The Centers for Medicare & Medicaid Services (CMS) has finalized its proposed rule requiring pharmaceutical manufacturers to disclose the Wholesale Acquisition Cost (WAC) in Direct-to-Consumer (DTC) television advertisements for certain prescription drugs and biological products (the Final Rule). The Final Rule will appear in the Federal Register on May 10, 2019 and will become effective on July 9, 2019.  It is largely unchanged from the proposed rule, which we previously blogged on here.

The Final Rule requires that any advertisement on TV (including broadcast, cable, streaming, or satellite) for a prescription drug or biological product for which reimbursement is available under Medicare or Medicaid must include the following statement:

“The list price for a [30-day supply of] [typical course of treatment with] [name of prescription drug or biological product] is [insert price]. If you have health insurance that covers drugs, your cost may be different.”

The “list price” to be inserted is the WAC, which is defined as the manufacturer’s published list price for the most recent month available, not including discounts or rebates. The list price should reflect the WAC for a typical 30-day regimen or typical course of treatment, as appropriate, and as determined on the first day of the quarter during which the advertisement is being aired on television or otherwise broadcast. For a drug with multiple indications, the list price to be used is the one for the course of treatment associated with the indication advertised. The statement must appear at the end of the advertisement in legible text with a style, font, and duration that allows it to be read easily. The preamble to both the Proposed Rule and the Final Rule (though not the regulation itself) states that manufacturers would also be permitted to include truthful and non-misleading information about a competing product’s current WAC, so long as the provision of such information is consistent with current law.

The Final Rule applies to prescription drugs for which payment is available, directly or indirectly, under Medicare or Medicaid, with the exception of products with a WAC of less than $35 per month for a 30-day supply or typical course of treatment. The only penalty for a failure to provide the statement would be inclusion of the manufacturer on a publicly available “shame” list on CMS’s web site. However, CMS states in the preamble to the Final Rule that it believes the primary enforcement mechanism will be the threat of private actions under the Lanham Act for false or misleading advertising, asserting optimistically that the threat of meritless lawsuits is “acceptably low.”

According to CMS, the Final Rule seeks to address the rising prices of prescription medicines and the impact that such costs have on the Medicaid and Medicare programs. It also seeks to address over-utilization of prescription drugs caused by patients requesting “costly drugs and biological products seen on television.” Finally, CMS asserts, in the Final Rule, that DTC advertising lacking information about a drug’s price is potentially misleading. CMS states that if patients better understand the costs associated with prescription drugs or biological products, they will make “good health care choices,” which will in turn promote efficiency in the Medicaid and Medicare programs. CMS rejected arguments that the WAC itself is misleading because it does not reflect actual out-of-pocket costs paid by consumers.  CMS cited a 2019 study published in the Journal of the American Medical Association as support for the proposition that consumers are better able to estimate their out-of-pocket costs knowing the WAC than without knowing it.

We will continue to report on drug pricing regulations and legislation at the federal and state level.

Responding to objections from New Jersey healthcare practitioners, hospitality and restaurant businesses, and the pharmaceutical industry, the New Jersey Attorney General published an amendment to the state’s rules restricting the acceptance of remuneration by prescribers from pharmaceutical manufacturers.  The final amendment, which appeared in the May 6 New Jersey Register and immediately became effective, relaxes some of the restrictions in the original rule (see our post on that rule here.)  Following are the significant changes from the original rule:

• Meals at Education Events: The original regulation permitted prescribers to accept “modest meals” provided through the event organizer at an education event, and a “modest meal” was defined as one with a fair market value of $15 or less.  The $15 limit has been removed.  In addition, the amendment clarifies that an education event includes an event that focuses on disease states and treatment approaches, and also includes an event that that meets the rule’s definition of “education event” even if FDA classifies that event as promotional.
• Promotional Programs: The prior rule on accepting modest meals provided by drug manufacturers during promotional activities remains in place and is still capped at $15 for lunch, but the cap on dinners has been increased from $15 to $30 (adjusted for inflation after 2018).  Also, the previous limit of four such meals per year has been removed.
• Bona Fide Service Fees: The Attorney General rejected recommendations that the existing cap on bona fide service fees accepted from all pharmaceutical manufacturers during any year be increased from the current $10,000.  Fees for research and for speaking at education events continue to be exempt from this cap, and the preamble clarifies that research includes both pre-market and post-market research.
• No application to devices: The regulation continues to apply only to gifts and payments from pharmaceutical manufacturers, but a helpful clarification has been added that the rules do not apply to prescribers’ interactions with pharmaceutical manufacturers that also manufacture medical devices if the interactions are directly solely to medical devices.

As FDA continues to approve biosimilar drug products, and as sponsors participate – or rather choose not to participate – in the Biologics Price Competition and Innovation Act (“BPCIA”) version of the patent dance, more questions arise about the remedies reference product sponsors have when certain steps are not followed.  As we have detailed extensively (here, here, here, and really any post tagged under the “biosimilars” category of the FDA Law Blog), new questions about the BPCIA patent dance continue to pop-up and make for interesting new lawsuits.  Such is the case with FDA’s April 25, 2019 approval of Samsun Bioepis’s Eticovo, a biosimilar to Amgen’s Enbrel, which has resulted in another lawsuit, this time asking the Court to enjoin marketing of Eticovo until it provides the 180-day notice required under the BPCIA.

In a Complaint filed on April 30, 2019, Amgen alleges that Samsung Bioepis infringed the multiple unexpired patents covering Enbrel.  Originally licensed in 1998, Enbrel is now approved for multiple indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis.  Samsung Bioepis’s Eticovo is approved for the same indications and route of administration, and it shares the same dosage form and strength as an approved version of Enbrel.  The suit alleges that Samsung Bioepis infringed five patents covering Enbrel and asks for a declaratory judgment that Samsung Bioepis has infringed and/or would infringe one or more claims of each of the patents at issue, as well as injunctive relief preventing Samsung Bioepis from commercial marketing consistent with the 180-day notice period under the BPCIA.

Samsung Bioepis declined to participate in the patent dance, as it is entitled to do under the Supreme Court’s 2017 decision in Amgen v. Sandoz, so Amgen brought this declaratory judgment action to enforce its patent rights under section 351(l)(9)(C) of the Public Health Service Act (42 U.S.C. § 262(l)(9)(C)).  But because Samsung Bioepis did not participate in the exchange of patent information, Amgen posits that it is “reasonable to infer that Bioepis might not provide notice to [Amgen subsidiary] Immunex in accordance with § 262(l)(8)(A).”  Indeed, Amgen alleges that “Bioepis is prepared imminently to begin to use, offer, for sale, and sell in the United States, and import into the United States, its etanercept biosimilar product.”  As such, Amgen seeks a temporary restraining order and injunction to prohibit Samsung Bioepis from commercial launch of Eticovo until 180 days after it provides notice of intent to market to Amgen’s subsidiary and Enbrel BLA holder (and co-Plaintiff) Immunex.

While the Supreme Court has determined that the patent dance and provision of the 351(k) biosimilar application is not mandatory, the Court further determined in Amgen v. Sandoz that the notice provision is.  But the Act doesn’t contemplate failure to provide this notice, and it is not clear what remedies are available at this juncture.  It’s not clear that a Court would grant injunctive relief here when there is no assurances that Samsung Bioepis is actually intending to launch in the near future (and without notice).

Patent remedies based on the submission of Samsung Bioepis’s aBLA are most likely available.  Certainly, in this situation, an aBLA sponsor would be launching at risk and potentially be liable for treble damages but like with premature at-risk launch of generic small molecule drugs, the bell can’t be unrung once the product floods the market.  That biosimilars are not automatically substitutable for their RLDs makes such an act less of a threat to Amgen’s market share.  But chances are high that an influx of Eticovo would still undercut Amgen’s Enbrel market, at least to some extent.  If there is no further recourse for Amgen other than the treble damages award arising from patent infringement, it raises questions of whether an at risk launch of a biosimilar will result in significantly smaller damages awards for reference product sponsors.  Is it possible that the treble damages award could be less than attorneys’ fees (we note that Amgen here is seeking attorneys’ fees)?  And if so, is treble damages enough to deter at risk launch when each biosimilar needs to find a way to get individual attention?  In other words, could the publicity of an at risk launch be worth the treble damages in news coverage and publicity?  Probably not but given all of the moving parts in the BPCIA and the uncharted market, it seems fair to say that “business decisions,” as opposed to legal decisions, may end up the driving force as this market develops.

As you may have noticed, FDA recently unveiled a new website.  As part of this redesign, FDA “enhanced” the Product-Specific Guidances (“PSG”) for Generic Drug Development web page.  The “enhanced” version of the website includes new database and search function features, export features, and paginated search results.  The new search functions will allow users to perform text searches of PSGs by active ingredient, by Reference Listed Drug application number, or Reference Standard application number and will allow further filtration of search results.  Of course, the guidances are still available to browse alphabetically rather than search (and there are 1685 of them for your reading pleasure).

As exciting as the new website is, FDA really buried the lead when it announced the new website.  In response to common complaints from industry, FDA has adopted a new resource for PSGs, a dynamic web page entitled “Upcoming Product-Specific Guidances for Complex Generic Drug Product Development.”  This web page contains a list of PSGs for complex generic products that are currently under development or for a which a revision is planned in the next year.  The list reflects FDA’s efforts to be transparent regarding plans for development and revision of PSGs so that sponsors can be aware of what is in the pipeline and discuss with FDA the appropriate testing as necessary.

Generic manufacturers have found that FDA’s bioequivalence recommendations for a given product may have changed during development of a generic.  Sometimes, these recommendations change after a product has been submitted but before FDA has completed its review, requiring sponsors to perform additional studies after submission.  In fact, this situation has occurred enough that Congress carved out an exception from the 180-day exclusivity tentative approval forfeiture provisions for it.  As Brian McCormick, Vice President & Chief Regulatory Counsel Teva Pharmaceuticals USA, Inc. explained during the Incentivizing Generic Competition Panel at FDLI’s Annual Conference last week, such changes to bioequivalence requirements “midstream” can throw off the years of planning that goes into large ANDA development programs and may have ripple effects in the development of other ANDA products in the pipeline.  To paraphrase Wag the Dog (and Abraham Lincoln): You don’t change horses in midstream.

While obviously no one advocates for the approval of a generic product with a less than robust demonstration of bioequivalence, transparency in the publication and the revision of these guidances would go a long way to alleviate some industry complaints.  To that end, FDA’s list of planned PSG revisions announces the PSGs in development, as well as those under revision in the next year, so that sponsors can plan accordingly.  According to Dr. Robert Lionberger, Director of FDA’s Office of Research and Standards, the intent of this list is to provide the notice and transparency that industry seeks to alleviate surprises that may arise after an application is submitted.  FDA is aware of the issue and is therefore attempting to be more open with sponsors about changes in the pipeline.

The PSG list information includes the active ingredient(s), route of administration and dosage form, and RLD application number.  Additionally, the PSGs undergoing revision are also assigned a “planned revision category.”  The revision categories are “Major Revisions,” “Minor Revisions,” and “Editorial Revisions.”  “Major Revisions” are defined as the revision of PSGs to include additional bioequivalence studies or evidence recommended to support FDA approval.  “Minor Revisions” are any revisions not considered major, including the removal of certain studies, providing alternative and less burdensome approaches to currently recommended studies, to add information on newly approved strengths of the RLD, or to make other recommendations that would not result in the requirement of a new bioequivalence study.  “Editorial Revisions” are non-substantive changes, updates of external references, corrections of grammatical issues, and changes to formatting.

This new system isn’t perfect.  Some companies rely on these PSGs years in advance of submitting an ANDA, so notice of new bioequivalence requirements only a year in advance might not be a panacea.  Further, the list only covers “complex” generics, and if there are any changes to PSGs for more basic generics, sponsors may not have the same transparency.  But there is little doubt that the Agency’s efforts to remediate at least some of the generic industry’s complaints in this area provides at least a bit of relief to sponsors.  We’ll have to see how well FDA keeps this list updated and how helpful this list actually is given how early some companies start development of new generics.  But if nothing else, FDA’s continued work to make the generic development process easier and more accessible demonstrates that the agency’s commitment to generic competition has not waned in the post-Commissioner Gottlieb era.

Hi-Tech Pharmaceuticals, Inc. (Hi-Tech) and its President and Chief Operating Officer filed suit in the U.S. District Court for the District of Columbia to enjoin FDA from continuing to seek removal of DMHA products from commerce through the issuance of warning letters and “pressure… to remove and destroy DMHA containing products.”  Plaintiffs allege that FDA has failed to meet its burden of proof in showing adulteration, as required by section 402(f)(1) of the FFDCA, and that the agency is circumventing its statutory obligation to engage in rulemaking to “formally ban” DMHA.

Plaintiffs argue that DMHA “is a natural constituent of walnut trees” with “an extensive history of use in dietary supplements,” and that “there is a significant body of scientific evidence supporting the safety of DMHA for human consumption.”  Although Plaintiffs do not explicitly state whether the DMHA in their products is naturally derived or synthetically produced, they assert that “[d]ietary ingredients include both naturally occurring and synthetically produced versions of the same ingredient,” and that “FDA has recognized the equivalence of natural vs. synthetically produced dietary ingredients in the context of several vitamins and other ingredients.”

Plaintiffs allege that FDA’s actions violate the Administrative Procedure Act in that they are contrary to law, exceed the agency’s statutory authority, and are arbitrary and capricious.  Plaintiffs further allege that FDA’s actions violate the Fifth Amendment by depriving Plaintiffs of due process.

As noted in the complaint, Hi-Tech is already engaged in litigation with the government over the regulatory status of DMAA.  That case is currently under review by the 11th Circuit Court of Appeals.  We’ll be keeping an eye on both cases as the litigation unfolds.

A recent decision out of Pennsylvania caught our eye, not because it applied a new enforcement strategy by FDA, but to the contrary, because it relied on FDA’s “oldie but goodie” Inspection Warrant authority.  Not a search warrant, which is subject to the same “probable cause” standard as all criminal search warrants, but an administrative tool that is rooted in the inspection provisions of the FDC Act, 21 U.S.C. § 374(a).  FDA admits it rarely uses this authority: “FDA does not routinely request inspection warrants in order to conduct investigations or inspections of regulated industry. However, warrants have been used effectively to gather information that has been refused improperly.”

FDA’s Regulatory Procedures Manual requires the following criteria to seek an inspection warrant:

1. FDA is entitled by statute or regulation to inspect the facility and to have access to the information which has been refused; and
2. there is a compelling FDA need for that information, and
3. the firm/individuals have refused to allow inspection or access to information in spite of a clear demonstration or explanation of appropriate statutory authority.

In the reported decision, In the Matter of Administrative Establishment Inspection, No. 1:18-MC-546, 2019 U.S. Dist. LEXIS 65476 (M.D. Pa. Apr. 17, 2019), FDA tried five times to inspect Spa & Organic Essentials after a nationwide outbreak of salmonella was linked to kratom distributed by the company.  Kratom is a food, as defined by the FDC Act, and Spa & Organic Essentials is subject to regulation by FDA as a food manufacturer and distributor.  Despite evidence linking the company to the contaminated kratom, the company refused to cooperate with FDA inspectors.  Thus, FDA turned to this rarely used tool, described as an “Inspection Warrant” by FDA, but termed an “Administrative Search Warrant” by the court.  The court issued the warrant on September 27, 2018, and FDA executed the warrant on October 3, 2018.  Both parties filed motions related to the warrant: Spa & Organic Essentials sought to quash the warrant, and FDA sought to require Spa & Organic Essentials to make statements and provide passwords for computers seized by FDA.

The court denied both motions.  The court recognized the strong deference afforded to the magistrate judge’s determination of probable cause, and also reinforced the well-settled proposition that “probable cause” in the criminal law sense is not required for an administrative warrant.  Rather, probable cause may be based on either:

• A particularized showing that the manufacturing plant targeted for the search is the location of suspected . . . violations; or
• A showing that the industry in general poses certain hazards to workers coupled with a showing that the targeted facility was selected at random as part of a general plan to pursue and eliminate suspected industry-wide violations.

The court concluded there was “ample probable cause for the FDA to conduct this search.”  The court was persuaded by the evidence linking Spa & Organic Essentials as the potential source for the salmonella-tainted kratom, and the company’s refusal to cooperate with other investigative measures.

The court denied as premature FDA’s request to compel the company to speak with investigators on the ground that the warrant did not affirmatively require the company to engage in testimonial conduct, just the seizure of records.   Thus, the court instructed FDA to take steps to first compel production of the information. But how can FDA take those steps? As noted above, the administrative warrant is rooted in the FDC Act inspection provisions. There is nothing in those provisions that requires an inspected entity to “allow” FDA to interview the entity’s employees. Thus, short of obtaining a criminal search warrant or getting a criminal subpoena, there is simply no step that FDA can take to compel interviews of the inspected entity.

This case serves as good reminder to all FDA-regulated entities of the arsenal of tools FDA has to conduct its regulatory oversight.  However the case also is a reminder of a key limitation on FDA’s inspectional authority, namely the absence of any statutory authority to compel any company employee to speak about any topic during an FDA inspection. Thus, regulated industry must remember that allowing its employees to speak during an FDA inspection is a purely voluntary decision, and not one that FDA has any statutory authority to compel under the FDC Act.  We assume FDA will only use the Inspection Warrant in limited circumstances, as proscribed by the RPM, but companies should know that a decision to refuse an inspection may be short-lived.

The Department of Justice (“DOJ”) has been touting for years the common interest that government and industry share in promoting an ethical corporate culture.  This week, DOJ reinforced the importance of a robust, well-designed, and effective corporate compliance program in DOJ’s determination of whether to prosecute, impose monetary penalties, and require compliance obligations on a company accused of misconduct.

In an updated guidance document, DOJ expands on the types of questions prosecutors should be asking to evaluate a company’s compliance program.  The questions fall under three main categories:

• Is the corporation’s compliance program well designed?
• Is the program being applied earnestly and in good faith? In other words, is the program being implemented effectively?
• Does the corporation’s compliance program work in practice?

If the questions are answered positively, then DOJ may decline to prosecute the company, focus efforts on prosecuting individuals, or provide leniency in the fine or imposition of a monitor.

For the first question, DOJ evaluates the comprehensiveness of the program (i.e., whether there is a clear message from the top that misconduct is not permitted).  To do this, DOJ instructs its attorneys to review a company’s policies and procedures for assigning responsibility, training, and disciplining.  DOJ specifically highlights the diligence process associated with M&A activities.  Although it is our experience that companies already include compliance issues as part of its due diligence, this recent statement by DOJ heightens the priority companies should place on these issues pre- and post-closing.

For the implementation question, the key issues relate to the commitment by management to foster the culture of compliance.  DOJ wants to see commitment from not just the Board of Directors or Senior Executives at a company, but also wants to see that “middle management” is reinforcing these standards.   And to evaluate the last category of questions, whether the program actually works, DOJ looks at how misconduct is identified, and whether there is adequate analysis and remediation of the misconduct once uncovered.

Notably, these same questions are those that drug and device companies routinely ask in the context of evaluating complaints about the company’s products.  The Quality System Regulation requires medical device companies to establish procedures to implement corrective and preventive action.  See 21 C.F.R. § 820.100.  These procedures must include an investigation of the cause of the issue, actions to correct and prevent recurrence of the issue, validation to ensure the actions are effective, and management oversight and review.  Similar requirements are imposed on drug manufacturers as part of complaint handling and adverse event reporting.  See, e.g., 21 C.F.R. §§ 211.198, 314.80.  Thus, a framework for addressing compliance issues should be very familiar to pharma and device companies.

Ironically, DOJ issued this guidance in the shadow of another DOJ policy that prohibits its lawyers from basing enforcement on violations of requirements set forth in guidance documents.  Nevertheless, this 18-page guidance document is worth close review by compliance officers.

Last week FDA issued a final guidance, Unique Device Identification: Convenience Kits, which clarifies FDA’s interpretation of a convenience kit for purposes of UDI labeling requirements.  We previously blogged on the draft version here.   As our readers know, the unique device identification system regulations require that the label and device package of a device must bear a UDI, unless an exception or alternative applies.  One such exception is for devices packaged within the immediate container of a convenience kit if the label of the convenience kit bears a UDI.  21 C.F.R. § 801.30(a)(11).

Unchanged from the draft guidance is FDA’s definition of a convenience kit: A convenience kit is “two or more different medical devices packaged together for the convenience of the user” (21 CFR 801.3).  FDA interprets this to mean a device that contains two or more different medical devices packaged together and intended to remain packaged together and not to be replaced, substituted, repackaged, sterilized, or otherwise processed or modified before being used by an end user.  FDA clarifies that “packaged together” means packed (e.g., wrapped or sealed) in a single container that is not intended to be unwrapped or unsealed before it is used by an end user.  Notably, the guidance does not apply to kits that contain devices co-packaged with drugs.

Kits that meet the definition of a “convenience kit” must include a UDI on the kit label and the individual devices within the kit are exempt from the requirement to bear a UDI.  21 C.F.R. § 801.30(a)(11).  Medical devices that are a part of kits that do not meet this definition must be individually labeled in accordance with applicable UDI requirements.

The final guidance includes additional examples and clarifications:

• First aid kits

Like the draft, the final guidance concludes that a first aid kit meets the definition of a convenience kit because the bandages, scissors, etc., are sealed in a single package and are not unpackaged until they are used by the end user.  Those components would not need to be individually labeled with a UDI, as long as a UDI is affixed to the immediate container of the kit.  The final guidance adds that end users may wish to replenish components of the first aid kit, rather than purchasing a new one as supplies run out.  In that case, the individual devices used to replenish or augment the first aid kit must bear a UDI because they were not part of the original convenience kit.

• Non-sterile orthopedic device set

This example is largely the same, with only stylistic differences from the draft.  As before, a collection of orthopedic implants and reusable instruments that are all supplied as non-sterile would not meet the definition of a convenience kit for UDI purposes.  Each of these devices is removed from its packaging and placed into a sterilization tray for cleaning and sterilization at some point prior to use.  Potentially unused components, which may be used later, will not remain packaged with the other components prior to use.  Therefore, each device in the set must comply with all applicable UDI labeling, data submission, and direct mark requirements.

• Single use disposable medical procedure kit

This example is also largely unchanged.  A sterile procedure kit consisting of various instruments, guide wires, graft passers, etc. would meet the definition of a convenience kit because the components all remain packaged together up until the point in time when the surgeon opens the tray for use on the patient.  The final guidance adds that this example is distinguishable from Example 2, in which the devices are intended to be sterilized prior to use and intended to be reassembled and restocked between uses.

• Sterile kit containing both single-use and reusable medical devices packaged together

This is a new example in the final guidance.  In this example, FDA describes a suture kit which contains single-use sutures and reusable stainless steel instruments, including forceps, needle holders, and scissors.  The kit is supplied sterile, but after the initial procedure in which the single use device (suture) is consumed, the labeler intends that the instruments may be reused on different patients, which requires reprocessing before each subsequent use.  FDA would consider this a convenience kit because the individual devices within the device are packaged together for the convenience of the user and not intended to be replaced, substituted, repackaged, sterilized, or otherwise processed or modified before the devices are used by an end user.  FDA notes, however, that because some devices in the kit are intended to be reprocessed and reused, those devices would be subject to direct mark requirements under 21 C.F.R. § 801.45.

• Different devices packaged together for the convenience of the user but the collection of devices is not itself a device

This is also a new example in the final guidance.  In this example, a labeler manufactures fluid-filled teething rings in a variety of shapes.  The labeler packages one teething ring of each shape together as a fixed quantity to create an item for retail with a higher profit margin and/or to allow each end user to select and use a particular model of teething ring according to preference.  This is not considered a convenience kit for UDI purposes because the devices packaged together are not collectively a device.

A few key points regarding this final guidance:

These additional examples help to clarify some of the takeaways we previously reported.  For example, the draft guidance implied that if any devices in a kit required sterilization prior to use, it could not be considered a convenience kit.  Based on the fourth example in the final guidance, however, there is a noteworthy exemption from this general rule.  If the product is initially provided as sterile, but requires sterilization after its first use, FDA would consider this a convenience kit.

We also note, as we did in our previous post, that the intent of the labeler informs the determination of whether a kit is a convenience kit for UDI purposes.  How the product is used has no bearing on the analysis.

FDA’s interpretation and application of the Best Pharmaceuticals for Children Act (“BPCA”), which provides for a 6-month add-on period of pediatric exclusivity has piqued our interest more than once over the years, leading to several posts (see, e.g., here, here, and here).  We now have another interpretation to add to the collection . . . .

By way of background, FDC Act § 505A provides an additional 6 months of patent and non-patent exclusivity to pharmaceutical manufacturers that conduct acceptable pediatric studies of new and currently-marketed drug products identified by FDA in a Written Request for which pediatric information would be beneficial.  Pediatric exclusivity extends all other types of Orange Book-listed patent and non-patent marketing exclusivity (e.g., 5-year, 3-year, and 7-year orphan drug exclusivity) an application holder may have under the FDC Act, provided that at the time pediatric exclusivity is granted there is not less than nine months of term remaining.

An important aspect of pediatric exclusivity is that it provides additional marketing exclusivity not just for the pediatric indications or formulations, but for all protected indications and formulations of that sponsor’s drug.  Thus, pediatric exclusivity attaches to the patent and non-patent marketing exclusivity for any of the sponsor’s approved drug products (including certain combination products) that contain the active moiety for which pediatric exclusivity was granted, and not to a specific drug product.  See National Pharmaceutical Alliance v. Henney, 47 F. Supp. 2d 37 (D.D.C. 1999).

In particular, FDC Act 505A(c), titled “Market Exclusivity For Already-Marketed Drugs,” states:

(1) IN GENERAL.—Except as provided in paragraph (2), if the Secretary determines that information relating to the use of an approved drug in the pediatric population may produce health benefits in that population and makes a written request to the holder of an approved application under section 505(b)(1) for pediatric studies (which shall include a timeframe for completing such studies), the holder agrees to the request, such studies are completed using appropriate formulations for each age group for which the study is requested within any such timeframe, and the reports thereof are submitted and accepted in accordance with subsection (d)(4)—

(A)(i)(I) the period referred to in subsection (c)(3)(E)(ii) of section 505, and in subsection (j)(5)(F)(ii) of such section, is deemed to be five years and six months rather than five years, and the references in subsections (c)(3)(E)(ii) and (j)(5)(F)(ii) of such section to four years, to forty-eight months, and to seven and one-half years are deemed to be four and one-half years, fifty-four months, and eight years, respectively. . . .

The exception referred to above (i.e., “Except as provided in paragraph (2)”) states:

(2) EXCEPTION.—The Secretary shall not extend the period referred to in paragraph (1)(A) or (1)(B) if the determination made under subsection (d)(4) is made later than 9 months prior to the expiration of such period.

The exception provision was added to the statute in September 2007 with the passage of the FDA Amendments Act (“FDAAA”).  Specifically, Title V of FDAAA reauthorized and amended the 2002 BPCA (Pub. L. No. 107-109, 115 Stat. 1408) to add the 9-month exception and remove (with some exceptions included in a FDAAA transition provision) former FDC Act § 505A(e), which permitted FDA to delay the acceptance or approval of an ANDA (or a 505(b)(2) NDA) by up to 90 days if an NDA sponsor submitted study results in response to a Written Request immediately prior to the expiration of any applicable period of patent or non-patent market exclusivity.  Former FDC Act § 505A(e) allowed sponsors to obtain a period of de facto pediatric exclusivity while FDA reviewed study results even if the Agency ultimately determined that the studies did not meet the terms of the Written Request.

FDA’s implementation of the exception provision at FDC Act § 505A(c)(2) (and its sister provision at FDC Act § 505A(b)(2)) has been relalatively free from controversy.  But a recent set of circumstances has raised some eyebrows.  In what appears to us to be a case of first impression, FDA granted a period of pediatric exclusivity shortly before the so-called “NCE-1” (New Chemical Entity) ANDA Paragraph IV submission date for a drug, resulting in a new NCE-1 submission date 6 months later.

The drug at issue is CORLANOR (ivabradine), 5 mg and 7.5 mg, Tablets, which FDA approved on April 15, 2015 under NDA 206143 and granted a period of 5-year NCE exclusivity that initially expired on April 15, 2020.  FDA issued the NDA holder a Written Request for pediatric studies in April 2015 (see here), and it appears, based on a very recent update to the Orange Book, that the NDA holder fairly responded to the Written Request and that the Agency granted pediatric exclusivity shorly before April 15, 2019.  That resulted in an extension to the NCE exclusivity period (identified in the Orange Book as “NCE *PED”) until October 15, 2020.

But should the exception at FDC Act § 505A(c)(2) also apply to the period that is the April 15, 2019 NCE-1 Paragraph IV submission date?  According to FDA, the answer is “No,” even though there was less than 9 months of term remaining in the NCE-1 period as of the date FDA granted pediatric exclusivity.

So what gives?  Well, it turns out that FDA does not consider the NCE-1 date to be a “period” under the statute, but rather a “reference.”

Let’s turn back to the language of the statute.  It says that if pediatric exclusivity is granted, then, for a drug product with 5-year NCE exclusivity, “the period referred to in subsection (c)(3)(E)(ii) of section 505, and in subsection (j)(5)(F)(ii) of such section, is deemed to be five years and six months rather than five years, and the references in subsections (c)(3)(E)(ii) and (j)(5)(F)(ii) of such section to four years, to forty-eight months, and to seven and one-half years are deemed to be four and one-half years, fifty-four months, and eight years, respectively. . . .”  The exception provision says that FDA “shall not extend the period referred to in paragraph (1)(A) or (1)(B) if the determination made under subsection (d)(4) is made later than 9 months prior to the expiration of such period.”

Thus, according to FDA, there are “periods” and “references” (or referenced periods?) under the statute that must be treated differently because the exception provision mentions only “the period.”  Thus, according to FDA, if pediatric exclusivity is granted immediately before the NCE-1 date, which is more than 9 month before the expiration of NCE exclusivity, then pediatric exclusivity will apply to the NCE-1 date (by operation of it applying to the NCE expiration date), and prevent ANDA Paragraph IV submission for an additional six months.  Any company that submits an ANDA beforehand will receive a rejection letter.

In 2016, the Animal League Defense Fund (ALDF) sued Hormel Foods Corporation, alleging that the company’s use of the terms “natural” and “no preservatives added” in advertising for its Natural Choice products violated the D.C. Consumer Protection Procedures Act.  Plaintiff alleged that the these claims materially misled consumers into believing that Hormel’s products are made from animals that are humanely raised and not “factory farmed” and that they do not contain preservatives or nitrates or nitrites that are not from natural sources.  The advertising claims were identical to the claims on the product labels.

Hormel moved for summary judgment claiming that the ALDF did not have standing to bring the case and that, in any event, the claim was preempted by federal law.

Like the Federal Food, Drug and Cosmetic Act (FDC Act), the Federal Meat Inspection Act (FMIA) and the Poultry Products Inspection Act (PPIA) prohibit the sale of meat and poultry products that are labeled in a false or misleading manner.   The FMIA and PPIA specifically preempt state labeling law and delegate the regulation of meat and poultry products to the USDA.  See 21 U.S.C. §§ 467e & 678 (“Marking, labeling, packaging, or ingredient requirements . . . in addition to, or different than, those made under this chapter may not be imposed by any State.”)  USDA has interpreted the laws as requiring that FSIS review and approve the labels.  Although some labels may be approved generically, labels with certain claims, including natural claims, must be reviewed and approved by USDA.  The USDA reviewed and approved Hormel’s use of the claims “natural” and “no preservatives added.”

The FMIA and PPIA do not regulate advertising and FSIS does not review and approve advertising claims.  ALDF argued that the advertising claims therefore were not preempted.  However, the court held that as long as manufacturer’s labels are approved by the USDA, the manufacturer can use those same claims in advertising.  State law challenges to those advertising claims are preempted.  Any other interpretation would result in confusion.  If USDA determines that a “producer can accurately use a term in a label . . . the producer should be able to use the same term in its advertising.”  Since USDA had made an affirmative decision that the claims of “natural” and “no preservatives added” were not misleading as applied to Hormel’s meat products a challenge to these claims used in advertising was preempted.  Challenges to advertising claims that are different in material ways from claims on approved labels would not be preempted.

FDA’s nutrition labeling rules have defined most nutrients based on chemical structure.  However, in light of evidence on allulose, FDA may need to reconsider that focus.

Allulose is a monosaccharide, and the nutrition labeling regulation defines sugars as mono- and disaccharides.  Thus, under the regulations, allulose counts as a sugar.  However, as explained in three citizen petitions and in comments to FDA’s nutrition labeling regulation, allulose is a special type of monosaccharide.  Apparently, although allulose is a monosaccharide, it does not behave like one. Allulose does not have the metabolic properties of other mono-(and di-)saccharides, such as glucose and sucrose,  it contributes less than 0.4 kcal/gram (vs. 4 kcal/gram for sucrose), and does not raise blood sugar levels like other sugars.  Moreover, allulose is not cariogenic (i.e., it does not contribute to tooth decay).

On April 10, 2015, Tate & Lyle Ingredients America LLC (Tate & Lyle) submitted a Citizen Petition requesting that FDA amend the nutrition labeling regulation to exempt allulose from being included as a carbohydrate, sugar and added sugar in the nutrition facts box.  Tate & Lyle claimed that inclusion of allulose as carbohydrates and (added) sugar in the Nutrition Facts box would lead to confusion for consumers, especially consumers that monitor blood glucose levels such as consumers with diabetes.  Although the Petition had been submitted before FDA issued the revised nutrition labeling regulation, FDA did not decide on a possible exemption of allulose.  Instead, it concluded that allulose, as a monosaccharide, would need to be included in the amount of the declaration of “Total Carbohydrate,” “Total Sugars,” and “Added Sugars.”  The final rule also did not address the caloric value for allulose.

Subsequently, FDA received two additional Citizen Petitions, one by Tate & Lyle and one by Food Lawyers, requesting that FDA adjust the caloric value for allulose.

Based on of the Citizen Petitions and the scientific evidence, FDA recognizes that it may need to reconsider its focus on chemical structure in determining whether allulose is a sugar.  While it is pondering its best course of action, FDA has issued draft guidance announcing that FDA intends to exercise enforcement discretion to allow manufacturers to exclude allulose from total and added sugars declarations and to use 0.4 calories per gram of allulose when calculating the calories from allulose in a serving of a product.

Comments to the draft guidance must be submitted by June 17, 2019.

In the press release announcing the draft guidance, FDA mentioned that we can expect additional guidance regarding the new nutrition labeling requirements, including a guidance for added sugars labeling on packages and containers of honey, maple syrup and certain cranberry products.  With the mandatory compliance date of Jan. 1, 2020 looming, this is welcome news.

As expected, Donald Trump has signed the Medicaid Services Investment and Accountability Act of 2019 (H.R. 1839), which, among other things, amends the Medicaid Drug Rebate statute to impose penalties for misclassifying innovator drugs as non-innovator drugs to reduce rebates.  We previously posted on this law when it passed the Congress on April 2 (see our previous post here).  The law is effective as of April 18, the date of enactment.

On April 16, the Food Safety & Inspection Service (FSIS) of USDA announced the publication of a proposed rule amending the labeling regulations for net content statements on meat and poultry.  FSIS proposes to remove the requirement for dual declaration of net weight and net content on packages that contain at least one pound or one pint, but less than four pounds or one gallon.

FSIS is proposing this action after receiving a petition submitted by a small meat processor in response to USDA’s request for ideas to better serve its customers.  As described in the preamble to the proposed rule, the requirement for dual declaration has created confusion for industry.  Under the proposed rule, establishments that produce meat and poultry products in packages containing at least 1 lb. or one pint and less than 4 lb. or 1 gal. will be allowed to express the weight or contents in one unit of measurement on the product label instead of using both measures — e.g., “Net Wt. 24 oz.” or “Net Wt. 1.5 lb.” rather than “Net Wt. 24 oz. (1.5 lb.).  Establishments would be allowed to use their current labels until they run out or may elect to use them indefinitely.

FDA regulations for net content statement include a similar requirement.  It will be interesting to see if someone petitions FDA to also amend its regulation.

Comments to the proposal must be submitted by June 17, 2019.

Last week FDA issued a final regulation regarding consumer antiseptic rubs.  In 2016, FDA had proposed that 28 active ingredients, including triclosan, are not eligible for evaluation under the FDA’s OTC Drug Review for use in consumer antiseptic rubs.   FDA requested but did not receive more data on those ingredients.  Three other active ingredients, ethyl alcohol, benzalkonium chloride, and isopropyl alcohol remain under consideration.  In the proposed rule (described here), FDA indicated that it needed more information to ensure that the ingredients are safe and effective; according to FDA, developing science and increased frequency of use have resulted in concerns about absorption and systemic exposure to the ingredients included in topical drug products, such as the consumer antiseptic rubs.  Thus, FDA has requested additional data, including so called MUsT information.  In the final rule, FDA reaffirms the need for these data on the three active ingredients that remain under consideration.  Similar data are needed for the health care antiseptics.  To the extent that there is overlap of studies needed for certain ingredients, the industry need not repeat the studies.  For example, data generated from a MUsT study sufficient to support a healthcare antiseptic indication will also be sufficient to support a consumer antiseptic indication, because the maximal usage across consumer settings is lower than the maximal usage in a healthcare setting.

The rule declaring the 28 ingredients ineligible for use in consumer antiseptic rubs is effective April 12, 2020.  Since only a small percentage of the consumer antiseptic rubs currently marketed in the United States contain any of the 28 active ingredients that have been determined ineligible, the impact of this final rule will be relatively minor.

In its press release, FDA mentions that this final rule completes its series of rulemakings  for OTC antiseptics to determine whether they are safe and effective.  Presumably the Agency referred to the series of rulemakings required under the consent decree with NRDC.  However, as readers of this blog know, FDA is not yet done.  The Agency deferred decisions on certain active ingredients for consumer antiseptic washes (benzalkonium chloride, benzethonium chloride, and chloroxylenol), health care antiseptics (benzalkonium chloride, benzethonium chloride, chloroxylenol, ethyl alcohol, isopropyl alcohol and povidone iodine), and, now, the consumer antiseptic rubs (ethyl alcohol, benzalkonium chloride and isopropyl alcohol).  FDA has not set a specific deadline for final action on these ingredients but instead will address their status “either after completion and analysis of ongoing studies to address the safety and effectiveness data gaps . . . or at a later date, if these studies are not completed.”  The deferral letters for each ingredient set forth initial deadlines for submission of a plan to address the outstanding data gaps.  Moreover, because FDA has not concluded that an active ingredient is GRAS/GRAE for any of the categories of the antiseptic drug products, the Agency has not yet addressed labeling and finished product efficacy testing.  Thus, once the safety studies have been done, assuming FDA finds at least one ingredient in a category GRAS/GRAE, further rulemaking will be needed.  In addition, rulemaking for the first aid antiseptics is not yet complete and in December 2018, FDA took only the first step on the path to a monograph for antiseptics for food handlers.  The timing of the remaining rulemaking is not subject to the consent decree.

As it previewed back in December, the government formally filed its motion to dismiss the high-profile False Claims Act case against Gilead Sciences, Inc.  This case has had a long history, beginning in 2010 when the Relators filed their original complaint.  After investigation, in 2013, the government declined to intervene in the action but did not at that time move to dismiss the case.  (This decision pre-dated the 2018 Granston memo, which directed  the Department of Justice (“DOJ”) to affirmatively seek dismissal in certain circumstances.)

The government likely rues its decision not to seek dismissal back in 2013, given that DOJ has been engaged in multiple rounds of briefing to dismiss the case in the ensuing six years.  Although the stated reason for aggressively seeking dismissal is “to avoid the additional expenditure of government resources on a case that it fully investigated and decided not to pursue,” the unstated concern appears to be to avoid an adverse ruling about the standard for “materiality” applied to False Claims Act cases.  The “materiality” issue has begged for more clarity since the 2016 ruling in Universal Health Services, Inc. v. United States ex rel. Escobar, 136 S. Ct. 1989 (2016), which requires a plaintiff to allege that a misrepresentation by the defendant was “material to the government’s payment decision.”

The factors the government considers in deciding to dismiss a matter, as outlined in the recent motion to dismiss brief, are instructive to the factors the government should be using in deciding whether to decline to intervene in the first place.  For example, in Gilead, the government claims:

In addition to preserving scarce resources, dismissal is also appropriate to prevent Relators from undermining the considered decisions of FDA and CMS about how to address the conduct at issue here.  .  .  .  In this case, FDA exercised continuing regulatory oversight of Gilead’s manufacturing processes, including multiple on-site inspections of Gilead’s facilities both before and after Relators filed their complaint.  FDA took the actions that it deemed appropriate.  Relators’ case now asks a jury to find that different action was nevertheless required.

Substituting “DOJ” for “Relators” in the above excerpt arguably should lead to the same result: that DOJ should not substitute its judgment when the affected agencies, FDA and CMS, have considered and taken actions they deemed appropriate.  Taking it one step further, these same factors support a finding that the company’s conduct was not material to the government’s payment decision, which in and of itself supports dismissal.  And these factors could extend outside the FCA world to require dismissal in all instances in which DOJ attempts to base a follow-on action using the same facts known to and addressed by the agency.

It will be interesting to see how the government distinguishes this case from others in which it has “already spent resources extensively investigating Relators’ claims, reviewing the merits of the case as presented by Relators, and monitoring the case after declination.”  If this is the standard, almost every FCA matter the government declines and that the Relator continues to advance should result in an affirmative motion to dismiss no later than the close of discovery.