As readers of this blog may recall, in March 2020, as part of the CARES Act, the FDC Act was amended to include statutory provisions that (1) reform and modernize the way over-the-counter (OTC) monograph drug products are regulated in the United States and (2) authorize FDA to assess and collect user fees from manufacturers of OTC monograph drug products and submitters of OTC monograph order requests.  New Section 744N(a) of the FDC Act, requires FDA to report annually on its progress in achieving the goals identified in the Over-the-Counter Monograph Drug User Fee Program (OMUFA) performance goals and procedures document.  On February 22, 2022, FDA issued its first annual OMUFA report covering FDA’s accomplishments during the period of March 27, 2020 (the date of the enactment of the CARES act) through September 30, 2021.

Despite the demands of the pandemic, FDA met many of its first year goals.  FDA

• issued a notice in the Federal Register announcing the availability of certain deemed final orders (DFO), and plans for modifying the regulations to make them consistent with the OTC monograph reform provisions.
• started posting DFOs on FDA’s new web portal called OTC Monographs@FDA.
• posted the first annual forecast for planned monograph activities.
• issued a request for proposals to secure information technology (IT) services in support of mandated technical requirements and awarded a contract to provide such IT services, somewhat ahead of its schedule.

Due to the pandemic hiring of new staff and delays in FDA’s collecting OMUFA fees which are required to fund new staff members, FDA did not reach its goal for hiring and onboarding new staff members.  Instead of the target 30 new staff members, it hired/onboarded only 13 staff members (i.e., 43% of the goal).  It remains to be seen how this delay in hiring will affect FDA’s ability to meet future goals.

In late December, as cases of Omicron were soaring, CDRH issued two draft guidance documents to prepare for the end of the public health emergency.  The pair of draft guidances laid out the transition for devices that are being marketed under an EUA and devices being marketed subject to enforcement discretion policies.  Copies of the guidances can be found here and here.

Below we discuss the transition plan for each of the types of devices.  At a high level, FDA will be allowing manufacturers a period of no less than 180 days to submit a premarket submission for devices marketed under an EUA or an enforcement policy.

Devices Marketed Under an Enforcement Policy

The draft guidance proposes a 180-day transition period from the implantation date (the “Transition Period”) for devices marketed under the enforcement discretion policies identified specifically in the draft guidance. Once FDA finalizes the guidance, it will identify the implementation date, which will be at least 45 days after the date of the final guidance. At the end of the Transition Period, FDA intends to withdraw the enforcement policies identified in the draft guidance.

The Transition Period will consist of three phases:

• Phase 1: Begins on the implementation date and will require manufacturers to comply with the requirements of 21 C.F.R. Part 803 (MDR reporting) for these devices;
• Phase 2: Begins 90-days after the implementation date and will require manufacturers intending to continue marketing of its devices after the Transition Period to:
  • Comply with the requirements of 21 C.F.R. Part 806 (corrections and removals);
  • Register and list with FDA pursuant to 21 C.F.R. Part 807 (note: listing can be completed without yet having a premarket submission number); and
  • FDA recommends that manufacturers of certain life-supporting and life-sustaining devices submit a “Notification of Intent” to FDA (as described in the guidance);
• Phase 3: Begins 180-days after the implementation date and will require:
  • Manufacturers not planning to continue marketing after withdrawal of the guidances to cease commercialization on or before this date; or
  • Manufacturers planning to continue commercial distribution to submit a premarket submission (e.g., 510(k), de novo) and have it accepted (i.e., through the refuse to accept process).

The draft guidance recommends that premarket submissions for these devices include a transition plan.  The details of which are described in the draft guidance.  For manufacturers that have an accepted premarket submission under review at the start of Phase 3, FDA does not intend to object to continued distribution of the devices until a final decision is made by the Agency on the submission.  How long a submission may remain under review is not clear.  At this time, FDA is continuing to grant applicants an automatic 360 days to respond to requests for additional information pursuant to its Effects of the COVID-19 Public Health Emergency on Formal Meetings and User Fee Applications for Medical Devices — Questions and Answers (Revised) (June 2020).  We have asked CDRH but not gotten a response as to how long this policy will remain in place.  It will be a huge difference for sponsors if they have effectively 12 months to respond to a request for additional information as compared to six months.  We urge FDA to clarify the relationship of this policy and the proposed transition plan in the final guidance.

The guidance provides additional details on how manufacturers who intend to cease distribution should disposition their devices.

Devices Marketed Under an EUA

FDA anticipates that it will publish in the Federal Register notice a date for termination of the EUA declaration (the “EUA Termination Date”).  The draft guidance states that the federal register notice will occur at least 180 days prior to the EUA Termination Date.  The draft guidance proposes allowing manufacturers to continue commercializing devices subject to an EUA so long as they submit a premarket submission and have it accepted prior to the EUA Termination Date.

In terms of when the EUA Termination Date will occur, it is important to remember that there are three separate emergency declarations, which could end at different times to trigger this transition for the applicable device types.  There are emergency declarations for (1) in vitro diagnostic devices for COVID; (2) personal respiratory protective devices; and (3) for other medical devices due to shortages.  These declarations could end at the same or different times thereby potentially creating different EUA Termination Dates for different device types.

The draft guidance recommends that manufacturers of certain life-supporting and life-sustaining devices (identified in the draft guidance) with approved EUAs notify FDA as soon as possible after this guidance is finalized whether or not they intend to continue marketing their device.  The content of the proposed notification is outlined in the draft guidance.

FDA recommends that the premarket submission for devices subject to an EUA include a “transition implementation plan” that addresses devices already in the field in the event of a positive or negative decision on the submission.

Until the end of the Public Health Emergency, FDA will continue to accept and review EUAs.

Last week, CDRH held a webinar to discuss the guidance documents.  There were many questions from industry—some could be answered and others couldn’t.  For example, there were numerous questions related to in vitro diagnostics and laboratory developed tests for COVID.  FDA did not answer any of those questions and referred the audience to the weekly COVID IVD townhalls held on Wednesdays.  The Agency did state that it was willing to consider postmarket data in submissions for these devices and urged sponsors to discuss its submission plans and data with it via the pre-submission process.

In our view, while the draft guidances are a reasonable start, they lack specificity for a number of device-specific issues.  Manufacturers will want to review the draft guidances carefully and reach out to CDRH if you have specific questions (DICE@fda.hhs.gov).

FDA is accepting comments on the draft guidances through March 23, 2022.  We have certainly heard from industry that there are those that think the proposed transition periods are both too short and too long.  It will be interesting to see what the final guidances look like.

On February 23, 2022, FDA published in the Federal Register a proposed rule that would replace the Quality System Regulation (QSR), at 21 C.F.R. Part 820, with a newly named Quality Management System Regulation (QMSR).  The QMSR omits many of the specific QSR requirements that currently appear in the regulations, and instead incorporates by reference an international standard for medical device quality management systems.  This international standard is the 2016 edition of ISO 13485, issued by the International Organization for Standardization (ISO).

The harmonization of the QSR with ISO 13485 has been in the works for some time.  FDA initially announced this plan in 2018, and it has previously appeared in FDA’s regulatory agenda.  The proposed rule, once finalized, will be the first time the QSR has been amended since 1996, when the QSR was updated pursuant to new authority granted to FDA via the Safe Medical Devices Act of 1990.

ISO 13485 is both widely used and largely duplicative of the QSR, with some slight differences.  It is very common for a medical device manufacturing facility both to be certified as compliant with ISO 13485 and to have quality system procedures designed to comply with the FDA’s QSR.  FDA acknowledges in the proposed rule that the “redundancy of effort to comply with two substantially similar requirements creates inefficiency.”

The proposed rule describes the history of ISO 13485, noting that it was first issued the same year as the last updates to the QSR—in 1996.  ISO 13485 has continued to evolve since 1996, and as described by FDA in the proposed rule, “[w]ith each revision . . . has become more closely aligned with, and similar to, the requirements in part 820.”  FDA now sees the alignment between the QSR and ISO 13485 as an “opportunity for regulatory harmonization.”

Interestingly, FDA says that it gained experience with ISO 13485 through the Medical Device Single Audit Program (MDSAP), which allows for inspections based on core ISO 13485 requirements.  Through MDSAP, FDA determined that ISO 13485 “provides a comprehensive and effective approach to establish a QMS for devices.”  Like MDSAP, the QMSR is FDA’s attempt to harmonize internationally recognized regulatory expectations with medical devices subject to US FDA jurisdiction.

The gap between QSR requirements and ISO standards has created confusion for companies that focused compliance only on ISO certification.  FDA investigators expecting to see detailed procedures setting forth each of the requirements of the QSR have been confounded by procedures containing different terminology or lacking elements specifically required by the QSR.  And FDA has issued Form 483s and Warning Letters to companies for failing to have adequate procedures in compliance with the QSR, despite those companies’ arguments that ISO compliance ensures safety and effectiveness.  See, e.g., FDA Warning Letter to San Up S.A. (Nov. 25, 2013).

The proposed QMSR removes all QSR provisions that FDA determined were substantially similar to requirements in ISO 13485.  These provisions are replaced instead with a new section that incorporates ISO 13485 into the regulations by reference.  The proposed QMSR specifically references the 2016 version of the ISO 13485 standard.  The proposed rule leaves open the possibility that FDA will need to amend the regulations in the future to incorporate by reference later versions of the standard.

ISO 13485, while largely duplicative to the QSR, is not a perfect fit with other existing FDA regulations.  To adapt ISO 13485 to the existing FDA regulatory framework, the proposed QMSR retains definitions of some terms that do not appear in ISO 13485 but are necessary to ensure alignment with the Federal Food, Drug, and Cosmetic Act (FDCA), such as the definitions for component, finished device, design validation, remanufacturer, and nonconformity.  Some existing terms have also been revised for better alignment with ISO 13485, such as replacing the defined term “management with executive responsibility” with “top management,” which is a term that appears in the ISO standard.

Additionally, the proposed QMSR includes a section on “clarification of concepts,” which draws parallels between terms used in the FDCA and implementing regulations and corresponding terms in ISO 13485.  For example, the term “organization” in the ISO standard should be read as being equivalent to the term “manufacturer” under the FDA regulatory framework, and “safety and performance” is equivalent to “safety and effectiveness.”

Though FDA determined that ISO 13485 is an adequate replacement for most of the existing QSR provisions, there are a few additional FDA-specific requirements.  The proposed QMSR includes sections on control of records and device labeling and packaging controls.  The section on control of records outlines how FDA expects documents to be approved with a date and signature, such as under the existing document control provisions, and how Unique Device Identifiers (UDIs) (an FDA-specific requirement) should be recorded on certain complaint and servicing records.  Additionally, the device labeling and packaging controls section align with other FDA requirements in 21 C.F.R. Part 801.

FDA has also included language in the QMSR to better adapt certain sections of ISO 13485 to other FDA requirements.  For example, the proposed regulation provides that, for compliance with the ISO section on “Identification,” a device must be labeled with a UDI.  Additionally, for compliance with the ISO section on “Reporting,” a manufacturer must submit medical device reports (MDRs) to FDA pursuant to 21 C.F.R. Part 803.

One area where ISO 13485 has additional requirements compared to the existing QSR is risk management.  As it stands, risk analysis is only briefly mentioned in the QSR in the context of design validation (21 C.F.R. § 820.30(g)), and a comprehensive risk management process is only implicitly required by the QSR.  In contrast, risk management is a key focus of ISO 13485.  To adapt to the QMSR, device manufacturers will need to consider whether they need to establish new risk management procedures, which could be a significant change to a quality management system.

While, in other countries, receipt of a certification of compliance with ISO 13485 by an independent auditor may be sufficient to establish an adequate quality system, the proposed rule makes clear that FDA does not intend to alter its current approach to inspections.  The proposed rule states that manufacturers with an ISO 13485 certificate are not exempt from FDA inspections, nor will FDA issue ISO 13485 certificates based on a successful FDA inspection.

FDA is providing 90 days for comment on the proposed rule, until May 24, 2022.  Additionally, once the rule is finalized, FDA plans to allow one year for companies to adapt to the new QMSR, although this one-year period is subject to comment along with other aspects of the proposed rule.  If finalized as is, companies that have limited its activities to FDA jurisdiction and have not focused on ISO certification will need to get up-to-speed on ISO 13485.  Companies that already tailor their processes to meet both QSR and ISO standards likely will welcome the QMSR, but still will need to review and revise their procedures to update to the new regulation.

With our second OPDP enforcement letter of 2022, FDA is making one thing clear: OPDP will find your promotional content—even when it may not look like promotional content.  While it’s not mind-blowing that OPDP would find a series of videos while scrolling Instagram (particularly when it’s flagged by FDA’s Bad Ad program), OPDP issued a Warning Letter on February 11 concerning a little-seen interview with the former CEO of CytoDyn discussing its investigational new drug product, leronlimab.  Let’s be clear here: the statements CytoDyn made about leronlimab in the interview are outrageous (more on that below)—that FDA found them problematic is not the interesting part.  What is interesting is that the video appeared on the YouTube channel of “one of the fastest growing financial media portals in the world,” and the link to the video on the cytodyn.com website was included under an “In the News” page.  At first blush, we were deja vu-ing all over again to FDA’s action against Aegerion back in 2013.  But the CytoDyn interview was different.

Proactive, the company behind the YouTube Channel that included the CytoDyn video, describes itself as “enabl[ing] companies and investors to connect intelligently.”  Proactive’s Terms and Conditions includes the following statement:

In exchange for publishing services rendered by the Company on behalf of any issuer named on the Site, including the promotion by the Company of the issuer in any Content on the Site, the Company receives from said issuer annual aggregate cash compensation in an amount equal to Twenty Five Thousand dollars ($25,000).

FDA notes this point in Footnote 1 of the Warning Letter, calling out the video and Proactive with the quote, “Proactive is a publisher and receives compensation for publishing content on this account for and on behalf of its clients.”  This footnote call-out may be easily missed, but it is critically important for FDA in establishing that the objectionable content is, in fact, promotional content that may be separate and apart from “the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media.”  21 C.F.R. §312.7.

This is not the first time FDA has admonished CytoDyn’s communications about leronlimab.  While not an OPDP enforcement letter, FDA took the rare step to publicly criticize the company last year for its communications about leronlimab.  At that time, FDA stated,

CytoDyn has publicly communicated differences in small subgroups from the CD12 trial (e.g., a sub-group analysis of 62 of the 394 patients studied) suggesting that the data demonstrated a mortality benefit in certain patients who had received leronlimab. Subgroup analyses have well-established limitations, especially in the context of a clinical trial that has failed to show a benefit in the overall study population. For example, subgroups are often small, and therefore imbalances are common. Here, the data from CD12 illustrated imbalances in mortality among subgroups, some favoring leronlimab and some favoring placebo. None of these analyses met statistical significance when using established and reliable analytical methods that correct for multiple comparisons. However, as noted above, such analyses may inform the design of future clinical trials investigating leronlimab for the treatment of COVID-19.

FDA may have taken this unusual step out of concerns that CytoDyn’s communications were not traditionally “promotional” and an OPDP Warning or Untitled Letter might not be appropriate.  After FDA’s public criticism, DOJ and the SEC subpoenaed the company and its executives seeking documents and information related to CytoDyn’s public statements about leronlimab.  According to Fierce Biotech, these investigations were disclosed in an SEC filing dated July 30.

The video that is the subject of the February 2022 OPDP Warning Letter, dated September 22, 2021, features an interview with then-CEO of CytoDyn, Dr. Nader Pourhassan.  The video, created four months after FDA’s public criticism of the company for communications about subgroup data on leronlimab and almost two months after the company announced it had received subpoenas from DOJ and SEC, shows Dr. Pourhassan again discussing leronlimab subgroup data from the same studies to which FDA previously objected.

As part of the discussion of leronlimab data in the sponsored video, Dr. Pourhassan describes a study that missed its primary and secondary endpoints as follows: “In the United States, we did a trial of 394 patients which included severe and critically ill population. In the critically-ill population, our results were really strong. . .”  He further describes a subgroup analysis as “Our critically-ill population [study] that we did in the United States when we gave a dose of leronlimab, the survival rate was 78%. Once we gave them another dose, the survival rate went up to 82%.”  Dr. Pourhassan asks the audience to “[I]magine, if 78% went to 82, the next one would be maybe 88, and then 95.”  He admits that he is “making up numbers,” but he hypothesizes that “if [study results] just follows the same pattern what we learned, this is going to be the most fantastic results anybody could ever imagined to have.”  He ends with the disclaimer “Now I’m not saying that’s what we’re going to get, but I’m saying that’s what the results are showing.”

Based on the nature of the sponsored interview, FDA concluded that the video is false and misleading and promotes leronlimab as safe and effective for the purposes for which it is being investigated.  Specifically, FDA explains “the video is extremely concerning because it significantly mischaracterizes the clinical trial data for leronlimab in the treatment of COVID-19, and the stated conclusions based on this mischaracterized data create a misleading impression regarding the safety and efficacy of the product.”  FDA therefore requests that CytoDyn disseminate corrective communications about these studies.

Typically, when corrective advertising is requested as part of an OPDP Warning Letter, the corrective advertising takes place in the same medium, directed toward the same audience, as the original violative communication.  Will we see more “Fake News” interviews with corrective information about leronlimab?  If so, Proactive Media may be the real winner in all of this.

Aside from the obvious lessons here (e.g., don’t call subgroup analyses from failed studies “really strong” results), it’s important to consider the different approaches taken by FDA based on the types of communications.  FDA’s initial approach was to correct misinformation through a public statement—sending an OPDP Warning Letter only when the communications could more clearly be tied as “promotional.”  And FDA did its research—it called out Proactive Media’s platform as a sponsored publication.  Given the rise in sponsorship “opportunities” on news platforms, and FDA’s interest in sponsored news segments, companies should be treating these opportunities the same way they would treat more traditional promotional communications and ensure truthful communications.

We return to the subject of FDA’s role in effectively blocking most rapid antigen COVID tests from the U.S. market.  There has not been a new rapid antigen test authorized during the past six weeks.

As we mentioned in our previous post, NIH’s ITAP program was stood up a few months ago to accelerate the validation of these tests and to help companies comply with FDA’s requirements.  That strategy has failed, too.

The new idea is for NIH’s ITAP program to pivot to serial screening.  NIH has been in communication with FDA to finalize a standardized clinical protocol for this purpose.  Unfortunately, based on what we have heard, the process of finalizing an acceptable protocol has hit an unexpected roadblock.  The issue is a conflict between ethical concerns versus study bias.

To explain: Nearly all COVID-19 in-vitro diagnostic trials are single point analyses.  This study design means that the study participant collects a single sample for both the antigen test and the Standard-of-Care device and the participant’s involvement in the study is completed in a single visit.  The participant will usually receive their Standard-of-Care result within 24 hours.

With a serial screening study, however, multiple samples are collected by the participant over a few days.  This fact means that it is possible for the participant to be aware of their “true” COVID-19 status while the trial is still on-going, thus biasing the results.  How does one solve this issue? In order to have an unbiased study the participants in the longitudinal trial should not have knowledge of their COVID-19 status.  At the same time, there are ethical concerns about withholding the Standard-of-Care result from the patient.  If it is withheld, the patient may delay treatment or infect others.

It is interesting that this issue has not surfaced publicly until now.  FDA has allowed serial screening since the issuance of the “Supplemental Template for Developers of Molecular and Antigen Diagnostic COVID-19 Tests for Screening with Serial Testing” on March 16th, 2021 (HPM Blog).  In fact, FDA has authorized a few devices with serial screening claims based on promises by the companies to conduct the studies post-authorization.  To our knowledge, none of those studies have been completed.  This ethical issue may be a reason.  Regardless, this issue seems to be holding up serial testing option.

What should FDA do?  To start, FDA could proceed down the trail that they have already blazed and continue to authorize devices for serial screening using only a single point analysis in order to rapidly expand the supply of tests to the US market.  A few of these tests are already on the market.  To compensate for the lower expected performance, FDA could limit the indications for use of all lateral flow antigen tests to be used in a serial fashion only provided that they meet a lower performance bar that is more consistent with the current state of the pandemic.

Alternatively, FDA could rethink its minimum requirement of 80% sensitivity for rapid antigen tests.  They need to come up with a testing and/or labeling approach that provides reasonable assurance of safety and effectiveness and also harmonizes with the nature of this technology.  The Europeans seem to have done it.  Surely, we can, too.  We floated a few potential solutions here and here.  Under the status quo, the American public will continue to make do without these tests.

On February 18, 2022, the US Consumer Product Safety Commission’s (CPSC) Office of Compliance and Field Operations issued a guidance for household substances not intended for household use under the Poison Prevention Packaging Act (PPPA). No, that is not a typo.  The revised immediately effective guidance states that products categorized as “household substances” and only intended for institutional use must be sold in special packaging under the PPPA guideline.

This guidance raises the fundamental statutory interpretation question of whether a substance can be a “household substance” if it is not intended for household use.  In the guidance, the CPSC answers that question in the affirmative.  In doing so, the CPSC does not address the fact that the PPPA does not cover substances not intended for household use.  As a result, the CPSC’s reasoning is at best incomplete, and at worst, internally inconsistent.

The heading of the guidance specifically states that it concerns product “not intended for household use.”  Yet, as CPSC acknowledges, the PPPA requires certain household substances to be packaged in accordance with special packaging standards.  CPSC further acknowledges that the term “household substance” is defined as “any substance which is customarily produced or distributed for sale for consumption or use, or customarily stored, by individuals in or about the household.”  CPSC then discusses exceptions to the requirement for special packaging and notes that the exceptions are limited and do not include products for institutional use, i.e., product not intended for household use.  But if  the PPPA applies only to product intended for household use then it does not need to include an exception for product not intended for household use, because those products are not regulated by the PPPA.

One way to interpret the guidance is that the CPSC is claiming that if a  substance is “customarily produced or distributed for sale for consumption or use, or customarily stored, by individuals in or about the household,” then all packages of that substance are “household substances” even if not intended or labeled for household use.  It is far from clear that this interpretation would withstand judicial scrutiny.  Regardless, as a matter of administrative law, the CPSC should explain its reasoning.

The CPSC acknowledges that “in commercial and institutional settings [] the risk to children is diminished” and, therefore, it will be exercising enforcement discretion with respect to allegedly noncompliant products intended to be used in such settings.   The non-exhaustive list of factors the CPSC staff will consider include :

• how and where the product is advertised, marketed, sold, labeled, and distributed;
• the nature and extent of a firm’s oversight of its distribution chain;
• the packaging configuration, type, and size;
• whether the ancillary instructions provided on the package [such as for storage, handling, or use] are intended for consumers; and
• product reviews and other evidence demonstrating the nature and extent of consumer use.

Other statements in the guidance suggest that CPSC’s guidance originates in concern that products intended for institutional or other non-household uses may end up in households anyway.  Companies marketing products for institutional use would be well-advised to consider CPSC guidance and the risk and possible safeguards to prevent that their products, even though not intended for household use, will end up in households.

Our readers probably know that we value and advocate for patient engagement as an essential component in the development of medical products (see our firm’s commitment here).  The COVID-19 pandemic cannot keep us from actively facilitating Externally-Led Patient-Focused Drug Development (EL-PFDD) meetings with the Food and Drug Administration (FDA) (see here) along with a legacy of patient engagement in pre-pandemic times (see our previous coverage on patient engagement activities here, here, here, here, here, here, and here).  While FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) have been in the limelight for championing approaches to patient engagement for drug development, the Center for Devices and Radiological Health (CDRH) has more quietly been plugging away at their own draft guidance on Patient Engagement in the Design and Conduct of Medical Device Clinical Investigations in September 2019 (see our previous coverage on it here).

On January 26, 2022, CDRH, along with CBER, released a final guidance document Patient Engagement in the Design and Conduct of Medical Device Clinical Studies (“Guidance”), which is the culmination of many years of efforts including FDA’s Patient Engagement Advisory Committee (PEAC) meetings in 2017 and 2018, and the Clinical Trials Transformation Initiative (CTTI) workshop in 2019.  The Agency’s goal is demonstrated in its definition of patient engagement:

“Patient engagement is defined as intentional, meaningful interactions with patients that provide opportunities for mutual learning, and effective collaborations.” 

To this end, this Guidance is intended to:

• “help sponsors understand how they can voluntarily use patient engagement to elicit experience, perspectives, and other relevant information from patient advisors to improve the design and conduct of medical device clinical studies;
• highlight the benefits of engaging with patient advisors early in the medical device development process;
• illustrate which patient engagement activities are generally not considered by FDA to constitute research or an activity subject to FDA’s regulations, including regulations regarding institutional review boards (IRBs); and
• address common questions and misconceptions about collecting and submitting to FDA patient engagement information regarding the design and conduct of a medical device clinical study.”

What would be the potential benefits if companies prospectively design medical device clinical studies with input from diverse patient advisors?  There are several examples that the Agency provided in the Guidance such as (1) streamlined data collection resulting in better quality data, (2) more relevant data on outcomes that matter to patients, and (3) fewer costly and time-consuming protocol revisions.  The Agency also acknowledges that patient engagement may be beneficial across the total product lifecycle, which is beyond the scope of the design and conduct of clinical studies.  This Guidance embodies the Agency’s belief that:

“Successful adoption of legally marketed medical devices increasingly depends on patient acceptance of that technology and patients being more engaged in the healthcare process, along with demonstrated public health benefits.”

The Guidance provides practical advice for device manufacturers to utilize patient engagement in clinical studies.  The Agency envisions a range of activities that may enhance the design and conduct of clinical studies through engagement with “patient advisors” – individuals who have experience living with a disease or condition, but who are not study/research participants themselves or caregivers of study/research participants.  This includes:

• Improving the informed consent document to ensure patients understand the information presented for the clinical study;
• Obtaining input on flexible options for follow-up visits and data collection techniques to reduce unnecessary burden on study/research participants;
• Working with patient advisors as needed during an ongoing study to discuss barriers to recruitment or other issues such as causes of study delays or challenges not anticipated before the study;
• Discussing views on which potential endpoints are meaningful in the treatment of the specific disease/condition;
• Informing the concepts that should be captured by patient reported outcome (PRO) measures in the clinical study to better reflect outcomes that are important to patients; and
• Informing the design of patient preference studies that may be used to inform the development of clinical studies or to help understand the benefit-risk tradeoffs among patients for the proposed treatment or multiple treatment options used for the disease/condition.

The Agency highlights that sponsors should gather input from patient advisors during the early planning phases of the clinical study so that their input can be incorporated while the study plan is being developed.  FDA not only endorses this for use by investigational device developers, but to be provided to the Agency to inform their own thinking.  For example, if clinical studies require submission of an investigational device exemption (IDE) application, the Agency encourages patient advisors’ input be included in the final protocols and informed consent documents in the IDE application for FDA review.  For the actual adoption of inputs from patient advisors, we hope that the Agency provides practical guidance on how those inputs could be incorporated in the IDE application or subsequent premarket submissions.

The Agency encourages sponsors to engage in early interactions with the relevant FDA office/division to obtain feedback upon appropriate design and any applicable regulatory requirements when considering incorporating input from patient advisors in the design or conduct of medical device clinical study.  For additional information on planning patient engagement, please see the CDRH’s Patient Science and Engagement Program.  A sponsor can use the Q-Submission Program to obtain FDA feedback on its patient engagement plan or patient-centered study design.

Finally, mark your calendars for the upcoming March 22, 2022 FDA webinar about this Guidance.  The FDA webinar information can be found here.  Hearing from patients at the outset can help lead to better clinical trial designs, expedited patient recruitment, and ultimately greater acceptance of new medical devices!

Last November, we explained FDA’s role in blocking over-the-counter (OTC) rapid antigen tests from the American market.  We identified as the main culprit FDA’s requirement that these tests achieve 80% sensitivity (positive percent agreement or PPA) even when a required percentage of low positive patients are included.  FDA has never publicly justified this 80% minimum, which until last October was an even stricter 90% minimum.  For reasons we explained in our prior post, this requirement is not a good fit with rapid antigen tests.

At the time, the Biden administration was standing up a new program at the National Institutes of Health (NIH) to help companies break through FDA’s brick wall.  The program is known as the Independent Test Assessment Program (ITAP).  We speculated that this program might simply be a public relations move.

Three months later, there is good news and bad news.  The good news is that the NIH’s program is real and has been offering helpful assistance to manufacturers seeking to obtain Emergency Use Authorization (EUA) approval from FDA for OTC rapid antigen tests.  The NIH is in regular contact with FDA to ensure they understand the agency’s latest requirements.  The NIH screens manufacturers to ensure they have reputable tests already in use in other countries with good supporting test data.  The NIH also only accepts manufacturers into the program if they can demonstrate the ability to provide high volumes (e.g., 20 million / month or more) of tests to the American market.

For those accepted, the NIH provides a comprehensive team of project management and scientific experts to help the manufacturer prepare a viable EUA application.  The silent killer of EUA applications is the disconnect between what FDA wants and the publicly available EUA templates.  Having a direct line to FDA through the ITAP program gives companies a clearer understanding about their prospects for authorization.  Additionally, the NIH assists with all the analytical and clinical testing, using protocols already vetted with FDA.  This testing is done by testing labs and clinical research organizations (CROs).  Because FDA trusts the NIH, the EUA review is likely to be prioritized and conducted quickly.  FDA will even accept a modular submission and review it on a rolling basis as the data comes in.  The upshot is potential for a rapid review and approval, provided the data are satisfactory.

The bad news is that NIH-assisted manufacturers are running into the same FDA brick wall as everyone else.  To our knowledge, five clinical studies conducted by NIH have failed to hit 80% sensitivity.  We understand NIH shared the details of these data with FDA.  Yet, recent FDA town halls with test developers suggest that FDA is not budging on performance.

Since the start of the pandemic, FDA has authorized a total of 17 OTC rapid antigen tests.  These 17 tests self-evidently have not been able to satisfy demand.  Subsequent to the rise of the omicron variant in the United States toward the end of 2021, FDA has only authorized a single OTC rapid antigen test, and that EUA was likely based on a study without a significant number of omicron patients.  Therefore, at present, it does not appear that the American market has any OTC rapid antigen tests optimized for the omicron variant.  The few tests FDA approved before the appearance of the omicron variant have not had their labeling updated to reflect their ability to detect omicron in a prospective clinical study.  We are moving backward, not forward in terms of having widespread OTC testing capability that is pertinent to current circumstances.

We understand that NIH is now going to try to obtain approval for tests labeled for serial use.  An example of serial use would be taking a test on a Monday and followed by a test on Wednesday.  In trial design, this type of intended use provides two opportunities to identify an individual as positive.  Although FDA still requires that a test labeled for serial use achieve a minimum 80% sensitivity, that is statistically more likely if the calculation is based on two tests rather than just one.

This option has been available all along but apparently has not proven attractive for most manufacturers.  While we have seen FDA grant serial screening claims to antigen tests, we have not seen FDA authorize an antigen test that required serial testing to meet the minimum performance requirement.  One of the reasons why it may not be common for manufacturers go out of their way to validate their devices for serial screening is that the complexity of the study to support this indication greatly expands the time, cost, and risk of failure.  If serial testing is required to bring a product to market it will likely shut out smaller manufacturers that have the potential to supplement the national testing supply after they ramp up production post-authorization.

It appears that we are at an impasse.  Unlike the rest of the world, this country has a shortage of OTC rapid antigen tests.  FDA has issued EUAs for very few, primarily due to the 80% sensitivity requirement.  What should be done?  Perhaps our legislators can intervene.  For one thing, they should require FDA to provide a detailed scientific justification for its 80% sensitivity requirement.  To date, FDA has failed to publicly explain its reasoning and justification for either the original 90% requirement or the more recent 80% requirement.

It might also be worthwhile for Congress to hold hearings, with medical and public health experts testifying, to come to a decision about the tradeoff between lowering the sensitivity threshold versus enabling widespread availability of OTC rapid tests.  A good case can be made that FDA has made the perfect the enemy of the good.  In the meantime, if the status quo continues, it is doubtful that Americans will ever have access to the widespread OTC testing that other countries are widely utilizing.

Hyman, Phelps & McNamara, P.C. (“HP&M”) is pleased and excited to announce that Dr. Ellis F. Unger has joined the firm as a Principal Drug Regulatory Expert.  Dr. Unger is a cardiologist and former Director of the Office of Drug Evaluation-I in FDA’s Office of New Drugs in the Center for Drug Evaluation and Research (“CDER”).  While at FDA, Dr. Unger’s Office oversaw the approval and regulation of scores of new drugs for cardiovascular, renal, neurological, and psychiatric disorders.

Dr. Unger, who is a 1971 recipient of the Rensselaer Polytechnic Institute Mathematics and Science Medal, earned a Bachelor of Science (magna cum laude) in chemistry from Wright State University in Dayton, Ohio, and a Doctor of Medicine from the University of Cincinnati College of Medicine in Cincinnati, Ohio.  He completed his cardiology training at The Johns Hopkins Hospital in 1987.  While at Johns Hopkins, and as a Senior Investigator in the Cardiology Branch of the NIH National Heart, Lung, and Blood Institute, Dr. Unger led a translational research program on promotion of angiogenesis. From 1997 to 2003, Dr. Unger served as a medical officer, team leader, and subsequently branch chief in FDA’s Center for Biologics Evaluation and Research (“CBER”).  After regulatory authority for therapeutic biologics was transferred from CBER to CDER in 2003, Dr. Unger joined CDER as the Deputy Director of the Division of Cardiovascular and Renal Products.  Dr. Unger transitioned to the Office of Drug Evaluation-I in 2009, and became its Director in 2012.

As a Principal Drug Regulatory Expert, Dr. Unger joins HP&M’s growing and stellar Drug Development Team, which is composed of a host of attorneys and regulatory experts who assist companies on a multitude of drug and biological product legal, regulatory, and policy issues.  “I am delighted to be joining HP&M in this role, and believe that my knowledge and experience will be synergistic with the amazing expertise of the Firm,” said Dr. Unger.

“We are thrilled and humbled that someone with Dr. Unger’s background has chosen to work with us.  His experience at FDA and insights into the FDA approval process broaden and strengthen our capabilities in ways that will benefit our clients,” said JP Ellison, HP&M’s Managing Director.  Drug development attorney (and guru) Frank Sasinowski commented: “We are honored to have Dr. Unger join us in aiding patients, researchers and sponsors bring new therapies to those in need of them.  Dr. Unger’s decades of dedicated service to advance our public health should find here the opportunity to extend that illustrious career even and ever further.”

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!