By Kurt R. Karst –      

Last Friday, ViroPharma Incorporated (“ViroPharma”) filed a Complaint and a Motion for Temporary Restraining Order And/Or Preliminary Injunction in the U.S. District Court for the District of Columbia challenging FDA’s approval of three ANDAs for generic versions of ViroPharma’s VANCOCIN (vancomycin HCl) Capsules (Case No. 1:12-cv-00584-ESH).  The lawsuit follows FDA’s April 9, 2012 response to a March 2006 petition for stay of action submitted by ViroPharma (and supplemented on several occasions since).  FDA largely denied ViroPharma’s requests and approved ANDAs for generic VANCOCIN (see our previous post here).  FDA determined that the Agency “has clear legal authority to recommend in vitro dissolution data to demonstrate generic vancomycin bioequivalence,” and that a December 2011 supplemental NDA FDA approved for VANCOCIN is not eligible for 3-year exclusivity because of the limitation on such exclusivity for a so-called “old antibiotic” like vancomycin set forth in FDC Act § 505(v) as added by Section 4 of the 2008 QI Act.

According to ViroPharma, FDA violated the Administrative Procedure act (“APA”) “by adopting and applying in vitro dissolution testing as the bioequivalence testing method for vancomycin, in direct conflict with the FDA’s own regulations, and by basing its approval of the three generic vancomycin ANDAs on this improper in vitro testing.”  In approving ANDAs for generic VANCOCIN, says ViroPharma, “FDA did not follow its own rules, the plain text of which require that bioequivalence be established through in vivo testing absent a waiver unavailable under the circumstances at issue here.  Accordingly, the agency’s ‘deviant action’ must be invalidated.”   FDA’s regulations at 21 C.F.R. Part 320 discuss the various requirements for bioequivalence testing, including the various types of tests available to meet in vivo or in vitro requirements. “Nowhere in § 320.22, or anywhere else in the regulations, does it state that FDA has discretion to approve ANDAs based solely on in vitro testing whenever it chooses and regardless of whether any of the circumstances in § 320.22 are satisfied,” says ViroPharma.

With respect to FDA’s denial of 3-year marketing exclusivity, ViroPharma alleges that FDA violated the APA and the FDC Act (§ 505(c)(3)(E)(iv) & § 505(j)(5)(F)(iv)).  According to ViroPharma:

FDA erred in concluding that every one of the recent fundamental and extensive changes to Vancocin’s labeling constitutes a “condition of use for which” Vancocin “was [previously] approved.”  To the contrary, virtually all of those changes, including in particular the new renal monitoring and dosing requirements, constitute new conditions of use not previously approved, and ViroPharma is therefore entitled to three-year exclusivity (running from December 14, 2011, to December 15, 2014) for its new label.  Critically, even if just one of Vancocin’s labeling changes qualifies for exclusivity, then the entire basis for the FDA’s rejection of exclusivity and hence for approving the generic vancomycin ANDAs is undermined. 

ViroPharma seeks an Order and Judgment holding unlawful and setting aside FDA’s in vitro bioequivalence method for vancomycin, FDA’s petition denial, and FDA’s ANDA approvals.  ViroPharma also seeks an Order and Judgment compelling FDA to grant a period of 3-year exclusivity for VANCOCIN, and enjoining FDA from granting further ANDA approvals.

The case has been assigned to Judge Ellen S. Huvelle, who is also handling a challenge to 180-day marketing exclusivity for a generic version of Cephalon’s PROVIGIL (modafinil) Tablets (see our previous post here).  Late last Friday, Judge Huvelle issued a Minute Order ordering the government to file its response to ViroPharma’s Motion for a Temporary Restraining Order by no later than Tuesday, April 17, 2012, at 5:00 PM, and also ordering that any party seeking to intervene to file its response by no later than Tuesday, April 17, 2012, at 5:00 PM.  A hearing on ViroPharma’s Motion for a Temporary Restraining Order is set for Thursday, April 19, 2012, at 2:30 PM.

ViroPharma’s challenge to FDA’s denial of 3-year marketing exclusivity is the second such challenge in recent weeks involving 3-year marketing exclusivity.  Currently pending before the D.C. District Court are Motions for Summary Judgment filed by FDA and AstraZeneca Pharmaceuticals LP (here and here) concerning FDA’s approval of ANDAs for generic versions of SEROQUEL (quetiapine fumarate) Tablets and the Agency’s decision, discussed in a March 27, 2012 Letter Decision, concerning the scope and applicability of 3-year marketing exclusivity in that case. 

By Karla L. Palmer –

Franck’s Lab Inc., a pharmacy that compounds veterinary drugs and whose bulk animal drug compounding activities were vindicated by a Florida federal district court last year, recently filed its Brief for the Appellees in the matter of United States v. Franck’s Lab, Inc., et al. (11th Cir. No.11-15350-BB).  Franck’s papers respond to the government’s earlier-filed opening brief arguing in favor of reversal of the district court’s decision.  As reported here, after engaging in a complex historical analysis of the statutory and regulatory framework concerning pharmacy compounding, the lower court denied the government’s request for an injunction against Franck’s animal dug compounding practices.  It held that FDA’s “maximalist position” of attempting to assert authority over traditional pharmacy compounding in the context of a pharmacist-veterinarian-patient relationship is contrary to the intent of the Federal Food, Drug and Cosmetic Act (“FDCA”). 

Franck’s Labs’ appellate brief describes how the government’s district court case rested solely on the FDA’s expansive authority to regulate pharmacy compounding of animal drugs as provided in the 1938 FDCA and nothing else.  Br. at 26.  Specifically, Franck’s Lab states that the government’s position below was a “per se” one: The 1938 FDCA prohibits all pharmacy compounding, which industry practice has continued only as a matter of FDA’s unreviewable enforcement discretion.  Thus, when Congress enacted the FDCA in 1938, it “quietly criminalized” all pharmacy compounding practices, yet had exercised enforcement discretion for 50 years.   

Franck’s chastises the government for purportedly abandoning on appeal its unsuccessful per se approach.  For example, the government argues on appeal that FDA’s authority to regulate animal drug compounding is found not only in the plain meaning and construction of the 1938 FDCA, but also in a host of various other authorities including: (1) statutory pronouncements including the Animal Medicinal Drug Use Clarification Act (“AMDUCA”) and the Food and Drug Administration Modernization Act of 1997 (“FDAMA”); (2) AMDUCA regulations; (3) compliance policy guides; and (4) case law.   

One by one, Franck’s picks off each of the government’s arguments, stating that the government did not assert them or unequivocally abandoned them at the district court.  Specifically, when addressing the government’s legal theory on appeal versus at the district court, Franck’s states that the “[G]overnment made clear that its legal theory in its papers and at various oral arguments that its case was based only on the “original law” of the 1938 statute (i.e., the government’s “per se” theory).  The government conceded as inapplicable to this case both AMDUCA (which “doesn’t touch compounded drugs.” Br. at 51); and FDAMA (which only intended to clarify application of the FDCA to compounded human drugs).  Br. at 23; 50-52.   

The Franck’s Labs appellees similarly state that the government raises other arguments that it abandoned below, including allegations that Franck’s engaged in illegal manufacturing in the guise of compounding, noting that the government’s argument below as not so constrained (i.e., the government asserted “from the get-go any kind of compounding,” using bulk ingredients “is unlawful”.)  Br. at 62.  Franck’s further claims that the government never attempted to promulgate an enforceable regulation that interprets the FDCA, FDAMA or AMCDUCA as prohibiting traditional pharmacy compounding of animal medications, which business FDA has recognized for over 50 years to be within the province of state laws.  Br. at 19.  Franck’s also argues that the government’s interpretation of the FDCA (a penal statute) invites arbitrary enforcement, rendering the government's understanding unconstitutional. 

Bolstering its argument, Franck’s Labs notes that, in five decades, FDA had never exercised its unreviewable enforcement discretion against a veterinary compounder other than Franck’s.  Thus, Franck’s Labs claims that the government’s enforcement action was at least arbitrary if not retaliatory, and thus not lawful enforcement activity.  Br. at 23.  In any event, Franck’s asserts, there can be no issue of whether the government may exercise enforcement discretion in this case, “unless the prohibition the government seeks to enforce exists.”  Br. at 60. 

The Washington Legal Foundation filed a brief of amicus curiae in support of affirmance of the lower court’s decision.  It adds that the FDA cannot be permitted to impose a new rule of general applicability on the compounding industry without engaging in notice-and-comment rulemaking pursuant to the Administrative Procedure Act, which point the district court strongly addressed in its ruling last year.  The Animal Health Institute and the Generic Animal Drug Alliance have each submitted a brief of amicus curiae in support of reversal of the lower court’s decision (here and here).  The government’s reply brief is due May 1. 

By Riëtte van Laack –

In an April 3, 2012 letter to FDA Commissioner Dr. Margaret Hamburg, Senator Richard Durbin (D-IL) requests that FDA take action against energy drinks containing “exceptionally high” levels of caffeine and other possibly stimulating substances such as guarana and ginseng. 

Caffeine is Generally Recognized as Safe (“GRAS”) for use in cola-type beverages at levels up to .02% – about 71mg in a 12 ounce beverage.  Sen. Durbin’s letter states that certain energy drinks contain 160 mg/16 oz. (not counting the caffeine from substances such as guarana). Based on a report by the Substance Abuse and Mental Health Services Administration, Sen. Durbin maintains that energy drinks pose potentially serious health risks, and that the consumption of energy drinks has been linked to a 10-fold increase in emergency room visits between 2005-2009.  The letter further states that, due to the “glossy marketing tailored to youth,” the consumption of energy drinks by adolescents has increased significantly. 

Citing FDA’s Draft Guidance concerning the distinction between conventional foods in beverage form and liquid dietary supplements, Sen. Durbin asks that FDA investigate energy drinks and determine whether they are properly marketed as dietary supplements.  He further requests that FDA enforce its regulatory limit on caffeine levels in beverages that are not dietary supplements, and also address any potential safety concerns posed by ingredients other than caffeine (such as guarana and ginseng).

Sen. Durbin’s letter places particular emphasis on the marketing of energy drinks, both in terms of its potential impact on young consumers’ behavior, and its impact on the regulatory status of the drinks.  Perhaps not coincidentally, FDA also took notice of marketing practices in its recent actions against caffeinated alcoholic beverages (see here) and caffeinated “breathable foods” (see here).

By Kurt R. Karst –      

In what might be the longest citizen petition response of all-time (87-pages!), FDA, on April 9, 2012, largely denied a March 17, 2006 petition for stay of action (here and here) (Docket No. FDA-2006-P-0007) submitted by ViroPharma Incorporated (“ViroPharma”) concerning the approval of ANDAs for generic versions of the company’s antibiotic drug, VANCOCIN (vancomycin HCl) Capsules (approved under NDA No. 050606).  FDA also states in the petition response that the Agency approved three ANDAs for generic VANCOCIN, including one from Akorn, Inc. (represented by Hyman, Phelps & McNamara, P.C.). 

ViroPharma supplemented the petition numerous times over the years, including a December 2011 submission claiming that changes to VANCOCIN’s labeling FDA approved on December 14, 2011 in an NDA Supplement should be eligible for a period of 3-year exclusivity that should prevent ANDA approvals until December 2014.  FDA determined that the VANCOCIN approval is not eligible for 3-year exclusivity because of the limitation on such exclusivity for a so-called “old antibiotics” like vancomycin set forth in FDC Act § 505(v) as added by Section 4 of the 2008 QI Act.  Specifically, FDA stated in the Agency’s decision that “the revision of the Vancocin label to incorporate clinical data that supports and refines labeling regarding already approved conditions of use, does not constitute approval for a condition of use that has not been ‘approved before the date of enactment’ within the meaning of [FDC Act § 505(v)(3)(B)].  Therefore, these labeling changes do not merit 3-year exclusivity under the limitation on such exclusivity for an Old Antibiotic subject to [FDC Act § 505(v)(3)].”

Given ViroPharma’s previous litigation concerning VANCOCIN (see, e.g., here and here), it came as no surprise when the company announced early on April 10, 2012 that it intended to file suit against FDA seeking an injunction to set aside the Agency’s ANDA approvals.  As of this posting, we have not seen any court filings.  We will update this post once the documents are available.  

UPDATE:

• See our April 16, 2012 post – The Other Shoe Drops: ViroPharma Sues FDA – Challenges Denial of 3-Year Exclusivity and ANDA Approvals 

By Ricardo Carvajal –

Warning letters issued by FDA since late February provide an indication of the types of violations that could trigger reinspection fees under the authority provided by the Food Safety Modernization Act (“FSMA”).  As we noted in a prior blog posting, FSMA authorized FDA to collect fees for a reinspection after a previous inspection that was classified as Official Action Indicated (meaning that significant objectionable conditions or practices were found and regulatory action is warranted to address non-compliance), and where non-compliance was materially related to food safety requirements (meaning the food is adulterated under FDC Act § 402 or misbranded under § 403). 

Warning letters to firms subject to reinspection fees now include the following notice:

Section 743 of the Act (21 U.S.C. § 379j-31) authorizes FDA to assess and collect fees to cover FDA's costs for certain activities, including costs related to re-inspection. A re-inspection is one or more inspections conducted subsequent to an inspection that identified non-compliance materially related to a food safety requirement of the Act, specifically to determine whether compliance has been achieved. Re-inspection-related costs means all expenses, including administrative expenses, incurred in connection with FDA's arranging, conducting, and evaluating the results of the re-inspection and assessing and collecting the re-inspection fees, 21 U.S.C. § 379j-31(a)(2)(B). For a domestic facility, FDA will assess and collect fees for re-inspection-related costs from the responsible party for the domestic facility. The inspection noted in this letter identified non-compliance materially related to a food safety requirement of the Act.  Accordingly, FDA may assess fees to cover any costs related to re-inspection.

Thus far, the above notice has been included in warning letters issued for alleged violations of requirements applicable to seafood HACCP, acidified foods, food allergen labeling, animal drug residues, and sanitation and pest control (see, e.g., here and here).  Given the broad range of circumstances under which reinspection fees could be assessed, firms would be well advised to manage their inspections and follow-up corrective actions accordingly.

By Kurt R. Karst –      

It was yet another exciting day in the Hatch-Waxman world when news broke Wednesday morning that Teva Pharmaceuticals USA, Inc. (“Teva”) and Cephalon, Inc. (“Cephalon”) filed a Complaint and Motions for a Temporary Restraining Order and Preliminary Injunction against FDA in the U.S. District Court for the District of Columbia “to vindicate their statutory rights” under the FDC Act with respect to Teva’s claim to 180-day marketing exclusivity for a generic version of Cephalon’s PROVIGIL (modafinil) Tablets, 100 mg and 200 mg, which is approved under NDA No. No. 020717 to improve wakefulness due to narcolepsy, obstructive sleep apnea, and shift work disorder.  The companies filed the lawsuit after FDA “signaled that it may seek to approve competing applicants for generic modafinil products as early as April 6 and notwithstanding Teva USA’s right to sole marketing exclusivity.”  Among other things, Teva and Cephalon requested in their lawsuit that the court enter a TRO “preventing FDA from approving any ANDA referencing PROVIGIL® other than Teva USA’s ANDA [No. 076596] until the Court resolves Plaintiffs’ motion for preliminary injunctive relief” and “order FDA to produce its decision regarding Teva USA’s exclusivity.”

180-day exclusivity for generic PROVIGIL is governed by the pre-Medicare Modernization Act (“MMA”) version of the FDC Act, under which exclusivity is patent-by-patent, thereby giving rise to the possibility of shared 180-day exclusivity.   That is, where there are, for example, two Orange Book-listed patents for a drug and different ANDA sponsors are first-to-file a Paragraph IV certification as to each patent, FDA has said that there is an “exclusivity standoff” (i.e., “whereby each ANDA applicant’s approval is delayed indefinitely” – see, e.g., here and here).  To resolve this “exclusivity standoff,”  FDA has determined that “when approval of an ANDA eligible for exclusivity is blocked by another applicant’s eligibility for exclusivity, the applicants that are eligible for the 180-day period of generic drug exclusivity may share the same exclusivity period.”  More recently (see here), FDA has clarified that pre-MMA, shared exclusivity is appropriate only where “two applicants have submitted paragraph IV certifications to two different patents, and one applicant was first to file a paragraph IV certification on one patent and the other was first to file on a different patent.”

PROVIGIL is listed in the Orange Book with information on two patents: (1) U.S. Patent No. RE37516 (“the ‘516 patent”), which expires on April 6, 2015; and (2) U.S. Patent No. 7,297,346 (“the ‘346 patent”), which which expires on May 29, 2024.  The ‘346 patent is a later-listed patent that did not appear in the Orange Book until December 2007.  On December 24, 2002, Teva and several other generic drug manufacturers submitted the first ANDAs to FDA containing Paragraph IV certifications to the ‘516 patent.  With respect to the ‘346 patent, Teva says that it alone was first-to-file a Paragraph IV certification on December 14, 2007, and that because shared 180-day exclusivity applies only in the circumstances discussed above, Teva alone has 180-day exclusivity. 

When Teva went to FDA to seek clarification as to 180-day exclusivity for generic PROVIGIL, however, Teva says that the Agency “signaled its belief that Teva USA may not be entitled to such exclusivity.”  That prompted the lawsuit.  But later in the day on Wednesday, Teva and Cephalon filed a notice with the D.C. District Court withdrawing their Motions for a Temporary Restraining Order and Preliminary Injunction, but reserving the right to renew them “as circumstances dictate.”

On Thurday morning, the circumstances that prompted the withdrawal notice became clear.  According to a Teva press release: “FDA has decided that its wholly owned subsidiary, Teva Pharmaceuticals USA, is sole first-to-file for both Orange Book patents listed for Provigil® (modafinil) and therefore Teva’s ANDA alone is entitled to 180-day exclusivity.  Cephalon launched generic Provigil® on March 29, 2012 and the FDA has also decided that such launch triggered the exclusivity.”  That last sentence caught our attention, as it raises the possibility of a future fight over the circumstances under which the marketing of an authorized generic might trigger 180-day exclusivity. 

UPDATE:

• Mylan Sues FDA Seeking Ruling That Teva Holds No Exclusivity for Its Generic Version of Provigil®:

“The Complaint alleges that Teva did not maintain valid paragraph IV (PIV) certifications as a result of its acquisition of Cephalon. The Complaint states that, once Teva became the owner of Cephalon, Teva could no longer infringe its own patents through a PIV certification and that Teva therefore is not entitled to exclusivity based on patent certifications. Mylan also alleges that FDA should have found that Mylan is the sole first filer on one of the Orange Book Patents for Provigil, that Teva abandoned its abbreviated new drug application (ANDA), and that FDA should have approved Mylan's ANDA for this product. Mylan is seeking an immediate order from the Court entitling it to exclusivity and immediate approval for its ANDA.

The Complaint also alleges that FDA's decision, which blocks Mylan and other generic entrants from launching their generic Provigil products, is unlawful. Mylan believes the Federal Trade Commission did not contemplate the current outcome when it imposed its conditions on the Teva/Cephalon merger. As a result of FDA's decision, only one party—Teva/Cephalon—is controlling 100% of the supply of product in the marketplace. This is despite the fact that Cephalon previously agreed to a Mylan launch of its generic product no later than April 6, 2012.”

By Carmelina G. Allis –

In a report released last week, the U.S. Government Accountability Office (“GAO”) provides the results from a study it conducted to determine whether FDA has met timeframe performance goals related to the completion of reviews for premarket notification (510(k)) submissions and premarket approval (“PMA”) applications. 

The study found that while FDA met performance goals for 510(k)s and the average number of submissions per year remained generally steady during fiscal year (“FY”) 2003 through FY 2010, the review times for 510(k)s increased.  Likewise, review times for PMAs also increased despite FDA meeting most performance goals for PMA applications.  There has also been a decrease in the number of 510(k) clearance determinations and PMA approvals.  In sum, FDA is taking longer to complete the reviews of 510(k)s and PMAs when the purpose of the user fee program was to streamline the regulatory process.

And who is responsible for this unintended effect?  While assuming some responsibility, FDA points a heavy finger at industry stakeholders.  We will explain this further below, after first providing a brief overview of the device user fee program and discussing the noteworthy GAO study results.

FDA’s Performance Goals.  FDA’s performance goals are defined in terms of “tiers.”  The goals required FDA to complete the review process for 90% of the 510(k)s within 90 days of submission (“Tier 1” goals), and complete the review process for 98% of 510(k)s within 150 days (“Tier 2” goals).  FDA completes the review process for a 510(k) if it issues an order declaring the device substantially equivalent (“SE”), not substantially equivalent (“NSE”), or advises the submitter that a 510(k) is not required.  Regarding PMAs, the FDA had to complete the review of 60% of original PMAs within 180 days of submission (“Tier 1” goals) and 90% of reviews within 295 days (“Tier 2” goals).  The review of a PMA is completed if the agency issues an approval order, an approvable letter, a major deficiency letter, a not approvable letter, or a denial order.  The agency committed to those goals as part of Congress’s enactment of the Medical Device User Fee and Modernization Act of 2002 (“MDUFMA”) (reauthorized in 2007), which authorized the FDA to collect user fees to support its medical device review process.  The user fee program is intended to streamline the review process.

The GAO Study and Performance Results.  The GAO study looked at performance goals for FY 2003 through FY 2010, and also at stakeholders’ concerns with FDA’s review processes and the steps FDA is taking to address those concerns.  Congress requested the study, because it is preparing to reauthorize the medical device user fee program this year.

In a nutshell, here are the most significant GAO findings:

510(k) Performance Goals:

• The time to final decision for 510(k)s has increased substantially, a rise of approximately 61 days.  When GAO added FDA’s time spent reviewing a submission (“on-the-clock FDA review time”) to the time where FDA waited for the sponsor to provide additional information (“off-the-clock time”), the resulting time to final decision increased 61% (from 100 days to 161 days) from FY 2005 through FY 2010.

• The average number of review cycles and requests for additional information have increased by 39% (1.47 cycles for FY 2003 to 2.04 cycles for FY 2010).

• The percentage of 510(k)s receiving a first-cycle decision of SE decreased from 54% for FY 2003 to 20% in FY 2010.

• The percentage of 510(k)s that received a final SE decision decreased from a high of 87.9% for FY 2005 to 75.1% in FY 2010.  Likewise, the percentage of NSE decisions increased from 2.9% in FY 2003 to 6.4% in 2010.

PMA Performance Goals:

• The review times for both original and expedited PMAs, as well as time to final decision, generally increased.  For example, average FDA review time for original PMAs increased from 211 days in FY 2003 to 264 days in FY 2008, but then fell in FY 2009 to 217 days.  Likewise, the average time to final decision for FY 2003 through FY 2008 fluctuated year to year, but increased form 462 days for FY 2003 to 627 days for FY 2008.

• The percentage of original PMAs approved at the end of the first review cycle fluctuated throughout the review period, but generally decreased from 16% in FY 2003 to 9.8% in FY 2009.

• The percentage of original PMAs that were ultimately approved also fluctuated throughout the years, but exhibited an overall decrease.  In FY 2003, 74% of original PMAs were approved, compared to 68.8% in FY 2008.

And why is it that review times have increased?  Why has the number of 510(k) clearances and PMA approvals decreased?  Industry is to blame, according to written comments from the Department of Health and Human Services (“HHS”) to the GAO report.  For example, the HHS written response states that, based on FDA reports, review cycles have increased because “more than 50 percent of 510(k) applications” have “quality issues,” which “require agency staff to prepare and issue additional information letters, resulting in additional review cycles.”  (No explanation – at least that was obvious to us – was offered as to why the review times for PMAs have increased.)

Certainly, it is true that issues with the quality of a submission can delay the review process.  However, Figure 3 on page 16 of the GAO report shows that from FY 2000 to about FY 2005, the average time to final decision for 510(k)s remained fairly steady at an average of about 100 days per FY.  After FY 2005, those times rose steadily peaking at about 160 days on average for FY 2010.  Were 510(k)s of better quality before FY 2005?  Or is it that starting at around FY 2005 FDA changed its standards for reviewing submissions?

We share the industry stakeholders’ views expressed to GAO that FDA has become more stringent in its review process.  The industry stakeholders interviewed by GAO stated that reviewers may be “requesting additional information more often due to a culture of increased risk aversion at FDA,” and noted that the “additional information being requested is not always critical for the review of the submission.”  This results in longer overall review times, because the sponsors’ time to gather information to address FDA’s requests increases with the number and complexity of FDA requests.  Moreover, industry stakeholders noted that review criteria sometimes change after a sponsor has submitted an application, or that reviews are inconsistent between reviewers and review groups.  Inconsistencies in the regulatory process also increase review times, because these often result in sponsors having to conduct additional studies in order to satisfy FDA’s new criteria for clearance or approval.

Concurrently, consumer advocacy groups have also vocally raised concerns with FDA’s regulatory process.  In particular, consumer advocates find objectionable the 510(k) “substantial equivalence” process under which most medical devices are authorized for marketing.  Because 510(k) devices are cleared on the basis of their equivalence to a legally marketed device, consumer critics say that the regulatory process does not require the stringent data gathering and testing that is required of PMA devices.  According to consumer advocacy groups, this lack of stringent oversight of 510(k) devices puts patients’ health at risk.

And the agency has listened to both industry and consumer advocacy groups, and is attempting to accommodate both their perspectives.  The FDA has embarked on an effort to evaluate and bolster the 510(k) program in a manner that has often seemed to give primary weight to alleviating consumers’ concerns.  For example, late last year the agency issued a draft document that updates predecessor guidance for when to submit a new 510(k) for modifications to a legally marketed 510(k) device.  As discussed in a prior post, the draft guidance makes substantive changes to existing policy and will result in more 510(k) submissions.

Simultaneously, the agency is trying to accommodate industry stakeholders’ concerns, and has been instituting changes to “improve the predictability, consistency, and transparency of both the 510(k) and [PMA] review programs,” as HHS explained in its written response to GAO.  For example, according to HHS’s letter, the agency “is developing an SOP for requests for additional information that clarifies when these requests can be made for 510(k)s . . . and the management level at which the decision must be made.”  No statements, however, were made on what FDA says is a major shortcoming: the quality of industry stakeholders’ submissions.

We do not know when the FDA will become more predictable, consistent, transparent, and efficient, or whether its current initiatives and guidance development practices will rightly balance both industry and consumer advocacy stakeholders’ interests.  In the meantime, as a quick solution, because FDA and industry “bear shared responsibility for the increase in [review] time[s] and will need to work together to achieve improvement,” should FDA offer submission writing workshops to industry stakeholders?  Just a thought. . . .

By Kurt R. Karst –      
 
We recently got our hands on a copy of the latest report FDA submitted to Congress on citizen petitions covered by FDC Act § 505(q).  The report, titled “Third Annual Report On Delays In Approvals Of Applications Related To Citizen Petitions And Petitions For Stay Of Agency Action For Fiscal Year 2010,” is required by FDC Act § 505(q)(3), which was added to the law by Section 914 of the 2007 FDA Amendments Act (“FDAAA”), Pub. L. No. 110-85 (2007), as amended by § 301 of Pub. L. No. 110-316 (2008).  We previously reported (here and here) on the other reports FDA submitted to Congress required by FDC Act § 505(q) and FDAAA.
 
FDC Act § 505(q) is intended to prevent the citizen petition process from being used to delay approval of ANDAs and 505(b)(2) applications.  Briefly, FDC Act § 505(q) provides that FDA shall not delay approval of a pending ANDA or 505(b)(2) application as a result of a citizen petition submitted to the Agency pursuant to 21 C.F.R. § 10.30 (citizen petition) or § 10.35 (petition for stay of action), unless FDA “determines, upon reviewing the petition, that a delay is necessary to protect the public health.”  Under FDC Act § 505(q), which FDA has interpreted to apply only to certain petitions submitted to the Agency after September 27, 2007, “[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.  (FDA has only missed the 180-day timeframe twice between FYs 2008 and 2010.)  In June 2011, FDA published final guidance on 505(q) petitions, and in January 2012, FDA issued a proposed rule to amend the Agency's citizen petition regulations to implement FDC Act § 505(q).  Over the years, FDA Law Blog has vigilantly followed 505(q) petitions with our FDC Act § 505(q) Citizen Petition Tracker. 
 
Under FDC Act § 505(q)(3) each FDA annual reports to Congress must specify: “(A) the number of applications that were approved during the preceding 12-month period; (B) the number of such applications whose effective dates were delayed by petitions referred to in paragraph (1) during such period; (C) the number of days by which such applications were so delayed; and (D) the number of such petitions that were submitted during such period.”  FDA says in the FY 2010 report that:

During the FY 2010 reporting period, the agency approved 29 505(b)(2) applications and 426 ANDAs.  No 505(b)(2) approvals were delayed because of the filing of a 505(q) petition.  One ANDA approval was delayed by nine days because of a pending 505(q) petition.  Twenty 50S(q) petitions were filed during the reporting period.  FDA did not miss the statutory deadline for responding to any 505(q) petitions during this reporting period.

FDA’s decision to delay the approval of one pending ANDA by 9 days – only the fourth ANDA delayed due to a 505(q) citizen petition – was based on Agency concerns “that if it approved the ANDA before resolving the issues raised in the petition and later concluded that one or more of the arguments against approval were meritorious, then the presence on the market of drug products that did not meet the requirements for approval could negatively affect the public health.”  Those concerns were addressed when FDA completed its analysis of the issues raised in the petition.
 
FDA’s report goes on to identify several relevant “trends,” some of which were flagged in the Agency’s FY 2009 report as “areas of concern,” including:

• Over the three year period during which we have been reviewing 505(q) petitions, the number of applications that have been delayed due to analysis of the issues raised in the 505(q) petitions is low: 4 ANDAs and no 505(b)(2) applications.

• FDA continues to receive 505(q) petitions from ANDA and 505(b)(2) applicants, and not solely from innovator companies.

• In many instances, the statutory deadline for responding to a 505(q) petition occurs before any related ANDAs or 505(b)(2) applications are ready for approval.

• FDA has received seria1 505(q) petitions, frequently from the same petitioner, about the same specific drug or class of drugs, sometimes requiring several separate responses about different aspects of the same product. . . .  Responding to such serial petitions requires the use of substantial FDA resources, on a repeated basis, over a protracted period of time.

• Since the passage of FDAAA, FDA has seen an increase in petitions for reconsideration of the agency's denial of 505(q) petitions, requiring the agency to readdress issues that already have been decided.

While FDA says that the jury is still out on whether or not FDC Act § 505(q) is accomplishing the stated goals of the legislation that created it, and that "additional experience and trend data are required," the Agency does express some concern that FDC Act § 505(q) "may not be discouraging the submission of petitions that do not raise valid scientific issues and are intended primarily to delay the approval of competitive drug products."  

Moreover, says FDA, "[w]e also believe that innovator companies may be implementing strategies to file serial 505(q) petitions and petitions for reconsideration in an effort to delay approval of ANDAs or 505(b)(2) applications for competing drugs."  Although not an instance of serial petition submission, FDA commented in a recent brief after being sued following the issuance of non-response denials to two petitions concerning quetiapine that "there is no evidence that Congress intended that 21 U.S.C. § 355(q) be used as a tool to allow NDA holders to seek advanced, substantive decisions from FDA so that they could seek judicial review of those decisions and effectively hold up approval of ANDAs.  Rather, Congress enacted this provision to prevent delays of ANDA approvals due to FDA’s consideration of issues raised in citizen petitions."  (Italics in original)  Additional analysis from FDA is expected in the Agency's next annual report on 505(q) petitions.

By Riëtte van Laack –
 
On March 30, FDA denied a petition submitted by the Natural Resources Defense Council ("NRDC") to ban bisphenol A ("BPA") in food packaging.  As FDA explains in its 15-page response, the science NRDC presented in the petition was insufficient to support a conclusion that currently approved uses of BPA are not safe.
 
As we previously reported, NRDC sued FDA for its failure to act on the environmental group's 2008 petition requesting that FDA ban BPA in food contact substances.  NRDC requested that FDA revoke all regulations permitting the use of BPA as a food additive and list BPA as a substance prohibited in human food. 
 
In its 15-page response to the NRDC petition, FDA details the limitations in the studies that NRDC cited in its support of its contention that the approved uses of BPA are not safe.  Limitations of studies cited by NRDC include a non-oral route of administration, small sample size, inappropriate statistical analysis, and failure to establish relevance to human health effects.  In light of ongoing federally financed studies to examine BPA's safety and recently published data regarding safety of BPA, FDA determined that “as a matter of science and regulatory policy, . . . the best course of action . . . is to continue [its] review and study of emerging data on BPA.”  FDA will continue to perform, monitor, and review new studies and data as they become available, and depending on the results, FDA will assess future regulatory decisions about BPA.
 
On its Consumer Update website, FDA announced that FDA scientists have recently determined that exposure to BPA through foods for infants is much less than had been previously believed and that the trace amounts of the chemical that enter the body are rapidly metabolized and eliminated. 
 
It is unlikely that the BPA issue will go away.  Just recently, on March 16, 2012, Rep. Edward Markey (D-Mass.) filed three separate petitions asking FDA to ban the use of BPA in infant formula and baby/toddler food packaging, in reusable food and beverage containers, and in canned food and beverage packaging (here, here, and here). 
 
Meanwhile, the controversy around BPA has resulted in the industry’s voluntary reduction of BPA in a number of packaging materials.  In fact, in February, 2012, the American Chemistry Council petitioned FDA to amend its food additive regulations “to no longer provide for the use of [polycarbonate resins made with BPA] in infant feeding bottles and spill-proof cups designed to help train babies to drink from cups because these uses have been abandoned.” 

By David B. Clissold & Ricardo Carvajal –

Last Friday, the FDA Center for Tobacco Products announced two new draft guidance documents for tobacco products.  The first guidance, entitled “Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke Under Section 904(a)(3) of  the Federal Food, Drug, and Cosmetic Act,” identifies 22 harmful or potentially harmful constituents ("HPHCs") in tobacco products and tobacco smoke.  Domestic manufacturers, or their agents, are to submit the required HPHC information for products they manufacture. For imported tobacco products, the required HPHC information is to be submitted by either the foreign manufacturer or the importer, or an agent, of the product.  The reporting obligations under section 904(a)(3) are effective June 22, 2012, but small tobacco manufacturers are afforded three additional months to comply.  For cigarettes, smoke must be tested for 18 HPHCs and the tobacco filler must be tested for six compounds.  Smokeless tobacco (e.g., snus, snuff, plug, chew, loose leaf) must be tested for nine HPHCs and roll-your-own tobacco must be tested for six.  FDA intends to use this list in part to comply with section 904(d)(1) of the Federal Food, Drug, and Cosmetic Act ("FDC Act"), which requires FDA to publish a list of HPHCs, by brand and by quantity in each brand and sub-brand, in a format that is understandable and not misleading to lay persons.

The second guidance is entitled “Modified Risk Tobacco Product Applications.”  Modified risk tobacco products ("MRTPs") are tobacco products that are sold, distributed, or marketed with a claim to reduce harm or the risk of tobacco-related disease.  Before an MRTP can be introduced or delivered for introduction into interstate commerce, an order from FDA under section 911(a) of the FD&C Act must be in effect with respect to the tobacco product.  This may be either an “exposure modification order” or “risk modification order” under section 911(g) of the FDC Act.  Under the draft guidance, an exposure modification order can be issued for an MRTP that reduces or eliminates exposure to a substance and for which the available scientific evidence suggests that a measurable and substantial reduction in morbidity and mortality is reasonably likely to be demonstrated in future studies.  For a risk modification order, the applicant must demonstrate that the product, as it is actually used by consumers, will significantly reduce harm and the risk of tobacco-related disease to individual tobacco users and benefit the health of the population as a whole taking into account both users of tobacco products and persons who do not currently use tobacco products. The draft guidance describes the numerous scientific studies and analyses an applicant should submit to demonstrate that a MRTP will significantly reduce harm or exposure to individuals and benefit the public health.  These studies include product analyses, nonclinical studies, studies in adult human subjects, and secondary data analyses and modeling.  Human studies will likely include clinical investigations, epidemiological studies, consumer perception studies, actual use studies and other studies that involve humans actually consuming or interacting with the product, its proposed labeling and/or marketing materials.

In a contemporaneous blog posting, Commissioner Hamburg explained the object of the guidance on HPHCs:

The detailed information that we receive will help FDA determine how best to make science-based decisions to reduce the terrible toll of tobacco-related disease and death. We also hope that by having to disclose this information, industry will voluntarily start to make their products substantially less addictive and harmful.

As for the guidance on MRTPs, the Commissioner stated:

We want to make sure consumers and the public have an accurate understanding of the health risks of tobacco products—so mistaken beliefs don’t cause them to start or continue using products that lead to preventable disease and death.

FDA will accept comments on these two draft guidance documents for the next 60 days.

By Kurt R. Karst –      

Fans of Saturday Night Live know popular Weekend Update correspondent Oscar Rogers (played by Kenan Thompson) and his three-step approach to addressing important issues of the day:  Step 1: Fix. Step 2: It. Step 3: FIXIT!  That approach sums up the “Generic Drug Application Review Fairness Act of 2012” (H.R. 4332), which Rep. Frank Pallone, Jr. (D-NJ) introduced last week.  The bill would make two important changes to the law – one with respect to 180-day exclusivity forfeiture, and another with respect to FDA’s Office of Generic Drugs (“OGD”).

180-Day Exclusivity Forfeiture.  Section 2 of H.R. 4332 deals with FDC Act § 505(j)(5)(D)(i)(IV), which is one of the six 180-day exclusivity forfeiture provisions added to the FDC Act by Title XI of the Medicare Modernization Act (“MMA”).  Under FDC Act § 505(j)(5)(D)(i)(IV), 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)). 

FDA has applied and discussed FDC Act § 505(j)(5)(D)(i)(IV) on many, many occassions, including in recent Citizen Petition responses – see, e.g., Docket No.  FDA-2011-P-0486 and Docket No. FDA-2010-P-0632.  Indeed, according to our data (see our popular 180-Day Exclusivity Tracker), FDC Act § 505(j)(5)(D)(i)(IV) has resulted in more forfeitures of exclusivity than any other forfeiture provision (probably even when combined).

FDA has very strictly and narrowly interpreted FDC Act § 505(j)(5)(D)(i)(IV), such that even an act of Mother Nature shutting down the Federal government and preventing FDA from granting tentative approval on the 30-month ANDA submission anniversary date has resulted in a forfeiture of 180-day exclusivity eligibility (see our “Snowmageddon” post here).  And FDA’s growing median ANDA approval time has not helped either.  With a median ANDA approval time of about 33 months today (about 17 months in 2003 when the MMA was enacted) and an ANDA backlog of about 2,800 applications at the end of February 2012, forfeitures are a real concern in the generic drug industry.  Then there’s FDA’s interpretation of FDC Act § 505(j)(5)(D)(i)(IV) that could result in an automatic forfeiture of 180-day exclusivity eligibility.  As we previously reported, FDA interprets FDC Act § 505(j)(5)(D)(i)(IV) such that when an ANDA sponsor who amends a long-pending ANDA to include a Paragraph IV certification to an Orange Book-listed patent and qualifies as a “first applicant,” that sponsor may simultaneously forfeit 180-day exclusivity eligibility for failure to obtain timely tentative approval because FDA counts 30 months from the ANDA submission date and not from the first Paragraph IV certification date. 

The Generic Drug Application Review Fairness Act of 2012 would go a long way to address some of the concerns the generic drug industry has had with FDC Act § 505(j)(5)(D)(i)(IV).  It would amend this section of the law to change the 30-month period to 60 months and to address FDA’s interpretation that could result in an automatic forfeiture of exclusivity.  Specifically, FDC Act § 505(j)(5)(D)(i)(IV) would be amended as follows:

(IV) FAILURE TO OBTAIN TEN TATIVE APPROVAL.—The first applicant fails to obtain tentative approval of the application within 60 months after the date on which—

(aa) the application is filed and initially contains a certification described in paragraph (2)(A)(vii)(IV), or

(bb) the application is amended to first contain such a certification,

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 so filed or amended. [(Emphasis added)]

FDC Act § 505(q)(1)(G), which extends the tentative approval period for certain citizen petitions, would also be amended to remove reference to 30-months. 

Amended FDC Act § 505(j)(5)(D)(i)(IV) would apply “only with respect to an application that is filed under[FDC Act § 505(j)] on or after the day that is 30 months prior to the date of the enactment of [H.R. 4332],” and “only if no [Paragraph IV certification] was made before such day with respect to the listed drug . . . .”  ANDAs submitted to FDA prior to the 30-month date described in the previous sentence and that on that date contained a Paragraph IV certification would be subject to the unamended version of FDC Act § 505(j)(5)(D)(i)(IV), thus setting up a pre-and post-Generic Drug Application Review Fairness Act regime (somewhat akin to the current pre- and post-MMA 180-day exclusivity regime).

Giving a nod to the Generic Drug User Fee Amendments (“GDUFA”) – see our previous post here – which is expected to be enacted later this year, H.R. 4332 would incrementally reduce the 60-month tentative approval period to 54 months in Fiscal Year 2013, 48 months in Fiscal Year 2014, 42 months in Fiscal Year 2015, 36 months in Fiscal Year 2016, and back to 30 months for Fiscal Year 2017 – the last year covered by “GDUFA I.”  The 60- to 30-month periods would apply to ANDAs submitted to FDA in that particular Fiscal Year that initially contain, or that are amended to initially contain, a Paragraph IV certification qualifying a sponsor as a “first applicant” eligible for 180-day exclusivity.

The Office of Generic Drugs.  Section 3 of H.R. 4332 would amend the FDC Act to add  § 505(j)(11) to elevate OGD within FDA’s Center for Drug Evaluation and Research (“CDER”):

(11) OFFICE OF GENERIC DRUGS.—

(A) OFFICE.—The Secretary shall maintain the Office of Generic Drugs as a separate office within the Center for Drug Evaluation and Research of the Food and Drug Administration.

(B) REPORTING.—The Director of the Office of Generic Drugs shall report directly to the Director of the Center for Drug Evaluation and Research.

OGD is currently housed within the Office of Pharmaceutical Science (“OPS”) (headed by Helen N. Winkle).  H.R. 4332 would take OGD out of OPS and make it an office on par with the Office of New Drugs.  It would also give the OGD Director (currently Keith Webber, Ph.D.) direct reporting to the CDER Director (currently Janet Woodcock, M.D.).

By Alan M. Kirschenbaum –

Two days ago, during argument before the Supreme Court on the Affordable Care Act ("ACA"), Justice Breyer referred to “loads” of miscellaneous provisions of the Act outside the core insurance provisions.  One of these is section 6004, which requires manufacturers and authorized distributors of record to submit information on drug samples to FDA annually beginning April 1, 2012 (this Sunday).  Today, FDA issued a brief draft guidance announcing that FDA will exercise its enforcement discretion to extend the deadline for reporting until at least October 1, 2012.  The guidance states that FDA will provide notice before revising this policy, indicating the possibly of a further extension.  By then, we will know whether this and “loads” of other ACA provisions will survive the Supreme Court’s decision, expected in June.  If and when required, the sample information will be submitted electronically through FDA’s Electronic Submissions Gateway. 

By Kurt R. Karst –      

Last week, the New York Times ran an editorial calling on Congress to enact legislation to address the U.S. Supreme Court’s June 23, 2011, 5-4 landmark decision in PLIVA Inc. v. Mensing, 131 S.Ct. 2567 (2011).  In Mensing, the Court ruled that FDA’s regulations preventing generic drug manufacturers from changing their labeling except to mirror the label of the brand-name, Reference Listed Drug (“RLD”) manufacturer (whose drug product is approved under an NDA) preempt state-law failure-to-warn claims against generic drug manufacturers, because generic drug manufacturers are unable to comply with both federal and state duties to warn.  Since the Court issued its decision, scores of court decisions have been issued dismissing litigation against generic drug manufacturers on Mensing grounds (including several decisions on the so-called RLD theory of liability – see our previous posts here, here, and here).  In addition, Public Citizen has petitioned FDA to amend its regulations to permit ANDA sponsors to revise their labeling through the Changes Being Effected (“CBE”) and Prior Approval Supplement (“PAS”) procedures (see our previous post here).  (FDA’s position, which the Court relied on, has been that the CBE and PAS procedures are not available to ANDA sponsors to add or strengthen label warnings.)  Now Congress will enter the fray. 

Earlier this week, Senator Patrick Leahy (D-VT) issued a press release saying that he plans to introduce legislation to legislatively reverse Mensing.  According to Sen. Leahy, Mensing “creates a troubling inconsistency in the law with respect to prescription drugs.”  This is a reference to the U.S. Supreme Court’s March 2009 decision in Wyeth v. Levine, 555 U.S. 555 (2009), in which the Court held that state-law tort actions against a brand-name drug manufacturers for failure to provide an adequate warning label are not preempted. 

FDA Law Blog has obtained a copy of Sen. Leahy’s draft bill, which is titled the “Patient Safety and Generic Labeling Improvement Act.”  The bill would amend the FDC Act to add new section 505(w):

(w) Notwithstanding any other provision of this chapter, the holder of an application approved under subsection (j) may change the ‘Warnings’ section of the labeling of a drug so approved in the same manner as the holder of an approved new drug application under subsection (b), unless the Secretary prescribes by rule another manner.

Legislation of this sort is not new.  Back in 2009, Sen. Ted Kennedy (D-MA) and Representative Frank Pallone, Jr. (D-NJ) introduced the “Medical Device Safety Act of 2009” (S. 540 and H.R. 1346) to legislatively reverse the Supreme Court’s pro-preemption decision in Riegel v. Medtronic, Inc., 552 U.S. 312 (2008).  That bill died on the vine. 

By Kurt R. Karst –      

In litigation that moved at breakneck speed on March 28, 2012, Judge Beryl A. Howell of the U.S. District Court for the District of Columbia denied AstraZeneca Pharmaceuticals LP’s (“AstraZeneca’s”) Motion for Temporary Restraining Order (Complaint here) seeking to vacate FDA’s March 27, 2012 approval of more than 10 ANDAs for generic versions of AstraZeneca’s blockbuster antipsychotic drug SEROQUEL (quetiapine fumarate) Tablets (NDA No. 020639), and to enjoin FDA from granting any further final ANDA approvals for the drug until the court decides the case on the merits. 

Judge Howell’s decision follows a March 23, 2012 (Friday) decision handed down by Judge Colleen Kollar-Kotelly denying AstraZeneca’s Application for Prelimiary Injunction and dismissing the case without prejudice.  In that case, AstraZeneca sought to enjoin FDA from granting final ANDA approvals for generic SEROQUEL as early as March 26, 2012, after FDA denied without comment two citizen petitions AstraZeneca submitted to FDA last year concerning labeling carve-out issues for generic versions of SEROQUEL (as well as an extended-release version of the drug, SEROQUEL XR (quetiapine fumarate) Extended-Release Tablets (NDA No. 022047)) – see our previous post here.  

On Monday, FDA and AstraZeneca fought over whether FDA must provide “advance notice” or “timely notice” to AstraZeneca of ANDA approvals.  That resulted in the issuance of an Order in which Judge Kollar-Kotelly noted that FDA must provide AstraZeneca timely notice after approving any ANDAs.  That notice was sent to AstraZeneca later in the day on Tuesday in the form of a Letter Decision in which FDA also addressed labeling carve-out and three-year exclusivity issues, stating:

AstraZeneca identified three portions of labeling that it argued are essential to the safe use of quetiapine for any purpose: (1) Table 2, which consists of metabolic effects data; (2) the boxed warning on suicidality; and (3) Section 5.2 warnings on clinical worsening and suicide risk. (For ease of reference, the boxed warning and Section 5.2 warnings are referred to collectively throughout as “suicidality warnings.”)  AstraZeneca has also asserted that Table 2 is protected by 3-year exclusivity such that approval of an ANDA referencing Seroquel may not occur until on or after December 2, 2012, when the last exclusivity period on a different AstraZeneca product – – Seroquel XR – expires.

FDA concurs that these portions of the labeling are essential to safe use of a generic quetiapine product referencing Seroquel for any indication, and the agency would not approve a quetiapine ANDA referencing Seroquel that omitted them.  FDA does not concur, however, that an ANDA referencing Seroquel is precluded from including Table 2 or the suicidality warnings by virtue of AstraZeneca’s 3-year exclusivity on certain indications for Seroquel XR.

AstraZeneca filed its TRO papers on Wednesday morning and the parties met in court later that day.  Later that night, Judge Howell issued her Order concluding that AstraZeneca “has not demonstrated a likelihood of success on the merits, particularly given the deference the Court must provide to agency actions and interpretations of its own organic statute, here, the [FDC Act].”

Although Judge Howell denied AstraZeneca’s TRO motion, FDA did not escape unscathed.  Judge Howell commented in her Order that:

The record in this case strongly suggests that the FDA has made “tactical decision[s]” to prevent the plaintiff “from seeking judicial review of FDA’s legal position,” Pl.’s Mot TRO, ECF No. 3, at 4, starting with the FDA denying, without comment on the merits, the plaintiff’s Citizen Petitions on the last day of the statutory deadline, 21 U.S.C. §355(q), and subsequently urging denial of the plaintiff’s application for a preliminary injunction on grounds that would avoid reaching the merits of the plaintiff’s complaint about the FDA’s legal position. . . .  Yet, a mere four days later, by March 27, 2012, the FDA had approved a number of ANDAs for generic versions of Seroquel.  Government counsel at the hearing on the TRO defended the FDA’s prior representations to the Court, without any apparent recognition that those representations could appear to be less than forthright about the status of FDA decision-making, since regardless of any representation made by the FDA, deference is due to the agency’s interpretation of the FDCA.  The consequences of the FDA’s tactics of “hiding the ball” of its position until March 27, 2012 are two-fold: consideration of the merits of the legal issues presented by the plaintiff’s complaint have been delayed, with the opportunity for judicial review of those issues last week lost and the expenditure of judicial resources of yet another Judge this week required.

Judge Howell’s comments are somewhat reminiscent of the frustration Judge John Bates expressed in another case in which exclusivity was disputed (see here).

In addition to denying AstraZeneca’s TRO motion, Judge Howell ordered FDA to supplement the administrative record by Friday with any additional relevant records and ordered FDA and AstraZeneca to submit by 5:00 PM this Friday an expedited briefing schedule.

By Jennifer D. Newberger –

On March 27, 2012, FDA announced the release of a final guidance document, “Factors to Consider When Making Benefit-Risk Determination in Medical Device Premarket Approval and De Novo Classifications.”  (A copy of FDA's March 28, 2012 Federal Register notice announcing the guidance is available here.)  Considering that FDA only released the draft guidance in August 2011, the issuance of the final guidance is remarkably fast.  Despite the speed with which FDA finalized this guidance, it seems to do a good job of addressing industry concerns with the draft guidance, and setting forth reasonable standards for benefit-risk determinations.

The one area in which the guidance falls short is its scope.  Unlike the draft guidance, which stated that, at least in “limited cases,” the benefit-risk determinations would be applicable to 510(k) notifications as well as premarket approval applications (“PMAs”), the final guidance applies only to PMAs and de novo petitions.  While the application of this guidance to de novo petitions will benefit sponsors who know upon submitting a 510(k) notification that the product will ultimately have to be brought to market via a de novo petition, and could therefore include benefit-risk information in the 510(k) submission, this is not always the case.  If a sponsor does not have this knowledge, it likely will not have put forth the risk-benefit discussion in its 510(k) submission.  This further supports current congressional proposals that would allow for an early determination of the appropriateness of a de novo review.

Notably absent from this scope are 510(k) notifications.  Because the vast majority of devices are brought to market through the 510(k) process, and because FDA regularly engages in benefit-risk determinations in its 510(k) decision-making process, it is not clear why the scope of the final guidance is more limited than that of the draft.  If FDA will be applying a different framework for considering the benefits and risks of devices cleared via the 510(k) process, it will be important for FDA to provide insight into that process as well.

The limited scope appears to be the one major area in which the final guidance takes away from the draft.  Otherwise, it addresses several of the concerns expressed by industry about benefit-risk determinations in response to the draft guidance.  Of note, the guidance states that “a ‘probable risk’ and ‘probable benefit’ do not include theoretical risks and benefits, and instead are ones whose existence and characteristics are supported by valid scientific evidence.”  This statement is significant, and seems designed to respond to assertions by sponsors that reviewers sometimes cite hypothetical risks unsupported by data as the basis for not approving or clearing a device.  Whether this practice will change as a result of this position in the guidance remains to be seen.

Additionally, while the draft guidance only briefly addressed patient tolerance for risk, the final guidance contains substantial discussion of patient tolerance for risk as well as perspective on benefit.  Including the perspective on benefit demonstrates FDA’s awareness that patients will not only consider risk in making their decisions about product use, but will also consider the benefits that may be achieved, despite the associated risk.  In this discussion, FDA acknowledges that “risk tolerance will vary among patients, and this will affect individual patient decisions as to whether the risks are acceptable in exchange for a probable benefit.”  The guidance further notes that “FDA would consider evidence relating to patients’ perspective of what constitutes a meaningful benefit when determining if the device is effective, as some set of patients may value a benefit more than others.”  Perhaps most importantly in this regard, the guidance states that “it may be appropriate to approve a device where only a minority of the intended patient population would accept the risks as weighed against the benefits if the information necessary for patients and health care practitioners to make well-informed decisions is available and can be presented in a manner that can be understood by the practitioners and patients.”  By incorporating this discussion of patient tolerance for risk and perspective on benefit, FDA is recognizing that patients and practitioners should ultimately be responsible for determining whether a certain risk is acceptable for that particular patient in light of the potential benefits. 

The guidance also would allow use of validated surrogate endpoints, rather than direct endpoints, for measuring clinical benefit, and notes that “FDA may consider the collection of postmarket data as a way to clarify the magnitude and effect of mitigations or as a way to develop additional information regarding benefits or risks for certain device types or in specific patient populations when making a benefit-risk determination.”  This use of postmarket data may alleviate some of the premarket data burdens of sponsors.  Of course, FDA has long had the ability to reduce premarket data requirements through postmarket data collection, but has made sparing use of that authority.

In general, this guidance has the potential to be very useful to sponsors of PMAs and de novo petitions, though unfortunately the same cannot be said for sponsors of 510(k) notifications.  FDA’s implementation of the guidance will, of course, determine its ultimate value.