By John A. Gilbert & Karla L. Palmer –

On Wednesday, April 13, 2011, the Drug Enforcement Administration (“DEA”) published an Interim Final Rule with a request for comments on the “Self-Certification and Employee Training of Mail-Order Distributors of Scheduled Listed Chemical Products.”  See 76 Fed. Reg. 20,518 (Apr. 13, 2011).  The Interim Rule implements the Combat Methamphetamine Enhancement Act of 2010 (“CMEA”), which President Obama signed into law on October 12, 2010, and we blogged about here.

Although retail distributors of these products have been subject to self certification and training requirements since 2006, the 2010 law establishes new requirements for mail-order distributors of scheduled listed chemical products (“SLCPs”), which are defined in the Controlled Substances Act (“CSA”) as products containing ephedrine, pseudoephedrine or phenylpropanolamine, and are marketed in the United States as non-prescription drugs, see 21 U.S.C. § 802(45). 

The new federal law requires mail-order distributors to self-certify to DEA in order sell SLCPs at retail if those retail sales are intended for personal use.  The DEA defines a “mail-order distributor” as a person who makes sales at retail of SLCPs for personal use, and uses the U.S. postal service or a private or commercial carrier to deliver the product to the customer.  The mail-order distributor’s required self-certification must include a statement that the distributor understands the regulatory requirements, and that its employees will receive the appropriate training prior to self-certification. 

After April 10, 2011, which is the date of the implementation of the CMEA, a mail-order distributor cannot sell SLCPs at retail unless it has self-certified through DEA’s website (and paid a $21.00 fee).  The self-certification requires the distributor to confirm the following: (1) The distributor understands that under federal law it can sell no more than 3.6 grams of SLCPs per day, or 7.5 grams in a thirty-day period, to each customer (versus a 9 gram monthly limit for face-to face sales); (2) the distributor’s employees have undergone DEA-required training prior to self-certification; and (3) the distributor is maintaining employee training records.  The distributor must submit a self-certification for each place of business where it sells the products at retail, which, for a mail-order distributor means, “at each location that prepares or packages products for distribution to customers, and each location where employees accept payment for such sales.”  Id. at 20,520.  The interim rule sets forth (in table form) a summary of requirements for mail-order sellers of SCLPs now in effect since the enactment of the CMEA.  Id. at 20,521  

The required content of the employee training has been developed by DEA and is available at its website, (http://www.deadiversion.usdoj.gov).  DEA states that employers “must use the content of this training in the training of their employees” who sell SLCPs.  An employer may supplement the required DEA training with its own content as well.  Id. at 20,520.  Starting on or after April 10, 2011, each employee of a mail order distributor who is responsible for delivering SLCPs directly to purchasers, or “who deals directly with purchasers by obtaining payment for the [SLCPs]” must undergo the training, and must sign an acknowledgement that he or she has received training prior to selling SLCPs. The record must also be kept in the employee’s personnel file. 

The interim rule implementing the law further provides that when a mail-order distributor files its initial self-certification, the DEA will assign it to one of twelve groups.  The expiration date of the self-certification for all regulated persons within any one group will be “the last day of the month designated for that group.”  The first certification period will run for a period of not less than 12 to not more than 23 months from the date of self-certification.  After this initial certification period expires, distributors must update their regulated persons must update their self-certification on an annual basis.  Id. at 20,521.

The interim rule’s preamble notes that “a mail-order distributor that knowingly or willfully self-certifies to facts that are not true is subject to fines and imprisonment by virtue of 18 U.S.C. § 1001.”  Id. 20,520. In addition, it is unlawful for mail-order distributors to “negligently fail to self-certify” under 21 U.S.C. § 830 (by an amendment to 21 U.S.C. § 842(a)(10)).

The interim rule is effective April 13, 2011.  Note, however, that the law requiring self-certification became effective on April 10, 2011 (180 days after its enactment on October 10, 2010).  DEA is soliciting comments on the interim rule, due on June 13, 2011.  The DEA found “good cause” to exempt this rule from notice and comment rulemaking that is normally required under the Administrative Procedure Act, because DEA asserts that the “requirements addressed by the [CMEA] in this rulemaking are self-implementing and changes in this rulemaking provide conforming amendments to make the language of the regulations consistent with that of the law.”  Id. at 20,519.

By Jennifer D. Newberger –

After more than fifteen years of related cases in the larger matter of The First Amendment v. Dietary Supplement Health Claims, FDA mostly won one.  And its winning card?  Knowing that the courts will not, and cannot, independently assess whether the scientific evidence provided to FDA to support a health claim for a dietary supplement constitutes “credible evidence.”  So, FDA drafted Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims (Jan. 2009), in which the Agency laid out the types of studies it believed may provide credible evidence of a health claim – including the way those studies should have been conducted and the data that should have been collected –and those that will not provide credible evidence.  Then, all a court has to do is ask if FDA followed the guidance document, without considering whether the standards the Agency put forth in the guidance document are a reasonable means of assessing credible evidence.

This appears to be the theory upon which the decision was reached in the case of Alliance for Natural Health US v. Sebelius (“Alliance II”).  In this case, plaintiffs challenged FDA’s decision declining to approve several health claims concerning the relationship between vitamins C and E and the risk for certain types of cancer.  Plaintiffs had submitted seventeen qualified health claims linking vitamins C and E with a reduction in the risk of certain types of cancer.  FDA denied thirteen of the claims entirely and permitted four others to be made as qualified claims with modified language.  In Alliance II, plaintiffs challenged FDA’s ruling on six of these claims – four that were denied outright, and two that FDA agreed to permit as qualified claims with modified language.

As a preliminary matter, the court stated that FDA need not conduct an empirical study on the efficacy of a disclaimer before an outright banning of a claim if there is either no evidence to support the claim, or the evidence in support of the claim is qualitatively weaker than evidence against the claim.  Such claims would qualify as unprotected commercial speech and are therefore not protected under the Central Hudson analysis.  However, empirical evidence of the inefficacy of disclaimers is required for FDA to ban a health claim that is based on some credible evidence.

Enter the guidance document.  At its core, the opinion indicated that if FDA properly applied the process outlined in the guidance document, and, based on that process, determined that no credible evidence existed to support the claim, or the evidence in support of the claim was qualitatively weaker than that against it, FDA’s decision would stand.  The court found this to be the case for each of the four claims that FDA banned outright, and therefore upheld FDA’s denial of these health claims.  (These claims were:  (1) Vitamin C may reduce the risk of lung cancer. The scientific evidence supporting this claim is convincing, but not conclusive. (2) Vitamin C may reduce the risk of colon cancer. The scientific evidence supporting this claim is persuasive, but not conclusive. (3) Vitamin E may reduce the risk of lung cancer. The scientific evidence for this claim is convincing, but not conclusive. (4) Vitamin E may reduce the risk of gastric cancer. The scientific evidence for this claim is persuasive, but not conclusive.)

The reason that FDA only “sort of” won this one is because the court remanded to FDA the two claims that FDA was willing to allow with additional modifications.  The court stated that the modifications “replaced plaintiffs’ claim[s] entirely” and were not sufficiently precise, concluding:  “Where the evidence supporting a claim is inconclusive, the First Amendment permits the claim to be made; the FDA cannot require a disclaimer that simply swallows the claim.” In other words, if FDA allowed a qualified health claim, the qualification cannot be so limiting as to essentially erase the relationship between a substance and the specified disease or health-related condition.

So where does this leave us?  By drafting the guidance document, FDA regained some of the control that it lost over the years regarding health claims and allowable disclaimers.  It has laid out the studies that it considers to constitute credible evidence, and no court is likely to question those determinations.  If a dietary supplement manufacturer intends to support a health claim with a study on FDA’s black list, it does so at its own risk.  But, if FDA approves a qualified health claim, it cannot modify the substance/condition relationship out of existence.  Only one thing is certain — this is not the last we will hear of The First Amendment v. Dietary Supplement Health Claims.

By Peter M. Jaensch - 

In the latest installment in the criminal prosecution of Lauren Stevens, an attorney formerly employed by GlaxoSmithKline ("GSK"), the U.S. Department of Justice announced on April 14, 2011, that a grand jury in the U.S. District Court for the District of Maryland has reindicted Ms. Stevens on six counts alleging that she obstructed an official proceeding, concealed and falsified documents to influence a federal agency, and made false statements to the FDA.

As we previously reported, Ms. Stevens was originally indicted on November 8, 2010 on what the Justice Department states were essentially the same charges. The earlier charges arose in connection with an FDA investigation of alleged off-label promotion of drugs by GSK.  The government alleged that, among other things, Ms. Stevens falsely denied that GSK engaged in any activity promoting off-label use, that she falsely denied that attendees at company promotional speaker events had been provided gifts and entertainment, and that evidence of these gifts as well as other documentary evidence were not included in the documents provided by the company to FDA.

However, that indictment was dismissed without prejudice by District Judge Roger W. Titus on March 23, 2011, citing concerns that the prosecutors had incorrectly explained the advice of counsel defense to grand jurors such that the instruction raised “grave doubts about the grand jury’s decision to indict.”  The absence of actual misconduct by the prosecutors was cited by the Judge in his determination that dismissal with prejudice was unwarranted.

The Government was not to be dissuaded from continuing to pursue this case.  Judge Titus has tentatively scheduled a new trial date for April 26, 2011.

By Kurt R. Karst –      

Since the U.S. Court of Appeals for the Federal Circuit issued its December 2009 decision in Forest Group, Inc. v. Bon Tool Co. concerning the maximum $500 per violation penalty for intentionally falsely marking a product (in that case, spring-loaded parallelogram stilts) with a patent in violation of 35 U.S.C. § 292, setting off a barrage of hundreds of false patent marking qui tam lawsuits (including challenges to the Constitutionality of the statute), we have followed with some passing interest the various legal (and legislative) twists and turns of the issue, because scores of lawsuits involve FDA-regulated products – see our previous posts here and here.  Although the Gray On Claims Blog recently reported that the number of false marking qui tam lawsuits appears to have slowed since the Federal Circuit’s March 15, 2011 decision in In re BP Lubricants USA Inc., in which the Court held that the particularity requirement of Fed. R. Civ. P. 9(b) applies to false marking cases, that did not stop Pharmaceutical Technologies, LLC (“PharmaTech”) from lodging a Complaint last week in the U.S. District Court for the District of Arizona (Phoenix Division) against Eisai, Inc. and Eisai Medical Research, Inc. (collectively “Eisai”) for allegedly falsely marking ARICEPT (donepezil HCl) Tablets.

What makes the Eisai/ARICEPT case of particular interest to us is PharmaTech’s use of FDA’s Orange Book and the allegation of false Orange Book “advertising.”  Although the Orange Book has be raised in some false marking cases (see, e.g., Hollander v. Ortho-McNeil-Janssen Pharmaceuticals, Inc., No. 2-10-cv-00836 (E.D. Pa.), it has not, to our knowledge, previously been used as the primary basis for filing a false marking complaint. 

ARICEPT Tablets is listed in the Orange Book with four unexpired patents – U.S. Patent Nos. 5,985,864 (“the ‘864 patent”), 6,140,321 (“the ‘321 patent”), 6,245,911 (“the ‘911 patent”), and 6,372,760 (“the ‘760 patent”) – and one expired patent – U.S. Patent No. 4,895,841.  The ‘760 patent is listed with a “delist requested” flag, indicating that the NDA sponsor requested that FDA remove the patent from the Orange Book, but that the Agency would not do so because of a Paragraph IV certification to that patent.  On November 26, 2010, FDA approved Ranbaxy’s ANDA No. 76-786 with a period of 180-day exclusivity that expires on May 28, 2011 based on Ranbaxy's Paragraph IV certifications to the ‘864, ‘321, ‘911, and ‘841 patents.  Waiting in the wings for the expiration of Ranbaxy’s 180-day exclusivity is Teva’s tentatively approved ANDA No. 77-344.

PharmaTech alleges in its false marking Complaint that Eisai has violated 35 U.S.C. § 292 by falsely advertising ARICEPT in the Orange Book as patented by the ‘864, ‘321, ‘911, and ‘760 patents with the purpose of deceiving the public, and that such alleged false marking has been a part of the reason for the delay in FDA’s approval of ANDA No. 77-344.  Specifically, PharmaTech states that Eisai statutorily disclaimed the ‘864 and ‘321 patents, but that they continue to be “advertised” in the Orange Book, and that “not one claim in either of the ‘911 patent or the ‘760 patent reads on Aricept® tablets.”  Thus, according to PharmaTech:

By maintaining its false Orange Book advertisings/listings for each of the ‘864 patent, the ‘321 patent, the ‘911 patent, and the ‘760 patent for Aricept® tablets – despite actual knowledge that none of those patents cover Aricept® tablets – Defendant(s) have, in the past and present, engaged in conduct that violates the false marking statute.  By way of that unlawful conduct, Defendants are also quelling competition in the United States market for Aricept® tablets, at least by manipulating the Hatch-Waxman Act in a manner that effectively and substantially delays the generic drug manufacturer, Teva Pharmaceuticals USA, Inc., from bringing its generic version of Aricept® tablets, which has been tentatively approved by the FDA, to market in the United States.

If PharmaTech is successful in its false marking lawsuit, it’s possible that other potential plaintiffs will be scouring the Orange Book for allegedly false Orange Book patent “advertisements” on which to hang a complaint.  Watch out!

Thanks to Sean Mahoney for bringing the PharmaTech Complaint to our attention.

By Kurt R. Karst –      

FDA has responded to requests included in two reports accompanying the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 (Public Law No. 111-80) – House Report No. 111-279 and Senate Report 111-39 – requesting information from FDA on generic Anti-Epileptic Drugs (“AEDs”), and in particular, whether there are increased risks to patients who are switched from a brand-name AED to an approved, bioequivalent generic version.  FDA concludes in the Agency’s 9-page report recently submitted to Congress that small analyses conducted by FDA do not show that generic AEDs are less effective than their brand-name counterparts, but that further study is necessary.

We initially reported on the Congressional requests in November 2009, and have been closely following the issue.  In November 2010, we reported that FDA responded to a request from New Jersey State Senator Joseph F. Vitale (D) concerning legislation that would require pharmacists in New Jersey to dispense epilepsy drugs from the same manufacturer as previously dispensed for certain patients, unless otherwise prescribed, and noted that FDA’s response seemed to give some foreshadowing as to what conclusions the Agency would include in its report to Congress.  That appears to be the case.

The report to Congress notes that:

Several small analyses conducted by FDA using data available in its Adverse Event Reporting System (AERS) do not provide evidence that generic anti-epileptic drug products are less effective than brand name products.  However, it is difficult to draw reliable conclusions about therapeutic equivalence from the AERS data because the adverse event reports are not necessarily representative of a random sampling of the patient population, nor can they be corrected for the relative market share of the various brand and generic products to determine if there is actually a difference in the incidence of adverse events for generic products.

In particular, FDA analyzed post-marketing surveillance reports of two AEDs for which safety and efficacy concerns were reportedly raised by stakeholders – Levetiracetam and Lamotrigine – for evidence of therapeutic inequivalence.  Based on FDA’s analyses, the Agency notes that the so-called “Weber effect” – a phenomenon that states that the number of reported adverse reactions for a drug increases until about the middle to the end of the second year of marketing – is likely “a factor contributing to increased patient complaints following switches from brand name to newly-approved generic anti-epileptic drugs.”  In addition, FDA says that “it is possible that the wide publicity given to negative literature about generic anti-epileptic drugs, much of which is disseminated by various epilepsy societies, may influence patients that recently switched to generics.”  Thus, according to FDA, “background breakthrough seizure and adverse event rates may be comparable whether the same patient is being treated with a generic drug or the brand drug, but because of the generic switch, the patient may be more likely to complain of adverse events and breakthrough seizures.” 

To better evaluate differences between brand and generic AEDs, FDA says in the report that some studies are in the works, including a study by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke intended to determine whether  some epilepsy patients respond differently to AEDs from different manufacturers, and a similar study designed by the Office of generic Drugs that will be performed under FDA’s Critical Path Program and that is intended “to evaluate bioequivalence of an ‘older’ generic AED, such as carbamazepine, and a ‘newer’ generic AED, such as zonisamide, versus their respective reference products.” 

With respect to AED bioequivalence testing, FDA states that the Agency “is currently exploring the pros and cons of narrowing the acceptance criteria for the 90 percent confidence interval for AUC for certain drugs.”  In April 2010, FDA’s Pharmaceutical Science and Clinical Pharmacology Advisory Committee held a meeting and discussed, among other things, tightening bioequivalence standards (e.g., from the current 80%-125% standard to 90%-111%) for drugs whose dosing must be carefully adjusted to avoid adverse events, including Narrow Therapeutic Index (“NTI”) drugs.  Although the advisory committee was supportive of tightening the bioequivalence standards for NTI drugs, FDA’s report to Congress notes that “not all anti-epileptic drugs are considered NTI drugs based on their efficacy and toxicity profiles.  Therefore, other selection criteria would need to be established as a basis for changing the current bioequivalence standards for the AEDs.”

By Dara Katcher Levy –

FDA’s Division of Drug Marketing, Advertising, and Communications (“DDMAC”) has announced that it will be holding a series of Enforcement Webinars that will provide an opportunity for attendees to ask DDMAC questions about the Warning and Untitled Letters it issues each quarter.  This pilot program “will support DDMAC’s mission to protect the public health by assuring prescription drug information is truthful, balanced and accurately communicated.” 

The first of its programs will be held on May 3, 2011, from 2:00 to 2:30 p.m. (ET) and will cover Warning and Untitled Letters issued by DDMAC from January 2011 to April 2011.  Given that the Webinar will only be a half hour, it is unclear whether DDMAC will be able to respond to all questions from attendees.  We note that DDMAC has issued 4 Letters between January and April 2011, down from 18 Letters issued between January and April 2010. We will see whether DDMAC will plan for longer webinars in the future, where the number of Letters issued in a given quarter may be greater than 4. 
The web address for the webinar is: https://collaboration.fda.gov/ddmac1/

Hat tip, Patrick O'Brien

By Kurt R. Karst –      

On occasion we dream about Hatch-Waxman and wake up in the morning with a burning question.  One of the recent questions we wondered about is whether FDA would take the position that an ANDA sponsor who amends a long-pending ANDA to include a Paragraph IV certification to a newly (and timely) listed patent in the Orange Book and qualifies as a “first applicant” would simultaneously forfeit 180-day exclusivity eligibility for failure to obtain timely tentative approval.  FDA’s answer to that question appears to be “yes” absent application of one of the statutory savings provisions. 

Under FDC Act § 505(j)(5)(D)(i)(IV), one of the six 180-day exclusivity provisions added to the FDC Act by Title XI of the Medicare Modernization Act (“MMA”), 180-day exclusivity eligibility is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

The 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .” (FDC Act § 505(q)(1)(G)). 

Under FDC Act § 505(j)(5)(D)(i)(IV), the date the 30-month period begins is the date of ANDA submission.  The statute does not specifically reference the date of the submission of a Paragraph IV certification.  Thus, the statute leaves open the possibility that an ANDA is initially submitted to FDA without a Paragraph IV certification, thereby beginning the 30-month period, and is only later amended to include the first Paragraph IV certification to an Orange Book-listed patent covering the Reference Listed Drug (“RLD”).  (Perhaps in the context of a later-listed patent, or where all ANDA sponsors initially – and post-MMA –  submitted Paragraph III certifications to all Orange Book-listed patents and one ANDA sponsor then changed a certification to a Paragraph IV.)  If, however, that first applicant-qualifying Paragraph IV certification is made more than 30 months after ANDA submission, then it seems that FDA could take the position that FDC Act § 505(j)(5)(D)(i)(IV) comes into play and 180-day exclusivity eligibility is automatically forfeited absent “a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed” or a decision by FDA that “approval of the [ANDA] was delayed because of a [citizen] petition.” 

Indeed, FDA appears to have been faced with a similar circumstance in the context of ANDA approvals for generic versions of DORYX (doxycycline hyclate) Delayed-Release Tablets.  Two ANDAs – ANDA No. 90-431 and ANDA No. 90-505 – were reportedly submitted to FDA in March 2008 at a time when patents could not be submitted to FDA for Orange Book listing for so-called “old” antibiotics.  Section 4 of the “QI Program Supplemental Funding Act of 2008” (the “QI Act”), which was enacted on October 8, 2008 and amended the FDC Act to add new § 505(v) – “Antibiotic Drugs Submitted Before November 21, 1997” – created Hatch-Waxman benefits for “old” antibiotics, including the ability to list patents in the Orange Book.  A QI Act transition provision also provides for 180-day exclusivity eligibility for each ANDA sponsor that not later than 120 dates after enactment of the QI Act (i.e., February 5, 2009) amended a pending application to contain a Paragraph IV certification to a newly-listed antibiotic drug patent on the RLD.  ANDA Nos. 90-431 and 90-505 were both amended to contain a Paragraph IV certification, qualifying the applications for 180-day exclusivity. 

According to one Doxycycline Hyclate Delayed-Release Tablets ANDA approval letter, FDA calculated the 30-month period under FDC Act § 505(j)(5)(D)(i)(IV) from the date of original ANDA submission (March 18, 2008) and not from the date of the amendment adding the exclusivity-qualifying Paragraph IV certification (most likely December 9, 2008), thereby resulting in a 30-month period ending in September 2010 instead of June 2011.  FDA approved both ANDA Nos. 90-431 and 90-505 on December 28, 2010 without having previously granted tentative approval.  Although FDA determined that the 30-month period under FDC Act § 505(j)(5)(D)(i)(IV) was missed, the Agency says that there was a change in or a review of the requirements for approval of the applications and a related citizen petition (Docket No. FDA-2008-P-0586) that saved them from forfeiting 180-day exclusivity eligibility. 

The Doxycycline Hyclate Delayed-Release Tablets ANDA approvals thus appear to stand for FDA’s interpretation that 180-day exclusivity eligibility can be forfeited where the first exclusivity-qualifying Paragraph IV certification is submitted to FDA more than 30 months after a first applicant’s ANDA is submitted to FDA.  A cursory review of FDA’s Paragraph IV Certification List shows that there may be a few cases in which FDA’s interpretation of FDC Act § 505(j)(5)(D)(i)(IV) could come into play and result in a forfeiture (absent application of one of the statutory savings provisions). 

Of course, there may be instances in which, despite a forfeiture of 180-day exclusivity eligibility under FDA’s interpretation of the start of the 30-month period, there is still some benefit to being a “forfeited first applicant,” as FDA discussed in the Agency’s September 2009 Letter Decision concerning 180-day exclusivity for Nateglinide Tablets – see our previous post here.  Any benefit, however, would only materialize if there are multiple first applicants and where at least one first applicant has not forfeited 180-day exclusivity eligibility.  In the case of a single first applicant, FDA’s interpretation of FDC Act § 505(j)(5)(D)(i)(IV) would result in a total forfeiture unless one of the statutory savings provisions applies.

Presumably FDA will explain its various interpretations of FDC Act § 505(j)(5)(D)(i)(IV) and the other forfeiture provisions in regulations the Agency is drafting to implement the 2003 MMA, although it might be a while until these regulations see the light of day.  We understand that FDA plans to issue two sets of proposed regulations.  The first set will reportedly deal with all of the MMA’s non-180-day exclusivity provisions and might be out by the end of 2011.  (We’ve heard that those proposed regulations currently total about 350 double-spaced pages.)  The second set of regulations will reportedly deal with 180-day exclusivity and is still under development. 

By Cassandra A. Soltis –

In an opinion dated April 6, 2011, Judge Beryl Howell of the U.S. District Court for the District of Columbia granted summary judgment for the FDA in a case challenging the dietary supplement good manufacturing practice (“GMP”) regulations.  Alliance for Natural Health U.S. v. Sebelius, No. 09-1523, 2011 U.S. Dist. LEXIS 37027 (D.D.C. Apr. 6, 2011).  The plaintiffs included Duke Pearson and Sandy Shaw, scientists who formulate dietary supplements and license their formulations to dietary supplement manufacturers and retailers, as well as two organizations affiliated with the dietary supplement industry – the Alliance for Natural Health USA, and the Coalition to End FDA and FTC Censorship.  The plaintiffs sought to have various provisions of the dietary supplement GMPs declared invalid and to have their enforcement enjoined. 

After concluding that the two scientist plaintiffs had standing, the court addressed the plaintiffs’ challenges to the GMP regulations – that (1) various GMP regulations exceeded FDA’s statutory authority to regulate dietary supplements, (2) some GMP regulations were unconstitutionally vague, in violation of the Due Process Clause of the Fifth Amendment, and (3) because of the vague sections of the GMP regulations, the regulations were arbitrary and capricious and an abuse of discretion under the Administrative Procedure Act ("APA"). 

Plaintiffs asserted FDA exceeded its statutory authority because Section 402(g) of the Federal Food, Drug, and Cosmetic Act ("FDC Act") prohibits FDA from issuing GMP regulations “that impose ‘standards for which there is no current and generally available analytical methodology.’”  Id. at *16-17.  The court explained that “the plaintiffs read this clause to mean that the FDA is only permitted to issue GMP regulations that are based on analytical methodologies and that these methodologies must also be current and generally available”; in “contrast, the FDA reads the clause to mean that if and when the FDA issues a regulation that incorporates a standard based on an analytical methodology, then that analytical methodology must be one that is current and generally available.”  Id. at *18-19. 

Before addressing the conflicting interpretations of the FDC Act, the court stated that the plaintiffs were precluded from contesting FDA’s regulatory authority because the plaintiffs failed to raise this issue during the rulemaking process.  Id. at *30.  (This serves as a good reminder to submit comments on proposed regulations when there are regulatory and legal concerns.)  Nevertheless, the court proceeded to analyze the plaintiffs’ challenge to FDA’s statutory authority using Chevron’s two-step process – an analysis we predicted would be critical to the outcome of this case.  Under Chevron step one, the court analyzed the statutory text, structure, and legislative history and “conclude[d] that the clear meaning of Section 402(g) is the FDA’s interpretation of the statute.”  Id. at *42.  The court explained that “[i]f the FDA imposes a standard that requires the use of an analytical methodology, the methodology must be current and generally available to manufacturers.  The statute does not mean that the FDA may only adopt GMP regulations that require the use of such an analytical methodology.”  Id.

Even though the court found the meaning of Section 402(g) to be clear, it proceeded to analyze this section under the second step of the Chevron analysis.  Under Chevron step two, “if a statute is ambiguous with respect to a specific issue, the Court must uphold the agency’s interpretation if it is ‘based on a permissible construction of the statute.’”  Id. at *43 (quoting Chevron U.S.A. Inc. v. Natural Resources Defense Council, Inc., 467 U.S. 837, 843 (1984)).  The court determined that, given all of the reasons that support FDA’s interpretation of the statute, “the Court could not conclude that the FDA’s construction of the statute is impermissible.”  Id.

Regarding the plaintiffs’ argument that certain GMP regulations are unconstitutionally vague, the court disagreed, explaining that, although certain terms like “adequate,” “qualified,” and “suitable” are not defined in the GMPs, the regulations essentially explain the meaning of the terms by providing “numerous details clarifying what the FDA means by ‘adequately installed and maintained plumbing,’” for example.  Id. at *48-49.  The court stated that “[t]here are clearly many applications of the challenged GMP regulations under which the regulations would not be impermissibly vague.”  Id. at *54.  For this reason, the court concluded that the regulations are not facially unconstitutional and “are not arbitrary and capricious under the APA.”  Id. at *57-58.

Hyman, Phelps & McNamara's Ricardo Carvajal will be speaking on the Reportable Food Registry at the American Conference Institute’s 2nd Advanced Summit on Food Safety Regulatory Compliance, taking place in Chicago from June 15-16, 2011.  See here for a copy of the brochure and to register for the conference.  Early bird registration rates expire on April 15.  Loyal readers of the FDA Law Blog may obtain a $200 discount by using discount code 801L11.HPM.

By Ricardo Carvajal –

FDA has a web page devoted to the Food Safety Modernization Act (“FSMA”) that provides ready access to useful information on the new law and on FDA’s implementation activities, including:

• the text of the law;
• Q&A’s;
• descriptions of the work groups charged with implementation;
• the text of relevant speeches by the Commissioner and Deputy Commissioner for Foods;
• interviews with senior staff;
• archived webcasts of public meetings; and
• translations of certain materials into several languages.

The page also provides a link to FDA’s Product Recall Page, which was revamped to be more user friendly as directed by the FSMA.

By Roger C. Thies –

On March 30, 2011, FDA publicly announced that it would not take enforcement action under certain conditions against pharmacies that compound hydroxyprogesterone caproate for injection for the reduction of the risk of certain preterm births in women who have had at least one prior preterm birth contrary to FDA's long standing policy to not permit pharmacy compounding of drugs that are commercially available and approved by FDA. See FDA, Compliance Policy Guide 460.200 – Pharmacy Compounding.  Please refer to our blog posting of March 31.

The Georgia Department of Community Health Medicaid Division, in reliance on FDA's refusal to enforce its own policies, has gone one step further.  According to a “Makena™ Position Statement,” in order to prescribe the FDA-approved drug instead of a compounded drug, a physician must demonstrate the medical necessity for the approved product instead of the compounded product notwithstanding FDA’s statement that “greater assurance of safety is provided by an approved product.”  This bizarre twist is a direct result of FDA deciding that a drug product’s cost and political pressure should dictate the Agency’s enforcement priorities.  Any manufacturer who decides to comply with FDA’s requests for approvals of marketed unapproved drugs and makes the investments in time and money to obtain approval must now ask itself whether it too will be punished by FDA’s apparent indifference to the Agency's enforcement policies.

By Carmelina G. Allis –

A March 24, 2011 warning letter from FDA cites a rarely invoked provision in the Investigational Device Exemption (“IDE”) regulations.  It is not clear whether this warning letter is an outlier or a harbinger of more aggressive inspections by the Division of Bioresearch Monitoring (“BIMO”).

The recipient of the letter was Valor Medical, Inc.  FDA alleged that the company violated 21 C.F.R. § 812.27(a) (and Section 520(g) of the Federal Food, Drug, and Cosmetic Act) by failing to submit two animal study reports in its IDE application.  That is the only violation listed in the letter.

Pursuant to 21 C.F.R. § 812.27(a), an IDE sponsor must submit “reports of all prior clinical, animal, and laboratory testing of the device . . . to justify the proposed investigation.”  Generally, sponsors submit reports of those tests that are relevant to the proposed investigation – they don’t just simply submit all of the tests conducted on the device.  For example, if an animal study was conducted on a prototype device that differs significantly in technology or design to the proposed device, the sponsor may not submit that information in the IDE.  The same would apply if the study was conducted, for example, using an animal model that proved to be inadequate to assess the device performance or its safety or effectiveness (necessitating a second study in a different animal model).  In both of those cases, the test results would not provide any valuable safety or effectiveness data regarding the proposed device, and the information would not be relevant to justifying the proposed investigation.

It is rare for a warning letter to cite § 812.27:  the only other one we can find is a warning letter issued to Staar Surgical in 2007.  That letter cited the company for withholding information regarding a human clinical study that the company had conducted prior to submission of the IDE.

FDA failed to describe in the Valor Medical warning letter the importance or relevance of the animal studies for purposes of the IDE study.  This is unfortunate because there is no way to judge whether the omitted animal studies were clearly relevant, or whether FDA has expanded its interpretation of what studies must be submitted.  

As noted, we are not sure if this warning letter is an outlier or a harbinger.  It does underscore that companies should carefully consider what studies are properly included in an IDE application.

By Ricardo Carvajal –

Rep. Henry Waxman, Ranking Member of the Committee on Energy and Commerce, sent FDA Commissioner Margaret Hamburg a letter urging the agency to investigate Kretek International’s (Kretek) marketing of clove-flavored cigars, and to ban flavored cigars that are “marketed for the purpose of circumventing” the recently effected ban on flavored cigarettes.  FDA banned the sale of flavored cigarettes in September 2009 under the authority of the FDC Act, as amended by the Family Smoking Prevention and Tobacco Control Act ("Tobacco Act").   The letter summarizes evidence of the dangers purportedly presented by clove-flavored tobacco products – including their use as “‘gateway’ products that introduce young people to smoking.”  The letter then details what it terms “a plan to subvert the FDA ban on flavored cigarettes by introducing a nearly identical product as a flavored cigar,” based on the Committee’s review of voluminous records provided by Kretek in response to the Committee’s request.  Although the letter gives no hint of how FDA could distinguish between flavored cigars marketed for the purpose of circumventing the ban on flavored cigarettes and those marketed for other (presumably legitimate) purposes, the letter might nonetheless find a welcoming ear at FDA.  As we noted in a prior posting, the agency has already signaled its intent to go after flavored cigarettes masquerading as cigars.

By Kurt R. Karst –      

Some court decisions just leave us scratching our heads after we read them, and the decision handed down last week by Judge Freda Wolfson of the U.S. District Court for the District of New Jersey in Medeva Pharma Suisse A.G. v. Par Pharmaceuticals, Inc., Case No. 3:10-cv-04008 (D.N.J., Mar 29, 2011), is one of them.  We’ve all heard of FDA’s 180-day exclusivity forfeiture “punts” under FDC Act § 505(j)(5)(D)(i)(IV), where a first applicant fails to obtain tentative (or final) ANDA approval within 30-months of application submission and FDA says that the Agency is not making a formal forfeiture determination at the time of ANDA approval and will do so only if another applicant becomes eligible for approval within 180 days after the first applicant begins commercial marketing.  Last week’s decision in Medeva, concerning a generic version of ASACOL (mesalamine) Delayed-Release Tablets, 400 mg, and in the context of a subsequent ANDA applicant’s standing to bring a declaratory judgment action to trigger a first applicant’s 180-day exclusivity, seems to create a new type of court-created punt. 

We’ll spare you a full recitation of the facts in this case, but here’s what you need to know . . . .   There are two patents listed in the Orange Book for Warner Chilcott Pharmaceuticals, Inc.’s (“Warner Chilcott’s”) ASACOL – U.S. Patent Nos. 5,541,170 (“the ‘170 patent”) and 5,541,171 (“the ‘171 patent”), both of which expire on July 30, 2013.  Par Pharmaceutical, Inc. (“Par”) is a subsequent ANDA applicant whose ANDA contains Paragraph IV certifications to the ‘170 and ‘171 patents.  FDA has not yet approved, or even tentatively approved, an ANDA for a generic version of ASACOL. 

Warner Chilcott (and Medeva Pharma Suisse A.G.) sued Par for infringement of the ‘170 patent, but not for the ‘171 patent.  Par filed papers seeking a declaratory judgment of non-infringement or invalidity with respect to both patents, presumably in an effort to trigger the first applicant’s 180-day exclusivity (reportedly Roxane, which submitted an ANDA in June 2007).  In response, Warner Chilcott offered Par a covenant not to sue only with respect to the ‘171 patent and then filed a Motion to Dismiss Par’s declaratory judgment action for lack of standing.  Warner Chilcott’s papers also note that the first applicant “may be deemed to have lost its 180-day exclusivity period as a result of a forfeiture event” (presumably under FDC Act § 505(j)(5)(D)(i)(IV) for failing to obtain timely tentative approval). 

Par opposed the Motion to Dismiss arguing that pursuant to the Federal Circuit’s decision in Teva Pharmaceuticals USA, Inc. v. EISAI Co., Ltd., 620 F.3d 1341 (Fed. Cir. 2010), “this Court has and should exercise jurisdiction over defendants’ declaratory judgment counterclaims,” and that any argument that the first applicant forfeited 180-day exclusivity eligibility is speculative.  Indeed, Par notes that in an August 2010 citizen petition response, “FDA announced particular bioequivalence requirements for mesalamine drugs,” and that as a result FDA might determine that there was a change in or review of the requirements for ANDA approval and that the first applicant’s failure to obtain timely tentative approval might be excused under the exception provision at FDC Act § 505(j)(5)(D)(i)(IV).  (And although we did not see anything to this effect in the various court filings, FDA could also extend the 30-month period under FDC Act § 505(j)(5)(D)(i)(IV) pursuant to FDC Act § 505(q)(1)(G), which states that if “approval of the [ANDA] was delayed because of a [citizen] petition [subject to FDC Act § 505(q)], the 30-month period under [FDC Act § 505(j)(5)(D)(i)(IV)] is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .”)  

Warner Chilcott’s Reply presses the company’s point that “[a]ny apprehension of potential litigation involving the ‘171 Patent has been extinguished by Plaintiffs’ express covenant not to sue.” 

Judge Wolfson, in her March 29, 2011 decision, punted on the issue of the appropriate standard for declaratory judgment jurisdiction in Hatch-Waxman Orange Book patent listing cases, and instead grabbed onto the first applicant’s potential forfeiture of 180-day exclusivity under FDC Act § 505(j)(5)(D)(i)(IV) as the basis for granting Warner Chilcott’s Motion to Dismiss Par’s declaratory judgment action with respect to the ‘171 patent.  According to Judge Wolfson:

Seizing on the Act’s language exempting a failure to obtain tentative approval “caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed,” 21 U.S.C. § 355(j)(5)(D)(i)(IV), Defendants argue that its allegations do not suggest that Roxane forfeited its eligibility because, in August 2010, the FDA announced a change to the bioequivalence requirements for a class of drugs covering Roxane’s application.  The flaw in Defendant’s argument is that this alleged announcement came four months after Defendants allege that Roxane’s 30-month tentative approval period had expired and, therefore, could not have been the cause of Roxane’s failure to obtain approval.  Moreover, nothing in the record suggests that an approval or extension of Roxane’s application from the FDA is imminent; in fact, at this juncture, more than 10 months after Roxane’s 30-month approval allotment has expired, the Court cannot discern whether an approval or extension will ever be granted.  Therefore, based on the allegations in Defendants’ counterclaim, and the plain language of the Act, Defendants have not sufficiently alleged that they are barred from entry into the market.  This means that any potential barrier that could result from a subsequent approval and reinstatement of Roxane’s market exclusivity is speculative at best, and does not meet the Article III requirement of actual or imminent injury for standing. [(emphasis in original)]

Of course, just because FDA responds to a citizen petition after the 30-month date for obtaining tentative approval (or final approval) has passed does not necessarily mean that FDA did not earlier change the requirements for ANDA approval . . .  or that a citizen petition affects the 30-month period pursuant to FDC Act § 505(q)(1)(G).   And what if FDA rules that the first applicant did not, in fact, forfeit 180-day exclusivity eligibility.  Would a subsequent applicant (here, Par) then have standing . . . . and if so, would it be too late to trigger a forfeiture event under the failure-to-market provisions?

Thanks to Shashank Upadhye for bringing the decision to our attention.

By John A. Gilbert & Peter M. Jaensch –

Following what appears to have been the stall of the Arkansas prescription-only Pseudoephedrine bill (House Bill 1444) in mid-March, on March 23, 2011, Arkansas enacted a new law in the effort to combat illicit methamphetamine production.  Act 588 of the 2011 Regular Session (formerly Senate Bill 437, introduced by Senator Percy Malone (D)), primarily modifies several existing sections of the Arkansas Code applicable to products containing ephedrine (“EPH”), pseudoephedrine (“PSE”), and phenylpropanolamine (“PPA”) with regard to their status as controlled substances, sales limitations, acceptable forms of purchaser identification, and pharmacists’ duties.  Among these provisions, however, the Act imposes two new requirements, which are likely to create concerns.

First, the Act imposes a new requirement on pharmacists to “make a professional determination, based on a pharmacist-patient relationship, as to whether or not there is a legitimate medical and pharmaceutical need for the drug” before making any OTC dispensation of any non-exempt product containing EPH, PSE, or PPA.  The vagueness of the provision is likely to make implementation difficult.  The Act is silent as to what condition or circumstance should satisfy the dispensing pharmacist that the “medical and pharmaceutical need for the drug” is “legitimate.”  The Act offers pharmacists some guidance by enumerating several factors they may consider in making the required determination: (1) “Prior medication-filling history;” (2) “Patient screening; and” (3) “Other tools that provide professional reassurance to the pharmacist that a legitimate medical and pharmaceutical need exists.”  The Act also encourages pharmacists to err on the side of caution – that is, refusing to dispense – by providing that “[a] pharmacy or pharmacist is not civilly liable for a determination [of medical or pharmaceutical need]  or for any refusal to dispense, sell, transfer, or otherwise furnish ephedrine, pseudoephedrine, or phenylpropanolamine based on a determination of age or identity.”

Second, the Act makes it unlawful to dispense any product containing PSE, PPA, or EPH without a prescription, unless, among other requirements, the purchaser can provide an Arkansas-issued Driver’s License or ID card, or an identity card issued by the U.S. Department of Defense for active-duty military personnel.  Essentially, the Act permits Arkansas residents to obtain OTC products, but requires any out-of-state customer to obtain a prescription for the same product.  It seems likely that this provision is intended to make Arkansas pharmacies less attractive to smurfers in neighboring Mississippi, which is a prescription-only state for PSE products, without burdening Arkansans with a prescription requirement.

In summary, while existing law at the both the federal and state level would prohibit a pharmacy or pharmacist from knowingly selling these products above established limits or from selling these if there is reason to believe that it would be used for illicit purposes, the Arkansas law arguably goes further and requires the pharmacist to make a medical judgment on whether the patient has a medical need for the product.