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.

By Riëtte van Laack –

On March 13, 2014, U.S. Senator Jack Reed (D-RI) and U.S. Representative Ed Whitfield (R-KY) introduced the “Sunscreen Innovation Act” (S. 2141 and H.R. 4250, respectively).  The proposed legislation would amend the FDC Act to include a process for the review of potential sunscreen active ingredients.  The Act formalizes FDA’s time and extent program for sunscreen active ingredients but imposes time limits on FDA’s review.

In 2002, FDA published final regulations permitting companies to submit a time and extent application (“TEA”) to begin the process to amend an over-the-counter (“OTC”) monograph to add a new active ingredient that has been marketed for a material time and a material extent in the United States or elsewhere.  See 67 Fed. Reg. 3060 (Jan. 23, 2002); 21 C.F.R. § 330.14.  Under this program, FDA will consider accepting a TEA for inclusion in the OTC drug monograph system of OTC drugs initially marketed in the United States after May 1972.  For OTC drugs with marketing experience outside the United States, FDA requires proof that the product: (1) was marketed outside the United States as an OTC drug for purchase by consumers; and (2) was “marketed OTC for a minimum of 5 continuous years in the same country and in sufficient quantity” (although more than a single country may be appropriate depending on the extent of marketing).  21 C.F.R. § 330.14(b).  If, after reviewing a TEA, FDA determines that an active ingredient is eligible for OTC monograph inclusion, FDA publishes an eligibility notice in the Federal Register requesting the submission of data demonstrating that  the drug is generally recognized as safe and effective (“GRAS/E”) for its intended use.  After reviewing the data, FDA may publish a proposed rule, and then a final rule incorporating the new active ingredient into an OTC monograph.  In order to market the product, the active ingredient also must be recognized in the United States Pharmacopeia-National Formulary.  See 21 C.F.R. § 330.14(i).

Although FDA indicated it would “strive to complete TEA evaluations in 90-180 days,” FDA has not approved the TEA for a single sunscreen active ingredient (or any other ingredient) since the regulation was adopted in 2002.  Only recently did FDA issue its first determinations that data were insufficient to establish GRAS/E status for the sunscreen ingredients amiloxate and diethylhexyl butamido triazone (here and here).  FDA had determined amiloxate and diethylhexyl butamido triazone eligible for the TEA program in 2003 and 2006, respectively. 

The proposed Act keeps the TEA program largely intact but sets a specific time frame for FDA’s review and specifies a role for the agency’s Nonprescription Drugs Advisory Committee (“NDAC”).  Existing FDA eligibility requirements will be maintained.  Eligibility determinations will be made by FDA Division of Nonprescription Regulation Development.  Currently pending ingredient submissions that FDA already has determined to be eligible for the TEA program, will be considered eligible for the new review and approval process (i.e., they need not be re-reviewed for eligibility).

Under the proposed Act, once FDA has determined that the ingredient is eligible, it must submit the ingredient application to NDAC for a safety and effectiveness recommendation.  During the review process, NDAC would receive data from the public and communicate with the application’s sponsor to seek clarifying or  additional information.  FDA must accept or reject the Committee's recommendation.

The Act requires that the new submissions be reviewed within 11 months and that the current backlog (six TEAs for sunscreen active ingredients are pending) must be reviewed within 8 months.  Moreover, as proposed, FDA would be required to submit reports to Congress regarding its progress. 

Unrelated to the TEA program, the proposed Act also requires that FDA issue determinations regarding testing and labeling of sunscreen sprays and labeling of sunscreen drug products with SPF above 50.

By Wes Siegner –

Does meeting the FTC legal standard for claim substantiation protect claims from action by the National Advertising Division (“NAD”)?  If you think the answer should be “yes,” read on.

FTC consent decrees often leave open the possibility that unsubstantiated claims may be resumed based on new data.  NAD takes a different position on the resumption of discontinued claims, as is made clear in a recent press release concerning the product Procera. 

As a matter of general NAD policy, if the advertiser in an NAD case has agreed to discontinue a particular type of claim, it may not, absent “extraordinary circumstances,” introduce new data to support the same or materially similar claims to those previously reviewed and rejected in an NAD compliance review.  Under NAD procedures, such cases ordinarily are automatically referred to the FTC for review.  Whether new studies that meet the legal test for substantiation have been conducted is irrelevant to the NAD.

In the case of Procera, NAD had issued a decision in 2009 recommending that the advertiser discontinue certain claims.  When NAD recently found that the advertiser was again making similar claims, NAD contacted the advertiser, which agreed to discontinue all but one of the similar claims.  According to the advertiser, the claim at issue was substantiated by data from a study that was completed after NAD’s 2009 review.

As NAD makes clear at the end of the press release, “an advertiser in an NAD proceeding may not, absent extraordinary circumstances, submit new evidence after the fact as support for claims that were the subject of an earlier proceeding.” 

In a conversation with Lee Peeler, President and CEO of the Advertising Self-Regulatory Council (ASRC) and Executive Vice President of the Council of Better Business Bureaus, we received ASRC’s explanation for the difference between NAD’s policy and the FTC’s approach.  According to Mr. Peeler, both the NAD and FTC begin from a common starting point: the legal requirement that all objective claims in advertising be substantiated BEFORE they are made.  Failure to have preexisting substantiation violates the FTC Act and self- regulatory standards.  Once a violation of either the FTC Act or self-regulatory standards has been determined the processes and the consequences sometimes diverge. 

Under most but not all FTC orders you are permitted to resurrect claims for which the FTC has found a lack of substantiation provided the claims are substantiated based on newly acquired evidence.  Of course, given the consent decree, if the advertiser is wrong the consequences can be severe, ranging from fines for every ad found to be in violation to civil or even criminal contempt.  We say “most” here because some FTC orders do contain outright prohibitions of certain types of claims and in those instances no subsequently acquired evidence is considered.

According to Mr. Peeler, effective self-regulation is necessarily different from effective government regulation.  The NAD process is a voluntary system that advertisers participate in.  Once an advertiser makes a commitment to discontinue certain claims, it is critical to the success of the system that the advertiser honor those commitments. The system operates on the good faith of the participants: there are no fines, penalties or sanctions other than referral.

Mr. Peeler views the NAD Procedures position on after acquired evidence as critical to the self-regulatory system.  “Otherwise”, Mr. Peeler said, “the self-regulatory system would become an ‘endless loop’ with no finality and no consequences for continuing to make the same claim over and over again as long as some new evidence was  introduced in each proceeding.  The speed and finality that have made the system so successful would be undermined. ”  Therefore, to discourage recidivism and conserve resources, NAD has adopted a policy of automatically referring to FTC any claims that NAD has already reviewed and that have been discontinued, even if the advertiser argues that new studies l support the claims. 

This policy is set forth in NAD’s published procedures, although the implications of the policy may not be clear to advertisers.  The NAD procedure at issue is ASRC Policies and Procedures § 3.8, “Closing a Case”:

When a case has been concluded with the publication of a NAD/CARU decision or, when a panel has turned over a decision to the Chair, and when the Chair has executed the procedures in Section 3.6 of these “Procedures,” the case will be closed and, absent extraordinary circumstances, no further materially similar complaints on the claim(s) in question shall be accepted by NAD/CARU, except as provided for in Section 4.1.

As stated more clearly in the Procera press release, the phrase “no further materially similar complaints on the claim(s) in question shall be accepted by NAD/CARU” in these written procedures means that NAD will refer such claims to the FTC.

Of course, advertisers are free to conduct new studies to support claims that NAD has rejected, and absent an FTC order or FDA rule prohibiting them, advertisers may legally make claims that are substantiated, even if NAD has found that, prior to the new studies, the same claim was not substantiated.  However, advertisers need to be aware that the repetition of NAD-rejected claims is likely to result in a referral to the FTC as a result of NAD’s policy for handling such claims.

The best approach is always to make sure you have substantiation for your claims BEFORE you make them.  If you are already subject to an FTC order or an NAD decision, it is best to consult with counsel and independent experts in the relevant scientific field before making covered claims.  For more on the FTC’s approach to claim substantiation go here.

By Dara Katcher Levy –

We have long been waiting for a company to sue FDA for failing to issue an export certificate.  Unfortunately, we may need to wait a bit longer for a case that will resolve the standards for when FDA must issue an export certificate.  Today, one can argue that FDA is “allowing” companies to sell products in the U.S. when FDA is unreasonably prohibiting the same products from being shipped outside the U.S.

As background, export certificates, while not mandated by the Federal Food, Drug, and Cosmetic Act (“FDC Act”), have become a practical requirement for many companies seeking to market their U.S.-manufactured products globally.  Foreign customers and importing countries generally require that these FDA-issued certificates accompany the import of a regulated product, and some countries rely on certain types of export certificates before issuing their own product approvals/registrations.  Under the FDC Act Section 801(e)(4), exporters may request, and if criteria are met FDA is required, to issue an export certificate within 20 days of a request. 

There are several types of export certificates (see here and here) that exporters may request – those that certify a product may be legally marketed in the U.S. as well as those that simply certify a product may be legally exported from the U.S.  A typical reason FDA may refuse to issue the first type of export certificate for a drug or device is FDA’s concern over whether the company is manufacturing the product in conformance with current good manufacturing practices (“cGMPs”) or FDA’s quality system regulations (“QSRs”).  In fact, FDA often refuses to issue these certificates if the company has received a Warning Letter relating to those regulations.  We are aware that in such circumstances, FDA has refused to issue an export certificate until the Warning Letter “close-out” process has been completed. As we have previously blogged, this close-out process can take many months and it is unclear whether the delay is due to industry failure to correct serious regulatory problems or whether FDA is unwilling to conduct prompt follow-up to confirm corrections.  FDA’s failure to timely issue a Warning Letter “close-out” in many instances may lead to its failure to issue an export certificate – even where the company may already be in substantial compliance.  When FDA fails to issue an export certificate, it can effectively destroy a company’s ability to market its U.S. manufactured product outside the U.S. although there may be no impact on the company’s sales in the U.S. market, because FDA has not taken enforcement action to block the domestic sales of relevant product.

We were eager to read Pharmaceutical Innovations, Inc. (“PI”)’s complaint seeking declaratory judgment and injunctive relief to compel the FDA to issue a Certificate to Foreign Government (“CFG”), a type of export certificate that certifies a product may be legally marketed in the U.S.  PI manufactures and markets ultrasound gel, which is regulated by FDA as a medical device.  As we read the complaint, and reviewed FDA’s website, we were curious as to PI’s assertion that FDA has not taken any action to restrain PI from distributing its devices in interstate commerce.  FDA’s website shows that, in addition to a Warning Letter relating to QSR violations, certain lots of PI’s products are the subject of an open Class I recall, and that Deputy U.S. Marshals, at FDA’s request, had seized certain lots of PI’s product in April 2012.  This action was undertaken less than one month before FDA’s denial of PI’s request for a CFG in May 2012.  In addition, the July 2011 Warning Letter to PI advises, “Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.”  According to FDA’s website, the PI Warning Letter has not, to date, been subject to “close-out.”

PI maintains that it is currently manufacturing and distributing its products in the U.S. with no action from FDA to restrain the manufacture or distribution of these products.  PI also maintains that it has “responded fully and completely to the warning letter as well as to subsequent FDA inspectional observations and has repeatedly expressed its desire to meet with FDA officials to address the issues raised therein.”  PI further alleges that FDA has not responded to numerous written communications and verbal requests to FDA representatives for a meeting.  It is unclear whether FDA still has concerns about the quality of PI’s product, or whether FDA resources are hampering its ability to issue a Warning Letter “close out.”  If the issue is the latter, FDA’s inability to timely issue a Warning Letter “close out” is unreasonably (and unfairly) harming the company’s ability to obtain a CFG.  If the former, one could argue that FDA’s failure to take further action against products in domestic commerce could be viewed as FDA “allowing” the company to distribute products that FDA would otherwise view as adulterated or misbranded.

We are anxious to see whether PI will be successful in its suit.  If not, we will wait to see whether, if the facts were different, a lawsuit filed by another company without a Warning Letter “close-out” could be successful in requiring FDA to issue an export certificate.

By Riëtte van Laack –

Defendants Wellness Support Network, and co-owners Robert and Robyn Held, marketed two diabetes products – Diabetic Pack and Insulin Resistance – as medical foods.  In 2005 and 2006, FDA issued two Warning letters to them (here and here), claiming the products were marketed as unapproved drugs.  In 2007, the FTC sent them a Civil Investigative Demand.  This culminated in a lawsuit filed by the FTC against them in 2010.

The FTC alleged that the Defendants’ promotion of “medical food” products intended to treat diabetes was deceptive and unsubstantiated.  According to the FTC, the Defendants marketed their products as clinically proven natural solutions for blood glucose control and diabetes.  Allegedly, the Defendants’ website posted “dramatic claims” of effectiveness, including “new diabetes break-through,” reduces the effect of diabetes, “money back guarantee,” a clinically proven solution with a 90% success rate and “no side effects guaranteed,” and various testimonials. 

On February 20, 2014, the U.S. District Court for the Northern District of California granted the FTC’s motion for summary judgment on liability, redress, and injunctive relief, and denied the defendants’ cross-motions.  

The Court had previously rejected the Defendants’ argument that the products as medical foods were not subject to the FTC requirements. The Court held that FDA regulations concerning medical foods were irrelevant to the FTC’s determination as to the validity of the advertising claims.  Medical foods are subject to the same standard as other products, i.e., whether the advertising claims are truthful and not misleading.

The Court’s recent decision also rejected Defendants’ First Amendment claims, ruling that the right of free speech does not extend to false, deceptive, or misleading commercial advertising.  The Court held that Defendants’ claims were false because the Defendants did not perform clinical studies and did not test the actual product; instead the Court ruled that the Defendants based their claims on information about certain of the products’ ingredients collected on the internet.

The Court found that the Company and the individual defendants were jointly liable, because both individuals were at least recklessly indifferent to the falsity of the material representations.  Robert Held founded and co-ran the Company and formulated the products based on his research on the internet.  Although there was no evidence that Robyn Held had been involved in the formulation of the products, or was involved in determining the accuracy of the claims, the Court deemed her liable based on the evidence that she played a significant role in running the Company of which she was a co-owner, was extensively involved in the development of advertising claims, knew that Robert had no relevant formal scientific or medical training, and knew that the products have never been clinically tested.

The Court ordered restitution of almost 2.2 million dollars based on the Defendants’ net revenue minus refunds.  It also imposed a broad injunction against the Defendants for a twenty-year period.  The Defendants are barred from making certain claims related to diabetes, metabolic syndrome, blood glucose levels, and insulin unless the claims are supported by at least two randomized, double-blind, placebo controlled clinical studies, conducted by different researchers, independently of each other, and results, considered in light of the entire body of relevant and reliable scientific evidence, are sufficient to substantiate that the representations are true.   Other claims are barred unless they are supported by “competent and reliable evidence.”

It is unknown whether the Defendants will appeal the decision.

By Ricardo Carvajal –

Sabra Dipping Co., LLC ("Sabra") submitted a citizen petition (Dokcket No. FDA-2014-P-0259) asking FDA to establish a standard of identity ("SOI") for hummus.  The proposed SOI would define hummus as “the semisolid food prepared from mixing cooked, dehydrated, or dried chickpeas and tahini” with one or more of several designated optional ingredients.  Chickpeas would have to be “the predominant ingredient by weight, except water,” and the finished product would have to contain at least 5% by weight tahini. 

As noted in the petition, FDA tentatively identified general principles for food standards in a notice of proposed rulemaking issued in 2005, and the petition frames it statement of grounds in accord with those principles.  The petitioner argues that the proposed SOI is needed to promote honesty and fair dealing in light of the growing popularity of hummus in the U.S., and “the introduction of dips and spreads that are not based on the traditional ingredients of chickpeas and tahini but nevertheless are labeled as ‘hummus.’”  The petition includes exhibits listing examples of such products.  The petitioner maintains that the SOI would eliminate “the potential for economic fraud and deception through the substitution or addition of ingredients that destroy the basic nature and essential characteristics of hummus.”  In support of the proposition that chickpeas and tahini are the essential characteristics of hummus, the petition points to recipes dating back to the 13th century, and to the fact that “hummus” is the Arabic word for “chickpea,” among other factors.  Although not noted in the petition, common dictionary definitions of “hummus” include references to chickpeas and sesame seeds (see, e.g., here).

The petitioner also maintains that the proposed standard would improve the nutritional quality of the food supply because the combination of chickpeas and tahini results in a product with improved protein quality.  The petitioner also notes that the proposed SOI would be consistent with food standards established in certain Middle Eastern countries, the EU, and by Codex.