By Kurt R. Karst –     

FDA’s implementation of the Generic Drug User Fee Amendments of 2012 (“GDUFA”) and adherence to the triad of key aims laid out in the accompanying Performance Goals and Procedures – Safety, Access, and Transparency – have been a bit of a roller coaster ride for the generic drug industry, the Office of Generic Drugs (“OGD”), and even us. 

It wasn’t too long ago that we were griping on this blog (see here) about a Manual of Policies and Procedures (“MAPP”) – MAPP 5200.3 – titled “Responding to Industry Inquiries with respect to Abbreviated New Drug Applications in the Office of Generic Drugs” that FDA published in September 2013 as part of the preparatory efforts in the lead-up to full GDUFA implementation beginning on October 1, 2014.  Although the stated intent of the MAPP is to “clarif[y] the general principles for handling inquiries with respect to [ANDAs] from the authorized representative for an applicant with an ANDA submission (the authorized inquirer) by Regulatory Project Management (RPM) staff in [OGD]” we were concerned it represented what we called the “UFAization” of OGD (i.e., the process by which an FDA component, after the enactment of a User Fee Act, becomes focused on so-called process enhancements to meet goals and commitments at the expense – both literally and figuratively – of those who are subject to such user fees.) 

We were a little more upbeat about news shared by FDA at the Generic Pharmaceutical Association’s (“GPhA’s”) 2013 Fall Technical Conference about GDUFA implementation, including year 1 accomplishments and the announcement that a  committee – the GDUFA Steering Committee – had been put together to oversee GDUFA implementation (see our previous post here).  We were even more encouraged when the news came out that the Department of Health and Human Services approved the reorganization of OGD into a “Super Office” and that a new reporting structure would be created, including the creation of a new Office of Generic Drug Policy to handle, among other things, Hatch-Waxman disputes (see our previous post here). 

On the downside, we have heard some complaints about FDA’s enhanced ANDA refuse-to-receive standards reflected in recent guidance and less-than-helpful responses to Controlled Correspondence, though we have not focused on either topic in a blog post.  And then there’s the issue of how OGD will handle the recent explosion in ANDA submissions, as reported by Bob Pollock at the Lachman Blog (see here).  

But what we’re here today to announce is what can only be described as a massive and unprecedented undertaking on the part of OGD to address what seems to be an outpouring of concern about the perceived effects of MAPP 5200.3.  In other words, OGD has heard industry’s concerns and wants to do something about it – at least to the extent the Office can do so. 

In a recent memorandum to the Commissioned Corps (“CC”) Officers serving in OGD, OGD’s Acting Director, Kathleen Uhl, M.D., says that OGD’s “recent process changes, while critical to improving review efficiency, have made it harder for industry to assess the status of their submissions, and to plan the market launch of generic medicines that are important to industry and consumers alike.”  As such, writes Dr. Uhl, CC Officers “will be placed in mission critical status until completion of a one-time, special initiative related to GDUFA implementation.”  And what is this “special initiative”?  “Beginning February 1,” writes Dr. Uhl, “OGD’s CC officers will conduct a complete inventory of all the original ANDAs in our queue, and provide each applicant with an update regarding the status of its ANDAs.”  

That’s right, ANDA sponsors will be receiving, on a rolling basis, information on all of their respective original ANDAs (and amendments to them) – but not supplements – pending at the Agency.  This covers ANDAs submitted to FDA pre-GDUFA and pending on October 1, 2012 (i.e., the backlog), and that are subject to the GDUFA goal of 90% action by the end of FY 2017.  It also includes ANDAs submitted to FDA in the full year 1 (Fiscal Year 2013) and partial year 2 (Fiscal Year 2014) GDUFA cohorts.  These two GDUFA cohort years have been referred to as the “GDUFA donut hole” because, other than first Paragraph IV submissions, there are no FDA performance goals associated with review and action on them.  Performance goals take effect on October 1, 2014 (Fiscal Year 2015), when OGD has agreed to review and act on 60% of original ANDA submissions within 15 months from the date of submission, among other goals.  Note, however, that action on an ANDA within 15 months does not necessarily mean approval of that application.  More likely, OGD will be issuing Complete Response Letters reflecting full division-level review of deficiencies from all relevant review disciplines, including inspections.  Certainly, that seems to be the trend – see here and here.  This also means that once OGD issues a Complete Response Letter, and a sponsor responds, there may be another call from industry to gain some transparency into ANDA status. 

Although ANDA sponsors will not be able to request prioritization of the ANDAs on their respective lists, FDA’s action goes a long way to give greater transparency to application status, and could help as companies plan for the future.  As Dr. Uhl notes, “[t]he inventory and update goes above and beyond our negotiated GDUFA commitments.  It represents an extra effort to improve transparency, and help stakeholders cope with some of the uncertainty and disruption created by GDUFA implementation.”

Thank you OGD for listening to your stakeholders and providing a greater level of transparency; and thank you CC Officers for dedicating your time to this special initiative!

By JP Ellison –

In a speech on January 29th at the CBI Pharmaceutical Compliance Congress that DOJ posted on its own website, U.S. Department of Justice Assistant Attorney General Stuart Delery set forth his views of the three ways that the government’s enforcement interests align with industry’s interests.  While the speech didn’t break any new ground, it serves as a reminder that pharmaceutical enforcement cases remain a DOJ priority and suggests that recent enforcement trends will continue.

AAG Delery Claimed that DOJ and industry shared the following:

1.  “[A] common interest in promoting ethical corporate culture instead of maintaining a compliance program in name only;”
2. “Transparency about the conduct [the government] investigate[s];” and
3. “[A] common interest in ensuring that corporate compliance is not only the right thing to do but also a winning business strategy.”

Promoting ethical corporate culture

AAG Delery stated that a “common thread” in recent cases was “that numerous individuals . . . saw signs that misconduct was taking place and did not act.”  In response to this observation, AAG Delery stated that DOJ has “put a renewed emphasis on identifying non-monetary measures that will help us to prevent the recurrent of misconduct.”  As examples of such measures, Delery pointed to the Ranbaxy civil consent decree, which required the company to create an Office of Data Reliability, and the Abbott Laboratories resolution (see our prior post here) which he described as “a resolution designed to ensure high-level accountability for the company’s compliance efforts.   Delery’s comments regarding DOJ’s goal of giving “companies the incentives—and tools—to craft better compliance practices in the future” suggests that companies may want to consider similar measures in their own compliance programs.

Transparency

As to the second shared goal, Delery cited to the common interest of the government and industry in being “clear about what misconduct gave rise to a civil or criminal resolution” so that both sides can “distinguish[] conduct that is lawful and even beneficial from conduct that is illegal and harmful.” Delery “emphasize[d] the importance of [the government] explaining the conduct that has given rise to the settlements we negotiate.”  He explained that   “transparency benefits the industry by clarifying the factual basis for the actions we take . . .  and by prompting other companies to avoid the same risks to patient health and safety.”

Making compliance make business sense

AAG Delery “recognize[d] that most pharmaceutical companies are trying to play by the rules.”  Delery explained that DOJ wants “to ensure that companies that are committed to doing things right have the opportunity to compete on a level playing field.”  Delery encouraged self-disclosure and stated that companies would receive credit for such actions.  Lastly he stressed that DOJ would “continue to insist on resolutions that eliminate any economic incentive to engage in and attempt to conceal unlawful conduct.”

The government’s pursuit of pharmaceutical manufacturers has yielded significant recoveries in recent years (see here).  Throughout 2014, we expect the principles set forth in AAG Delery’s speech to be reinforced through investigations, prosecutions, and resolutions that reflect the points made in this speech, and we will keep the readers of this blog updated on those developments as they occur.

By John R. Fleder –

On October 2, 2013, HP&M posted the following on this blog:

On September 26, 2013, the United States Attorney for the District of Colorado announced that he had filed a six count criminal Information against Eric and Ryan Jensen.  The government alleges that the defendants violated the FDC Act by introducing adulterated cantaloupes into interstate commerce.  The government also alleges that the cantaloupes bore Listeria monocytogenes and 33 people died.  It is quite curious (we are being charitable here) that the government’s press release alleges that 147 people were hospitalized as a result of sales of the cantaloupes, but those allegations appear nowhere in the criminal Information!

The prosecution is a misdemeanor case, and does not allege any criminal “intent” on the part of the defendants.  There is no public indication that the defendants are prepared to plead guilty and/or cooperate with the government against others.  This fact pattern strongly suggests that this case is an old style Park criminal prosecution where the government files criminal charges under the FDC Act against company officials, without allegations that the defendants intended to violate the law and without a plea bargain that a misdemeanor prosecution is a settlement of more serious felony charges.  Our speculation is that a thorough government investigation here failed to turn up evidence that the defendants violated the FDC Act “with the intent to defraud or mislead,” which would be necessary to commence felony charges under the FDC Act.  In fact, the government used a grand jury to investigate this case, even though it can file a criminal Information involving misdemeanor charges without using a grand jury.

The second interesting twist in this case is that arrest warrants were issued for the defendants.  Arresting defendants charged only with misdemeanors was certainly not the norm with regard to old style Park prosecutions.  Typically, the defendants were simply notified of the charges and came to court voluntarily to enter their guilty or not guilty pleas.

Recent events have demonstrated that this case is indeed what this writer calls an old fashioned Park criminal prosecution.  The government filed criminal charges under the FDC Act against company officials, without allegations that the defendants intended to violate the law and without a plea bargain that demonstrated that a misdemeanor prosecution was a settlement of more serious felony charges.

On January 28, 2014, the United States District Court for the District of Colorado sentenced the two defendants to five years probation, based on their guilty pleas to the six count criminal Information.  They were also placed in home detention for six months, required to complete 100 hours of community service, and ordered to pay a total of $150,000 in restitution.  The court did not impose any fine “because Defendants have no ability to pay a fine.”

On January 17, 2014, the government filed a somewhat remarkable “Sentencing Statement.”  It argued that the relevant offense level for this case was 9.  When a criminal case fits into the offense level of 9, a court must require some jail time unless it orders substitute measures such as home detention, under Sentencing Guideline 5B1.1.  The government stated that it agreed with the United States Probation Office that the recommended sentence should be probation.  The government explained that “any offense that results in 33-40 deaths [which deaths resulted from the sales of the adulterated canteloupes by defendants’ company] is a serious offense.”  Nevertheless, “the seriousness of the offense is tempered in this case by the lack of a willful, intentional or knowing state of mind.  These defendants were at worst negligent or reckless in their acts or omissions.”

The government then discussed what it described were mitigating circumstances, namely what the defendants did after they discovered that their company’s fruit was tainted.  The government stated that the defendants: sought to voluntarily recall the fruit; through their counsel offered cooperation and assistance in the government’s investigation; and addressed the victims and their families “in an attempt to provide the victims a sense of comfort and closure,” waiving what the government called “constitutional protections in favor of addressing sensitive victim issues.”

The government also made a somewhat remarkable claim that it has already seen a significant difference in how food safety is viewed as a result of this prosecution.  It asserted (without citation) that “A recognition that shoddy compliance with food safety standards and statutes potentially exposes those in the distribution chain to criminal liability has been taken seriously by the food industry in light of this prosecution.”  That statement should be beneficial to the food industry in a variety of contexts.

It is interesting that the government did not explicitly ask for home detention or community service for the defendants even though the Court later imposed those requirements.

So what do we take away from this case:

1. This is perhaps the first recent case where the government has actually gone on record stating that it believed that defendants prosecuted under 21 U.S.C. 333(a) lacked any criminal intent.  In most or all other recent cases the government has stood silent on whether a defendant prosecuted under this statute had any criminal intent;
2. Even conduct that leads to a substantial number of deaths will not necessarily warrant jail time;
3. Defendants can take remedial steps after the “crimes” have been committed which will substantially reduce the sanctions that the government will seek and that a court will impose;
4. For better or worse, the Park Doctrine is indeed alive, at least to the extent that it was applied in this case; and
5. Based on comments made by the government in its Sentencing Statement, it appears that the prosecutors concluded that when deaths occur, the government believes it is obliged to seek criminal sanctions regardless of whether the people prosecuted have any wrongful intent.

By Delia A. Deschaine –

Various members of industry recently joined together in filing a citizen petition with FDA.  Citizen Petition, Docket No. FDA-2013-P-1711 (hereinafter “Citizen Petition”). The Citizen Petition responds to a statement made by CDER Director, Janet Woodcock, M.D. in October 2013 that FDA intends to issue a scientific and medical evaluation and recommendation that DEA reschedule all hydrocodone combination products from their current placement in Schedule III to Schedule II.  The petitioners argue that reclassifying all combination hydrocodone products is inappropriate for myriad of public policy reasons.  Thus they request that FDA instead recommend DEA reclassify only hydrocodone combination products that contain hydrocodone bitartrate in a strength of 5 mg or higher.  Citizen Petition at 2.  While the petition is brief, it touches on several critical points that FDA and DEA will likely consider in determining whether to move forward with the rescheduling.

To name a few points, the petitioners assert that reclassifying all hydrocodone products will have “numerous unintended consequences, including depriving vulnerable patient populations of access to critically-needed pain medications.”  Id. at 2.  The petitioners estimate that nearly 100 million Americans suffer from chronic pain and, thus, require opioid treatment for long periods of time.  Id. at 3.  These patients will also be negatively impacted by the reclassification of all strengths of hydrocodone products,  as the drug will become more costly to acquire, and, therefore, less available.  See id.  Further, the petitioners state that the “upscheduling of hydrocodone combination products would require patients to see their doctor for office visits with greater frequency simply to refill a prescription,” and “[a]s FDA could imagine, such a policy change would impose heavy burdens  . . . on patients, caregivers and the health care system . . . .”  Id.   (Unlike substances in Schedule III of the Controlled Substances Act, prescribers are not permitted to write refill prescriptions for controlled substances listed in Schedule II.) 

The Citizen Petition is not the first response to the proposal to reclassify hydrocodone combination products, and likely not the last.  FDA and DEA have battled for years over the appropriate placement of hydrocodone combination products.  See prior post, here. The issue most recently attracted public attention in April 2012, when Congress declined to legislatively reclassify hydrocodone combination products.  See prior post, here.  Instead, Congress ordered FDA to convene a working group to discuss the risks and benefits of reclassification, which it did in January 2013.  Although FDA signaled its intent to issue a recommendation that DEA move forward with the reclassification by the end of the year (a departure from the position it took a few years ago, as petitioners noted), no public statement has been made that FDA did so.  We note, however, that FDA is not required to publish its recommendation in the Federal Register and historically has not done so.  For that reason, the four-page Citizen Petition may flush out whether FDA has or intends to issue its recommendation soon. (Pursuant to 21 U.S.C. § 355(q), FDA must respond to a citizen petition within 150 days if the petition may delay the approval of a pending 505(b)(2) or Abbreviated New Drug Application.) 

Nevertheless, as the petitioners recognize, a DEA reclassification would likely have broad-sweeping implications for all members in the pharmaceutical chain of distribution.  See prior post, here.  These costs include compliance with the physical security requirements imposed on registrants for Schedule II controlled substances (i.e., that they be physically stored in secure cabinets or vaults (depending on the amount).  See 21 C.F.R. §§ 1301.71(a), 1301.72.  Currently, many pharmacies store hydrocodone combination products in safes or spread out shelves with other prescription drugs, and wholesalers store those products in cages (as opposed to vaults for Schedule II substances), as permitted by DEA.  Id. § 1301.72.  If hydrocodone products are reclassified in Schedule II, many pharmacies and wholesalers will need to alter their storage and security controls due to the widespread use and thus supply of these medications.  See id. § 1301.71(c) (requiring registrants to “expand[] or extend[]” their physical security controls “when [they] become inadequate as a result of a controlled substance being transferred to a different schedule”).  This may include vault construction or alteration which is difficult and costly, given DEA’s precise regulatory specifications.  Id. § 1301.72. 

Because Schedule II prescriptions may not be refilled, the reclassification of hydrocodone would also likely impose additional costs on practitioners who routinely prescribe combination hydrocodone to patients requiring long-term opioid treatment.  Those costs may include administrative expenditures (e.g., supplies and support staff) necessary to handle an increased frequency of in-office visits by their patients.  Payers, such as Medicare, Medicaid, and private insurance, bear some of the burden of subsidizing these costs.  See Medicare Program; Revisions to Payment Policies Under the Physician Fee Schedule, Clinical Laboratory Fee Schedule & Other Revisions to Part B for CY 2014, 78 Fed. Reg. 43,282 (July 19, 2013) (discussing how administrative expenditures factor into the Medicare physician fee-for-service rates).

On balance, the petitioners argue, reclassifying only certain higher strength products serves to “protect[] vulnerable patient populations which rely on such medication without sacrificing the ability of DEA to target enforcement of drug products likely to be abused (i.e., products in 5 mg strength and above).”  Citizen Petition at 3-4.

The hydrocodone rescheduling petition relates to the many initiatives that FDA has recently taken to address concerns regarding the widespread misuse and abuse of opioids.   See, e.g., prior post, here. (discussing FDA’s new labeling for all extended release opioid drugs and biologics).  Despite these efforts, FDA recently came under scrutiny by lawmakers and state attorneys general for its approval of a single-entity hydrocodone drug (making it the first available U.S. hydrocodone drug in Schedule II), without requiring the drug to possess “abuse-deterrent technology.”  See prior post, here.  FDA did so despite finding earlier that year that drug manufacturer, Purdue, had withdrawn Oxycontin for safety or efficacy reasons, in the wake of FDA’s approval of a tamper-resistant formula for that drug.  Id.  FDA reasoned that its policy is to consider whether abuse-deterrent technology is necessary to ensure adequate safety of a drug on a “product-by-product” basis.  Id.  In response, The Pharmacists Planning Service, Inc. (“PPSI”) filed a petition with FDA (Docket No. FDA-2013-P-1606) requesting that FDA add “drug-abuse deterrent technology to all hydrocodone schedule II products.”  The petition listed concerns regarding the abuse of opioids generally, and, specifically, hydrocodone.  Id.  Interestingly, PPSI stated that “[it] has encouraged the FDA reschedule this hydrocodone/apap to schedule II.”  Id. at 2.

For now, we wait with curiosity to see whether, and how, FDA considers the arguments made in these petitions in issuing its scheduling recommendation to DEA.

By Riëtte van Laack –

On December 26, FDA sent Warning Letters (here and here) to Accera, Inc. and NVN Therapeutics.  Accera Inc. markets a product, Axona, as a medical food “for the clinical dietary management of the metabolic processes associated with mild to moderate Alzheimer’s disease,” whereas NVN Therapeutics markets GlucoreinTM PCOS as a medical food for the “dietary management of Polycystic Ovarian Syndrome ("PCOS") by reducing the incidence of metabolic syndrome and insulin resistance.”  FDA alleges that these products are misbranded as medical foods because, according to FDA, there are no distinctive nutritional requirements or unique nutrient needs for individuals with mild to moderate Alzheimer’s disease and for PCOS.

Why is this worth a blog post, you ask?  To our knowledge, these are the first two Warning Letters in which FDA asserts yet another requirement for medical foods.  Under FDA’s “narrow interpretation,” medical foods must not only meet all the requirements of FDA’s regulation, 21 C.F.R. 101.9(j)(8), they also must be intended for “the patient who is seriously ill or who require use of the product as a major component of a disease or condition’s specific dietary management.”  Although the Agency mentioned this requirement in the 2007 guidance and the draft 2013 guidance (see our previous post here), so far, the Agency had not mentioned this limitation in Warning Letters.  More important, the Agency has not provided any authority for adding this requirement.

Biosimilars (or follow-on biologics) are a hot topic these days – and getting hotter – whether one talks about FDA’s draft guidance documents (see here), battles brewing in state legislatures around the country concerning substitution (see here), the flurry of citizen petitions submitted to FDA concerning biosimilar naming (see here), controversy concerning the “patent dance” procedures of the Biologics Price Competition and Innovation Act of 2009 (see here), or the applicability of the BPCIA to older biological products (see here).  

On February 4, 2014, the Federal Trade Commission (“FTC”) will hold a workshop addressing some of these issues: “Follow-On Biologics Workshop: Impact of Recent Legislative and Regulatory Naming Proposals on Competition.”  (The final agenda for the February 4th workshop was announced earlier this week.)  And just two days later, on February 6, 2014, from 12:00-1:00 PM EST, experts from Hyman, Phelps & McNamara, P.C. and Dechert LLP will discuss the implications of and issues with the new biosimilar approval process created by the BPCIA and other major takeaways from the FTC workshop.  Topics to be covered during the February 6th webinar will include: (1) Current status and next steps for the FDA’s implementation of a biosimilar approval process; (2) Major takeaways from the FTC’s February 4 workshop on biologics; and (3) Intellectual property issues in the run-up to the first biosimilar approval. 

Registration for the webinar is free and can be made here.  Webinar speakers include Hyman, Phelps & McNamara, P.C.’s James C. Shehan and Dechert LLP’s Daniel M. Becker, M.D., Mike Cowie, and George G. Gordon.  Please confirm your webinar attendance by February 5, 2014.  Further details, including how to connect to the webinar, will be provided closer to the program.

By Ricardo Carvajal –

The Institute of Medicine (“IOM”) published a summary report of the workshop on caffeine in food and dietary supplements that IOM convened last August at FDA’s request.  As noted in the introduction to the summary, the summary presents statements, recommendations, and opinions of individual participants, and does not reflect the consensus of the IOM, nor is it intended to constitute a comprehensive review of the subject.  Nonetheless, the summary may be of use to those who were unable to attend the workshop and have an interest in the issues that were addressed, including:

• Regulation of caffeine in the U.S.
• Intake and exposure to caffeine
• Safety signals and surveillance
• Exploring safe caffeine exposure levels for vulnerable populations
• Caffeine Effects on the Cardiovascular System 
• Caffeine effects on the central nervous system and behavioral effects associated with caffeine consumption
• Other compounds impacting caffeine effects

In a concurrently issued press release, FDA touted the summary as “extremely informative” and reiterated that the agency is “especially concerned with products that may be attractive and readily available to children and adolescents, without careful consideration of their cumulative impact.”  FDA also noted that it continues to investigate adverse event reports for energy drinks and other caffeinated products, with public safety as the agency’s “top priority,” and that the new online adverse event reporting system for dietary supplements “will make it easier for the FDA to detect dietary supplements that pose risk for a range of reasons, including excessive levels of caffeine.” 

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.