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.

By Kurt R. Karst –      

In a decision and accompanying Order handed down on March 27, 2012, Judge Richard J. Leon of the U.S. District Court for the District of Columbia ordered that FDA “immediately notify any and all state correctional departments which it has reason to believe are still in possession of any foreign manufactured thiopental that the use of such drug is prohibited by law” and that such drug product be returned immediately to FDA, and that FDA “be permanently enjoined from permitting the entry of, or releasing any future shipments of, foreign manufactured thiopental into interstate commerce.” 

Judge Leon’s decision (which follows his recent ruling against FDA on the Agency’s regulation requiring the display on cigarette packages of graphic warnings – see our previous post here) stems from a February 2011 lawsuit (amended in July 2011) brought against FDA by death row inmates in three states over the importation of unapproved thiopental sodium, one of the drugs used by some states to administer a lethal injection, alleging violations of the Administrative Procedure Act (“APA”) and the FDC Act (see our previous post here).  In issuing his decision, Judge Leon granted the Plaintiff inmates’ Motion for Summary Judgment and Declaratory Relief on Counts I and III (concerning alleged APA violations – 5 U.S.C. § 706(2)(A)) and denied FDA’s Motion to Dismiss and/or for Summary Judgment.

Although FDA contended that the Plaintiffs in the case lacked standing to bring their claims for failure to adequately show injury or causation, Judge Leon found otherwise.  “For standing purposes, an increased risk of future harm is a category of the injury-in-fact prong. . . .  Here, the threatened injury – that unapproved foreign thiopental will fail to anesthetize plaintiffs properly during execution, causing conscious suffocation, pain, and cardiac arrest – is, to say the least, severe,” wrote Judge Leon.  “Because unapproved thiopental exposes plaintiffs to the risk that the drug will not function as intended, plaintiffs have shown at least a ‘modest’ increment of risk that the use of foreign thiopental in their executions would result in conscious suffocation, pain, and cardiac arrest.”  Having dealt with the injury prong, Judge Leon turned to causation and FDA’s contention that there is no causal connection between Plaintiffs’ threatened injury and FDA’s failure to reject unapproved foreign thiopental.  “The threatened injury, however, arises directly from defendants' actions,” wrote Judge Leon.  FDA’s “admission of foreign thiopental shipments allows state [departments of correction] to use thiopental in their lethal injection protocols.  In so doing, plaintiffs’ risk of conscious suffocation, pain, and cardiac arrest increases.  Thus, plaintiffs have standing to pursue their claims.”

Moving on the Plaintiffs’ Count I – that FDA violated the APA (5 U.S.C. § 706(2)(A)) by improperly allowing shipments of a misbranded and unapproved new drug to enter the U.S. contrary to the FDC Act – Judge Leon pointed to the word “shall” in FDC Act § 801(a).   That statutory provision concerns imports and states, in relevant part, that “[i]f it appears from the examination of such [imported] samples or otherwise” that the product violates the FDC Act’s misbranding or new drug approval requirements, “then such article shall be refused admission.”  Although FDA contended that the FDC Act does not impose a mandatory duty on the Agency to refuse admission of an import, Judge Leon said in his opinion that the statute is crystal clear:  In FDC Act § 801(a) “Congress’ intent was for ‘shall’ to impose a mandatory obligation on [FDA] to refuse to admit the misbranded and unapproved drug, thiopental, into the United States.”

FDA’s Heckler defense – that is, that under the U.S. Supreme Court’s decision in Heckler v. Chaney, 470 U.S. 821 (1985), (another death row inmate case) FDA’s decision not to take enforcement action with respect to thiopental sodium is not subject to judicial review because “agency refusals to institute investigative or enforcement proceedings are committed to agency discretion” (internal citation and quotation omitted) – fell on deaf ears.  “[A] decision to admit or exclude an imported product is not the type of discretion – like prosecutorial discretion – that the Supreme Court considered in its decision in Heckler,” wrote Judge Leon.  “Unlike in Heckler, here, the FDA’s decision did not involve a decision whether to initiate enforcement proceedings against a violator of the Act; rather, it involved a decision to ignore an administrative directive.”

Turning to Plaintiffs’ Count III – that FDA violated the APA (5 U.S.C. § 706(2)(A)) by departing from longstanding Agency policies and undermining the purpose of the FDC Act – Judge Leon ticked off some examples of where FDA has been inconsistent with the Agency’s own regulations and policies insofar as importation of unapproved drugs into the U.S. is concerned, and said that FDA failed to proffer a reasoned explanation for such inconsistencies.  This all led Judge Leon to conclude his opinion with a rather colorful statement: “In the final analysis, the FDA appears to be simply wrapping itself in the flag of law enforcement discretion to justify its authority and masquerade an otherwise seemingly callous indifference to the health consequences of those imminently facing the executioner’s needle.  How utterly disappointing!”

By Kurt R. Karst –      

In a decision that if left intact could have far-reaching implications for FDA, the U.S. District Court for the Southern District of New York recently granted a Motion for Summary Judgment filed by the National Resources Defense Council (“NRDC”) and three other member groups of “Keep Antibiotics Working” (a coalition of health, consumer, agricultural, environmental, humane and other advocacy groups) – the Center for Science in the Public Interest, the Food Animal Concerns Trust and the Union of Concerned Scientists – and denied FDA’s Cross-Motion for Summary Judgment in a case concerning the withdrawal of approval for subtherapeutic uses of penicillin and tetracyclines in animal feed. 

As we previously reported, the NDRC, et al. filed a Complaint in May 2011 seeking to compel FDA, by a court-ordered deadline, to withdraw approval for subtherapeutic uses of penicillin and tetracyclines in animal feed and to issue a final response to two Citizen Petitions submitted to the Agency – one on March 9, 1999 (Docket No. FDA-1999-P-1286) and another on April 7, 2005 (Docket No. FDA-2005-P-0007).  Both petitions relate to Notices of an Opportunity for Hearing (“NOOHs”) FDA issued in 1977 on proposals to withdraw approval of all subtherapeutic uses of penicillin in animal feed   and nearly all subtherapeutic uses of tetracyclines (oxytetracycline and chlortetracycline) in animal feed because of a threat to human health.  Although hearings were requested, FDA never held them or otherwise took action on the proposed withdrawals. 

FDA, on the Agency’s own initiative, denied both petitions on November 7, 2011 (here and here) (just one day before FDA’s response to NDRC’s Motion for Summary Judgment was due) saying in both responses that “for various reasons the Agency has decided not to institute formal withdrawal proceedings at this time and instead is currently pursuing other alternatives to address the issue of antimicrobial resistance related to the production use of antimicrobials in animal agriculture.”  One of those “other alternatives” is laid out in FDA’s June 2010 draft guidance No. 209 – The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals – which FDA says provides “a pathway to achieving the same goals as those advocated by [Plaintiffs], i.e., judicious use of medically important antimicrobials.”   The draft guidance provides a “framework for policy regarding the appropriate or judicious use of medically important antimicrobial drugs in food-producing animals,” including  “1) limiting medically important antimicrobial drugs to uses in food-producing animals that are considered necessary for assuring animal health; and 2) limiting such drugs to uses in food-producing animals that include veterinary oversight or consultation.”

Several weeks after denying the 1999 and 2005 citizen petitions, FDA, on December 22, 2011, issued a Federal Register notice withdrawing the 1977 NOOHs saying, among other things, that “FDA is engaging in other ongoing regulatory strategies developed since the publication of the 1977 NOOHs with respect to addressing microbial food safety issues.”  As FDA did in the citizen petition denials, the Agency referenced draft guidance No. 209, saying that it represents a “pathway to achieving the same goals contemplated by the 1977 NOOHs.”  FDA also commented that notwithstanding the NOOH withdrawals, the Agency “remains concerned about the issue of antimicrobial resistance.”

Undeterred by FDA’s actions, the NRDC promptly alleged that FDA withheld agency action in violation of both the Administrative Procedure Act (“APA”) (5 U.S.C. § 706(1)) and FDC Act § 512(e)(1), which states (similar to its NDA counterpart at FDC Act § 505(e)(1)) in relevant part that FDA:

shall, after due notice and opportunity for hearing to the applicant, issue an order withdrawing approval of an application filed pursuant to [FDC Act § 512(b)] with respect to any new animal drug if the Secretary finds . . . . (B) that new evidence not contained in such application or not available to the Secretary until after such application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when such application was approved, evaluated together with the evidence available to the Secretary when the application was approved, shows that such drug is not shown to be safe for use under the conditions of use upon the basis of which the application was approved . . . . 

After initially determining that FDC Act § 512(e)(1) requires FDA to take certain “discrete actions” subject to APA review, U.S. Magistrate Judge Theodore H. Katz addressed in his 55-page decision whether FDA is legally required to proceed with the NOOH hearing and withdrawal process.  In a resounding “yes” to this question, Magistrate Judge Katz wrote in his opinion that:

Here, the statute unambiguously commands the Secretary to withdraw approval of any new animal drug that he finds not shown to be safe, provided that the sponsor of the animal drug has notice and an opportunity for a hearing.  The statute does not explicitly state the order in which this process must occur. 

FDA contended that the Secretary can only issue a finding after a hearing, while the NRDC contended that FDA’s obligation to provide notice and opportunity for a hearing is triggered by the Agency’s initial finding.  Magistrate Judge Katz found the Plaintiffs’ interpretation more palatable:

The Court finds that Plaintiff’s interpretation provides a common sense reading of the statute based on its text and grammatical structure.  The statute states that “[t]he Secretary shall after due notice and opportunity for hearing to the applicant, issue an order withdrawing approval of a[] [NADA/ANADA] if the Secretary finds . . . [that a drug is not shown to be safe] . . . .”  The “after due notice and opportunity for hearing” clause is setoff by commas and immediately precedes the words “issue an order withdrawing approval,” indicating that the “notice” clause modifies the “issue an order” clause and not the findings clause.  Accordingly, the statute only requires the Secretary to give notice and provide an opportunity for a hearing before issuing an order of withdrawal and not before making findings.  Under this reading, if the Secretary finds that an animal drug has not been shown to be safe, he is statutorily required to withdraw approval of that drug provided that the drug sponsor has notice and an opportunity for a hearing.  [(Internal citations omitted)]

Magistrate Judge Katz wrote in his opinion that a decision that FDC Act § 512(e)(1) requires FDA to issue notice and an opportunity for a hearing whenever the Agency finds that a new animal drug is not shown to be safe is consistent with how courts, including the U.S. Supreme Court in FDA v. Brown & Williamson Tobacco Corp., 529 U.S. 120, 134 (2000), have interpreted the NDA counterpart provisions at FDC Act § 355(e).  See Mylan Labs., Inc. v. Thompson, 389 F.3d 1272, 1281 (D.C. Cir. 2004), Dobbs v. Wyeth Pharms., 797 F. Supp. 2d 1264, 1270-71 (W.D. Okla. 2011).

In ordering FDA to initiate withdrawal proceedings for the relevant NADAs and ANADAs, Magistrate Judge Katz was careful to note the limits of his decision, stating: “Although the Court is ordering the FDA to complete mandatory withdrawal proceedings for the relevant penicillin and tetracycline NADAs/ANADAs, the Court is not ordering a particular outcome as to the final issuance of a withdrawal order.  If the drug sponsors demonstrate that the subtherapeutic use of penicillin and/or tetracyclines is safe, then the Commissioner cannot withdraw approval.”

The district court decision was almost immediately hailed by Representative Louise Slaughter (D-NY) in a press release as a “landmark decision.”  As we previously reported, Rep. Slaughter, who is the only microbiologist in Congress, has shown a keen interest in FDA’s action (or lack thereof) related to antibiotic use in animal agriculture.  Rep. Slaughter is the author of the Preservation of Antibiotics for Medical Treatment Act, which would, among other things, phase out the non-therapeutic use in livestock of medically important antibiotics.

FDA has not yet indicated whether or not the Agency will appeal Magistrate Judge Katz’s decision.  We’d be a bit surprised if the Agency decides not to appeal given FDA’s likely view that it intrudes on the Agency’s ability to set regulatory priorities.  Moreover, the decision, if not appealed (or if affirmed on appeal), could open the door for third parties to seek a court order to compel FDA to initiate withdrawal proceedings for a particular drug product, provided the precursors that exist in this case exist in another case. 

By Carmelina G. Allis –

Amid recent reports alleging safety and effectiveness issues with a number of implant devices, a bipartisan group of Senators have introduced a bill entitled the “Ensuring Safe Medical Devices for Patients” (S. 2193).  This bill is intended to strengthen FDA’s postmarket surveillance of devices.  If enacted, this legislation would:

• Expand the Postmarket Risk Identification and Analysis System under Section 505(k)(3)(C) of the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to devices.  This System currently applies to drugs, but would require that FDA establish and maintain procedures for, among other things, the active adverse event surveillance of devices.

• Require the agency to give priority in the Postmarket Risk Identification and Analysis System to Class II and Class III devices that are implantable, life-supporting or life-sustaining, or pose significant risk to users; and

• Amend Section 519(f) of the FDC Act to require that the agency implement the Unique Device Identification System no later than 1 year after the date on which final regulations are issued.  This bill also would require that the agency issue final regulations on a Unique Device Identification System no later than December 31, 2012.  The Food and Drug Administration Amendments Act of 2007 mandates that the agency establish a Unique Device Identification System that would require devices to bear a unique identifier that would identify the device through distribution and use, including information on the lot or serial number.  The agency has held public meetings and workshops on the matter (see here), but 5 years after the provision’s enactment FDA has yet to issue draft regulations. 

Overall, this proposed bill would strengthen FDA’s postmarket surveillance of medical devices and complement the Medical Device Reporting requirements in 21 C.F.R. Part 803.  It will also enhance the agency’s Sentinel Initiative, which was launched in 2008 to complement existing FDA systems for tracking adverse event reports of regulated products. 

By Kurt R. Karst –      

In a 33-page decision handed down late last Friday, Judge Colleen Kollar-Kotelly of the U.S. District Court for the District of Columbia denied AstraZeneca Pharmaceuticals LP’s (“AstraZeneca’s”) Application for Prelimiary Injunction and dismissed without prejudice the action AstraZeneca filed on March 12, 2012 seeking to enjoing FDA from granting final ANDA approval for a generic version of the company’s blockbuster antipsychotic drug SEROQUEL (quetiapine fumarate) Tablets (NDA No. 020639) as early as March 26, 2012 (as well as an extended-release version of the drug, SEROQUEL XR (quetiapine fumarate) Extended-Release Tablets (NDA No. 022047)).  As we previously reported, AstraZeneca filed the lawsuit after FDA denied two citizen petitions the company submitted to FDA last year concerning labeling carve-out issues for generic versions of the drugs (Docket No. FDA-2011-P-0662 and Docket No. FDA-2011-P-0663).  FDA denied the petitions within the 180-day statutory period under FDC Act § 505(q) without comment on the merits of the issues raised in the petitions, stating that “[t]here is no evidence that in enacting [FDC Act § 505(q)], Congress intended to short-circuit the application review process or to vitiate an ANDA or NDA applicant’s procedural rights by requiring that the Agency make decisions that constitute final Agency action regarding the approvabilty of a certain aspects of pending applications on a piecemeal basis outside of the process established under the Act and regulations.” 

Afer reviewing FDA’s Opposition to AstraZeneca’s Application for Prelimiary Injunction, in which FDA argued that the action was not ripe for review and that AstraZeneca “must await an FDA decision before it can raise a judicially reviewable claim,” Judge Kollar-Kotelly directed AstraZeneca to “show cause” why the lawsuit should not be dismissed without prejudice if the court were to find that AstraZeneca’s claim is not yet ripe.  AstraZeneca promptly filed its brief addressing the issue (and replying to FDA’s opposition brief) and inviting the court to hold the action in abeyance for an indefinite period to wait and see whether it ripens into a justiciable case or controversy.  FDA filed a surreply to AstraZeneca’s brief reiterating the Agency’s position that the company’s claims are not ripe and saying that “FDA would voluntarily provide timely notice of approval of any ANDA for a generic version of Seroquel or Seroquel XR to AstraZeneca and the Court, even if this case were dismissed without prejudice.” 

Considering the record as a whole, Judge Kollar-Kotelly concluded that AstraZeneca failed to make the clear showing necessary to grant a preliminary injunction, and that each of the four factors a court considers in deciding whether or not to grant preliminary injunctive relief did not weigh in AstraZeneca’s favor.  Focusing much of her decision on the “likelihood of success on the merits” factor, Judge Kollar-Kotelly concluded that the action is not ripe:

[T]he Court has no doubt that the substantive issues raised by AstraZeneca in this action are not presently fit for judicial review.  AstraZeneca may have its own views as to the scope of its new patient population exclusivity and the relationship between that exclusivity and ANDAs submitted by potential generic competitors, but the FDA mayor may not decide to give final approval to competing generics and it mayor may not decide to give final approval in a manner that would interfere with AstraZeneca's interpretation of its new patient population exclusivity.  At this juncture, the Court simply is not in a position to project whether the FDA will ultimately decide to give final approval to a competing generic, when that hypothetical deci sion might happen, or what relationship the agency's proffered rationale for that hypothetical decision would have to the specific claim raised by AstraZeneca in this action. Absent further administrative action, the Court cannot say how the legal arguments tendered by AstraZeneca in this case will matter or even whether they will matter at all. . . .

Regardless of what AstraZeneca may believe, it is beyond cavil that this litigation does not involve the sort of “questions oflaw and undisputed facts” that might justify immediate judicial intervention.  Nor is the Court willing to assume, as AstraZeneca apparently is, that the outcome of, and basis for, the FDA's decisions on pending generic applications is preordained. . . .  This action is not, in short, presently fit for judicial review. If judicial intervention ever proves to be necessary, it should wait until the FDA's “decision has been fonnalized and its effects felt in a concrete way by the challenging parties.”  [(Internal citations omitted)]

While Judge Kollar-Kotelly noted that AstraZeneca might want to seek judicial intervention in an expedited proceeding if and when the FDA grants final ANDA approval, she commented that “any concern in this regard is ameliorated somewhat by the fact that the FDA has already voluntarily bound itself to provide AstraZeneca with advance notice of its intention to issue a final decision adverse to AstraZeneca and represents that it will consent to expedited briefing in the event preliminary relief is sought in the future.”

AstraZeneca had relied heavily in its briefs on the D.C. Circuit’s 2010 decision in Teva Pharmaceuticals USA, Inc. v. Sebelius, 595 F.3d 1303 (D.C. Cir. 2010), to support the company’s position that it was entitled to relief now, before ANDA approval and in light of FDA’s petition denials.  Judge Kollar-Kotelly, however, found AstraZeneca’s reliance on that decision to be misplaced and distinguished it from AstraZeneca’s case.

First, by the time the plaintiff brought suit in Teva, the FDA had already made its position abundantly clear. . . .  The same cannot be said here, where the FDA may or may not decide to give final approval to one or more competing generics and it may do so for any number of reasons. . . . Second, the single dispositive issue in Teva was a pure question of statutory interpretation and the parties’ competing interpretations were categorical and “impervious . . . to factual variation.”  By contrast, in this case, there are open questions about the status of pending applications for competing generics and their relationship to AstraZeneca’s interpretation of its new patient population exclusivity.  [(Internal citations omitted)]

Instead, wrote Judge Kollar-Kotelly, AstraZeneca’s case more closely resembles the D.C. Circuit’s 1999 decision in Pfizer Inc. v. Shalala, 182 F.3d 975 (D.C. Cir. 1999), in which the Court, in the context of a challenge to a citizen petition denial before final ANDA approval, “found the most prudent course was to await a final decision from the FDA, when the plaintiff would be in a position to address any other arguments ‘aris[ing] from the agency’s final approval- if and when it is given’” [(Internal citations omitted)].

In addition to denying AstraZeneca’s Application for Preliminary Injunction, Judge Kollar-Kotelly declined to hold the action in abeyance pending FDA’s decision on generic quetiapine approvals:

This Court simply is not in a position to prophesy whether the FDA will ultimately decide to give final approval to a competing generic, when that hypothetical decision might happen, or what relationship the agency’s proffered rationale for that hypothetical decision would have to the specific claim raised by AstraZeneca in this action.  Indeed, the Court is mindful that the precise “controversy” envisioned by AstraZeneca in this action may never ripen into a dispute amenable to judicial review. [(Emphasis in original)]

Will Monday, March 26, 2012 (today) see the fire drill-type procedures that we have seen before in Hatch-Waxman ANDA approval litigation?  We’ll all know soon enough.  In that regard, we will update this post with relevant information.

UPDATES:

• March 26th AstraZeneca Press Release – "Notwithstanding the Court’s decision, the Company continues to believe strongly in the merits of its position and is evaluating its options."
• On Monday morning, AstraZeneca filed a Motion To Amend March 23, 2012 Order To Require FDA To Provide Advance Notice of Final Decision Adverse to AstraZeneca.  The “advance notice” requested is at least two business days of any FDA decision to grant final ANDA approval.
• On Monday afternoon, FDA filed its Opposition to AstraZeneca’s motion (above).  FDA says: “Defendants oppose AstraZeneca’s motion to amend the order to require that FDA give advance notice of at least two business days before FDA approves a generic version of Seroquel or Seroquel XR.  To the extent that this Court misunderstood FDA’s voluntary offer to provide ‘timely’ notice as meaning ‘advance’ notice before an ANDA will be approved, the defendants suggest that the court’s decision be amended to reflect FDA’s intention, which is that timely notice means that FDA will provide notice within a short time after an ANDA has been approved.”
• AstraZeneca’s Reply to FDA’s Opposition: “FDA can give AstraZeneca advance notice without implicating [21 C.F.R. § 314.430(d)(1)]: a simple, ‘FDA intends to grant final approval to an ANDA for a generic version of Seroquel in two business days’ would suffice.”
• This afternoon, Judge Kollar-Kotelly issued an Order denying AstraZeneca’s Motion To Amend March 23, 2012 Order To Require FDA To Provide Advance Notice of Final Decision Adverse to AstraZeneca.

By JP Ellison –

We previously reported on the oral arguments in the Supreme Court case Sackett v. EPA that raised the question of when agency action was sufficiently final to allow a party to seek review in federal court.  Earlier this week the Supreme Court handed down its decision in a unanimous 9-0 ruling that the EPA’s compliance order was final agency action reviewable in federal court under the APA.  The Court’s decision is an important one, but readers of the decision will find few definitive answers as to its broader implications.

We don’t think it will take long for an FDA regulated entity to cite Sackett as the basis of challenging an FDA Warning Letter, or other agency enforcement action that the agency claims is not final.  If nothing else, Sackett makes is clear that an agency’s characterization of its enforcement activities as a means to achieve “voluntary compliance” is not dispositive on the issue of whether agency action is final.  See, .e.g., FDA Regulatory Procedures Manual, 4-1 (“Warning Letters are issued to achieve voluntary compliance . . . ”) available here. 

The success of a Sackett-based argument that a Warning Letter —or other agency action— constitutes final agency action will turn on the specific context.  In Sackett, the Court identified several aspects of the EPA compliance orders that contributed to the conclusion that the orders constituted final agency action:

• the order determined rights or obligations; 
• legal consequences flowed from the issuance of the order; and 
• the order marked the consummation of the agency’s decision-making.

Many FDA Warning letters would seem to satisfy these criteria.  See, e.g., letters posted here (Withholding approval of drug applications and imposition of import alert) and here (no premarket approval and federal agencies advised of warning letter to consider when awarding contracts).  Other agency action may similarly meet these criteria.  It may be that one result of Sackett will be a thorough review of agency correspondence in an attempt to insulate future agency action from court review. 

In addition, based on the facts at issue in Sackett and Justice Ginsburg’s concurring opinion in the case, one could see federal agencies arguing that to the extent that Sackett is at all applicable, it only governs in those instances when the question is whether the agency has jurisdiction.  There is nothing in the Court’s opinion that imposes such a limitation, however. 

In any event, while Sackett provides an opening to challenge FDA’s position on what is final agency action, including but not limited to the position that it “does not consider Warning Letters to be final agency action on which it can be sued” (see our previous post here), such an argument needs to be carefully considered and crafted to maximize its chances for success.

By Jennifer D. Newberger –

On March 20, 2012, FDA published a notice in the Federal Register announcing a public meeting to discuss proposed recommendations (here and here) for the reauthorization of the Medical Device User Fee Act (“MDUFA”) for fiscal years 2013 through 2017.  77 Fed. Reg. 16239 (March 20, 2012).  The recommendations, dated February 17, 2012, stem from meetings between FDA, the medical device industry, and other stakeholders, and may be revised based upon input received at the public meeting and from written comments.

The draft recommendations include the following proposals:
1. Process Improvements
2. Review Performance Goals
3. Shared Outcome Goals
4. Infrastructure
5. Independent Assessment of Review Process Management
6. Performance Reports
7. Discretionary Waiver

We highlight below the proposals that seem intended to respond specifically to industry’s concerns about FDA’s management of the pre-market review process.

Process Improvements

There are eight separate items within this one proposal, two of which appear to potentially have the greatest impact on pre-market review:  pre-submissions and patient safety and risk tolerance.

Pre-Submissions.  In this proposal, FDA has agreed to institute a “structured process” for managing pre-submissions, which include “a formal written request from an applicant for feedback from FDA which is provided in the form of a formal written response or, if the manufacturer chooses, a meeting or teleconference in which the feedback is documented in meeting minutes.”

As part of this structured process, FDA states that it will provide initial feedback to the applicant by email at least three business days prior to the meeting.  This feedback will include “written responses to the applicant’s questions; FDA’s suggestions for additional topics for the meeting or teleconference, if applicable; or, a combination of both.”

Most notably, FDA states that it “intends that feedback the Agency provides in a Pre-Submission will not change, provided that the information submitted in a future investigational device exemption (“IDE”) or marketing application is consistent with that provided in the Pre-Submission and that the data in the future submission do not raise any important new issues materially affecting safety or effectiveness.”  While this still gives FDA substantial flexibility to change its mind, the intent that the feedback is final is a change from current practice, in which FDA often feels free not to adhere to the preliminary advice it gave to a sponsor.  For sponsors to benefit from this new approach, they will need to clearly think through all the issues on which they would like FDA’s feedback, frame very specific questions to address those issues, and be sure to clarify any answers that do not appear to respond adequately to the question posed.

Patient Safety and Risk Tolerance.  FDA states that it intends to “fully implement final guidance on the factors to consider when making benefit-risk determinations in medical device premarket review.”  FDA issued draft guidance on this topic in August 2011, discussed here.  In addition to finalizing the guidance, FDA states that it will meet with patient groups “to better understand and characterize the patient perspective on disease severity or unmet medical need” and will also “increase its utilization of FDA’s Patient Representatives as Special Government Employee consultants to CDRH to provide patients’ views early in the medical product development process and ensure those perspectives are considered in regulatory discussions.”

Taking patient perspectives into consideration may be helpful, particularly in the premarket review of innovative devices intended to address unmet medical needs.  In addition to meeting with patients, FDA should carefully consider the comments it received on the draft guidance prior to its implementation, and incorporate and revise the guidance as needed to address those comments. 

Review Performance Goals

A common concern expressed by industry is that FDA takes too long to complete its premarket review.  In this recommendation, FDA is proposing to “ramp-up” the percentage of submissions that will meet the stated review time goals during each of the years in the five year MDUFA time frame.

The length of the review time is often due to the number of deficiency letters a sponsor may receive.  In this proposal, FDA states that, when it issues a deficiency letter, the letter will be based “upon a complete review of the submission and will include all deficiencies.  Any subsequent deficiencies will be limited to issues raised by the information provided by the applicant in its response, unless FDA concludes that the initial deficiencies identified do not adequately address important new issues materially relevant” to the pending determination.  Though FDA will still have the ability to send more than one deficiency letter, perhaps this goal will encourage FDA to do a very thorough review of the submission and consider all factors before sending the letter.  Managers should carefully review proposed additional deficiency letters to ensure the reviewers are not raising new issues that could have been raised in the original letter, but, due to the reviewer’s own mismanagement or oversight, were not.

Independent Assessment of Review Process Management

FDA will award a contract to a private, independent consulting firm that will publish findings on high-priority recommendations within 6 months of the contract award, and will publish its final comprehensive findings and recommendations within 1 year of the contract award.  FDA will publish an implementation plan within six months of receipt of each set of recommendations, and will then incorporate the findings and recommendations into its management of the premarket review program.  Though on its face it seems like a good idea to have a third party assess the review process management, this idea is not completely dissimilar from FDA’s contract with the Institute of Medicine (“IOM”) to review the 510(k) program and provide recommendations.  It is not clear that FDA has, at this time, implemented any of the recommendations provided by the IOM, and there is no guarantee that it will act differently with regard to the third party recommendations.  Hiring a consulting group certainly will not have any short-term beneficial impact.  While an outside assessment may be valuable, there are many ways in which this can become an exercise in generating a report that gets lots of attention but has no impact on actual practices.

The draft proposals appear intended to address several of the key concerns raised by industry about premarket review.  As with all FDA proposals, only time will tell whether FDA will follow its own recommendations, and, if so, whether implementation of those recommendations will have the desired results.

By Ricardo Carvajal –

A divided 6th Circuit panel affirmed a lower court’s ruling that some provisions of the Family Smoking Prevention and Tobacco Control Act (“Tobacco Act”) are unconstitutional, but others are not.  As we noted in a prior posting, a federal district court ruled in November 2009 that certain provisions of the Tobacco Act violated the First Amendment, namely (1) the mandate that cigarette and smokeless tobacco labeling and advertising use only black text on a white background, and (2) the prohibition on statements suggesting that a tobacco product is safe or less harmful because it is regulated or inspected by FDA, or is in compliance with FDA regulations.  The 6th Circuit affirmed the first of these determinations, but reversed the second on the ground that the prohibition does not extend to non-commercial speech (e.g., speech by journalists, scientists, and politicians) and therefore should not have been analyzed under strict scrutiny.  Rather, the prohibition extends only to commercial speech that the court deemed “inherently misleading and patently false,” and therefore not entitled to First Amendment protection.

In its November 2009 decision, the district court also ruled that certain provisions of the Tobacco Act did not violate the First Amendment, namely (1) the required warnings on cigarette and smokeless tobacco packages, including “color graphics depicting the negative health consequences of smoking,” (2) the restrictions on distribution of samples, continuity programs, and promotion of brands through event sponsorship and merchandise, , and (3) the prohibition on labeling or advertising claims suggesting reduced risk in the absence of FDA approval as a modified risk tobacco product.  The 6th Circuit affirmed all of these determinations, with one exception: the restriction on continuity programs (i.e., “the distribution of free gifts in consideration for a tobacco purchase”) was deemed overbroad.

The three-judge panel split on the question of the constitutionality of the color graphics requirement.  Applying Zauderer’s rational basis standard, the majority concluded that the requirement is constitutional “[b]ecause graphics can present factual information regarding the health risks of using tobacco, and because this information alleviates the possibility of consumer confusion.”  The dissent demurred, citing the recent D.C. district court decision finding that the graphic images selected by FDA for inclusion in its final rule are “neither designed to protect the consumer from confusion or deception, nor to increase consumer awareness of smoking risks; rather, they were crafted to evoke a strong emotional response calculated to provoke the viewer to quit or never start smoking” (see our prior posting on that decision here).  However, as noted by the majority, the selection of those images took place after the district court’s grant of summary judgment in the instant case. 

There are numerous other points of difference between the majority and concurring/dissenting opinions rendered by the panel.  Those differences, together with differences between the 6th Circuit and D.C. district’s First Amendment analyses, suggest that the Supreme Court will have the opportunity to opine on the constitutionality of the Tobacco Act before too long.  We note that the D.C. district court decision has been appealed to the D.C. Circuit, which is scheduled to hold oral argument on April 10th.