By Kurt R. Karst –      

In a recent, 95-page decision from the U.S. District Court for the Eastern District of Pennsylvania in In re Wellbutrin XL Antitrust Litigation, the court once again tackled the issues of “sham” citizen petitions, liability under the Sherman Antitrust Act, and Noerr-Pennington immunity.  The court previously addressed citizen petitions alleged to be shams in In re Flonase Antitrust Litigation, 795 F. Supp. 2d 300 (E.D. Pa. 2011).

As a general matter, the standard for demonstrating a sham petition is pretty high.  Under the Noerr-Pennington doctrine, 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.  See Eastern Railroad Presidents Conference v. Noerr Motor Freight, Inc., 365 U.S. 127 (1961); United Mine Workers v. Pennington, 381 U.S. 657 (1965).  Immunity extends to citizen petitions submitted to FDA.  The Noerr-Pennington doctrine is grounded in the First Amendment protection of political speech, and “upon a recognition that the antitrust laws, ‘tailored as they are for the business world, are not at all appropriate for application in the political arena.’” City of Columbia v. Omni Outdoor Advertising, Inc., 499 U.S. 365, 380 (1991) (quoting Noerr, 365 U.S. 127, 141 (1961)).

Noerr-Pennington immunity is not absolute.  When petitioning activity “ostensibly directed toward influencing governmental action[] is a . . . sham to cover what is . . . nothing more than an attempt to interfere directly with the business relationships of a competitor[, then] the application of the Sherman Act would be justified.”  Noerr, 365 U.S. at 144.  The sham exception requires that a petition be “(i) ‘objectively baseless,’ and (ii) ‘an attempt to interfere directly with the business relationships of a competitor through the use of the governmental process – as opposed to the outcome of that process – as an anticompetitive weapon.’”  Primetime 24 Joint Venture v. Nat’l Broad. Co., 219 F.3d 92, 100-01 (quoting Prof’l Real Estate Investors, Inc. v. Columbia Pictures Indus., Inc., 508 U.S. 49, 60 (1993) (“PRE”)).

In re Wellbutrin XL Antitrust Litigation stems from a July 2008 Complaint alleging that Biovail and GlaxoSmithKline (“GSK”) violated the Sherman Antitrust Act by conspiring to prevent generic versions of WELLBUTRIN XL (bupropion HCl) Extended-Release Tablets (NDA No. 021515) from entering the market by filing sham Hatch-Waxman patent infringement lawsuits (and then entering into agreements with generic companies to settle the lawsuits), and by submitting a sham citizen petition to FDA.  In granting Motions for Summary Judgment filed by Biovail and GSK, the court found that the patent infringement lawsuits and Biovail’s citizen petition “do not fall within the sham exception to Noerr-Pennington immunity.”  (The court did not decide whether the settlement agreements independently violated the antitrust laws, as that issue is still being briefed.)

The citizen petition at issue in the case was filed on behalf of Biovail on December 20, 2005 (Docket No. FDA-2005-P-0366; formerly Docket No 2005P-0498) and requested that FDA require that any ANDA for a generic version of WELLBUTRIN XL satisfy four criteria:

(1) All bioequivalence trials should calculate and evaluate parameters based on concentrations of the parent drug and active metabolites [(namely, the hydroxy-, threo-, and erythro-metabolites)].
(2) Any generic formulation should be shown, based on the above criteria, to be bioequivalent to Wellbutrin XL, sustained-release and immediate-release bupropion.
(3) The bioequivalence studies described above should be conducted at steady-state evaluating the performance of the dosage form based on AUC, Cmax, [and] Cmin.
(4) Data using FDA’s in vitro approach for evaluating the effect of alcohol on the performance of the controlled-release dosage form should be required to ensure the absence of “dose dumping” if the drug is consumed with alcohol.

The court termed these requests as the “metabolites evaluation request,” the “bioequivalence drift request,” the “steadystate request,” and the “dose dumping request,” respectively.

On December 14, 2006, FDA granted in part and denied in part the petition stating that:

FDA will require ANDA applicants for generic bupropion HCl extended-release tablets to demonstrate bioequivalence to Wellbutrin XL, but not to Wellbutrin SR and Wellbutrin.  FDA expects ANDA applicants for generic bupropion HCl extended-release tablets to measure the metabolite hydroxybupropion in their bioequivalence studies, but does not expect ANDA applicants to measure the metabolites threohydrobupropion and erythrohydrobupropion.  FDA also does not intend to require ANDA applicants to conduct steady-state bioequivalence studies.  FDA asked ANDA applicants for generic bupropion HCl extended-release tablets to submit data from in vitro dissolution studies addressing the performance of the drug-release mechanism in the presence of alcohol and expects to consider this data in its review of each ANDA.

Biovail, in the company’s Motion for Summary Judgment, made four arguments in favor of summary judgment with respect to the sham citizen petition allegations:

(1) First, that because the dose dumping request was granted, and the metabolites evaluation request was granted in part, the entire petition is immunized from antitrust liability under the Noerr-Pennington doctrine; (2) Second, that any competitive harm is immune from antitrust liability because it resulted from government decision; (3) Third, that even if the entire petition is not immunized, the unsuccessful requests were not objectively baseless; and (4) Finally, that even if the unsuccessful requests were objectively baseless, the plaintiffs have not shown that they caused any delay.

As an initial matter, the court found that the hydroxy-metabolite and dose-dumping petition requests that FDA granted are, by definition, non-sham.  The cound found so notwithstanding an argument proffered by the plaintiffs in the case that “petitioning the FDA to do something it has already done or to act on an issue about which it is already aware cannot be characterized as successful or objectively reasonable.”  Instead, said the court, the “standard for objective baselessness is a forward-looking standard from the point in time when the suit or petition was filed. . . .  To examine post hoc whether it was the petition that caused the government to reach a certain outcome would be contrary to the forward-looking language in PRE.”

Moving on to Biovail’s argument that “if a citizen petition includes more than one request, the entire petition is not a sham if at least one of the requests has objective merit” (i.e., whether a mixed petition is immune under Noerr-Pennington), the court said that it is an “interesting” issue, but one that does not need to be decided in the case, because “the plaintiffs have not shown any evidence that the unsuccessful and arguably sham requests in the Citizen Petition actually delayed FDA approval of the generic ANDAs any further than the delay caused by the successful requests.”  Nevertheless, the court went on to examine this issue further, and, relying on the court’s previous decision in In re: Wellbutrin SR Antitrust Litigation, No. 05-396, 2006 WL 616292 (E.D. Pa. Mar. 9, 2006), commented that “it is theoretically possible that a . . . sham request in a petition can cause antitrust damage above and beyond the delay caused by the non-sham claim – i.e., that the injury will exceed the portion of the conduct that is protected by Noerr-Pennington immunity.” 

With respect to Biovail’s government action immunity and unsuccessful request arguments, the court, as with the mixed petition issue, said that these issues do not need to be decided because the plaintiffs did not show that they caused antitrust injury above and beyond any delay from the successful, non-sham petition requests.  Nevertheless, the court considered and commented on each issue, first disagreeing with Biovail’s government action immunity argument, and second, indicating that there was no reasonable expectation of success of the petition requests that were ultimately unsuccessful (i.e., denied by FDA). 

So, the “interesting” issues the court commented on but did not need to decide with respect to allegedly sham citizen petitions and the extent to which there is Noerr-Pennington immunity will have to wait for another day.  But query whether that day will ever come given FDA’s timeframe under FDC Act § 505(q) (as added by the 2007 FDA Amendments Act) for responding to certain citizen petitions. 

By Kurt R. Karst –      

We’re not economists, but we’re interested in the topic insofar as it concerns Congress’ consideration of FDA-related legislation, such as H.R. 5651, the FDA Reform Act of 2012, which is on tap for consideration by the U.S. House of Representatives later this week.  Like its counterpart in the U.S. Senate, S. 3187, the FDA Safety and Innovation Act, which passed out of that chamber last week (see our previous post here), H.R. 5651 would reauthorize old (PDUFA and MDUFA) and establish new (GDUFA and BsUFA) user fee statutes, and create several new provisions of law.  (There are several differences between the bills we won’t get into here.)  On the same day the Senate passed S. 3187, the Congressional Budget Office (“CBO”) released a cost estimate of H.R. 5651.  That’s where things got interesting for us on the economics front. 

Under current law – the Statutory Pay-As-You-Go Act of 2010 – there are enforcement procedures governing federal budgeting that are intended to ensure that most new spending is offset by spending cuts or added revenue elsewhere.  This is known as the pay-as-you-go, or “PAYGO,” requirement.  The CBO analyzes bills Congress is considering, evaluates the net changes in outlays and revenues that are subject to PAYGO procedures, and issues costs estimates.

Accordingto the CBO’s cost estimate of the FDA Reform Act of 2012, “enacting H.R. 5651 would reduce budget deficits by approximately $72 million over the 2013-2017 period and increase them by $247 million over the 2013-2022 period.”  That estimate would have been worse if it weren’t for Section 863 of the introduced version of H.R. 5651 the CBO reviewed when putting together the estimate. 

As we previously reported, Section 863 would amend FDC Act § 505(q) to shorten the timeframe FDA has to respond to certain citizen petitions.  By way of background, FDC Act § 505(q) was added to the law as part of the FDA amendments Act of 2007 and is intended to prevent the citizen petition process from being used to delay approval of ANDAs and 505(b)(2) applications.  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 current FDC Act § 505(q), “[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.  The original version of H.R. 5651 would give the statutory 180-day FDA response timeframe a haircut, reducing the period by 30 days (to 150 days). 

According to CBO’s May 24th cost estimate of H.R. 5651:

CBO expects that other provisions of H.R. 5651 would reduce the average price charged for drugs in the market.  We estimate that the provision with the greatest effect on market entry by lower-priced generic drugs is section 863.  It would reduce by 30 days the statutory timeframe for final agency action relating to certain citizen petitions that ask for a stay of FDA approval on a pending generic drug application.  (Under the bill, the limitation on the determination period would be 150 days.) . . . .

CBO estimates that implementing section 863 and other provisions that shorten administrative timeframes for review of certain petitions would reduce direct spending for mandatory health programs by $168 million over the 2013-2022 period.

Although we suspected that the citizen petition provisions in H.R. 5651 might be intended as an offset for other provisions in the bill, the CBO’s statements surprised us.  After all, FDA’s response to a 505(q) citizen petition does not dictate ANDA or 505(b)(2) application approval (though that is believed to be the case for pre-505(q) petitions).  Moreover, between Fiscal Years 2008 and 2010, FDA delayed less than a handful of pending applications (e.g., one ANDA by 9 days in FY 2010) due to a 505(q) citizen petition, according to the Agency’s most recent annual report (see our previous post here).  So it is unclear where all of the savings are coming from. 

Given this, you can imagine our surprise when the so-called “suspension” version of H.R. 5651 came out last Friday.  According to a summary of the bill, “[t]he Suspension Document contains technical changes and the addition of language in Section 863 that the Committee believes will result in the bill reducing mandatory spending by roughly $350 million over ten years.  With the addition of this languager [sic], H.R. 5651 is pay-go compliant.”

The tweaked version of Section 863 in the suspension version of H.R. 5651 maintains the 150-day FDA response timeframe in the introduced version of the bill, but would amend FDC Act § 505(q) to include citizen petitions concerning biosimilar applications submitted under PHS Act § 351(k).  Specifically, Section 863 states:

SEC. 863. FINAL AGENCY ACTION RELATING TO PETITIONS AND CIVIL ACTIONS.

Section 505(q) (21 U.S.C. 355(q)) is amended—

(1) in paragraph (1)—

(A) in subparagraph (A), by striking “subsection (b)(2) or (j)” inserting “subsection (b)(2) or (j) of the Act or 351(k) of the Public Health Service Act”; and

(B) in subparagraph (F), by striking “180 days” and inserting “150 days”;

(2) in paragraph (2)(A)—

(A) in the subparagraph heading, by striking “180” and inserting “150”; and

(B) in clause (i), by striking ‘‘180-day’’ and inserting ‘‘150-day’’; and

(3) in paragraph (5), by striking “subsection (b)(2) or (j)” inserting “subsection (b)(2) or (j) of the Act or 351(k) of the Public Health Service Act”.

To our knowledge, FDA has received only a single citizen petition concerning PHS Act § 351(k) biosimilar applications – Abbott’s April 2, 2012 petition concerning HUMIRA (adalimumab) (see our previous post here) – which, of course, did not include a FDC Act § 505(q) certification.  Although there will certainly be more citizen petition concerning biolsimilars, it is unclear where all of the CBO’s projected savings will come from.  It seems more likely that FDA, with a 150-day response timeframe, will issue more non-response petition denials. 

REMINDER:  HP&M is hosting a webinar, Garbage Runs, Fake Identities, and Surprise Home Visits; Strategies to Deal With FDA’s Nontraditional Investigative Tools, on Wednesday, June 20, 2012 from 12:30 – 2:00 p.m. ET.  Click here to register.

By Kurt R. Karst –      

After days of debate and a slew of proposed amendments, the U.S. Senate passed S. 3187, the FDA Safety and Innovation Act, on Thursday afternoon by a roll call vote of 96-1.  Senator Bernie Sanders (I-VT), who cast the lone vote against passage, issued a statement explaining his vote.  A similar process may unfold in the U.S. House of Representatives as that chamber considers its version of a legislative package, H.R.5651, the Food and Drug Administration Reform Act of 2012.  H.R. 5651 is ready for a floor vote, and House Republicans have indicated that they want to get a final bill to the President by July 4th.  Late on May 24th, the Congressional Budget Office released a cost estimate of H.R. 5651.  Both the Senate and House bills reauthorize old (PDUFA and MDUFA) and establish new (GDUFA and BsUFA) user fee statutes, and create several new provisions of law.

Over the past week, somewhere in the neighborhood of 40 amendments to S. 3187 were introduced in the Senate – see here, here, here, and here for the text of those amendments.  That number was winnowed down to less than 20 amendments, which the Senate debated and voted on on Thursday, including votes on a couple of high-profile issues (e.g., reimportation and patent settlement agreements).  Among other things, the Senate did not consider items such as an amendment from Sen. Orrin Hatch (R-UT) to repeal the medical device excise tax and generic drug labeling and preemption legislation.  (The National Association of Attorneys General recently sent a letter to members of the Senate Judiciary Committee expressing support for the Patient Safety and Generic Labeling Improvement Act.)

Below is an overview of how the chips fell for each amendment considered and a brief summary of each amendment (except Senate Amendment No. 2122, a substitute version of  S. 3187, which was agreed to by unanimous consent, and the text of which is available here).  

Amendments Agreed To By Unanimous Consent Or Voice Vote

Amendment No. 2125 (Sen. Cardin) – Ensuring Adequate Information Regarding Pharmaceuticals For All Populations, Particularly Underrepresented Subpopulations, Including Racial Subgroups:  The amendment would require FDA to “review and modify, as necessary, the [FDA’s] communication plan to inform and educate health care providers, patients, and payors on the benefits and risks of medical products, with particular focus on underrepresented subpopulations, including racial subgroups.”

Amendment No. 2141 (Sen. Cardin) – Report On Small Business:  FDA is required to submit a report to Congress (not later than one year after the date of enactment) that includes: “(1) a listing of and staffing levels of all small business offices at [FDA], including the small business liaison program; (2) the status of partnership efforts between [FDA] and the Small Business Administration; (3) a summary of outreach efforts to small businesses and small business associations, including availability of toll-free telephone help lines;  (4) with respect to the program under the Orphan Drug Act (Public Law 97-414), the number of applications made by small businesses and number of applications approved for research grants, the amount of tax credits issued for clinical research, and the number of companies receiving protocol assistance for the development of drugs for rare diseases and disorders; (5) with respect to waivers and reductions for small business under [PDUFA], the number of small businesses applying for and receiving waivers and reductions from drug user fees . . . ; (6) the number of small businesses submitting applications and receiving approval for unsolicited grant applications from [FDA]; (7) the number of small businesses submitting applications and receiving approval for solicited grant applications from [FDA]; (8) barriers small businesses encounter in the drug and medical device approval process; and (9) recommendations for changes in the user fee structure to help alleviate generic drug shortages.”

Amendment No. 2121 (Sen. Grassley) – Protections For The Commissioned Corps Of The Public Health Service:  This amendment offers whistleblower protections and prohibits retaliatory personnel actions.

Amendment No. 2129 (Sen. Grassley) – Regulations On Clinical Trial Registration; GAO Study Of Clinical Trial Registration And reporting Requirements:  The amendment requires the issuance of a proposed rule on the registration of “applicable clinical trials” by “responsible parties” under PHS Act § 402(j) (as amended by § 801 of the FDA Amendments Act of 2007) not later than 180 days after the date of enactment, and the promulgation of a final rule not later than 180 days after the issuance of the proposed rule.  Not later than two years after the issuance of the final rule, the Government Accountability Office (“GAO”) would be required to report on the rate of compliance and non-compliance of clinical trial registration, results reporting, and the completeness of reported data.  If problems are found, then the GAO is to make recommendations for administrative or legislative actions to increase compliance.

Amendment No. 2151 (Sen. Manchin) – Hydrocodone Scheduling:  The amendment reclassifies the scheduling of hydrocodone so that all drug products containing hydrocodone would be Schedule II controlled substances under the Controlled Substances Act.  Although hydrocodone is currently a Schedule II controlled substance, when combined with certain other drugs it is in Schedule III. 

Amendment No. 2126 (Sen. Reed) – Compliance Date For Rule Relating To Sunscreen Drug Products For OTC Human Use:  The amendment states that “[i]n accordance with the final rule issued by the Commissioner of Food and Drug entitled ‘Labeling and Effectiveness Testing; Sunscreen Drug Products for Over-the-Counter Human Use; Delay of Compliance Dates’ (77 Fed. Reg. 27591 (May 11, 2012)), a product subject to the final rule issued by the Commissioner entitled ‘Labeling and Effectiveness Testing; Sunscreen Drug Products for Over-the-Counter Human Use’ (76 Fed. Reg. 35620 (June 17, 2011)), shall comply with such rule not later than – (1) December 17, 2013, for products subject to such rule with annual sales of less than $25,000 and (2) December 17, 2012, for all other products subject to such rule.”  Senator Reed recently sent a letter to FDA expressing concern about the Agency's delay in putting sunscreen standards into effect.  The delay was also criticized by the Environmental Working Group, which is seeking certain information from FDA on the issue.

Amendment No. 2142 (Sen. Leahy) – Freedom Of Information Act (“FOIA”): The amendment concerns the receipt and protection of confidential information obtained from foreign government agencies relating to drug inspections, and states that FDA shall not be required to disclose under FOIA (or any other provision of law) “any information relating to drug inspections obtained from a foreign government agency” if certain conditions are met. 

Amendment No. 2145 (Sen. Portman) – Interstate Drug Monitoring Efficiency and Data Sharing Act of 2012:  The Attorney General would be required to “establish national interoperability standards to facilitate the exchange of prescription information across State lines by States receiving grant funds” under the Harold Rogers Prescription Drug Monitoring Program and the Controlled Substance Monitoring Program not later than one year after the date of enactment.

Amendment No. 2131 (Sen. Coburn) – Independent Assessment Of The Drug And Biologic Application Review Process:  The amendment requires FDA to “contract with a private, independent consulting firm capable of performing the technical analysis, management assessment, and program evaluation tasks required to conduct a comprehensive assessment of the process for the review of” applications under FDC Act § 505(b) and § 505(j) for drugs and PHS Act § 351(a) and § 351(k) for biologics.  “The assessment shall address the premarket review process of drugs by [FDA], using an assessment framework that draws from appropriate quality system standards, including management responsibility, documents controls and records management, and corrective and preventive action.”  Among other things, FDA would be required to “analyze the recommendations for improvement opportunities identified in the assessment, develop and implement a corrective action plan, and ensure its effectiveness.”

Amendment No. 2146 (Sen. Portman) – Synthetic Drug Abuse Prevention Act of 2012:  This amendment would make certain “cannabimimetic agents” Schedule I controlled substances under the Controlled Substances Act.

Amendments Not Agreed To

Amendment No. 2111 (Sen. Bingaman); Not agreed to by a 28-67 vote – Ensuring That Valid Generic Drugs May Enter The Market:  This amendment proposed to amend the FDC Act’s provisions with respect to “first applicant” status and 180-day marketing exclusivity for certain ANDA sponsors to address patent settlement agreements (or what opponents call “pay-for-delay” agreements). 

Amendment No. 2108 (Sen. Murkowski); Not agreed to by a 46-50 vote – Analyses Of Application For Approval Of genetically-Engineered Fish:  This amendment would have prevented FDA’s approval of any genetically modified marine or anadromous organism from taking effect until certain requirements are me. 

Amendment No. 2107 (Sen. McCain); Not agreed to by a 43-54 vote – Safe And Affordable Drugs From Canada:  The amendment would have required FDA to promulgate regulations permitting individuals to import into the United States a prescription drug (other than a controlled substance) that: “(1) is purchased from an approved Canadian pharmacy; (2) is dispensed by a pharmacist licensed to practice pharmacy and dispense prescription drugs in Canada; (3) is purchased for personal use by the individual, not for resale, in quantities that do not exceed a 90-day supply; (4) is filled using a valid prescription issued by a physician licensed to practice in the United States; and (5) has the same active ingredient or ingredients, route of administration, dosage form, and strength as a prescription drug approved by [FDA].”

Amendment No. 2109 (Sen. Sanders); Not agreed to by a 9-88 vote – Conditions On Award Of Drug Exclusivity:  The amendment proposed to terminate marketing exclusivity for drugs and biologics if the person to which such exclusivity was granted or any person to which such exclusivity is assigned commits certain violations or fails to report certain violations.
 
Withdrawn Amendments

Amendment No. 2132 (Sen. Coburn) – FDA Employee Performance Awards:  The amendment proposed to establish a system by which a portion of performance awards would be connected to the evaluation of the employee’s contribution to the goals under the various user fee agreements.  The GAO recently issued a report concerning this topic, titled “Employee Performance Standards for the Timely Review of Medical Product Applications.”

Amendment No. 2130 (Sen. Burr) – Transparency In FDA User Fee Agreement Negotiations:  The amendment would have added the following with respect to PDUFA, MDUFA, GDUFA, and BsUFA: “Notwithstanding any other provision of this section, Members of Congress or their designated staff may be present at any negotiation meeting conducted under this subsection between [FDA] and the regulated industry, if a Member of Congress decides to attend, or have his or her designated staff attend on his or her behalf.  Any staff designated under the preceding sentence may be required to comply with applicable confidentiality agreements.”

Tabled Amendments

Amendment No. 2143 (Sen. Paul); Tabled by a 78-15 vote – Dietary Supplements:  Among other things, the amendment would have prohibited the Federal government from taking “any action to prevent use of a claim describing any nutrient in a food or dietary supplement . . . as mitigating, treating, or preventing any disease, disease symptom, or health-related condition, unless a Federal court in a final order following a trial on the merits finds clear and convincing evidence based on qualified expert opinion and published peer-reviewed scientific research that – (1) the claim is false and misleading in a material respect; and (2) there is no less speech restrictive alternative to claim suppression, such as use of disclaimers or qualifications, that can render the claim non-misleading.”

Amendment No. 2127 (Sen. Durbin); Tabled by a 77-20 vote – Registration Of Facilities With Respect To Dietary Supplements:  The amendment proposed to require all dietary supplement facilities to register with FDA.  Such registration would include: (1) a description of each dietary supplement product manufactured by such facility; (2) a list of all ingredients in each such dietary supplement product; and (3) a copy of the label and labeling for each such product.  Failure to comply with registration requirements would result in misbranding of the products.  Senator Durbin's statement on the amendment is available here.

By Kurt R. Karst –   

FDA’s recent approval of ANDAs for generic versions of sanofi-aventis’ (“sanofi’s”) blockbuster blood thinner drug PLAVIX (clopidogrel bisulfate) Tablets (approved under NDA No. 020839) upon the May 17, 2012 expiration of a period of pediatric exclusivity associated with Orange Book-listed U.S. Patent No. 4,847,265 (“the ‘265 patent”) was preceded by a sideshow that brings to light an interesting tension between the Hatch-Waxman Amendments and FDA’s Pre-Launch Activities Importation Request (“PLAIR”) program.  As we previously discussed, FDA’s PLAIR program allows, on a case-by-case basis, the importation and warehousing of finished drugs where an application for drug approval (i.e., an NDA or ANDA) is pending approval and where the import and warehousing will expedite the commercial launch of the drug once FDA approves an application.

Apotex, Inc. (“Apotex”) is one of several companies that years ago submitted an ANDA to FDA seeking approval of generic PLAVIX and whose applications each contained a Paragraph IV certification to the ‘265 patent.  Apotex submitted is application – ANDA No. 076274 – to  FDA in 2001, prior to the enactment of the Medicare Modernization Act (“MMA”), and was the first filer with respect to the ‘265 patent, thereby making Apotex eligible for 180-day exclusivity.  In March 2002, Sanofi sued Apotex for infringement of the ‘265 patent in the U.S. District Court for the Southern District of New York, thereby triggering a 30-month stay of approval of Apotex’s ANDA.  FDA first approved ANDA No. 076274 on January 20, 2006, after the 30-month stay expired in May 2005 without a relevant court decision.  Almost six months later, on August 8, 2006, Apotex began commercially marketing its generic clopidogrel drug product at risk of an adverse court decision, thereby triggering the company’s 180-day exclusivity under the pre-MMA statute.  Sanofi quickly sought a permanent injunction barring Apotex from further marketing the drug product, and on August 31, 2006, the district court granted the injunction pending the outcome of the case.  (Apotex subsequently petitioned and sued FDA – see here and here – to recover 180-day exclusivity.  The lawsuit was voluntarily dismissed in April 2009, and FDA denied Apotex’s petition as moot on May 17, 2012.) 

In June 2007, the New York District Court ruled that Apotex failed to prove that the ‘265 patent is invalid and entered a permanent injunction.  Apotex appealed the decision, but in December 2008, the U.S. Court of Appeals for the Federal Circuit affirmed the district court’s decision.  On June 22, 2009, FDA converted the final approval of ANDA No. 076274 to a tentative approval to conform the status of the ANDA to the district court’s June 2007 Order issued pursuant to 35 U.S.C. 271(e)(4).  That Order (as amended) states in relevant part:

5. Plaintiffs are entitled to permanent injunctive relief.  [Apotex is] hereby permanently enjoined from engaging in the commercial manufacture, use, offer to sell or sale within the United States, or importation into the United States of drug products as claimed in [the ‘265 patent], until the expiration of [the ‘265 patent] and any period of pediatric exclusivity that may be granted.

6. Pursuant to 35 U.S.C. § 271(e)(4) and 21 U.S.C. § 355a [(FDC Act § 505A)], the effective date of [Apotex’s ANDA No. 076274] shall be reset until the later of expiration of (i) [the ‘265 patent] and (ii) any period of pediatric exclusivity that may be granted. [(Emphasis added)]

Fast forward to 2012 . . . .

In April, Apotex submitted a PLAIR to FDA seeking the Agency’s permission to import a substantial amount of generic PLAVIX into the United States in anticipation of FDA approving ANDA No. 076274 on May 17, 2012.  (FDA granted Apotex a PLAIR on May 7th.)  After making the PLAIR request, Apotex filed a motion under Fed. R. Civ. P. 60(b)(6) to modify the New Your District Court’s June 2007 amended judgment by adding the bolded clause below:   

[Apotex is] hereby permanently enjoined from engaging in the commercial manufacture, use, offer to sell or sale within the United States, or importation into the United States of drug products as claimed in [the ‘265 patent], until the expiration of [the ‘265 patent] and any period of pediatric exclusivity that may be granted, except for importation by Apotex to its own warehouse facilities prior to the expiration of the pediatric exclusivity period to the extent such importation is permitted by [FDA] pursuant to a [PLAIR] made by Apotex and granted by the FDA.

In support of its motion, Apotex argued that if the company “is unable to ship goods to customers on May 17, 2012 (because Apotex cannot even begin to import goods to its warehouses until May 17th) Apotex will be at an extreme and undue commercial and competitive disadvantage” vis-à-vis other ANDA applicants who might be in a position to launch their drug products immediately upon FDA approval.  Sanofi opposed the motion saying, among other things, that Apotex’s motion was not made within a reasonable time and that a modification would harm sanofi.  The district court denied the motion on May 10th.  Apotex promptly appealed the decision to the Federal Circuit, which, on May 15th, also denied Apotex’s requested relief, saying that summary reversal of the New York District Court’s decision is not appropriate. 

Although a sideshow in the decade-old clopidogrel patent infringement litigation, the dispute over Apotex’s PLAIR could very well signal the beginning of something much larger.  To our knowledge, it is the first Hatch-Waxman case in which FDA’s PLAIR program has been raised as an issue.  And it probably won’t be the last, as the PLAIR program gains increasing attention and as companies increasingly seek to import finished drug product into the United States in anticipation of FDA approval.  Companies – both brand and generic – may seek to have PLAIR-related language incorporated into agreements and court orders. 

REMINDER:  HP&M is hosting a webinar, Garbage Runs, Fake Identities, and Surprise Home Visits; Strategies to Deal With FDA's Nontraditional Investigative Tools, on Wednesday, June 20, 2012 from 12:30 – 2:00 p.m. ET.  Click here to register.

By JP Ellison –

Virtually all of the mainstream and trade press outlets have covered the recent Abbott resolution with the U.S. Department of Justice regarding allegations of off-label promotion of Abbott’s drug Depakote.  Undoubtedly, the $1.5B price tag and that coverage have made most readers of this blog familiar with the basic facts of the global resolution which has civil, criminal, and administrative aspects.

Much of Abbott will sound familiar to those who follow off-label investigations, prosecutions, and settlements.  The government alleged — and in connection with a misdemeanor plea to misbranding under the FDC Act, Abbott admitted to — unlawful off-label promotion of its drug (see here and here).  In a civil settlement under the Federal False Claims Act, in which there was no admission of liability, Abbott resolved related claims that it caused false claims to be submitted to government healthcare programs.  As the traditional third leg of this global resolution, Abbott entered into a Corporate Integrity Agreement with the HHS OIG.

Beyond these basic facts, what broader questions or answers are presented by this resolution?  First, it is important to remember that this so-called “(C) plea,” represents an agreement with the government, but not necessarily the final word.  As we know from the Purdue agreement, another high profile case from the Western District of Virginia, the judge (in this case Judge Wilson) may have questions for the parties at the September 21, 2012 sentencing hearing.  As you may recall, in the Purdue case, the judge in that case (Chief Judge Jones) posed a series of written questions to the parties before accepting the plea. 

Second, unlike the Purdue case in which four high level individuals also pled guilty, in the present case, no individual pleas were announced in connection with the Abbott resolution, and the publicly available documents contain standard reservation/limitation language, so there is no indication whether additional charges may be brought.  Given the government’s recent statements regarding prosecuting responsible corporate officers (see here and here), one cannot rule out that possibility, however. 

Third, and in keeping with the issue of enforcement actions against individuals, as was the case with the Purdue case, the resolution of the exclusion issue appears limited to the entities, which raises the question of whether (regardless of any criminal prosecution), high level executives may be the subject of exclusion actions (see our previous post). 

Fourth, the first three questions may be addressed indirectly by the terms of probation imposed in the Abbott plea.  As part of the plea, The CEO of the relevant Abbott entity and the Board of Directors have annual certification obligations.  While it is certainly possible that the government could pursue additional sanctions against individuals in parallel with these obligations, it is also possible that these provisions represent the negotiated resolution of individual accountability in connection with this matter.

Fifth, the terms of the Abbott probation and related requirements for the Abbott “Responsible Entity” to ensure that certain policies and procedures are in place, is a reminder of broad authority of courts—and in connection with negotiated plea agreements — the Department of Justice, to impose terms as conditions of corporate probation.  The Organizational Probation provisions of the Sentencing Guidelines were controversial when first promulgated because they raised questions of whether probation offices could or should have the type of wide-ranging authority contemplated by the Guidelines.  In many resolutions similar to Abbott, forward-looking compliance provisions have largely been contained in corporate integrity agreements with the HHS OIG, not the DOJ plea agreements, although in some respects, the use of corporate monitors, particularly in connection with deferred and non-prosecution agreements, was an attempt to achieve probation-like oversight outside the probation office structure.  If nothing else, the Abbott resolution shows that there is significant flexibility within criminal sentencing framework to address a variety of potential compliance issues.

We will be following this case, both to see how the plea agreement is received by the court as well as to see whether its terms of probation become standard in future settlements.

By Riëtte van Laack –

On May 21, 2012, the FTC posted the 345-page Administrative Law Judge’s ("ALJ’s") Initial Decision in In the Matter of POM Wonderful LLC et al. ("POM") (FTC Docket No. 9344).  The ALJ upheld the FTC’s Complaint insofar as the FTC asserted that POM made deceptive claims in some (but not all) advertisements that its products (100% juice and POMs supplements) would treat, prevent, or reduce the risk of heart disease, prostate cancer, and erectile dysfunction because these claims were not supported by sufficient competent and reliable evidence.

However, the ALJ’s Order is a stunning rejection of the FTC’s theory that POM was legally required to have double-blind, randomized placebo-controlled clinical trials to make the claims that the FTC attacked.  The ALJ’s order would merely bar POM from making certain claims unless POM possesses competent and reliable scientific evidence to support the claim.  As clarified in the Initial Decision, however, this standard is not defined as double-blind, randomized, placebo-controlled clinical studies.  In fact, according to the ALJ:

[for health benefit] claims . . . made in connection with a food, or food-derived product that is safe, and that is not being offered as a substitute for medical treatment, double-blind, randomized, placebo-controlled clinical trials, such as those required by the Food and Drug Administration, are not required.  However, . . . claims that a food or food-derived product treats, prevents or reduces the risk of a disease, . . . competent and reliable evidence must include clinical studies, although not necessarily double-blind, randomized, placebo-controlled clinical trials, that are adequate to show that the product did treat, prevent, or reduce the risk of disease.

The ALJ also rejected the Commission’s attempt to require POM to get prior FDA approval for certain claims.  The ALJ held that the FTC’s proposed requirement that POM would be prohibited from making any disease claim in the future unless the claim had been approved or authorized by FDA “would constitute overreaching.”

Both the FTC Staff which prosecuted this case and POM can seek review of this decision by the five FTC Commissioners.  We expect that both parties will seek that review. We also expect that it will take many months before the FTC Commissioners rule on the appeals.

By Jennifer M. Thomas & John R. Fleder –

Last week, the Federal Trade Commission (“FTC”) announced a $40 million settlement with Skechers USA, Inc. (“Skechers” or “the Company”) to resolve charges that the Company made deceptive and unfounded claims that its Shape-up sneakers would help consumers lose weight, strengthen and tone their buttocks, legs, and abdominal muscles.  The FTC also claimed that Skechers made deceptive claims about its Resistance Runner, Toners, and Tone-ups shoes.  See Complaint 12- 16, Federal Trade Commission v. Skechers USA, Inc., No. 1:12-cv-01214 (N.D. Ohio May 16, 2012).

Like the FTC’s similar settlement with Reebok in 2011, reported here, the Skechers settlement provides “compliance nuggets” that can help all advertisers better understand the FTC’s current policies and priorities.  Importantly, the settlement contains a definition of “adequate and well-controlled human clinical study” that likely represents the FTC’s current understanding of that phrase as applied to weight-loss studies:

a clinical study that is randomized, controlled (including but not limited to controlled for dietary intake if testing for weight loss or a reduction in body fat), blinded to the maximum extent practicable, uses an appropriate measurement tool or tools, and is conducted by persons qualified by training and experience to conduct and measure compliance with such a study.

Stipulated Final Judgment and Order for Permanent Injunction and Other Equitable Relief 3-4, No. 1:12-cv-01214 (N.D. Ohio May 16, 2012).

Further, the settlement reinforces the FTC’s prior view that even multiple clinical studies may not satisfy the substantiation standard unless (1) the study results correlate to claims; (2) the study design and data are reliable; and (3) the individual or entity conducting the study is independent of the advertiser.  The FTC claimed that Skechers characterized two of its Shape-ups studies as “independent case studies,” when in fact they were not independent because they were conducted by a chiropractor — Dr. Gautreau — who was a compensated endorser for Shape-ups, and was married to a Skechers senior vice president of marketing.  Complaint at 7.  The FTC’s complaint called into question the reliability of the studies conducted by Dr. Gautreau, alleging that of the four studies Skechers sponsored in support of its Shape-up claims, one lacked a control group, and data from a second were altered or incomplete such that some participants were falsely reported as having lost weight and/or reduced their body fat percentage when in fact they had gained weight and/or increased their body fat percentage.  Id. at 7-8.  The FTC also alleged that some of the second study’s participants were personally connected to the researchers.  Id.

Finally, with this settlement the FTC continues a pattern of focusing on weight-loss claims and imposing a high standard for substantiation on marketers who make such claims.  Under the terms of its FTC settlement, if Skechers chooses to make weight-loss claims in the future the Company will need two adequate and well-controlled human clinical studies, conducted by different researchers independently of each other, to substantiate those claims.  Stipulated Final Judgment at 5-6.  Only one adequate and controlled human clinical study is required for strengthening claims, but it must be at least six weeks in duration.  Id.

By Michelle L. Butler –

Abbott Laboratories (“Abbott”) recently submitted a citizen petition to FDA regarding biosimilars under the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  Specifically, the citizen petition requests that FDA not accept for filing, file, approve, or discuss with any company any application or any investigational new drug application (“IND”) for any biosimilar that cites as its reference product any product for which the biologics license application (“BLA”) was submitted to FDA prior to the date on which the BPCIA was enacted.  The citizen petition focuses on Abbott’s approved BLA for Humira® (adalimumab), but it requests the same treatment for all BLAs submitted to FDA prior to the March 23, 2010 enactment date of the BPCIA as part of the Affordable Care Act.

The grounds for the citizen petition are that approving a biosimilar that relies on a reference product approved under a BLA pursuant to section 351(a) of the Public Health Service Act (“PHS Act”) would constitute a taking under the Fifth Amendment to the U.S. Constitution that requires just compensation.  The citizen petition argues that the Constitutional issue raised is timely and urgent given the fact FDA has already received numerous requests for pre-IND meetings for proposed biosimilar products.  Petition at 7.

Abbott’s argument in the citizen petition is as follows:

• The information contained in a BLA is trade secret information under both federal and state law.

• Abbott has invested significant resources in developing Humira and obtaining approval of the Humira BLA and has taken care to protect the trade secret information contained in the Humira BLA.

• Until the passage of the BPCIA, the PHS Act and FDA’s implementing regulations, as well as repeated statements by FDA and FDA’s practice, made it clear that information contained in a BLA could not be used for the benefit of competitors and that FDA lacked authority to approve a follow-on product that relied on an approved BLA. 

• Given the considerable investment Abbott made in its BLA and the statutory scheme as implemented by FDA, Abbott has a reasonable, investment-backed expectation that its trade secret information would be protected.

• By its nature, the abbreviated pathway for approval of a biosimilar would use the trade secret information contained in a BLA.  This is the case despite FDA’s statements in the 505(b)(2) context that it relies on the “findings” of safety and effectiveness and does not directly use the trade secret information. 

• Use of the information in the Humira BLA to approve a biosimilar would upset Abbott’s reasonable, investment-backed expectation and therefore effect a taking.

• A taking without just compensation violates the Fifth Amendment. 

• FDA should not interpret the statute in a way that would result in the imposition of large liabilities on the United States and should therefore apply the BPCIA prospectively only.

The citizen petition discusses in some detail the jurisprudence under the takings clause of the Fifth Amendment, describing Ruckelshaus v. Monsanto Co., 467 U.S. 986 (1984), as holding that “when an applicant submits trade secret data as part of a license application, at a time when the government has provided assurances through law, regulation and/or agency guidance that the data will not be used by the agency to benefit a competitor of that applicant, later ‘consider[ation of] those data [by the agency] in evaluating the application of a subsequent applicant’ would frustrate the applicant’s ‘reasonable investment-backed expectation’ that the data would, instead, remain inviolate.”  Petition at 11 (quoting Monsanto, 467 U.S. at 1011).  The citizen petition further states that “[t]he principles set out in Monsanto establish that FDA would take property, and the government would be required to pay just compensation, were FDA to use trade secrets, submitted in a reference product BLA before the BPCIA’s enactment, in the course of evaluating and approving a biosimilar application.”  Petition at 12.  In order to avoid the Constitutional issue, FDA should grant the relief requested by Abbott and not accept for filing, file, approve, discuss, or otherwise take any action with regard to any IND or BLA for a product for which the reference product BLA was submitted prior to March 23, 2010.

One thing the citizen petition does not address is whether the statutory scheme provided in the BPCIA, including 12-year exclusivity for reference products, provides the requisite just compensation to keep the bargain from running afoul of the takings clause.  Interestingly, the citizen petition incorporates arguments raised by Constitutional law scholar Richard A. Epstein in a paper published last year.  Abbott supported Mr. Epstein's research on the project.

By Riëtte van Laack –

Last week, the Food Safety and Inspection Service (“FSIS”) issued a proposal to lift the general prohibition against the use of sodium benzoate, benzoic acid, and sodium propionate in meat and poultry.  Historically, the use of these substances in meat and poultry has been prohibited because they might conceal damage or inferiority or make a meat or poultry product appear better or of greater value.  See 9 C.F.R. § 424.23.  Notwithstanding the general prohibition, FSIS can allow specific uses of the substances in meat and poultry, but the agency must do so through rulemaking.

In 2007, Kraft Foods petitioned FSIS to amend the regulations and allow the use of certain combinations of sodium benzoate and sodium propionate, and other already permitted substances as antimicrobials in certain ready-to-eat (“RTE”) meat and poultry products.  Subsequently, in 2010, Kemin Food Technologies petitioned FSIS to permit the use of the same substances (but in different combinations) in various RTE meat and poultry products.  Both Petitions included data regarding the suitability of the formulations as antimicrobial (specifically as anti-listerial) agents and data regarding the effect of the substances on the shelf life and other quality parameters.  In support of safety, the Petitions referred to FDA’s GRAS affirmation regulations, 21 C.F.R. §§ 184.1021, 184.1733, and 184.1784.  However, those GRAS affirmation regulations were promulgated in 1973 and 1979, a time period during which use of these substances was generally prohibited in meat and poultry.

FSIS states that it concluded, based on data included in the Petitions, that the proposed uses of sodium benzoate, benzoic acid, and sodium propionate are suitable, i.e., do not mask or conceal damage or inferiority and do not extend shelf life of the RTE meat and poultry products.  However, instead of engaging in rulemaking to allow the specific uses that are the subject of the Petitions, FSIS proposes to lift the general prohibition on the use of these substances altogether.  By lifting the general prohibition rather than amending the regulations to allow specific uses, FSIS avoids future rulemaking regarding additional uses of these substances.  As explained in the proposal, under a 2000 Memorandum of Understanding (“MOU”), FSIS and FDA collaborate on the review of submissions each agency receives regarding the use of food ingredients used in the production of meat or poultry products.  Under this MOU, FDA evaluates safety of the intended use and FSIS evaluates suitability of the intended use.  When FSIS concludes that an ingredient is safe and suitable for its intended use, FSIS includes the ingredient in FSIS Directive 7120.1. This determination does not involve FSIS rule making. 

Comments are due by July 6, 2012.

REMINDER: HP&M is hosting a webinar, Garbage Runs, Fake Identities, and Surprise Home Visits; Strategies to Deal With FDA's Nontraditional Investigative Tools, on Wednesday, June 20, 2012 from 12:30 – 2:00 p.m. ET.  Click here to register.

By Kurt R. Karst –      

A lot has happened since we last updated our Generic Drug Labeling Carve-Out Citizen Petition Scorecard in October 2011.  At that time, AstraZeneca had only recently submitted two citizen petitions concerning quetiapine fumarate (SEROQUEL and SEROQUEL XR).  Petitions, FDA decisions, lawsuits, and court decisions have abounded since.  So we thought it was high time for us to update our popular scorecard and add a few more bells and whistles, such as FDC Act § 505(j)(10) Citizen Petitions and Approval Precedents (see our previous post here for background), and, given the increasing frequency with which FDA issues petition decisions without comment, a section on Non-Response Denials of Labeling Carve-Out Citizen Petitions.  But before you jump down this post to our updated scorecard, let’s take a minute to take stock of the last 7+ months . . . .

FDA has responded to a several labeling carve-out petitions over the last few months.  Some of the responses have been no comment denials, including responses to petitions on generic SEROQUEL and SEROQUEL XR concerning the scope and applicability of 3-year exclusivity.  (In that case, FDA ultimately issued a letter decision explaining how the Agency handled the exclusivity vis-à-vis generics.)  And just last week, FDA denied without comment another petition concerning generic CRESTOR (rosuvastatin calcium) Tablets.  In that response, FDA said that given the status of patent infringement litigation “it is unnecessary for FDA to analyze the precise contours of AstraZeneca’s 3-year exclusivity and its consequences, if any, for the labeling of proposed [ANDA and 505(b)(2) products] at this time.” 

FDA has also issued petition decisions providing the Agency’s initial interpretations of two relatively new provisions of the FDC Act.  First, in denying a petition concerning generic DORYX (doxycycline hyclate) Delayed-Release Tablets, FDA interpreted FDC Act § 505(j)(10), which was added to the statute by Sec. 10609 of the Affordable Care Act (the so-called “generic loophole” provision).  Second, in denying a petition concerning generic VANCOCIN (Vancomycin HCl) Capsules, FDA interpreted the availability of 3-year exclusivity for an “old antibiotic” under FDC Act § 505(v) as added by the 2008 QI Act (see our previous post here). 

FDA’s petition decisions have also ended up in court.  Both before and after approving generic versions of SEROQUEL, AstraZeneca sued FDA (see our previous posts here and here).  The U.S. District Court for the District of Columbia denied AstraZeneca’s Motion for Temporary Restraining Order seeking to vacate FDA’s ANDA approval decisions and to enjoin the future approvals.  On April 11, 2012, FDA filed a Motion to Dismiss the case.  FDA was also sued after approving generic VANCOCIN and denying ViroPharma’s citizen petition.  The D.C. District Court promptly denied ViroPharma’s Motion for a Temporary Restraining Order and/or Preliminary Injunction, and in doing so deferred to FDA’s interpretation of the QI Act (among other things).

Generic Drug Labeling Carve-Out Citizen Petition Scorecard

FDA Citizen Petition Responses Permitting a Labeling Carve-Out

• FDA Response, Docket Nos. 2001P-0495, 2002P-0191, FDA-2002-P-0003 (June 11, 2002) – ULTRAM (tramadol HCl)
• FDA Response, Docket Nos. 2001P-0495/PRC, 2002P-0191/PRC, FDA-2002-P-0003/PRC (Mar. 31, 2003) – ULTRAM (tramadol HCl)
• FDA Response, Docket No. FDA-2003-P-0074 (Apr. 6, 2004) – REBETOL (ribavirin)
• FDA Response, Docket No. FDA-2005-P-0368 (Dec. 1, 2006) – OXANDRIN (oxandrolone)
• FDA Response, Docket No. FDA-2006-P-0274 (Mar. 13, 2008) – ETHYOL (amifostine)
• FDA Response, Docket No. FDA-2007-P-0169 (Apr. 25, 2008) – MARINOL (dronabinol)
• FDA Response, Docket No. FDA-2008-P-0304 (June 18, 2008) – ALTACE (ramipril)
• FDA Response, Docket No. FDA-2008-P-0069 (July 28, 2008) – CAMPTOSAR (irinotecan HCl)
• FDA Response, Docket No. FDA-2006-P-0073 (Nov. 18, 2008) – PULMICORT Respules (budesonide inhalation suspension)
• FDA Response, Docket Nos. FDA-2008-P-0343 & FDA-2008-P-0411 (Dec. 4, 2008) – PRANDIN (repaglinide)
• FDA Response, Docket No. FDA-2008-P-0343/PRC and PSA & FDA-2008-P-0411 (June 16, 2009) – PRANDIN (repaglinide)
• FDA Response, Docket No. FDA-2009-P-0411 – ACTOS (pioglitazone HCl) & ACTOPLUS MET (March 15, 2010) (pioglitazone HCl; metformin HCl)
• FDA Response, Docket No. FDA-2009-P-0601 (June 17, 2010) – NAROPIN (ropivacaine HCl monohydrate)
• FDA Response, Docket No. FDA-2010-P-0087 (July 30, 2010) – LYRICA (pregabalin) 
• FDA Response, Docket No. FDA-2010-P-0545 (Feb. 24, 2011) – XYZAL (levocetirizine dihydrochloride)
• FDA Response, Docket No. FDA-2011-P-0128 (May 11, 2011) – XIBROM/BROMDAY (bromfenac)
• FDA Response, Docket No. FDA-2011-P-0702 (Feb. 8, 2012) – DORYX (doxycycline hyclate)
• FDA Letter Decision, Related to Docket Nos. FDA-2011-P-0662 & FDA-2011-P-0663 (Mar. 27, 2012) – SEROQUEL (quetiapine fumarate)
• FDA Response, Docket No. FDA-2006-P-0007 (Apr. 9, 2012) – VANCOCIN (Vancomycin HCl) Capsules

FDA Citizen Petition Responses Not Permitting a Labeling Carve-Out

• FDA Response, Docket No. FDA-2003-P-0002 (Sept. 20, 2004) – RAPAMUNE (sirolimus)
• FDA Response, Docket No. FDA-2010-P-0614 (May 25, 2011) – COLCRYS (colchicine)

Pending Labeling Carve-Out Citizen Petitions

• Docket No. FDA-2007-P-0294 – ACTOS (pioglitazone)
• Docket No. FDA-2007-P-0113 – THALOMID (thalidomide)
• Docket No. FDA-2009-P-0581 – BAYTRIL (enrofloxacin) (Animal Drug)
• Docket No. FDA-2009-P-0597 – Fluticasone Propionate and/or Salmeterol Xinafoate Products
• Docket No. FDA-2010-P-0403 – VAGIFEM (estradiol)
• Docket No. FDA-2011-P-0482 – VAGIFEM (estradiol)  

Non-Response Denials of Labeling Carve-Out Citizen Petitions

• FDA Response, Docket No. FDA-2011-P-0662 (Mar. 7, 2012) – SEROQUEL (quetiapine fumarate)
• FDA Response, Docket No. FDA-2011-P-0663 (Mar. 7, 2012) – SEROQUEL XR (quetiapine fumarate) 
• FDA Response, Docket No. FDA-2011-P-0823 (May 11, 2012) – CRESTOR (rosuvastatin calcium)

BPCA Section 11 Pediatric Labeling Citizen Petitions

• FDA Response, Docket No. FDA-2001-P-0053 (January 24, 2002) – BPCA Implementation
• FDA Response, Docket No. FDA-2002-P-0289 (May 21, 2003) – ALPHAGAN (brimonidine)
• FDA Response, Docket No. FDA-2010-P-0545 (February 24, 2011) – XYZAL (levocetirizine dihydrochloride) 

FDC Act § 505(j)(10) Citizen Petitions and Approval Precedents

• FDA Response, Docket No. FDA-2011-P-0702 (Feb. 8, 2012) – DORYX (doxycycline hyclate) Delayed-Release Tablets
• ANDA No. 076786, Donepezil Hydrochloride Tablets, 5 mg and 10 mg
• ANDA No. 078388, Donepezil Hydrochloride Orally-Disintegrating Tablets, 5 mg, and 10 mg
• ANDA No. 077431, Exemestane Tablets, 25 mg
• ANDA No. 076361, Levofloxacin Tablets, 250 mg, 500 mg, and 750 mg
• ANDA No. 077179, Amlodipine besylate and Benazepril HCl Capsules, 5 mg (base)/40 mg and 10 mg (base)/40 mg

Moot/Withdrawn/“Dead” Labeling Carve-Out Citizen Petitions

• Docket Nos. FDA-2004-P-0426 & FDA-2003-P-0081; FDA Letter Decision – SKELAXIN (metaxalone) (see our previous post here)
• Docket No. FDA-2001-P-0445 – NEURONTIN (gabapentin) Capsules
• Docket No. FDA-2005-P-0368 (Petition for Reconsideration; Dec. 5, 2006) – OXANDRIN (oxandrolone)
• Docket No. 1997P-0178 – TORADOL (ketorolac tromethamine)

By Riëtte van Laack –

On May 8, 2012, the Food Safety and Inspection Service (“FSIS”) published three sets of regulations mandated by the 2008 Farm Bill: (1) regulations requiring that meat and poultry plants promptly (within 24 hrs) notify FSIS that a contaminated or misbranded product has been released into commerce; (2) regulations requiring that meat and poultry plants prepare written recall procedures; and (3) regulations that require that plants document the mandatory annual reassessment of their HACCP plans, and the reason for actions taken pursuant to that reassessment.  The final regulations are similar to the proposed regulations published in 2010 (see our previous post here). 

Although the requirement to notify FSIS of the release into commerce of a contaminated product resembles the reporting duty under the Reportable Food Registry for foods under FDA jurisdiction, FSIS’s regulation is broader.  The reporting duty applies to any violation, including misbranding, and is not limited to only those instances that involve a reasonable probability of serious adverse health consequences or death.  Reporting, however, can be done by a phone call, e-mail, fax or other communication method.

Under the new regulations, any new meat or poultry plant must develop written recall procedures in order to receive a Federal Grant of Inspection.  The compliance date for already existing facilities depends on the size of the plant.  Plants with 500 or more employees have six months to develop their written recall procedures and plants with less than 500 employees have 12 months to develop such procedures.  FSIS intends to make model recall procedures available.

Current regulations require that meat and poultry plants reassess their HACCP plans at least once a year.  The new requirement to prepare written documentation about this reassessment is added to aid FSIS verification that plants comply with the regulations.  Moreover, FSIS anticipates that this documentation will aid in identifying emerging issues and provide assurance that plants address emerging hazards that the Agency identifies during the year.

The requirements for prompt notification and written recall procedures are expected to help facilitate the prompt removal of unsafe meat and poultry products from commerce.  

By Ricardo Carvajal –

April was a busy month for nanotechnology at FDA.  The agency issued two draft guidance documents worthy of close examination for those with an interest in the use of emerging technologies, including nanotechnology, in the cosmetic and food industries.  Further, FDA denied a citizen petition asking the agency to stop the marketing of sunscreen drug products that contain engineered nanoparticles of zinc oxide and titanium dioxide.

The first draft guidance document, Safety of Nanomaterials in Cosmetic Products, begins by emphasizing manufacturers’ responsibility to substantiate the safety of their products prior to marketing.  It then notes that different properties of materials might emerge at the nanoscale such that standard safety tests “may not be fully applicable,” and that such tests “may need to be modified or new methods developed” to address effects on toxicity and functionality.  The remainder of the guidance discusses nanomaterial characterization and toxicology considerations in some detail, and encourages manufacturers who wish to use nanomaterials in cosmetics to consult with FDA.

The second draft guidance document, Assessing the Effects of Significant Manufacturing Process Changes, Including Emerging Technologies, on the Safety and Regulatory Status of Food Ingredients and Food Contact Substances, Including Food Ingredients that are Color Additives, is not strictly limited to nanotechnology.  However, it is clear that changes in manufacturing processes that arise as the result of the use of nanotechnology are a principal concern.  As with the cosmetics guidance discussed above, the food guidance begins by emphasizing manufacturers’ responsibility to ensure that their products are safe and lawful.  It then discusses the legal framework for food and color additives, as well as FDA’s approach to assessing the safety of food substances.  Finally, it presents considerations and recommendations for assessing the potential impacts of significant manufacturing changes (e.g., changes in starting materials, catalysts, or manufacturing technologies) on safety and regulatory status.

FDA cites both of the above guidance documents in its partial denial of a citizen petition submitted by the International Center for Technology Assessment ("ICTA") in May 2006.  That petition, which preceded the creation of FDA’s Nanotechnology Task Force, asked the agency to create a new regulatory framework specific to nanoscale particles, and for product recalls and a development moratorium for sunscreen drug products that contain engineered nanoparticles of zinc oxide and titanium dioxide.  FDA’s response to the citizen petition lays out a thorough defense of the agency’s current approach to nanotechnology – including the agency’s position that adoption of a nanotechnology-specific regulatory framework currently is not appropriate “as a matter of science and policy.”

Although FDA cites progress in its response to the challenges posed by nanotechnology, the latest report on the National Nanotechnology Initiative ("NNI") by the President’s Council of Advisors on Science and Technology ("PCAST") concludes that “individual agency contributions” to the NNI strategic plan “lack the cohesion of an overarching framework.”  Currently, FDA is one of only a few agencies that have a strategic research plan for nanotechnology.  According to PCAST, “[t]he process for producing the strategic plan is still agency-driven, which could limit the broader NNI vision to those objectives that agency officials feel are sufficiently within reach.  Also lacking is a clear connection between the goals and objectives of the NNI strategic plan and those of individual agencies.”  PCAST makes numerous recommendations in relation to strategic planning, program management, metrics to track progress, and efforts to address environment, health, and safety risks.  As noted in the PCAST report, research and development in nanotechnology continue to be of great interest to governments and industries worldwide.

By Jennifer D. Newberger –

On May 7, 2012, Representative Lois Capps introduced the “Sentinel Assurance for Effective Devices Act of 2012” (H.R. 5341), many elements of which were also included in the House of Representatives Energy and Commerce Health Subcommittee user fee bill (see here).  The primary purpose of the bill seems intended to allow FDA to more regularly collect, review, and trend adverse event data for medical devices.  The bill accomplishes this in two ways:  First, it would amend the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to include medical devices in the postmarket risk analysis and identification system currently applicable only to drugs.  Second, it would require FDA to issue a final rule regarding a unique device identification (“UDI”) system by December 31, 2012.

With regard to the first purpose, the bill would amend section 505(k)(3)(C) of the FDC Act to expand the postmarket risk identification and analysis system established under that section to include and apply to devices.  This would require FDA to establish and maintain procedures for risk identification and analysis based on electronic health data, and to provide for “active adverse event surveillance” using federal health-related electronic data and private sector health-related electronic data, such as medical device utilization data, health insurance claims data, and procedure and device registries.  It would also require FDA to identify trends and patterns regarding the data accessed by the system, and to create reports concerning adverse event trends, patterns, incidence, and prevalence.  The bill states that FDA should give priority to postmarket risk identification and analysis with respect to class II and class III devices.

The second part of the rule is to encourage FDA to finally issue in final form the UDI rule it was mandated to promulgate in the Food and Drug Administration Amendments Act of 2007.  When implemented, (1) the label of a device will bear a unique identifier, unless an alternative location is specified by FDA or unless an exception is made for a particular device or group of devices; (2) the unique identifier will be able to identify the device through distribution and use; and (3) the unique identifier will include the lot or serial number if specified by FDA.  These features are intended to make devices easier to track for purposes of adverse event and recall tacking.  The Sentinel Assurance Act would require FDA to implement the UDI system for class III devices within one year after the date final regulations are issued; within three years for implantable, life-sustaining, and life-supporting devices; and within five years for all other devices.

This bill is undoubtedly one more attempt to obtain information about the safety (or risk) of medical devices.  Notably absent, however, is what FDA would do with the data obtained.  Simply gathering data without clear plans for how to use the information may impose resource burdens without commensurate benefits. Presumably it would be up to FDA to determine how best to use this information.  Hopefully, this determination will include input from stakeholders to assure it is appropriately and meaningfully used.

Hyman, Phelps & McNamara P.C. invites you to register for our webinar, “Garbage Runs, Fake Identities, and Surprise Home Visits: Strategies to Deal With FDA's Nontraditional Investigative Tools,” which is scheduled to take place on Wednesday, June 20, 2012 from 12:30 – 2:00 p.m. ET. 

From routine on-site inspection to rummaging through trash bins outside your facility, FDA and other government agents have shown increasing willingness to obtain information outside of just conducting regulatory inspections of company facilities.  This webinar will provide an overview of popular, and not so well-known, tactics that the government uses, followed by a discussion of strategies to help your company to prepare for, and if necessary, respond to them.  Participants will gain an understanding of how to deal with the government's demands for information, directed to the company, its current employees, and even former employees, while protecting the company's interests.

The webinar will feature HP&M attorneys Doug Farquhar, John Fleder, and Anne Walsh, who bring the full perspective of experience in government enforcement, including a former Assistant U.S. Attorney, the former Director of DOJ's Office of Consumer Litigation, and a former Associate Chief Counsel at FDA.  They will:

• Share insights from their experiences in the government; 
• Describe trends on government enforcement efforts using these investigative techniques; 
• Analyze publicly disclosed cases; 
• Provide strategies for preparing your company before the government even begins its scrutiny, and responding when the government arrives; and
• Answer participants' questions during the webinar

You can register for this free webinar here.  Please contact Lisa Harrington (lharrington@hpm.com) with any questions.

By Kurt R. Karst –      

Two new reports were published this week analyzing FDA’s performance under the Prescription Drug User Fee Act (“PDUFA”).  The reports – one from the California Health Institute (“CHI”) and The Boston Consulting Group (“BCG’), and another from the Tufts Center for the Study of Drug Development (“CSDD”) – come on the heels of a report from the Government Accountability Office saying that FDA has met most of the Agency’s PDUFA performance goals for priority and standard original NDA and BLA submissions and for priority and standard original efficacy supplements to approved NDAs and BLAs.  The reports also surfaced just a day before the House Energy and Commerce Committee takes up consideration of legislation (H.R. 5651) to ensure the continuation of existing FDA user fee programs for drugs and devices, to create new user free prograns for biosimilars and generic drugs, and that includes a host of other provisions including drug and device regulatory reforms (see here).  (The U.S. Senate’s version of the bill is S. 2516 – the FDA Safety and Innovation Act.) 

The CHI/BCG report, titled “Managing Priorities: Therapeutic Area Variation in FDA Drug Regulation,” updates a February 2011 CHI/BCG report, titled “Competitiveness and Regulation: The FDA and the Future of America’s Biomedical Industry,” that examined FDA’s drug and biologic approval performance over the past several years.  The new report also presents new data on FDA performance differences based on therapeutic area.

According to the CHI/BCG analysis, “[i]n 2009, the average drug approval time marginally improved from the PDUFA III period (by 1.3 percent) to 14.5 months.”  Although a review of submissions through Fiscal Year 2011 “suggests improvement in approval times,” according to the report, “[l]ooking at new drugs submitted to the Agency in 2008 . . . shows approval timelines getting longer; 45 percent of those submissions remained in process more than a year before the Agency took regulatory action.”

Moving on to therapeutic area variations in FDA performance, the CHI/BCG report says that while oncology, infectious disease, and orphan diseases are “bright spots,” there are significant review time deviations depending on a product’s therapeutic area.  For example, “between 2000 and 2011, oncology and antiinfective drugs . . . experienced the fastest reviews, on the order of 10-15 months,” while “[f]or other categories – cardiovascular, central nervous system, gastro-intestinal, respiratory, etc. – average review times stretched from 20 to 30 months” (see the figure below from the report). 

“No single factor explains differences in performance among therapeutic areas,” says the report, but rather, a confluence of factors.  “Some fields may be scientifically more complicated, with fewer biomarkers or with poorly understood mechanisms of action for novel drugs.”  In addition, regulatory pathways in the areas of diabetes, obesity, and cardiovascular disease, which “exert enormous, and growing damage on health, . . . are fraught with uncertainty.”  This leads the report authors to recognize that “PDUFA V is essential to provide the Agency the core resources it needs to regulate drugs,” but that more work is needed to “[bring] drug approvals into better alignment with public health needs [with] continuous improvements in management, infused with science and common sense.”

The CSDD report, titled “User fee era in U.S. currently poses mixed regulatory burden for sponsors,” shows the results of a top-tier industry working group that was asked to consider two questions in light of the various regulatory enhancements that were made as part of the 2007 FDA Amendments Act (“FDAAA”):  “1) Has there been a detectable increase in the regulatory burden pre-FDAAA vs. post-FDAAA? and 2) What specific requirements/actions in the approval process are particularly problematic?”  According to the Tufts CSDD Impact Report, among other things:

• The regulatory burden from the pre- to post-FDAAA period largely decreased for New Molecular entity (“NME”) NDA and new BLA approvals in the number of Complete Response letters, share of multi-cycle approvals, average number of FDA-sponsor meetings, number of countries in which product was launched, and increase in annual regulatory budget.
• The regulatory burden from the pre- to post-FDAAA period increased for supplemental NDA and BLA approvals in the number of Complete Response letters and regulatory outsourcing. 
• The difference between optimal and sub-optimal sponsor experiences with the FDA review process was less for NME NDAs and new BLAs than for NDA and BLA supplements.  FDA information requests and first cycle actions were shown to have the most consistent impact on a sponsor’s regulatory experience. 

Christopher-Paul Milne, an associate director at Tufts CSDD and who conducted the assessment, commented in a press release that “[w]hile user fees have helped to streamline and speed up the drug review and approval process in the Untied States over the last two decades, certain requirements on developers remain especially problematic . . . PDUFA V provides an opportunity to resolve some of these issues and concerns.”

UPDATE:

• On May 10th, the House Energy and Commerce Committee passed H.R. 5651 by a roll call vote of 46-0.  An amendment submitted by Rep. Joe Barton (R-TX) to reduce the amount of PDUFA, MDUFA, GDUFA, and BSUFA fees by 20% if FDA does not make “adequate progress” toward achieving the agreed upon application review goals was withdrawn.