By JP Ellison –

In a recent post we described the Generic Pharmaceutical Association’s amicus brief in the POM case, which urged the Supreme Court to “be cognizant of the differences” among FDA regulated products.  In particular, GPhA urged that ‘[e]ven if petitioner is allowed to proceed with certain aspects of its claim, the Court should make clear that such a decision does not license second-guessing explicit FDA approvals, and in particular, FDA approvals under the agency’s authority to review and approve the licensing, labeling, and marketing of pharmaceuticals.”  That admonition from GPhA was brought to mind by a recent district court ruling regarding Lanham Act claims against a manufacturer of generic buproprion hydrochloride, in a case brought by the brand manufacturer.

The regulatory history of buproprion is described here in detail, but suffice it to say, FDA determined generics to be bioequivalent, and then reversed course a number of years later.

In the Lanham Act case, in an unusually long footnote, the district court ruled that “Plaintiff has alleged numerous instances in which Defendant made literally false statements as to the bioequivalence of [the generic].”

The generic defendant moved to dismiss.  The court characterized the defendant’s argument as follows:

Defendant, in its motion to dismiss, claims that the Food Drug and Cosmetics Act (the “FD&C”) delegates decisions of bioequivalence to the FDA. Defendant argues that Plaintiff is attempting to relitigate the decision of the FDA and/or privately enforce the FD&C, both of which are prohibited. Furthermore, Defendant claims that as the FDA originally designated Budeprion XL as bioequivalent to Wellbutrin XL, the statement cannot be false or misleading as a matter of law and private litigation over that fact is precluded.

After a review of the Lanham Act legal landscape regarding FDA regulated products, the district court sets forth the following analysis:

In the matter sub judice, the Court notes that initially the FDA approved of the ANDA for Budeprion XL and, in doing so, approved of it as bioequivalent to Wellbutrin XL. Compl. ¶¶ 27, 36-39. If Budeprion XL retained that FDA approval then Plaintiff’s claim under the Lanham Act, as it relates to statements alleging bioequivalence, may very well have been preempted under the Lanham Act. See Sandoz, 902 F.2d at 231. The FDA, however, subsequently determined that Budeprion XL was not bioequivalent to Budeprion. Defendant argues that the FDA’s previous decision “does not change history” and that the 2012 decision is “a new decision based on new information.” Def.’s Mem. 22, ECF No. 14, Apr. 3, 2013. Defendant claims that this later decision did “nothing to change the fact that Budeprion was, until that change of position, rated AB and found bioequivalent,” and that the “FDA’s change of position cannot be the basis for retroactive liability”. Def’s Mem 23.

Defendant’s argument misstates Lanham Act liability, Plaintiff’s theory of the case, and the preclusive effect of an FDA decision upon a private Lanham Act action. Lanham Act liability is triggered by literally false statements and does not require intent, knowledge, recklessness, or negligence on the part of the Defendant, thus good faith reliance on the FDA’s previous decision is not dispositive. See, e.g., Novartis Consumer Health, Inc., 290 F.3d at 586; U.S. Healthcare, Inc., 898 F.2d at 922-923. FDA findings have a preclusive effect on Lanham act liability not because “mere compliance with the FDCA or with FDA regulations will always (or will even generally) insulate a defendant from Lanham Act liability,” Pom Wonderful LLC v. Coca-Cola Co., 679 F.3d at 1178, but rather because courts should not second guess the scientific determinations of the FDA as the FDA is better suited and statutorily enabled to make such decisions, Sandoz, 902 F.2d at 231. As the FDA has allegedly found that the two drugs are not bioequivalent, the FDAs scientific findings would not preclude the Court from eventually making a determination that Wellbutrin XL and Budeprion XL were not bioequivalent.

The court goes on to note other bases upon which it concluded that the complaint states a claim, but as to the above, the upshot of the court’s analysis is that even though FDA initially determined that the product was bioequivalent, it reversed course, and therefore, a Lanham Act claim was not barred.  Although the court suggests that this does not constitute second-guessing FDA, it is hard to see how FDA’s decision is not second-guessed if Lanham Act liability can attach during a time when FDA’s bioequivalence decision was in effect.  More generally, the court’s reasoning seems to raise the prospect that a company could be subject to Lanham Act liability for something that the FDA had specifically authorized if the agency later changed its mind.

A denial of a motion to dismiss is not appealable, so this case will likely play out in the district court for the immediate future.  If nothing else, this case reinforces our view that the steady stream of Lanham Act cases involving FDA regulated products will continue.

By JP Ellison –

We previously posted (here and here) about the Supreme Court case that will be argued next month in which the parties are debating the proper interplay between the Federal Food, Drug, and Cosmetic Act (“FDC Act”) and the Lanham Act.  Briefly, the issue in the case is whether POM’s Lanham Act false and misleading advertising claims against Coke’s Minute Maid product are barred because those claims are based on the labeling of a product regulated by the U.S. Food and Drug Administration (“FDA”) under the FDC Act.

Last week, amicus briefs were filed by the Solicitor General, the Generic Pharmaceutical Association (“GPhA”), several state attorneys general, and the International Trademark Association.  The SG’s brief and the GPhA brief were filed in support of neither party.  The state attorneys’ general and ITA briefs were filed in support of POM.

Although filed in support of neither party, the SG’s brief was supportive of POM in that it reiterated the view expressed in the brief the SG filed when the Court was deciding whether to take the case that the Lanham Act claim should have been allowed “insofar as it concerns features of the juice’s label that are not specifically addressed by the FDCA or FDA’s regulations.”  In the merit brief, the SG argued that the “Lanham Act claim is barred only to the extent the FDCA or FDA regulations specifically require or authorize the challenged aspects of the . . . label.” in further explaining the government’s position, and rejecting the argument that something akin to conflict preemption was required, the SG argued that “impossibility is not the proper standard for finding preclusion here.” Rather, according to the SG, a Lanham Act claim should be barred when “it would directly contravene FDA’s judgment by declaring misleading what the expert agency expressly found nonmisleading.”  At the same time, the SG reiterated its view that the 9th Circuit, which had decided the POM case, employed “faulty reasoning” in concluding something akin to “‘so-called field preemption’ cases.”  The SG argued that “Congress did not intend the FDCA or its implementing regulations to occupy the field of juice labeling to the exclusion of other federal laws.”  

The GPhA amicus brief, although also filed in support of neither party, read as though more aligned with Coca-Cola/Minute Maid’s position.  Perhaps more importantly to its members, the GPhA brief stressed that regardless of what the Supreme Court decided with respect to food products, pharmaceuticals and other products such as devices, were regulated and approved differently than foods.  Accordingly, GPhA urged the Court, in announcing any rule, to “be cognizant of the differences” among FDA regulated products.  The state attorneys general and ITA briefs argued for a more expansive interpretation of the permissible scope of the Lanham Act than either the SG or GPhA.

Typically, other than the SG’s office, amici do not request and are not given oral argument time before the Court, so this is likely the last word for most of those submitting amicus briefs.  To date there is no indication whether the SG’s office will participate in the oral argument.  If the SG’s office does participate, I’m hoping that one of the Justices asks how the position put forward by the SG would operate in an instance in which the FDA had “specifically authorized” conduct via a guidance document, enforcement discretion, Orange Book listing, or some other action, but not in regulations. 

Regardless of the Court’s decision later this year, Lanham Act litigation involving FDA regulated products is unlikely to subside. We’ll be monitoring the oral argument and decision in this case and other Lanham Act cases of interest.

By Kurt R. Karst –

It was only about a year ago when the topic du jour was generic drug labeling and whether federal law – the FDC Act and FDA’s implementing regulations – preempts state-law product liability claims (failure-to-warn, design defect, failure-to-conform/update, etc.) against generic drug manufacturers.  In fact, we were so inundated with generic drug labeling preemption issues at the time that we titled a March 13, 2013 post “Preemption, Preemption, and More Preemption.”  

Well, it’s happened again.  It seems that hardly a day goes by now without something new happening in the generic drug labeling preemption arena.  Of course, back in 2013, the hubbub was all about the U.S. Supreme Court’s consideration of Mutual Pharm. Co., Inc. v. Bartlett, 133 S. Ct. 2466 (2013) (subsequently decided) and the Court’s previous decisions in PLIVA Inc. v. Mensing, 131 S.Ct. 2567 (2011) (holding that FDA’s regulations preventing generic drug manufacturers from changing their labeling except to mirror the label of the brand-name manufacturer preempt state-law failure-to-warn claims against generic drug manufacturers, because it is impossible for generic drug manufacturers to comply with both federal and state duties to warn) and Wyeth v. Levine, 555 U.S. 555 (2009) (holding that a state-law tort action against a brand-name drug manufacturer for failure-to-warn is not preempted).  In Bartlett, the Court held that state-law design-defect claims that turn on the adequacy of a drug’s warnings are preempted by the FDC Act and under the Court’s decision in Mensing.  The fallout of those decisions (in addition to a multitude of court decisions all over the map, such as in Pennsylvania – see our previous post here – and a recent decision out of Illinois in Dolin v. Smithkline Beecham Corp. concerning brand-name manufacturer liability for a generic version of its drug product) was FDA’s November 13, 2013 proposal (see our previous post here) to allow generic drug manufacturers to independently update product labeling (with respect to product safety) through the Changes Being Effected (“CBE-0”) supplement process that is currently only available to brand-name drug manufacturers whose products are approved under an NDA. 

FDA’s ANDA CBE-0 proposal has resulted in the bivouacking of various parties in anticipation of what could be many skirmishes and a protracted battle over the future of the generic drug industry. 

Not long after FDA published its proposal, several Republican members of Congress expressed “grave concerns” about the proposed rule in a letter to FDA Commissioner Margaret Hamburg, M.D.  As we previously reported, the lawmakers express the belief that FDA’s proposal “would conflict directly with the statute, thwart the law’s purposes and objectives, and impose significant costs on the drug industry and healthcare consumers,” and requested that the Agency “explain and reconsider this departure from decades of settled practice.”  FDA lodged its response in a a February 26, 2014 letter to the lawmakers.  In that response, FDA cites to the Agency’s Preliminary Regulatory Impact Analysis concerning some of the cost issues raised by the lawmakers, and also clarifies the proposal.  For example, FDA comments that “[d]uring its review of a generic drug manufacturer’s [CBE-0] supplement, FDA would consider submissions by the brand drug manufacturer and other generic drug manufacturers related to the safety issue and determine whether the labeling update is justified and whether modifications are needed.”  In that case, “FDA would make an approval decision on proposed labeling changes for the generic drug and the corresponding brand drug at the same time, so that brand and generic drug products have the same FDA-approved labeling.”

The Generic Pharmaceutical Association (“GPhA”) has also expressed its own concerns about FDA’s proposal.  In February, GPhA put out an Overview and Assessment of FDA’s proposal saying that it is unjustified and unwarranted (see our previous post here).  A follow-up economic assessment concludes that FDA’s proposal, if implemented, would result in an estimated $4 billion in additional U.S. health care costs annually.  More recently, GPhA hosted a briefing on Capitol Hill highlighting its concerns about the proposal, and showcased a March 6, 2014 letter sent to FDA by myriad healthcare organizations saying that “FDA and others need to fully explore the potential unintended consequences that the Rule may have on patient access and national health care costs,” and that “[p]ermitting labeling changes for generic drugs without FDA approval counters 30 years of law requiring generic and brand medicines to have the same labels.”

Those forces in favor of FDA’s November 2013 proposed rule are also gathering.  Last week, just three days after a hearing on FDA’s proposal before the House Committee on Energy and Commerce Subcommittee on Health was postponed, a group of Democrat lawmakers announced that they had sent a letter to FDA supporting the proposal. 

According to the bicameral group of lawmakers, who urge FDA to prioritize the release of a final rule, the Agency’s proposal “is critically important to ensure that the public is informed as soon as possible when new safety information becomes available, and to ensure that labeling for a prescription drug remains up-to-date even when the branded drug is no longer being marketed or has not undergone a labeling update to reflect newly discovered risks.”  And not only does “[e]mpowering a drug manufacturer to update certain safety information while FDA reviews the change, instead of requiring prior FDA approval” (emphasis in original) make good sense they say, because it “will allow generic drug manufacturers to communicate safety information in a timely way,” but it helps incentivize generic drug manufacturers given concers about tort liability:

The Proposed Rule achieves an important public safety goal by restoring these incentives for generic manufacturers to warn consumers of safety risks.  Especially in light of resource constraints facing FDA, the potential for tort liability provides an important tool in incentivizing compliance with existing reporting obligations, to the benefit of American consumers.

This is certainly not the last word we’ll hear about FDA’s proposal.  As noted above, we’re just in the set-up stage to the battle.

By John A. Gilbert, Jr. & Larry K. Houck –

A bill introduced in the Maryland House of Delegates, HB 0596, would require wholesale distributors to notify their pharmacy customers at least thirty days prior to “imposing a limit on the quantity” of prescription drugs or devices distributed to the pharmacy.  The bill would further require wholesale distributors to provide updates, at least weekly, on the quantity of the drug or device available to the pharmacy while a limitation is in effect. 

The bill is likely intended to assist pharmacies in managing inventories and avoid potential shortages for their patients, however, it would create significant hardships for distributors to anticipate shortages related to manufacturer availability.  For example, a wholesale distributor may not know a month out that it may not have adequate drug or device inventory for sale to pharmacy customers.  In addition, the bill, if enacted, would create potential conflicts with Drug Enforcement Administration (“DEA”) regulations that require distributors, manufacturers and other registrants to design and operate a system to disclose suspicious controlled substance orders and to report such orders to the local DEA office.  21 C.F.R. § 1301.74(b).  Suspicious orders include orders of unusual size, orders that deviate substantially from a normal pattern and orders of unusual frequency.  Id. 

In order to comply with DEA’s current interpretation and enforcement of this regulation, most distributors have designed systems to include “thresholds” or limits as part of a program to identify, review, evaluate and report suspicious orders.  Moreover, once a distributor has identified a suspicious order, they are obligated to report this order to DEA and, logically, should not fill this order (or future orders for controlled substances) until these issues are resolved.  Distributors also may not want to disclose the thresholds or specific components of their compliance systems to customers to avoid customers attempting to circumvent the limits.  Therefore, decisions by distributors to report and not fill orders as required by DEA regulations could violate the proposed Maryland bill’s thirty day notification requirement.

The proposed legislation warrants monitoring and will need to be amended to resolve conflicts with federal law.  As of January 2014, there were 978 wholesale distributors licensed by Maryland.  

By Anne K. Walsh –

Yes, this post relates to yet another off-label settlement between a pharmaceutical company and the federal government.  But some aspects of this recent settlement, coupled with other recent cases, might indicate noteworthy trends in how these cases are being resolved.  The defendants are Endo Health Solutions, and its subsidiary, Endo Pharmaceuticals Inc., based in Malvern, Pennsylvania.  The drug is Lidoderm, a prescription drug patch that FDA approved to treat pain associated with post-herpetic neuralgia, or PHN.  The government alleged (here and here) that Endo marketed Lidoderm for general, non-PHN related pain indications, including lower back pain, diabetic neuropathy, and carpal tunnel syndrome.  The company’s global settlement included a civil payment of $171.9 million, a criminal fine of $20.8 million, and a Corporate Integrity Agreement governing the company’s ongoing practices. 

Two U.S. Attorney’s Offices bifurcated the matter, with the civil investigation managed by the U.S. Attorney’s Office in Philadelphia, and the criminal investigation handled by the Northern District of New York.  Dealing with multiple U.S. Attorney’s Offices can be complicated, but we have seen improved cooperation between multiple offices in recent cases.

Endo managed to escape a corporate criminal charge by entering into a deferred prosecution agreement (“DPA”) with the government.  In the DPA, the company admitted to certain criminal conduct, and agreed to pay a criminal fine and to impose enhanced compliance measures (many of the compliance provisions appear to overlap with the requirements of the Corporate Integrity Agreement).  The DPA will not be final until it is accepted by the court.

The government used asset forfeiture techniques to buttress the criminal penalty.  As part of the resolution, the parties agreed to settle an in rem action the government had brought against a $10 million wire transfer intended for Endo Pharmaceuticals.  It is unclear from the publicly available pleadings how the government traced the wire transfer, but suffice it to say that money transfers of this magnitude do not go unnoticed when a company is in the crosshairs of a criminal investigation.  The government argued that the money constituted proceeds from a violation of the FDC Act, and therefore was subject to asset forfeiture under 18 U.S.C. § 981(a)(1)(C).  As part of the criminal plea, the parties agreed to forfeit the $10 million wire transfer, plus pay an additional $10 million monetary fine.  Asset forfeiture is a powerful tool for the government, and one law enforcement agencies particularly prefer because the money is earmarked to further fund their investigative efforts.

By Robert A. Dormer –

Every breath you take
Every move you make
Every bond you break
Every step you take
I'll be watching you

Every single day
Every word you say
Every game you play
Every night you stay
I'll be watching you

Our apologies to Sting and The Police, but we were reminded of the lyrics from “Every Breath You Take” the other day when we learned about the “Automated Litigation Tracking System” being run by the Office of General Counsel of the Department of Health and Human Services, the parent agency of FDA.  As a law firm that is involved in litigation with FDA on a fairly regular basis, we are certainly not surprised that HHS and FDA would want to know relevant information about companies or individuals who are suing the government or who are defendants in cases brought by the government. We were, however, surprised to learn about the Automated Litigation Tracking System that is located at the old Parklawn Building in Rockville, Maryland where many of us FDA alumni used to work. With recent disclosures about National Security Agency surveillance and the report last week [http://oversight.house.gov/wp-content/uploads/2014/02/FDA-Staff-Report-final.pdf] from Senator Charles Grassley (R-IA) and Congressman Darrell Issa (R-CA) about FDA monitoring of employee emails we thought this might be a timely topic.

According to the government’s description of the litigation tracking system, records are maintained on individuals “who are involved in litigation with the Department [of HHS] or the United States (regarding matters within the jurisdiction of the Department) either as plaintiffs or defendants in both civil and criminal matters.”  Also included are individuals who “either file administrative complaints[s] with the Department or are the subject of administrative complaints initiated by the Department …” and individuals “who are named parties in cases in which the Department believes it will or may become involved ….”  What is not clear is the type or extent of records that are automatically tracked.  We hope that only publicly available information is tracked and maintained but does that include for example court records from divorce proceedings or child custody cases?  What about financial contributions to political candidates?  The government’s description says only that the records contain information to identify “the people involved in each case.”  We are aware, for example, that FDA is tracking company websites using this system.  What else is FDA tracking?

Among the “routine uses” of this information are communications “with, among others, Federal, State, and local law enforcement agencies, private individuals, public and private hospitals, allegedly negligent parties, private attorneys, insurance companies, the United States Attorney and other Federal officials and agencies, individual law enforcement officers and tribal officials.  These communications are all for the purpose of investigating, settling, or denying claims and subsequent litigation action.”

Although we don’t pretend to know the extent to which FDA is tracking companies it regulates, it is prudent to assume that if your company is (or may be) in litigation with FDA – or is potentially subject to enforcement action – FDA is watching every move you make, every step you take.

By Allyson B. Mullen –

On February 18, 2014, the FDA issued the Final Guidance “Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff” (the “Pre-Sub Guidance”).  FDA, Guidance for Industry and FDA Staff, Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff (February 2014).  Subsequently, on February 26, 2014, FDA held a webinar regarding the Pre-Sub Guidance (the “Webinar”).  During the Webinar, FDA explained the key provisions of the Pre-Sub Guidance, and discussed various types of requests for feedback that are covered by the guidance.  FDA will be posting a transcript, audio recording and slides will be available here. 

As you may remember from our earlier post, a draft of the Pre-Sub Guidance was issued in July 13, 2012.  The draft guidance was issued to document the expansion of the pre-Investigational Device Exemption ("IDE") program to include requests for feedback on other device pre-market submission types such as premarket approval ("PMA") applications, humanitarian device exemption ("HDE") applications, and premarket notification (510(k)) submissions.  The draft guidance also broadened the program to include devices regulated by the Center for Biologics Evaluation and Research ("CBER"). 

Since the issuance of the draft guidance, the Pre-Sub program has been a useful mechanism for applicants and study sponsors to obtain feedback from FDA.  Similarly to the draft guidance, the Pre-Sub Guidance provides direction as to when a Pre-Sub is particularly useful.  For example, a Pre-Sub is recommended (i) before conducting a long-term or material investigation of a new device, particularly, if the device involves novel technology, a “first of a kind” indication for use, or does not have a clear regulatory pathway, and (ii) before conducting a clinical study without an IDE, including clinical studies outside the US, non-significant risk clinical studies and IDE exempt studies.  Pre-Sub Guidance at 9-10.  Although the Pre-Sub process can be useful in many situations, it is not for everything, including general information requests or questions regarding FDA policy or procedures, and requests for clarification regarding technical guidance documents.  Id. at 12. 

The Pre-Sub Guidance has been expanded from its draft form (obvious from its length alone, growing from 35 pages to 53 pages).  The Pre-Sub Guidance encompasses Pre-Subs and also various meetings with FDA, including:

• Formal early collaboration meetings to provide direction regarding development and testing of devices that require a clinical study(ies) to support their pre-market applications (“Determination Meetings” pursuant to Section 513(a)(3)(D) of the Federal Food, Drug, and Cosmetic Act (the “Act”) and “Agreement Meetings” pursuant to Section 520(g)(7) of the Act);
• Meetings required no later than 100 days after receipt of a PMA application (“Day-100 Meetings” pursuant to Section 515(d)(3) of the Act);
• Informal meetings to discuss additional information requests on pending pre-market submissions (“Submission Issue Meetings”);
• Requests for determination regarding whether a proposed clinical study is exempt from or subject to the IDE regulations, and if a study is subject to the IDE regulations, whether a study is significant risk or non-significant risk (“Study Risk Determinations”); and
• Meetings to inform or educate FDA about devices in development and/or planned submissions without requesting feedback (“Informational Meetings).

79 Fed. Reg. 9226, 9227 (Feb. 18, 2014).  All Pre-Subs and meeting requests will be referred to by FDA as “Q-Subs” and will be assigned a Q number (Q followed by two digits for the year and four digits representing the order in which it was received).  Pre-Sub Guidance at 5.  Appendix 1 of the Pre-Sub Guidance contains recommendations for each type of Q-Sub.  Id. at 31.

The major changes in the final Pre-Sub Guidance from the draft guidance include:

• Revisions to broaden the overview of possible mechanisms for FDA feedback prior to a planned submission;
• Reorganization to include a discussion of the various request types first, followed by a section regarding meeting procedures, which applies to all feedback mechanisms that request a meeting or teleconference; 
• Revisions to include an acceptance review process, including an acceptance checklist for all Q-Subs; and 
• Revisions to clarify that if more than one year has passed since the Agency provided feedback on a Q-Sub and the applicant has not submitted an application to the Agency, the applicant can confirm the validity of the prior feedback by calling the lead reviewer or the branch chief.

79 Fed. Reg. at 9928.  Regular readers of our Blog will also be happy to hear that the Pre-Sub Guidance states that applicants must submit an eCopy, thereby correcting the inconsistency that existed between the draft guidance and the eCopy Guidance.  Pre-Sub Guidance at 6.  Applicants should ensure that their Pre-Submissions comply with the requirements of the final guidance document for the eCopy Program for Medical Device Submissions (the “eCopy Guidance,” we previously blogged on the guidance here and here.) 

One other administrative change that FDA emphasized during the Webinar was the change to the process for meeting minutes.  Following the meeting or teleconference, the applicant should draft meeting minutes and submit the draft (including any slides from the meeting) to the Document Control Center (“DCC”) within 15 calendar days of the teleconference or meeting. In the draft guidance, meeting minutes were submitted to the lead reviewer following the meeting.  In the Pre-Sub Guidance, the draft minutes will be logged as a formal amendment to the Q-Submission. The Webinar presenters explained that FDA will review and edit the meeting minutes, if necessary, within 30 days of receipt.  FDA’s edited version, if edits were made, will become the final record of the meeting/teleconference 15 calendar days after the applicant receives FDA’s edits, unless the applicant submits a “meeting minutes disagreement” during that timeframe.  A “meeting minute disagreement” should be filed by the applicant as an amendment to the Q-Sub through the appropriate Document Control Center.  Id. at 29.  These procedures underscore how the process has been greatly formalized compared to the Pre-IDE process.

Although FDA received comments regarding the timeframe for providing responses to Pre-Subs (a goal of 75 to 90 days in the draft guidance), this time frame has not changed for Pre-Subs.  However, the Pre-Sub Guidance does contain a helpful chart with the feedback timeframes for each type of Q-Sub:

Id. at 5.  During the Webinar, FDA explained that the Q-Sub review timeline will not change if the underlying pre-market submission has been granted priority review.

The most interesting of the changes to the Pre-Sub Guidance is certainly the addition of the Q-Sub Acceptance Checklist (Appendix 2), which applies to all Q-Subs except for PMA Day 100 Meeting requests.  Id. at 47.  FDA intends to perform an “Acceptance Review” within 14 calendar days of receiving a Q-Sub that includes a valid eCopy.  Id. at 6.  As explained during the Webinar, the Acceptance Review will be performed by the reviewing branch at the Center.  The Acceptance Review is intended to “(1) determine if the request meets the definition of the identified Q-Sub type and (2) determine if a qualifying request is administratively complete.”  Id.  If the submission does not include sufficient information to allow the Agency to make these determinations then the applicant will receive a notice indicating the reasons that the submission was not accepted.  During the Webinar, FDA explained that it will begin performing the Acceptance Review in the next few weeks. 

In addition, the Webinar presenters stated that the Acceptance Review will be performed in parallel with the timeframes listed in the table, above.  For example, if an applicant submits a Submission Issue Meeting request, the first 14 days of the 21 day timeframe for review will be allocated to the Acceptance Review.  Thus, the total timeframe for Submission Issue Meeting review will be 21 days, not 35 days (14 days for Acceptance Review + 21 days for substantive review).  In fact, FDA noted during the Webinar that it understands the urgency of Submission Issue Meetings, and plans to perform the Acceptance Review for these Q-Subs in less than 14 days, if possible.

The Pre-Sub Guidance attempts to distinguish the Acceptance Review from the 510(k) and PMA Refuse to Accept (RTA) Policies by not including a list of required elements, which need to be in a Q-Sub in order for it to be accepted.  In fact, the Pre-Sub Guidance indicates that, if the Q-Sub includes the basic information necessary for FDA to provide the requested feedback and/or identify the appropriate attendees for scheduling of a meeting or teleconference, then “additional clarifying or explanatory information” can be provided after acceptance upon request of the lead reviewer, if needed. 

We certainly hope that the Pre-Sub Acceptance Review has better success than the 510(k) RTA process (some of the issues with the 510(k) RTA process are discussed in our recent post here).  As of September 2013, approximately 60% of all newly filed 510(k)s were refused under the RTA.  CDRH Meeting FDASIA Goals, Confirms Compliance Re-Org, DEVICES & DIAGNOSTICS LETTER (FDA News, Falls Church, V.A.), Sept. 30, 2013, at 1.  If 60% of new Pre-Subs are refused under the Pre-Sub Guidance’s Acceptance Review, it would unduly delay requests for feedback that are often times meant to take place early in the development and planning process.  Thus, this could cause delays to device approvals/clearances and/or initiation of clinical trials for new devices, which could discourage companies from conducting clinical trials in the United States (note: one of FDA’s strategic priorities for 2014-2015 is to encourage sponsors of clinical trials to conduct those trials in the United States rather than overseas and to do so early in the device development process (see our earlier post here).  Even with this added administrative hurdle for applicants to navigate, we expect that the Pre-Sub Program will continue to be a useful process for applicants to receive feedback from FDA prior to or in connection with nearly any type of device pre-market submission and/or clinical study design.

By Delia A. Deschaine & Larry K. Houck –

In just shy of three months following receipt of the Department of Health and Human Services (“HHS”)’s rescheduling recommendation, see prior post here, DEA announced the issuance of a Notice of Proposed Rulemaking (“NPRM”) Thursday to reschedule all hydrocodone combination products (“HCPs”) from schedule III to schedule II.  For prior discussions on this issue, see our prior posts here, here, and here.

DEA’s NPRM includes a summary of its findings regarding the eight factors it is required to consider to transfer HCPs to schedule II.  21 U.S.C. § 811(a), (c).  Following a brief background on the history of the current placement of HCPs in schedule III, DEA explained that it reviewed the scientific and medical evaluation sent by HHS and completed its own eight-factor analysis pursuant to 21 U.S.C. § 811(c).  DEA concluded that based on the eight-factor analysis, it finds “these facts and all other relevant data constitute substantial evidence of high potential for abuse of HCPs.”  For a discussion of the utility of dual oversight of drug scheduling by FDA and DEA, see here and here.

Rescheduling HCPs from schedule III to schedule II will impact every legitimate controlled substance handler including patients.  Rescheduling will impose more stringent regulatory requirements upon manufacturers, distributors, dispensers such as pharmacies and physicians, importers and exporters.  For example registrants can only transfer schedule II substances between themselves via a triplicate, sequentially-numbered DEA Form 222 Official Order Form or its electronic equivalent while registrants may transfer schedule III drugs with invoices, packing slips or other records.  Prescriptions for schedule II substances, with limited exceptions, typically may only be written for a 30-day supply (based on various state laws and insurance company requirements), and pharmacies must receive original prescriptions before dispensing.  Prescriptions for schedule III controlled substances may be written, oral or faxed.  Pharmacists cannot refill schedule II prescriptions; but if authorized to do so, can refill schedule III prescriptions up to five times within a six month period.  Manufacturers and distributors must secure schedule II substances in a safe, steel cabinet or vault while schedule III substances may be stored in a less secure controlled substance cage or other enclosure.  (Notably, DEA also states in the NPRM that “[m]any manufacturers and exporters are likely to have sufficient space in their existing vaults to accommodate HCPs,” though DEA “understands that some manufacturers, exporters, and distributors will need to build new vaults or expand existing vaults to store HCPs.”)

DEA’s NPRM is also interesting in light of recent changes in the availability of hydrocodone products.  When DEA first proposed to reschedule HCPs, there were no single-entity hydrocodone products approved for use in the United States.  However, on October 25, 2013, FDA approved Zohydro, making it the first, and only, single-entity hydrocodone product approved in the United States.  Zohydro is a schedule II controlled substance because single-entity hydrocodone products have been placed in schedule II since Congress first enacted the Controlled Substances Act.  Some groups have expressed concerns about the approval of Zohydro, noting its lack of abuse-deterrent technology.  See, e.g., The Pharmacists Planning Service, Inc., Citizen Petition (Docket No. FDA-2013-P-1606) (requesting that FDA add “drug-abuse deterrent technology to all hydrocodone schedule II products” (emphasis added); Letter from State Attorneys General to Margaret Hamburg, M.D., Commissioner, FDA (Dec. 10, 2013) (opposing Zohydro approval).  According to DEA’s NPRM, Zohdyro is projected to launch this month.  DEA’s NPRM to move HCPs to schedule II leaves open the question of whether the request to add abuse-deterrent technology will be expanded to apply to these products as well. 

Interested persons may file comments on the NPRM on or before April 28, 2014.  Interested persons “adversely affected or aggrieved” by the proposed rule may file a request for hearing on or before March 31, 2014.

By Jay W. Cormier & Anne K. Walsh –

It was a big day in January 2009 when FDA finally issued guidance for manufacturers governing the distribution of medical journal articles and reference publications.  While some guidance was better than no guidance, FDA received several comments asking for clarification on how the principles applied to medical textbooks, and also received two citizen petitions asking for information on how FDA might view the distribution of information in clinical practice guidelines ("CPGs"), which are recommendations for clinicians to use when making decisions for individual patient care.  As a result, last Friday, FDA issued a new Draft Guidance revising the 2009 document to expand FDA’s guidance on good reprint practices to apply to medical reference texts and CPGs. 

In the preamble to the new revised draft guidance, FDA makes clear that it continues to solicit comment concerning various aspects related to the guidance, such as information relating to “scientific exchange,” responses to unsolicited requests for information relating to unapproved or uncleared uses, and distribution of health care economic information to payors.  The new guidance document, when finalized, will repeal and replace the 2009 Reprint Guidance. 

Substantively, the Draft Guidance includes all of the principles and recommendations contained within the existing 2009 Reprint Guidance.  FDA emphasizes that all distributed materials should not:

• Be false or otherwise misleading;
• Recommend or suggest use of the product in such a way that the product is dangerous to health when used in the manner suggested; nor
• Be marked, highlighted, summarized, or characterized by the manufacturer, in writing or orally, to emphasize or promote an unapproved use.

But because reference texts and CPGs are generally much longer and cover a wider range of topics than a journal article, the issues are more nuanced than a simple journal article.  Accordingly, the new Draft Guidance adds two sections that detail specific recommendations governing these types of documents.

Reference Texts

Readers can reference the document for details, so we will not reiterate them all here.  The key elements for distributing a reference text containing information about an unapproved or uncleared use are that the text:

• Be based on a systematic review of the existing evidence;
• Be independently published;
• Be the most current version;
• Be written by experts in the subject area;
• Be peer-reviewed by other subject area experts;
• Be widely available through normal independent distribution channels;
• Not be distributed with any product promotional materials;
• Include a permanently affixed, and prominently displayed statement disclosing (1) the distributing manufacturer, (2) that some of the uses described in the text may be unapproved or not cleared by FDA; and (3) whether any specific authors have a financial interest in the manufacturer or its products; and
• If there are one or more chapters that primarily discuss unapproved or uncleared uses, be accompanied by the approved product label (or indications of use for a 510(k) cleared device).

If only part of a reference text is distributed, the guidance requires that:

• The overall reference text meets the requirements above;
• The permanently affixed, prominently displayed statement is placed on the distributed part of the reference;
• The affixed statement includes all known significant risks associated with the unapproved or uncleared use; 
• The distributed part of the reference text be unaltered, unabridged, and extracted directly from the original referent text; and
• It be distributed with a copy of the approved product label (or indications of use for a 510(k) cleared device).

Clinical Practice Guides

Any CPG that includes information on unapproved or uncleared uses must meet Institute of Medicine (IOM) standards for whether it is a “trustworthy” guideline.  According to IOM, a guideline is “trustworthy” if it:

• Is based on a systematic review of the existing evidence;
• Is developed by experts in the subject area;
• Considers important patient subgroups and patient preferences;
• Is transparently developed and funded such that biases are minimized;
• Provides logical relationships between treatment recommendations, health outcomes, and includes the quality and strength of the underlying evidence; and
• Is reconsidered and revised as new information becomes available.

Similar to reference texts, FDA lays out several requirements for CPGs that are distributed in their entirety, and additional requirements if only a section is used.
 
Although draft guidance is rarely an example of clarity, on the whole, the Draft Guidance provides helpful information regarding how manufacturers should think about reference texts and CPGs.  For those who have been applying the 2009 Reprint Guidance to these texts, compliance with the Draft Guidance should be relatively straightforward.

The Draft Guidance is open for public comment for 60 days, until May 2, 2014. 

By Riëtte van Laack –

Last week, FDA announced the long awaited proposal for revisions to the regulations (here and here) for the format and mandatory information included in the Nutrition Facts Box (“NFB”) and the Supplement Facts Box (“SFB”), and for the calculation of the serving size and reference amount customarily consumed (“RACC”).

The prepublication version of these two proposals consists of more than 550 pages, though the published version is a more manageable 150 pages.  FDA’s press release, facts sheets, Q&As, and some other materials provide a quick overview of the major changes.  In future blog posts we will discuss some of the proposed changes in more detail.

Changes to the NFB

FDA proposes to change the presentation of the information presented in the NFB.  The proposed changes are summarized in a marked-up NFB that is shown below.

Besides the changes in presentation of the information, FDA also proposes significant changes to the information included in the NFB.  The proposal includes the following changes:

• “Calories from Fat” are out, “Added Sugars” are in;
• Declaration of Vitamin D and Potassium will become mandatory; declaration of vitamin A and C will become voluntary;
• Potassium will be listed as a mineral, not under sodium;
• In addition to %DV for minerals and vitamins, the actual amount of vitamins and minerals must be declared;
• Changes in the DV for a large number of vitamins and minerals, including increases in the DV for vitamin C and D and decreases in the DV for biotin and thiamin;
• Calculation of the amount of Dietary Fiber will change;
• Because there are no analytical methods to verify compliance with the labeling requirements (e.g., added sugars and dietary fiber), manufacturers will be required to maintain records to verify the declarations of specific nutrients in the NFB.  
• The footnote in the NFB will also change, but FDA has not yet determined how.

The proposed changes also apply to the SFB for dietary supplements.

Changes to Serving Size

The serving sizes used in the NFB are based on reference amounts customarily consumed (RACCs).  The current RACCs (included in 21 C.F.R. § 101.12) are based on data from surveys in the 70s and 80s.  However, consumption patterns have changed and so have serving sizes.  For example, according to surveys in the 70s and 80s, consumers customarily consumed a ½ cup of ice cream.  Nowadays, consumers (apparently) customarily consume twice as much, i.e., 1 cup of ice cream.  Yogurt used to be consumed in 8 oz portions but more recent data show that nowadays it is customarily consumed in 6 oz portions.

The change in RACCs will lead to changes in the serving size.  FDA also proposes to amend some of the required procedures to determine serving size, amend the definition of a single serving container, and require that containers that contain 2-4 times the serving size include an additional column of nutrition information for the whole container.  Examples of products that will be affected by this new requirement include a 24-ounce soda bottle, a 19-ounce can of soup, and a pint of ice cream.  

FDA proposes an effective date of 60 days after publication of the final rules and a compliance date 2 years after the effective date.

Comments are due by June 2, 2014. 

By Kurt R. Karst –  

It’s “Exclusivity Week”!  First there was FDA’s Draft Guidance that, if finalized, would reinterpret the 5-year New Chemical Entity (“NCE”) exclusivity provisions of the FDC Act to award NCE exclusivity to a newly approved Fixed-Dose Combination (“FDC”) drug containing an NCE and a previously approved drug.  That announcement was immediately followed by an FDA response to three Citizen Petitions denying NCE exclusivity to previously approved FDCs (see our previous post here).  Then there was FDA’s decision on the scope of 3-year new clinical investigation exclusivity applicable to PLAN B One-Step (levonorgestrel) Tablets (see our previous post here).  

The latest “Exclusivity Week” entrant is Amarin Pharmaceuticals Ireland Limited (“Amarin”).  On February 27, 2014, Amarin, which is represented in court by Covington & Burling LLP (Hyman, Phelps & McNamara, P.C. represented Amarin before FDA), filed a Complaint in the U.S. District Court for the District of Columbia challenging FDA’s February 21, 2014 Exclusivity Determination that Amarin’s VASCEPA (icosapent ethyl) Capsules, 1 gram, which FDA approved under NDA No. 202057 on July 26, 2012, is not eligible for NCE exclusivity.  Instead, FDA awarded 3-year exclusivity, as Amarin announced last Friday. 

In a nutshell, FDA’s rationale for denying NCE exclusivity is that eicosapentaenoic acid (“EPA”), “the single active moiety in Vascepa, was also an active moiety contained in another, previously approved drug, Lovaza (omega-3-acid ethyl esters) Capsules (Lovaza).”  FDA approved LOVAZA on November 10, 2004 under NDA No. 021654.  But, of course, in reality, the issue is much more . . . shall we say . . . complex than the nutshell description, because FDA needed to address NCE exclusivity in the context of naturally derived complex mixtures.  In doing so, FDA articulated a rather interesting postition, and one that FDA hinted at in a recent response (in footnote 18) to a Citizen Petition (Docket No. FDA-2013-P-0148) concerning LOVAZA.  (There, FDA stated: “A naturally derived mixture that constitutes the active ingredient of a drug product may contain more than one active moiety.”).  According to FDA’s VASCEPA Exclusivity Determination:

You urge FDA to adopt an approach in which the entire mixture is considered to constitute both the single active ingredient and the single active moiety of the drug, rather than focusing on the individual component molecules in making either determination.  This “one-to-one” relationship between active ingredient and active moiety generally exists in drugs with “simple” active ingredients that consist of a single molecule and thus can be applied’without difficulty in that context.  In addition, for some naturally derived mixtures which are so poorly characterized that it is difficult to determine with any certainty as to which molecules in the mixture are consistently present or potentially are responsible for the physiological or pharmacological activity of the drug, or where there is no precise way of identifying the molecules or ions that are consistently present and active in the mixture, identifying the entire mixture as the active moiety of the drug may be appropriate.  In such cases, each new version of such a naturally derived mixture would be eligible for 5-year NCE exclusivity; that exclusivity, however, typically would not block submission or approval of an application for any subsequent drug product that contains a similar active ingredient (exhibiting a similar lack of characterization), because FDA cannot determine whether the subsequent drug product contains the same active moiety as in the previously approved drug.

While this approach is born of necessity for some poorly characterized mixtures, nothing in the statute or regulations requires that this approach be maintained for all naturally derived mixtures.  In cases where at least part of the mixture is well characterized and some components of the mixture that are consistently present and active are identifiable or have been identified, an approach in which the mixture is identified as both the active ingredient and the active moiety appears inconsistent with the definition of active moiety as a “molecule or ion. . . responsible for the physiological or pharmacological action of the drug substance.”  The approach that is the most consistent with the relevant definitions, facts, and policies present in this case is one in which the entire mixture is the single active ingredient, but that active ingredient may contain more than one component active moiety.  This approach recognizes that there can be a “one-to-many” relationship between the active ingredient and its component active moieties.

FDA then proceeds to lay out three criteria for when the Agency will consider certain component molecules of a naturally derived complex mixture to be previously approved active moieties for the purpose of determining a subsequent drug’s eligibility for NCE exclusivity. 

(1) Characterization: The previously approved mixture has been characterized such that one or more specific molecules in the mixture have been identified;

(2) Consistent Presence: The evidence demonstrates that one or more specific molecules identified in criterion 1 are consistently present in the mixture; and

(3) Activity: The evidence demonstrates that the molecule or molecules identified in criteria 1 and 2 are responsible at least in part for the physiological or pharmacological action of the mixture, based on a finding that they make a meaningful contribution to the activity of the mixture.

“If these criteria are met,” says FDA, “the molecule or molecules would be identified as the active moiety or moieties of a naturally derived mixture. ”  And if “such a molecule is an active moiety in a subsequently approved drug, it will be considered a previousy approved active moiety” and NCE exclusivity will be denied.  Applying these criteria to VASCEPA, FDA determined that the EPA active moiety in VASCEPA is also an active moiety in LOVAZA, and the Agency denied NCE exclusivity.

Amarin alleges in its Complaint that FDA’s exclusivity decision is contrary to law:

The controlling statutes grant 5-year exclusivity to any new drug, no “active ingredient (including any ester or salt of the active ingredient)” of which has been previously approved by FDA. It is undisputed that the “active ingredient” of Lovaza is an undifferentiated fish oil mixture. That mixture is not the same as Vascepa’s active ingredient (icosapent ethyl). Nor is the mixture an ester or salt of icosapent ethyl, or vice versa. In refusing to recognize Vascepa’s 5-year statutory exclusivity, FDA has improperly substituted the words “active moiety” for the statute’s words (“active ingredient”). FDA has also concluded (in violation of the statute and regulations) that a drug with a complex mixture as its single active ingredient may have multiple active moieties, none of which is a salt or ester of the active ingredient.

Citing to several precedent approvals where FDA granted NCE exclusivity, such as with CONDYLOX (podofilox) (NDA No. 019795), QUTENZA (capsaicin) (NDA No. 022395), various lung surfactant drug products, including SURVANTA (beractant) (NDA No. 020032), INFASURF (calfactant) (NDA No. 020521) and CUROSURF (poractant alfa) (NDA No. 020744), and other approvals where FDA applied a presumption in favor of NCE exclusivity (see our previous posts here and here), Amarin alleges that FDA’s denial of NCE exclusivity for VASCEPA is arbitrary and capricious:

FDA has repeatedly recognized 5-year exclusivity for pioneer drugs in materially indistinguishable circumstances involving drug products with multiple constituents. In denying Amarin’s request for similar treatment, FDA disowned these relevant Agency precedents and failed to offer a reasonable explanation for its reverse in policy or for applying its new approach retroactively to Vascepa.

Moreover, Amarin alleges that FDA’s application of its newly announced policy to VASCEPA is without observance of procedure required by law.  “FDA must continue to apply its past policy that the active moiety of a complex mixture is the mixture itself until FDA revises that interpretation of the applicable regulations through notice-and-comment rulemaking.”

Amarin is seeking declaratory and injunctive relief and a vacatur of FDA’s denial of NCE exclusivity.  Specifically, Amaring wants a declaratory judgment that VASCEPA is protected by the FDC Act’s NCE exclusivity provisions; a declaratory judgment that FDA may not accept for filing any ANDA or 505(b)(2) NDA citing VASCEPA as a listed drug until after the expiration of NCE exclusivity; and both a preliminary and permanent injunction prohibiting FDA from accepting any ANDA or 505(b)(2) NDA for a generic version of VASCEPA until permitted under the FDC Act’s NCE exclusivity provisions.  In addition, Amarin asks the court to set aside any ANDA or 505(b)(2) NDA FDA may have already accepted for generic VASCEPA until permitted under the statute’s NCE exclusivity provisions. 

By JP Ellison –

On February 25th, the Solicitor General’s Office weighed in on whether the Supreme Court should take up a case involving False Claims Act allegations arising out of alleged off-label promotion of a drug. 

The case is Nathan v. Takeda, and the United States Court of Appeals for the Fourth Circuit ruled that the qui tam relator, Nathan a sales representative, had not pled fraud with particularity.  Nathan filed a cert. petition alleging a split among the circuits.  Specifically, Nathan claimed that the 4th, 6th, 8th, and 11th Circuits (see our post on an 11th Circuit decision here) all require allegations “that specific false claims actually were presented to the government for payment” while the 1st, 5th, 7th, and 9th Circuits  apply a more flexible standard. 

As readers of this blog know, allegations of off-label promotion by company sales representatives have resulted in eye-popping settlements, (see for example, posts here  and here.

Company sales representatives are typically quite familiar with company marketing practices, but usually have little or no knowledge regarding the submission of any actual claims for reimbursement submitted by healthcare providers so the stakes in this debate are significant.

Despite recognizing “inconsistent conclusions” from lower courts regarding “the precise manner” that a qui tam relator must follow to plead fraud with particularity, the SG’s office recommended that the court deny cert. in this case.  The government, which has racked up huge recoveries in health care fraud cases, argues that a “per se” rule—requiring details of particular false claims—is wrong, but nevertheless says that the Court should not take up this case. 

We previously posted about another case in which the SG’s office opined that the lower court decision was wrong, but that the Court should not review the case.  That case is now set for oral argument on Monday April 21st.  We’ll be watching this case closely to see whether the SG’s recommendation in Nathan v. Takeda receives similar treatment.

By John R. Fleder –

In litigation brought by or against FDA, the agency frequently seeks to avoid a “jump-ball” by arguing that FDA’s position is entitled to deference by the court.  That argument is consistently made in civil cases and has been made in some criminal cases.  A Supreme Court ruling on February 26, 2014, raises a serious question regarding whether a deference argument is available to the government in certain criminal cases.

In United States v. Apel, the Supreme Court (Chief Justice Roberts) stated that the Court has “never held that the Government’s reading of a criminal statute is entitled to any deference.”  Slip Op. at 9.

One wonders what this means in the context of the FDC Act.  Is the suggestion that the government’s position regarding the meaning of a criminal statute is not entitled to deference applicable at all to the FDC Act?   If so, is Chief Justice Roberts’s conclusion limited to criminal, rather than civil, cases decided under the FDC Act?  If Justice Roberts conclusion is applicable to the FDC Act, it would surely be applicable to FDA’s interpretation of 21 USC 333(a), 333 (b)(1), 333(c), 333(d) and 333(e).  Perhaps a court would rule that FDA’s interpretation of other provisions of the FDC Act are not entitled to deference when those other provisions are being interpreted in a criminal case.

Time will tell if criminal defendants choose to rely on Apel and whether they are successful.

By Riëtte van Laack –

The Over-the-Counter (“OTC”) drug regulatory framework was established by FDA more than 40 years ago in the OTC Drug Review.  The procedure was intended to lead to a monograph which described the active ingredients and conditions that are generally recognized as safe and effective (“GRASE”) for each of more than 60  categories of OTC drugs.  The rulemaking procedure for evaluating each category of OTC drug products involved a three part rulemaking process, including an Advanced Notice of Proposed Rulemaking (representing the recommendations of an independent advisory review panel), a Tentative Final Monograph (“TFM,” or proposed rule) and a Final Monograph (or final rule).  If an OTC drug meets the requirements detailed in a final monograph, it is GRASE and does not require approval of a new drug application or any other individual review by FDA.

In a February 24, 2014 Federal Register notice, FDA announced its opinion that the OTC Drug Review needs critical examination.  The agency indicates that it has determined that the OTC monograph system is not efficient, does not allow for rapid product innovation, and is not designed to respond quickly to newly emerging information. 

FDA identifies a number of challenges of the current system.  For example:

• A large number of products is currently marketed under TFMs (FDA claims there are more than 150 TFMs).  Under FDA’s enforcement policy, OTC drug products that were on the market at the time the review began may remain on the market pending finalization of the monograph.  This includes products for which FDA has insufficient data to determine safety and effectiveness.
• Changes to a final monograph require notice and comment rulemaking, thus limiting FDA’s ability to respond promptly to emerging safety data.  
• With some exceptions, the OTC review is limited to active ingredients in specific dosage forms that were available at the inception of the review.  Thus, this system does not easily accommodate innovative changes to OTC drug products, e.g., new combinations or new dosage forms of active ingredients.

FDA invites comments on the strengths and weaknesses of the existing OTC Drug Review and on some preliminary concepts for modernizing the process.  The agency also invites suggestions on how to develop a system that (ideally) will:

• use modern standards for safety and efficacy;
• provide an efficient and speedy mechanism for finalizing the remaining TFMs;
• allow for innovative changes to drug products;
• provide FDA with the ability to respond promptly to emerging safety or effectiveness concerns for monograph products;
• allow FDA to address pediatric use and labeling where appropriate; and
• allow FDA to obtain information about the final formulation of individual OTC drug products or establish testing standards for the final formulation.

Comments need not address all challenges of the current system.

The public hearing is scheduled for March 27 and 28, 2014.  Written comments, however, may be submitted until May 12, 2014.

By Allyson B. Mullen & Jeffrey N. Gibbs –

The end of 2013 marked the first anniversary of CDRH’s Refuse to Accept Policy for 510(k)s (the “RTA”).  FDA, Guidance for Industry and FDA Staff, Refuse to Accept Policy for 510(k)s (December 2012).  Therefore, we thought it would be a good time to reflect on how well the RTA has been working (or not working) from our perspective.  The stated intent of the RTA is modest: “to assess whether a submission is administratively complete.”  RTA at 2.  Like others in the device regulatory space, we had our reservations about the RTA when it was issued.  You may remember from our prior post, we were concerned that reviewers may need to do a substantive review of the submission in order to complete the RTA checklist (thus, making the RTA more than an administrative check of completeness).  Based on the RTA comments we have seen (and heard), it seems that our substantive-review concerns understated the issues created by this policy. 

As of September 2013, CDRH reported that approximately 60% of all newly filed 510(k)s were refused under the RTA.  CDRH Meeting FDASIA Goals, Confirms Compliance Re-Org, DEVICES & DIAGNOSTICS LETTER (FDA News, Falls Church, V.A.), Sept. 30, 2013, at 1.  According to Dr. Jeffrey Shuren, Director of CDRH, the majority of the refusals were caused by the failure to provide shelf life and biocompatibility information.  Id.  However, the RTA comments we are familiar with have not been that simple (or well founded).  To illustrate, we wanted to share, in no particular order, some of our top (or worst) RTA comments from 2013.

• In response to a 510(k) for a condom, in which the applicant supplied the required biocompatibility data, the applicant was cited in the RTA checklist for failure to specifically state whether the condom was patient contacting, and if so, for more or less than 24 hours.  It seems obvious to us that a condom, solely by virtue of its well known intended use, is patient contacting, and (we would hope) for less than 24 hours.  Even if the reviewer did not know this, the answer to the comment was, in fact, clearly stated in the submission itself.
• In response to a 510(k) in which the applicant cited its compliance to a Special Controls Guidance Document for labeling of the particular device type, the Center responded with an RTA comment asking for an explanation of how following the guidance satisfied the requirements of 21 C.F.R. § 807.87.  The guidance contained labeling requirements.  Labeling is a required element under 21 C.F.R. § 807.87.  It would seem self explanatory that by conforming the proposed device labeling to the requirements of the Special Controls Guidance Document that the applicant was complying with the labeling requirement in 21 C.F.R. § 807.87(e).  But, either it was not so obvious to the reviewer, or everything needs an explanation when it comes to the RTA.
• One set of RTA comments cited the applicant for the failure to provide “a table format with short summary/discussion clearly labeled ‘SE comparison discussion’” in the 510(k) summary.  We remember the good old days when a 510(k) summary could just contain a few sentences comparing the proposed and predicate devices in terms of intended use and technological characteristics.  Now, you had better not forget to replicate your full substantial equivalence table.  Also, this is just one example of the 510(k) summary comments that companies have been receiving during the RTA review.  In our view, 510(k) summary comments are inappropriate at the RTA stage since the 510(k) summary is a synopsis of the basis for a determination of substantial equivalence, and at the RTA stage no determination as to substantial equivalence is being made.  Moreover, summary tables tend to change during the 510(k) review process.  Furthermore, parsing the details of the 510(k) summary seems unrelated to the ability of the FDA to review the 510(k) itself – the stated purpose of the RTA.
• In response to a 510(k) for a device that is exempt from the requirement of adequate directions for use under the Act because the device’s use is commonly understood by the ordinary person, the Center noted in the RTA that although “the submission stated that the device is exempt from section 502(f)(1) of the Act (common instructions for use),” “the labeling still did NOT include a indications for use (IFU) that is IDENTICAL to the IFU; which is a requirement of the RTA-checklist” (emphasis added).  If there is a requirement for device labeling to contain an IFU statement when the device is exempt from the requirement of adequate directions for use, we would expect the Center would have referenced the CFR rather than the RTA as support for this requirement.  It is striking that the RTA guidance is now creating a “requirement,” rather than simply ensuring that 510(k)s “meet[] a minimum threshold of acceptability” to be accepted for substantive review.  
• As we have previously blogged about, in response to a software 510(k), the Center indicated that the submission could not be accepted because the applicant had not demonstrated that the proposed software complied with the Draft Guidance for the Content of Premarket Submissions for Management of Cybersecurity in Medical Devices (underlined for emphasis).  In effect, an administrative checklist is being combined with a draft, non-binding document to create substantive requirements before FDA will proceed with fulfilling its statutory obligation to review 510(k)s.
• In response to a 510(k) for a vinyl glove, the Center noted the following deficiencies in the RTA, “information regarding whether the device contains software is not provided,” and “information regarding whether the device requires EMC and Electrical Safety evaluation is not provided.”  Yes, this 510(k) was for the type of vinyl glove worn by the doctor when doing a patient exam.  Gloves do not contain software; that should be self-evident.  The RTA clearly stated that the information was not applicable, “however, the submission did not state [this].”  Once again, common sense seems to be subordinated to a checklist. 
• Lastly, one reviewer asked for the six-month shelf life rationale for a device during the RTA review.  It is a substantive question, not a procedural one.  Also, there is no reason for the question since the RTA simply asks if “proposed shelf life/expiration date [is] stated.”  The application met the “requirement.”  Asking for a rationale went beyond the checklist.  The shelf life was stated and the reviewer should have moved on.

We have also heard of the Center citing typos and misprints in RTAs.  For example, in response to one 510(k), FDA cited the applicant for having two page 75s (rather than a page 75 and a page 76).  In another instance, an applicant received an RTA comment stating that although the applicant cited the correct classification regulation for the proposed device, the wrong classification name was provided.  It turned out that the applicant used the device name from the product code rather than the name from the classification regulation.  In the comment, FDA told the applicant the correct classification name (would it not have been easier for FDA to simply note that themselves as they reviewed?).

Last September, Director Shuren said that the intent of the RTA was to return “low quality submissions” thereby “reducing inefficiencies caused by the need to review poorly or incomplete applications.”  CDRH Meeting FDASIA Goals, Confirms Compliance Re-Org at 1.  Based on the examples we have seen, we question whether the 60% of rejected submissions are really “low quality,” or, if the Center is being overly picky (and in some instances failing to use common sense), and consequently, has created a process that actually further delays the overall review time for 510(k)s rather than improving it.  In a recent discussion with Karen Becker of Precision for Medicine, she told us that on average it is taking her clients approximately four weeks to respond to the RTA comments.  This length is due to a number of factors, for example sometimes they have discussed the comments with the reviewers to ensure that all questions are being addressed completely so that there is only one RTA, rather than multiple rounds.  

Since we know we are only seeing a fraction of the RTA comments, we are inviting you, our readers, to share your RTA experiences and comments.  We are opening up our comments section to allow you to include, in the comments below, examples of problematic RTAs. 

One final note: CDRH’s final Pre-Submission Guidance also contains a checklist (blog post is forthcoming).  Thus, Pre-sub’s can now be rejected for administrative reasons.  We certainly hope that CDRH does not convert the pre-sub checklist into yet another potential trap for companies.