By Kurt R. Karst –      

Earlier ths week, Apotex Corp., Roxane Laboratories, Inc., and Actavis Elizabeth LLC  (collectively “Counterclaim Plaintiffs”) filed their opposition to Actelion Pharmaceuticals Ltd.’s and Actelion Clinical Research, Inc.’s (collectively “Actelion’s”) Motion for Judgment on the Pleadings and to Dismiss Counterclaims in a lawsuit filed last September in the U.S. District Court for the District of New Jersey seeking declaratory relief that Actelion is under no affirmative duty or obligation to supply prospective ANDA applicants with its brand-name drug products TRACLEER (bosentan) Tablets and ZAVESCA (miglustat) Capsules for purposes of bioequivalence testing and ANDA submission.  As we previously reported (here, here, and here), the case is the first preemptive lawsuit filed by a brand-name company whose drug products are covered by restricted distribution programs – either a Risk Evaluation and Mitigation Strategies program with Elements To Assure Safe Use created by the 2007 FDA Amendments Act, such as TRACLEER, or a restricted distribution program adopted and implemented by the brand-name manufacturer, such as ZAVESCA.  The Counterclaim Plaintiffs have alleged that Actelion abused its monopoly power in violation of Sections 1 and 2 of the Sherman Act and the New Jersey Antitrust Act.

Actelion maintains that it is the company’s “right to choose with whom it does business,” and that this “fundamental right” dooms the Counterclaim Plaintiffs’ antitrust counterclaims and clearly support Actelion’s request for declaratory relief.  Moreover, says Actelion, citing Verizon Communications, Inc. v. Law Offices a/Curtis V. Trinko, LLP, 540 U.S. 398 (2004) for purposes of Sherman Act Section 2, any exceptions to the rule that a unilateral refusal to deal by an alleged monopolist does not give rise to antitrust liability (i.e., where a refusal to do business is contrary to a prior course of dealing, or where a refusal relates to an “essential facility”) do not apply in this case. And, says Actelion, there are alternatives to the ANDA approval route that companies can use, such as the submission of a “full” 505(b)(1) NDA or a 505(b)(2) NDA.

As an initial matter, Counterclaim Plaintiffs allege in their 70-page opposition memorandum that Actelion’s reliance on Trinko to support its case is misplaced.

Actelion’s entire argument rests on its belief that Trinko immunizes a firm from antitrust scrutiny for refusing to deal with its would-be competitors.  Although this interpretation of Trinko is incorrect, Actelion’s argument fails in any event because its refusal to sell Counterclaim Plaintiffs drug samples is merely one component of the larger exclusionary scheme challenged here. . . . [Actelion’s] conduct goes far beyond a typical “refusal to deal” and falls well within the classic definition of unlawful monopolization. . . .  The problem with Actelion’s heavy reliance on Trinko is that it at best only addresses Actelion’s liability for refusing to sell drug samples directly to Counterclaim Plaintiffs.  The Third Circuit [in LePage’s, Inc. v. 3M, 324 F.3d 141 (3d Cir. 2003)], however, has held that the proper inquiry is whether the defendant’s alleged actions “considered together” evidence an overall anticompetitive scheme. (Internal citations omitted)

Applying this Third Circuit standard, say Counterclaim Plaintiffs, the court must deny Actelion’s motion. 

Counterclaim Plaintiffs go on to argue that even if this were a pure “refusal to deal” case, Trinko does not create a bright-line rule to justify Actelion’s requested relief.  For starters, say Counterclaim Plaintiffs, “unlike Trinko, where there was already a scheme of regulation in place to safeguard the public interest . . . no such regulatory scheme exists to serve as ‘an effective steward of the antitrust function’ here.” (Internal citation omitted)  Moreover, both of the Trinko exceptions (i.e., prior course of dealing and essential facilities) are available and applicable here, argue Counterclaim Plaintiffs.

As to Actelion’s argument that, for purposes of applicability of the essential facilities exception, companies can avail themselves of an alternative to the ANDA approval route and seek FDA approval of an NDA, Counterclaim Plaintiffs say that argument is nonsensical.  First, insofar as it means companies submit “full” 505(b)(1) NDAs, the argument undermines the Hatch-Waxman Amendments.  Second, insofar as it means companies submit 505(b)(2) applications for a generic version of the drugs, “Actelion’s claim . . . is simply wrong,” because that route is not available for duplicates of approved brand-name drugs.  Moreover, it bears noting that a 505(b)(2) application for an alternative version of a brand-name drug may require the sponsor to obtain sample of the drug for purposes of conducting bridging studies. 

By Anne K. Walsh –

On March 4, 2013, less than three months after oral argument, the Ninth Circuit issued its ruling in United States v. Harkonen, a closely watched case implicating First Amendment issues in the off-label promotion context.  As we previously reported (here and here), in 2009, a jury had convicted Harkonen of wire fraud for issuing a press release fraudulently describing clinical trial results about the drug Actimmune.  The District Court in the Northern District of California sentenced Harkonen to 3 years probation, 6 months home detention, community service, and a $20,000 fine.  Both parties appealed to the Ninth Circuit.

Harkonen challenged the conviction, arguing that the First Amendment barred his prosecution.  The Ninth Circuit applied a two-part analysis: (1) whether sufficient evidence supports the verdict; and (2) if so, whether the facts as found by the jury establish the core constitutional facts.  The Ninth Circuit emphasized that the First Amendment does not protect fraudulent speech.  Therefore, the court identified the core constitutional issue in Harkonen’s case as whether there was sufficient evidence to support the jury’s finding that the press release was fraudulent.  Deferring to the jury’s findings on the elements of the wire fraud charge, the Ninth Circuit affirmed the wire fraud conviction. 

Interestingly, the Ninth Circuit footnoted that “Harkonen presented the evidence that most firmly supported his case for the first time at sentencing.”  This is likely a reference to expert declarations Harkonen sought to introduce purporting to show a plausible scientific (and thus truthful) basis for the statements contained in the allegedly fraudulent press release.  The Ninth Circuit noted that it was limited to considering evidence that was before the jury, and therefore could not consider the expert declarations first raised at Harkonen’s sentencing.

The Court also rejected Harkonen’s other arguments, one of which relied on a 1902 U.S. Supreme Court case for the proposition that “genuine debates over whether a given treatment caused a particular effect” could not be considered fraudulent.  American School of Magnetic Healing v. McAnnulty, 187 U.S. 94 (1902).  “Harkonen’s request that we reverse his conviction because he was engaging in a genuine scientific debate is hardly different than arguing that he is innocent; genuine debates of any sort are, by definition, not fraudulent.”

On its cross-appeal, the Government argued that the district court had erroneously ruled on the “intended loss” and “vulnerable victim” enhancements in the U.S. Sentencing Guidelines.  Originally the Government had asked for a 10-year prison sentence and a $1 million fine.  The Ninth Circuit did not provide much explanation, but simply stated that the district court made clear its conclusions in imposing a shorter sentence with no imprisonment.

On the heels of the Second Circuit’s decision in United States v. Caronia, some had thought that the Ninth Circuit would provide the requisite circuit split to allow the Supreme Court to take on the First Amendment issue raised in Caronia.  The Harkonen case is distinguishable, however, because the jury convicted Harkonen of wire fraud, which required a finding that the statements Harkonen made were fraudulent.  Therefore, unlike Caronia, the Harkonen case did not present a potential First Amendment defense based on truthful and non-misleading statements about an unapproved use.  For more information about the potential ramifications of Caronia, see the HP&M Webinar.

As for Harkonen, the saga continues.  Not only did he lose this appeal and recently have his state medical license revoked, he now faces potential exclusion from federal health care programs, which would effectively preclude him from working in the pharmaceutical industry during the period of exclusion.  

By Ricardo Carvajal –

The Notification of Opportunity to Initiate a Voluntary Recall that FDA recently issued to a pet treat manufacturer gives a good indication of the type of evidence and circumstances that can prompt the agency to exercise its new mandatory recall authority.  Before mandating a recall under FDCA section 423, FDA must first determine that there is a reasonable probability that the food is adulterated under section 402 or misbranded under section 403(w) and that use of or exposure to the food will cause serious adverse health consequences or death to humans or animals.  FDA must then give the manufacturer the opportunity to initiate a voluntary recall. 

In this instance, FDA determined that the food in question was adulterated under section 402(a)(1), in that the food was contaminated with Salmonella, and also adulterated under section 402(a)(4), in that the food was manufactured under insanitary conditions whereby it may have been contaminated with Salmonella.  FDA relied on testing of finished products conducted by the State of Colorado’s Department of Agriculture that purportedly showed the presence of Salmonella.  Those products were collected at the manufacturing facility and also off the shelves at leading retailers.  FDA also relied on its own testing of finished products, and of environmental testing that purportedly showed contamination of food contact surfaces.  FDA made heavy use of genetic analysis to draw links between Salmonella-positive samples from different products manufactured at different times, and also between products and environmental swabs.  In addition, FDA relied on evidence of insanitary conditions allegedly observed throughout the facility.

In a hint at potentially worse consequences, FDA’s Notification stated: “Your facility created, caused or was otherwise responsible for this reasonable probability of adulteration under section 402” – the standard for the suspension of a facility’s registration under section 415.

By Kurt R. Karst –      

Finally!  A Hatch-Waxman lawsuit that is not overly complex and not difficult to unravel.  Late last week, Sun Pharma Global FZE, Caraco Pharmaceutical Laboratories, Ltd., and Sun Pharmaceuticals Industries, Ltd. (collectively “Sun”) filed a Complaint and a Motion for a Temporary Restraining Order and a Preliminary Injunction in the U.S. District Court for the District of Columbia (Case No. 1:13-cv-00277-ABJ) against FDA seeking, among other things, entry of a judgment declaring that the company is entitled to 180-day exclusivity for a generic version of Novartis Corporation’s ZOMETA (zoledronic acid) Injection, 4 mg/5 mL (or 0.8 mg (base)/mL).

ZOMETA is approved under NDA No. 021223 and is listed in the Orange Book with three product entries.  Product 001 is identified as “EQ 4MG BASE/VIAL” and was approved on August 20, 2001.  It is a lyophilized version of the drug that is no longer marketed, and is listed in the discontinued section of the Orange Book.  Product 002 – the product at issue in the lawsuit – is identified as “EQ 4MG BASE/5ML.”  It was approved on March 7, 2003 and is a non-lyophilized version of the drug.  Finally, Product 003 is identified in the Orange Book as “EQ 4MG BASE/100ML.”  It was approved on June 17, 2011, and, like Product 002, is currently marketed.

Product 002 is listed in the Orange Book with two patents: (1) U.S. Patent No. 4,939,130 (“the ‘130 patent”), which expired on September 2, 2012, but is subject to a period of pediatric exclusivity that expired on March 2, 2013; and (2) U.S. Patent No. 8,324,189 (“the ‘189 patent”), which expires on May 29, 2025, and is subject to a period of pediatric exclusivity that expires on November 29, 2025.  The ‘130 patent has been listed in the Orange Book for Product 002 since 2003.  (It was originally scheduled to expire on July 24, 2007, but was granted a patent term extension.)  The ‘189 patent was issued on December 4, 2012, and, according to Sun, was timely listed in the Orange Book on January 2, 2013. 

FDA’s Paragraph IV Certifications List identifies June 11, 2008 as the first date on which an ANDA containing a Paragraph IV certification was submitted to FDA seeking approval of Product 002.  That product is identified on FDA’s list as ZOMETA (zoledronic acid) Injection “0.8 mg (base) /mL,” which corresponds to 4 mg/5 mL.  Because the first ANDA containing a Paragraph IV certification was submitted to FDA years before the ‘189 patent was listed in the Orange Book (or even issued), such ANDA must have included a Paragraph IV certification to the ‘130 patent.  Moreover, because the first ANDA for a generic version of Product 002 was submitted to FDA after December 8, 2003, 180-day exclusivity is governed by the Medicare Modernization Act (“MMA”).  Under the MMA, 180-day exclusivity eligibility can be forfeited under one (or more) of the six forfeiture provisions at FDC Act § 505(j)(5)(D).

Sun reportedly submitted ANDA No. 202746 to FDA on January 10, 2011 containing a Paragraph III certification to the ‘130 patent, and reportedly amended that ANDA on January 3, 2013 with a Paragraph IV certification to the ‘189 patent.  According to Sun, the company “should be awarded First Filer status because when Sun filed its Paragraph IV certification [the ‘189 patent], no other ANDA for Zometa® Product 002 was previously filed that contained a Paragraph IV certification and there is no basis in the law or regulations for FDA to approve any other ANDA’s until FDA determines whether SUN has first to file status.” (Emphasis in original)  FDA has already tentatively approved several ANDAs for generic ZOMETA, and the Agency is likely poised to approve several ANDAs for generic versions of Product 002 on Monday now that the period of pediatric exclusivity on the ‘130 patent has expired.  (ANDA No. 202746 is not on the list of tentatively approved applications.)   

Despite Sun’s allegations, the facts in this case seem to point in another direction.  According to a patent infringement lawsuit Novartis filed in July 2008 against Teva Parenteral Medicines Inc. (“Teva”) in the U.S. District Court of Delaware (Case No. 1:08-cv-00459), Teva submitted two ANDAs – ANDA Nos. 078576 and 078580 – for generic versions of ZOMETA (apparently Product 001 and Product 002) containing Paragraph IV certifications to the ‘130 patent.  Based on ANDA submission dates identified in the court docket, that would make Teva the first applicant eligible for 180-day exclusivity.  But 180-day exclusivity for Product 002 (as well as Product 001) has been forfeited.  Indeed, there appear to be several bases for forfeiture. The most obvious forfeiture is patent expiration (FDC Act § 505(j)(5)(D)(i)(VI)); however, failure to obtain tentative approval (FDC Act § 505(j)(5)(D)(i)(IV)), ANDA withdrawal (FDC Act § 505(j)(5)(D)(i)(II), and amendment of certification (FDC Act § 505(j)(5)(D)(i)(III) may also be possibilities.  In other words, Sun’s lawsuit may be short-lived.  As this case moves forward over the next day, we will post periodic updates.

UPDATE:

• The following Minute Order was entered late on March 1st: “During a telephone conference held on this date at which counsel for plaintiff as well as counsel from FDA and DOJ participated, counsel for defendants represented to the Court that FDA will not approve any ANDAs for the drug product at issue in this case until the Court has had an opportunity to address plaintiff's motion for temporary restraining order and preliminary injunction [Dkt. # 2] during a hearing on March 4, 2013.  Accordingly, consistent with the Court's oral ruling during the telephone conference, it is ORDERED that defendants shall file a response to plaintiff's motion by 10:00 am on Monday March 4, 2013. A hearing is scheduled for March 4, 2013 at 11:00 am in Courtroom # 3 before Judge Amy Berman Jackson.”
• On March 1st, FDA issued a letter decision finding that 180-day exclusivity for generic ZOMETA Product 002 was forfeited.
• On March 1st, Sun submitted a citizen petition to FDA requesting that the Agency not approve any affected ANDAs.
• On March 3rd, Sun supplemented its Motion for a Temporary Restraining Order and a Preliminary Injunction motion.
• The following Minute Order was entered on March 3rd: “It is ORDERED that defendants file with the Court by March 4, 2013 at 10:00 am, any application containing a Paragraph IV certification for the same drug for which plaintiffs claim first filer status that was submitted before plaintiffs' application, as well as any documents that reflect notice provided to Novartis of the application that the FDA has deemed to be the first.”
• The following Minute Order was entered on the morning of March 4th: “In light of the in camera submission made by defendants on this date in response to the Court's Minute Order of March 3, 2013, it is ORDERED that before the hearing scheduled for 11:00 am on this date, defendants provide a redacted copy of the documents included in the submission to counsel for plaintiffs, or be prepared to explain to the Court at the hearing why that is not possible.”
• On the afternoon of March 4th, the court issued a Notice of Dismissal stating: “Pursuant to Rule 41(a)(1)(A)(i) of the Federal Rules of Civil Procedure, Plaintiffs Sun Pharma Global FZE, Caraco Pharmaceutical Laboratories, Ltd., and Sun Pharmaceuticals Industries, Ltd., hereby dismiss the above captioned action.”

By Jeffrey K. Shapiro – 

FDA has just issued a draft guidance document titled “Distinguishing Medical Device Recalls from Product Enhancements and Associated Reporting Requirements” (Docket No. FDA-2013-D-0114) intended to clarify how to distinguish product “corrections” from product “enhancements.”  Although the draft guidance would be applicable to all kinds of devices, this issue is particularly prevalent with software based products, since software in distributed devices is easily and often updated, creating the potential that an update could legally be considered a “correction.”  As will be discussed, the draft guidance is a disappointment on several levels.

Legal Framework

As background, FDA defines a recall as a correction or removal of distributed product that FDA considers to be in violation of the Federal Food, Drug, and Cosmetic Act (FDCA) or other laws it administers (21 C.F.R. § 7.3(g)).  A correction is defined as the repair, modification, adjustment, relabeling, destruction, or inspection of a device without physical removal from its point of use (id. § 806.2(d)).  A removal has the same definition as a correction except there is physical removal of the device from the point of use (id. § 806.2(i)).

A correction or removal should be conducted under the procedures in 21 C.F.R. Part 7.  It also must be reported to FDA within 10 working days under 21 C.F.R. Part 806 if it is initiated to reduce a risk to health or to remedy a violation of the FDCA caused by the device that may present a risk to health (id. § 806.10(a)).  The correction or removal of a device that only involves a “minor” violation of the FDCA is a market withdrawal and not a recall (id. § 806.2(h)).  A correction or removal of device that has not been marketed or has not left the “direct control” of the manufacturer is a stock recovery rather than a recall (id. § 806.2(l)).  However, it is not a stock recovery if any “portion of the lot, model, code, or other relevant unit … has been released for sale or use” (id.).

Evaluating the Draft Guidance:  The Good, The Bad, and the Ugly

The Good.  The draft guidance provides greater clarity as to when a device is considered violative under the FDCA, such that a correction or removal to address the violation constitutes a recall.  The draft guidance advises (lines 219 271) that a device is violative if it is (i) adulterated under the FDCA due to a failure to perform as intended or to meet specifications, or (ii) misbranded under the FDCA due to labeling that is false or misleading or otherwise inaccurate or that fails to meet other specific labeling requirements.

Additionally, product enhancement has never been defined in FDA’s regulations.  The draft guidance helpfully provides a working definition (lines 141-146):

Product enhancements include, but are not limited to, changes designed to better meet the needs of the user, changes to make the product easier to manufacture, and changes to the appearance of the device that do not affect its use.  A product enhancement is both (1) a change to improve the performance or quality of a device, and (2) not a change to remedy a violation of the [FDCA] caused by the device.  A product enhancement is not a medical device recall.

Unfortunately, these clarifications pretty much exhaust the useful aspects of this draft guidance.

The Bad. The bad thing about this draft guidance is that it creates a new reporting requirement under 21 C.F.R. Part 806 that appears to be unauthorized by either the FDCA or Part 806.  The relevant discussion occurs in lines 100-102 and Section VI, lines 415-429.  The minimal reasoning supplied to support this new requirement is difficult to understand if not completely incoherent.

The draft guidance indicates that a product enhancement initiated to reduce a risk to health must be reported even though it is not a recall.  This assertion is not logically supported by either Part 7 or Part 806.  A recall under Part 7 is defined as a correction or removal of distributed product.  Such a correction or removal, in turn, must be reported under Part 806 if it is intended to reduce a risk to health.  But a device modification that is not a recall is also by definition not a correction or removal.  Since Part 806 only requires reporting of a subset of corrections and removals, a modification that is not a correction or removal logically cannot be reportable under Part 806.

Tellingly, the draft guidance does not cite any legal authority for this new reporting requirement.  It could not have done so, because FDA is granted authority in Section 519(g) of the FDCA to issue a regulation requiring firms to report “any correction or removal of a device” within certain parameters.  Nothing in Section 519(g) or Part 806 authorizes FDA to require reporting of product enhancements that are not corrections or removals (i.e., not recalls), nor has Part 806 ever been so interpreted – until now.

Even worse, the draft guidance seems to suggest that FDA’s position applies to product modifications implemented exclusively in the manufacture of new units, with distributed units being left unchanged.  For instance, two of the three examples given of reportable modifications are design or manufacturing changes not likely to be implemented for distributed units, and therefore are not likely to be corrections or removals.  It appears that the draft guidance is intended to require that every single modification be evaluated as to whether it would reduce a risk to health, and if so, it must be reported under Part 806.

The determination whether a modification reduces a risk to health is not easy.  Yet, the draft guidance would magnify the number of times a firm must wrestle with this question.  Previously it has been reserved for the determination whether a correction or removal is initiated to reduce a risk to health.  Under FDA’s new reporting requirement, it would be necessary to make this determination for virtually every device modification, even if it does not qualify as a correction or removal.

To implement this brand new requirement, FDA suggests a new type of Part 806 report that would identify the device modification as an enhancement rather than a recall.  If FDA concurs that it is an enhancement, the action would not be treated as a recall, but the agency would provide advice on “appropriate premarket and postmarket actions necessary to address the information contained in the 806 report.”  This statement may have unwittingly revealed the motivation behind this new requirement.

One can imagine that FDA would use the flood of Part 806 reports from this new requirement to gain greater visibility to product modifications that firms have concluded do not require a new 510(k).  The agency undoubtedly would use the opportunity to begin issuing letters directing that 510(k) filings be submitted for these modifications when the agency disagrees with the determination.  The agency has taken a similar approach when firms with in vitro diagnostic devices seek Clinical Laboratory Improvement Act (CLIA) waivers from FDA.  These waiver reviews give FDA visibility to device modifications implemented via letter to file, and FDA uses these reviews as an opportunity to issue directives requiring new 510(k)s.  The same thing would surely happen if FDA were to review all the new Part 806 reports.

FDA’s new approach raises serious questions about criminal and civil liability.  A violation of Part 806 causes devices to be misbranded under Section 502(t) of the FDCA.  A firm distributing misbranded devices in commerce is subject to criminal and civil liability.  Accordingly, firms might feel compelled to report virtually all modifications, to ensure that they are not exposed to significant criminal and/or civil liability should FDA or the Department of Justice choose to second guess whether a change was implemented to reduce a risk to health.  Yet, this unprecedented reporting requirement requires a statutory change and cannot lawfully be accomplished merely by issuing a guidance.  Section VI of the draft guidance should be withdrawn.

The Ugly.  A guidance such as this one is supposed to clarify FDA’s enforcement of its regulations, with special attention to interpretational issues that have arisen over the years.  This draft guidance does no such thing.  Instead, for the most part, it merely regurgitates regulatory provisions set forth in Parts 7 and 806.  The following examples higlight the absence of meaningful guidance:

• The draft guidance reminds us (lines 299-300) that Part 806 requires a report within 10 working days from the time the firm “initiates” a recall.  Part 806 does not define “initiates” and the draft guidance does not attempt to clarify what it means.  A common sense interpretation would be that a recall is initiated when communications are sent to device users notifying them of a correction or removal.  In practice, however, at least some FDA districts have said that initiation occurs when a firm subjectively “decides” or “becomes aware” that a recall is needed.  This interpretation of the regulation is legally questionable and is a trap for the unwary.  The draft guidance should have provided a clear definition with legal support and practical examples.

• To determine whether a modification reduces a “risk to health,” the draft guidance suggests performing a Health Hazard Evaluation (HHE) based on the factors set forth in 21 C.F.R. § 7.41 and provides a bulleted list of factors that FDA considers (lines 366-406).  None of this information is new, particularly to anyone who has ever read § 7.41 or completed FDA’s HHE form.  Much more guidance is needed on this complicated question.

• Is a safety improvement an enhancement over baseline safety or is it addressing a failure of the product to perform as intended?  This question is often difficult to answer, especially for software changes.  Yet, the draft guidance offers a mere six sentences of very general advice (lines 219-236) and provides only three actual examples, all involving battery life (line 238).  The draft guidance should have provided more examples, and it could profitably have devoted half a dozen or more to software alone.

• Under the regulations, a correction or removal based on a minor violation or no violation is called a “market withdrawal” and excluded from classification as a recall (21 C.F.R. §§ 7.3(j), 806.2(h)).  The draft guidance fails to clarify what might constitute a “minor violation.”  It even fails to mention market withdrawal as a possibility in the decision making flow chart (line 272).

• The draft guidance confirms that “[o]nly marketed devices can be recalled” and that “devices that have not entered the market fall within the definition of a stock recovery” (lines 202-204).  However, footnote 3 states that “if a change is made to newly manufactured, unreleased lots of a model that is in commercial distribution, that change is not considered a stock recovery.”  This footnote is confusing and probably should have been the subject of an extended discussion in the text.  It appears to mean that a change made to product held in inventory meets the definition of a recall, even if other product in the field is not recalled.  If so, FDA’s position is likely based upon the definition of a “stock recovery” in § 7.3(k) and § 806.2(l).  These legal citations should have been included.  It would also have been helpful if the other interpretational issues concerning stock recovery had been addressed (e.g., what does it mean for devices to be within the “direct control” of a manufacturer?).

• There are subtle differences between the definitions in Part 7 and Part 806 of the terms “stock recovery” and “correction.”  It would have been helpful to have some commentary reconciling the differences and addressing whether they are meaningful or not.  The draft guidance never discusses the discrepancies in the definitions.

All in all, FDA should recall this draft guidance for a substantial overhaul.  Section VI needs to be withdrawn completely.  The remainder of the draft guidance needs to be expanded with careful commentary on the difficult interpretational issues that have arisen over the years under Parts 7 and 806, so that it goes beyond superficial regurgitation of regulatory provisions.  Hopefully, FDA will issue a second draft for public comment, since this draft will require substantial revision in order to be useful, and the public should be given an opportunity to comment again before the guidance is finalized.

An article published by Law360 and co-authored by H. Keeto Sabharwal and Dennies Varughese of Sterne Kessler Goldstein & Fox PLLC, and Kurt R. Karst of Hyman Phelps & McNamara PC, examines whether, and to what extent, a successful Inter Partes Review (“IPR”) challenge by a subsequent ANDA sponsor might cause a forfeiture of 180-day exclusivity under the failure-to-market forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I) added by the 2003 Medicare Modernization Act.

The IPR proceedings present a new wrinkle in patent litigation and were created with the September 16, 2011 enactment of the Leahy-Smith America Invents Act (“AIA”).  The U.S. Patent and Trademark Office (“PTO”) has already taken several steps to implement the new IPR procedures.  As Mr. Sabharwal and Mr. Varughese explained in a 2012 article, the IPR is an administrative patent challenge proceeding at the PTO that serves as a parallel or alternative to district court litigation to adjudicate patentability of issued patents.  (The IPR procedures replaced the old inter partes re-examination procedures.)  IPR petitions are filed with the PTO’s Patent Trial and Appeal Board (“PTAB”), which adjudicates the cases.  The PTAB has already received at least three relevant IPR petitions relating to Hatch-Waxman cases – two concerning patents on moxifloxacin (IPR2013-00012 and IPR2013-00015), and another concerning a patent on fosamprenavir (IPR2013-00024).

Under the failure-to-market 180-day exclusivity forfeiture provisions, there must be two events (i.e., “bookends”) to calculate a “later of” event between items (aa) and (bb).  The first bookend date under item (aa) is the earlier of the date that is 75 days after ANDA approval or 30 months after ANDA submission.  The (bb) part of the equation (i.e., the other bookend) provides that the (bb) date is “the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a [Paragraph IV] certification qualifying the first applicant for the 180-day exclusivity period,” one of three events occurs – two of which are relevant here:

(AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.

(BB) In an infringement action or a declaratory judgment action described in [FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA)], a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

The (AA) and (BB) court decision events under item (bb) can be triggered in patent infringement litigation by “the first applicant or any other applicant (which other applicant has received tentative approval).”

While a final, unappealed district court judgment of patent invalidity would operate to trigger forfeiture under the failure-to-market forfeiture provisions, it is unclear whether patent nullification by the PTAB in an IPR proceeding would similarly qualify to trigger forfeiture  According to the authors of the new paper:

Under a strict reading, one might argue that a PTAB decision would not qualify because the decision would not be from “an infringement action … or declaratory judgment action,” as recited in the statute. Instead, IPR is a post-issuance challenge to the patent, which necessarily does not involve claims of patent infringement.

And the same argument may apply to any Federal Circuit affirmance of a PTAB decision.  Although such a Federal Circuit affirmance would be a final court decision, it arguably would not be from “an infringement action … or declaratory judgment action.” Even so, a PTAB nullification decision may nevertheless form the basis for further district court action that could lead to forfeiture.  A Federal Circuit affirmance, at the very least, would be binding on a district court and would form the basis for a simple motion for entry of
judgment in a district court action that could then trigger forfeiture. And because this district court judgment would be based on a Federal Circuit ruling, it is unlikely to be appealed.

Once final, judgment would trigger the 75-day window period leading up to the forfeiture.

Of course, this is still all speculation; however, as the PTAB begins to make IPR decisions, it seems likely that the issue will ripen and need to be addressed.

By Kurt R. Karst –      

On Tuesday, February 26th, Representatives Henry Waxman (D-CA) and Louise Slaughter (D-NY) announced the introduction of H.R. 820, the Delivering Antimicrobial Transparency in Animals Act of 2013 (“DATA Act”).  Introduction of the DATA Act comes just as the U.S. Senate Committee on Health, Education, Labor, & Pensions is scheduled to hold a hearing on reauthorization of two animal drug user fee agreements – the third iteration of the Animal Drug User Fee Amendments (“ADUFA III”) (proposed statutory text and goals letter available here and here) and the second iteration of the Animal Generic Drug User Fee Act (“AGDUFA”) (proposed statutory text and goals letter available here and here) – and several months after Rep. Waxman first announced his intention to introduce the DATA Act and after gathering input on a discussion draft of the bill.  Representative Slaughter, who is a microbiologist, has shown a keen interest in antibiotic use in animal agriculture and has been a critic of FDA’s efforts to address the issue (see our previous post here).  She is the author of the 2011 Preservation of Antibiotics for Medical Treatment Act, which was intended to phase out the non-therapeutic use in livestock of medically important antibiotics, among other things.

The DATA Act would amend FDC Act § 512(l) to require drug manufacturers to obtain and provide to FDA enhanced information on how their antimicrobial drugs are used in the food-producing animals for which they are approved.  The bill is also intended to improve the timing and quality of the data that FDA publicly releases on antimicrobial drug use in food-producing animals.  According to a summary of the bill:

[T]he DATA Act will, for the first time, require large-scale producers of poultry, swine, and livestock to report data on the medicated feeds provided to their animals. The bill would require these producers to submit data to FDA detailing the type and amount of antibiotics and other antimicrobials contained in the feed they use. If the medicated feed is under a Veterinary Feed Directive (VFD), more detailed information must be provided to FDA, including the quantities, dosages, and duration of time the medicated feeds were provided to the animals.

The DATA Act would also require the HHS Secretary to coordinate with the Secretary of Agriculture to improve the collection of data and information on the use antimicrobial drugs in or on food-producing animals, and require the U.S. Government Accountability Office (“GAO”) to evaluate FDA’s antimicrobial data collection process and the Agency’s voluntary approach to reducing or eliminating injudicious use of antimicrobials in animals. 

ADUFA II directs FDA to prepare and publish annual summaries of antimicrobial animal drugs sold or distributed for use in food-producing animals.  The data are derived from information submitted by sponsors of antimicrobial new animal drugs who each year must submit to FDA a report regarding, among other things, their distribution data for antimicrobial animal drugs distributed domestically and exported for use in food-producing animals (see FDA’s annual reports here).  A September 2011 GAO report, titled Agencies Have Made Limited Progress Addressing Antibiotic Use in Animals, suggests that this information is insufficient to support a meaningful analysis of the possible relationship between antimicrobial resistance and the use of medically important antibiotics in food-producing animals.  In July 2012, FDA published an Advance Notice of Proposed Rulemaking requesting comments as to how the Agency might be able to obtain more detailed information about the use of antimicrobial animal drugs when the drugs are used in numerous species, including non-food producing animals (see our previous post here). 

The DATA Act would also require FDA to promptly finalize a guidance document issued in April 2012 in draft form, titled New Animal Drugs and New Animal Drug Combination Products Administered in or on Medicated Feed or Drinking Water of Food-Producing Animals: Recommendations for Drug Sponsors for Voluntarily Aligning Product Use Conditions with GFI #209.  The guidance is intended to provide sponsors with specific recommendations on how to supplement their approved marketing applications to align with FDA’s guidance on the judicious use of medically important antimicrobial drugs in food-producing animals.

In addition to activity on the legislative front, FDA is embroiled in litigation over the withdrawal of approval of certain uses of certain classes of antibiotics in food-producing animals.  As we previously reported, the National Resources Defense Council sued FDA in 2011 and initially sought to compel the Agency, by a court-ordered deadline, 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 and to issue final responses to two Citizen Petitions relating to hearing notices FDA issued in 1977 on the Agency’s withdrawal proposals.  FDA has not fared well in the litigation, which is on appeal to the U.S. Court of Appeals for the Second Circuit (Docket Nos. 12-2106 and 12-3607).

By Larry K. Houck –

The Government Accountability Office (“GAO”) has issued a report assessing the approaches states have taken to restrict the sales of pseudoephedrine (“PSE”), an ingredient commonly found in over-the-counter cold and allergy medications and a primary ingredient in clandestinely manufactured methamphetamine.  U.S. Gov’t Accountability Office, GAO-13-204, Drug Control: State Approaches to Control Access to Key Methamphetamine Ingredient Show Varied Impact on Domestic Drug Labs (2013).  The report concludes that electronic tracking systems help enforce sales limits but has not reduced “meth lab” incidents due to smurfing, the practice of recruiting individuals or groups to purchase up to the legal limit at multiple retailers, then aggregating quantities for meth production.  Meth lab incidents include law enforcement seizures of labs, dumpsites, chemicals and glassware.  The report finds that requiring PSE to be available by prescription appears to have helped reduce lab incidents but with unclear impact on consumers and limited impact on the health care system.

Beginning in about 2004, states and jurisdictions began taking efforts to regulate PSE at the point of sale.  Congress enacted the Combat Methamphetamine Epidemic Act of 2005 (“CMEA”), which set daily sales and monthly purchase limits, and requires retailers to keep PSE behind the counter and to maintain a written or electronic logbook of sales.  Nineteen states have implemented electronic reporting to track PSE sales and to determine if purchasers are in compliance with state purchase limits.  Two states, Oregon and Mississippi, and sixty-three Missouri cities and counties, require a prescription for PSE products.

The GAO analyzed data from the Drug Enforcement Administration’s (“DEA’s”) National Seizure System on lab seizure incidents from 2002 through 2011 to identify trends in domestic meth lab incidents.  To determine the impact of electronic tracking systems on meth lab incidents, the GAO analyzed data on the number of meth lab incidents reported in Kentucky, Missouri and Tennessee, where electronic tracking has been in place the longest.  The GAO assessed the impact of the prescription-only requirement in Oregon, Mississippi and their border states by analyzing data on meth lab incidents. 

Interestingly, as the GAO points out, meth lab incidents nationwide dropped to a low of 6,951 incidents in 2007, and has increased since, numbering 15,314 in 2010.  The 2010 incident total is more than twice the number of 2007 incidents.

Of the nineteen states that have implemented electronic reporting systems to track PSE sales, seventeen use the National Precursor Log Exchange (“NPLEx”) system and two states use a system developed in-house or by another vendor.  Under these systems, retailers report PSE sales to a centralized database that can determine whether a customer has or will exceed the federal or state PSE purchase limits.  Most of these systems query the database, notify the retailer if the sale would violate the daily or monthly limit and deny sales when a state or federal limit has been reached.  All sales in states using the NPLEx system are linked so the system blocks customers who try to purchase more than the permissible amount in another NPLEx state.  Electronic tracking systems make PSE sales information more accessible to law enforcement for investigation of potential PSE diversion, locating meth labs and prosecuting individuals.  Law enforcement officers in Indiana and Tennessee have noted that because NPLEx blocks customers from exceeding purchase limits, would-be purchasers associated with meth labs are not as readily identifiable and investigations take longer and are more labor intensive.

The GAO found that meth lab incidents in states that have implemented electronic tracking have not declined due in part to smurfing and the “one pot method” of methamphetamine manufacture.  Meth lab incidents in Oklahoma, Kentucky and Tennessee, the states that have been using electronic tracking the longest, are at their highest levels since implementation of federal and state PSE sales restrictions.  These states experienced initial declines in meth lab incidents from 2004 through 2006, but lab incidents have continued to rise since 2007.  While the systems block attempts by a customer with a single identification to purchase PSE in excess of the legal limits at one or more locations, smurfers have taken to using several different fake IDs to purchase above the legal limit without being detected or blocked. 

The number of reported meth lab incidents in Oregon and Mississippi declined followed by their prescription-only approach.  Reported meth lab incidents in Oregon had declined by 63 % in 2005 from 2004.  The number of reported meth lab incidents continued to decline in subsequent years after placement of PSE behind the counter and implementation of the CMEA and prescription requirements.  After adoption of the prescription requirements in Mississippi in 2010, the number of reported meth lab incidents declined by 66 % in 2011.  The report notes that declines were also observed in states neighboring Oregon and Mississippi because of regional or reporting factors.  State and local law enforcement officials in Oregon and Mississippi credited the reduction of meth lab incidents in those states to the prescription requirement.  Predictably, officials have reported observing related declines in the demand and utilization of law enforcement, child welfare and environmental cleanup services related to meth labs.

GAO notes that according to the Oregon High Intensity Drug Trafficking Area (“HIDTA”), while the number of reported meth labs there has declined, crystal meth remains “highly available” as Mexican traffickers import finished meth from labs outside the state.  The prescription-only approach in Oregon and Mississippi does not preclude residents from traveling to neighboring states to purchase PSE without a prescription.  However, in Arkansas it is now illegal to dispense PSE unless the customer presents a prescription or an Arkansas driver’s license or ID card, and Alabama requires individuals residing in a prescription-only state to provide a valid prescription for PSE.  Law enforcement officials in Oregon and Mississippi have reported no instances from their meth lab investigations in which PSE has been obtained through prescription forgery, illegal or improper prescribing or “doctor shopping” patients who obtain prescriptions from more than one doctor.  The prescription requirement appears to have reduced PSE sales in Mississippi (sales data is unavailable for Oregon), but the impact on customers is unknown.  Customers incur costs for traveling to and visiting a physician.  Customers may be able to obtain a PSE prescription via telephone.  The GAO observes that there has been no substantial healthcare workload increases required to issue PSE prescriptions and there has been no increase of medical appointments for patients seeking PSE products.  In addition, customers have not shifted from PSE to phenylephrine. 

The GAO report provides state lawmakers with a number of issues to consider about implementing electronic reporting systems, requiring a prescription to purchase PSE or weighing some other approach to further restrict sales of PSE used in the clandestine manufacture of methamphetamine.

By Jennifer D. Newberger –

FDA issued a proposed rule to amend its regulations on acceptance of data from medical device clinical studies.  The primary proposed changes include:

• Requiring that clinical studies conducted outside the United States to support any submission to FDA, including a 510(k) or IDE, be conducted in accordance with good clinical practices ("GCPs");
• Adopting a definition of GCPs;
• Amending the IDE and 510(k) regulations to address requirements for FDA acceptance of data from clinical studies conducted within the United States;
• For PMAs, updating standards for accepting data from outside the United States by replacing the requirement to be in compliance with the Declaration of Helsinki with compliance with GCPs;
• Amending Parts 807 and 812 to incorporate GCPs into the requirements for FDA acceptance of data from studies outside the United States to support a 510(k) or IDE; and
• Amending Part 812 to impose different requirements for nonsignificant risk versus significant risk studies conducted outside the United States, mirroring the current IDE regulations.

FDA believes that taking these steps will “help provide greater assurance of the quality and integrity of the data obtained from clinical studies conducted outside the United States and submitted in support of an application or submission to FDA.”  By eliminating the requirement to comply with the Declaration of Helsinki and replacing it with the GCP standard “provides a unifying approach, which may simply [trials outside the United States] and decrease the regulatory burden on sponsors.”  The GCP requirements also will make acceptance of foreign data for device studies more consistent with those for drugs and biologics. 

By Ricardo Carvajal & JP Ellison –

The U.S. Department of Justice ("DOJ") announced the indictment of former officials of the Peanut Corporation of America ("PCA") for their alleged role in the distribution of peanut products that were implicated in a 2008-2009 national outbreak of salmonellosis.  In part, the indictment charges PCA’s former president, vice-president, plant operations manager, and QA manager with conspiracy to defraud PCA’s customers, introduction of adulterated and misbranded food into interstate commerce with intent to defraud or mislead, and obstruction of justice.  Possible sanctions include fines, imprisonment, and forfeiture to the government of any property derived from proceeds that can be traced to the offenses.

The indictment alleges that defendants:

• shipped products prior to receiving test results and failed to inform customers when test results confirmed the presence of Salmonella;
• shipped products that had tested positive for Salmonella;
• retested products after initial tests confirmed the presence of Salmonella, and shipped products on the basis of subsequent negative test results;
• shipped products manufactured at plants not approved by customers;
• substituted imported products for the domestic products specified by customers;
• substituted non-organic products for the organic products specified by customers;
• falsified Certificates of Analysis ("COAs") in numerous ways; and 
• repeatedly lied to FDA inspectors during the course of their investigation.

As noted in DOJ’s press release, “an indictment is merely an allegation.”  Nonetheless, the indictment can be expected to refocus scrutiny on the adequacy of certain approaches to supplier verification and acceptance/rejection of ingredients.  As we noted in a prior posting, FDA did not include provisions that require supplier approval and verification in its proposed rule on preventive controls, which was recently issued under authority granted to FDA by the Food Safety Modernization Act ("FSMA").  However, FDA requested comment on that issue and might include related requirements in the final regulation.  The results of the PCA investigation could well influence FDA’s thinking on the issue, given the relative ease with which PCA is alleged to have defrauded a number of purchasers ranging from specialty manufacturers to multinational companies. 

By Kurt R. Karst –      

In a widely anticipated move, Momenta Pharmaceuticals, Inc. and Sandoz Inc. have petitioned the U.S. Supreme Court to review the August 3, 2012 judgment of the U.S. Court of Appeals for the Federal Circuit, in which a divided (2-1) Federal Circuit panel ruled that the scope of the Hatch-Waxman “safe harbor” provision at 35 U.S.C. § 271(e)(1) is broad and exempts from infringement any commercial activity where FDA requires that a record of that activity be maintained, even if no record is ever submitted to the Agency.  The Supreme Court case, Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc., has been assigned Docket No. 12-1033. 

As we previously discussed, the case involves a generic version of LOVENOX (enoxaparin) and U.S. Patent No. 7,575,866 (“the ‘866 patent”) assigned to Momenta that generally relates “to methods for analyzing heterogeneous populations of sulfated polysaccharides” such as enoxaparin.  Momenta sued generic drug sponsor Amphastar in the U.S. District Court for the District of Massachusetts for patent infringement alleging that Amphastar infringed the ‘886 patent by manufacturing for commercial sale enoxaparin using the patented method.  Relying on the Federal Circuit’s decision in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir. 2011), the District Court ruled that Amphastar’s activity fell outside of the “safe harbor” provision at 35 U.S.C. § 271(e)(1).  In Classen, which concerned whether a vaccine license holder was required to report to FDA certain adverse event information, the Federal Circuit held that 35 U.S.C. § 271(e)(1) “does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained.” 

On appeal, the Federal Circuit disagreed with the District Court and vacated an injunction in the case.  The Federal Circuit explained that its decision is not inconsistent with Classen “because the information submitted is necessary both to the continued approval of the ANDA and to the ability to market the generic drug,” and that in this case, “the submissions are not ‘routine submissions’ to the FDA, but instead are submissions that are required to maintain FDA approval. . . ,” thereby bringing them within the scope of the 2171(e)(1) safe harbor.   

During the pendency of the Federal Circuit’s consideration of Momenta, the U.S. Supreme Court had been asked to review the Classen decision.  See GlaxoSmithKline v. Classen Immunotherapies, Inc. (Docket No. 11-1078).  Ultimately, the Supreme Court decided not to hear the case, but not before the U.S. Solicitor General filed an amicus brief urging the Court to deny certiorari.  According to the U.S., although the Federal Circuit “erred in stating that section 271(e)(1)’s safe harbor encompasses only activities undertaken to obtain the FDA’s pre-marketing approval of generic products . . . there is no longer any practical need for theis Court’s intervention in light of the Federal Circuit’s subsequent decision in Momenta.”  Moreover, states the U.S., if “postapproval studies involve the use of patented inventions solely for uses reasonably related to the development and submission of information to the FDA, the plain language of Section 271(e)(1) precludes any claim for patent infringement.”  (Thus, if the U.S. Solicitor General is asked to file a brief in the Amphastar/Sandoz appeal, it is not difficult to discern what that brief will say.)

Amphastar and Sandoz present the following question to the U.S. Supreme Court:

Whether the use of a patented invention in the course of post-approval manufacture of a drug for commercial sale, where the FDA requires that a record of that manufacturing activity be maintained, is exempted from liability for patent infringement under Section 271(e)(1) as “solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs.

According to Petitioners, the Federal Circuit’s Classen and Momenta decisions are irreconcilable and fundamentally wrong:

Both Classen and the ruling below give the wrong scope to the safe harbor provision and together they leave its meaning in an intolerable state of uncertainty.  The Federal Circuit has shown no willingness to correct its interpretation or to provide the needed certainty.  In the absence of guidance from this Court, future panels will have two purportedly binding precedents from which to choose.  District courts are left adrift with two conflicting compasses, each purporting to be definitive.  Companies attempting to chart their own courses have no idea whether they are free to use patented inventions or whether such use will subject them to infringement liability.  The pharmaceutical industry cannot wait for the Federal Circuit to get it right (or wrong) a third or fourth time.

Absent review, the ruling below will undermine pharmaceutical industry investment in life-saving and life-enhancing innovations.  Each drug the pharmaceutical industry brings to market requires enormous investment. That investment is predicated on the protection provided by the patent laws: protection for innovators, during a patent’s term, from unlicensed, commercial competition from their own invention.  The court of appeals’ sweeping interpretation of Section 271(e)(1) calls into question the value of a great many pharmaceutical patents.

Regardless of whether or not the U.S. Supreme Court decides to take up the Momenta case, a final decision could have significant implications on the budding biosimilars industry where method patents play an important role.  Indeed, it is possible that FDA could require, as a condition of approval, that all biosimlar sponsors for a particular product use a particular analytic method that is under patent by a reference product sponsor.  As the law currently stands, the Section 271(e)(1) safe harbor would appear to exempt infringement in such circumstances.

In a new Contemporary Legal Note published by the Washington Legal Foundation (“WLF”), titled “Federal Taint Teams And Attorney-Client Privilege In Corporate Criminal Investigations,” Hyman, Phelps & McNamara P.C. Director Douglas B. Farquhar explores issues surrounding privileged material and so-called “taint teams” when government investigators seize company materials that may be used to build a criminal case.  “Taint teams,” which are described in the U.S. Attorneys’ Manual (Section 9-13.420(E)) as “privilege teams,” are supposed to determine what material is privileged, and to ensure that agents and prosecutors working on an investigation and prosecution do not gain direct or indirect access to secrets (usually attorney-client privileged material).

Mr. Farquhar describes how “taint teams” operate, highlights some areas of concern about attorney-client privileged information, and recounts the skepticism that some courts have expressed about the ability of “taint teams” to provide a fair assessment of whether a privilege applies to certain seized company material.  “In an era with more frequent revelations of serious prosecutor conduct,” writes Mr. Farquhar, “defense counsel and courts are left to wonder what prosecutorial misconduct has not been discovered or disclosed.  Prosecutors tend to work pretty closely together within the Department of Justice, and, although aspersions are not intended to be cast on the vast majority of federal prosecutors, the author and many other defense counsel can recount incidents where prosecutors engaged in ethically questionable conduct to increase the likelihood of a successful prosecution, or to produce pressure to accept an offered plea bargain.”

By Jennifer D. Newberger –

The Food and Drug Administration Amendments Act of 2007 (“FDAAA”) amended the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to require certain medical device submissions to include, “if readily available – (A) a description of any pediatric subpopulations that suffer from the disease or condition that the device is intended to treat, diagnose, or cure; and (B) the number of affected pediatric patients.”  (See our FDAAA summary and analysis here.)

To implement that requirement, on April 1, 2010, FDA published a proposed rule along with a direct final rule.  FDA ultimately withdrew the direct final rule because it received “significant adverse comment[s].”  After considering the comments, on February 19, 2013, FDA issued a supplemental notice of proposed rulemaking to implement the pediatric submission requirements.  It issued a draft guidance document the same day addressing how industry can comply with those requirements.

One aspect of the proposed rule that resulted in negative comments was FDA’s request for information on “potential” pediatric uses.  The comments noted that requiring information on potential uses was inconsistent with the language of the statute, and would require sponsors to speculate as to possible uses and subpopulations.  FDA agreed, and removed references to potential pediatric uses.

The proposed rule now requires sponsors to include “readily available” pediatric information in any HDE, PMA or PMA supplement, or PDP.  FDA does not interpret 30-day notices to be PMA supplements for purposes of the proposed rule.  Furthermore, it notes that an applicant submitting a PMA supplement need not provide previously submitted information, but may reference the previous application that contained that information.  If new addition has become “readily available” since the prior submission, the PMA supplement must include that information.

The proposed rule defines “readily available” as “available in the public domain through commonly used public resources for conducting biomedical, regulatory, and medical product research.”  The draft guidance expands on this by providing examples, including “bibliographic databases of life sciences and biomedical information (such as MEDLINE and PubMed) and online scientific and medical publishers (such as the Public Library of Science (PLoS) and the Cochrane Library).”

The draft guidance also clearly states that because the submitted pediatric use information will be available to the public as part of the annual report required by FDAAA to be submitted to Congress, the submitted information “should exclude proprietary, trade secret, and commercial confidential information about the device.”

The proposed rule and draft guidance also address the following important issues:

• Pediatric patients are defined as “patients who are 21 years of age or younger (that is, from birth through the 21st year of life, up to but not including the 22d birthday) at the time of the diagnosis or treatment.”
• Pediatric subpopulations include neonates, infants, children, and adolescents, and the draft guidance provides the age ranges included within each subpopulation.
• The information provided should come from a data source that has data only on U.S. subjects.  If there is no readily available information on U.S. subjects, or if the estimate of pediatric patients is considered unreliable, the sponsor may rely on information obtained from data on non-U.S. subjects.  In that case, the sponsor should include a discussion about the applicability of the non-U.S. data to the U.S. patient population.
• If no information about pediatric uses or subpopulations is readily available, the sponsor must indicate that it made a “reasonable effort” to provide the information, and must also provide documentation of the search performed, including the search engines used and key words searched.
• The draft guidance includes a table intended to serve as an example of how the information should be presented.  The table includes information on the approved or proposed device indication; pediatric incidence; pediatric prevalence; pediatric subpopulation/age range; specific device/component; and the source used to identify the information.

Perhaps the question of greatest importance to sponsors is what FDA will do with the pediatric device use information.  According to the draft guidance, “FDA would like to use this data to determine unmet pediatric needs in medical device development.  Once unmet needs are identified, FDA will be better able to coordinate efforts of stakeholders, device manufacturers and FDA staff to promote new device development and proper labeling of existing medical devices for pediatric use.”  It is not clear how FDA will use the pediatric information to meet this noble, if vague, intent.

By Carmelina G. Allis –

As reported in FTC Watch Issue No. 823 (Feb. 13, 2013), the Federal Trade Commission has plans to increase enforcement actions against mobile apps – including mobile medical apps.

During a Consumer Protection Conference sponsored by the American Bar Association earlier this month, FTC Commissioner Julie Brill and the former head of the agency’s Bureau of Consumer Protection, David Vladeck, discussed the agency’s renewed focus on advertising and consumer protection, and the need for more aggressive enforcement action against health claims, social media apps, and medical apps.

Commissioner Brill specifically referenced FTC’s action during the fall 2011 ordering a company to stop making claims that its mobile medical app could cure acne.  As we previously blogged, that was FTC’s first case targeting health claims related to a mobile medical app sold in Apple’s iTunes Store and Google’s Android Marketplace under the names “AcneApp” and “Acne Pwner.”  The mobile apps claimed that the colored lights emitted from the mobile devices could treat acne.

The marketers of the acne apps were fined and the FTC barred them from making any further claims on the mobile apps without competent and reliable scientific evidence.  As Commissioner Brill explained during the Conference, the laws that apply to traditional kinds of companies also apply to “cutting-edge social media apps,” because there “’isn’t any mobile ‘exceptionalism’ going on.’”

Despite FTC’s action against the maker of the acne apps, we are not aware of FDA initiating an enforcement action against that company.  As we previously blogged, FDA has proposed to exert regulatory authority over select mobile medical apps that meet the “device” definition in the Federal Food, Drug, and Cosmetic Act, and that are either used as an accessory to a regulated medical device, or transform a mobile platform into a regulated medical device.  The FDA regulatory landscape for these products, although somewhat defined, is still being carved out, and enforcement actions against mobile medical app developers do not appear to be at the top of FDA’s agenda.

The FTC, however, apparently has a different agenda on mobile apps.  So if you market a mobile medical app, bear in mind the FTC initiative.

By Kurt R. Karst – 

A recent report from the National Institutes of Health (“NIH”) Council of Councils Working Group on the Use of Chimpanzees in NIH-Supported Research leaves unanswered questions about the future utility of FDA’s so-called “Animal Efficacy Rule” for NIH-funded research intended to develop medical countermeasures. 

The NIH Working Group report is rooted in recommendations made by the Institute of Medicine (“IOM”) in a December 2011 report, titled “Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity,” in which the IOM concluded that most current biomedical use of chimpanzees is unnecessary.  The IOM also recognized, however, that chimpanzee use could still serve an important role in some research areas, but recommended that such use be governed by a set of principles and criteria.  The NIH, which accepted the IOM report, charged a working group with, among other things, developing a plan of action to implement the guiding principles and criteria identified in the IOM report.  In the interim, NIH implemented a policy of not funding new research projects involving chimpanzees, but currently funded research may continue.  The policy remains in effect until the NIH considers and issues policy implementing the IOM recommendations.

According to the NIH Working Group report, on which the NIH is seeking public comment:

For rare but serious diseases, product-driven studies may need to consider the FDA Animal Rule.  This greatly raises the expectations for the applicability of animal model studies and would raise expectations about the true value of data from chimpanzee experiments.  For example, the combination of animal and strain of pathogen used would likely be selected so that lethality occurred in untreated animals but not in treated animals.  If a decision were made to use chimpanzees, it might be necessary to use staged experiments with smaller numbers of animals per study along with data accumulated from multiple studies.  Whether the FDA Animal Rule would accommodate this is unknown.

FDA’s “Animal Efficacy Rule,” which was finalized in May 2002 (see here), provides that in certain circumstances, and where where human efficacy trials are not feasible or ethical, animal studies can be relied on to provide substantial evidence of effectiveness of a drug or biological product.  Specifically, FDA can rely on the evidence from animal studies to provide substantial evidence of the effectiveness of a drug or biological product when:

1. There is a reasonably well understood pathophysiological mechanism for the toxicity of the chemical, biological, radiological, or nuclear substance and its amelioration or prevention by the product;
2. The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well characterized animal model for predicting the response in humans;
3. The animal study endpoint is clearly related to the desired benefit in humans, which is generally the enhancement of survival or prevention of major morbidity; and
4. The data or information on the pharmacokinetics and pharmacodynamics of the product or other relevant data or information in animals and humans is sufficiently well understood to allow selection of an effective dose in humans, and it is therefore reasonable to expect the effectiveness of the product in animals to be a reliable indicator of its effectiveness in humans.

Evaluation of the drug or biological product for safety in humans is still required, and cannot be addressed by animal studies alone.  In addition, approval under the Animal Efficacy Rule is subject to certain postapproval commitments.

FDA has been working to address various elements of the Animal Efficacy Rule by issuing guidance on animal models and by developing an Animal Model Qualification Program (see here, here, and here).  Thus far, only a few products have been approved under the Animal Efficacy Rule.  In February 2003, FDA approved NDA No. 020414 for pyridostigmine bromide to increase survival after exposure to Soman "nerve gas" poisoning.  In December 2006, FDA approved NDA No. 022041 for CYANOKIT (hydroxocobalamin for injection) for the treatment of known or suspected cyanide poisoning.  In April 2012, FDA approved NDA supplements for LEVAQUIN (levofloxacin) Injection, Tablets, and Oral Solution for the treatment and prophylaxis of plague due to Yersinia pestis in adults and pediatric patients 6 months of age and older.  And in December 2012, FDA granted a license (BLA No. 125349) for raxibacumab injection to treat inhalational anthrax. 

The NIH Working Group report is not inconsistent with a 2011 consensus report from the National Research Council, titled “Animal Models for Assessing Countermeasures to Bioterrorism Agents.”  That report addresses the challenges stemming from developing and testing medical countermeasures against biothreat agents in animal models.  Among other things, the report recommends the development of a comprehensive strategy to reduce the dependency on nonhuman primates by maximizing the value of data derived from all research.