Because a drug is designated an “Orphan” if it is intended to treat a “rare condition,” the condition itself always has been integral to Orphan Drug Exclusivity.  Indeed, the condition for which the product is intended to treat dictates the prevalence calculation by which FDA determines eligibility for an Orphan Drug Designation.  But the scope of Orphan Drug Exclusivity has always been based on the indication for which the product has been approved.  In yet another blow to FDA’s implementation of the Orphan Drug Act—specifically Orphan Drug Exclusivity—the Eleventh Circuit, in Catalyst v. FDA, ruled that limiting Orphan Drug Exclusivity to the indication, rather than the condition designated, is inconsistent with the plain language of the statute.  And last week, FDA officially withdrew approval of an amifampridine drug product approved for a pediatric subset of an Orphan-protect condition due to this broadened scope of Orphan Drug Exclusivity.

In 2009, Catalyst’s drug Firdapse (amifampridine phosphate) received Orphan Drug Designation for Lambert-Eaton Myasthenic Syndrome (“LEMS”), and FDA subsequently approved Firdapse in November 2018 for the treatment of LEMS in adults with 7 years of Orphan Drug Exclusivity.  However, a competitor, Jacobus, had developed its own amifampridine product for the treatment of LEMS, Ruzurgi, which it had been giving away for free under FDA’s Expanded Access provisions.  But, anticipating Catalyst approval and with it the end to Expanded Access, Jacobus submitted an NDA for approval of Rugurzi in August 2017, which FDA Refused to File, and Jacobus refiled in June 2018.  Given the timing, FDA recognized that the Firdapse Orphan Drug Exclusivity would block approval of Ruzurgi for the treatment of LEMS in adults, so FDA “administratively divided” Jacobus’s NDA into two parts: one for the treatment of adults and one for the treatment of pediatric patients to “allow for independent action in these populations.”  In so doing, FDA believed that it could approve Ruzurgi for the treatment of pediatric patients because Catalyst’s Orphan Drug Exclusivity was limited only to the indication for which Firdapse was approved: LEMS in adults.  Thus, the Agency could and would approve Ruzurgi for pediatric patients in May 2019—notwithstanding the fact that Jacobus had performed no clinical trial in children, that the LEMS pediatric patient population was negligible, and that the clinical testing reflected that Ruzurgi clearly was intended to be used in adults.

Upon Ruzurgi approval, Catalyst sued FDA alleging multiple violations of the Administrative Procedure Act.  Catalyst argued that the plain language of the Orphan Drug Act prohibited FDA from approving the “same drug” for the “same disease or condition” as Firdapse, and FDA’s approval of Ruzurgi approved the “same drug” (amifampridine) for the “same disease or condition” (LEMS) as Firdapse.  In other words, Catalyst argued that LEMS is a single disease or condition, and thus the scope of its exclusivity covered the entire LEMS condition regardless of whether patients are adults or children.  Catalyst also argued that the Ruzurgi labeling is “false or misleading” because it suggests that the drug could be used for adult patients with LEMS even though Ruzurgi was approved only in pediatric patients.

After a magistrate recommendation, the District Court for Southern Florida held that “same disease or condition” in the Orphan Drug Act is ambiguous and deferred to FDA’s interpretation, which awarded Orphan Drug Exclusivity based on the approved indication rather than the designated condition; the Court also found that the allegations of false or misleading labeling targeting adults were not supported by law.  Catalyst appealed up to the Eleventh Circuit.

In reviewing the statutory interpretation argument, the Eleventh Circuit determined that the term “same drug or condition” in the Orphan Drug Exclusivity statutory provisions, codified at 21 U.S.C. § 360cc(a), is not ambiguous and plainly refers to the “rare disease or condition” for which the drug “was designated under 21 U.S.C. § 360bb.”  Thus, the scope of the Orphan Drug Exclusivity is limited to the designated disease or condition under 21 U.S.C. § 360bb rather than the indication approved.  Because the disease for which Firdapse was designated was LEMS—not LEMS in adults—and because LEMS is the same disease in all patients—adult or pediatric—FDA could not approve another sponsor’s NDA for amifampridine for the treatment of LEMS in any patient population.  Thus, absent a demonstration of clinical superiority, the Court held that FDA’s approval of Ruzurgi during the Firdapse 7 years of Orphan Drug Exclusivity violated the APA.  As a result of this decision, FDA officially withdrew approval of the Jacobus NDA in February 2022.

On the facts of this case, it is difficult to criticize the Eleventh Circuit’s decision.  Jacobus did not do any pediatric testing yet received approval in pediatrics less than a year into Catalyst’s 7 years of Orphan Drug Exclusivity.  FDA’s push to approve Ruzurgi seemed to be a clever attempt to introduce competition and bring costs down in reaction to congressional pressure after Catalyst announced it would raise prices of the drug, upsetting Congress and leading to a hearing.  But clearly FDA’s ploy backfired.  (And indeed, there is little question that this was a ploy.  FDA rarely “administratively divide[s]” an NDA, and FDA has rejected designations of pediatric subsets for orphan drugs in light of PREA since 2018.)  To FDA’s chagrin, rather than embracing the questionable de facto subset at issue here to address pricing concerns, the Court broadened the scope of all Orphan Drug Exclusivity.

Catalyst invested the money to legally bring an important product to market for an orphan population—exactly what Congress intended with the Orphan Drug Act and exactly what Orphan Drug Exclusivity was intended to reward—but FDA’s actions immediately undercut any return on that investment.  Rubbing salt into that wound is that Jacobus did minimal (if any) testing in the intended patient population, raising questions of how much of an investment Jacobus actually made.

Keep in mind, Jacobus could have tried to break Catalyst’s Orphan Drug Exclusivity.  In that case, Jacobus would need to demonstrate clinical superiority.  But Jacobus could not do that because Ruzurgi is identical to Firdapse, because the condition does not differ in adults and kids, and because Jacobus performed no clinical testing in kids.  In other words, there is no basis for breaking Firdapse exclusivity.  And there is no basis for a pediatric orphan subset, as any orphan subset requires that a “characteristic or feature of the drug (e.g., mechanism of action, toxicity profile, prior clinical experience) why the drug will be limited to use in the subset of question.”  Obviously, that could not occur here where the drug products in question are identical.  The Court’s decision here, given the facts, is equitable and in accordance with the Act.

On the other hand, the implications here are much broader than Catalyst or LEMS.  Now, the entire designated condition represents the scope of Orphan Drug Exclusivity even if the product is indicated for a narrower condition.  It encourages sponsors to seek as broad a designation as possible—assuming the population can stay under 200,000—to ensure the broadest market protection possible; the larger the designation, the wider blockade on market entry.  Blocking approval for the entire designated condition where initial approval is only for a narrow indication would effectively deprive patients falling under the broader condition but not the specifiorc indication to use products off-label, depriving potentially vulnerable patients of important dosing and warning information.  Did Congress really intend for the Orphan Drug Act to block approval for orphan subsets?

Nevertheless, the Court had a tough call to make.  And FDA is not happy with this decision, which is not surprising since the last thing FDA needs is another big L.  But like in the Depomed litigation, FDA’s reading of the Orphan Drug Act went too far, and, like the Depomed litigation, it will take an act of Congress to overturn this decision.  Through the grapevine, we’ve heard that legislative fixes to this decision are being shopped around Congress.  For such a fix to be effective, Congress will need to clarify the language and expressly limit the scope of exclusivity to that approved indication.  But, until then, as Quiet Riot once said (in an entirely different context), the scope of Orphan Drug Exclusivity is “Condition Critical” (rather than indication indispensable?).

Since March 2020 when the Coronavirus Aid, Relief, and Economic Security Act (CARES Act) was signed into law establishing section 505G of the Food, Drug, and Cosmetic Act (FD&C Act) (see our blog post here), the regulated community has been eager to engage with FDA to understand both the procedural and substantive requirements for submitting an OTC monograph order request (OMOR) and an OMOR meeting request.  In the almost two years since monograph reform became law, FDA has not granted meeting requests to discuss OMORs, but has accepted the meeting requests and placed them in a queue for future consideration once pertinent performance goals are applicable.  FDA has now issued a long-awaited guidance about the process.  We should note that although it has been long-awaited, FDA has issued the guidance within the timelines outlined in the OMUFA Performance Goals letter  (Goals Letter).

The draft guidance for industry, Formal Meetings Between FDA and Sponsors or Requestors of Over-the-Counter Monograph Drugs (the Monograph Meeting Guidance) describes the guidance as fulfilling three requirements imposed on FDA by the CARES Act:

• To establish procedures under which meeting requesters[1] can meet with appropriate FDA officials to obtain advice on the studies and other information necessary to support submissions under section 505G of the FD&C Act (e.g., OTC monograph order requests or OMORs), other matters relevant to the regulation of nonprescription drugs, and the development of new nonprescription drugs under section 505G.
• To establish procedures to facilitate efficient participation in joint meetings by multiple meeting requesters and/or organizations nominated by them to represent their interests.
• To issue guidance that specifies the procedures and principles for formal meetings between FDA and meeting requesters for OTC monograph drugs.

The Monograph Meeting Guidance describes Type X, Y and Z meetings essentially as they are set out in the Goals Letter.  FDA has adopted a tiered meeting framework not unlike the Type A, B and C meeting categories established under the Draft Guidance for meetings with sponsors of PDUFA products (the PDUFA Guidance). Specifically,

• Type X meetings are limited to:
  • A meeting that is necessary for an otherwise stalled OTC monograph order development program to proceed. For example, a meeting that is requested by a meeting requester within 3 months of FDA’s issuing a refuse-to-file letter for an OMOR submitted by that meeting requester.
  • A meeting that is necessary to address an important safety issue that needs immediate action when the meeting requester learns about a safety issue related to an OTC monograph drug that is marketed or being developed.

As with Type A meetings under the PDUFA Guidance, FDA directs meeting requesters to contact FDA to discuss the appropriateness of the request.

• Type Y meetings are intended for milestone discussions during the monograph order development program and are the following:
  • Overall Data Recommendations Meetings to discuss the overall data recommended to support:
    • A positive general recognition of safety and effectiveness (GRASE) determination for an OTC monograph drug containing a specific active ingredient or subject to some other condition of use after FDA has stated its intent to make that final GRASE determination
    • An OMOR submission when a meeting requester has an interest in initiating an OMOR (i.e., meeting requester has not yet begun an OTC monograph order development program). This seems comparable to a preIND meeting request under the PDUFA program.

• • Pre-OMOR Submission Meeting (which appears similar to a preNDA or preBLA meeting) used when nearing completion of a development program for an OMOR for the requester to present a summary of the data supporting the OMOR in order to:
    • Discuss the proposed format for the OMOR
    • Obtain FDA feedback on the adequacy of the proposal for the OMOR submission, such as the format and content of the anticipated OMOR, including presentation of data, structure of dataset, acceptability of data for submission, as well as the projected submission date of the OMOR
    • Discuss the appropriate categorization of an OMOR (e.g., Tier 1 or Tier)

Importantly, the Monograph Meeting Guidance states that FDA will not grant more than one Type Y meeting to discuss a specific OTC monograph order development program or conditions or use for a specific OTC monograph.  Although the guidance is not explicit on the point, presumably this means one meeting per sponsor or group (as described below).

• A Type Z meeting is any meeting that is not a Type X or Type Y meeting.

The meeting formats (face to face, teleconference/videoconference, written response only) and recommended information for inclusion in a meeting request also are very similar to what are recommended for a meeting under the PDUFA Guidance with one significant difference.  For an OTC meeting request, a statement of whether the requester intends to discuss information exempt from disclosure under section 505G(d) of the FD&C Act or other laws should be included.  More on disclosure and confidentiality of OTC meetings below.

Timing for meetings to be scheduled and briefing books submitted are the same as the PDUFA meeting correlates except that all Type Y meetings must be scheduled 70 days from receipt of the request.  Meeting package content recommendations include the expected elements, but also include specific guidance on the numbering of questions. FDA notes that it generally will not provide preliminary responses for Type X meetings.

FDA includes the usual reminder that meetings may not be recorded, and, somewhat surprisingly, includes a statement that it reserves the right to end a meeting immediately if “attendees are not behaving professionally.”

Two unique aspects of OTC monograph meetings are covered in the new guidance – joint meetings involving multiple requesters and confidentiality in the otherwise public OTC monograph process.  The concept of joint meetings was included in the CARES Act to potentially provide for a more efficient procedure for FDA to provide feedback on specific proposed monograph changes of interest to more than one party.  In the guidance, FDA suggests that if there are multiple requesters, they consider forming an industry working group (IWG) with a single point of contact for interacting with the FDA and such agreements among the members as they may deem necessary for their collaboration.  FDA specifically notes that all members of an IWG who are subject to monograph user fees under section 744M of the FD&C Act must not have unpaid user fees and that the designated point of contact for the IWG is responsible for ensuring the discussion during the meeting is consistent with the IWG’s agreements on confidentiality.

On the subject of confidentiality, the guidance largely references the statute provisions, but notes that although certain information about a formal meeting may be publicly available, a formal meeting is not open to the public.

One issue of interest not addressed in the new guidance is how FDA intends to handle the meeting requests that were submitted prior to issuance of the Monograph Meeting Guidance.  Even those requesters that followed the PDUFA Guidance seem to run a good chance of being rejected because these requests likely do not include a statement of whether the meeting requester intends to discuss information exempt from disclosure.  It is not clear whether those requests will need to be amended and then will be treated as a new request that goes back to square one or more importantly, Day 1.  If a requester knows that their original request falls short of this or other recommendations in the guidance, it bears considering whether it makes sense to remedy those shortcomings and resubmit.

[1] In a curious battle of words, FDA has abandoned the language of the statute which refers to “requestors” in favor of “meeting requesters” which is defined in the new guidance as “sponsors or requestors for an OTC monograph drug”.  We note that a search for “requestor” in the Merriam-Webster dictionary online provided the result “[t]he word you’ve entered isn’t in the dictionary”.  Perhaps Congress uses an earlier edition.

The Drug Enforcement Administration (“DEA”) recently issued another Final Order revoking a pharmacy registration based on the failure of the pharmacy to meet its corresponding responsibility, more specifically, the failure to identify and resolve red flags.  While the Final Order does not necessarily introduce any new red flags, it does appear that DEA is attempting to refine these requirements and impose bright line standards related to “red flags” and the need for documentation, which are not currently defined in the statute or regulations.

On December 22, 2021, new DEA Administrator Anne Milgram revoked the DEA registration of Gulf Med Pharmacy (“Gulf Med”) following issuance of an Order to Show Cause and Immediate Suspension of Registration.  Gulf Med Pharmacy; Decision and Order, 86 Fed. Reg. 72,694-72,735 (Dec. 22, 2021).  In short, DEA alleged that Gulf Med, a small, independent pharmacy in Cape Coral, Florida, “repeatedly ignored obvious red flags of abuse or diversion and filled prescriptions without exercising its corresponding responsibility to ensure that they were issued for legitimate medical purpose, in violation of federal and state law” between March 2017 and August 2019.  Id. at 72,694.  DEA investigated Gulf Med because it was one of the top ten purchasers of oxycodone, hydromorphone and hydrocodone in Florida.  Id. at 72,698.   Administrator Milgram found that Gulf Med failed to exercise its corresponding responsibility by repeatedly dispensing controlled substances pursuant to prescriptions that exhibited “obvious red flags of diversion without documenting the resolution of those red flags.”  Id. at 72,727.

This most recent case highlights again the ongoing issue of what are obvious red flags and how  a registrant must document resolution of such red flags to the satisfaction of DEA.  DEA regulations state that a pharmacist has a corresponding responsibility not to fill a prescription unless it is issued for a “legitimate medical purpose by an individual practitioner acting in the usual course of [their] professional practice.”  21 C.F.R. § 1306.04(a).  The person who knowingly fills such  prescription is subject to administrative, civil and criminal penalties.  Id.

As cited in the Gulf Med decision DEA has held that corresponding responsibility prohibits “the filling of a prescription where the pharmacist or pharmacy ‘knows or has reason to know’ that the prescription is invalid.”  Holiday CVS, L.L.C. d/b/a CVS/Pharmacy Nos. 219 and 5195; Decision and Order, 77 Fed. Reg. 62,316, 62,341 (Oct. 12, 2012) (quoting Bob’s Pharmacy & Diabetic Supplies; Revocation of Registration, 74 Fed. Reg. 19,599, 19,601 (Apr. 29, 2009)).  Agency precedent has evolved over the years to define corresponding responsibility as requiring a pharmacy to resolve “red flags” before dispensing a prescription:

[A] pharmacist or pharmacy may not dispense a prescription in the face of a red flag (i.e., a circumstance that does or should raise a reasonable suspicion as to the validity of a prescription) unless he or it takes steps to resolve the red flag and ensure that the prescription is valid.

Holiday CVS, 77 Fed. Reg. at 62,341; see Jones Total Healthcare Pharmacy, L.L.C. and SND Health Care, L.L.C.; Decision and Order, 81 Fed. Reg. 79,188, 79,218-19 (Nov. 10, 2016); East Main Street Pharmacy; Affirmance of Suspension Order, 75 Fed. Reg. 66,149, 66,150 (Oct. 27, 2010).  So, a pharmacy must not dispense a prescription unless it resolves any red flags surrounding it.

In Gulf Med, DEA emphasized that “[r]ed flags are circumstances surrounding a prescription that cause a pharmacist to take pause, including signs of diversion or the potential for patient harm.”  Gul Med at 72,703.  Administrator Milgram found that the presence of a red flag does not prohibit a pharmacist from filling a prescription, but “means that there is a potential concern with the prescription, which the pharmacist must address and resolve, and … make a record of its resolution, assuming it is resolvable.”  Id.

In particular, the DEA and its expert witness, focused on several specific red flags that Gulf Med failed to identify or failed to identify and document the resolution.

a.  Cocktail Medications

Controlled substance combinations known to be abused or diverted when consumed together that significantly increase a patient’s risk of death or overdose are referred to as “cocktail medications.”  Gulf Med Pharmacy at 72,695.  DEA’s expert concluded that Gulf Med repeatedly dispensed high doses of opioids, (hydromorphone, oxycodone and morphine sulfate extended release) with high doses of other central nervous system depressants such as benzodiazepines (e.g., alprazolam, clonazepam, or diazepam) or muscle relaxants (e.g., carisoprodol) that are dangerous when consumed together.  Id.  This combination, the “Trinity” cocktail, “is highly dangerous and is widely known to be abused and/or diverted.”  Id.  DEA’s expert explained that combination of an opioid and benzodiazepine is dangerous because both drugs depress the patient’s central nervous system.  Id. at 72,719.  Gulf Med repeatedly filled prescriptions for Trinity cocktail medications without any indication that pharmacists addressed or resolved their risk of abuse or diversion.  Id. at 72,695.  The Administrator found that dispensing cocktail medications requires documentation of investigation and resolution, which Gulf Med pharmacists failed to do.  Id. at 72,730.

b.  Improper Dosing for Pain Management

DEA’s expert opined that proper pharmacologic dosing of pain management patients receiving both long-acting and short-acting opioids is to use larger, scheduled doses of long-acting opioids to control chronic pain with smaller, as-needed doses of short-acting opioids for breakthrough pain.  Id. at 72,695.  She explained that such dosing requires reducing the quantity of the short-acting opioid to obtain the same level of pain control.  The expert concluded that prescribing a larger daily dose of short-acting opioids than long-acting opioids does not make pharmacologic sense.  Id.  The Administrator found that Gulf Med failed to resolve this red flag.  Id. at 72,730.

c.  Long Distances Traveled

The Government alleged that Gulf Med regularly filled prescriptions for patients who traveled “an unusual distance” to obtain their prescriptions.  Id. at 72,696.  DEA’s expert opined that patients traveling long distances to obtain or fill controlled substance prescriptions can be indicative of diversion and/or abuse and therefore a red flag that must be addressed prior to dispensing.  Id.  The ALJ determined that the Government failed to prove the distances traveled to fill prescriptions, ranging between 30 to 50 miles round trip, and the Administrator found it unnecessary to weigh in on that allegation.  Id. at 72,729-30.

d.  Payment in Cash

Cash payment for controlled prescriptions rather than payment by insurance (or worker’s compensation) is another red flag.  The expert explained that insurance companies frequently reject suspicious controlled prescriptions that may be related to drug abuse or diversion, for example prescriptions for the same patient filled by multiple pharmacies.  Id. at 72,696.  Some patients choose to pay cash to avoid insurance rejections that would alert pharmacists of potential abuse or diversion.  Cash payments are especially suspicious when the patient bills insurance for other prescriptions but pays cash for controlled prescriptions.  Id.  The Administrator agreed that cash payments were a red flag and outside the usual course of professional practice for Gulf Med when it failed to resolve and document their resolution in light of the other red flags.  Id. at 72,730.

e.  Price Gouging

DEA’s expert indicated that price gouging, charging more than the market rate for controlled prescriptions, is another red flag that may indicate drug abuse or diversion.  Id. at 72,696.  She explained that legitimate patients, who can fill their prescriptions anywhere, will switch pharmacies to pay the fair market price while a “highly suspect patient can only fill prescriptions at a suspicious pharmacy and must pay whatever price that suspicious pharmacy sets.”  Id.   Inflated prices for controlled prescriptions are a red flag, especially when prices are substantially higher than the market prices charged by local pharmacies.  Filling controlled substance prescriptions at inflated cash prices also demonstrates that a pharmacy “has knowledge that it is filling prescriptions that are not legitimate, as its inflated prices reflect a ‘risk premium’ that the pharmacy charges to account for the risk it is taking by filling illegitimate prescriptions.”  Id.  DEA’s expert contacted representative local pharmacies to determine a “baseline of normalcy (i.e., legitimate pricing).”  Id.  The Government alleged that Gulf Med charged certain patients two to three times the market rate for their controlled medications.  Id. at 72,697.

Most if not all of these red flags have been discussed in prior DEA administrative decisions.   However, this decision appears to paint with an even broader brush that the mere presence of certain facts, e.g., a cash payment, a patient travelling from some undefined “long distance” or patients receiving a combination of drugs are de facto red flags that must be resolved and documented before filling the prescription.  For example, does DEA expect that a pharmacy must document and justify the filling of any cash prescription?  What about a case where a pharmacy is filling a prescription for a combination of drugs for a known hospice patient?  What documentation is required in these cases?  And if such resolution/documentation is not required in every case,  what is the standard or criteria: greater than some percentage of payments in cash or a travelling distance over 30 miles?

The extent of the red flags in Gulf Med may have certainly justified revocation, but we are concerned that DEA is establishing a standard that would require pharmacies, particularly the thousands of small independent pharmacies, to meet a standard of documentation that would be burdensome and unnecessary, or face significant penalties,  However, it seems that is the way that DEA itself is waving the “red” flag.

In what is sure to be a process that will take potentially years to complete, FDA completed its final review of twelve bulk substances to be used in compounding by Section 503B Outsourcing Facilities.   FDA announced its decision in both a Federal Register Notice, and in a separate public announcement released on January 28th (here).  This is all part of the lengthy process where Section 503B statutorily directs FDA to establish the Section 503B Bulks List by: (1) publishing a notice in the Federal Register proposing bulk drug substances to be included on the list, and including the rationale for such proposal; (2) providing a period of not less than 60 calendar days for comment on the notice; and (3) publishing a notice in the Federal Register designating bulk drug substances for inclusion on the list.  Unlike the lists for Section 503A formal notice and comment rulemaking is not required. See Section 503A(d).

FDA reviewed the substances pursuant to its final policy published in 2019 (finalized after some significant litigation blogged about here about how FDA conducts that review), and determined that the following four drug substances made the List 1 cut: diphenylcyclopropenone (DPCP) for topical use;  glycolic acid for topical use in concentrations up to 70 percent; squaric acid dibutyl ester (SADBE) for topical use; and trichloroacetic acid (TCA) for topical use. FDA importantly noted that these bulk drug substances are not components of “any currently FDA-approved drugs.”  FDA identified eight other substances for which it completed the review process, and determined that it is not including the substances on the final Section 503B Bulks List 1 at this time.  These substances include the following:  diazepam, dipyridamole, dobutamine hydrochloride (HCl), dopamine HCl, edetate calcium disodium, folic acid, glycopyrrolate, and sodium thiosulfate (except for topical administration).  FDA’s notice focused on the fact that these bulk substances are components of FDA-approved drugs and nominations did not sufficiently show that the FDA-approved product had an attribute that made it medically unsuitable to treat certain patients, and/or that the drug must be compounded from a bulk substance rather than from an FDA-approved product – all of which appears to be an extremely difficult showing for compounders to make.

The latest 503B Lists are linked here.  FDA published its notice about its review — and proposed inclusion and/or exclusion — of all but one of these substances in July 2020.  (FDA proposed to remove dipyridamole and multiple other substances from the list in 2019).  FDA has not completed its review of the other 11 other substances that were the subject of FDA’s 2020 Federal Register notice.  Substances that were also included in the July 2020 notice and for which the Section 503B compounding industry is awaiting the “thumbs up or thumbs down” include the following: hydroxyzine HCl, ketorolac tromethamine, labetalol HCl, mannitol, metoclopramide HCl, moxifloxacin HCl, nalbuphine HCl, polidocanol, potassium acetate, procainamide HCl, sodium nitroprusside, and verapamil HCl.

Well, OPDP is kicking off 2022 in a big way – taking on an Eli Lilly Instagram post with video for Trulicity.  This is the second time in a little over a month that Eli Lilly has found itself caught in OPDP’s cross-hairs.  On the heels of a December 2021 Untitled Letter about Lilly’s multi-part infomercial supporting migraine-treatment Emgality, OPDP sent Lilly its first Untitled Letter of the new year on January 19, 2022 over the company’s Instagram posts for Trulicity, a biologic licensed “as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus” and “to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors.”  Given that FDA issued only four Untitled Letters total in 2021, it’s notable that FDA has issued two to Eli Lilly in the span of five weeks.

What makes this letter a significant way to start off 2022 is the promotional platform at issue—Instagram, and the promotional material type—a post with a video presentation.  The Instagram square has previously been a focus of OPDP’s, but this is the first time (to our knowledge) OPDP has taken issue with an Instagram post including a video component.  And while we haven’t seen the video that is the subject of the letter (only screenshots), we are, quite frankly, surprised it took OPDP this long to object to this type of promotion.

In the case of the Lilly Instagram posts, FDA expressed concern that the Instagram posts create a misleading impression with respect to the safety and effectiveness of a drug subject to a Boxed Warning rendering the drug misbranded.  The post contained a video entitled 10,080 Minutes that “prominently communicates that Trulicity can help ‘lower A1C along with diet and exercise,’” but “fails to adequately communicate Trulicity’s FDA-approved indication and the limitations of use” thereby creating a “misleading impression about the scope of the FDA-approved indication.”  Further, though any relevant discussion is redacted, the Untitled Letter suggests that FDA had previously provided comments to Lilly about its Trulicity promotion more generally.

That the 10,080 Minutes video did not prominently limit its “lower A1C” claims to adults with type 2 diabetes mellitus and did not adequately include any Limitations of Use raised OPDP concerns given the “serious risks of this product.”  Indeed, OPDP recognized that the ad did include the indication and limitations of use but explained that the presentation was not sufficient:

OPDP notes that the indication and the limitations of use are presented only in small, fast-paced scrolling font in a small window below the video, relegated to the bottom of the post, competing for the consumer’s attention with several distracting video elements (fastpaced visuals, frequent scene changes, busy scenes, large-moving superimposed text, and a strong fast-moving musical beat) that detract from the communication of the indication and limitations of use. Therefore, this presentation does not mitigate the misleading impression created by the post.

FDA further emphasized that an assessment of promotional communications not only include representations made or suggested but “the extent to which the promotional communication fails to reveal facts material in light of the representations made or with respect to consequences that may result from use of the drug as recommended or suggested in promotional communication.”  And though those material facts may be present, sometimes that just isn’t enough:

The post prominently presents benefit claims and representations about Trulicity emphasized by colorful, compelling, and attention-grabbing fast-paced visuals that take up the majority of the post in a video with frequent scene changes, busy scenes, and large-moving superimposed text along with other competing modalities such as the strong, fast-moving musical beat. In contrast, the risk information is in a small window relegated to the bottom of the post and is presented using fast-paced, scrolling, small font that is difficult to read and cannot be adequately processed or comprehended by consumers.

It’s therefore the lack of fair balance and the omission of warning and precaution information that “creates a misleading impression about the drug’s safety” while the “overall effect . . . undermines the communication of the important risk information” and “misleadingly minimizes the risks associated with the use of Trulicity”—even if the necessary information is there.  (While we recognize that OPDP also cited the absence of “material information from the warning and precaution for hypoglycemia with concomitant use of insulin secretagogues or insulin” this was the last issue cited and likely not the basis for issuing the Untitled Letter.)

These issues are not new—although the fact that this is an Instagram post with video raises a new context for considering them.  Back in 2016 and 2019 we reported on FDA’s objections to TV commercials that included fast-paced “compelling and attention grabbing visuals” (note the similar language) as they were competing for the consumer’s attention while the major statement conveyed risk information.  Here, the visuals in the video, including large font text for benefits, overshadowed the smaller, scrolling text that conveyed risk.  That FDA took action is not surprising – particularly given the product has a Boxed Warning and OPDP has previously identified promotional material for drugs with serious risks as one of its enforcement priorities.  Not to mention the posts had been submitted through OPDP’s Bad Ad program.

So what’s the takeaway here?  CONTEXT (citing the great Roger Thies, IYKYK) —it’s a core tenet of promotional review.  When reviewing a promotional piece, the reviewer is not just looking at the piece itself, but also needing to understand the audience, the platform, how will it appear or be used, etc.  It’s not enough to review screenshots of a banner ad—one needs to know how long each presentation remains on the screen before moving to the next and whether text is legible and can be read and understood given changing visuals.  Platforms are also important—for instance, would a compliant audio/visual DTC TV commercial be compliant if it was shown on an LCD screen with no sound in a doctor’s waiting room?

Companies need to be aware of who is consuming their social media content and how it is being consumed.  Scrolling, small-font text at the bottom of an ad will rarely be able to compete with benefit information presented “above the line.”  And ultimately, decisions need to be made about whether the promotion is really Insta-worthy.

FDA has released its Proposed Rule of National Standards for Third-Party Logistics Providers (“3PLs”) and Prescription Drug Wholesale Distributors (“WDDs”).  The Drug Supply Chain Security Act (“DSCSA”), enacted back in November 2013, directed FDA to create national licensure standards for wholesale distributors and 3PLs within two years of its enactment (i.e., 2015).  So, FDA is more than a bit tardy, but this has obviously been a significant Agency undertaking, at least as measured by the need to grapple with 50 disparate states’ (and DC’s) requirements – and their various regulatory entities – as part of the process.  The rule, when finalized, will replace existing 21 C.F.R. Part 205 (Guidelines for State Licensing of Wholesale Prescription Drug Distributors).  The comment period for the Proposed Rule will remain open until June 4, 2022 (120 days after publication).  The Rule, if enacted in its current form, will have sweeping implications throughout the supply chain, but particularly for WDDs and 3PLs.  We anticipate this being our first of several blog posts on the Proposed Rule and its potential implications in the coming weeks.

As the title suggests, the Proposed Rule sets national licensing standards for both federal and state licensure for WDDs and 3PLs.  The preamble to the Proposed Rule cites heavily to a 2013 report prepared by the National Association of Board of Pharmacy (“NABP”) titled Wholesale Drug Distribution: Protecting the Integrity of the Nation’s Prescription Drug Supply as well as NABP’s Model State Pharmacy Act and Model Rules.  Currently, the licensure of both WDDs and 3PLs is left to the states, which has resulted in a patchwork of confusing and contradictory regulatory requirements across the country.  As a small example, almost all states license WDDs, but not all license 3PLs, and the DSCSA specifically prohibits states from requiring that 3PLs be licensed as WDDs, which affected several state laws in existence at the time of the DSCSA’s 2013 passage.  See 21 U.S.C. § 360eee-4(b)(2).  The inconsistencies across the states also currently mean that, for example, a 3PL based in Washington state would not need a license in its home state because Washington does not license 3PLs, but if the 3PL ships into California, then it would need to be licensed there as a non-resident 3PL.

The rule also intends to included certain conforming changes to other regulations such as formal evidentiary hearing requirements under 21 C.F.R. Part 12, because the proposed regulation as drafted permits wholesale distributors and 3PLs to request a formal evidentiary public hearing under Part 12 for review of decisions affecting the denial, suspension, or revocation of 3PL or wholesale distributor licenses issued by the Agency.

The 3PL and WDD  licensure rules will take effect in 2 and 1 years, respectively, after publication of the final rule.  State licensing requirements that currently apply to WDDs and 3PLs will only be preempted once the Proposed Rule is finalized and takes effect.  For the time being, WDDs and 3PLs with state licensing obligations should continue to renew their current licenses.  FDA notes, “When finalized, the national standards set forth in the proposed rule will provide greater assurance that these supply chain participants are sufficiently vetted and qualified to distribute products, further strengthening the supply chain and the safety of prescription drugs provided to American consumers.”

Interestingly, the Proposed Rule also addresses the so-called “5% rule,” an inconsistently defined regulatory scheme in most states providing that sales of drugs by retail pharmacies to other entities (as opposed to dispensing to patients) would not be considered “wholesale distribution,” so long as the total dollar volume of these sales does not exceed 5 percent of the total dollar volume of that retail pharmacy’s annual prescription sales.  The Proposed Rule thus intends to “codify” the 5% rule, but such sales would be limited to licensed practitioners for office use.

The Proposed Rule also sets forth standards applicable to, and the requirements for approval of, third-party organizations involved in the licensure and inspection process, which are referred to as “approved organizations.”  Many states already rely on accreditations from third parties such as the National Association of Board of Pharmacy (“NABP”) when licensing WDDs. We imagine that the “approved organization” standard under the final rule will be similar.  For example, at least 4 states (i.e., Indiana, Iowa, North Dakota, and Wyoming) require WDDs to hold NABP “Drug Distributor Accreditation” (formerly known as Verified-Accredited Wholesale Distributors or “VAWD”) before a state license will be issued; and many other states have long accepted VAWD accreditation as a critical part of their licensure vetting process.  We also note that NABP recently announced a new application process for its Drug Distributor Accreditation program.  This likely telegraphs to industry that a particular third party organization — NABP — will play an even more significant (and national) licensing role once the rule is finalized.

The Proposed Rule will not apply to drug manufacturers: FDA stated that it “considers the activities of a manufacturer, as defined at section 581(10) of the FD&C Act, when distributing its own drug, as excluded from the definition of wholesale distribution and not subject to the requirements that apply to wholesale distributors.”  Proposed Rule at 30.  This seems similar to DEA’s understanding of “coincident” activities of the registrant’s business that do not need a separate registration.  In addition, wholesale distributors and 3PLs that only handle medical devices will not be affected by the Rule because the distribution of medical devices is not considered “wholesale distribution” under the DSCSA.  21 U.S.C. § 353(b).

Look forward to future posts on this topic. If you have any thoughts or comments for future topics or posts on this issue, let us know!

I don’t mean to be so pessimistic, but 18 months after opening a docket requesting comments on potential “modernizations” for the Orange Book and one year after the passage of the Orange Book Transparency Act, FDA issued its Report on Orange Book reform essentially concluding that that “there is not a consensus view around” Orange Book modernization.  Instead, the FDA Report notes that “the comments received [on the Orange Book docket] provided a variety of different and sometimes competing views on the types of patent information that should be included in, or removed from, the Orange Book,” and “[t]he diversity of viewpoints on these topics indicate a need to examine these issues more closely . . . .”  To that end, FDA announced that it would take the public input it has received and form a working group to address efforts to “modernize the Orange Book, improve transparency, and provide useful information to regulated industry and the public” by…considering the comments that it has supposed to have been considering all along.

Let’s take a step back.  The Orange Book has always been a favorite topic around here (as demonstrated by Kurt Karst’s continued adventures with a hard copy—London most recently), and we were very excited when FDA released the 42nd edition of the Orange Book for 2022 on January 24.  And we were even more excited when that release was followed closely by an FDA Report on the comments submitted to FDA in 2020 and 2021 on the listing of patent information in the Orange Book.  But that Report was a bit of a letdown, as FDA explained that “the comments received provided a variety of different and sometimes competing views” and thus the Agency would not yet take any action.  But none of those “competing views” were novel or unexpected.  This is because generic and innovator sponsors both rely heavily on the Orange Book patent listings but typically for different purposes.  That they would have different opinions—and that combination product sponsors or other stakeholders would have different opinions—on the patents that should be listable in the Orange Book is expected and should have been anticipated by FDA.

Nevertheless, after an interesting history and overview of the origin and use of the Orange Book, FDA described the comments it received on the five areas of interest announced in the Federal Register.  When FDA opened the relevant docket, the Agency asked questions about modernization of the Orange Book generally, as well as about listing of drug product patents, method-of-use patents, REMS patents, and digital application patents.  FDA twice reopened the comment period, including once in response to the Orange Book Transparency Act, to ensure that all commenters had the opportunity submit recommendations as to the types of patent information that should be included in or removed from the Orange Book.  The 24 comments FDA eventually received came from academia, pharmaceutical industry associations, brand and generic drug manufacturers, biopharmaceutical research companies, consulting firms, law firms, intellectual property and drug pricing advocacy groups, biotechnology and trade organizations, information services companies, a pharmacist, and a patient.

FDA addressed each inquiry and responsive comments in turn, but the comments overall were similar—everyone has different ideas.  FDA asked whether and how it could clarify patent listing requirements, and due to the open-ended nature of its questions, the Report explained that FDA received comments on a range of topics with a range of perspectives:

• Commenters were split on whether the Orange Book should include additional patents, as some argued that additional listings would facilitate generic competition while others argued that expansive listing would unjustly extend monopolies. Another commenter suggested that FDA limit listable patents only “to patents protecting innovations that improve health and have been demonstrated to do so through clinical testing . . . .”  One comment took a different approach and requested that FDA address the conundrum that arises when the current Orange Book listings are manipulated such that listing of ineligible patents prolongs generic approval while omission of eligible patents, and subsequent litigation on those patents, prolongs launch.  Several comments just wanted more information included in the Orange Book about both the patents and the drug products themselves.
• Digital health and combination product patents received significant attention. It is clear that commenters thought that complex product patent listing needs more clarity, as patent listing requirements for drug-device combination patents are not clear.  However, commenters all had different perspectives about the best way to address these patents.  One commenter, for example, suggested that any component of a drug product that factors into a therapeutic equivalence evaluation should be listed in the Orange Book while several others thought that only patents that reference the drug substance itself should be listed.  Others thought that listing should depend on the scope of FDA’s review of the device component, the clinical use of the device or app, whether the device or app is integral to the drug product, or simply if the patent reasonably could be asserted.
• Finally, several commenters addressed REMS. Again, commenters were split: Some believed REMS should be listed because the statute does not exclude them from eligibility and some believed that listing them spurs anticompetitive behavior.
• One comment asked FDA to revise the Orange Book to further discuss the Agency’s position on method-of-use patents and skinny labels.

In response to these comments, FDA convened a working group but declined to provide recommendations to Congress that would help address these issues.  The Orange Book Transparency Act required FDA to summarize these comments in the Report, but it also required FDA to submit a summary of “any actions the Agency is considering taking in response to these comments.”  But FDA proposed no such actions.  Without consensus, and because the comments suggest that “there are a variety of equities and issues to be considered in examining this topic and that some of these issues are still evolving,” FDA provided no plans to further modernize the Orange Book.

For now, FDA “will build upon the efforts of the working group that reviewed the comments and will create a multidisciplinary working group within the Agency to evaluate whether additional clarity is needed regarding the types of patent information that should be included on, or removed from, the Orange Book.”  The Agency however has made no commitments—nor has it even hinted at—revising the Orange Book.  Further, the Report notes that a GAO Report on the Orange Book due to Congress in 2023 “may help inform the Agency’s thinking” on Orange Book issues, which suggests that we should not expect any changes or clarifications in the near future.  With no further action in sight, and with all of this equivocating leads, it seems to us that FDA remains on the Road to Nowhere with respect to Orange Book modernization.

The Justice Department’s Prescription Interdiction and Litigation (PIL) task force strikes again?  Not quite yet, but maybe soon, as explained below.

The United States filed a Complaint against Texas entities Zarzamora Healthcare LLC,  Rite-Away Pharmacy and Medical Supply #2– and its Pharmacist-in-Charge (PIC), and part owner.  The Press Release announces and the Complaint alleges that the defendant entities illegally filled opioid controlled substances that ignored numerous “red flags” of diversion.  In addition, the Complaint alleges inappropriate dispensing to numerous individuals, multiple DEA recordkeeping violations, improper alteration of prescriptions, and violations Texas law and federal corresponding responsibility obligations required of pharmacists that dispense opioid prescriptions.  Like other recent federal enforcement actions involving opioids against pharmacies filed by the Department of Justice’s Consumer Protection Branch (here and here for example) and local U.S. attorneys’ offices since 2019, the Complaint seeks monetary and permanent injunctive relief (see 21 U.S.C. §§ 832(f)(1) and 882(a)).  Interestingly, in particular for a pharmacy CSA enforcement matter, the Complaint also alleges the knowing operation of Rite-Away Pharmacy and Medical Supply #2 to unlawfully distribute controlled substances as a prohibited “drug-involved premises” in violation of 21 U.S.C. § 856.  Specifically, a person “maintains a drug-involved premises by (1) knowingly opening, leasing, renting, using or maintaining any place for the purpose of unlawfully distributing a controlled substance, or (2) managing or controlling any place and knowingly maintaining that place available for use for the purpose of unlawfully distributing a controlled substance. 21 U.S.C. § 856.” (Complaint ¶ 38.)  Penalties for a violation of section 856 are not more than “$250,000 for each violation occurring on or before November 2, 2015, and not more than $379,193 for each violation after November 2,2015, or two times the gross receipts either known or estimated that were derived from each violation attributable” to defendants.  Id. ¶ 118.

While injunctive enforcement tools have been statutorily available for years, they were first successfully dusted off in 2019 to assist the government in its efforts to stem the tide of inappropriate dispensing in the wake of the country’s opioid crisis (blogged about here).  Use of a federal civil injunction action is likely effective in these situations because it may serve to more efficiently terminate the offending DEA registrant’s – and, importantly, other non-registrant defendants’ — ability to handle controlled substances at the outset of an enforcement action.  It may also obviate the need for DEA to take administrative action, which is solely applicable to a DEA registrant and not the offending entity’s non-registrant owners, employees, or pharmacists.

Notwithstanding the powerful effect of a federal injunction action to “halt” offending conduct in its tracks, this time the District Court is ensuring that the Government complies with fairly straightforward procedural hurdles before temporarily or preliminarily enjoining named defendants from handling controlled substances.

Specifically, the Government filed the Complaint for a permanent injunction, and then moved for a preliminary injunction seeking an order to immediately stop defendants from handling and dispensing controls. The District Court denied the Government’s motion for a preliminary injunction because it failed to comply with the most rudimentary of procedural steps — notice to defendants:

[Fed. R. Civ. P.] Rule 65(a)(1) expressly prohibits courts from issuing a preliminary injunction absent “notice to the adverse party.”  Because Plaintiff has provided no notice to defendants, the Court is precluded from issuing any preliminary injunction.  And, although Rule 65(b)(1) permits courts to “issue a temporary restraining order without written or oral notice to the adverse party or its attorney,” they may only do so if:

(A) specific facts in an affidavit or a verified complaint clearly show that immediate and irreparable injury, loss, or damage will result to the movant before the adverse party can be heard in opposition; and

(B) the movant’s attorney certifies in writing any efforts made to give notice and the reasons why it should not be required.

Because the Government also failed to provide the Court a written certification in order to comply with Fed. R. Civ. P. Rule 65(b)(1)(B), the Court lacked authority to issue a temporary restraining order as well.  Thus, regardless of what the Government must surely believe is an exceedingly compelling need to cause defendants imminently to stop dispensing opioids, the failure to comply with simple but wholly necessary procedural hoops caused the Court to deny the Government’s requests.  While the Government is likely to obtain either a settlement or its requested injunctive relief down the road, it is at least interesting that the quicker federal injunction hit was not quite effective here.  Will this identical fact pattern repeat itself in similar opioid injunction enforcement matters? Unlikely…

We are working to keep up with OPDP’s posts over the past few weeks and a blog on its most recent letter to Lilly is forthcoming!

With apologies to Rob Base and DJ EZ Rock, it took more than “two” to get this Emgality DTC TV commercial right (insert snare drum here please).  Reading the Untitled and Closeout Letters to Eli Lilly regarding DTC TV promotion for Emgality, as well as Lilly’s recently posted response to FDA, this blogger couldn’t help but be reminded of the principles articulated in FDA’s long-withdrawn Draft Guidance on “Help Seeking” and Disease Awareness Communications – particularly the discussions about when disease awareness promotion is coupled with a product reminder or full product ad.  The Letters, and the withdrawn Draft Guidance for that matter, raise the not-so existential question about when disease awareness materials become product promotion.  Despite the Draft Guidance being withdrawn for over 6 years, the concepts articulated in it often come into play when reviewing disease awareness materials.  Speaking from a bit of experience, this has led to countless field direction memos instructing sales reps on how to pivot from their opening disease awareness presentations to their product details in an effort to keep these two types of communications separate.

But the Emgality promotion at issue here is different than the typical disease awareness communications where companies employ the “pivot” technique.  Here, Lilly created a “complete TV broadcast” that was made up of three distinct components to be aired sequentially.  Component 1 was a disease state component – identified as “The Journey Forward: Ryan Murphy” or “The Journey Forward:  Allysa Seely.”  (Note that Allysa Seely is a Paralympian gold medal triathlete, and swimmer Ryan Murphy is a 2016 Olympian and gold medalist.)  These two videos, which both began with a voiceover that stated, “Lilly presents The Journey Forward,” could be used alternatively as Component 1 and discussed the burden of migraine and its symptoms with the following content:

• “I do a whole bunch of different things to try to prevent migraine because for me the pain is really tough” (Ryan Murphy TV Ad)
• “I’ve leaned on all kinds of doctors and professionals for help” (Ryan Murphy TV Ad)
• “When I was younger, I used to say that my brain hurt” (Allysa Seely TV Ad)
• “By the time I was in college, migraine had me hiding from light and sound, it was isolating” (Allysa Seely TV Ad)

In its Untitled Letter, FDA cited the “The Journey Forward” ads as including “brought to you by Emgality proud partner of Team USA.”  FDA alleged that because the TV ads contained representations or suggestions relating to Emgality’s indication for use, they were required to include risk information as well adequate provision for the dissemination of the PI or a brief summary as required by 21 C.F.R. § 202.1(e)(1).  In addition, because the ads referenced migraine, the ads should have included “material information regarding Emgality’s full FDA-approved indication,” notably, that Emgality is indicated for the preventive treatment of migraine in adults.  FDA did not otherwise challenge the content of the disease awareness portion of the ad.

Lilly clarified in its Response that “brought to you by Emgality” was Component 2 of what Lilly described as the three component “complete TV broadcast.”  Component 1 was one of the disease awareness videos cited by FDA, Component 2 was “brought to you by Emgality,” and lastly, Component 3 was a full Emgality DTC TV commercial that included risk information as well as adequate provision for the dissemination of the PI.  Because all three components were to be aired sequentially, with Component 3 including risk information and adequate provision, the complete broadcast was balanced and included Emgality’s full FDA-approved indication – thus addressing the issues cited by FDA in the Untitled Letter.  Lilly also confirmed that each airing of the TV broadcast content included all three components.

In defending the complete broadcast, Lilly called out similar elements from each of the individual components as demonstrating its intent to have all three viewed sequentially.  Interestingly, this same point was made by FDA in viewing Components 1 and 2 as its own cohesive ad with “a clear beginning, middle, and end to the presentation.”  FDA’s Closeout Letter is particularly helpful in describing some of the perceptual similarities between Components 1 and 2, which included background music that plays continuously through the presentation, the same voiceover artist introducing Component 1 and voicing “brought to you by Emgality” (Component 2), and the same “style” and “color” for the opening and closing presentations.

It’s understandable that Lilly would create an ad with three separate components that had flexible uses.  Creating TV commercials ain’t cheap nor is the air time for them.  Being able to leverage different commercial lengths and platforms helps ensure the most bang for your buck.  And in this case the presentation would be compliant whether each component was shown individually, or, when combining all three sequentially.  But if the three segments were intended to be combined sequentially for a complete TV broadcast, why wasn’t the complete TV broadcast submitted to FDA on Form FDA 2253?

In its Response, Lilly stated that, “Component 1 did not contain a reference to Emgality and thus the file was not submitted to OPDP on Form FDA 2253.”  While this may be true, an overt reference to the drug may not be the only thing that renders a communication product promotion.

Whether disease awareness and help seeking materials can be considered product promotion is a hotly contested area.  FDA enforcement letters and FDA’s withdrawn Draft Guidance shed light on the Agency’s thinking.  In its Draft Guidance, FDA made clear that:

the mere appearance of the company’s name in conjunction with a disease reference could trigger the act’s advertising or labeling requirements, depending on the overall meaning and context of the communication. Similarly, depending on meaning and context, FDA might have jurisdiction over statements regarding the benefits of a product class to which a company’s drug or device belonged, even if the communication in which the statements occurred did not mention any specific product. Where FDA does not have jurisdiction, the agency may nevertheless take appropriate action (e.g., issuing a public statement or referring the matter to the FTC) where we believe a communication is false or misleading, or includes an unbalanced presentation of the benefits and risks of a particular product class.

This content is likely one of the reasons for FDA’s withdrawal of the Draft Guidance in 2015 – the same year that FDA suffered one of the most significant blows regarding First Amendment protections for pharmaceutical manufacturer speech.  The sweeping statement that the mere name of a company and a disease state could trigger the Act’s advertising or labeling requirements may have had a chilling effect on the way companies chose/choose to engage in disease state education.  In Lilly’s case, while this blogger does not believe that Component 1 should automatically be deemed Emgality promotion merely because it included Lilly’s name and discussed migraine, the context and circumstances of its presentation, including its use with more traditional Emgality promotion, should be taken into consideration.  There would have been little downside to submitting to FDA Component 1 as Emgality promotion, particularly because it was intended to be used with Emgality-branded communications and was otherwise consistent with what could be said in promotion.

This situation is also vastly different from “help seeking” communications that center mostly around treatment without mentioning the treatment name.  For example, a year after the Draft Guidance’s publication, FDA issued an  Untitled Letter to Pfizer for, among other things, a 27-minute infomercial on arthritis and joint pain relief.  FDA took the position that:

The infomercial points to and describes benefits from taking a specific prescription drug therapy from Pfizer, though it does not mention Celebrex or Bextra by name. The infomercial features patient testimonials and statements from healthcare providers that promise complete pain-free relief, freedom of movement, and dramatic effects on “quality of life” in terms of personal activities and work-related activities for arthritis patients, linking these benefits to a specific drug therapy, and solicits patients to seek out that specific medicine. Pfizer’s name is featured at the beginning, end, and throughout the infomercial.

In this case, the 27-minute infomercial, which never mentioned the name of a drug, otherwise described “a powerful prescription medicine that’s giving people back their lives” without making reference to the drug’s risks or providing a brief summary/adequate provision for PI dissemination.  And remarkably, Pfizer submitted the infomercial to FDA on Form FDA 2253 but seemingly took the position that because no product name was mentioned, it did not need to meet traditional advertising and labeling requirements.

So back to Lilly – if Lilly were to have submitted Component 1 as Emgality promotion on Form FDA 2253, would that have eliminated or minimized Lilly’s ability to use it as a standalone piece that does not otherwise include fair balance and adequate provision for PI dissemination?  To the extent that Component 1 was not otherwise referencing Emgality treatment, and was simply about migraine, this blogger argues Lilly should not be so limited.  FDA would be significantly overreaching by claiming that Lilly could not utilize Component 1 as appropriate disease awareness material simply because the communication included Lilly’s name and may have been utilized in other contexts as product promotion.

One of the questions this blogger often receives is how different disease awareness materials need to be from branded product promotion.  Often companies get hung up on perceptual similarities with product promotion, without focusing on the substance of their communications.  For this blogger, disease awareness presentations do not always need to look different from product promotional materials – the key is the context of the communication and whether the disease awareness material includes information that would otherwise not comply with traditional product promotion.  Companies that seek to engage in disease awareness promotion often do so to raise awareness about the burden of disease and its impacts on quality of life.  To effectively educate on disease, communications may address subjects that go beyond what can be discussed in traditional product promotion – whether it is a symptom that may lead to a disease diagnosis but for which the drug has not shown efficacy in treating, or in discussing further reaching impacts the disease may have on quality of life that could be construed as unsubstantiated implied claims for a treatment.  These are the “pivot” situations, where it is helpful to clearly distinguish disease education from product promotion.   That said, companies should not shy away from owning other disease state materials as product promotion under appropriate circumstances, and that ownership shouldn’t limit the company’s ability to appropriately leverage those communications in capacities other than traditional product promotion.

Closed-loop control systems, which adjust device output based on information received from a sensor to keep a variable at a reference position, are common in many medical devices.  There are numerous examples where device output is controlled to maintain a physical measurement, such as pressure, at a set point.  When the variable of interest is a physiologic measurement, the patient becomes part of the closed-loop control system and clinician involvement in responding to changes in the patient’s condition can be reduced, leading to the emergence of new types of risks.

On December 23, 2021, CDRH released a draft guidance document, Technical Considerations for Medical Devices with Physiologic Closed-Loop Control Technology (PCLC Draft Guidance) that describes design, testing and labeling considerations to characterize and control the unique risks associated with physiological closed-loop controlled (PCLC) devices.  The PCLC Draft Guidance defines a PCLC device as a system consisting of physiologic-measuring sensors, actuators, and control algorithms that adjusts or maintains a physiologic variable (e.g., mean arterial blood pressure, depth of anesthesia) through automatic adjustments to delivery or removal of energy or article (e.g., drugs, or liquid or gas regulated as a medical device) using feedback from a physiologic-measuring sensor(s).  PCLC Draft Guidance at 4.

Premarket applications for PCLC devices should describe the PCLC device using functional block diagrams and provide descriptive content on control algorithms, sensors, user interface and system safety features.  Safety features can include:  fallback modes that the device enters when unsafe conditions are detected; transparent entrance and exit criteria for initiation and cessation of automated therapy; constraints on delivered energy or article, such as upper/lower limits and total amounts delivered over time; data logging; and alarms.  The PCLC Draft Guidance recommends that patient-related hazards, especially inter- and intra-patient variability, device-related hazards, and use-related hazards be evaluated as part of the risk analysis.

We found the discussion on testing of PCLC devices the most interesting.  A PCLC device will need to be tested via a broad range of assessments, including those common to many device types, with additional testing specific to PCLC devices. The PCLC Draft Guidance provides specific recommendations related to animal testing, testing using mathematical and computational models and human factors testing.  We were interested to see that clinical testing does not appear to be a major focus for these devices, though it is mentioned as a possible means of validation.  Given the complexities of PCLC devices, the PCLC Draft Guidance recommends use of the pre-submission process to receive Agency feedback, especially on animal test protocols, use of mathematical models and human factors testing.

The PCLC Draft Guidance recommends verification of PCLC devices include demonstration that sensors, actuators, and safety features meet all specifications and that the PCLC system response meets specifications during normal and foreseeable worst-case conditions and during foreseeable functional and clinical disturbances.  Parameter sensitivity analysis can be performed to demonstrate that the device meets specifications across all combinations of adjustable parameter values.  Validation specific to PCLC devices should cover user interactions and demonstrate that the PCLC device performs as intended and that its response supports safe and effective operation during normal and foreseeable worst-case conditions.  Id. at 21-22.

Entirely virtual testing refers to testing that is performed completely in a simulated computer environment.  Id. at 26.  Hardware-in-the-loop testing is performed using computational models of the patient’s physiology interfaced with the PCLC device hardware.  Id. at 27.  Credibility of models used in these types of assessments should be evaluated according to the draft guidance, Assessing the Credibility of Computational Modeling and Simulation in Medical Device Submissions, which we blogged about here.  Both of these types of assessments using computational models allow for simulation across a wide range of scenarios including inter-patient and intra-patient variability and uncertainty.  Inclusion of device hardware in hardware in-the-loop testing can be useful in identifying system failure modes and hardware limitations.

The PCLC Draft Guidance emphasizes the need for a robust user training program that is incorporated into human factors evaluations.  Training should be developed such that trainees experience complacency, automation bias, and loss of situational awareness, which are all risks introduced with PCLC technology.  Training should also include automation failure to give users practice responding to these situations.  Id. at 29.  Human factors testing can include simulated or actual use testing.  Because automation-related use error might not be predictable, human factors testing conducted in a clinical setting is recommended to enable realistic and meaningful evaluation. Id. at 28.

Overall, the PCLC Draft Guidance provides important considerations for the design and testing of devices incorporating PCLC technology that should benefit development of these devices and future interactions with the Agency.

On December 10, 2021, FDA issued a discussion paper titled 3D Printing Medical Devices at the Point of Care seeking feedback on FDA regulatory oversight of various 3D-printing scenarios, in order to inform future policy development.

This discussion paper is not the first time that FDA has grappled with the tricky regulatory questions presented by 3D printing.  In October 2014, FDA held a public workshop titled “Additive Manufacturing of Medical Devices: An Interactive Discussion on the Technical Considerations of 3D Printing.”  In May 2016, FDA released a draft guidance document titled “Technical Considerations for Additive Manufactured Devices” (see our blog post on the draft guidance here), which was finalized in 2018 (see our blog post on the final guidance here).  This guidance document is still in effect today.

The recent discussion paper is not a guidance document and FDA says it is not intended to convey any current policy.  Rather, it is meant to present various scenarios related to use of 3D‑printed devices at the point of care, along with a series of discussion questions seeking input from industry and other stakeholders.

The discussion paper starts with an acknowledgment of the benefits of 3D printing at the point of care.  Specifically, that it allows for fast production of “patient-matched devices” (i.e., devices that are fitted specifically to a patient’s anatomy), and anatomical models for surgical planning.  3D printing has also allowed for production of medical devices such as face shields, face mask holders, nasopharyngeal swabs, and ventilator parts during device shortages caused by the COVID-19 pandemic.

However, the discussion paper summarizes, there are a number of regulatory challenges associated with 3D printing, including (1) ensuring devices are safe and effective; (2) ensuring appropriate controls are in place for design and manufacturing so that product specifications are met; (3) clarifying which entities are responsible for compliance with regulatory requirements; and (4) ensuring that point-of-care facilities have the necessary training and expertise to produce 3D-printed devices.

The discussion paper provides an overview of FDA’s current approach to regulation of 3D-printed devices.  In brief, such devices can be commercially distributed to the general public for non-medical purposes without FDA regulation (e.g., use in education, construction, art, and jewelry).  Additionally, general purpose manufacturing equipment, including 3D printers and mills, are not subject to FDA regulation if not specifically intended to produce medical devices.  FDA does regulate 3D printing equipment and activities when intended to produce regulated medical devices (i.e., products intended for medical purposes).  The regulatory requirements for the devices that are 3D-printed generally govern the responsibilities of the entities that are manufacturing and distributing the 3D printing equipment for that use at the point of care.

The proposed regulatory approach in the discussion paper incorporates several high-level concepts:

• The extent of FDA oversight should correspond with the risks of the printed device and the 3D printing of the device at the point of care;
• The device specifications should not change based on the location of manufacture (i.e., a traditional manufacturing site vs. the point of care);
• The capabilities available at a point-of-care healthcare facility can help mitigate production risks;
• Entities involved in 3D printing of devices should understand their regulatory responsibilities under the Federal Food, Drug, and Cosmetic Act; and
• FDA intends to leverage existing regulatory controls for the regulation of 3D printing at the point of care, including existing standards and processes.

The discussion paper outlines three illustrative scenarios, to facilitate discussion and feedback from stakeholders.

The first scenario is a healthcare facility using a medical device 3D-printing production system.  FDA is seeking feedback on the challenges that a manufacturer of a 3D-printing system may face in being responsible for FDA regulatory requirements for devices that are 3D-printed by independent healthcare facilities, including with respect to adverse event reporting.  FDA also asks questions about the challenges related to any post-production manufacturing steps that may be undertaken by a healthcare facility after the device is printed.

The second scenario is a traditional manufacturer that is co-located at or near the healthcare facility site, where the 3D printing is conducted by the manufacturer to supply devices to the healthcare facility.  In this scenario, FDA is interested in the possibility of frequent design changes that may occur in response to clinical feedback (e.g., requests for different sizes or geometries after a printed device is examined by a healthcare provider).  FDA also asks whether there are any specific considerations in this co-location scenario that differ from traditional non-3D printed manufacturing processes for devices.

The third scenario is a healthcare facility that has assumed all traditional manufacturer responsibilities, including complying with all FDA regulatory requirements that apply to traditional device manufacturers.  The discussion paper notes that healthcare facilities already have internal quality systems in place that could be adapted to compliance with device regulatory requirements (e.g., complaint handling and adverse event reporting processes) and staff trained in the maintenance of equipment.  FDA is seeking feedback on which parts of FDA’s regulatory framework would be the easiest for healthcare facility’s to implement, and which would present the greatest challenges.

Separate from these three scenarios, the discussion paper seeks feedback on considerations for “very low risk” devices.  FDA has not yet defined “very low risk,” but the discussion paper states that it is considering developing a list of characteristics that would help identify very low risk devices.  The discussion paper includes a question for stakeholders on a proposed list of considerations in identifying these devices (e.g., intended use, device class, whether the device requires sterilization).  For these devices, FDA is considering exercising “regulatory flexibility” when these devices are 3D-printed at a healthcare facility, which we assume refers to some level of enforcement discretion with regard to compliance with manufacturing regulatory requirements.

The discussion paper states that FDA will use the feedback submitted to the public docket it has opened (Docket No. FDA-2021-N-1272) to inform future policy development.  Comments may be submitted until February 7, 2022.

Since the August 2021 decision in GSK v. Teva, the generic industry has been waiting with bated breath to see whether the section viii carve-out (and thus skinny-labeled generic drugs) will survive.  With the District Court of Delaware’s January 4 decision in a similar case (brought by GSK’s lawyers), Amarin v. Hikma, the generic industry can have some hope.  Relying heavily on the Federal Circuit’s contention that the decision in GSK v. Teva was a “narrow, case-specific review,” Judge Andrews dismissed Amarin’s suit against Hikma in which Amarin alleged that Hikma’s skinny-labeled generic icosapent ethyl induced infringement of Amarin’s method-of-use patents.  The Court, however, would not dismiss similar allegations as applied to health insurer.

In the wake of GSK v. Teva, in which the Federal Circuit reversed the District Court of Delaware’s decision to overturn a jury verdict finding that Teva induced infringement of GSK’s method-of-use patents covering carvedilol, several Reference Listed Drug (“RLD”) sponsors sued generic manufacturers marketing skinny-labeled versions of their products under the same induced infringement theory that prevailed in GSK v. Teva.  (The Federal Circuit twice reversed the District Court decision at issue in GSK v. Teva, but Amarin v. Hikma was filed in November 2020 after the Court’s first decision issued in October 2020.)  One of those RLD sponsors, Amarin, sued generic sponsor Hikma for induced infringement of method-of-use three patents listed in the Orange Book for Amarin’s Vascepa (icosapent ethyl) after FDA approved Hikma’s product with the patented use carved out, alleging that Hikma’s approved label “is ‘not skinny-enough.’”  Amarin also sued Health Net, an insurer that provides coverage for both Vascepa and Hikma’s generic.

The procedural background of Amarin v. Hikma (unlike that of GSK v. Teva) is simple:  Amarin received FDA approval for Vascepa as adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia in 2012 (referred to as the “SH indication”) and as an adjunct to statin therapy in patients with elevated triglyceride levels and established or risk factors for cardiovascular disease in 2019 (the “CV indication”).  Amarin listed Vascepa in the Orange Book with multiple patents, including several method-of-use patents covering only the CV indication.  In accordance with the statutory “section viii” provision, FDA approved Hikma’s generic product referencing Vascepa in May 2020 omitting information pertaining to the patented CV indication.

Five months later, Amarin sued Hikma for induced infringement arguing, essentially, that Hikma’s labeling does not adequately carve out Amarin’s protected method of use concerning the CV indication and thus induced infringement of Amarin’s patents.  Specifically, Amarin alleged that Hikma’s label “teaches CV risk reduction” due to “a notice regarding side effects for patients with CV disease” and an absence of a statement that the generic “should not be used for the CV indication….”  Hikma countered that the notice of side effects for patients with CV disease is a warning, not an instruction to use the product in CV patients, and that Hikma has no duty to provide a statement discouraging an infringing use.  The Court agreed with Hikma, finding that a warning “is hardly instruction or encouragement.”  The Court also explained that the Federal Circuit has already rejected Amarin’s argument that generic labels must contain a clear statement discouraging use of the patented indication.  Further, the Court noted, Amarin did not sufficiently plead that Hikma, “took affirmative steps to induce” infringement in its labeling.

Amarin also argued that Hikma’s non-label claims—public statements, including press releases and its website—induced infringement by stating that Hikma’s product is the “generic equivalent to Vascepa” and that Vascepa “is indicated, in part” for the SH indication while citing to sales numbers for Vascepa in all indications.  Amarin also took issue with the statement on Hikma’s website that its generic icosapent ethyl is “AB rated” in the “Therapeutic Category: Hypertriglyceridemia.”  Ultimately, the Court explained that the question here is whether these statements are sufficient to support inducement “without a label or other public statements instructing as to infringing use.”  The Court said that they are not, as these statements “might be relevant to intent but they do not support actual inducement.”  “Intent alone is not enough; Amarin must plead an inducing act.”

The Court took pains to distinguish Hikma’s labeling and promotion from Teva’s in GSK v. Teva.  There, the Court explained, Teva’s promotion of carvedilol for as a cardiovascular agent that is a generic of GSK’s Coreg for the “treatment of heart failure,” as well as its direction to the partially carved-out labeling—as opposed to Hikma’s more general “AB rated” language—differentiated GSK v. Teva from this case.  The Court again made sure to emphasize language from GSK v. Teva explaining that “it is still the law that ‘generics could not be held liable for merely marketing and selling under a “skinny” label omitting all patented indications, or for merely noting (without mentioning any infringing uses) that FDA had rated a product as therapeutically equivalent to a brand-name drug.”

Taking induced infringement for skinny labeling in a different direction, Amarin also sued health insurer Health Net.  Amarin alleged that Health Net’s formulary placement induces infringement of Amarin’s method-of-use patents covering Vascepa.  Specifically, Health Net lists Hikma’s generic in a lower tier than Amarin’s Vascepa, making the product available for a lower co-pay when the generic is dispensed.  Given state automatic substitution laws, Amarin alleges that Health Net’s placement of Hikma’s generic on the formulary “leads to substitution on ‘all VESCEPA (sic) prescriptions, not just the prescriptions directed to the’ SH indication.”

The Court denied Health Net’s Motion Dismiss, finding that Amarin pled enough facts to allege that Health Net knew of Amarin’s CV patents, made affirmative acts to induce infringement by placement on the formulary, and had specific intent to induce based on the listing of the patented indication on the insurer’s generic icosapent ethyl capsules prior authorization form.  Thus, the court concludes, “Health Net’s placement of generic icosapent ethyl on a preferred tier encourages the substitution of the generic for the branded drug, including for the patented indication.”  The issue, explained the Court, is the incentives the formulary puts in place to prescribe the generic regardless of the indication.  Whether Health Net induced infringement is a “factual question” that cannot be resolved on a motion to dismiss.

As we have learned from GSK v. Teva, Amarin’s case against Hikma could still end very differently if it is appealed to the Federal Circuit.  In GSK v. Teva, the District of Delaware was certain that Teva’s promotion did not induce infringement of GSK’s patent, going as far as to overturn a jury verdict, but the Federal Circuit reversed.  Amarin could appeal this dismissal, and the Federal Circuit could do the same here and reinstate the case.  So, while generic sponsors may have a brief reprieve from concerns that the skinny-label is altogether dead, the Federal Circuit could kill it once again.  Thus, until the Federal Circuit addresses this case, it’s difficult to read too much into the decision here.  Of course, if the Federal Circuit doesn’t hear this case, the Court’s fact-specific inquiry suggests that the implications of GSK v. Teva are less far-reaching than initially believed.

The case against Health Net introduces another wrinkle to the skinny-label debate though.  That insurers may have some liability for induced infringement merely by listing a skinny-labeled generic on a formulary could dissuade health insurers from covering skinny-labeled generics.  This would either force patients to brand-name products or to pay out of pocket for generics; in either scenario, it would increase prices for patients.  But thus far Amarin’s allegations have only survived a Motion to Dismiss; it’s entirely possible that this theory of induced infringement is rejected by the Court sometime in the future.

We still have a way to go until there’s certainty with respect to the future of the skinny label.  GSK v. Teva is still awaiting a decision from the Federal Circuit on Teva’s request for rehearing from the full panel, Amarin may appeal the Hikma decision, and the claims against Health Net must still be litigated.  So while we’re hesitant to say that the skinny-label has been resuscitated, we’re not ruling out the possibility of resurrection.

Hyman, Phelps & McNamara, P.C. is the largest dedicated FDA law firm, and we need attorneys to help our clients bring pharmaceutical drugs and medical devices to market.  Our ideal candidates have experience working at FDA (CDER, CDRH, CBER, or OCC), or have at least two years working in private practice with a sophisticated FDA practice group.  Our firm culture is collaborative, the work environment is flexible, and the subject matter is intellectually stimulating.   If you want to join our team, please send your resume to Anne Walsh, awalsh@hpm.com.

“EKRA” refers to the Eliminating Kickbacks in Recovery Act, which was part of the Substance Use – Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act of 2018.  EKRA is codified at 18 U.S.C. § 220 and was described on HP&M’s blog here.  Until recently, no federal court had had occasion to interpret EKRA.  That changed on October 18, 2021 when the Federal District Court for the District of Hawaii handed down a decision that construed key terms in the statute.

I.   The Eliminating Kickbacks in Recovery Act (“EKRA”)

In general, EKRA prohibits, knowingly and willfully, soliciting, receiving, paying or offering kickbacks in exchange for referring to, inducing a referral to, or using the services of a recovery home, clinical treatment facility, or laboratory.

EKRA defines “recovery home” as “a shared living environment that is, or purports to be, free from alcohol and illicit drug use and centered on peer support and connection to services that promote sustained recovery from substance use disorders.”  18 U.S.C. § 220(e)(5).  “Clinical treatment facility” is defined as “a medical setting, other than a hospital, that provides detoxification, risk reduction, outpatient treatment and care, residential treatment, or rehabilitation for substance use, pursuant to licensure or certification under State law.”  18 U.S.C. § 220(e)(2).  “Laboratory” is defined broadly as “a facility for the biological, microbiological, serological, chemical, immuno-hematological, hematological, biophysical, cytological, pathological, or other examination of materials derived from the human body for the purpose of providing information for the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health of, human beings.”  42 U.S.C. § 263a.  Note that while EKRA was passed as part of a bill to combat the opioid crisis, its definition of “laboratory” applies to lab activities far beyond those involving opioid or other drug testing.

EKRA is also broadly written because it applies to all “health care benefit” programs.  A “health care benefit program” is defined as “any public or private plan or contract, affecting commerce, under which any medical benefit, item, or service is provided to any individual, and includes any individual or entity who is providing a medical benefit, item, or service for which payment may be made under the plan or contract.”  18 U.S.C. § 24(b) (emphasis added).  Note that EKRA’s reach is broader than the Anti-Kickback Statute, which applies only to “federal healthcare programs” — e.g., Medicare, Medicaid, Tricare, etc.

EKRA also contains several exemptions.  18 U.S.C. § 220(b).  In particular, the employee exemption, relevant to the S&G Labs Haw., Ltd. Liab. Co. v. Graves case described below, states that it is not unlawful to pay an employee/independent contractor (as part of a bona fide employment relationship) to the extent that the employee’s payment does not vary by the following:

(A) the number of individuals referred to a particular recovery home, clinical treatment facility, or laboratory;

(B) the number of tests or procedures performed; or

(C) the amount billed to or received from, in part or in whole, the health care benefit program from the individuals referred to a particular recovery home, clinical treatment facility, or laboratory.

18 U.S.C. § 220(b)(2).

EKRA violations constitute a criminal offense with a maximum sentence of up to 10 years imprisonment and/or a $200,000 fine for each violation of the statute.

II.   S&G Labs Haw., Ltd. Liab. Co. v. Graves, No. 19-00310 LEK-WRP, 2021 U.S. Dist. LEXIS 200365 (D. Haw. Oct. 18, 2021)

A.   Background Facts

S&G Labs Hawaii, LLC (“S&G Labs”) is a Hawaiian laboratory company that performs various lab testing services including toxicology (for both legal and illicit substances) and COVID testing.  These lab tests are performed for physicians, substance abuse treatment centers and other types of organizations.

The litigation between S&G Labs and Graves involved multiple claims and counterclaims, many of which are not related to EKRA.  This summary will focus on the EKRA issue and facts pertinent to that issue.

S&G Labs’ pay structure was important to the Court’s decision regarding the EKRA issue.  S&G Labs alleged during the litigation that they are paid on a “per test” basis by third party insurers, government agencies under the Medicare and Medicaid programs, and direct “self-pay” by some individuals.  S&G Labs has no contractual relationships with the entities that referred clients to S&G Labs.  Specifically, S&G Labs has no contracts with any physicians, substance abuse counseling centers, or other organizations in need of having individuals tested.   S&G Labs receives no compensation from physicians, substance abuse treatment centers, or other similar types of organizations who refer individuals for testing.  Those “clients” are free to cease using the services of S&G Labs and direct their patients to other medical lab testing companies at any time.  S&G Labs Haw., Ltd. Liab. Co. v. Graves, 2021 U.S. Dist. LEXIS 29248, at *2-3 (D. Haw. Feb. 17, 2021).

Graves was an employee of S&G Labs whose job was to oversee client accounts.  His job was governed by an employment contract that contained both salary provisions and restrictive covenants.  Graves was compensated by receiving a $50,000 salary.  Graves also received 35% of the monthly net profits generated by his client accounts and a portion of the 35% monthly net profits generated by the accounts handled by the S&G Labs’ employees who Graves managed.  Id. at *4.  Graves’s employment contract also prohibited the following:  engaging with any business competitor, making disparaging remarks about S&G Labs, soliciting current employees to resign from S&G Labs and soliciting particular clients while an employee and for two years post-employment.  Id. at *4-6.

B.   EKRA Issue

The EKRA issue in this case centered on how Graves was compensated.  S&G Labs received legal advice in 2018/2019 that, under EKRA, employee compensation could not vary based on the number of lab tests performed or revenue received by S&G Labs.  S&G Labs, therefore, concluded that they could not pay Graves 35% of the monthly net profits generated by his client accounts and a portion of the 35% monthly net profits generated by the accounts handled by the S&G employees who Graves managed.

S&G Labs and Graves, however, could not reach agreement on a new compensation model.  Ultimately, Graves alleged that S&G Labs breached his employment contract.  S&G Labs argued that Graves’s employment contract became illegal and, thus, unenforceable.  The issue for the Court was, therefore, what effect did EKRA’s enactment have on Graves’s employment contract?  The district court was required to engage in statutory interpretation to answer this question.

C.   District Court’s Holding

The Court first held that S&G Labs is a “laboratory” as defined by EKRA.  S&G Labs Haw., Ltd. Liab. Co. v. Graves, 2021 U.S. Dist. LEXIS 200365, at *29 (D. Haw. Oct. 18, 2021).

The Court next interpreted the statutory terms “remuneration” and “individual” as those terms are used in EKRA.

(a) Offense.–Except as provided in subsection (b), whoever, with respect to services covered by a health care benefit program, in or affecting interstate or foreign commerce, knowingly and willfully–

…

(2) pays or offers any remuneration (including any kickback, bribe, or rebate) directly or indirectly, overtly or covertly, in cash or in kind–

(A) to induce a referral of an individual to a recovery home, clinical treatment facility, or laboratory; or

(B) in exchange for an individual using the services of that recovery home, clinical treatment facility, or laboratory.

18 US.C. § 220(a) (emphasis added).

EKRA does not define these terms, so the Court looked to the Anti-Kickback Statute.  Applying the definitions in the Anti-Kickback Statute, the Court defined “individual” as “an individual, a trust or estate, a partnership, or a corporation (citing, 42 U.S.C. § 1301(a)(3)) and concluded that “for purposes of the anti-kickback statute, an “individual” is not an artificial entity.”  Id. at *31-32.

The Court relied on Section 1301(c) to define “remuneration” as including payments from an employer to an employee.  Specifically, Section 1301(c) states:

Whenever under this chapter or any Act of Congress, or under the law of any State, an employer is required or permitted to deduct any amount from the remuneration of an employee and to pay the amount deducted to the United States, a State, or any political subdivision thereof, then for the purposes of this chapter the amount so deducted shall be considered to have been paid to the employee at the time of such deduction.

42 U.S.C. § 1301(c) (emphasis added).

The Court interpreted EKRA in the same manner as the Anti-Kickback Statute because, as the Court explained, an act should “be interpreted as a symmetrical and coherent regulatory scheme, one in which the operative words have a consistent meaning throughout.”  S&G Labs Haw., Ltd. Liab. Co. v. Graves, 2021 U.S. Dist. LEXIS 200365, at *30 (D. Haw. Oct. 18, 2021), citing Gustafson v. Alloyd Co., 513 U.S. 561, 569 (1995).

Applying the definitions of “individual” and “remuneration” the Court concluded that EKRA applied to Graves and his employment contract.  And, importantly, Graves’s salary structure constituted remuneration under EKRA.  However, because Graves was not paid for use of S&G Labs services, “[t]he critical issue is whether Graves’s remuneration was to induce a referral of an individual to S&G.”  Id. at *32, citing 18 U.S.C. § 220(a)(2)(A).

The Court noted that Graves’s salary structure undoubtedly induced him to generate business for S&G Labs.  However, Graves’s clients were physicians/physician offices — not individual patients in need of lab services.  Moreover, S&G Labs is not directly compensated by their clients (e.g., physicians and substance abuse counseling centers).  S&G Labs is primarily compensated by patient’s insurance providers.  EKRA, however, prohibits kickback payments in exchange for inducing “individual” referrals and in exchange for “individuals” using a laboratory’s services.  18 U.S.C. § 220(a)(2).  The Court, therefore, concluded that Graves’s employment contract using commission-based incentives did not violate EKRA because his clients were not “individuals” as that term is used in EKRA.  The Court further noted that the EKRA’s exceptions were inapplicable because “Graves’s commission-based compensation from S&G [Labs] was a payment made by an employer to an employee, and it was determined based upon the number of tests that S&G performed.  Thus, the exception in § 220(b)(2) would not apply to Graves’s compensation under his Employment Agreement.”  S&G Labs Haw., Ltd. Liab. Co. v. Graves, 2021 U.S. Dist. LEXIS 200365, at *34-35 (D. Haw. Oct. 18, 2021).

III.   Conclusion

EKRA is a broadly written statute that applies to all lab services billed to any public or private health insurance.  EKRA also applies to lab activities beyond those involving drug testing.  All labs must be aware of EKRA to avoid paying illegal kickbacks to generate business.

In this specific case, there was no evidence cited, and the Court did not analyze, whether or not Graves may have aided and abetted or been involved in a conspiracy with his clients.  In future cases, there will likely be a different result where a lab employee conspires with a client to refer “individuals” back to the employee’s lab in exchange for a kickback.  Moreover, other courts may decide that remuneration based on the volume of referrals induced by an employee is unlawful pursuant to EKRA, despite the fact that the employee does not personally refer or use the lab services him/herself.

The S&G Labs case is one of the first cases that has interpreted EKRA, and it is unlikely to be the last.  This case may be appealed and there will certainly be more cases in the future to interpret the statute.  EKRA is also a new law and the U.S. Department of Justice has not, as of yet, prosecuted many cases under EKRA.  Therefore, the scope of the statute has not yet been extensively judicially tested.  Much like the Anti-Kickback Statute, we anticipate that EKRA will be tested more often over the next several years.

Hyman, Phelps & McNamara, P.C. (HP&M) is pleased to announce that Sara W. Koblitz has become the firm’s newest Director.  Sara’s practice covers the intersection of FDA regulatory issues and Intellectual Property, including the Hatch-Waxman Amendments, the Biologics Price Competition and Innovation Act, and the Orphan Drug Act, biosimilars, and the Orange Book.  She assists pharmaceutical drug companies of all sizes on product lifecycle management, as well as regulatory strategies related to obtaining FDA approval, exclusivity, and patent listing.  Sara also has been heavily involved in FDA-related litigation and interpretation of the Federal Food, Drug, and Cosmetic Act.

Sara joined the firm from a well-recognized intellectual property firm in 2017.  Her full bio can be found here.