Id. ¶ 370, at 48.  It is clear that the INCB is not satisfied with either the state initiatives or the current federal response, concluding that the “use of cannabis in some states of the [U.S.] has not yet been adequately addressed by the federal Government in a manner consistent with the provisions of the drug control Conventions.”  Id. at 37.  Thus, as far as the INCB is concerned, the federal government should do more to ensure compliance with the international treaties.

It is worth noting that the Single Convention on Narcotic Drugs of 1961 recognizes the use of cannabis for medical and scientific purposes.  However, as noted by the INCB, the international treaty sets out specific requirements for establishment, administration, and monitoring of medical marijuana programs as stated in articles 23, 28 and 30.  Id. ¶ 169, at 23-24.  The INCB does not believe that many existing programs in the U.S. and in other countries comply with these restrictions.  Id. ¶ 374, at 49.  Moreover, use of cannabis for recreational use, such as is authorized in the Netherlands and some U.S. state initiatives, e.g., Colorado, would never be sanctioned under the international treaties.

In summarizing the INCB report at todays’ plenary session, INCB President Raymond Yans reiterated his concern about cannabis use in some countries, including the United States.  For its part, the U.S. delegation responded to Mr. Yans’ statements asserting that:  the U.S. remains committed to upholding the international treaties, the U.S. federal government will monitor the cannabis initiatives in Colorado and Washington and make sure they do not lead to new threats, and is committed to maintaining communication with INCB and reduce misunderstandings.

The U.S. continues to be an ardent supporter of the international drug control treaties and an aggressive and vocal voice against drug abuse.  However, the state marijuana initiatives, especially those authorizing recreational use, may affect the U.S.’ traditional “high road” approach at least in regard to marijuana use – pun intended.

Stay tuned for more news from the 2014 CND.