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.

By Kurt R. Karst –      

FDA’s issuance of three long-awaited and highly anticipated draft biosimilar guidances earlier this year (see our previous post here) seems to have hardly whet industry’s appetite for information on the Agency’s interpretation of Section 351(k) of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  (A follow-up presentation from FDA on the draft guidances is available here and here.  Another draft guidace on “Submission of Clinical Pharmacology Data as Evidence of Biosimilarity for Biologics and Protein Products” is on FDA’s guidance agenda for later this year.)  Like Renée Zellweger’s character in the movie “Jerry Maguire,” who at a key scene in the film utters the line “You had me at hello” after listening to a long speech from the sports agent character played by Tom Cruise beginning with the word “hello,” industry’s attention seems to be immediately captured by FDA’s mere mention of the word “biosimilars.”  (Indeed, it seems to create a feeding frenzy of sorts.)   So we thought we would throw out another “hello” from FDA.

As we previously reported, shortly after FDA released the three draft biosimilars guidances, the Agency denied outstanding requests in two citizen petitions submitted to the Agency in April 2003 (Docket No. FDA-2003-P-0003) and April 2004 (Docket No. FDA-2004-P-0214) by the Biotechnology Industry Organization and Genentech, Inc. concerning the submission and approval of 505(b)(2) applications under the FDC Act for “biotechnology-derived products” or “follow-on therapeutic proteins.”  Apparently there was a third pre-BPCIA citizen petition submitted to FDA in January 2009 (Docket No. FDA-2009-P-0004).  The two-page citizen petition submitted by Therapeutic Proteins, Inc. simply requests that FDA “allow acceptance of applications for marketing authorization of equivalent forms of biological drugs” (i.e., certain protein and peptide products); or, as FDA’s rephrases the “ask”:  “that FDA accept an ANDA submitted under section 505(j) of the FD&C Act for a protein or peptide product intended to be the ‘same’ as a product that previously was approved under either the FD&C Act or the PHS Act.”  FDA’s six-page response granting in part and denying in part the petition appears to provide further insight into FDA’s thinking on biosimilars approval. 

As FDA notes in the Agency’s petition response, “the availability of an abbreviated approval pathway for a protein or peptide product that seeks to rely, to some extent, upon a previously approved product is governed by the statutory authority under which the previous product was approved or licensed as well as by scientific considerations.”  The ANDA pathway, says FDA, may be used to approve protein and peptide products only where the Reference Listed Drug was approved under FDC Act § 505(c), “the state  of the science is adequate to demonstrate that the active ingredient is the same as the active ingredient of the RLD, and other statutory requirements are met.”  Continuing on, FDA says that with current science highly complex proteins may not be suitable for the ANDA approval pathway:

Because of the complexity of protein molecules and limitations of current analytical methods, it would be difficult for manufacturers of proposed protein products to demonstrate that the active ingredient in their proposed product is identical to the active ingredient in an already approved product.  Therefore, the 505(j) approval pathway, which is predicated on a finding of the “same” active ingredient, will not ordinarily be available for more structurally complex molecules. [(Italics in original)]

Because of the difficulties associated with demonstrating sameness of complex products necessary for ANDA approval, the 505(b)(2) application pathway, which has a “sufficiently similar” standard, may be the better bet, according to FDA.  “The 505(b)(2) approval pathway may be used for a protein or peptide product that is demonstrated to be sufficiently similar to an approved product to permit scientifically justified reliance on certain existing information (e.g., FDA’s finding of safety and/or effectiveness for an approved drug product) to support approval” (italics in original).

FDA’s petition response (like the Agency’s draft guidances) raises a host of unanswered questions.  For example, what series of tests – a la enoxaparin might or might not suffice to demonstrate “sameness” for ANDA purposes for a particular complex protein product during the transition period described in § 7002(e) of the BPCIA (ending on March 23, 2020), and how will FDA handle such products once the transition period ends?  Such questions will likely be addressed in time and on a product-specific basis as sponsors seek FDA’s advice and guidance. 

By Ricardo Carvajal –
         
Linda Birnbaum, Director of the National Institute of Environmental Health Sciences and the National Toxicology Program, published an editorial discussing the most recent evidence that certain environmental chemicals, including suspected endocrine disruptors such as BPA, “can have effects that would not necessarily be predicted from their effects at high doses” – referred to as the “low dose hypothesis.”  As the editorial puts it, “the question is no longer whether nonmonotonic dose responses are ‘real’ and occur frequently enough to be a concern; clearly these are common phenomena with well-understood mechanisms.”  The upshot is that “chemicals with hormonal activity can have effects at external doses that are often considered safe by the regulatory community.”

With regard to BPA specifically, FDA is expected to announce later this month whether the agency will act to amend or rescind BPA’s approved food additive uses – a move compelled in part by a lawsuit filed by the Natural Resources Defense Council.  It will be interesting to see whether evidence of nonmonotonic dose responses plays any part in FDA’s decision.

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By Kurt R. Karst –      

As myriad failure-to-warn cases against generic drug manufacturers work through the judicial system in light of the U.S. Supreme Court’s June 23, 2011, 5-4 landmark decision in PLIVA Inc. v. Mensing, 131 S.Ct. 2567 (2011), as well as a recent petition to the Court concerning Kentucky common law, plaintiffs’ attorneys have increasingly attempted to design around Mensing with new theories of liability.  (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.)  One such “design around” theory we’ve prevously discussed is the so-called “RLD theory of liability,” which posits that FDA’s regulations impose new or additional responsibilities on an ANDA sponsor whose drug product is unilaterally designated by FDA as an RLD in the Orange Book when the brand-name NDA RLD is no longer marketed.  Under this theory, plaintiffs’ attorneys argue that the Court’s Mensing decision is inapplicable and that a court should employ the impossibility preemption analysis utilized in the U.S. Supreme Court’s March 2009 decision in Wyeth v. Levine, 555 U.S. 555 (2009), applicable to brand-name drug products approved under an NDA.

Earlier this year, the U.S. District Court for the Northern District of Georgia (Atlanta Division) handed down the first federal court ruling on the RLD theory of liability in Moore v. Mylan, Inc., No. 11:1-cv-03037-MHS (N.D. Ga. Jan. 5, 2012).  As we reported, Judge Marvin H. Shoob shot down RLD theory arguments concerning Mylan’s RLD version of DILANTIN KAPSEALS (extended phenytoin sodium) Capsules approved pursuant to an ANDA suitability petition, stating in his opinion that the plaintiff failed to show “how Mylan acquired all of the same rights as a brand name drug manufacturer simply by manufacturing one drug that was an RLD” and how “Mylan’s manufacture of one RLD converted Mylan into a brand name drug manufacturer with the right to use the [Changes Being Effected (‘CBE’)] process to change the label of any of its drugs . . . .”

A trio of recent federal court decisions have followed Moore.  In each case, the courts rejected plaintiffs’ RLD theories of liability. 

In Cooper v. Wyeth, Inc., No. 09-cv-929-JJB (M.D. La. Mar. 6, 2012), which concerns metoclopramide, plaintiffs argued that “becoming an RLD at some point for metoclopramide oral solution imbues Teva with NDA duties and liability for metoclopramide tablets,” a pharmaceutically inequivalent drug allegedly ingested by plaintiffs.  Giving great weight to FDA statements on RLD status (see, e.g., 72 Fed. Reg 39,629 (July 19, 2007)), the court found ruled that “Teva does not hold NDA status by virtue of becoming an RLD and thus does not bear the burden of its brand name counterpart.  It is the FDA that is responsible for mandating changes in labeling, and as Mensing recognized, NDA-approved drug makers alone retain duties above and beyond those of generic drug makers.”  That’s some pretty nice language for generic drug manufactures!

In another Louisiana decision also concerning metoclopramide – Morris v. Wyeth, Inc., No. 09-cv-0854 (W.D. La. Feb. 21, 2012) – the court denied plaintiff’s motion to alter and/or amend the court’s October 19, 2011 judgment dismissing the generic drug manufacturers from the case.  Plaintiffs asserted that “a generic manufacturer, which has a product classified as an RLD, has the same discretion as a brand name manufacturer to unilaterally change the product’s warning label,” and as such, FDA’s “regulations do not preempt a failure to warn claim against a generic drug manufacturer if its drug is classified as an RLD.”  Citing Moore, the court rejected ths argument saying that “it assumes, without authority, that the FDA considered TEVA to be a brand name manufacturer with the requisite duty to unilaterally change its product’s labeling simply because FDA designated TEVA’s metoclopramide as the RLD.”

Finally, in In re Darvocet, Darvon & Propoxyphene Products Liability Litigation, MDL Docket No. 2226 (E.D. Ky. Mar. 5, 2012), the court dismissed myriad claims against manufacurers of generic versions of DARVON (propoxyphene), including plaintiffs’ RLD theory of liability.  (Our friends over at Drug and Device Law Blog previously discussed the decision – see here.)  Citing both the Moore decision and the same Federal Register notice relied on by the court in Cooper, the court stated in its decision that plaintiffs provided “no authority to support their contention that when a generic drug manufacturer becomes an RLD holder, it is thereby empowered to independently change the drug’s warning label,” and that “is unpersuaded that Mylan and Watson are subject to liability based on their status as RLD holders.”

In addition to the four federal court decisions dismissing RLD theory of liability claims, there is a growing number of state courts that have also considered and rejected this theory. 

• Sincoskie v. West-Ward Pharms., No. MER-L-2643-10 (N.J. Super. Ct. Law Div. Nov. 4, 2011) (Transcript of Motions):  In a ruling from the bench, the court held that warnings-based claims against a generic drug designated by FDA as the RLD are equally preempted as those against any other generic drug manufacturer.  The court, accordingly, held that the claims against the manufacturer whose generic drug had been designated as the RLD must be dismissed.
• Yamane v. Wyeth, No. 08-1-349K (Cir. Ct. Haw. Jan. 3, 2012):  The court held that claims against generic drug manufacturers for failure to warn are barred by Mensing.  The court found that FDA’s designation of a generic drug as the RLD does not change that result, and that manufacturers of the RLD are entitled to the full protections of Mensing. 
• Robinson v. Mylan Pharms., Inc., No. 0247 (Phil. Ct. Comm. Pleas. Dec. 2, 2011):  The Philadelphia Court of Common Pleas, in consolidated litigation over generic phenytoin, dismissed all claims brought by certain plaintiffs against the generic drug manufacturers as preempted.  Among other things, the plaintiffs argued that FDA’s RLD designation of the defendants’ product precluded preemption.  Despite these arguments, the court ordered that all claims brought by the plaintiffs at issue against the generic drug manufacturers be dismissed.

By Larry K. Houck –

The Drug Enforcement Administration (“DEA”) has published a Final Rule increasing initial registration and renewal fees for all registrants.  77 Fed. Reg. 15,234 (Mar. 15, 2011).  DEA published the applicable Notice of Proposed Rulemaking (“NPRM”) on July 6, 2011, which was reported here on July 12, 2011.  76 Fed. Reg. 39,318 (July 6, 2011).

DEA has also posted several explanatory documents on the Diversion Control website at: www.deadiversion.usdoj.gov.  Documents posted on the website include a Registration Fees Fact Sheet, Letter to Registrants, Economic Impact Analysis, and New Fee Schedule Fee Calculations.

DEA stated that the increased fees are necessary to recover the full costs of Diversion Control program “so that it may continue to meet the programmatic responsibilities set forth by statute, Congress, and the President.”  Without the fee increases, DEA continued, the Diversion Control Program “will be unable to continue current operations, necessitating dramatic program reductions and possibly weakening the closed system of [controlled substance] distribution.”

The federal Controlled Substances Act (“CSA”) authorizes DEA “to charge reasonable fees relating to the registration and control of the manufacture, distribution, and dispensing of controlled substances and to listed chemicals.”  21 U.S.C. § 821.  DEA is required to set registration fees “at a level that ensures the recovery of the full costs of operating the various aspects of” the Diversion Control Program.  21 U.S.C. § 886a(1)(C).  Thus, DEA must set registration fees that are not only “reasonable” but also cover all costs of the Diversion Control Program.

DEA last increased registration fees in August 2006, setting those fees to cover the “full costs” of the Diversion Control Program for Fiscal Years 2006 through 2008.  DEA noted that total obligations for the Diversion Control Program increased by 49 percent from Fiscal Year 2007 to Fiscal Year 2010.

DEA cited a number of factors justifying the fee increase including:

• Expanding the use of Tactical Diversion Squads comprised of DEA diversion investigators and special agents, state and local law enforcement and regulatory officers conducting criminal investigations;
• Increased scheduled registrant investigations and inspections;
• Increased drug scheduling actions;
• Responding to the expanding number of synthetic substances such as synthetic cannabinoids and synthetic cathinones; and
• Establishing and maintaining information technology systems for registrants.

DEA used a weighted-ratio methodology to determine the reasonable fee for each category of registrant that needed to be collected during Fiscal Year 2012 through Fiscal Year 2014 to cover the costs of the Diversion Control Program then divided by the weighted number of estimated registrants.

DEA received 195 comments to the NPRM and responded to them in the Final Rule.  One registrant recommended that Diversion Control Program funds would be better used to provide for adequate staffing for Program functions involving quota requests, scheduling, and policy and regulatory interpretations to be more responsive to the regulated community.  DEA responded that it monitors and adjusts the number of employees assigned to different Program tasks that include responding to registrant inquiries.  DEA observed that it maintains a continuously updated robust website that is an information source for registrants.  DEA suggested that “[w]hile awaiting a response from” DEA, “registrants are encouraged to review the …website for information and guidance, and to seek assistance from their local DEA offices and state licensing bodies.”  It has been our experience that registrants typically seek guidance and information only after it is unavailable elsewhere.

DEA will begin collecting the increased fees on April 16, 2012.

By Ricardo Carvajal –

The U.S. District Court for the Northern District of Connecticut has ruled that FDA’s qualified health claim (“QHC”) regarding the relationship between green tea and the risk of breast and prostate cancer violates the First Amendment.  In a prior posting, we commented on Fleminger, Inc.’s constitutional challenge to FDA’s QHC.  We won’t belabor the history here, as it is recounted in the court’s decision.  Suffice to say that Fleminger proposed this QHC: “Green tea may reduce the risk of breast and prostate cancers.  The FDA has concluded that there is credible evidence supporting this claim although the evidence is limited.”  FDA modified the claim to read:  “Green tea may reduce the risk of breast or prostate cancer.  FDA does not agree that green tea may reduce the risk because there is very little scientific evidence for the claim.”  The court ruled that FDA’s disclaimer effectively negated the claim, and was therefore an impermissible restriction on speech.

Although FDA’s QHC was found unconstitutional, the news is not all bad for FDA.  Applying the framework established by the Supreme Court in Central Hudson, the court reached the following conclusions:

• “It is beyond doubt that the FDA’s interest in preventing consumer confusion and protecting public health is a substantial interest which justifies the FDA’s imposition of appropriate disclaimers in connection with qualified health claims.” 
• “FDA has a substantial interest in preventing consumers from assuming the FDA has approved the qualified health claim….  Absent the FDA’s express agreement, a proposed health claim cannot include specific reference to the ‘FDA’ in its marketing.”
• The First Amendment does not compel FDA to permit the use of a proposed disclaimer that is inaccurate and misleading (e.g., use of the phrase “credible but limited evidence” where an association between a substance and reduced risk of a disease is found in a single case-control study, but contradicted by two stronger studies).
• “[T]he First Amendment does not require the FDA in every case to conduct an empirical study in connection with a petition for a qualified health claim demonstrating that the petitioners’ proposed disclaimer language is misleading or inaccurate or that consumers will mistakenly believe that the FDA approved the proposed health claim.”  FDA’s “expert assessment and analysis of the level of scientific evidence” can suffice.
• FDA’s disclaimer must “strike a reasonable fit between the government’s ends and the means chosen to accomplish those ends.”  The FDA’s characterization of the evidence supporting the claim as “very little scientific evidence” was accurate, and therefore passed muster.  However, the requirement to place the disclaimer “FDA does not agree that green tea may reduce that risk” immediately after the claim “drinking green tea may reduce the risk of breast or prostate cancer” effectively negated the claim.

Notably, the court dismissed the relevance of the settlement in Alliance for Natural Health U.S. v. Sebelius, which provided for the use of a disclaimer similar to the one rejected as unconstitutional in this case.  Although the court recognized that FDA has an “interest in using consistent disclaimer language,” the disclaimer in the Alliance case “was not the subject of any court’s review under the First Amendment and is not identical to the disclaimer at issue.”  FDA must now take another stab at drafting a permissible disclaimer – one guaranteed to be parsed very closely.

By Kurt R. Karst –      

As we noted at the end of a post earlier this week (see here), we thought a lawsuit against FDA over the approval of generic versions of AstraZeneca’s quetiapine fumarate franchise – i.e., SEROQUEL (quetiapine fumarate) Tablets (NDA No. 020639) and SEROQUEL XR (quetiapine fumarate) Extended-Release Tablets (NDA No. 022047) – might be on the horizon after the Agency issued a March 7, 2012 non-response denial with respect to two September 2011 AstraZeneca citizen petitions concerning labeling carve-out issues for generic versions of the drugs (Docket No. FDA-2011-P-0662 and Docket No. FDA-2011-P-0663).  We just didn’t think the lawsuit would be on FDA’s doorstep so soon. 

On March 12, 2012, AstraZeneca filed a Complaint and a Motion for Summary Judgment Or, In The Alternative, Application For Preliminary Injunction in the U.S. District Court for the District of Columbia saying that FDA’s non-response petition denial violated the Administrative Procedure Act (“APA”) and should be set aside.  AstraZeneca seeks declaratory and injunctive relief, including a preliminarily injunction enjoining FDA from granting final approval for any ANDA for a generic version of SEROQUEL or SEROQUEL XR until the case can be decided on the merits or after Sunday, December 2, 2012 (whichever comes first), and a permanently injunction enjoining FDA from approving any quetiapine fumarate ANDA until after December 2, 2012. 

As we previously reported in our last Generic Drug Labeling Carve-Out Citizen Petition Scorecard update in which we highlighted the AstraZeneca petitions, SEROQUEL and SEROQUEL XR are listed in FDA’s Orange Book with various periods of patent and non-patent exclusivities.  U.S. Patent No. 4,879,288 (“the ‘288 patent”), the pediatric exclusivity for which expires on March 26, 2012, is listed in the Orange Book for both quetiapine drug products and is the date on which some folks anticipate that FDA might approve a generic version of SEROQUEL with labeling that omits information covered by the two periods of “NPP” (New Patient Population) exclusivity from prior NDA supplement approvals of SEROQUEL for the treatment of schizophrenia in adolescents 13 to 17 years of age and the treatment of bipolar mania in children and adolescents 10 to 17 years of age.  The pediatric exclusivity applicable to the two periods of exclusivity coded as NPP expire on June 2, 2013.

SEROQUEL XR is listed in the Orange Book with two patents – the ‘288 patent and U.S. Patent No. 5,948,437 expiring on May 28, 2017 – as well as several periods of 3-year new clinical investigation exclusivity.  Four of those periods of 3-year exclusivity have expired but are subject to unexpired periods of pediatric exclusivity that end on April 8, 2012.  A fifth period of 3-year exclusivity coded as “I-618” and defined in an Orange Book addendum as “ADJUNCTIVE THERAPY IN THE TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD)” expires on December 2, 2012 and is not subject to a period of pediatric exclusivity. 

In its citizen petitions and in court filings, AstraZeneca raises issues with the possible omission (or inclusion) in generic drug labeling of, among other things, information in Table 2 of the products’ labeling concerning glucose-related data and information.  AstraZeneca argues that the omission of such information in generic drug labeling would make a generic product less safe or effective for the remaining non-protected conditions of use of SEROQUEL or SEROQUEL XR and that the inclusion of such information would run afoul of the company’s exclusivity rights.  According to AstraZeneca:

FDA has periodically required AstraZeneca to revise its label to include new information concerning the use of Seroquel.  Some of this new information in the Seroquel label is based on Seroquel XR protected data that cannot be included in a generic drug’s labeling until the associated data exclusivity periods have expired.  If FDA were to permit a generic to omit such information from its labeling – after requiring its inclusion in the labeling for Seroquel – the agency would run afoul of the Administrative Procedure Act's prohibition on arbitrary and capricious agency action.  [(Emphasis added)]

FDA has already tentatively approved several ANDAs for generic versions of both SEROQUEL and SEROQUEL XR.

Given FDA’s non-response petition denials, some might have thought AstraZeneca would be in a bind.  There is no substantive, “on the merits” petition decision for them to challenge.   Nevertheless, AstraZeneca filed suit saying that FDA’s failure to provide a substantive decision violates the APA: 

By refusing to grant AstraZeneca's Citizen Petitions, and in departing from its past practices in refusing even to reach the merits of those Petitions, FDA seeks to deprive AstraZeneca of its rights to due process and meaningful judicial review, and to insulate its unlawful conduct from judicial scrutiny under the [APA].  AstraZeneca accordingly seeks a ruling from this Court that FDA is prohibited from granting final approval to any generic version of Seroquel or Seroquel XR until after December 2, 2012, the expiration of AstraZeneca's statutory exclusivity rights protecting clinical data that must be included in the label of any generic version of those products.

AstraZeneca is seeking an expedited briefing schedule.  We’ll keep you updated as the case progresses. 

By Jennifer M. Thomas & Jeffrey N. Wasserstein –

Many pharmaceutical companies sponsor prescription drug coupons and other cost-savings programs to help reduce the burden of co-payments and co-insurance.  Lawsuits filed against nine pharmaceutical companies in four federal district courts on March 7 by various union health plans allege that the drug-makers violated anti-trust laws and the Racketeer Influenced and Corrupt Organizations Act (“RICO”) when they provided coupon programs to privately-insured consumers that subsidize all or part of the cost-sharing obligation (co-pay or co-insurance) for a branded prescription drug or drugs.  (A list of the lawsuits and links to the Complaints are provided at the end of this post.)  Cost-sharing obligations for prescription drugs are used by private health care plans in part to encourage plan participants to use lower-cost generics instead of branded drugs.  (Most coupons exclude government health care beneficiaries due to the federal health care program antikickback statute.)

According to the plaintiffs, by routinely reducing co-pays through their coupon programs, the corporate defendants in these lawsuits allegedly undermined the cost-sharing arrangements set up by the health plans with their members, and thereby caused the plans to (1) pay higher reimbursements for the subsidized drug than the true cost of the drug; and (2) pay for more brand-name drugs, at higher prices, instead of lower-cost generics.  According to the complaint, health care plans have no way of knowing whether a manufacturer’s coupon or savings program has been used to cover the co-pay for a drug covered by the plan, and therefore pay the same reimbursement even though part of the cost of the drug has been subsidized by the manufacturer.  The complaints allege that the drug companies’ interference with insurance cost-sharing arrangements violates federal law.

First, the complaints allege that the pharmaceutical companies’ co-pay coupon programs constitute substantive RICO violations and a conspiracy to violate RICO.  According to the complaints, the coupons constitute illegal kickbacks amounting to health care fraud under 18 U.S.C. § 1347.  Further, the programs allegedly cause false information about drug prices to be submitted to the plaintiff health care plans, which results in the plans reimbursing the original price of the branded prescription drug rather than the lower subsidized price.  Since the programs could not be carried out without using the mail and internet, they are alleged repeated violations of 18 U.S.C. § 1341 (mail fraud) and 18 U.S.C. § 1343 (wire fraud).  According to the complaints, the pharmaceutical companies acted overtly to carry out this fraud by hiring and forming an enterprise with vendors that administered and arranged for payment of the co-pays to the pharmacies.  (The vendors are not named as defendants in the cases.)

Second, the coupon programs allegedly violate 15 U.S.C. § 13(c)’s prohibition on commercial bribery, because they bribe consumers with co-pay/co-insurance subsidies in order to induce them to purchase branded drugs that cost their insurance plans more.  According to the complaints, the coupon programs pay off fiduciaries (in this case, consumers) who control purchasing decisions (brand-name versus generic drugs) that are to be paid for by another (the health care plans).  These payoffs cause significantly increased expenditures by the health care plans, which end up purchasing more branded prescription drugs.

The complaints seek declaratory judgment, an injunction against current and future coupon and savings programs, attorneys’ fees and costs, and treble damages under 18 U.S.C. § 1964(c) and 15 U.S.C. § 15(a).

It is too soon to tell if these cases will have legs, or if they will be quickly dismissed.  It is difficult to characterize the coupon and other cost-savings programs as fraudulent when they are so publicly promoted.  Indeed, every time one walks into one’s physician’s office or pharmacy, one sees multiple coupon offers, and the complaints themselves characterize the co-pay subsidies as "open and notorious."  But companies should follow the lawsuits to see if they need a course correction in how they handle coupons programs. 

Case List:

• Plumbers and Pipefitters Local 572 Health and Welfare Fund v. Novartis Pharmaceuticals Corp., No. 33-av-00001 (D.N.J., Mar. 7, 2012) (Complaint)

• Plumbers and Pipefitters Local 572 Health and Welfare Fund v. Merck & Co., Inc., No. 33-av-00001 (D.N.J., Mar. 7, 2012) (Complaint)

• New England Carpenters Health and Welfare Fund v. Abbott Laboratories, No. 12-cv-01662 (N.D. Ill., Mar. 7, 2012) (Complaint)

• New England Carpenters Health and Welfare Fund v. GlaxoSmithKline LLC, No. 12-cv-01191 (E.D.Pa., Mar. 7, 2012) (Complaint)

• New England Carpenters Health and Welfare Fund v. AstraZeneca, Inc., No. 12-cv-01192 (E.D.Pa., Mar. 7, 2012) (Complaint)

• Amer. Federation of State, County and Municipal Employees District Council 37 Health & Security Plan v. Amgen, Inc. and Pfizer, Inc., No. 12-cv-01123 (E.D.N.Y., Mar. 7, 2012) (Complaint)

• Amer. Federation of State, County and Municipal Employees District Council 37 Health & Security Plan v. Bristol-Meyers Squibb Co. and Otsuka America Pharmaceutical, Inc., No. 12-cv-01124 (E.D.N.Y., Mar. 7, 2012) (Complaint)

By Ricardo Carvajal –

FDA published its Food Safety Modernization Act ("FSMA") Domestic Facility Risk Categorization for FY2012, which distinguishes domestic high-risk ("HR") food facilities from non-high-risk (NHR) food facilities for purposes of determining frequency of inspection.  For now, the determination of whether a facility is HR will depend primarily on four factors.  FDA will consider:

• “The known safety risks of the food manufactured, processed, packed, or held at the facility,” as determined by Class I recalls and outbreaks of foodborne illness.  “Known safety risks” of a food “are based on broad, industry-level food commodity categories, e.g., bakery, leafy vegetables, spices.” 
• “The compliance history of a facility, including with regard to food recalls, outbreaks of foodborne illness, and violations of food safety standards.”  This will be determined by the type and number of prior inspection classifications in the previous five fiscal years (i.e., a single classification as “Official Action Indicated,” or three or more classifications as “Voluntary Action Indicated”).
• The type of establishment and type of activity at the facility (e.g., manufacturing, packing, storage).
• The number of years since the last inspection. 

As FSMA implementation progresses, other factors will come into the mix (e.g., “the rigor and effectiveness of the facility’s hazard analysis and risk-based preventive controls”).  Facilities would do well to review the Risk Categorization to determine whether they are likely to be categorized as HR, and therefore can expect to see FDA inspectors with greater frequency.