The ability to successfully obtain FDA approval is critical to the success of a medical device.  However, sometimes even the most dedicated of efforts fall flat when FDA says “No.”  What then?  What can you do if FDA says it believes there is not an adequate predicate device for your product? Or if FDA is requiring an overly burdensome clinical study? Or imposing data requirements that were not applied to your competitor's similar 510(k) six months earlier?

Hyman, Phelps & McNamara, P.C.'s Jeffrey K. Shapiro is presenting in a June 21, 2011 audio conference on the appeals processes available for medical device companies when FDA takes an adverse action during premarket review of a 510(k) or PMA.  He will discuss practical tips and advice on how to resolve a dispute with FDA so that a 510(k) or PMA can move forward.

Details about the audio conference are available here.  Sign up now!

By Kurt R. Karst –      

Like Yogi Bear, who is always on the lookout for a better way to procure pic-i-nic baskets, we are always on the lookout for innovative strategies companies come up with to protect their market exclusivity.  Two strategies have recently come by our desks – one from a brand-name company related to New Chemical Entity (“NCE”) exclusivity covering INVEGA (paliperidone) Extended-release Tablets, and another from a generic manufacturer related to 180-day exclusivity for a generic version of GEMZAR (gemcitabine) for Injection.  Both companies appear to have successfully protected their  marketing exclusivities.  How did they do it?  Queue up the “How It’s Made” theme song . . . .

Paliperidone

FDA approved INVEGA on December 19, 2006 under NDA No. 21-999 and granted the sponsor, Ortho-McNeil-Janssen Pharmaceuticals, Inc. (“Ortho”), a period of 5-year NCE exclusivity that expires on December 19, 2011.  Since then, FDA has granted Ortho several periods of 3-year new clinical investigation exclusivity for INVEGA in connection with NDA supplements, as well as a period of pediatric exclusivity earlier this year.  FDA’s grant of pediatric exclusivity extends by 6 months Orange Book-listed patent and non-patent exclusivities, and in particular, the period of NCE exclusivity for INVEGA until June 19, 2012. 

Shortly before the time FDA granted pediatric exclusivity (based on a pre-September 27, 2007 Pediatric Written Request), Ortho requested that FDA list U.S. Patent No. 5,158,952 (“the ‘952 Patent”) in the Orange Book for NDA No. 21-999, presumably because the ‘952 Patent “claims the drug for which the applicant submitted the [NDA] or which claims a method of using such drug and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture, use, or sale of the drug.”  FDC Act § 505(b)(1).  The ‘952 Patent, which is the only patent listed in the Orange Book for INVEGA, expires on April 9, 2012, but pediatric exclusivity would have been in effect until October 9, 2012 (or about four months after the pediatric extension on the NCE exclusivity period expires).  Would have been, you ask?  Yes, but we’ll get to that in a moment . . . .

Under the FDC Act, 5-year exclusivity prevents the submission of an ANDA (or a 505(b)(2) application) for 5 years, unless the applicant submits a Paragraph IV patent certification to an Orange Book-listed patent on the listed drug relied on for approval, in which case the ANDA (or 505(b)(2) application) can be submitted after four years.  Pediatric exclusivity granted under FDC Act § 505A extends the 5-year and 4-year periods out by an additional 6 months.  In the case of INVEGA, the 4-year ANDA/Paragraph IV certification period went from December 19, 2010, to June 19, 2011.

By submitting the ‘952 Patent to FDA for Orange Book listing, Ortho created the opportunity for an ANDA sponsor to submit an application containing a Paragraph IV certification to the ‘952 Patent beginning on June 19, 2011, instead of June 19, 2012.  So how do you prevent an ANDA sponsor from getting a 12-month head start on the review of its application based on a Paragraph IV certification to an early-expiring Orange Book-listed patent?  You disclaim the patent and dedicate the remaining term to the public and request that FDA remove the patent from the Orange Book.  That’s exactly what happened with the ‘952 Patent.  On June 1, 2011, Ortho dedicated the ‘952 Patent to the public, and on June 2, 2011 – a little more than two weeks before an ANDA could be submitted – Ortho requested that FDA delist the patent from the Orange Book.  

Gemcitabine

Under the FDC Act’s 180-day exclusivity failure-to-market forfeiture provisions (FDC Act § 505(j)(5)(D)(i)(I)), there must be two events (i.e., “bookends”) to calculate a “later of” event between items (aa) and (bb).  The first bookend date under item (aa) is the earlier of the date that is:

(AA) 75 days after the date on which the approval of the application of the first applicant is made effective under subparagraph (B)(iii); or

(BB) 30 months after the date of submission of the application of the first applicant

The (bb) part of the equation (i.e., the other bookend) provides that the (bb) date is “the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a [Paragraph IV] certification qualifying the first applicant for the 180-day exclusivity period,” one of three events occurs:

(AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.

(BB) In an infringement action or a declaratory judgment action described in [FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA)], a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

(CC) The patent information submitted under [FDC Act § 505(b) or (c)] is withdrawn by the holder of the application approved under subsection (b).

The (AA) and (BB) court decision events under item (bb) can be triggered in patent infringement litigation by “the first applicant or any other applicant (which other applicant has received tentative approval),” while the (CC) event would occur as the result of the NDA sponsor requesting that FDA delist Orange Book-listed patents. 

In the case of a generic version of Lilly’s GEMZAR (gemcitabine) for Injection, 200 mg/vial and 1 gram/vial, TEVA Parenteral Medicines, Inc. (“Teva”) submitted the first ANDA to FDA containing a Paragraph IV certification, thereby qualifying the company as a first applicant eligible for 180-day exclusivity.  That ANDA, ANDA No. 77-983, was submitted to FDA in November 2005.  Several other generic drug manufacturers submitted ANDAs to FDA containing Paragraph IV certifications to Orange Book-listed patents on GEMZAR, including APP Pharmaceuticals, Inc. (“APP”) and Sun Pharmaceuticals (“Sun”); however, all of these applicants submitted their applications subsequent to Teva’s ANDA submission.  As such, final approval for these ANDAs is prevented until Teva’s 180-day exclusivity has been triggered and run or is forfeited. 

FDA tentatively approved APP’s ANDA No. 90-242 on September 24, 2009.  FDA tentatively approved Sun’s ANDA No. 78-433 on March 4, 2008.  Sun was involved in patent infringement litigation with Lilly with respect to a patent on which Teva qualified for 180-day exclusivity.  The district court ruled in Sun’s favor, and Lilly appealed to the U.S. Court of Appeals for the Federal Circuit.  In July 2010, a panel of Federal Circuit judges affirmed the district court decision.  Lilly petitioned the Court for a panel rehearing/rehearing en banc, which the Court denied on November 1, 2010.  On November 12, 2010, the Federal Circuit issued its mandate. 

FDA considered the date of issuance of the mandate to be a final court decision for purposes of triggering the 75-day clock under FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA).  The date that is 75 days after November 12, 2010, and that is the item (bb) bookend date for a forfeiture calculation, was January 26, 2011.  The item (aa) bookend date (i.e., the date that is 30 months after the date of submission of Teva’s application) was in May 2008.  The later of the item (aa) and item (bb) dates, and the date on which a forfeiture of 180-day exclusivity would have occurred was January 26, 2011.  However, FDA approved ANDA No. 77-983 on January 25, 2011, just one day short of the forfeiture date for 180-day exclusivity eligibility. 

From what we can surmise, unresolved manufacturing issues probably meant that ANDA No. 77-983 was not in an approvable position, thereby placing the company at risk of a forfeiture of 180-day exclusivity as a result of the November 12, 2010 discussed above.  According to a Teva press release, Teva entered into a “commercialization, manufacture and supply agreement” with APP (which already held a tentative approval for the company’s ANDA No. 90-242), under which “APP will manufacture Gemcitabine HCI for Injection and will receive a license from Teva to market the product within Teva’s 180-day exclusivity.”  What we infer from this is that Teva and APP reached an agreement under which Teva was able to use/transfer information from the tentatively approved APP ANDA and include that information in Teva’s ANDA, thereby placing Teva’s ANDA in an approvable position.  Although longstanding FDA policy requires ANDA sponsors to recertify to Orange Book-listed patents when submitting an amendment for a formulation change, such a recertification would not be triggered when two formulations are quantitatively and qualitatively (“Q1/Q2”) the same.  If the APP and Teva gemcitabine formulations were Q1/Q2 the same, which was presumably the case, then FDA would not have required Teva to recertify to any GEMZAR patents.  

By Peter M. Jaensch & Alan M. Kirschenbaum –

The Office of the Inspector General (“OIG”) of the Department of Health and Human Services has issued a favorable Advisory Opinion on a manufacturer-sponsored patient reminder program for a vaccine, concluding that OIG will not seek penalties under the Federal health care program antikickback law.  The reminder program relates to two vaccines marketed by an unnamed pharmaceutical manufacturer.  The original vaccine was approved in 2000 for the immunization of infants and toddlers against pneumococcal bacterial infection.  In 2010, the manufacturer introduced an expanded vaccine that treats all of the bacterial strains covered by the original vaccine plus additional ones.  Like the original, the expanded vaccine is the only FDA-approved pneumococcal conjugate vaccine for children six weeks to five years old, and except where contra-indicated, the expanded vaccine is universally recommended.  The expanded vaccine is recommended for children who have never received the vaccine.  For children who completed the original vaccine course, one supplemental dose of the expanded vaccine is recommended.

To promote completion of the vaccine course, the vaccine manufacturer offers healthcare insurers and providers a cost-free service to remind the parents of children receiving the vaccine to make appointments for their next or supplemental doses.  Children are only eligible for reminders if they have either (1) received at least one dose of the vaccine, but not completed the full course, or (2) completed the course of the original vaccine, but not received the supplemental dose.  Insurers and providers may receive these reminder services either from the manufacturer or from a third-party contractor retained by the manufacturer.  In either case, the service is cost-free to the insurer or provider.  The reminders are delivered either by postcard or automated telephone call, or both. 

The Advisory Opinion notes that these reminders do not mention any specific product, nor do they direct the patient’s parent to any particular healthcare provider.  Instead, they alert parents that their children may have “missed a vaccine shot,” or, in the case of the supplemental dose, “not received a recommended vaccine,” and they advise parents to contact the child’s health care provider to find out if an appointment should be scheduled.  All communications disclose that the manufacturer has provided financial support for the reminders.

In its analysis, the OIG first repeats its long-standing position that free goods or services provided to potential referral sources may constitute prohibited remuneration under the antikickback law.  The OIG notes that the reminder program confers an economic benefit on providers by relieving them of an expense they would otherwise incur and by encouraging parents to arrange a visit with the provider for administration of the vaccine to the child.  Nevertheless, the OIG concludes that the program does not present a case for enforcement, enumerating several reasons: 

1. There is “little opportunity to influence referrals,” because reminders are sent only to the parents of children who have already been prescribed and received at least one dose of the vaccine. 
2. The financial support of the vaccine manufacturer is disclosed to the parents.
3. The manufacturer offers the Program to all health insurers and healthcare providers equally, rather than “target[ing] any particular referral source.”
4. The administration of the expanded vaccine is the standard of care and universally recommended except where contra-indicated.  Thus, the reminder program will not likely result in overutilization.
5. The reminders do not recommend a specific vaccine, and therefore are unlikely to decrease patient freedom of choice or result in unfair competition.
6. The reminder program increases the quality of healthcare services.

Manufacturer-subsidized reminder programs are widespread in the industry and take a variety of forms.  The most common is the prescription refill reminder program, where manufacturers pay a service fee to a chain pharmacy to distribute reminders to the pharmacy’s patients when it is time to refill the manufacturer’s drug.  Reminder programs must be structured carefully because they may implicate not only the antikickback law, but also patient privacy laws and consumer protection laws.  (We have reported on the status of subsidized communications to patients under the HIPAA privacy provisions.)  With regard to the antikickback law, it is encouraging that the OIG has recognized that these programs have a public health benefit and may be structured in a non-abusive, transparent manner that does not influence any treatment decisions.

By Riëtte van Laack –

Recent FDA enforcement actions suggest that FDA will diligently pursue companies that have received Warning Letters for certain violations – and that have allegedly failed to clean up their act.

U.S. Marshals recently seized product from UAS Laboratories (“UAS”), a probiotics dietary supplement distributor (see here), and Wyldewood Cellars (“Wyldewood”), a winery, marketing elderberry juice concentrate (see here). Both companies had previously received Warning Letters that claims for their products caused the products to be illegal drug products.

In 2005, FDA issued a Warning Letter to UAS stating that claims for its probiotic supplements that the products prevented diseases, including cold, flu, and yeast infections, caused the products to be illegal drug products. According to the recent Complaint, a 2007 inspection showed that UAS did remove the identified claims from its website.  However, during a March 2011 inspection, FDA allegedly learned that the UAS website again included disease claims for the products.  When, as recently as May 14, 2011, these claims had not been removed, FDA filed a Complaint for Seizure of the products.  UAS filed an answer to FDA’s Complaint denying that its products are drugs and asserting the affirmative defense that FDA’s claim is barred by the doctrines of laches, estoppel and waiver.

Wyldewood received a Warning Letter in 2006 informing the company that therapeutic claims on the label and website for elderberry juice concentrate, including claims that it may prevent colds and flus, caused the product to be an illegal new drug. FDA claims that, although the company committed to removing the offending claims, an FDA inspection in 2011 showed that Wyldewood continued to use similar claims.  Subsequently, FDA filed its Complaint for Seizure of the elderberry juice concentrate.

These two seizure actions send a strong message that FDA may well follow up on Warning Letters for certain violations.  Moreover, even if an alleged offending company brings its products in compliance, the company may be subject to increased scrutiny and more frequent inspections.  Although seizure is a somewhat cumbersome enforcement mechanism, the standard paragraph in Warning Letters regarding FDA’s enforcement powers should not be interpreted as an empty threat.  As evidenced by these recent actions, the Agency can use its seizure authority, even when there is no imminent threat to public health or safety.  FDA may well make similar use of its enhanced administrative enforcement authorities under the FDA Food Safety Modernization Act once those authorities are fully implemented.

By Kurt R. Karst –      

Earlier this week, FDA announced the availability of a final guidance document, titled “Citizen Petitions and Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act,” explaining the Agency’s interpretation of this statutory provision added to the law by § 914 of the 2007 FDA Amendments Act (“FDAAA”), Pub. L. No. 110-85 (2007), as amended by § 301 of Pub. L. No. 110-316 (2008).  The final guidance is quite similar to the draft guidance FDA issued in January 2009 (see our previous post here), except for FDA’s discussion in the final guidance of what the Agency requires for complete certification and verification statements.

For the uninitiated, FDC Act § 505(q) is intended to prevent the citizen petition process from being used to delay approval of ANDAs and 505(b)(2) applications.  Specifically, FDC Act § 505(q) provides that FDA shall not delay approval of a pending ANDA or 505(b)(2) application as a result of a citizen petition submitted to the Agency pursuant to 21 C.F.R. § 10.30 (citizen petition) or § 10.35 (petition for stay of action), unless FDA “determines, upon reviewing the petition, that a delay is necessary to protect the public health.”  Under FDC Act § 505(q), which FDA has interpreted to apply only to certain petitions submitted to the Agency after September 27, 2007 (FDAAA’s enactment date), “[FDA] shall take final agency action on a petition not later than 180 days after the date on which the petition is submitted.”  FDA may not extend the 180-day period “for any reason,” including consent of the petitioner, and may summarily deny a petition submitted with the primary purpose of delaying ANDA or 505(b)(2) application approval.  FDC Act § 505(q) does not apply to all citizen petitions.  Excluded from the new law are petitions that relate “solely to the timing of the approval of an application pursuant to subsection (j)(5)(B)(iv)” (i.e., 180-day exclusivity), and petitions that are submitted by an ANDA or 505(b)(2) applicatin sponsor that seek “only to have [FDA] take or refrain from taking any form of action with respect to that application.”  Petitions subject to FDC Act § 505(q) must include a specific certification, and petition supplements and comments must include a specific verification statement.  The statements must disclose when information supporting the petition, supplement, or comment became known to certain parties and must identify the parties in interest.

FDA Law Blog vigilantly follows 505(q) petitions and we regularly update our popular FDC Act § 505(q) Citizen Petition Tracker. with new petitions and decisions.  As we reported earlier this year in a two-part post (here and here), FDA has submitted reports to Congress detailing the Agency’s experience with 505(q) citizen petitions and describing several Agency initiatives to encourage early submission of certain petitions so that the petitions can be received in time to avoid a delay in ANDA or 505(b)(2) application approval.

FDC Act § 505(q)(1)(H) says that FDA “shall not consider a petition for review unless the party submitting such petition does so in written form and the subject document is signed and contains” a certification stating:

I certify that, to my best knowledge and belief: (a) this petition includes all information and views upon which the petition relies; (b) this petition includes representative data and/or information known to the petitioner which are unfavorable to the petition; and (c) I have taken reasonable steps to ensure that any representative data and/or information which are unfavorable to the petition were disclosed to me.  I further certify that the information upon which I have based the action requested herein first became known to the party on whose behalf this petition is submitted on or about the following date: _______________.  If I received or expect to receive payments, including cash and other forms of consideration, to file this information or its contents, I received or expect to receive those payments from the following persons or organizations: _______________.  I verify under penalty of perjury that the foregoing is true and correct as of the date of the submission of this petition.

Similarly, FDC Act § 505(q)(1)(I) says that FDA “shall not accept for review any supplemental information or comments on a petition unless the party submitting such information or comments does so in written form and the subject document is signed and contains” a verification stating:

I certify that, to my best knowledge and belief: (a) I have not intentionally delayed submission of this document or its contents; and (b) the information upon which I have based the action requested herein first became known to me on or about _______________.  If I received or expect to receive payments, including cash and other forms of consideration, to file this information or its contents, I received or expect to receive those payments from the following persons or organizations: __________.  I verify under penalty of perjury that the foregoing is true and correct as of the date of the submission of this petition.

FDA’s final 505(q) citizen petition guidance document cautions petitioners to strictly adhere to the statutory certification statement:  

As part of our determination of whether a petition contains the complete 505(q) certification, we will evaluate whether (1) the language of the certification in the petition exactly mirrors the language provided in section 505(q) and (2) the petitioner provided a date on which the information first became known to the party on whose behalf the petition is submitted. Because section 505(q) sets forth the exact words to be used in the certification, we will consider a certification to be deficient if every word in the petitioner’s certification does not match every word of the certification provided in section 505(q).  In other words, the petitioner’s certification must correspond verbatim to the certification in section 505(q).  For example, if, rather than using the phrase “first became known to the party on whose behalf this petition is submitted,” the petitioner substitutes the phrase “first became known to me,” we will consider the certification to be deficient.  We believe this interpretation is mandated by the statutory language because section 505(q) specifies the exact text of the certification. [(Emphasis added)]

FDA also cautions petitioners to use specific dates:

Section 505(q) also requires that the petitioner provide in the certification the date on or about which the information first became known to the party.  Section 505(q) includes a blank space in the certification for that information.  We consider a “date” to include a month, day, and year.  Therefore, we will consider a certification to be deficient if the petitioner has not provided the month, day, and year on or about which the information first became known to the party on whose behalf the petition is submitted.  For example, if the petitioner provides “May 2010” as the date in the certification, we would consider the certification to be deficient.  The text of the certification provided in section 505(q) includes a qualification that the petitioner learned of the information “on or about the following date.”  Therefore, we believe the certification would accommodate instances in which a petitioner may not know the exact date on which it became aware of the information.  To the extent that a petitioner believes further explanation of the date is needed, we believe that the blank space in the certification allows for the insertion of additional information. In addition, there may be instances in which different types of information became known to the petitioner over a period of time.  In that case, the petitioner should provide each estimated relevant date and identify the information associated with the particular date.  We caution that when adding information, the petitioner should ensure that the words of the certification (except for what is provided in the blank space) continue to exactly match the words of the certification as provided by section 505(q).  [(Emphasis added)]

The same FDA interpretations apply to verification statements included in petition supplements and petition comments.  FDA says in the final guidance that “[a]s with our approach to the certification . . . , we will consider a verification to be deficient if it does not exactly mirror the words of the verification in section 505(q)(1)(I) of the Act or if the petitioner or commenter does not provide a month, day, and year for the ‘date’ in the verification” (emphasis added).

And while we’re on the topic of citizen petitions, we note that the U.S. District Court for the Eastern District of Pennsylvania recently issued an opinion in In Re Flonase Antitrust Litigation.  The case stems from three different lawsuits filed by various parties alleging that GlaxoSmithKline (“GSK”) violated the antitrust laws by submitting sham citizen petitions to FDA pre-FDAAA and initiating a baseless lawsuit challenging FDA’s approval of generic FLONASE (fluticasone propionate) Nasal Spray.  (As we previously reported, last year the district court denied GSK’s motion to dismiss.)  GSK moved for summary judgment, arguing that its conduct is protected from antitrust liability under the First Amendment and by the Noerr-Pennington doctrine, under which private entities are immune from antitrust liability in petitioning the government to influence the passage or enforcement of laws, even if the laws they advocate for would have anticompetitive effects.  Judge Anita B. Brody denied GSK’s motion for summary judgment, saying that “genuine issues of fact remain as to whether GSK’s conduct was objectively baseless, and thus constitutes ‘sham’ petitioning not entitled to Noerr-Pennington immunity.”

By Peter M. Jaensch –

In what a federal grand jury charges was a several-months-long effort in 2010 to maintain their job security, a clinical trial investigator and clinical trial coordinator in Kansas allegedly falsified clinical drug trial study data in submissions to the Food and Drug Administration (“FDA”).

Following an investigation by FDA, on June 2, 2011, the U.S. Attorney’s Office for the District of Kansas announced the Grand Jury Indictment of Wayne Spencer, MD, and Lisa Sharp. According to the Indictment, in July 2009, Lee Research Institute (“LRI”) was engaged by Schering-Plough (“Schering”) to conduct a clinical study evaluating the safety of Schering’s ragweed sublingual tablet in adults 50 and older with ragweed-induced rhino conjunctivitis. Dr. Spencer, an LRI employee, was the Principal Investigator on the study. Ms. Sharp served as both Director of Clinical Trials for LRI and as the Lead Clinical Research Coordinator on the Schering study. The five-count Indictment charges each defendant with one count of conspiracy (in violation of 18 U.S.C. § 371), three counts of mail fraud (in violation of 18 U.S.C. § 1341), and one count of failure to maintain adequate records (in violation of 21 U.S.C. § 331(e)).

The factual bases for these charges center on the alleged inclusion of ineligible study participants and falsification of related records. According to the Indictment, from about January through May, 2010, Dr. Spencer and Ms. Sharp conspired to falsify data for this study, so as to “remain in the clinical drug trial” and “receive monies from Schering/Plough.” The indictment alleges that Dr. Spencer and Ms. Sharp accomplished this by: (1) enrolling LRI employees who were under 50 years old as study participants under false names; (2) falsely recording physical examinations of these participants that were never performed; (3) fraudulently signing multiple documents on these participants’ behalf without their knowledge; (4) concealing these improper enrollments by scheduling their visits only when LRI’s executive director was not present; and (5) falsely affirming that these participants met the inclusion criteria for the study. The Indictment also alleges that this conduct caused LRI to receive three payments for the study totalling approximately $32,000.

Despite these relatively small financial gains, if convicted, the defendants face significant penalties. According to the U.S. Attorney’s Office press release, each defendant faces up to 5 years imprisonment and a $250,000 fine on the conspiracy charge, up to 20 years imprisonment and a $250,000 fine for each mail fraud count, and up to 3 years imprisonment and a $10,000 fine for the failure to maintain adequate records count.

By Susan J. Matthees –

The DOJ has announced that a New Jersey jury found two dietary supplement companies and their owner and managers guilty of criminal contempt for allegedly violating a Consent Decree that had enjoined them from engaging in certain conduct.
 
In 2009, the government filed a complaint against Mohamed Desoky and his companies, Quality Formulation Laboratories, Inc. (“QFL”), and American Sports Nutrition, Inc., for allegedly introducing into interstate commerce dietary supplements that were adulterated and misbranded.  The products were allegedly produced under insanitary conditions (for instance, an FDA investigator claimed to have noted numerous live and dead rodents in the manufacturing area), and the product labels allegedly failed to disclose a major food allergen.  Mr. Desoky and his companies entered into a Consent Decree of Permanent Injunction in 2010 that restrained and enjoined them from directly or indirectly receiving, manufacturing, preparing, packing, labeling, and distributing any article of food, including dietary supplements, until certain conditions had been met and FDA provided written notification of authorization to resume operations.

Shortly after the Consent Decree was signed, FDA agents conducted an inspection of QFL’s facility and allegedly found evidence that some manufacturing and packing continued at the facility after the Consent Decree was signed, even though FDA claimed that it had not authorized the facility to reopen.  FDA also found that employees were being transported from the QFL facility to a new facility in order to continue manufacturing, packing, and shipping dietary supplements.  As a result, the government filed criminal contempt charges against Mr. Desoky, his companies, and his sons, who allegedly helped Mr. Desoky set up his new facility even though they knew about the Consent Decree.  

In September 2010, even after being charged with criminal contempt, QFL allegedly continued operations without FDA’s approval, and shipped finished product to at least one customer.  An undercover FDA agent performed a pick-up of finished food products from QFL in January 2011, and one of Mr. Desoky’s sons allegedly loaded the truck for distribution.  After contempt charges were filed, the case went to trial in the District of New Jersey, and a jury returned a guilty verdict. 

It is often thought that companies and their executives can end their disputes with FDA by entering into a Consent Decree.  In fact, FDA often shifts its resources from companies that FDA has sued to other companies once the company that has been sued settles the case.  However, this case shows that FDA can and sometimes does pursue contempt sanctions against persons who FDA believes have violated the terms of a Consent Decree.  As a result, companies entering into Consent Decrees must be prepared to understand and follow FDA’s interpretation of a Consent Decree or risk contempt sanctions if the company fails to do what FDA is expecting the company to do.  Alternatively, a company and its executives can litigate the injunction suit by not signing a Consent Decree.  Contempt sanctions can be very serious, including possible jail time and heavy fines.

This case may also be an indication that FDA intends to take dietary supplement GMPs seriously and will be vigilant to go after dietary supplement manufacturing facilities.  Dietary supplement GMPs became effective in June 2008 for large companies, June 2009 for medium companies, and June 2010 for companies with fewer than 20 employees.  Last year, FDA issued its first Warning Letter for alleged violations of dietary supplement GMPs, and last month dietary supplement GMPs survived a court challenge.  This case may be one of many future challenges against firms that allegedly manufacture dietary supplements in violation of GMP regulations.

The Food and Drug Law Institute (“FDLI”) will host an intensive one-day, must-attend conference on June 24, 2011, at the Westin City Center in Washington, DC, titled “Brands, Generics and Hatch-Waxman: New Challenges; Unabated Controversy.”  The conference will cover myriad Hatch-Waxman issues, including 180-Day Exclusivity, New Drug Application Exclusivities and Patent Term Extensions, Patent Certification/Litigation, and Regulatory Strategies and Conundrums, and boasts a virtual who’s who of presenters from the Hatch-Waxman legal community.  Among other presenters are FDA’s Elizabeth H. Dickinson, Associate Chief Counsel for Drugs, Office of the Commissioner, Caroline Holland, Chief Counsel and Staff Director, Subcommittee on Antitrust, Competition Policy, and Consumer Rights, Judiciary Committee, U.S. Senate, and C. Scott Hemphill, Professor of Law, Columbia Law School.

According to the program description:

The constant array of lawsuits, petitions, and administrative challenges regarding 180-day exclusivity, patent listings, and patent-term extensions have addressed important issues during the last year, resolving some but further complicating others.  This program will provide an in-depth analysis of these ongoing issues.  The Program will also address antitrust considerations associated with Hatch-Waxman patent and administrative challenges and the interplay between Hatch-Waxman and the newly authorized biosimilars approval pathway.

Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst, a member of the conference planning committee, is a speaker on the 180-Day Exclusivity panel.  Others on that panel moderated by David G. Adams, Partner, Chairman, FDA Group, Venable LLP, are Ms. Dickinson, Mr. Hemphill, and Michael D. Shumsky, Partner, Kirkland & Ellis LLP.

You can register for the event on FDLI’s website here, or by contacting FDLI’s Customer Service at (202) 371-1420.  We look forward to seeing you at the conference.

By Nisha P. Shah & Kurt R. Karst –

The U.S. Government Accountability Office (“GAO”) recently issued a report required by the FDA Amendments Act of 2007 (“FDAAA”) concerning the effects of the Pediatric Research Equity Act (“PREA”) (FDC Act § 505B) and the Best Pharmaceuticals for Children Act (“BPCA”) (FDC Act § 505A) on the study and labeling of drug and biological products for pediatric use.   The GAO found that at least 130 products (80 products under PREA and 50 under the BPCA) have been studied for use in children since FDAAA’s enactment on September 27, 2007.  Despite this success, the GAO says in its report that “FDA lacks an important internal control that would allow it to manage its review process to ensure that the agency and sponsors are meeting the law’s requirements and that FDA is meeting its own mission, goals, and objectives during the period of its review of the application.”

The BPCA and PREA are sometimes referred to as the “carrot and stick” approach to obtaining pediatric labeling.  PREA (the stick) requires sponsors to conduct pediatric studies in various pediatric age groups for certain drug and biological products, and to submit the results and proposed labeling changes to FDA with a marketing application.  FDA may waive (partially or fully) the PREA requirement or defer the submission pediatric study results until after product approval.  Under the BPCA (the carrot), FDA issues a written request to a sponsor to conduct pediatric studies for products that may have important health benefits in children.  A sponsor can decline FDA’s request; however, if the sponsor completed the requested studies, FDA grants six months of marketing exclusivity for the drug or biological product.  Additionally, a sponsor can request that a product that must be studied under PREA to be studied also under the BPCA to allow the sponsor to be eligible for six-months of  pediatric exclusivity. 

For drugs approved under the FDC Act, pediatric exclusivity attaches to any unexpired patent and non-patent marketing exclusivities listed in the Orange Book for any of the sponsor’s approved drug products (including certain combination products) that contain the active moiety for which pediatric exclusivity was granted.  For biological products licensed under the PHS Act, pediatric exclusivity extends by six months the 12- and 4-year reference product exclusivity periods described at PHS Act § 351(k)(7).  Pediatric exclusivity also extends by six months the 7-year period of orphan drug exclusivity applicable to a biological product.  For both drug and biological products, the law contains a similar exception with respect to the applicability of pediatric exclusivity.  Specifically, for post-September 2007 written requests, pediatric exclusivity will not apply to a particular period of patent or non-patent exclusivity if FDA grants pediatric exclusivity “later than 9 months prior to the expiration of such period.” 

According to the GAO report, FDA claimed that about 830 applications subject to PREA were submitted to FDA from September 27, 2007 to June 30, 2010, but FDA could not provide an exact number.  The Pediatric Review Committee (“PeRC”), a FDA committee responsible for assisting in the review of pediatric study results, completed reviews for 449 applications, 80 of which contained the results of pediatric studies (59 were drug applications and 21 were biological product applications).  The GAO claims that FDA could not provide information on the remaining 381 applications.  The GAO also found that FDA granted a full or partial waiver or deferral to more than half of the applications it received under PREA (237 waivers and 131 deferrals).  Under the BPCA, 50 products have been studied between the 2007 reauthorization through June 30, 2010, all of which were for drug products.  According to FDA officials, FDA granted pediatric exclusivity to 44 of the 50 drugs.  The report indicated that sponsors for five of the six drugs that did not receive exclusivity submitted only partial responses to FDA’s requests. 

Since the 2007 reauthorization of PREA and the BPCA, all of the 130 drug and biological products with studies completed and applications reviewed by FDA had labeling changes.  In comparison, in the prior nine years, 256 products had pediatric study-related labeling changes agreed upon by FDA and the sponsor.  According to the report, the top three categories of labeling changes are: (1) expansion of pediatric age groups approved in the label, (2) safety and effectiveness were not established in pediatric populations and a description of the study conducted was added, and (3) new and enhanced pediatric safety information was included. 

The GAO interviewed stakeholders, including drug and biological product sponsors, concerning challenges to conducting pediatric studies, which include:

• “confusion about how to comply with PREA and BPCA due to a lack of current guidance from FDA … [since] the most recent PREA guidance is draft guidance from 2005 and that the most recent BPCA guidance was revised in 1999;”
• “since PREA and BPCA are subject to reauthorization every 5 years, some of the statutory requirements for studies could change while studies are under way or as they are being planned; therefore, there is uncertainty as to the requirements that will apply when they conduct the studies;”
• “complying simultaneously with … PREA and BPCA, and the [EU] Paediatric Regulation;” and
• “the lack of economic incentives presents a challenge to sponsors’ willingness to conduct pediatric studies voluntarily, as under BPCA,” particularly for products that are nearing the end of their market exclusivity or are off-patent because of the lack of economic benefit associated with conducting pediatric studies.  This is because once a drug or biological product is off-patent, the sponsor cannot receive pediatric exclusivity for conducting such studies. 

The GAO recommended that FDA implement a system “to track applications upon their submission and throughout its review process and maintain aggregate data, including the total number of applications that are subject to PREA and whether those applications include pediatric studies.”  HHS officials stated that an update to a tracking system, which was completed in May 2011, will allow FDA to track applications subject to PREA.  Although the GAO acknowledged the benefits of an improved tracking system, the GAO also responded that it was unclear whether the data system would allow FDA to track and aggregate data about applications that are currently under review.

Separate from the GAO report, the Institute of Medicine (“IOM”) has convened an ad hoc committee to examine pediatric studies conducted under the BPCA and PREA.  Among other things, the committee is reviewing and assessing a representative sample of PREA and BPCA studies and related labeling changes, and is supposed to issue a report offering “recommendations for ensuring pediatric testing of biological products.”

ADDITIONAL READING:

• FDA Pediatric Drug Development Website
• PhRMA Statement on Tremendous Success of BPCA and PREA
• IOM Meeting Materials on Pediatric Studies Conducted under the BPCA and PREA

By Carmelina G. Allis –

The “Menaflex” is a collagen meniscus implant intended to reinforce damaged meniscal soft tissue.  ReGen Biologics, Inc. obtained 510(k) clearance for the Menaflex in 2008 as a Class II device.  On March 30, 2011, FDA rescinded this clearance.  Last week, ReGen filed suit based upon the theory that FDA lacks authority under the Food, Drug, and Cosmetic Act (“FDCA”) to rescind a 510(k) clearance.  ReGen seeks a declaratory judgment that the Menaflex may be legally marketed in the U.S. as a Class II device.  The lawsuit was brought in the U.S. District Court for the District of Columbia and follows a petition ReGen filed last month with the U.S. Court of Appeals for the District of Columbia Circuit – see our previous post here – seeking review of the March 30, 2011 order.  ReGen has presumably filed two lawsuits to eliminate any argument by the government that the suit was filed in the wrong court.  Over the years, FDA has challenged suits filed in district courts or alternatively in a court of appeals by claiming that the plaintiff sued in the wrong court.  Filing in both courts, as ReGen did, should eliminate that potential argument in one of the courts.

The review of ReGen’s Menaflex 510(k) resulted from allegations that the agency’s review of the submission had departed from “FDA processes, procedures and practices.” Those allegations apparently stemmed, in part, from documents sent to U.S. Congressmen by FDA reviewers that raised questions about the integrity of the 510(k) review process for the Menaflex device.

In October 2010, FDA rescinded the 510(k) substantial equivalence determination alleging that the device does not have the same intended use as predicate surgical meshes.  ReGen’s complaint alleges that the agency’s determination is inconsistent with the findings of two Advisory Panels, and contrary to the conclusions of Dr. Daniel Schultz, the CDRH Director who granted 510(k) clearance.  The product is now subject to the more burdensome Class III, premarket application (“PMA”) approval requirements.

According to the complaint, counsel for the company asked FDA counsel “to identify the statutory or regulatory basis” for the rescission order, to which agency counsel declined to answer “stating that disclosure of the statutory basis for the order would be the equivalent of providing ‘legal advice,’ and that it is FDA’s policy not do so.”

The complaint alleges that FDA’s actions forced the company into bankruptcy, and have “create[d] substantial uncertainty in the device industry because the FDA could decide to revisit other products that were legally classified through the 510(k) premarket notification process without observing lawful processes.”

FDA has not yet responded to the complaint.  FDA has always asserted that the FDCA grants the agency authority to rescind 510(k)s, but that interpretation is not explicitly provided in the FDCA.  In contrast, there is a provision expressly granting FDA authority to withdraw a PMA approval (section 515).  FDA also has authority to ban devices that are unsafe (section 516) or to reclassify a device from Class II to Class III if information emerges that warrants reclassification (section 513).  FDA did not invoke those explicit procedures in this case.  The agency issued a proposed rule setting forth a procedure for rescission in 2001, but it was never finalized. 

It may be true that at least one court has ruled that FDA has implicit statutory authority generally claimed by administrative agencies to undo a decision based upon outright fraud or clear administrative error.  But the ReGen case seems to involve rescission of a 510(k) because a new set of agency officials arrived at a different judgment than their predecessors.

By Jamie K. Wolszon & Jeffrey N. Gibbs –

FDA has issued a draft guidance that would limit the sale and distribution of “Research Use Only” (RUO) and “Investigational Use Only” (IUO) products.  (A copy of the Federal Register notice announcing the guidance is available here.) While most of the restrictions set out in the policy are consistent with the current practices of many companies, in several key areas the agency’s proposals would substantially curb the sale of RUO and IUO labeled products. 

Most significantly, FDA has departed from the well-established practice of determining intended use based on the manufacturer’s conduct, rather than how a customer uses a product.  FDA states in the draft guidance that a manufacturer must stop sales of its RUO or IUO product to a customer once the manufacturer knows – “or has reason to know” – that the customer is using the product for a diagnostic use, even if the manufacturer makes no diagnostic claims or statements. 

Long-standing Requirements for both RUOs and IUOs Retained
 
Several of the basic requirements to qualify as an RUO or an IUO have not changed.  To be IUO, all labeling for “a product being shipped or delivered for product testing prior to full commercial marketing (for example, for use on specimens derived from humans to compare the usefulness of the product with other products or procedures which are in current use or recognized as useful)” must bear the statement, prominently placed: “For Investigational Use Only. The performance characteristics of this product have not been established.’’

Meanwhile, to be RUO, product must be in the laboratory research phase of development, and not represented as an effective in vitro diagnostic product.  In addition, all labeling must bear the statement, prominently placed: “For Research Use Only. Not for use in diagnostic procedures.’’

The existing regulation has left the category “RUO” ill-defined.  In the draft guidance, FDA explains that “the focus of manufacturer-initiated studies is typically to evaluate design, limited-scale performance, and issues such as usability of the test.” FDA provided the following examples of RUO products:

• Tests that are in development to identify test kit methodology, necessary components, and analytes to be measured;
• Instrumentation or other electrical/mechanical components under development to determine correct settings, subcomponents, subassemblies, basic operational characteristics, and possible use methods;
• Reagents under development to determine production methods, purification
  levels, packaging needs, shelf and storage life, etc.

FDA also recognizes that products “intended for use in non-clinical laboratory research with goals unrelated to development of a commercial product, such as discovering and developing novel and fundamental medical knowledge related to human disease and conditions,” (emphasis added) could qualify as RUO. The guidance provides as examples “instruments and reagents intended for use in research attempting to isolate a gene linked with a particular disease when such instruments and reagents are not intended to produce results for clinical use.”

This is a narrower interpretation of “research” than is commonly understood.  It is not clear what is FDA’s basis in confining the category of research products to ones used to advance “novel and fundamental” objectives.  It is clear that this limitation will be both difficult to apply and controversial.

Defining Intended Use Based on Actual Use
 
FDA states that in determining whether a product is properly marketed as RUO or IUO, it will consider the manufacturer’s statements and claims about its product.  This is a well-established regulatory principle.  However, FDA also said it would consider the manufacturer’s knowledge of the customer’s intended use.

FDA may consider a manufacturer’s knowledge of the purposes for which its customers offer and use its IVD product, and the manufacturer’s provision of technical support for those activities, to be evidence that the IVD product is intended to be used for such purposes. The weight of this evidence will vary with the circumstances.

Specifically, in addition to promotion by the manufacturer, FDA says it will consider the following factors as indicating that a device is not RUO or IUO:

• “[S]tatements in any labeling, advertising, or promotion of the IVD product that suggest that clinical laboratories can validate the test through their own investigational procedures and subsequently offer it for clinical diagnostic use as a laboratory developed test;” 
• “Sales to clinical laboratories that the manufacturer knows, or has reason to know, use the IVD product in clinical diagnostic use in an investigation or otherwise, and support (including technical support) for those activities.” 
• assistance “in the validation or verification of the performance of a test that the manufacturer know is used in clinical diagnosis.”

FDA also advises manufacturers of products labeled as RUO or IUO that if they discover that a clinical laboratory to which it sells its IUO or RUO device is using these IUO or RUO labeled products for a non-investigational diagnostic use, “it should halt sales for such use or comply with FDA regulations for IVD products, including premarket review requirements.”  (Emphasis added).  This position that a company should discontinue sales to a customer because that customer is using the product in a manner outside the labeling may be unprecedented.  Significantly, the draft guidance includes no provision for manufacturers first to inform the customer that it must stop diagnostic use or take other measures to alter the manner of usage.  Rather, FDA is apparently saying that the manufacturer has no option but to cease sales immediately.

Import of RUOs

Although IVD products intended solely for research use are generally exempt from most regulatory requirements, foreign manufacturers who import RUO IVD products into the U.S. are not specifically exempt from establishment registration and device listing requirements. FDA states in the guidance that it intends to exercise enforcement discretion “with respect to establishment registration and device listing requirements for persons who manufacture, propagate, compound, or process imported IVD products intended solely for research use.”  The agency has established specific codes to use for import of RUO products.  This information will provide FDA with more specific insights into which RUO products are being imported.

Many aspects of the draft guidance are not surprising, and are consistent with the practices adopted by many companies.  However, FDA’s stance that RUO and IUO manufacturers must “halt” sales to a customer because its use of an RUO or IUO product for diagnosis is a major departure.  Moreover, FDA’s reliance on customer conduct to define intended use has implications for other products beyond those labeled RUO and IUO, by determining intended use through customer behavior, not manufacturer’s conduct.  In addition, the narrowed definition of RUO will be both difficult to apply and likely have unintended negative consequences.

Comments to this proposed draft guidance are due by August 30, 2011.

By Kurt R. Karst –      

Last week, in a seven-page response, FDA denied an October 18, 2010 Citizen Petition submitted on behalf of Lupin Limited (“Lupin”) requesting that FDA determine that Teva Pharmaceuticals USA, Inc.’s (“Teva’s”) ANDA No. 79-081 for a generic version of COMBIVIR (lamivudine and zidovudine) Capsules, and that contains the first Paragraph IV certification to an Orange Book-listed patent on the Reference Listed Drug (“RLD”), is not eligible for 180-day exclusivity.  In its response, FDA affirms that the plain language of the definition of a “first applicant” at FDC Act § 505(j)(5)(B)(iv)(II)(bb) as added by the 2003 Medicare Modernization Act (“MMA”) simply requires a Paragraph IV certification, regardless of what Orange Book-listed patent that certification concerns. 

COMBIVIR is listed in the Orange Book with two unexpired patents – U.S. Patent No. 5,859,021 (“the ‘021 Patent”), which expires on May 15, 2012, and U.S. Patent No. 5,905,082 (“the ‘082 Patent”), which expires on May 18, 2016 and is subject to a period of pediatric exclusivity that expires on November 18, 2016.  Teva submitted ANDA No. 79-081 to FDA on June 26, 2007 containing a Paragraph IV certification to the earlier-expiring ‘021 Patent, and a Paragraph III certification to the later-expiring ‘082 Patent.  In October 2008, Teva reportedly amended its ANDA to contain a Paragraph IV certification to the ‘082 Patent.  In the meantime, Lupin submitted an ANDA in January 2008 containing Paragraph IV certifications to both the ‘021 and ‘082 patents. 

Under the FDC Act as amended by the MMA, a “first applicant” qualifies for 180-day exclusivity.  The term “first applicant” is defined as “an applicant that, on the first day on which a substantially complete application containing a [Paragraph IV certification] is submitted for approval of a drug, submits a substantially complete application that contains and lawfully maintains a [Paragraph IV certification] for the drug.”  Lupin argues in its Citizen Petition that Teva is “not a lawful ‘first applicant’” based on its Paragraph IV certification to the earlier-expiring ‘021 Patent.   Instead, Lupin says that it is the correct “first applicant” based on its Paragraph IV certification to the later-expiring ‘082 Patent.  FDA’s petition response boils Lupin’s Citizen Petition arguments down to the following: “According to Petitioner, Teva fails to qualify as a first applicant because its ANDA (1) cannot be considered to have contained a valid paragraph IV certification, (2) cannot be considered to have been substantially complete, and (3) cannot be considered to have lawfully maintained a paragraph IV certification.”

Hewing close to the statutory language, FDA reasons in its petition response that:

Regardless of Teva’s reason for initially challenging only the ‘021 patent, its paragraph IV certification to that patent qualified it for exclusivity.  The statute provides that an applicant submitting a paragraph IV certification will be a “first applicant” (i.e., eligible for exclusivity) if on the first day any applicant submits a substantially complete application containing a paragraph IV certification, the applicant “submits a substantially complete application that contains and lawfully maintains a [paragraph IV certification]” (section 505(j)(5)(B)(iv)(II)(bb) of the Act (emphasis added)).  The plain language of the MMA requires “a” certification; it does not require a first applicant to be the first to challenge with a paragraph IV certification more than a single patent or even the latest expiring patent.  If Teva was the first to file a paragraph IV patent certification for a listed patent for Combivir (and otherwise meets the statutory requirements), that is adequate in these circumstances; we need not second guess the particular strategy Teva has employed in its patent challenge.

Given this reasoning, FDA concludes that Teva, not Lupin, is a “first applicant” eligible for 180-day exclusivity based on Teva’s Paragraph IV certification to the ‘021 Patent contained in ANDA No. 79-081 (which the Agency approved on May 25, 2011).  A similarly strict reading of the statute also appears to be reflected in another recent FDA decision in which the Agency interpreted the 30-month date under FDC Act § 505(j)(5)(D)(i)(IV) for purposes of 180-day exclusivity forfeiture.

By Ricardo Carvajal –

FDA issued a letter of enforcement discretion for the use of certain qualified health claims on the labeling of an infant formula marketed by Nestle Nutrition (Gerber).  The claims provided in FDA's letter are:

• Very little scientific evidence suggests that, for healthy infants who are not exclusively breastfed and who have a family history of allergy, feeding a 100% Whey-Protein Partially Hydrolyzed infant formula from birth up to 4 months of age instead of a formula containing intact cow's milk proteins may reduce the risk of developing atopic dermatitis throughout the 1st year of life and up to 3 years of age.
• Little scientific evidence suggests that, for healthy infants who are not exclusively breastfed and who have a family history of allergy, feeding a 100% Whey-Protein Partially Hydrolyzed infant formula from birth up to 4 months of age instead of a formula containing intact cow's milk proteins may reduce the risk of developing atopic dermatitis throughout the 1st year of life.
• For healthy infants who are not exclusively breastfed and who have a family history of allergy, feeding a 100% Whey-Protein Partially Hydrolyzed infant formula from birth up to 4 months of age instead of a formula containing intact cow's milk proteins may reduce the risk of developing atopic dermatitis throughout the 1st year of life and up to 3 years of age. FDA has concluded that the relationship between 100% Whey-Protein Partially Hydrolyzed infant formulas and the reduced risk of atopic dermatitis is uncertain, because there is very little scientific evidence for the relationship.
• For healthy infants who are not exclusively breastfed and who have a family history of allergy, feeding a 100% Whey-Protein Partially Hydrolyzed infant formula from birth up to 4 months of age instead of a formula containing intact cow's milk proteins may reduce the risk of developing atopic dermatitis throughout the 1st year of life. FDA has concluded that the relationship between 100% Whey-Protein Partially Hydrolyzed infant formulas and the reduced risk of atopic dermatitis is uncertain, because there is little scientific evidence for the relationship.

In addition, FDA expects any of the above claims to be followed by the paragraph below:

Partially hydrolyzed formulas should not be fed to infants who are allergic to milk or to infants with existing milk allergy symptoms. If you suspect your baby is already allergic to milk, or if your baby is on a special formula for the treatment of allergy, your baby's care and feeding choices should be under a doctor's supervision. [(Emphasis in original.)]

The claims appear to be “D” level claims – the weakest claims for which FDA has been willing to grant the exercise of enforcement discretion.  Conventional wisdom holds that such claims are of limited value to industry.  Nonetheless, Gerber promptly touted the third of the four claims listed above in a full page ad in the New York Times – perhaps evidence that a “D” level claim is better than no claim at all. 

By Jamie K. Wolszon –

Trade reports recently indicated that FDA intended to issue by the end of May a draft guidance outlining its policy for “Research Use Only” (“RUO”) and “Investigational Use Only” (“IUO”) products such as reagents and instruments.  Last week FDA posted on its website a draft guidance setting forth its vision on the appropriate sale and distribution of those products.  (A copy of that draft guidance is available here.)  FDA later removed the document from the website, but not before multiple companies had obtained and circulated the document widely.  It is unclear what will be in the draft RUO/IUO guidance if and when FDA issues the document.  The agency may make revisions to the document that was posted last week.   

However, if adopted in the form it was posted, the document is likely to generate some controversy regarding a number of aspects.  Two of the elements that are particularly likely to draw attention are: (1) FDA states that if a manufacturer is aware that a customer is using the RUO or IUO product for diagnostic purposes, that the manufacturer should “halt” selling the product to the customer; (2) FDA states that products “intended for use in non-clinical laboratory research with goals unrelated to development of a commercial product, such as discovering and developing novel and fundamental medical knowledge related to human disease and conditions,” could qualify as RUO, along with RUO products intended to further refine or develop the assay.  This caveat that RUO eligibility depends on being intended to develop “novel and fundamental medical knowledge” is a tightening of FDA’s definition of RUO.

By Kurt R. Karst –      

Last Friday, Nostrum Pharmaceuticals, LLC (“Nostrum”) lodged a Complaint against FDA in the U.S. District Court for the District of New Jersey seeking declaratory and injunctive relief arising from the Agency’s decisions on pre-Medicare Modernization Act (“MMA”) 180-day exclusivity with respect to Nostrum’s ANDA No. 76-697 for a generic version of CARBATROL (carbamazepine) Extended-release Capsules, 300 mg, which FDA approved on May 20, 2011.  On that same day, FDA approved two other strengths under Nostrum’s ANDA – 100 mg and 200 mg – after the Agency determined that another applicant, CorePharma, forfeited post-MMA 180-day exclusivity eligibility.  Those strengths are not at issue in the lawsuit.  At issue is FDA’s application of the so-called “holding-on-the merits” standard with respect to one Orange Book-listed patent on which Nostrum qualified for 180-day exclusivity (U.S. Patent No. 5,912,013 (“the '013 Patent”)), and FDA's interpretation that 180-day exclusivity terminates with the July 5, 2011 expiration of another patent on which Nostrum qualified for 180-day exclusivity (U.S. Patent No. 5,326,570 (“the ‘570 patent”)).  Lerner, David, Littenberg, Krumholz & Mentlik, LLP and Hyman, Phelps & McNamara, P.C. represent Nostrum in the lawsuit.

CARBATROL is listed in the Orange Book with two patents – the '013 Patent, which expires on June 15, 2016, and the ‘570 Patent, which expires on July 5, 2011.  Nostrum was the first company to submit an ANDA containing a Paragraph IV certification to each patent, thereby qualifying the company for 180-day exclusivity based on each patent.   Under the pre-MMA statute, 180-day exclusivity is patent-by-patent and is triggered by the earlier of: (1) the first commercial marketing of the drug by a first filer; or (2) “the date of a decision of a court in [a patent infringement action] holding the patent which is the subject of the certification to be invalid or not infringed.” 

With respect to the court decision trigger to pre-MMA 180-day exclusivity, FDA stated in an April 11, 2006 letter to ANDA applicants that the Agency:

interprets the language of the court decision trigger provision . . . to require a court decision with an actual “holding” on the merits that the patent is invalid, not infringed, or unenforceable.  The holding must be evidenced by language on the face of the court’s decision showing that the determination of invalidity, noninfringement, or unenforceability has been made by the court. 

FDA’s May 20, 2011 Letter Decision concerning 180-day exclusivity for Carbamazepine Extended-release Capsules says that Nostrum’s exclusivity with respect to the ‘013 patent was triggered by a June 14, 2009 ruling in Shire Labs, Inc. v. CorePharma, LLC, C.A. 06-2266 (D.N.J.), in which the court entered a final judgment of its previous order granting CorePharma's motion for summary judgment of non-infringement of the '013 patent.  According to FDA, this “holding is adequate as a basis to trigger the running of exclusivity as to the '013 patent,” and thus “Nostrum's exclusivity with respect to the '013 patent has expired.”

Nostrum says in its May 27, 2011 Complaint that the June 2009 order “did not qualify as the type of order that can trigger the start of Plaintiff's 180 day marketing exclusivity period with respect to the '013 Patent,” and that “FDA's determination denying Plaintiff its entitlement to 180 day exclusivity based on the '013 Patent is an arbitrary, capricious and unlawful decision that this Court should set aside.”  Instead, says Nostrum, the court should rule that Nostrum “is entitled to 180 day marketing exclusivity based on Plaintiff's paragraph IV certification to the '013 Patent because the referenced 2009 court decision did not, and could not, trigger the running of Plaintiff's exclusivity period for the '013 Patent.”

With respect to exclusivity stemming from the ‘570 patent, FDA ruled that Nostrum is eligible for 180-day exclusivity, which was triggered on May 20, 2011 when Nostrum began commercial marketing.  The ‘570 patent, however, expires on July 5, 2011.  Nostrum says in its Complaint that:

Based on FDA's past decisions and on its publicly announced policy, FDA, upon expiration of the '570 Patent on July 5, 2011, will likely unlawfully approve pending ANDAs for Carbamazepine Extended release Capsules 300 mg in violation of 21 U.S.C. § 355(j).  FDA's approval of other ANDAs for extended release 300 mg Carbamazepine will deny Plaintiff, by more than four months, its right to exclusively market its 300 mg Carbamazepine drug product for the entire 180 day exclusivity period to which Plaintiff is entitled, causing Plaintiff to suffer irreparable harm.

Nostrum seeks declaratory judgments with respect to 180-day exclusivity for both the ‘013 and ‘570 patents, as well as a preliminary and permanent injunction prohibiting FDA from approving another ANDAs for Carbamazepine Extended release Capsules, 300 mg, “until the expiration of Plaintiff's full 180 days of marketing exclusivity based on either the '013 Patent or the '570 Patent.”