By Jeffrey K. Shapiro –

FDA has issued a new draft guidance on the custom device exemption.  Comments are due by March 17, 2014.  This schedule puts FDA on track to finalize the guidance by July 9, 2014, as required under section 617 of the Food and Drug Administration Safety and Innovation Act (“FDASIA”) (Pub. L. 112-144).  (See our FDASIA summary here at pages 41-42.)

What is the custom device exemption?  It is a long standing provision in Section 520(b) of the Federal Food, Drug, and Cosmetic Act (“FDCA”) that allows device manufacturers to distribute devices designed to accommodate unique  patient conditions without premarket application (“PMA”) approval under Section 515 of the FDCA.  The exemption does not relieve the manufacturer of the usual post market regulatory requirements that apply to medical devices.

Congress revamped the custom device exemption in FDASIA.  Some of the changes were more clarifying than substantive, but a few new concepts were added.  Those who need to consider the applicability of a custom device exemption should review the amended statute and draft guidance and ignore the existing regulation (21 C.F.R. § 812.3(b)), which has not been updated. 

The following is a paraphrase of the custom device requirements in the revised statute.  For a device to qualify, all of these requirements must be met:

• It is created or modified to comply with the order of a physician or dentist.
• In order to comply, the device necessarily deviates from an otherwise applicable premarket approval requirement in Section 515 of the FDCA.
• It is not generally available in finished form through labeling or advertising for commercial distribution in the U.S.
• It is designed to treat a unique pathology or physiological condition that no domestically available device can treat.
• It is intended to meet the needs of a physician or dentist in treating a patient, or will be used by the patient on order of the physician or dentist.
• It is assembled by components or manufactured and finished on a case by case basis to accommodate the unique needs of the physician/dentist or patient.
• It may have common standardized design characteristics, material and chemical composition, and manufacturing processes as commercially distributed devices.

If a device meets these requirements it may be distributed as a custom device, with three further limitations:

• The condition being treated must be sufficiently rare that a clinical study is impractical.  (This limitations codifies an interpretation that FDA has long applied.)
• Multiple units of the device may qualify for the exemption, but no more than five units per year.
• The manufacturer must annually notify FDA if it is producing custom devices.

FDA’s guidance does a good job of explaining how the agency will enforce these requirements.  We will not reiterate the entire guidance here, since it is largely self explanatory.  The flow chart on page 19 of the draft guidance is especially useful. 

A few points are worth highlighting:

• FDA interprets the five unit per year limitation to exclude extra devices provided in different sizes if the unused devices are returned.  Also, multiple devices for multiple anatomical locations (e.g., bilateral hip replacements) will count as one unit if used in the same reporting year.  [Draft Guidance, lines 229 264.]
• FDA explains that the a device is either patient-centric or physician/dentist centric.  The distinction is between a device that treats a rare patient need and leaves the practice with the patient versus a device that fulfills a special need in the physician/dentist practice that stays with the practice.  [Draft Guidance, lines 279 285.]  It is left unexplained what types of devices might fulfill a physician/dentist special practice need.  It would have been helpful if examples had been provided; all of the examples appear to relate to patient needs.
• FDA reiterates its long standing interpretation precluding “patient specific” or “patient matched” devices from qualifying for the custom device exemption.  These are devices “in which ranges of different specifications have been approved or cleared to treat patient populations that can be studied clinically. . . .  The final manufacturing of these devices can be delayed until the physician provides imaging data or other information . . . to finalize the specifications of the device within . . . cleared or approved ranges. As a result, the device is specifically tailored for the patient.”  [Draft Guidance, lines 329 343.]  Thus, contact lenses or customizable orthopedic implants would typically not qualify for the custom device exemption. 

A final stylistic point: the draft guidance continues FDA’s increasing practice of providing guidance through lengthy question and answer sections.  This practice is somewhat helpful in ensuring that specific questions are answered.  But the use of lengthy questions in headings and subheadings makes it more difficult to find information, not less so.  FDA should revert to using key word topic headings and subheadings; these are a tried and true way of showing the reader where information may be found.

By Anne K. Walsh –

While the mid-Atlantic region was paralyzed under 4 to 8 inches of snow, it was business as usual for the Tenth Circuit Court of Appeals in Colorado.  On January 21, 2014, the court issued an opinion affirming the felony conviction of John Schulte, former CEO of The Spectranetics Corporation, for making a false statement to the government.  

The woes of the company date back to 2008, when a former employee alleged that it was marketing unapproved devices brought into the country illegally.  The company’s Board of Directors ordered an internal investigation, but the investigation did not result in any finding of wrongdoing.  Later that year, the government learned of the same allegations brought to the Board, and quickly executed a search warrant.  It was during this search that Schulte voluntarily agreed to provide an interview to federal law enforcement agents.  The statements he made during that interview five and a half years ago continue to haunt him today.

As readers may recall (see our previous post here), the company entered into a settlement with the government in 2009 in which it agreed to pay a $5 million civil penalty.  The government decided not to criminally prosecute the company, and instead allowed the company to enter into a non-prosecution agreement that required cooperation in the government’s ongoing criminal investigation of certain individuals, including Schulte. 

In 2010, the government indicted Schulte on twelve separate counts, but after a four-week jury trial in 2012, a jury acquitted him of all but one of those counts: making false statements under 18 U.S.C. § 1001.  The court’s sentence was lenient, requiring only one year of probation, a $5000 fine, and 100 hours of community service.  (The court rejected the government’s sentencing request for two years of prison and three years of probation.)  

Schulte appealed this conviction on the grounds that the statements were not false, that the government failed to prove the necessary intent to give false information, and that the statements were not material to the government’s investigation.  The Tenth Circuit addressed these legal issues in turn, the details of which can be reviewed in the opinion.  The court ultimately concluded that there was no fundamental ambiguity about the questions to which Schulte responded, and that there was sufficient evidence provided at trial that the statements Schulte made were false.

The moral of the story is that company employees should be aware of the impact of any communications with the government, whether in the context of a search warrant or a routine site inspection.  In the case against Schulte, the law enforcement agent was in possession of very detailed information, as evidenced by the 48-page affidavit that the agent had prepared to support the search warrant.  In contrast, Schulte agreed to speak off-the-cuff, without having the benefit of reviewing information to refresh his recollection.  The government rejected Schulte’s three attempts to recant or correct those statements after Schulte’s counsel reviewed documents after the interview.  It is possible the government was more aggressive against Schulte because it was “offended” that Schulte had lied, which may have been avoided had Schulte been better prepared in advance of the interview.

Company employees should be advised on the importance of candor, and should be well-prepared before talking with the government about any substantive matters.  With or without counsel present, all company employees speaking to the government on any topic should avoid the temptation to answer all questions posed by the government.  Generally, a company employee has no legal obligation to answer any question unless subpoenaed or ordered by a court.  Thus, before answering any question, the employee should be certain that the answer being provided is correct.  If there is any doubt, the employee has the right to inform the government that she will need to do further checking before answering the question.  Although an employee might want to be “helpful” to FDA, or to her corporate employer, an employee can be (and has been) criminally prosecuted if the information turns out to be untrue, despite good intentions.

Also, with the benefit of hindsight, it is clear that the result of this case would be profoundly different had Schulte not voluntarily spoken with the government.  Recall that the underlying focus of the investigation related to allegations that the company and its employees marketed unapproved devices in violation of the Federal Food, Drug, and Cosmetic Act (FDCA).  Yet, the company settled the matter with a non-prosecution agreement, likely motivated by the government’s acknowledgement that the evidence supporting an FDCA violation was weak.  Schulte was acquitted of eleven of the twelve charges the government brought against him, the majority of which related to counts under the FDCA.  With respect to the other indicted individuals, the government dropped all charges against one, the one who proceeded to trial with Schulte was acquitted of all charges, and the last individual pled guilty to a single count of concealing a felony in exchange for probation.  Thus, the only two criminal charges that resulted from the government’s intense prosecution and trial did not even relate to the FDCA. 

It also bears mention that the jury rejected the government’s theory that Schulte and others were liable under the Responsible Corporate Officer doctrine, a topic which we are following closely (see our previous post here).

By Kurt R. Karst – 

In a Januarry 22, 2014 letter to FDA Commissioner Margaret Hamburg, M.D. signed by 28 members of Congress, lawmakers express “grave concerns” about FDA’s November 2013 proposed rule 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.  As we previously reported, the proposal is quite clearly intended to undercut generic drug labeling preemption arguments and was made in response to various U.S. Supreme Court rulings, and in particular the Court’s ruling in PLIVA, Inc. v. Mensing, 131 S. Ct. 2567 (2011).

“We strongly believe that such a rule would conflict directly with the statute, thwart the law’s purposes and objectives, and impose significant costs on the drug industry and healthcare consumers,” write the lawmakers, who request that FDA “explain and reconsider this departure from decades of settled practice.”  House Energy and Commerce Committee Chairman Fred Upton (R-MI) reiterated this message in a press release announcing the letter to FDA.  (A similar press release was issued by Senator Lamar Alexander (R-TN), the senior Republican on the Senate health committee.) The letter goes on to note that a bedrock principle of generic drug approval has been the same labeling requirement, which FDA has adhered to for decades and that “Congress has also embraced . . . , as we have declined to change it in every food and drug law we have passed since 1992.” 

But even putting the same labeling requirement to one side for a moment, the lawmakers say that FDA’s proposal threatens to undermine the purpose of the Hatch-Waxman Amendments:

Allowing generic manufacturers to unilaterally change their labeling means potentially dozens of drugs that are chemically and biologically identical might nonetheless bear different safety information, confusing patients and prescribers alike.  The labeling on the generic products should be ide tical to the labeling on the branded product so providers and patients are comfortable with the risks and benefits of the product they are using regardless of the name of the company on the bottle or vial.

In a move that is likely to provide much fodder for comment on FDA’s proposal (as well as in any litigation that might ultimately result if FDA finalizes the proposal), the lawmakers ask that FDA respons to a series of questions by Febryary 5, 2014:

1. For the period of time after a generic drug has submitted a CBE-0 supplement, please explain how the generic drug’s label will be “the same as the labeling approved for the requirements included in sections 505(j)(2)(A)(i)-(v) of the Hatch-Waxman Act extend beyond the date of approval?

2.  Please explain the benefit of having proposed label changes published on a public website before FDA consideration, undermining FDA’s current role as the gatekeeper and deciding authority for changes to a drug’s label.

3.  Please provide the names of any executive branch employees outside the FDA who were involved in the decision to proceed with this proposed rule or who participated in drafting or reviewing it.

4.  What is FDA’s policy on when an adverse event needs to be listed on the label?  Are there standards around the prevalence or severity of the adverse event that are necessary before it rises to a labeling change?

5.  What is the expected cost to the FDA to review the CBE-0 submissions in a timely manner and establ sh and update the website, and from where does the FDA propose drawing resources to meet these costs?  How will the agency prioritize submissions and what is the estimated time or review?

6.  Please describe in detail how FDA arrived at the estimated cost orthe rule of $4,237 to $25,852 per year and estimates it will receive 20 CBE-0 supplements annually from approximately 15 ANDA holders.  Please explain how the agency derived these estimates.  Did FDA conduct any analysis of how long it takes a manuhlcturcr to prepare a CBE supplement and how much it costs?  Did FDA conduct any analysis of what it will cost manufacturers to institute new procedures for monitoring safety and enectivencss of drugs?  Did FDA conduct any analysis of the effect the proposed rule will have on drug prices?  Please provide all documents and communications regarding the cost-benefit analysis.

7. Generic drug manufacturers can currently propose labeling changes with FDA as a result of newly acquired safety information.  Please provide statistics for how many times this is done in comparison to brand name manufacturers and the current causes of any delay when using that process.  Please provide any evidence that would indicate generic drug manufacturers are not submitting required adverse event reports or otherwise not meeting their post-market surveillance requirements[.]

8.  The proposed rule notes a 2010 study of FDA safety-relatcd drug labeling changes that found the me ian time from initial approval of the drug product to label change was 11 years.  Please provide this study and all support ing documentation to the Committee(s).  Please also provide statistics showing how long it takes FDA to make a decision once a label change is suggested.

9.  Please explain why the prior approval supplement process alone cannot be used effectively to change generic and brand drug labels, and the current causes of any delay when using that process.  Please provide any evidence that would indicate generic drug manufacturers are not updating their label upon FDA approval of a change to the label of the reference brand drug.

10.  As an alternative approach, did the FDA consider permitting generic drug manufacturers to use a modified CBE process by which the agency has an opportunity to assess a proposed labeling change before introducing it into the market?  What does the agency believe would be the pros and cons of using this approach as opposed to the CBE-0?  Did the agency conduct a cost benefit analysis of such an approach?

11.  Did the agency consider the impact the proposed rule would have on over-the-counter (OTC) drugs?  If so, please submit any such analysis and explain how FDA envisions the proposed regulation applying to OTC drugs.

The letter closes on a strong note expressing the lawmakers’ disdain of the FDA proposal and the process undertaken by the Agency to move forward with a “solution” to the “problem” resulting from the U.S. Supreme Court’s ruling:

A number of processes already exist through which generic drug manufacturers can share new safety information and propose a label change to FDA without disrupting the market.  If the agency believes those methods are inadequate, it cannot simply ignore written statute.  FDA has an obligation to share those concerns with Congress and work together on a legislative solution.

Indeed, that’s exactly what the last line of the Court’s decision in PLIVA said: “Congress and the FDA retain the authority to change the law and regulations if they so desire” (emphasis added).

By Kurt R. Karst – 

In a notice that will appear in the Federal Register later this week, FDA is announcing the establishment of a public docket (Docket No. FDA-2014-N-0032) to receive input and suggestions on ways to improve the quality of ANDAs (original, amendments, and supplements) submitted to the Agency’s Office of Generic Drugs (“OGD”) and on how to best communicate those suggestions to the generic drug industry.  Specifically, FDA is seeking comment “about any difficulties sponsors are having developing and preparing their ANDA submissions that FDA could help address, for example by providing more or better information to industry.”  The notice is the latest move by FDA as OGD transitions into “Super Office” status (see our previous post here) and as the Agency ramps up and braces for Generic Drug User Fee Amendment (“GDUFA”) review and performance metrics beginning in Fiscal Year 2015.  While FDA states in the notice that “[m]ore complete, higher quality ANDA submissions will positively affect the availability of low-cost, high-quality generic drugs to the public,” on a more selfish note, higher quality ANDA submissions may also go a long way to help OGD meet the performance goals agreed to with industry back in 2012 and to avoid multiple review cycles.

Afer providing several examples of common, recurring deficiencies in ANDA submissions (e.g., hot spot problems such as “[s]ignificant flaws in the design of a drug product such that the proposed product will not be able to meet all conditions of use of the reference listed drug”), FDA encourages comment on four questions:

1. What aspects of the ANDA application process are confusing or not well defined?

2. What problems do ANDA applicants encounter when developing a submission that FDA could help address?

3. Prior to GDUFA, were ANDA submissions consistently slowed or stalled at certain recurring review points post-filing?  If so, why?

4. How should FDA share suggestions for improving ANDA submissions with industry, beyond issuing regulatory guidance?

Although FDA’s request may well garner some comments griping about recent changes in the ANDA review process, it seems to be a positive move by the Agency to improve the yield on ANDA approval actions.  And it may just be the tip of the iceburg. . . . we’ve heard rumors that other deliverables are on tap for publication later this year, including a Manual of Policies & Procedures on ANDA prioritization, guidance on the complex amendment tiers described in the GDUFA goals document,  and guidance on Controlled Correspondence (which is also the subject of GDUFA performance metrics).

By Wes Siegner –

On September 18, we alerted food researchers that FDA had added new language to a final IND guidance that would require FDA approval of an investigational new drug application (IND) for many food studies now conducted without the burden of filing an IND, and for most, if not all, clinical studies intended to support the benefits of any medical food.  Our September 18 blogpost warned that a new section that FDA had added, without any advance notice, to the final guidance had the potential to severely restrict the growing field of research into the positive health effects of a variety of food and food ingredients.

The negative effects of FDA’s growing tendency to regulate food research under the onerous drug regime by requiring INDs was a key topic that was addressed by an NIH-funded University of Maryland study conducted from 2010 to 2012.  The University of Maryland convened a multidisciplinary Working Group, of which I was a member, to make recommendations for more efficient regulation of the promising area of probiotics.  The journal Science published the final White Paper produced from this study in October 2013 (see here).  "Probiotics: Finding the Right Regulatory Balance," Science 18 October 2013: Vol. 342 no. 6156 pp. 314-315. Clinical researchers who participated in this study related experiences where FDA as a matter of routine required costly and lengthy safety studies in human subjects under INDs for probiotics, even where that probiotic had been consumed safely for decades or even centuries.  One of the many important conclusions that the Probiotics Working Group reached was a simple and elegant solution to the IND dilemma that FDA’s final IND guidance illustrates – “If proposed research is to investigate non-drug claims for a food or dietary supplement, an IND should not be required even if the researchers use a disease endpoint.”  Working Group White Paper, page 31 (Recommendations).  This solution appropriately focuses on the final intended use of the product and avoids needless regulatory interference with the study of safe food products and ingredients.

FDA has now granted researchers and others an important potential reprieve by reopening the comment period to the final guidance.  The new comment period, applicable to research on both food and cosmetic products, is 60 days from publication in the Federal Register.  Although comment periods for guidance are flexible, it is recommended that comments be submitted within the allotted 60 days to maximize the chance that they will be factored into any decision to revise the guidance.  It is important that any researchers, Universities, or businesses planning to conduct clinical studies in the future into the health benefits of foods and food ingredients push FDA to revise the final guidance to avoid an IND requirement for studies that are intended to support claims for foods, including medical foods, foods for special dietary use, and dietary supplements.

By Riëtte van Laack –

On January 13, FDA announced the availability of two guidances concerning beverages and liquid dietary supplements: “Distinguishing Liquid Dietary Supplements from Beverages” and “Considerations Regarding Substances Added to Foods, Including Beverages and Dietary Supplements.”  Both guidances are derived from FDA’s 2009 draft guidance “Factors that Distinguish Liquid Dietary Supplements From Beverages, Considerations Regarding Novel Ingredients, and Labeling for Beverages and Other Conventional Foods.” 

Compared to the 2009 draft guidance, the final guidance “Distinguishing Liquid Dietary Supplements from Beverages” provides considerably more information, including specific examples, on the factors FDA considers when determining whether the product is a conventional food or a dietary supplement.  As mentioned in the draft guidance, FDA considers labeling and advertising, product name, product packaging, serving size and recommended daily intake, directions for use, marketing practices and composition.  Where the draft guidance merely listed these factors, the final guidance discusses each factor and provides specific examples. 

Although these examples are helpful, they do not always provide insight into FDA’s reasoning, and some of the distinctions do not appear logical.  For example, the Agency does not explain how it decided that the terms iced tea and coffee “generally would be considered to represent a liquid product as a conventional food,” whereas the use of the term tea is not “associated exclusively” with a conventional food.  Another point of confusion is FDA’s assertion that it strains “common sense to interpret DSHEA as authorizing the creation of a dietary supplement whenever any dietary ingredient is added to any conventional food.”  However, FDA does not appear to have a problem with the marketing of that dietary ingredient as a dietary supplement to be added to a “liquid delivery system,” provided that they are not represented as an alternative to beverages or for beverage use.  

Although in most circumstances a combination of factors will determine whether the product is represented as a conventional food, FDA appears to take the position that use of the term “refresh” or “rehydrate” foreclose dietary supplement status because such statements represent the product for use as a beverage, taste, refreshment, and thirst-quenching ability.  Also, product names that use conventional food terms such as “beverage,” “drink,” “water,” or “soda” cause the product to be a conventional food.

Of course, the guidance includes the boilerplate language that guidance and does not establish “legally enforceable responsibilities.”  Nonetheless, FDA can be expected to refer to this guidance in warning letters and other “enforcement actions.”  Manufacturers and distributors of liquid dietary supplements would be well advised to review the final guidance and consider possible repercussions for their business.

The guidance concerning distinction between beverages and liquid dietary supplements still includes a relatively short section related to the regulatory requirements for ingredients for beverages and dietary supplements.  However, to highlight this issue and “improve accessibility” FDA issued a separate guidance on this subject.  According to the Federal Register notice, this guidance is intended to remind manufacturers and distributors of conventional foods and dietary supplements about the requirements for substances added to conventional foods and non-dietary ingredients (e.g., excipients) added to dietary supplements.  This guidance does not contain anything new and merely summarizes long-established requirements and regulations.

By Jeffrey N. Wasserstein & Delia A. Stubbs –

For years, those of us who followed FDA’s attempt to provide guidance related to social media felt like Vladimir and Estragon from Samuel Beckett’s Waiting for Godot.  FDA initially promised guidance by the end of 2010.  But, like Godot, the guidance never came.  On January 13, after years of anticipation by industry, Godot finally made a cameo appearance as FDA issued a draft guidance titled, “Fulfilling Regulatory Requirements for Postmarketing Submission of Interactive Promotional Media for Prescription Human and Animal Drugs and Biologics.”  Unfortunately, much as Vivian Mercier described Waiting for Godot as “a play in which nothing happens, twice,” FDA’s guidance dances around the issues that industry has been asking and focuses primarily on process rather than substance.  Specifically, FDA addressed how and when a company is required to submit promotional materials that appear on social media platforms to FDA. 

Enforcement and Scope 

Generally, companies are required to submit promotional materials to FDA at the time of initial dissemination.  Promotional labeling relating to prescription drugs for humans are submitted on Form FD-2253.  FDA recognized that compliance with postmarketing submission requirements poses unique difficulty for “real time” communications (e.g., blog posts, comments on a website, and twitter feeds), namely, the requirement that the firm submit specimens of promotional material “at the time of initial dissemination.”  Guidance at 2.  FDA, thus, stated its intent to exercise enforcement discretion “due to the high volume of information that may be posted within short period of time” if the firm “submits interactive promotional media in the manner described in the guidance.”  Id. at 2.

The draft guidance applies to human prescription drugs, prescription and OTC veterinary drugs, and FDA-approved biologics, but does not apply to veterinary biological products regulated under the Virus-Serum Toxic Act.  Id. at 1, n. 3.  Nevertheless, as FDA’s draft guidance briefly touches on when a firm may be responsible for the content of certain social media, which may have enforcement ramifications regarding provisions of the FDCA act unrelated to submissions (e.g., off-label promotion), medical device companies likely should also pay close attention to the draft guidance. 

Influence and Control: What Qualifies

FDA stated that “in determining whether a company is “accountable” for a promotion, it will look to whether the firm or anyone on its behalf “is influencing or controlling” the product promotion or communication.  Guidance at 2.  FDA clarified that “[a] firm is responsible for product promotional communications on sites that are owned, controlled, created influenced or operated by, or on behalf of the firm.” Id. at 3.  Control, according to the Guidance, is more than mere ownership. “[I]f the firm collaborates on or has editorial, preview or review privilege over the content provided then it is responsible for that content.”  Id. at 3, 4.  Moreover, “[a] firm is responsible for promotion on a third-party site if the firm has any control or influence on the third-party site, even if that influence is limited in scope.”  Id. at 4 (emphasis added).  By way of example, FDA stated “when a firm provides on its product website an online forum that gives users the opportunity to post comments about the use of its product . . . the firm is responsible for submitting to FDA the product website.”  Id. at 3-4.  Also, “if [a] firm make suggestions on the placement of its promotional messages on an independent third-party site, the firm is responsible for submitting to FDA the promotion along with the surrounding pages to FDA.”  Id. at 4.  However, “[i]f a firm that provides mere financial support (e.g., through an unrestricted educational grant) and has no other control or influence . . . it is not responsible for the content on that site.”  Id. at 4.  Likewise, “[i]f a firm is merely providing promotional materials to a third-party site, but has no control over placement of those materials within the site” and no other control of the site, the firm is responsible only for and required to submit the content that it passed on to the site.  Id. at 4. 

This is a fairly expansive view of control.  While one might agree that having input or editorial rights over the material provides some level of control, it is hard to see how having preview or review privileges, without the concomitant right to alter the content, equals control.  If a Web-based publisher of medical content agrees to give a prescription drug advertiser preview rights without allowing them to alter the content, it seems a mere courtesy rather than a degree of control.

Also, FDA stated that a firm is responsible for content “generated by its employees or any agents acting on behalf of the firm who promote the firm’s product.”  Id. at 4.  Thus, “if an employee or agent of a firm, such as a medical science liaison or paid speaker (e.g., a key opinion leader) acting on the firm’s behalf, comments on a third-party site about the firm’s product, the firm is responsible for the content its employee or agent provides.”  Id. at 4.  Also, a “firm is responsible for the content on a blogger’s site if the blogger is acting on behalf of the firm.”  Id. at 4.  Likewise, a firm is responsible for and required to submit a “comment made by a sales representative on an independent third-party site about a product’s release mechanism” and “a blog to FDA that is maintained by the firm’s representative and about the firm’s product.”  Id. at 5.

FDA also addressed sock puppetry, although it did not use that term (it would have amused us if it had).  Sock puppetry is online deception, where one pretends to be someone one is not, generally in order to praise the actual person or to anonymously disparage another.  FDA recommends that a regulated company clearly disclose its involvement on social media sites through the use of the company’s name or logo as part of the communication or site.  Employees or third parties acting on behalf of the company should likewise identify their affiliation with the company.

Perhaps to assuage concern about broad-based liability, FDA comforted (we use that term lightly) that “a firm is generally not responsible for user-generated content (“UGC”) that is truly independent of the firm (i.e., is not produced by, or on behalf of, or promoted by the firm in any particular).  Id. at 5.  It specified that it “will not ordinarily view [UGC] on firm-owned or firm-controlled venues such as blogs, message boards, and chat rooms as promotional content on behalf of the firm as long as the user has no affiliation with the firm and the firm had no influence on the UGC.”  Id. at 5. While informative, to some limited extent, this does not address the issue of whether a regulated company would need to correct misinformation or off label discussions placed on site or platform controlled by the company.  Like our friends Vladimir and Estragon, we’ll have to keep waiting for that issue to be addressed.

What Do Firms Have to Submit and How

In general, FDA’s draft guidance requires firms to submit “at the time of initial display” the “entirety of sites for which it is responsible” including interactive and real-time components contained therein.  Id. at 6.  FDA’s draft guidance suggests that it is referring here, to sites over which it has review authority or other dominion or control, as discussed above.  See id.  With respect to UGC, FDA stated its preference that firms “allow FDA to view and interact with the submission in the same way as the end user” through the use of such tools as “working links” but, in the alternative, indicated it will accept screenshots.  Id. at 6.  Likewise, for third-party sites, “where the firm’s participation is limited to user-generated content, a firm should submit the home page, the interactive page, and the firm’s first communication, at time of initial display.”  Id. at 6.

FDA will then permit a firm to update its submission monthly via the provision of list of relevant sites or screenshots of relevant content, depending on whether the site is unrestricted (in other words, whether FDA has access to it).  Id. at 6.  For unrestricted sites, FDA will permit a firm to submit an updated listing of the sites in which it remains an active participant.  Id. at 7.  No screenshots of content are required.  Id. at 6.  For restricted sites, however, FDA clarified “screenshots or other visual representations of the site should be submitted monthly.”  Id. at 7.  Otherwise, for submissions related to restricted sites, FDA clarified “[f]irms should submit all content related to the discussion (e.g., all UGC about the topic) which may or may not include independent UGC.”  Id. at 7.

Written comments on the draft guidance may be submitted within 90 days.

By Kurt R. Karst –      

It’s been quite some time since FDA established a public docket soliciting comment on an ANDA approval/Hatch-Waxman issue.  But FDA revived the process earlier this week when the Agency issued a “Dear NDA/ANDA Applicant” letter (Docket No. FDA-2014-N-0087) concerning approval of generic versions of Hospira, Inc.’s (“Hospira’s”) PRECEDEX (dexmedetomidine HCl) Injection, 100 mcg (base)/mL packaged in 200 mcg(base)/2 mL single-dose vials, which FDA approved on December 17, 1999 under NDA No. 021038. 

PRECEDEX is currently approved in three strengths and for two indications: (1) sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting; and (2) sedation of non-intubated patients prior to and/or during surgical and other procedures.  FDA’s Orange Book currently lists two patents for the 100 mcg (base)/mL packaged in 200 mcg(base)/2 mL single-dose vials strength at issue: (1) U.S. Patent No. 4,910,214 (“the ‘214 patent”), which expired on July 15, 2013, but was subject to a period of pediatric exclusivity that expired earlier this week on January 15, 2014; and (2) U.S. Patent No. 6,716,867 (“the ‘867 patent”), which expires on March 31, 2019, but is subject to a period of pediatric exclusivity that expires on October 1, 2019.  The ‘214 patent is listed in the Orange Book as a drug product (formulation), drug substance (active ingredient), and method-of-use patent.  The ‘867 patent is listed in the Orange Book as a method-of-use patent with a “U-1472” patent use code, which is defined in an Orange Book addendum as: “INTENSIVE CARE UNIT SEDATION, INCLUDING SEDATION OF NON-INTUBATED PATIENTS PRIOR TO AND/OR DURING SURGICAL AND OTHER PROCEDURES.” 

The PRECEDEX Orange Book patent listings were not always as they appear today.  Information on another patent – U.S. Patent No. 5,344,840 (“the ‘840 patent”) – was listed for the drug in November 2008.  The ‘840 patent, which expired on September 6, 2011 (and well before FDA’s March 12, 2013 grant of pediatric exclusivity), was listed as a method-of-use patent with a “U-912” patent use code, which is defined as: “SEDATION OF NON-INTUBATED PATIENTS PRIOR TO AND/OR DURING SURGICAL AND OTHER PROCEDURES.”  In addition, the ‘867 patent was, until earlier this month, listed with a “U-572” patent use code defined as “INTENSIVE CARE UNIT SEDATION.”  That’s right . . . . there was a change to the patent use code for the ‘867 patent.  And that change may be the reason why FDA did not approve any ANDAs on January 15, 2014 for generic PRECEDEX when pediatric exclusivity applicable to the ‘214 patent expired and that contain a “section viii” statement to omit (i.e., “carve out”) from proposed labeling information protected by the ‘867 patent.

We’ve seen patent use code changes before.  Indeed, in Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S, 132 S. Ct. 1670 (2012), the U.S. Supreme Court considered a use code change in the context of PRANDIN (repaglinide) Tablets and ruled that “[a] generic manufacturer may employ the counterclaim provision [of the FDC Act] to force correction of a use code that inaccurately describes the brand’s patent as covering a particular method of using a drug” (see our previous post here).  But the FDC Act’s counterclaim provision is not at issue in the case of PRECEDEX.  In fact, that provision (at FDC Act §505(j)(5)(C)(ii)(I) for ANDAs and at FDC Act § 505(c)(3)(D)(ii)(I) for 505(b)(2) applications) is inapplicable in the case of a “section viii” carve-out, because the statute requires “a patent infringement action against the [ANDA] applicant.” 

Given the unique situation relative to generic PRECEDEX, FDA is seeking comment on three sets of questions.  FDA’s questions raise some pretty interesting issues, including whether an ANDA “carve-in” is permissible, and whether a patent use code change can be considered late-listed.  Specifically, FDA is soliciting comment on the following questions:

1.  Does the breadth of the new use code description for the ‘867 patent foreclose ANDA applicants from gaining approval for any of the approved indications (or for any subset of those indications) before the ‘867 patent expires?  For example, would it be permissible as a scientific, regulatory, and legal matter for an ANDA applicant to submit a statement under 21 U.S.C. §355(j)(2)(A)(viii) and a corresponding carve out that results in an approval for a subset of the second approved indication, i.e., an approval explicitly limited to procedures outside of an intensive care setting?  In this context, is it acceptable to add new words to the approved indication to limit the indication to exclude only that portion of the indication that is covered by the use code (i.e., to exclude sedation of non-intubated patients in the ICU setting only)?  If you believe a carve out of this type is permissible, if you wish, you may submit a side by side of the indication section of the labeling for dexmedetomidine hydrochloride injection showing the carve out that you believe would be acceptable.

2.  Whether the fact that Hospira changed the use code information outside of the 30-day window after the patent issued means that the use code change is late listed as to any ANDAs pending with a section viii statement at the time the use code was changed?  See 21 C.F.R. § 314.53(c), (d).  If so, would any ANDA with an existing section viii statement be entitled to retain that statement (and corresponding carve out) under 21 C.F.R. § 314.94(a)(12)(vi), notwithstanding the change in use code?

3.  What relevance, if any, to a determination of whether the use code change was timely submitted is the fact that Hospira previously listed the ‘840 patent with very similar use code information to that now listed for the ‘867 patent, and did not change the use code for the ‘867 patent until after the ‘840 patent expired?  

Initial comments are due to FDA by the close of business on January 24, 2014.  Commenters submitting in the initial comment period may respond to comments from other commenters, and must submit those responses to FDA by the close of business on January 31, 2014. 

It is unclear how long after January 31, 2014 it will take FDA to make a decision and issue a letter decision.  If history is any indication of future events, then FDA’s decision on the questions raised in the Agency’s solicitation and FDA’s decision on pending ANDAs may end up in court in the not too distant future. 

By Kurt R. Karst –      

FDA’s Office of Orphan Products Development (“OOPD”) recently revised its Standard Operating Procedures and Policies (“SOPP”) concerning review of orphan drug designation requests to provide the Office’s policies on designating products for two diseases: scleroderma and pulmonary hypertension.  The second version of the SOPP (available here) updates the first version of the document from November 2010 (see our previous post here), and is the first update since FDA issued issued a final rule on June 12, 2013 amending the Agency’s 1992 orphan drug regulations (see our previous post here).

As we previously reported, the SOPP is used by FDA’s OOPD for the review of orphan drug designation requests and provides some interesting (and useful) insight into the Office’s policies.  The appendicies to the SOPP are particularly useful.  Several of the appendicies describe OOPD policy on general issues such as “Scientific Rationale Supporting a Request for Orphan Drug Designation” (Appendix B), “Medically Plausible or Orphan Subsets Supporting a Request for Orphan Drug Designation” (Appendix C), and “Recombinant Products and Orphan Drug Designation” (Appendix E).  The 2010 version of the SOPP included a single disease-specific appendix: “Lymphoma as the Subject of a Request for Orphan Drug Designation” (Appendix D). 

The second version of the SOPP adds two disease-specific appendicies: “Scleroderma as the Subject of a Request for Orphan Drug Designation” (Appendix F), and “Pulmonary Hypertension as the Subject of a Request for Orphan Drug Designation” (Appendix G).  Both diseases have been the subject of dozens of orphan drug designation requests submitted to OOPD (at least 18 for scleroderma and 36 for pulmonary hypertension) and  several designations, according to OOPD’s Orphan Drug Designations and Approvals Database.  Interestingly, both additions to OOPD’s SOPP point to the European Medicines Agency’s (“EMA’s”) orphan drug designation policies (see here) as supportive of OOPD’s decisions.  This might signal greater cooperation between FDA and EMA on orphan drug issues and an effort to have consistent views on rare diseases.

Scleroderma as the Subject of a Request for Orphan Drug Designation.  According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases, although scleroderma “is often referred to as if it were a single disease, scleroderma is really a symptom of a group of diseases that involve the abnormal growth of connective tissue, which supports the skin and internal organs.”  This group of diseases falls into two main classes: localized scleroderma and systemic sclerosis.  Systemic sclerosis has two main types: limited disease and diffuse disease. 

OOPD states in the SOPP that prior to 2009, the Office “designated products for the treatment of systemic sclerosis because the combined prevalence for both localized and systemic sclerosis was under 200,000.”  In 2009, however, the National Institutes of Health noted that the U.S. prevalence of scleroderma was 300,000, and thus over the 200,000 person prevalence threshold for orphan drug designation purposes.  From that point forward, explains OOPD, the Office “has asked sponsors requesting orphan drug designation for the use of their product for the treatment of systemic sclerosis why the product could not be used to treat localized scleroderma and to include that population in their prevalence estimate if there was no reason to exclude them.”  In other words, to obtain designation, a sponsor needed to explain what aspects of the drug product resulted in an orphan subset of a non-rare disease or condition.  As FDA explained in the preamble to the Agency’s 2013 final rule, “[u]nder FDA’s longstanding approach, eligibility for orphan subsets rests on whether use of the drug in a subset of persons with a non-rare disease or condition may be appropriate but use of the drug outside of that subset (in the remaining persons with the non-rare disease or condition) would be inappropriate owing to some property(ies) of the drug, for example, drug toxicity, mechanism of action, or previous clinical experience with the drug.”

Despite OOPD’s post-2009 orphan subset approach to scleroderma, the SOPP states that “one could make the case that localized scleroderma is a different disease than systemic sclerosis,” as “[l]ocalized scleroderma does not progress to systemic sclerosis.”  Morover, the SOPP notes that “the EMA considers systemic sclerosis to be distinct from localized scleroderma for the purposes of orphan drug designation.”

Given these considerations, OOPD states the Office’s current policy that “for the purposes of orphan drug designation, OOPD will now consider systemic sclerosis to be a different disease or condition than localized scleroderma.”  As such, “[s]ponsors requesting orphan drug designation for the use of their products for the treatment of systemic sclerosis will no longer be required to make the case that their product would not be effective in treating localized disease or include the patients with localized disease in their prevalence estimate.”  This policy went into effect on April 3, 2013.  Several weeks later, on May 14, 2013, OOPD designated Sanofi’s 2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indan-2-carboxylic acid for the treatment of patients with systemic sclerosis.  The designation followed the EMA’s March 12, 2013 orphan drug designation of the product for the treatment of systemic sclerosis (see here). 

Pulmonary Hypertension as the Subject of a Request for Orphan Drug Designation.  The World Health Organization (“WHO”) describes pulmonary hypertension as “a condition in which there is high blood pressure in the lung arteries,” and has divided the disease into five groups based on the cause of the condition and treatment options.  Historically, OOPD has designated products for the treatment of Pulmonary Arterial Hypertension (“PAH”), generally; however, as the Office notes in the SOPP, “it was not clear if PAH was treated as a different disease or condition from the other WHO groups of pulmonary hypertension or if PAH was treated as an orphan subset of pulmonary hypertension.”

After consulting the review division in FDA’s Center for Drug Evaluation and Research concerning what constituted the disease or condition when discussing pulmonary hypertension, “[i]t was determined that the results of studies of products intended for the treatment of pulmonary hypertension were not generalizable from one WHO classification of pulmonary hypertension to another,” and it was noted that the pathologies and treatments were different between groups.  As a result, OOPD clarifies in the SOPP that the five WHO classifications of pulmonary hypertension represent different diseases or conditions for orphan drug designation purposes.  “This clarification does not affect prior designations of products for [PAH] (WHO classification group I),” notes OOPD.  As with scleroderma, OOPD refers to its European orphan drug counterparst to support its decision, stating that in Europe PAH is considered “to be a different disease or condition from other WHO classification groups of pulmonary hypertension,” and that products have been designated for PAH and for chronic thromboembolic pulmonary hypertension (WHO group 4).  Moreover, says OOPD, European officials have “opined that it was supportable to consider the 5 groups that comprise the WHO classification of pulmonary hypertension to be different diseases or conditions for the purpose of orphan drug designation.”

By Kurt R. Karst –

So much of what we do and think about each day inevitably leads us back to one topic: Hatch-Waxman.  Take, for example, Polar Vortex 2014.  That recent event got us thinking about two things: Snowmageddon 2011, and how warm we hope it will be on the beach in Summer 2014.  Snowmageddon 2011 brough us back to thinking about a March 2011 blog post we wrote on the storm’s effects on FDA approval decisions, including ANDAs for drug products eligible for a period of 180-day exclusivity.  And thoughts about the beach in Summer 2014 brought to mind (for some reason) a quote from Warren Buffett: “You never know who’s swimming naked until the tide goes out.”  That saying applies well to ANDA 180-day exclusivity, because you don’t necessarily know whether or not a first applicant has forfeited eligibility for exclusivity – even though a statutory deadline has been missed – until FDA acts like the tide and reveals which ANDA applicant has (or does not have) exclusivity.  (Clearly, the mind works in strange and indescribable ways.)

Going back to our March 2011 post, we expressed concern about how FDA might handle 180-day exclusivity forfeiture decisions under FDC Act § 505(j)(5)(D)(i)(IV) during a government or other emergency shutdown (which happened during Snowmageddon).  That provision, added by the 2003 Medicare Modernization Act, states that 180-day exclusivity eligibility is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed. 

The 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which [FDA] received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .”  FDC Act § 505(q)(1)(G). 

The 2012 FDA Safety and Innovation Act (“FDASIA”) made further changes with respect to the application of FDC Act § 505(j)(5)(D)(i)(IV) to certain ANDAs.  For example, for an ANDA submitted to FDA between January 9, 2010 and July 9, 2012 initially containing a Paragraph IV certification (or that is amended during that time to first contain a Paragraph IV certification), the time to obtain timely tentative approval (or final approval if tentative approval is not warranted) is 40 months during the period of July 9, 2012 and September 30, 2015, and not 30 months (see our previous post here).

FDA’s initial interpretation of the exception provision at FDC Act § 505(j)(5)(D)(i)(IV) – i.e., “unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed” – was very narrow.  For example, FDA explained in an October 2008 decision that “[t]his express description of the circumstances in which exclusivity will not be forfeited for failure to obtain tentative approval makes it clear that, under other circumstances in which an applicant has failed to obtain tentative approval, regardless of what party might be responsible for that failure, the first applicant will forfeit exclusivity” (emphasis added).  (Many of the instances in which FDA has applied the exception provision are detailed here.)  More recently, however, FDA has shown some willingness to allow some wiggle room.  For example, as we previously noted, FDA has considered and rejected as too draconian “but for” causation in its application of FDC Act § 505(j)(5)(D)(i)(IV).

In any case, it was our belief back in 2011 that if the 30-month date at FDC Act § 505(j)(5)(D)(i)(IV) fell on a date that was during a government or other emergency shutdown, FDA would decide that an ANDA sponsor forfeited 180-day exclusivity eligibility if action was not taken on the application the day before the shutdown.  We commented that “this is the position FDA took during Snowmageddon, such that if the 30-month date . . . fell on February 8-11, 2010, and FDA failed to act on an application by February 7, 2010, then an ANDA sponsor would have forfeited 180-day exclusivity.”  It turns out that no approval action was taken for any of the at-risk ANDAs when the government reopened on February 12, 2010, so no Snowmageddon-related forfeiture decisions had to be made. 

We took this unofficial position one step further and commented that “[t]his ‘day before approach’ is the same approach FDA takes when the 30-month deadline falls on a weekend or a Federal holiday.”  And, in fact, that’s what we believe FDA’s thinking on the topic was initially.  But FDA has never actually had to decide – through a reasoned decision-making process – whether or not an approval action on the day after a weekend or holiday results in a grant or forfeiture of 180-day exclusivity eligibility when the 30-month (or 40-month) deadline pursuant to FDC Act § 505(j)(5)(D)(i)(IV) fell on that previous weekend or holiday. 

Way back in March 2009, FDA did approve one “weekend application” – ANDA No. 078515 for Drospirenone and Ethinyl Estradiol Tablets, 3.0 mg/0.02 mg (28-Day Regimen) – and affirmed in the approval letter that applicant’s eligibility for 180-day exclusivity.  That exclusivity-bearing ANDA was received by FDA as of September 29, 2006, and was approved (without the need for tentative approval) on Monday, March 30, 2009.  That’s one day outside of the 30-month window.  We highly doubt, however, that FDA thought through the exclusivity issue when the Agency approved the ANDA and affirmed exclusivity eligibility.

How to handle 180-day exclusivity for “weekend applications” and “holiday applications” is likely to come up again, however.  In fact, we combed through ANDA records, looked over FDA’s ANDA Paragraph IV Certifications List, and identified at least two instances that may someday ripen into an official FDA decision on the issue.  The first concerns a generic version of EPZICOM (abacavir sulfate, 600 mg and lamivudine, 300 mg) Tablets.  FDA is believed to have received ANDA No. 079246 as of September 27, 2007.  Thirty months later was Saturday, March 27, 2010; however, FDA tentatively approved the ANDA on Monday, March 29, 2010.  The second instance is quite recent and concerns a generic version of DEXILANT (dexlansoprazole) delayed-release capsules, 60 mg.  FDA is believed to have received ANDA No. 202294 as of August 25, 2010.  Forty months later (because this ANDA is subject to the FDASIA provision noted above) was Wednesday, December 25, 2013 (Christmas); however, FDA tentatively approved the ANDA on Thursday, December 26, 2013. 

How will FDA ultimately resolve 180-day exclusivity for “weekend applications” and “holiday applications,” allowing the tide to go out and reveal who has (or does not have) exclusivity eligibility?  We don’t know for sure, but we note that there are myriad instances in which statutory deadlines that fall on a weekend or holiday are moved to the next day – even in the Hatch-Waxman context.  Consider, for example, FDA’s regulation at 21 C.F.R. § 314.107(f) on computation of the 45-day clock for purposes of filing a patent infringement lawsuit in response to notice of a Paragraph IV certification.  That regulation states that “[t]he 45-day clock . . . begins on the day after the date of receipt of the applicant’s notice of certification by the patent owner or its representative, and by the approved application holder.  When the 45th day falls on Saturday, Sunday, or a Federal holiday, the 45th day will be the next day that is not a Saturday, Sunday, or a Federal holiday.”

By Jennifer D. Newberger –

On January 10, 2014, FDA issued a final rule amending the PMA regulations to require inclusion of information relating to pediatric subpopulations that suffer from the disease or condition that a device is intended to treat, diagnose, or cure, and the number of affected pediatric patients.  These requirements are mandated by section 515A of the Federal Food, Drug, and Cosmetic Act (FDC Act), added by the Food and Drug Administration Amendments Act of 2007 (FDAAA).  This information will be included in the annual reports submitted to Congress by FDA as required by section 515A(a)(3) of the FDC Act, which must contain the number of approved devices for which there is a pediatric subpopulation that suffers from the disease or condition that the device is intended to treat, diagnose, or cure, and the review time for each such device application.

Implementation of the final rule comes after FDA published a proposed rule and companion direct final rule on April 1, 2010.  Due to receipt of significant adverse comments, FDA withdrew the direct final rule.  After withdrawal of the rule, FDA issued a supplemental notice of proposed rulemaking on February 19, 2013, to seek public comment on the re-drafted proposed rule.  We previously posted on this issue here.  FDA received four additional comments on the proposed rule after withdrawing the direct final rule.

As mandated by section 515A(c) of the FDC Act, “pediatric subpopulation” is defined to have the same meaning given to the term in section 520(m)(6)(E)(ii), namely, to include one of the following populations:  neonates, infants, children, or adolescents.  Though section 515A does not define the age group intended to be included in “pediatric patients,” section 520(m)(6)(E)(i) defines pediatric patients to include those who are 21 years of age or younger at the time of diagnosis or treatment.  FDA is adopting this same definition of “pediatric patients” for purposes of section 515A, despite comments suggesting that age 18 should serve as the upper bounds for pediatric patients.

Perhaps the greatest change made from the proposed to final rule was elimination of language in the proposed rule requiring applicants to include “potential pediatric uses” in their submissions rather than actual, known pediatric uses.  After significant feedback from industry—and, perhaps, a closer look at the language of section 515A—FDA concluded that “section 515A of the FD&C Act does not require sponsors to speculate as to possible pediatric uses and possible subpopulations.”  Of course, if sponsors wish to include that information, FDA “would find the information useful in support of advancing pediatric device development.”

Another change from the proposed to final rule is the submission types that must include the pediatric information.  As provided in the statute, both the proposed and final rules state that section 515A applies to PMAs, HDEs, and PDPs, but there was some question as to the extent to which the pediatric information requirement applies to PMA supplements.  Originally, FDA proposed that it would apply only to the subset of PMA supplements that propose a new indication for use.  In the final rule, however, FDA states that, to be consistent with the statutory requirements, the requirement applies to all PMA supplements.  At the same time, FDA notes that, consistent with the statute, it does not consider 30-day notices submitted under 21 C.F.R. § 814.39(f) to be PMA supplements for purposes of the final rule.  Additionally, if an applicant who previously submitted the required pediatric information later submits a PMA supplement, it may include the previously submitted information by reference rather than providing the same information.  If additional information about pediatric use has become “readily available” since the prior submission, that information should be included. 

FDA has defined “readily available” to mean “available in the public domain through commonly used public resources for conducting biomedical, regulatory, and medical product research.”  21 C.F.R. § 814.3(t).  In its draft guidance issued on the same day as the supplemental notice of proposed rulemaking, FDA expanded on this definition of “readily available” 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).”  Presumably these examples will be present in the final guidance FDA states it will be issuing on this subject.

What FDA still has not answered is how it will use this pediatric information (other than to provide the report to Congress).  As we noted in our blog post about the supplemental notice of proposed rulemaking, FDA stated in the draft guidance that its intent is to use the information 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.”  Perhaps the final guidance will clarify more precisely what this means.

By JP Ellison –

We previously reported that Pom Wonderful had sought Supreme Court review of the 9th Circuit’s decision that POM’s labeling-based claims against Coke’s Minute Maid products could not proceed under the Lanham Act because such labeling was the province of the FDA and the FDC Act.  In that earlier post we also discussed the brief filed by the United States Solicitor General arguing that the 9th Circuit’s decision was wrong, but that the Court should not grant cert. in the case.  Last Friday the Supreme Court, against the recommendation of the Solicitor General, granted cert. and will hear the case.  Two Justices, Alito and Breyer, did not take part in the vote to grant cert., suggesting that they also will not participate in the case at the merits stage.  We’ll closely follow this case (Docket No. 12-761), which could provide important guidance on not only FDC Act-related Lanham Act claims for food products, but for drugs, devices, and cosmetics as well.

By Delia A. Stubbs –

Pursuant to 21 U.S.C. § 811(h), DEA may temporarily place substances in Schedule I of the List of Controlled Substances upon a finding that such action is necessary to avoid an imminent hazard to public health and safety.  Using that authority, on January 10, 2013, DEA published a notice of its intent to temporarily place four synthetic cannabinoids in Schedule I:  quinolin-8-yl 1-pentyl-1H-indole-3-carboxylate (PB-22; QUPIC); quinolin-8-yl 1-(5-fluoropentyl)-1H-indole-3-carboxylate (5-fluoro-PB-22; 5F-PB-22); N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (AB-FUBINACA); and N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (ADB-PINACA).  Schedules of Controlled Substances: Temporary Placement of Four Synthetic Cannabinoids into Schedule I (“Notice”), 79 Fed. Reg. 1,776 (Jan. 10, 2014) (to be codified at 21 C.F.R. Part 1308).

In its Notice, DEA explained that synthetic cannabinoids form “a large family of compounds that are functionally (biologically) similar to  . . . the main active ingredient in marijuana [(THC)].” Id. at 1,777.  It clarified that “synthetic cannabinoids, however, are not organic, but are chemicals created in a laboratory.”  Id.  As required, DEA made findings regarding the cannabinoids’ history and current patterns of abuse; the scope, duration, and significance of that abuse; and what, if any, risk they pose to the public health.  See 21 U.S.C. § 811(h)(3).  Like similar temporary scheduling notices for synthetic cannabinoids, see here, DEA noted that these substances first emerged for research purposes in the 1980’s, and since then, numerous synthetic cannabinoids have been identified as product adulterants and seized by law enforcement.  Notice at 1,778.  It found “[t]he vast majority of cannabinoids are manufactured in Asia,” and “[t]hey are sold under hundreds of different brand names, including ‘Spice,’ ‘K2,’ ‘Blaze,’ ‘Red X Dawn,’ ‘Paradise,’ ‘Demon,’ ‘Black Magic,’ ‘Spike,’ ‘Mr. Nice Guy,’ ‘Ninja,’ ‘Zohai,’ ‘Dream,’ ‘Genie,’ ‘Sence,’ ‘Smoke,’ ‘Skunk,’ ‘Serenity,’ ‘Yucatan,’ ‘Fire,’ and ‘Crazy Clown.’  Id. at 1,777.  DEA noted a sharp uptick in forensic and poison control reports regarding the substances since February 2013.  Id. at 1,778.  Relevant to the public health factor, DEA found noteworthy an incident that occurred in late August 2013, where 22 persons ranging from age 16 to 57 presented to emergency rooms in Brunswick, Georgia with symptoms such as “the inability to stand, foaming at the mouth, violence towards police . . . and memory lapse.”  Id. at 1,779.  The patients reportedly ingested a synthetic cannabinoid called “Crazy Clown,” which was later identified to contain ADB-PINACA.  Id.  Likewise, DEA found that, in September 2013, 221 patients visited emergency departments in Colorado after consuming “Black Mamba.”  Id.  The patients suffered from symptoms such as “having no gag reflex, inability to breathe on their own, hallucinations and psychotic episodes.”  Id.  “Laboratory analysis of samples from the Colorado incident confirmed that the substance abused in the ‘herbal incense’ products was ADB-PINACA.”  Id. at 1,778.

DEA’s emergency scheduling follows its increase in regulatory actions to address concerns about synthetic cannabinoids and other “synthetic/designer” drugs, such as synthetic cathinones, since 2011.  See prior posts, here, here, here, and here.  DEA Administrator, Michele Leonhart, recently highlighted these concerns before Congress, stating “[t]hese insidious substances are often marketed directly to teenagers and young adults as a ‘legal’ alternative to other illicit substances . . . .  In reality, they are incredibly dangerous, with users having unpredictable and sometimes deadly reactions . . . .”  Michele Leonhart, Statement Before the H. Comm. on Appropriations (Apr. 12, 2013).  Likewise, in its Notice, DEA warned that “[t]here is an incorrect assumption that these products are safe.”  Id. at 1,777.  It explained that “[s]ince abusers obtain these drugs through unknown sources, the identity, purity, and quantity of these substances is uncertain and inconsistent, thus posing significant adverse health risks to users.”  Id. at 1,779.

DEA’s temporary scheduling takes effect 30 days from the date it is published in the Federal Register.  Id.  The Agency stated that it will not be taking public comment.  Id. at 1,780.   The Notice states that any final order will impose the administrative, civil, criminal sanctions and regulatory controls applicable to Schedule I substances under the CSA on the manufacture, distribution, possession, importation, exportation, research, and conduct of instructional activities of these substances.

By Riëtte van Laack –

On January 7, the FTC announced an initiative “Operation Failed Resolution” stating that it wants to protect consumers against deceptive weight loss claims.  Among other things, the FTC announced actions against four companies for advertising fad weight-loss products, issued an updated guidance for media and developed a website called “Fat Foe” that mimics commonly used allegedly deceptive weight loss claims.

FTC’s enforcement actions against products allegedly marketed with bogus weight loss claims

As part of its initiative, the FTC announced enforcement actions against four different companies marketing foods, cosmetics or dietary supplements.

• Sensa

The FTC filed a complaint against Sensa for marketing its product as a food that you could sprinkle on your food and “watch the pounds come off.”  According to the FTC, the company did not have the science to back up this and other claims however.  Alleged deficiencies in the clinical studies include lack of blinding and use of a placebo, failure to account for subjects that do not complete the study, and failure to monitor the subjects’ diet and exercise.  In addition, Sensa allegedly failed to disclose that its consumer endorsers had received compensation in exchange for their endorsement.  According to the complaint, sales of Sensa in the United States from 2008 through 2012, totaled nearly $364 million.  To settle the case, Sensa will pay 26.5 million dollars into a fund to be used for consumer refunds.  The FTC will post information on how consumers can file a claim for a refund, at a later date.

The Sensa settlement agreement makes an exception for studies on conventional foods recognizing that a conventional food “need not be placebo controlled or double blind if placebo control or blinding cannot be effectively implemented given the nature of the intervention.”  Defendants have the burden to prove that a placebo control or blinding is not feasible.  To our knowledge, this is a first.   

• L’Occitane

The case against L’Occitane involves slimming claims for skin creams.  According to the complaint, L’Occitane marketed its products with claims that they “trim 1.3 inches in just 4 weeks” of thighs.  Although the company claimed that it had clinical evidence to support these claims, the FTC disagreed.  According to the FTC, the evidence relied on consisted primarily of results from a single unblinded, uncontrolled clinical trial and L’Occitane exaggerated the results of the trial; the average reported reduction in thigh circumference was less than one quarter of an inch. 

• HCG Diet Direct

The third case concerns HCG Diet Direct.  Allegedly, the company marketed its homeopathic product HCG direct, purported to contain human chorionic gonadotropin, with claims that consumers could lose as must as a pound a day merely by putting drops under the tongue before meals.  HCG Diet Direct was one of the seven companies that received the November 2011 joint FTC-FDA warning letters.  A judgment of three million, two hundred twelve thousand, three hundred ten dollars for consumer redress is suspended due the defendants’ claimed inability to pay.

• LeanSpa, LLC

The FTC’s fourth case concerns a partial settlement with LeanSpa, LLC, an operation that allegedly deceptively promoted acai berry and “colon cleanse” weight-loss supplements through fake news websites.  Under this proposed settlement, the LeanSpa settling defendants will surrender assets valued at an estimated $7.3 million.

Updated guidance for media outlets on spotting bogus weight-loss claims in advertising

As part of its initiative, the FTC also issued an updated guidance for media to recognize bogus weight loss claims, “Gut Check.”  This guidance instructs media outlets on how to screen advertisements for facially deceptive weight loss claims, so that they will refuse to publish or to air deceptive ads.  While the FTC has the authority to sue media outlets for running deceptive ads, based on statements made at the FTC’s press conference announcing this guidance, the FTC does not intend to pursue action against media.  Instead, it appears to be looking for media’s voluntary cooperation.  The updated guidance includes tips on testimonials and an online tutorial.  

As part of “Gut Check,” the FTC is sending letters to 75 broadcasters and media outlets to update them on how to spot bogus claims in weight loss ads.

Additional consumer education materials

The FTC has also created a website advertising a fake weight loss product called “FatFoe.”  FatFoe is not a real weight loss product.  The ad is intended to warn consumers about diet rip-offs and provides further guidance on how to spot false weight loss.

Commissioners question the “standard” requirement for two randomized clinical trials

On the same day that the FTC announced its cases regarding the weight loss products, it also announced a case against GeneLink, a business advertising customized dietary supplements to treat diseases (see here).

All of the (proposed) settlements, including the Genelink settlement, define “competent and reliable evidence,” for the relevant products as well-controlled human clinical studies (randomized controlled trials or RCTs).  However, there appears to be disagreement within the Commission about whether this high standard is justified under all circumstances.  Notably, Commissioners Ohlhausen and Wright issued separate statements (here and here), in which they, among other things, raise questions regarding the requirement for two RCTs to satisfy the standard of “competent and reliable scientific evidence” for other than weight loss claims.  Commissioner Wright writes that “[t]he optimal amount and type of evidence to substantiate a future claim will vary from case to case,” and urges the Commission to consider whether this requirement “strikes the right balance between deterring deceptive advertising and preserving for consumers the benefits of truthful claims.  Commissioner Ohlhausen similarly expresses concern that “[a]dopting a one-size-fits-all approach to substantiation by imposing such rigorous and possibly costly requirements for . . . a broad category of health- and disease-related claims may, in many instances, prevent useful information from reaching consumers in the marketplace and ultimately make consumers worse off.”  She advocates use of the factors from Pfizer, Inc., 81 F.T.C. 23 (1972), rather than requiring two RCTs without consideration of the specific claim and science at issue.

By Kurt R. Karst –      

With primary briefing over (briefs here, here, and here), and a December 13, 2013 Oral Argument before Judges Griffith, Kavanaugh and Randolph concluded, we were waiting with bated breath for the U.S. Court of Appeals for the District of Columbia Circuit to rule on K-V Pharmaceutical Company’s (“KV’s”) appeal of a September 2012 decision from the U.S. District Court for the District of Columbia that stymied the company’s efforts to “restore” orphan drug exclusivity for the pre-term birth drug MAKENA (hydroxyprogesterone caproate) Injection, 250 mg/mL, the compounded version of which is known as “17P.”  In an interesting turn of events, the DC Circuit issued an unpublished judgment on January 7, 2014 ordering and adjudging that the DC District Court’s September 6, 2012 order dismissing KV’s claims be vacated and that the case be remanded to the district court for reconsideration in light of the DC Circuit’s July 23, 2013 decision in Cook v. FDA, 733 F.3d 1 (D.C. Cir. 2013), and the November 27, 2013 enactment of the Drug Quality and Security Act (“DQSA”), Pub. L. No. 113-54, 127 Stat. 587 (2013).  In Cook, the DC Circuit largely affirmed a March 2012 decision from the DC District Court permanently enjoining FDA from permitting the entry of (or releasing any future shipments of) foreign manufactured thiopental into interstate commerce (see our previous post here).  Title I of the DQSA, the Compounding Quality Act, concerns state and federal oversight of compounding of human drugs (see our previous posts here and here summarizing the DQSA).  

As we previously reported (here, here, and here), KV filed a Complaint and a Motion for Temporary Restraining Order and Preliminary Injunction alleging that FDA and the Department of Health and Human Services violated myriad provisions of the FDC Act, the Administrative Procedure Act (“APA”) § 706(2), and the Due Process Clause of the Fifth Amendment to the U.S. Constitution by failing to take sufficient enforcement action to stop the unlawful competition with MAKENA by pharmacies that compound 17P.  FDA filed a Motion to Dismiss arguing, among other things, that KV’s claims are not justiciable for lack of standing, and that even if KV can establish standing, certain Agency statements concerning compounded 17P are not subject to judicial review under the APA because FDA’s decisions not to take enforcement action are committed to the agency’s discretion under Heckler v. Chaney, 470 U.S. 821 (1985).  In Chaney, the U.S. Supreme Court held that “an agency’s decision not to prosecute or enforce, whether through civil or criminal process, is a decision generally committed to an agency’s absolute discretion,” and as such, is presumed to be unreviewable under the APA. 

After finding that KV alleged sufficient facts to support standing, the D.C. District Court found KV’s first three Counts concerning orphan drugs (FDC Act § 527(a)), compounding (FDC Act § 503), and new drug approval (FDC Act §§ 505(a) and 301(d)) unreviewable, because APA § 701 “precludes judicial review of final agency action, including refusals to act, when review is precluded by statute or ‘committed to agency discretion by law,” and because Chaney is controlling.  Addressing Count IV of KV’s Compliant alleging that FDA violated FDC Act § 801(a) by permitting foreign-manufactured active pharmaceutical ingredient to be imported into the United States for compounding into 17P, the court found that the Count failed to state a claim.

The DC Circuit’s decision to vacate the DC District Court’s decision and remand the case to the district court for reconsideration follows a string of letters submitted to the Court over the past several months after the completion of briefing, but before the December 13th Oral Argument, concerning Cook and the DQSA.  In those letters (available here, here, here, here, and here) KV and FDA dispute the relevance of the Cook decision and the DQSA’s provisions to the case at hand.  So back to the DC District Court we go . . . and perhaps someday appealed again up to the DC Circuit.