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.

Hyman, Phelps & McNamara, P.C. (HP&M) is pleased to announce Adrienne R. Lenz has become its first Principal Medical Device Regulation Expert.  Adrienne joined HPM in September 2017.  In her time with HPM, she has made significant contributions to the firm and its clients.

Prior to joining HP&M, Adrienne worked as an independent regulatory consultant and consultant with Emergo.  She has also held positions in regulatory affairs, quality assurance, and test engineering at GE Healthcare and Smiths Medical.

As a Principal Medical Device Regulation Expert, Adrienne will continue to provide consulting to medical device and combination product manufacturers. Adrienne assists clients with a wide range of pre and postmarket regulatory topics including developing regulatory strategy, preparing regulatory submissions, drafting regulatory policies and procedures, and addressing enforcement matters.

In the premarket area, Adrienne prepares IDEs, 510(k)s, de novos, and PMAs. She also prepares pre-submissions, and assists clients in preparing for and represents clients at pre-submission meetings with FDA. In the postmarket area, she advises clients on complaint handling, MDRs, field actions, and QSR compliance.  Adrienne’s full bio can be found here.

Happy New Year!

On January 1, 2022, the recently revised version of the PhRMA Code on Interactions with Health Care Professionals went into effect. We summarized the major revisions to the Code in a blog post when it was released in August 2021. Many of the updates relate to drug manufacturer practices with regard to speaker events, including meals, choice of venue, and attendance.

Although the PhRMA Code is a voluntary code of conduct, drug manufacturers should consider updating their marketing policies and practices to align with the new Code. The updated Code incorporates the latest guidance from the Office of Inspector General at the U.S. Department of Health and Human Services (OIG). This includes a November 2020 Special Fraud Alert wherein OIG explained its enforcement focus regarding speaker programs. (We blogged about the Alert here).

Another reason drug manufacturers may want to update their marketing policies are the numerous state requirements tied to the Code. Several states, including Connecticut, California, District of Columbia, Massachusetts, and Nevada, have adopted or incorporated the Code in their statutes or regulations. In some cases, a revised PhRMA Code adds obligations for manufacturers to update their practices. For example, California’s drug marketing law requires pharmaceutical companies to adopt an internal marketing compliance policy that aligns with the PhRMA Code. See Cali. Health & Safety Code § 119402(b). If the Code is revised, the California law gives companies six months to update internal policies to conform to the new version. Other jurisdictions like D.C. require sales representatives to comply with the Code “as it may be amended or republished from time to time.” See D.C. Municipal Regulation § 8305.11.

Given these state requirements, following the PhRMA Code is not only an approach to mitigate litigation risk – it is an explicit requirement for manufacturers that interact with health care practitioners in a state that has adopted or incorporated the Code.

As we approach our third year of COVID, one of the major questions from March 2020 eerily echoes today: where are all the COVID tests?  The situation now, of course, is very different and much more favorable than two years ago.  Unlike March 2020, numerous tests by multiple manufacturers have been reviewed by FDA and are being distributed.  There is also a wide variety of tests, including PCR assays, antigen tests, and antibody tests, and at least 16 over-the-counter assays (4 of which were authorized in the past month).  And yet, there is still a dramatic shortfall in the number of tests available.  There are innumerable accounts of desperate scavenger hunts for a COVID assay (link), and a photograph taken by one of us (Jeff) at the local library depicts an all too common scene.

There are multiple explanations for the current inadequate number of tests (link), including government policies on test procurement, manufacturers’ decisions to curtail production when demand fell this summer, the extraordinarily rapid spread of the omicron variant, and surges in demand brought on by the holidays.  But while the advent of omicron unquestionably precipitated the immediate critical shortage, limitations on the availability of COVID tests in the United States was a vulnerability long before the emergence of this variant (link).  As we chronicle in an article that appears in the current edition of the Food and Drug Law Journal, FDA’s policies for reviewing COVID assays, have been a contributing factor.

Over the past two years, FDA has played a central role as gatekeeper for COVID tests.  This role is one that has sporadically received attention (link) but which has not undergone a detailed analysis.  To help fill that void, our article takes an in-depth look at FDA’s policies since the emergence of the pandemic in the United States.  This article (link), which is made available with the permission of the Food and Drug Law Institute, examines multiple facets of FDA’s regulation of COVID assays.

The onset of COVID brought unprecedented challenges to FDA.  There is no question that the agency has devoted herculean efforts and resources to reviewing and authorizing COVID assays.  As of the latest count, FDA has granted more than 420 Emergency Use Authorizations (EUAs) for COVID In Vitro Diagnostics (IVDs) (25 of which were laboratory developed tests).  And that total understates the agency’s efforts to address the critical need for testing, which have included holding 75 Town Hall meetings and issuing eight EUA submission templates.

At the same time, as our article discusses, the agency has taken steps that have unnecessarily impeded the introduction of assays.  For example, the agency has abruptly changed its policies, leaving numerous tests in regulatory limbo and unavailable for use.  The agency’s prioritization scheme has been opaque and confusing, and its implementation has kept COVID tests off the market and hampered decision-making by IVD companies.  The strict data requirements for tests intended to be used with asymptomatic patients led to a lack of tests available for that use.  Ultimately, FDA took the unprecedented step of affirmatively encouraging the off-label use of tests authorized for symptomatic patients to be used off-label for asymptomatic patients.  As we learned first-hand through our counseling of scores of companies, and as has been reported in the media (link), the unpredictability of FDA policies had a chilling effect on product development and submissions.

FDA’s approach to laboratory developed tests (LDTs) has been perhaps one of the most remarkable examples of the impact of agency regulation on test development and availability).  As we’ve blogged about on many occasions (see, e.g., link, link, link, link), FDA’s LDT policy has been fraught for decades, and the consequences of unresolved jurisdictional issues were made manifest during the pandemic.

As we describe in the article, at the outset of the pandemic FDA blocked labs from offering COVID LDTs without an EUA, choosing instead to rely solely on the CDC’s assay.  When that assay turned out to be flawed (link), there were no alternate laboratory tests available because labs had been discouraged from developing them.  Only after weeks of the country flying blind in the face of the viral onslaught did FDA permit labs to offer testing while they prepared EUA requests for submission.  In August 2020, the Department of Health and Human Services intervened, directing FDA to stop requiring EUAs for LDTs in the absence of rulemaking.  This policy was reversed in November 2021, and laboratories were given 60 days to submit EUA requests (the deadline is January 14th) (link).  Given the inadequate testing capacity and the surging demand in the United States, it is inexplicable that FDA would take any steps that could increase burdens on test developers and potentially reduce test availability without an extraordinary reason – which FDA did not offer.

Our article closes with a strong recommendation that FDA take a close look at what has gone well with its review of COVID IVDs – and a lot has – and where improvements are needed.  Mistakes cannot be glossed over.  Under FDA’s quality system requirements, device manufacturers must review all available sources of information to identify quality problems, institute meaningful corrective and preventative actions when appropriate, and then verify effectiveness.  We should expect no less from FDA itself when it comes to self-evaluation of the impact of its testing policies on pandemic preparedness.

In the past few decades, multiple new and deadly etiologic agents have arisen.  SARS-CoV-19 will not be the last one.  The next time, the United States – and FDA – need to be much better prepared to facilitate widespread testing.

* In recognition of the wide and eclectic musical tastes of our HPM Blog followers, this blog post title alludes to the music of both Pete Seeger and Taylor Swift.

The authors acknowledge and thank Charlie Snow for his assistance in preparing this blog post.

On December 23, 2021, CDRH released as a draft guidance, Assessing the Credibility of Computational Modeling and Simulation in Medical Device Submissions (Draft Guidance).  Computational modeling and simulation (CM&S) can sometimes be useful to demonstrate the safety and effectiveness of medical devices or incorporated into devices.  FDA indicates that they receive regulatory submissions with such computational modeling, but the submissions “often lack a clear rationale for why models can be considered credible for the context of use.” Draft Guidance at 4.

The Draft Guidance describes a nine-step framework for evaluating the credibility of CM&S information submitted in pre-market applications.  A computational model is “the numerical implementation of the mathematical model performed by means of a computer.” Draft Guidance at 8.  The National Institute of Biomedical Imaging and Bioengineering describes computational modeling as “the use of computers to simulate and study complex systems using mathematics, physics and computer science.” NIH, Computational Modeling (May 2020).  Weather forecasting is an example of computational modeling and simulation for which most of us are familiar.  Similar techniques can be used to model complex biological systems. The Draft Guidance applies to physics-based or mechanistic CM&S and not statistical or data-driven CM&S, such as those incorporating artificial intelligence or machine learning.

The Draft Guidance describes four types of CM&S that can potentially be used to support a regulatory submission, by either being used to provide evidence to support a device’s safety and effectiveness or by being incorporated within the device, itself:

• In Silico Device Testing, which are computational models that simulate medical device performance. Draft Guidance at 5.
• CM&S used within medical device software, which is use of computational modeling within medical device software to perform device functions. at 6.
• In Silico Clinical Trials, where “device performance is evaluated using a ‘virtual cohort’ of simulated patients with realistic anatomical and physiological variability representing the indicated patient population.”
• CM&S-based qualified tools, which are tools for developing or evaluating a medical device that can be submitted to CDRH under the Medical Device Development Tools (MDDT) Program.

In the Draft Guidance, credibility is defined as “trust in the predictive capability of a computational model.” Id. at 4.  The guidance assesses credibility using key concepts from FDA-recognized standard ASME V&V 40 Assessing Credibility of Computational Modeling through Verification and Validation: Application to Medical Devices.  However, where the ASME standard assumes the ability to perform traditional validation activities, the Draft Guidance provides a more general framework that additionally incorporates non-traditional validation evidence.

A nine-step framework is presented for assessing credibility for purposes of a regulatory submission of the four types of computational modeling described above.  The first steps are to (1) describe the question of interest, (2) describe context of use and (3) model risk.  Next, (4) credibility evidence, either previously generated or planned, is identified and categorized, followed by (5) defining credibility factors and setting prospective credibility goals.  Prospective adequacy assessment is then performed (6) to answer the question, “will the credibility evidence be sufficient to support using the model for the context of use given the risk assessment?” Id. at 10.  Credibility evidence is then generated (7) by executing the proposed studies and/or analyzing previously generated data.  A post-study adequacy assessment (8) is conducted to determine if credibility goals were met, followed by preparation of a credibility report (9).

Key concepts from the framework are then presented in detail within the Draft Guidance, including points of consideration for each type of CM&S, where applicable.  The question of interest should describe the question that is being addressed using the model and along with other sources of information.  When considering the context of use, it should be the specific role and scope of the computational model used to address the question of interest.  The Draft Guidance recommends that a model’s risk, defined as “the possibility that the computational model and the simulation results may lead to an incorrect decision that would lead to an adverse outcome” is assessed according to the ISO 14971 and ASME V&V 40 standards.  Id. at 9.

Credibility evidence is evidence that could support the credibility of a computational model.  Id. at 8. There are three types of credibility evidence (code verification, calculation verification, validation) and ten distinct categories within these three types of credibility evidence that are discussed in the Draft Guidance.

Code verification provides evidence demonstrating that a computational model implemented in software is an accurate implementation of the underlying mathematical model.  Calculation verification determines the solution accuracy of a calculation.  Both calculation verification and validation of the model may be provided through a number of types of evidence, including: general non-context-of-use evidence, evidence generated using bench-top conductions to support the current context of use, evidence generated using in vivo conditions to support the current context of use, evidence generated using bench-top conductions to support a different context of use, and evidence generated using in vivo conditions to support a different context of use.  Validation can additionally be provided by population-based evidence, emergent model behavior, model plausibility and model calibration evidence.  Model calibration evidence is an assessment of the fit of simulation results against the data used to develop the model; while it can support the validation of the model, it alone cannot be used to validate the model.

Although a pre-submission is optional, the Draft Guidance suggests it may be useful to receive Agency feedback on the model risk assessment and prospective adequacy assessment.  A Credibility Assessment Plan is suggested for inclusion in pre-submissions.  For regulatory submissions, the Draft Guidance recommends inclusion of a Credibility Assessment Report.  The structure for both a Credibility Assessment Plan and Credibility Assessment Report are provided in Appendix 2 of the Draft Guidance. Id. at 34-36.

For regulatory and legal professionals, the Draft Guidance provides information that will help ensure regulatory submissions provide appropriate documentation to support the credibility of computational modeling and simulation information provided to support the safety and effectiveness of medical devices.  As FDA indicates, it is especially important to consider these issues within the clinical context (conditions of use).  A model that is credible in one context may not be credible in another.  We are interested to hear from engineers as to whether this guidance will also prove helpful in developing and validating CM&S.

We reported in August that CMS proposed to rescind the Most Favored Nation (MFN) drug pricing interim final rule issued in the latter days of the Trump regime.  Today, CMS finalized that proposal, effectively putting an end to the concept of international reference pricing as a means to limit drug prices.  The bipartisan idea of international reference pricing generated considerable controversy during its short lifetime.  The November 2020 rule was promptly challenged in four lawsuits, one of which resulted in a nationwide preliminary injunction against its implementation.  Though regulatory implementation was stymied, international reference pricing was carried over by Democrats into the drug pricing provisions of H.R. 5376, the Build Back Better Act, which passed the House on November 19.  However, the approach has been rejected in the version of the Build Back Better Act that is slowly taking shape in the Senate.  (See section 129001 of the most recent Finance Committee text.)  Rather than using foreign prices as benchmarks, that legislation would use a specified percentage of the non-federal average manufacturer price (NFAMP) reported by manufacturers to the Department of Veterans Affairs, in order to set a ceiling on Medicare Part B and D drug payment for selected high cost brand drugs.  With today’s action by CMS, the idea of international reference pricing for drugs has reached its demise in both the Congress and the Administration.

Since California passed AB 824: Preserving Access to Affordable Drugs in September 2019, the Association for Accessible Medicines (“AAM”) has been trying to invalidate the law, which imposes a presumption of anticompetitive effect on any Paragraph IV patent settlement in which the generic sponsor receives “anything of value,” including an exclusive marketing license or promise not to launch an authorized generic, from the patent holder.  Intended to target “reverse payment” settlement agreements, in which a brand company pays a first-filer ANDA holder to delay launch, the California law shifts the burden of proof to the drug sponsors to demonstrate that any Paragraph IV settlement agreement is not an antitrust violation.  In other words, the California law assumes that every potential Paragraph IV patent settlement is anticompetitive, and the pharmaceutical manufacturers must show that the settlement is not anticompetitive to avoid upwards of $20 million in fines.  Unsurprisingly—and understandably given the evidentiary hurdle imposed, as well as the amount of proprietary information that must be disclosed for all Paragraph IV patent settlement agreements—industry was not happy.

Thus, as soon as AB 824 went into effect in January 2020, AAM sued California alleging that AB 824 violates the dormant Commerce Clause because it extends to entities and agreements that are not located in California.  Ultimately though, the Eastern District of California denied AAM’s request for a preliminary injunction “primarily due to the nature of Plaintiff’s pre-enforcement attack on AB 824,” determining that AAM “failed to establish a likelihood of success on the merits or raise serious questions going to the merits.”   The Court also determined that AAM failed to establish an irreparable harm that was both likely and imminent.  AAM appealed, but the Ninth Circuit ultimately determined that AAM failed to demonstrate that its members had an Article III injury in fact and therefore lacked associational standing to bring claims on its members’ behalf.  The case was dismissed without prejudice.

Litigation Take 2: AAM filed suit again in the Eastern District of California on August 25, 2020, once again seeking injunctive relief based on allegations that AB 824 is unconstitutional.  AAM argued that AB 824 violates the dormant Commerce Clause by regulating out-of-state conduct; is preempted by federal patent law in view of FTC v. Actavis, 510 U.S. 138 (2013) and the BPCIA; violates the constitutional prohibition on excessive fines under the Eighth Amendment; and violates due process by burden-shifting with no meaningful opportunity to rebut the presumption applied.  This time, in spite of California’s contention otherwise, AAM argued that it has standing because several members have suffered “concrete economic” harm from AB 824.  Because an AAM member company submitting a Declaration stating that it “decided to pull out of a settlement negotiation for a pay-for-delay settlement agreement and chose instead to continue litigating a patent-infringement lawsuit at significant cost due to concerns about enforcement of AB 824,” the Court found the claim prudentially ripe and sufficient for purposes of standing.

With respect to the merits, the Court only addressed (here) the merits of the dormant Commerce Clause Claim because that argument alone was strong enough for the relief requested.  AAM argued that AB 824 directly regulates out-of-state commerce because it is not limited to settlements entered in California or between California entities; conversely, California argued that AB 824 does not regulate conduct occurring wholly outside of California.  The Court applied the “extraterritoriality theory” which precludes states from unduly burdening interstate commerce.  Under that theory, any statute that directly controls commerce outside the boundaries of the state exceed the limits of that state’s authority.  Recognizing that the Supreme Court rarely has held that statutes violate the extraterritoriality doctrine, the Court nevertheless explained that “AB 824 may reach the kind of settlement agreements . . . in which none of the parties, the agreement, or the pharmaceutical sales have any connection with California,” in violation of the doctrine.

California disagreed and told the Court that AB 824 applies only to agreements in California because manufacturers could omit California sales from any agreements subject to 824, but, said the Court, nothing in AB 824 limits the statute to only California settlements.  Because, as written, AB 824 could apply to settlements in which none of the parties, the agreement, or pharmaceutical sales have any connection with California, the statute violates the dormant Commerce Clause.  Further, AB 824’s civil penalties provision is violative, as it could levy substantially significant penalties on parties with no connection to California.  Thus, AAM “is likely to succeed in showing that AB 824 violates the dormant Commerce Clause.”

Because AAM members will be unable to recover monetary damages against the state even if AAM is successful, the Court determined that the monetary injury here constitutes irreparable harm absent a preliminary injunction.  And California could not demonstrate that the balance of equities tip in its favor due both the economic injury for pharmaceutical companies and the lost savings from slowed generic and biosimilar market entry.  As AAM explained, AB 824 will lead—and has already led—to delays in availability of generic medicines and driven manufacturers to withdraw Paragraph IV ANDAs.  This potential harm was not balanced by the need for California to have additional tools to address collusive agreements and its theory that the presumption ultimately will lower drug prices in California.

So AAM’s suit lives to see another day, and California is enjoined from enforcing AB 824.  California has pledged to continue the fight.  For now, California will have to continue to dream.  And we imagine we’ll see you back in 2022 for California Dreaming Part 5.