The FDA is legally established as a law enforcement agency.  But its structure and activities have also generated its own “branding” as a trusted independent validator of medical devices.

This public trust gives FDA tremendous power.  If a device has not undergone FDA’s premarket review (even if lawfully exempt), it often causes consternation among potential customers.  Likewise, if FDA issues negative public statements about the safety of marketed devices or the compliance status of a company, there can be a significant and lasting market impact.

The use of this power is not new for FDA.  Historically, FDA has made public a variety warning letters about violations available to the public (and it continues to do so).  It also publicizes adverse event reports and  recalls, market withdrawals and safety notices. In Class I recalls, the agency may issue its own press release.  FDA issues device safety communications.  FDA makes public some information on inspection results.

During the pandemic, however, CDRH has qualitatively increased its use of public lists and other information to leverage the FDA brand to protect the public health.

A few examples:

CDRH allows commercial manufacturers to distribute diagnostic test kits to perform assays to detect SARS-CoV-while the manufacturer is preparing its EUA request, provided that the manufacturer provides instructions for use of the test and posts data about the test’s performance characteristics on the manufacturer’s website.  CDRH is relying upon this “[t]ransparency to mitigate potential adverse impacts from a poorly designed test by facilitating better informed decisions by potential purchasers and users.”  The manufacturers and their tests are listed here, and the list expressly notes whether a test is “unauthorized” or “authorized.”

This approach has not been an unalloyed benefit to manufacturers.  Some customers are unwilling to purchase products based upon notification and insist on waiting for an EUA to issue.  That reflects the power of FDA’s brand.  But other customers are perfectly happy to do so.  For instance, some sophisticated clinical laboratories may feel that they have an adequate ability to validate the tests and do not need to rely on FDA’s validation.

As another example, CDRH maintains a list of tests that affirmatively should no longer be used or distributed here.

As a third example, CDRH issued enforcement discretion guidance allowing thermographic cameras to be commercially distributed for detecting fever during the pandemic.  Upon finding that some firms are marketing the cameras in violations of the guidelines, FDA has issued warning letters.  That much is not unusual (except for the demand for a response within 48 hours).  But FDA also has redeployed these technical and legalistic warning letters into a plain English warning against using the products:

FDA is advising consumers not to purchase or use certain products that have not been approved, cleared, or authorized by FDA and are being misleadingly represented as safe and/or effective for the mitigation, prevention, treatment, diagnosis, or cure of COVID-19. Your firm will be added to a published list on FDA’s website of firms and websites that have received warning letters from FDA concerning the sale or distribution of COVID-19 related products in violation of the Act. This list can be found at https://www.fda.gov/consumers/health-fraud-scams/fraudulent-coronavirus-disease-2019-covid-19-products. Once you have taken actions to address the sale of unapproved, uncleared, and unauthorized products . . . and any appropriate corrective actions have been confirmed by the FDA, the published list will be updated to indicate that your firm has taken such corrective actions.

Other examples:

SARS-CoV-2 Reference Panel Comparative Data | FDA (list of molecular tests and their performance against a reference panel).

EUA Authorized Serology Test Performance | FDA (list of serology tests and their expected performance).

Independent Evaluations of COVID-19 Serological Tests (Frederick National Laboratory for Cancer Research results of serology test performance – authorized and not authorized).

As a final example, in response to a great deal of (often deliberate) misinformation circulating in the public domain about the meaning of “FDA registered” and “FDA certified,” CDRH has published an explainer.

FDA took these steps in the crush of responding to the pandemic.  But they point to a broader potential after the pandemic.  We have gotten to the point where there has been wide and deep integration of internet-based research into business and consumer decision‑making.  It is now easy to quickly find FDA’s lists and other information they may put out.  For this reason, although the pandemic may have acted as a catalyst, FDA’s more aggressive use of publicity is likely to expand in the years to come.

Congress should keep an eye on how FDA evolves its use of publicity in order to ensure that this power is used responsibly.  Still, Congress will no doubt appreciate that this approach permits FDA to achieve a public health impact more quickly and at lower cost than might otherwise be the case.

Finally, the song title quoted in the title of this post is from Gilbert & Sullivan’s The Mikado.  The pertinent lyrics:

“I’ve got a little list.

I’ve got a little list.

Of society offenders

Who might well be underground

Who never would be missed – who never would be missed!”

On March 16th, 2021 CDRH announced a major policy change for the EUA program in an effort to expedite screening testing for the pandemic. Screening is the testing of asymptomatic individuals who do not have known or suspected exposure to COVID-19 in order to make individual decisions based on the test results.  This new supplemental template provides recommendations for device manufacturers with the goal:

to streamline the authorization of screening tests with serial testing. The recommendations apply to test developers who seek an EUA from the FDA for certain screening tests prior to conducting certain performance evaluations with asymptomatic individuals.

This is a major departure from previous policy as testing prior to authorization was only permissible in very limited cases for devices used only in High Complexity CLIA labs. It is important to note that this new pathway is only available to manufacturers of molecular and antigen tests.  Serology tests are not mentioned in this announcement.

Serial testing as defined by FDA is the “testing the same individual multiple times within a few days.”  The thinking behind this strategy is the testing of a single patient across multiple days would increase the chances of detecting infection even when using devices with lower sensitivity.  FDA’s expectations for a device’s Sensitivity/Specificity increase when you traverse across the continuum of indications.  We provide an example for antigen tests below (Table 1).

Table 1 – Performance Expectations by Indication in FDA’s EUA Templates (Antigen)

The key section of this announcement is where FDA identifies what indications may be eligible for this new program:

For example, in certain circumstances, a [point-of-care] test or an at-home test could be authorized for over-the-counter (OTC) use without the need for validating its use in asymptomatic individuals prior to authorization.

This statement has the potential to be both very powerful and very frustrating for industry.  In Table 2 below there is a breakdown of the data expectations for Point-of-Care, Prescription Home Use, and OTC Home Use with an asymptomatic claim.  What you can see from the information, in the various EUA templates laid-out in this fashion, is that ‘Prescription Home Use’ and ‘OTC Home Use’ are very similar in their requirements.  It is, therefore, reasonable to expect FDA to blur the line between ‘Prescription Home Use’ and ‘OTC Home Use’ when considering asymptomatic testing.  It was very surprising, however, to read that this new policy may also apply to devices validated for Point-of-Care.  The differences in data requirements between ‘Point-of-Care’ and ‘OTC Home Use’ are substantial.  Devices authorized for Point-of-Care are not validated to the same degree with respect to Robustness (Flex Studies), Human Factors (Human Usability), the data required to substantiate performance for Point-of-Care (POC) may have been largely retrospective testing.  This difference is due, in part, to the intended users – tests intended for POC are typically used by healthcare providers whereas home tests are used by lay people.

The inclusion of Point-of-Care in this new policy implies that a manufacturer can take their authorized test, supplement the EUA with the additional information describing serial testing and obtain an OTC Home-Use indication. As of March 16, there are twenty (20) molecular EUAs and one (1) Antigen EUA with an attribute of ‘screening’ according to FDA’s website.  Of these tests, eight (8) are Direct-to-Consumer (DTC) and two (2) are Over-the-Counter (OTC). To date, there are no Point-of-Care EUAs with a screening attribute.

Table 2 – Tests Recommended by FDA Stratified by Indication

Supplemental Template for Developers of Molecular and Antigen Diagnostic COVID-19 Tests for Screening with Serial Testing (Example Template)

The administrative section at the top of this new template echoes the announcement indicating that this policy applies to Point-of-Care indications:

This template is intended to provide supplemental recommendations for developers of molecular and antigen tests seeking claims for screening with serial testing without studying asymptomatic individuals prior to authorization, including for point-of-care (POC) and at-home tests.

While the intention of the policy is to increase testing availability FDA does not want manufacturers to misconstrue this as a paradigm shift with an opportunity to resurrect denied EUAs from the grave.

These recommendations will generally not be applicable to developers with tests for which data has already demonstrated poor performance (e.g., less than 80% PPA) for testing asymptomatic individuals.

FDA later goes on to seemingly contradict themselves on the next page of the template by stating:

As discussed in the Antigen Template for Test Developers, strategies for serial testing with less sensitive tests (i.e., PPA <80%) may be able to be support authorization

FDA gives the following example as a modification to the intended use:

…individuals without symptoms or other epidemiological reasons to suspect COVID-19 infection, when tested twice over two (or three) days with at least 24 hours (and no more than 36 hours) between tests.

As written, this implies that there is no expected modification to the intended use setting or user as a result of this policy change.

The template does indicate that FDA intends to push as much of the clinical validation as possible to a post-marketing commitment in order to expedite the authorization of new tests.  While this recommended study size is small, 20 asymptomatic positives individuals, it has been increasingly more difficult to find asymptomatic positives naturally within the population, and that challenge is likely to continue to grow.  It is not clear from this template how long FDA will give these companies to compete these post-authorization studies.

The template closes with a final recommendation for labeling:

Proposed labeling should clearly identify the population in which the test’s performance has been validated, and clearly identify any populations included in the intended use for which the test’s performance has not yet been established and will be established during the above referenced post-authorization study.

This final section further confuses what is expected of manufacturers as it implies that the post-authorization study is the only data requirement to expand the EUA claim to a new patient population.

This announcement from FDA generates a rollercoaster of emotion starting with cautious optimism, to elation, and finishing with confusion. This policy raises major administrative questions that need to be answered in full if this new program is to have a chance at success.

Can a manufacturer take an existing Point-of-Care or Rx-Only EUA and convert it to an OTC Authorization, if they commit to conducting an additional clinical study post-authorization?

It is our review of the policy that, as written, it appears that the answer is yes. However, the policy never mentions the non-clinical tests that FDA typically requires for Home-Use tests and whether those will also need to be performed, either pre- or post-market, to support the expanded indication Point-of-Care authorized tests.  Without additional clarifications on the part of FDA, manufacturers will be left scratching their heads and unsure as to what FDA expects in EUAs moving forward.

The next “FDA Virtual Townhall” is Wednesday March 24^th at 12:15 pm (ET).  See you there.

On Friday, March 12th FDA posted a letter to healthcare providers about performance concerns regarding the Roche Molecular Systems, Inc. cobas SARS-CoV-2 & Influenza Test for use on cobas Liat System.  This public letter appears to be the culmination of a dialogue between Roche and FDA.  Roche’s root cause analysis investigation has identified two potential causes for the false positives:

• Roche identified that the assay tubes may sporadically leak, causing an obstructed optical path in the Liat analyzer, producing abnormal PCR growth curves. This could lead to invalid or erroneous positive results, particularly for the Flu B test. If a tube leak occurs, later testing runs may have an increased likelihood of false positive Flu B results.

• Roche determined that abnormal PCR cycling in the reaction tubes may also produce abnormal PCR growth curves, leading to erroneous results. The issue is sporadic and may be caused by multiple factors happening at the same time, such as hardware positioning, volume movement, and curve interpretation. This issue may cause false positive results for multiple analytes (Influenza A, Influenza B and/or SARS-CoV-2) in a single testing run.

In response, FDA recommended three actions by users:

1. Monitor for unexpected clusters of positive Flu B results, as this may indicate the cobas Liat System has experienced a tube leak.
2. Repeat tests when two or three analytes are positive. Different results on the repeat test may indicate abnormal PCR cycling.
3. Stop using the cobas Liat System and contact Roche if you suspect either of these two issues has occurred.

This letter is not the first FDA has posted for Clinical Laboratory and Point-of-Care staff.  It is actually the fourth one since October 2020 and the eighth such notice flagging in‑vitro diagnostic performance issues or concerns during the pandemic.

These notices have hit each of the three major classes of in-vitro diagnostic products used for the nation’s pandemic response, PCR, Serology, and Antigen Tests.  Here are three relatively recent examples:

PCR

• Genetic Variants of SARS-CoV-2 May Lead to False Negative Results with Molecular Tests for Detection of SARS-CoV-2 – Letter to Clinical Laboratory Staff and Health Care Providers (Posted 01/08/2021)

Antigen

• Potential for False Positive Results with Antigen Tests for Rapid Detection of SARS-CoV-2 – Letter to Clinical Laboratory Staff and Health Care Providers (Posted 11/03/2020)

Serology

• Important Information on the Use of Serological (Antibody) Tests for COVID-19 – Letter to Health Care Providers (Posted 04/17/2020)

The full list of FDA’s “Letters to Health Care Providers” can be found here.

As we proceed through this pandemic, it is becoming more critical that manufacturers be as vigilant as ever with post-market surveillance to flag performance issues early in order to be able to investigate and identify potential root causes.  Prompt investigation and correction is always preferable to pulling a test that works out of the marketplace.  It is in no one’s best interest to lose testing capacity and we hope that FDA is affording companies of all sizes the same opportunity that Roche has been given to investigate and correct rather than be forced to pull an assay from distribution.

On February 17th, 2021 the Biden Administration announced an expansion of the Federal strategy to test the population for SARS-CoV-2 with a three pronged approach:

1. Expand COVID-19 testing for schools and underserved populations ($650 Million);
2. Ramp up the domestic manufacturing of testing supplies and raw materials ($815 Million); and
3. Increase genomic sequencing of the virus to better prepare for the threat of variants ($200 Million).

Each of these goals requires significant and targeted investment at all levels of the diagnostics supply chain from testing locations to finished device manufacturers to the suppliers of raw materials.

The administration has set aside a total of $1.665 billion dollars across all three initiatives. The $650 million dollar investment into new testing is intended to translate into 25 million new tests delivered monthly to regional hubs across the US that are under the auspices of DoD and HHS.  It is not clear from the administration’s announcement what the total number of tests that are expected to be realized by this investment, but the news is still overwhelmingly positive for manufacturers still working their way through the EUA process. This initiative puts an emphasis on targeted testing of the population that will occur outside the traditional laboratory setting. This is consistent with a shift in FDA’s focus for diagnostic tests from CLIA Lab runs assays to non-laboratory sites such as Point-of-Care and Home Use. HPM recently released a blog post on FDA’s changing priorities (“Beware EUA Deprioritization”)

The lion’s share of the monies ($815 million) is slated for domestic manufacturing of testing materials.  Specifically, filtered pipette tips, nitrocellulose, and injection molded reagent container closures. This additional investment is heartening news as many manufacturers have experienced delays in device development over the last 12 months that are directly traceable to the ability to source samples, reagents, controls, and basic testing supplies.  The infusion of federal money toward domestic manufacturing may favor EUAs that bolster the domestic supply chain.

The final pool of monies ($200 million) is slated to address an ever-increasing concern for the pandemic which is the mutation of the SARS-CoV-2 virus and the rise in new mutant strains that may impede our march toward herd immunity and a return to normalcy. This increased funding for virus sequencing may aid in the rapid identification of new variants and allow for the development of multi-valent vaccines or boosters to maintain the efficacy of the vaccination program.  This money will likely not impact the EUA work that the Center for Devices and Radiological Health is doing in the review of new diagnostic EUAs.

This announcement comes amidst a series of public notices and statements from FDA regarding their concern with genetic mutations of the virus impeding the performance of diagnostic tests. On February 4th 2021, FDA provided a “Coronavirus (COVID-19) Update” where the agency stated:

For diagnostics, we have been monitoring for new mutations, identifying and working with developers of tests whose performance may be adversely impacted by them, and communicating with the public when helpful information becomes available. At this time, we believe the risk that the currently known mutations will impact overall testing accuracy of molecular tests is low. Moving forward, we are considering expanding the role of in silico monitoring by sponsors prior to and following authorization to assess for mutations that impact the performance of the test, test designs to minimize the impact of new mutations and ways to label authorized products to be transparent about what we know the test can detect.

This update was followed-up later in the month on February 22nd, 2021 with a new policy “Policy for Evaluating Impact of Viral Mutations on COVID-19 Tests.”  With issuance of this policy statement, FDA is putting industry on notice that due to the rise of mutations, post-authorization monitoring of assay performance will be a key consideration for an EUA. In this policy FDA states:

During FDA’s review of an EUA request for a COVID-19 test, FDA intends to consider the performance of the test across all known variants, as well as the developer’s plans for post authorization monitoring.

For industry, the only way to keep up with new mutations is to run an analysis through a sequence database, like the one maintained by the National Center for Biotechnology Information (NCBI). It is expected that this increased funding will improve the quality of databases that are used to monitor the pandemic and that industry uses to evaluate inclusivity of their tests.

In this policy update, FDA also gives granular feedback to industry on FDA’s expectations for developers of molecular diagnostic tests. However, the feedback for developers of Serology and Antigen tests is high level with more feedback from the Agency being promised in future updates to the EUA templates.  In light of FDA’s policy, companies with pending EUAs or those who are in the process of preparing their submissions to FDA should be proactive and develop plans for the evaluation of mutations as FDA has applied new thinking and requirements retroactively to EUA reviews.

Perhaps when you’re carving out a patented method of use?  Well, at least that’s what GSK is arguing.  As the now-infamous GSK v. Teva case makes its way through the Federal Circuit once again to address what many have called the death-knell to skinny-labeling (also called a “section viii statement” or a “carve-out”), Teva is poising for a fight to save the practice.  Framing the issue in the Petition for Rehearing briefing, Teva, like much of the generic industry, argues (with support from former Rep. Waxman) that the Federal Circuit decision upends the statutorily-enacted Hatch-Waxman carve-out.  GSK, on the other hand, characterizes the issue as a fact-specific inquiry into whether Teva’s generic carvedilol adequately carved out enough of a patented method-of-use included in GSK’s Reference Listed Drug (“RLD”) Coreg’s labeling.  The Federal Circuit reheard arguments on this case in February 2021.  And, as we wait for a new opinion that could have huge implications for generic drugs, we bring this (belated) update.

To jog your memory: In October 2020, the Federal Circuit issued a big blow to the generic drug industry when it reinstated a jury verdict awarding GSK $235 million in damages from Teva resulting from the generic company’s alleged “induced infringement” of a GSK patent through skinny-labeling.  As we explained back in October, the Hatch-Waxman Amendments permit generic drug companies to “carve-out” a patent-protected method-of-use included in the labeling of the RLD so long as such a carve-out does not compromise the safety or effectiveness of the product for the conditions of use remaining in the labeling.  The resulting “skinny-labeled” generic can still be listed in the Orange Book with an “A” therapeutic equivalence code because such ratings look only to the drug product itself rather than the approved indications.  As a result, a skinny-labeled “A”-rated generic drug can be, and indeed automatically will be, substituted for the brand drug regardless of the reason the product is prescribed.  Effectively, GSK argues, even though the statute provides for such a carve-out, even though FDA’s Orange Book states that the generic is therapeutically equivalent to GSK’s product, and even though the pharmacy is legally required to substitute an AB-rated generic for brands in most states (absent doctor’s orders otherwise), the mere truthful promotion of Teva’s skinny-labeled version of GSK’s Coreg (carvedilol) as AB-rated constitutes induce infringement.  And, for all intents and purposes, both the jury and the Federal Circuit agreed, making sweeping statements indicating to industry that even the carved-out label may be enough to induce infringement (“[p]recedent has recognized that the content of the product label is evidence of inducement to infringe”).

Understandably, the Federal Circuit decision led to a panic in the generic industry.  Skinny-labeling has been around for decades—countless generic drugs have marketed their skinny-labeled drugs as therapeutically equivalent to their Reference Listed Drug.  Now, even though some of those patents have expired and carved-out language added into the generic labeling, there’s no telling how many cases for induced infringement may be in the wings.  Given this uncertainty in the industry, many have expressed concern about whether generic drug sponsors will proceed with patent carve-outs and whether any resulting hesitancy will result in increased drug prices.

It is no surprise then that Teva promptly petitioned the Federal Circuit for a rehearing en banc.  Framing the issue as “whether induced infringement can be used to nullify a provision of the Hatch-Waxman Amendments,” Teva argued (as many in the press have) that if describing a skinny-labeled product as the generic equivalent of the RLD “can be inducement, as the majority held, every skinny-labeled generic is at risk, and the carve-out statute is a dead letter.”  GSK, on the other hand, opens its Response to Teva’s Petition with a strong statement: “This case does not implicate the fate of section viii carve-outs.”  Instead, GSK explains, that the case is much narrower than Teva portends as it “merely reaffirmed that section viii is not a get-out-of-jail-free card for generics who do not fully carve out the patented use from their labels.”  GSK explains that Teva did not thoroughly carve out all of GSK’s patented use, and it’s the label’s claims that induced infringement, not the AB-rating promotion.  GSK concedes that the Federal Circuit opinion never actually noted that the “partial label instructed the patented method,” but argues that “that finding is implicit in, and necessary to, its decision.”   

On February 9, 2021, the Federal Circuit vacated the October 2, 2020 judgment and withdrew the controversial opinion.  The Federal Circuit granted a panel rehearing (rather than en banc), which occurred on February 23, 2021.  But rather than address the overarching issue of induced infringement by way of skinny labeling, the Court limited the appeal—or at least the rehearing—to evidence to support the jury verdict of induced infringement.  In other words, the Court declined to address whether skinny-labeling itself is induced infringement and theoretically will look only to the specific promotion used to allegedly induce infringement.  This limitation could provide for a much narrower decision than the October 2, 2020 decision, but the Court did leave room for itself to make a broader decision, stating that “[w]e find all other issues to be sufficiently briefed.”

While FDA did not submit an Amicus Brief, Henry Waxman—the namesake of the legendary Hatch-Waxman Amendments that created the skinny-label practice—did.  Others joined Rep. Waxman in submitting Amicus Briefs, including Apotex, Novartis, Mylan, a consortium of professors, Knowledge Economy International, the Association for Accessible Medicines, and the R Street Institute in support of Teva.  These briefs focused on the policy aspects—health, economic, and patent policy.  No Amicus Briefs were filed in support of GSK or the Federal Circuit’s decision.

The Federal Circuit reheard the case on February 23, 2021.  From all accounts, the panel listened to the narrowed questions about the facts at issue here (i.e., whether Teva’s skinny-labeled carvedilol carved out enough language) rather than the overarching concerns about the death of the carve-out.  This makes sense given the parties and the venue: a patent case should be specific to the patents-at-issue, not a validation of a statutory provision.  However, we can’t help but think about the arguments that might arise if this case were strictly about statutory interpretation.  How would the Court reconcile the implicated conflict between the patent statutory scheme (induced infringement) and the Hatch-Waxman Act (carve-outs)?  Obviously, patent and FDA cases overlap often: innovation is critical to the drug industry and patents are critical to innovation, thus ANDA litigation, 30-month stays, etc.  But, effectively, this case would force the Courts to determine whether to protect innovation or whether to protect accessibility—the very balance that Congress sought to achieve in adopting the Hatch-Waxman Amendments.  Given the limited oral argument, it’s unlikely that the Federal Circuit will go that far in this case, as it will probably issue a very narrow decision that allows the skinny-label to live another day, but the Federal Circuit did leave room to address the entire issue.  But all we can do now is wait to see if the Federal Circuit believes that Teva’s carvedilol labeling was skinny enough or whether the Federal Circuit’s initial decision applies more broadly.

The Senate recently reintroduced legislation that would promote research into medical use of marijuana.  The legislation would also importantly correct a deficiency in prior law and the Drug Enforcement Administration’s (“DEA’s”) recent rulemaking related to synthetically derived CBD.

Marijuana remains classified as a schedule I controlled substance under the federal Controlled Substances Act.  Because drugs in schedule I are defined to have “no currently accepted medical use in treatment in the United States,” distribution except in very limited circumstances of any product containing marijuana remains illegal at the federal level.  21 U.S.C. § 812(b)(1)(B).  To date, only certain drugs containing THC such as Marinol, and hemp-derived CBD with less than 0.3 percent delta-9-tetrahydrocannabinol (“THC”) have been excluded form Schedule I.  Yet despite federal law, 36 states and the District of Columbia have authorized the manufacture, distribution and use of marijuana and/or its constituents including THC and cannabidiol (“CBD”) for a wide-range of differing medical indications.

We reported in January how after more than four years DEA finally issued its final rule on registering additional manufacturers of marijuana for research.  (For our post, see The Long and Winding Road: DEA Issues Final Marijuana Registration Rule, Jan. 8, 2021.)  Congress, however, has not been sitting idly with respect to cannabis research.  Senators Dianne Feinstein (D-CA), Chuck Grassley (R-IA) and Brian Schatz (D-HI) re-introduced a bill with bipartisan support in the Senate that seeks to expand medical research with marijuana and CBD by removing some of the restrictive regulatory roadblocks.  The Senate unanimously passed an identical bill during the waning days of the last Congress.  Senator Feinstein, re-introducing the Cannabidiol and Marihuana [sic] Research Expansion Act on February 4th observed, “If the science shows that marijuana and its derivatives, including CBD can effectively treat serious medical illnesses, we should enable products containing these substances to be brought to the market with FDA approval.  But in order to make this determination, we must reduce the barriers currently impede important research.”  Feinstein, Grassley, Schatz Introduce Bill to Expand Cannabidiol, Marijuana Research, Press Release, Feb. 5, 2021.

The bill, S. 253, would promote cannabis research by requiring the Attorney General (by delegation, DEA) to register researchers if Health and Human Services (“HHS”), National Institutes of Health (“NIH”), or another federal agency that funds scientific research reviews and approves their research protocol and they employ adequate security measures to prevent diversion.  DEA would have to approve registration applications or request supplemental information within 60 days, then approve or deny registrations within 30 days after receiving supplemental information.

The bill would also expedite the process to increase the quantity of cannabis for research and facilitate protocol changes without requiring researchers to reapply.  Researchers seeking to increase drug quantities would only have to notify DEA instead of both DEA and FDA.  Researchers seeking to amend approved protocols involving changes to drug quantity or type, its source or storage, tracking or administration conditions must only notify DEA at least 30 days before implementation.  Their request would be deemed approved unless DEA objects within 30 days.  The agency can only object if additional security safeguards are required.  HHS would maintain authority over research protocols, including changes in administration, dosing and number of patients.  The bill requires DEA to issue regulations related to these changes within a year.

In addition to requiring DEA to process cannabis researcher applications within a certain timeframe, the bill imposes time constraints by when the agency must move on bulk marijuana manufacturer applications.  For bulk marijuana manufacturers, DEA would have to approve or request supplemental information for applications to manufacture for research solicited in the Federal Register within 60 days of receiving an application, then approve or deny the application within 30 days of receiving required supplemental information.  Requiring DEA to move on marijuana manufacturer applications is a welcome advancement of the registration process as some of the 38 marijuana manufacturer applications received by DEA lingered for four years after the agency announced that it would issue additional registrations in August 2016.

The bill streamlines development of FDA-approved drugs using marijuana and CBD by:

• Allowing accredited universities and medical schools, practitioners and manufacturers with a schedule I registration to manufacture, distribute, dispense and possess marijuana for medical research aimed at drug development or commercial production;
• Requiring DEA to license manufacturers and distributors for the commercial production of FDA-approved marijuana or CBD drugs; and
• Allowing DEA-registered institutions to import or export marijuana or CBD to conduct medical research for drug development.

Within one year of enactment, HHS must report to Congress on potential therapeutic effects of marijuana and CBD on serious medical conditions, and their effects on the human body, the adolescent brain, and on cognitive abilities, including the ability to operate vehicles and heavy equipment.  HHS will also report on the research barriers of marijuana grown in states that have legalized its use, and recommend how to overcome them.

The bill would allow physicians to discuss the potential harm and benefits of marijuana derivatives like CBD, as treatment with patients.

The bill also corrects a non-sensical interpretation stated in DEA ‘s August 21, 2020 interim final rule that non-plant, synthetic CBD is a schedule I substance regardless of whether its THC content on a dry weight basis is at or below the 0.3% level for non-controlled hemp-derived CBD.  The bill would amend the definition of marijuana in the CSA to exclude the synthetic equivalent of hemp-derived CBD containing less than 0.3% THC.  It makes no sense to treat synthetic CBD as a schedule I controlled substance when its abuse potential, little as it may be, is less than hemp-derived CBD.  The bill would allow researchers and others to handle synthetic CBD without having to comply with DEA registration, recordkeeping and security requirements.

A number of organizations support the bill including the American Medical Association, American Academy of Pediatrics, American Society of Addiction Medicine, Friends of the National Institute on Drug Abuse, National Cannabis Industry Association and the National Organization for the Reform of Marijuana Laws.

The bill has been referred to the Committee on the Judiciary.

Last Thursday March 11, the American Rescue Plan Act of 2021 was signed by President Biden.

Out of the hundreds of pages of this COVID relief legislation, our pinpoint focus here is on several pages relating to Medicaid coverage and drug rebates.  The legislation requires Medicaid and the Children’s Health Insurance Program (CHIP) to cover COVID-19 vaccines, vaccine administration, testing, and treatments, without cost sharing, for all eligible beneficiaries during the public health emergency and for one year after it ends.  Sec. 9811(a)(1), (2).  The legislation also makes clear that COVID therapies and preventive measures are subject to rebates under the Medicaid Drug Rebate Program if they are “covered outpatient drugs” as defined in the Medicaid Drug Rebate statute.  Sec. 9811(a)(4).  As with other vaccines, COVID-19 vaccines remain excluded from the Medicaid Drug Rebate Program.  Sec. 9811(a)(4).

A question arises whether an unapproved drug authorized under an emergency use authorization (EUA) is a covered outpatient drug subject to Medicaid rebates.  Under a literal reading of the definition of a covered outpatient drug, such a drug must be approved under section 505 or 506 of the FDC Act or section 351 of the Public Health Service Act.  An EUA is authorized under section 564 of the FDC Act and is not an approval pursuant to those provisions.  However, in a somewhat related context, CMS has suggested that an EUA is an “approval” under the FDC Act.  COVID-19 Frequently Asked Questions (FAQs) for State Medicaid and Children’s Health Insurance Program (CHIP) Agencies, p.18, fn. 3.   Hopefully CMS will provide guidance on this point.

Of broader consequence to drug manufacturers generally, effective January 1, 2024, the legislation sunsets the cap on the total Medicaid unit rebate amount that was instituted by the Affordable Care Act.  Sec. 9816.  (The House version of the bill had this change taking effect January 1, 2023, but the effective date for the change was extended by one year by the Senate.)  The total calculated Medicaid rebate amount is comprised of the basic rebate and the additional rebate, which is a penalty imposed for raising a price at a rate greater than the rate of inflation.  Without a cap, the rebate can be more than the average manufacturer price (AMP) of the drug.  The Affordable Care Act capped the rebate at 100% of the AMP so that a manufacturer would not pay a higher rebate for a drug than its AMP.  According to the House Report, CBO estimates that eliminating this cap will increase the amount of rebates that manufacturers pay Medicaid and will reduce direct spending in Medicaid by $15.9 billion over the 2021-2030 period.

I would be lying if I said I hadn’t expected this most recent OPDP Untitled letter.  OK, maybe not THIS letter.  Some background: Back in November 2020, after an article was published about the ethical questions surrounding “Sponcon,” (sponsored content – for those not hip to the lingo), I pulled up Khloe Kardashian’s Twitter feed to check out her recent ad for Nurtec ODT.  I stared at the ad, and then spent an embarrassingly long amount of time debating with myself as to whether placing scrolling ISI right below Khloe Kardashian’s bust made it more OR less likely to be noticed.  I passed my phone to my husband and asked him to tell me about the Nurtec ODT safety information.  Eyes glazed, he responded, “there’s safety information?”  I had my answer.

This most recent OPDP letter (the first Untitled Letter of 2021), objects to a sponsored video – and is similar to OPDP’s last Warning Letter to CooperSurgical.  Parallels between the two letters include the offending material being a sponsored video (not otherwise re-distributed by the company on different platforms), no Form 2253 submission, and complaints lodged through FDA’s Bad Ad program.

This letter is significant for a number of reasons (not the least of which is that I now can’t simply refer to the “Kardashian Letter” as it may create confusion about which letter I’m referencing).  What’s fascinating (to me) is that OPDP includes in second place its allegations that risks were minimized in the video, prioritizing the offending efficacy claims.  And what are those efficacy claims?  The first of which is that Nurtec ODT “works in about 15-30 minutes.”   The second is that Nurtec ODT was a “gamechanger” and “other medications would give me rebound headaches, and this one doesn’t . . .”

In 2012, an Untitled Letter based on these claims would be expected.  But in 2021, given the significant drop in OPDP enforcement letters and post publication of FDA’s Guidance on Medical Communications Consistent with the FDA-Required Labeling (Guidance), are these the type of claims to trigger an OPDP Untitled Letter?  The claims, themselves, seem awfully similar to specific examples FDA includes in its Guidance, which permits product communications consistent with the FDA-required labeling even if those communications are not based on substantial evidence.  From the FDA Guidance:

Q.4.        What are examples of the kinds of information that could be consistent with the FDA-required labeling for a product?

A.4.        The following are examples of some general types of information that could be consistent with the FDA-required labeling. . . Information based on a comparison of the safety or efficacy of a medical product for its approved indication to another medical product approved for the same indication . . . Information about the onset of action of the product for its approved indication and dosing/use regimen (e.g., the FDA-required labeling for a product approved to treat major depressive disorder does not contain information about onset of action before the point in time designated as the study’s endpoint, and a firm’s product communication provides information indicating that the product shows an effect relative to the control at 2 weeks).

So what happened here?  What happened seems to be the absence of any evidence to support Ms. Kardashian’s claims other than her personal experience.  Consistency with the FDA-required labeling is not the only factor to consider when determining whether a communication is truthful and non-misleading.   Claims must still be supported by evidence that is scientifically appropriate and statistically sound.  “The amount and type of evidence needed to support a particular CFL promotional communication depends in part on the topic addressed by the communication. For example, different evidence would be needed to support a long-term efficacy presentation than would be needed to support a presentation about a product’s mechanism of action. The amount and type of evidence needed also depends on the particular representations or suggestions that are made about any given topic in the communication.”  Guidance at 12.  Therefore, despite these claims representing a truthful experience for Ms. Kardashian, the letter points out that they are misleading because OPDP is unaware of any data that supports these statements, generally.

OPDP further cites the video as misleading “because it fails to present information relating to the contraindications, warnings, precautions, and adverse reactions for Nurtec ODT with a prominence and readability reasonably comparable with the presentation of information relating to the benefits of Nurtec ODT. Specifically, the video contains claims and/or representations about the benefits of Nurtec ODT in the audio portion, while the risk information is presented in text only format and in small font. Moreover, the risk information only appears briefly for four seconds at the end of the video, after the close of the Spokesperson’s presentation, where it is unlikely to draw the viewer’s attention.”   OPDP’s views as expressed in this letter are not new; 21 C.F.R. §202.1(e)(1) provides that advertisements broadcast through media such as radio or television include information relating to the major side effects in the audio or audio and visual parts of the presentation.  It is not sufficient to have safety information presented solely on screen when efficacy is provided through audio.   Content and format considerations with regard to presenting risk information in broadcast promotional material has been an issue reiterated in FDA’s (Draft) Guidance on Presenting Risk Information and has also been the subject of OPDP research.

Circling back to initial perceptions about the similarities between this Untitled Letter and the recent CooperSurgical  Warning Letter, it’s notable that both relate to TV broadcast videos that were “sponsored” by the company, not re-distributed on other platforms, and not submitted to FDA on Form 2253.  With the increasing number of television shows that allow third parties to sponsor content, industry should be particularly cautious when availing itself of these opportunities.  Depending on the context, interviews with your spokespeople and sponsored TV/News segments about your products may subject you to liability even if you are not in complete control over the content and do not otherwise re-distribute it.

It’s not just drug companies that push the limit on marketing their products – see our posts about recent OPDP warning letters.  Medical device companies are fighting for any edge to differentiate their products too.  Even before COVID-19 brought an onslaught of new players to the FDA-regulated space, many sophisticated medical device companies used to include FDA’s logo on marketing materials to imply that FDA had endorsed their products.  The misuse of the logo became so pervasive that FDA issued an official “FDA Logo Policy,” which warns that “[u]nauthorized use of the FDA logo may violate federal law and subject those responsible to civil and/or criminal liability.”  Despite this threat, FDA continues to cite companies for misuse of the logo.  See, e g., Warning Letter issued to Silkprousa LLC (Aug. 18, 2020) (“Your device is also misbranded under section 502(a) of the Act, 21 U.S.C. § 352(a), because your labeling on the package of your device and your website uses the FDA logo.  The FDA logo is for the official use of the FDA and not for use on private sector materials.”).

The COVID-19 pandemic has caused companies to exercise even more creative license in an attempt to differentiate products that might otherwise appear interchangeable (e.g., 3-ply disposable face masks).  We have seen the advent of the “FDA Registration Certificate,” which looks like an official government document, and sometimes includes the FDA logo (illegal by itself), the establishment registration number, or a screenshot of the FDA establishment registration database showing the company’s registration status.  Any savvy FDA lawyer knows that registration alone does not convey information about the company or product’s regulatory compliance status, and certainly does not imply FDA approval or endorsement of a product, but not all of us can be savvy FDA lawyers.

On March 3, 2021, FDA announced that it had told 25 companies that produce these so-called “FDA Registration Certificates” to stop issuing them.  We have not yet seen the letters FDA issued to the certificate-producing companies, and it’s unclear whether FDA will follow-up with enforcement action if these companies fail to cease distribution of these documents (and if so, on what grounds).

In conjunction, FDA released a new webpage titled “Are There ‘FDA Registered’ or ‘FDA Certified’ Medical Devices?  How Do I Know What is FDA Approved?”  Spoiler alert: the answer to the first question is No. The key points FDA highlights are:

• When a facility registers its establishment and lists its devices, the resulting entry in the FDA’s registration and listing database does not denote approval, clearance, or authorization of that facility or its medical devices.
• The FDA does not issue any type of device registration certificates to medical device facilities.
• Firms that misleadingly display certificates alongside information about and photos of a device for sale in the United States to imply review or approval by FDA of the device misbrand the device in violation of the Federal Food, Drug, and Cosmetic Act.

FDA also provided detailed directions for identifying a product’s status – whether it has been approved or cleared, or authorized under an Emergency Use Authorization.  Circling back to the grammatically curious title of this blog post, FDA’s point is that registration “don’t mean a thing” “if it ain’t got that” 510(k) clearance, PMA approval, de novo classification or EUA authorization – not as catchy as when Ella Fitzgerald and Duke Ellington sing it.

Welcome to the latest edition of Hyman, Phelps & McNamara, P.C.’s monthly wrap up of food, beverage and supplement news, including regulations, guidances, events, and whatever else is catching our eye.

Food & Beverage

• Transition: As of this writing, Janet Woodcock is Acting Commissioner of Food and Drugs; Norris Cochran is Acting Secretary of Health & Human Services; and Tom Vilsack was just confirmed as Secretary of Agriculture (again!).
• 3D printed ribeye? An Israeli company unveiled what is being described as a “3-D printed rib-eye” made with  “3-D bioprinting technology.” The company claims to have been in discussions with USDA and FDA for the past two and a half years.
• Food Supply Chain Focus at the WH. The President signed an Executive Order to help create more resilient and secure supply chains for critical and essential goods, and agricultural commodities and food production are a key sector that will be the focus of a year-long review.
• Keep those essential workers safe! FDA published a new web page with information to help employees in the food and ag sector communicate about COVID-19 vaccines in their workplace.
• Prop 65: OEHHA announced a (virtual) public hearing on March 11, 2021, at 10:00 a.m. and extended the time for submitting comments to the proposed rule regarding short form warnings to March 29 to accommodate the hearing.
• Baby food report. The House Subcommittee on Economic and Consumer Policy, Committee on Oversight and Reform released a report alleging “dangerous” levels of heavy metals in baby foods. Shortly thereafter, FDA published a response in the form of a Constituent Update in which the agency assured the public that “FDA regulations and monitoring help to ensure the safety of baby foods sold or manufactured in the United States.”
• US Food Supply is Safe! FDA and USDA issued a statement that food and food packaging have not been linked to spread of COVID-19.
• Costs of Foodborne Illness: USDA published a report on the cost of foodborne illnesses; the report is a bit short on conclusions but the cost continues to increase. This is not particularly surprising since last year CDC reported a continued increase in incidence of foodborne diseases.
• Speaking of Pathogens in Food: Center for Science in the Public Interest together with several other public interest organizations and individuals submitted a petition to FSIS/USDA requesting that FSIS engage in rulemaking to 1) establish enforceable finished product standards for Salmonella types of greatest public health concern and Campylobacter and 2) require poultry establishments to identify and control food safety risks within their supply chain. FSIS opened a docket on regulations.gov for comments which must be submitted by April 6, 2021.
• Organic wild caught fish? NOP just announced a town hall meeting regarding wild caught fish.

Supplements

• More transition. Steven Tave is leaving the Office of Dietary Supplement Programs and moving to the Office of Regulatory Affairs at FDA.  Cara Welch will be acting director of ODSP starting March 15.
• Warning Letters. FDA issued warning letters to 10 companies for selling dietary supplements that claim to treat depression and other mental health disorders.
• Criminal Sentencing. A former dietary supplement company executive was sentenced to prison for his role in fraudulently selling popular workout supplements that caused liver damage.  A number of executives have already been sentenced in this ongoing fraud investigation.
• Nanotech-related claim requires substantiation. NAD recommended discontinuation of a claim touting a nanotech oral delivery system for glutathione as the first effective alternative to injections. NAD found the supporting in vitro and in vivo pilot studies did not constitute a reasonable basis for the claim.

More on Cannabis

• Just under the wire: We wrote last month about USDA finalizing the framework for the Establishment of a Domestic Hemp Production Program, which takes effect on March 22. Our colleague Larry Houck provides more insight.

Coming up:

• The deadline for submission of comments on labeling of cell-cultured seafood products is coming up on March 8.
• The American Conference Institute’s popular “FDA Boot Camp” – now in its 36th iteration – is scheduled to take place (virtually, of course) March 24-25, 2021, and is co-chaired by HPM’s own Kurt Karst.
• Riëtte van Laack will be discussing “Nutrient Content, Health and Other Claims” at FDLI’s Introduction to Food Law and Regulation, March 16-18.

If you tuned in to FDA’s weekly Virtual Town Hall Meeting on February 10th, 2021 you would have seen a short presentation by Toby Lowe (CDRH/OHT-7) describing a recent funding announcement from HHS OASH, Office of Assistant Secretary for Health, and the DoD. This “Area of Interest” (AOI) funding announcement is a call for proposals from industry.

you may request investment funding for capacity expansion and provide price quotes for raw materials, test components, supplies, et cetera for COVID-19 point-of-care tests and other IVDs. This is an expedited process that’s coordinated by HHS and OASH and DoD to support the government’s COVID-19 response to rapidly increase manufacturing capabilities within the diagnostic supply chain.

This funding announcement is not a unique occurrence, in fact, there is a whole group at HHS with a mandate to expand testing supplies and testing capacity through targeted investments.  The COVID-19 Testing and Diagnostic Working Group (TDWG) has been built around four central goals:

• Understand the diagnostic supply chain, including projected production and potential constraints and bottlenecks;

• Work with state public health and laboratory leadership, diagnostics manufacturers, and commercial labs throughout the country;

• Provide technical assistance to leverage existing testing infrastructure and resources based on available tests; and

• Distribute certain testing supplies, focusing primarily on point-of-care technologies, to support states’ testing goals.

This funding announcement is yet another indication, in a string of recent public statements and actions on the part of FDA, that the federal government is shifting time, energy, and resources from the CLIA Lab base testing to testing in non-laboratory settings, like Point-of-Care and people’s homes.  HPM recently released a blog post on FDA’s changing priorities (“Beware EUA Deprioritization”).

A link to the funding announcement can be found here.  The deadline to apply is March 7th.  (And for those Arrested Development fans, we’ll end with a link to the Banana Stand.)

Well, it’s been busy for OPDP (and the Rx Ad/Promo bloggers over at the FDA Law Blog).  After getting off to a slow start in 2021, OPDP issued yet another Warning Letter, apparently the day after its first.  Unlike the first letter, this OPDP Warning Letter to CooperSurgical appeared “quietly” on FDA’s general Warning Letters page, and without the accompanying fanfare of a CDER press release and Twitter campaign (as we blogged about previously).  When checking the status of OPDP’s Warning Letters page, we were surprised (shocked, really) to see that all Warning Letters had been removed and the page had been updated to reflect only Untitled Letters.  We’re not happy with this development – having OPDP letters in a single location was incredibly useful when evaluating enforcement trends.

This newest Warning Letter about a video for Paragard (intrauterine copper contraceptive), ticks off several OPDP priority boxes – the product has a broad patient base with a video (airing on TV) that could be considered a wide-reaching promotional campaign, CooperSurgical was the subject of a previous OPDP letter for similar product promotion, and the video was brought to OPDP’s attention through the FDA Bad Ad program.

The offending video, entitled “Paragard: Family Planning During The Pandemic,” is no longer available, but appeared on WBTS’s The Hub Today, a Boston lifestyle and entertainment show.  FDA states that CooperSurgical failed to submit a copy of the video at the time of initial dissemination under cover of Form FDA-2253, and FDA’s description of the issues is short and to the point.  The video is described as providing claims and representations about the uses and benefits of Paragard, but failing “to communicate any risk information about the product.”  FDA specifically notes that referring viewers to the product specific website for further information did not mitigate the “complete omission” of risk information from the video.

CooperSurgical previously received an Untitled Letter in 2019 for a Paragard DTC TV advertisement for omitting important risk information.  OPDP so notes in this letter, stating that the new video appears to promote Paragard without presenting the serious risks in truthful and non-misleading manner, “despite concerns previously expressed by OPDP.”    The 2019 TV ad had also been reported to FDA under the FDA Bad Ad Program.

It’s likely OPDP may have been moved to issue the Warning Letter because of the perception that the sponsor did not address FDA’s objections to the previous video in the new one.  Rather than making the safety information more thorough, the new video seems to omit even more risk information.  Another factor may have been the large viewing audience that may have seen the video, which was broadcast on television.  This may also make the corrective communication FDA requests in the Warning Letter more challenging.

What is interesting and difficult to discern is whether CooperSurgical considered the video to be Paragard “promotion” and whether CooperSurgical had full control over the content of the video.  While the video is no longer available, OPDP describes the original broadcast on the lifestyle and entertainment show as promotional material that included the statement “sponsored by PARAGARD.”  Contrast this with OPDP’s 2019 Untitled Letter to Aclaris about a video interview that was broadcast on ABC’s The View, where OPDP cited the video as promotion and included reference to Aclaris’s Form 2253 submission, as well as the company’s re-posting of the video on the Eskata Facebook page and Aclaris LinkedIn page.  While industry may sponsor certain scientific and educational activities and not have those activities considered product promotion, there are guardrails, and DTC TV videos likely fall outside of them.   And, company intent about whether material is product “promotion” may ultimately be irrelevant to FDA’s determination.

As the end of the COVID pandemic appears into view, the Center for Devices and Radiological Health (CDRH) appears to be taking steps toward shedding at least part of its Emergency Use Authorization (EUA) caseload.

Under Section 564(a)(1) of the Federal Food, Drug, and Cosmetic Act, FDA has discretion whether to issue an EUA.  Under Section 564(c), FDA may only issue an EUA if the following criteria are met:

• The product may be effective in diagnosing, treating, or preventing the disease or condition.
• The known and potential benefits outweigh the known and potential risks.
• There is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating such disease or condition.

CDRH is increasingly declining to review EUA requests and terminating pending EUAs.  Two rationales are typically offered.  One rationale is that, given the volume of EUAs, a particular EUA is simply not a priority.  CDRH usually provides little or no additional information about why a product is not a priority.

A second rationale is that that there are already adequate supplies available in the market.  Based on this finding, the requirement in the last bullet, above, is not met and an EUA cannot issue.

Even if CDRH has issued prior EUAs in a product category, supply conditions may change.  Indeed, the issuance of prior EUAs may have helped better supply the market.  CDRH’s position is that it cannot continue issuing EUAs if there are adequate alternatives in the market.

CDRH has adopted deprioritization across a range of product categories.  Diagnostics have been particularly hard hit, but they are not alone.

Here are three examples:

• In the past few months, CDRH deprioritized antibody serology tests for COVID. It then proceeded to terminate pending EUAs and declined to accept new ones.
• A PCR test for COVID may still receive an EUA if indicated for, e.g., point of care, but CDRH has deprioritized some tests on the ground that they were indicated only for laboratory use.
• The umbrella EUA for face masks does not extend to masks made with antimicrobials. In theory, it should be possible to obtain an individual EUA for an antimicrobial face mask.  The reality is that CDRH is unwilling to expend resources reviewing such an EUA; they are deprioritized.

There is little or nothing that can be done to challenge FDA’s prioritization decisions.  Section 564 gives the agency very broad discretion.  Therefore, if firms are considering pursuit of an EUA, they should be wary.  To avoid wasting money, firms need to assess the deprioritization risk carefully.

Of course, it is not that easy to assess this risk, especially when FDA institutes deprioritization based on changing market conditions.  Also, not all product categories are treated the same way.  In some, CDRH may suddenly simply stop accepting new EUAs.  In other categories, CDRH may be skeptical but still be willing to authorize a product.  For instance, in some cases, they may be willing to review an EUA if (and only if) a manufacturer has the capability to produce in high volume or for a non-laboratory setting.

CDRH could help everyone better assess deprioritization risk by creating a public database of deprioritized product categories, with designations as to whether they are entirely or only partially subject to deprioritization.  If not a database, CDRH could perhaps at least provide prioritization updates on their EUA FAQ web page.  This increased transparency would help firms better align themselves to CDRH’s priorities.

Bottom line:  In every new EUA project, firms should factor in deprioritization as one of the risks to be concerned about.  Even after a firm expends considerable resources, a subsequent shift in CDRH’s priorities could prevent a product from obtaining an EUA.

In the world of EUAs, caveat emptor rules the day.

It seems as if the “hemp” debate has been raging forever.  Yet only a little over two years have passed since enactment of the Agricultural Improvement Act of 2018, the “Farm Bill,” in December 2018 that amended the Agricultural Marketing Act of 1946 directing the Department of Agriculture (“USDA”) to establish the regulatory framework for a domestic hemp production program.  Now USDA has issued the final regulations governing that program at lightning speed compared with other federal cannabis-related initiatives.  Establishment of a Domestic Hemp Production Program, 86 Fed. Reg. 5596 (Jan. 19, 2021).  USDA’s Agricultural Marketing Service (“AMS”), the delegated authority to administer the domestic hemp production program, received almost 6,000 comments after issuing an interim final rule on October 31, 2019.  Agricultural Marketing Service, Establishment of a Domestic Hemp Production Program; Document IDs AMS-SC-19-0042-0001 & AMS-SC-19-0042-4666, Regulations.gov (last visited Feb. 23, 2021).

The Farm Bill mandates that USDA establish and administer a national hemp production program.  As a reminder, “hemp,” as defined in the Farm Bill and final rule, is “the plant species Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis.”  7 C.F.R. § 990.1; see also 7 U.S.C. § 1639o(1).  Cannabis with a THC level exceeding 0.3 percent is marijuana, a schedule I controlled substance under the federal Controlled Substances Act.  Plants and plant material exceeding 0.3 percent THC concentration must be disposed of by a DEA-registered reverse distributor or law enforcement officer.  86 Fed. Reg. 5604.  In the alternative, non-conforming plants and materials can be “remediated” plowing the plants, composting into “green manure” for use on the same land, tilling, disking, burial, or burning.  Id.

The Farm Bill allows States and Indian Tribes wishing to exercise primary authority over hemp production within their territory to submit their own production plans for USDA approval.   USDA has approved 45 State and Tribal plans though not all States and Tribes have implemented their programs.  86 Fed. Reg. 5596.  USDA has also accepted production applications under its program since October 2019 and has issued 380 producer licenses.  86 Fed. Reg. 5608.  Licenses issued prior to final rule’s publication will remain in effect until their original expiration.  Id.  USDA will not issue production licenses to producers within States or Tribal territories that have a production plan pending for USDA approval and will deny applications from individuals in States or Tribes with USDA-approved plans.  Id.

The Farm Bill set general requirements on licensing, recordkeeping about the land where hemp is produced, testing for delta-9-tetrahydrocannabinol (“THC”), disposing of non-conforming plants, and conforming to compliance provisions and procedures for handling violations.

USDA Hemp Production Program

Hemp production in States or Tribal territories lacking a USDA-approved State or Tribal plan must comply with USDA hemp program requirements.  Producers must hold a valid license prior to producing hemp.  7 C.F.R. § 990.21(a)(1).  Applicants must provide contact information and a current criminal history report.  7 C.F.R. § 990.21(3).  A completed application serves as consent to comply with USDA requirements.  7 C.F.R. § 990.71(a)(3).  Persons with a state or federal felony conviction related to controlled substances are ineligible to produce hemp for ten years following the conviction date.  7 C.F.R. § 990.20(b).  Licenses are valid for three years and must be renewed prior to expiration.  7 C.F.R. § 990.21(a)(6), (b).  Producers of hemp for research must also obtain a USDA license.  7 C.F.R. § 990.21(d)(1) (effective Mar. 22, 2021).  Only research institutions registered with DEA to handle marijuana can maintain hemp testing over the acceptable THC level to the end of their study; all other licensees must ensure the disposal of non-conforming plants.  7 C.F.R. § 990.21(d)(2) (effective Mar. 22, 2021).

Producers must

1. Report hemp crop acreage to USDA’s Farm Services Agency (“FSA”) within 30 days of planting hemp;
2. Provide street address and geospatial location where hemp will be produced, and acreage or indoor footage dedicated to hemp production and hemp license; and
3. No earlier than 30 days prior to harvesting, have a trained agent collect samples from the flowering tops of the plant for THC level testing. 7 C.F.R. § 990.23; .24 (effective Mar. 22, 2021).

Hemp cannot be harvested prior to samples being taken.  7 C.F.R. § 990.24(e).

Producers cannot harvest any later than 30 days after sample collection and failing that, test a second pre-harvest sample of the lot.  7 C.F.R. § 990.26(a); (b) (effective Mar. 22, 2021).  Only lots with the acceptable THC level may enter commerce; plants exceeding that THC level are marijuana and must be disposed of by a DEA-registered reverse distributor or law enforcement or remediated on-site.  7 C.F.R. § 990.26(d); .27(a) (effective Mar. 22, 2021).  Producers must notify USDA of their intent to dispose of or remediate non-compliant plants and submit verification.  7 C.F.R. § 990.27(b) (effective Mar. 22, 2021).

Laboratories must:

1. Ensure the validity and reliability of test results;
2. Have effective disposal procedures for non-conforming plants;
3. Test samples for total THC using post-decarboxylation or other USDA-approved methods; and
4. Hold a DEA registration to test after December 22, 2022. 7 C.F.R. § 990.25(a); (e); (g) (effective Mar. 22, 2021).

Recordkeeping

Producers must maintain records of hemp plant acquisition, production and handling, and storage, as well as disposal and remediation of non-conforming cannabis plants.  7 C.F.R. § 990.32(c) (effective Mar. 22, 2021).  They must maintain records and reports for at least three years, and records must be available for inspection by USDA employees and representatives.  USDA inspectors and representatives must have access to any premises where hemp plants may be held.  7 C.F.R. § 990.32(d) (effective Mar. 22, 2021).

Reports

Producers must report disposal or remediation within 30 days after completion.  Reports must include producer’s name and address, license number, geospatial location, or other valid land descriptor for the production area subject to disposal or remediation and date of completion.  7 C.F.R. § 990.71(b) (effective Mar. 22, 2021).  Producers must also annually report lot, location type, geospatial location, total planted acreage, total acreage disposed and remediated, and total harvested acreage.  7 C.F.R. § 990.71(c) (effective Mar. 22, 2021).  Producers are also responsible for ensuring that laboratories testing samples report test results to USDA (informal testing conducted throughout the growing season for THC concentration need not to be reported to USDA).  7 C.F.R. § 990.71(d) (effective Mar. 22, 2021).  The test report must contain for each sample tested:

• Lot identification number for the sample;
• Laboratory name;
• Date of test and report;
• Identification of any pre-harvest or post-harvest retest; and
• Test result. Id.

Audits

USDA may audit hemp producers’ records for completeness and accuracy, and conduct on-site visits to farms, storage facilities, and locations affiliated with licensees’ hemp operation.  USDA audits may be conducted every three years and can focus on current crop year and previous crop years.  7 C.F.R. § 990.28(a), (b).  USDA will provide reports to producers within 60 days of an audit’s conclusion.  USDA requires a corrective action plan to correct a negligent violation, which USDA will approve or deny within 60 days of receipt.  7 C.F.R. § 990.28(d).  USDA may also revoke a producer’s USDA license for one year or until the producer becomes compliant.  7 C.F.R. § 990.28(d) (effective Mar. 22, 2021).

Enforcement

Producers are not subject to more than one negligent violation per calendar year.  7 C.F.R. § 990.29(a) (effective Mar. 22, 2021).  Negligent violations include failure to provide an accurate legal description of land where hemp is produced, production of hemp without a license, and production of cannabis that exceeds the acceptable hemp THC level.  7 C.F.R. § 990.29(a)(1)-(3).  USDA issues a notice of violation for each negligent violation requiring a corrective action plan from the producer.  Corrective action plans will be in place for a minimum of two years and include:

• The date by which the producer will correct violations;
• Steps the producer will take to correct violations; and
• Procedures that will demonstrate compliance that must be submitted to USDA. 7 C.F.R. § 990.29(b).

USDA will revoke the license of producers who commit negligent violations three times within five years, and they will be ineligible to produce hemp for five years.  7 C.F.R. § 990.29(e).

If USDA determines that a producer has violated the terms of their license or the regulations with a “culpable mental state greater than negligence,” it will immediately report the licensee to the U.S. Attorney General and the chief law enforcement officer of the State or Indian territory where the production is located.  7 C.F.R. § 990.29(f)(1).

USDA may issue a notice of suspension to a producer if they have violated a provision of the regulations or failed to comply with a written order from USDA related to negligence.  7 C.F.R. § 990.30(a).  Producers whose license has been suspended may appeal the suspension but cannot produce hemp during the suspension.  7 C.F.R. § 990.30(c), (d).  Producers whose licenses have been suspended and not restored on appeal may have their license restored after a waiting period of one year from the suspension date.  7 C.F.R. § 990.30(e).  USDA may also require a producer whose license has been suspended to operate under a corrective action plan to fully restore their license.  7 C.F.R. § 990.30(f).

USDA will revoke a license immediately if the licensee:

• Pleads guilty to, or is convicted of, any felony related to a controlled substance;
• Made any materially false statement to USDA or its representatives with a culpable mental state greater than negligence; or
• Is found to be growing cannabis exceeding the acceptable hemp THC level with a culpable mental state greater than negligence or has negligently violated the regulations three times in five years. 7 C.F.R. § 990.31.

Producers can appeal license denials, suspension, and revocations.  7 C.F.R. § 990.40; .41.  The regulations, under 21 C.F.R. § 990.42, also set forth the process for States and Tribes to appeal USDA actions on their hemp production plans.

State and Tribal Hemp Production Programs

The USDA final rule, tracking the Farm Bill, requires USDA-approved State and Tribal programs to include many of the same components as USDA’s program.  USDA exercises oversight of State and Tribal programs first by reviewing and approving their plans, then by conducting audits to ensure compliance with the Farm Bill and final rule.  States and Indian Tribes must submit their program plan to USDA for approval before implementation.    

State and Tribal plans must collect, maintain, and report to USDA, for each licensed or authorized producer, contact information, a legal description of the land on which the producer will produce hemp including geospatial location, and the producer’s license number and status.  7 C.F.R. § 990.3(a)(1).

In addition, State and Tribal plans must include procedures for:

• Sampling hemp, requiring agents to collect hemp within 30 days prior to harvest for THC testing. 7 C.F.R. § 990.3(a)(2)(i) (effective Mar. 22, 2021);
• Identifying through testing whether the hemp sample contains THC concentration exceeding the acceptable hemp THC level by validated testing methods using post-decarboxylation or similar methods (only DEA-registered laboratories registered may test hemp after December 22, 2022). 7 C.F.R. § 990.3(a)(3) (effective Mar. 22, 2021);
• Disposing of or remediating cannabis plants if the tests exceed the acceptable THC level by DEA-registered reverse distributors, law enforcement or remediation on-site. 7 C.F.R. § 990.3(a)(6) (effective Mar. 22, 2021); and
• Conducting annual inspections of a random group of producers to verify compliance. 7 C.F.R. § 990.3(a)(7) (effective Mar. 22, 2021).

USDA Approval and Audits

USDA must approve or disapprove State and Tribal plans within 60 days of receipt.  States and Tribes must submit amended plans if, after disapproval, they still wish to have primary regulatory authority over hemp production within their territory.  7 C.F.R. § 990.4(a), (b).

USDA may audit State and Tribal programs to determine compliance with their approved plans every three years but can adjust audit frequency based on performance, compliance issues, or other relevant factors identified and provided to State/Tribal governments.  7 C.F.R. § 990.5(a).  USDA audits can include:

• Resources and personnel administering and overseeing programs;
• Licensing and compliance review of hemp producers;
• Sampling and lab testing requirements and components;
• Disposal and/or remediation of non-conforming plants to ensure correct reporting;
• Results of and methodology used for annual inspections of producers; and
• Information collection procedures and accuracy. 7 C.F.R. § 990.5(b) (effective Mar. 22, 2021).

USDA will provide reports to State and Tribal governments within 60 days after completing audits.  USDA will advise of non-compliance and corrective measures required to bring programs into compliance.  States/Tribes will develop a corrective plan that must be reviewed and approved by USDA.  7 C.F.R. § 990.5(c)(1).  If USDA determines the State or Tribe is non-compliant after the second audit, it may revoke approval for one year or until the program becomes compliant.  7 C.F.R. § 990.5(c)(2).

Reports

States and Tribes with approved plans must submit a monthly report to USDA providing contact information and license status for every producer.  Monthly reports to USDA must contain:

1. For each new licensed producer who is an individual, their full name, license or authorization identifier, business entity Employee Identification Number, address, telephone number, and email address;
2. For each new licensed producer that is an entity, their full name; business address; license or authorization identifier; and full name, title, and email address of each employee for whom the entity is required to submit a criminal history report;
3. For producers in prior reports whose reported information has changed, the previously reported information and the new information;
4. Status of each producer’s license; and
5. Indication, if applicable, of no changes during the current reporting cycle. 7 C.F.R. § 990.70(a) (effective Mar. 22, 2021).

States and Tribes must also submit monthly reports notifying USDA of any occurrence of non-conforming plants or plant material and the disposal or remediation record by the producer.  Disposal and remediation reports must include:

1. Producer’s name and address;
2. Producer’s license or authorization identifier;
3. Location, such as lot number, location type, and geospatial location or other descriptor for the production area subject to disposal or remediation;
4. Disposal or remediation completion date; and
5. Total acreage. 7 C.F.R. § 990.70(b) (effective Mar. 22, 2021).

State and Indian Tribes must also report annually to USDA the total acreage planted, harvested, and disposed/remediated within their territory.  7 C.F.R. § 990.70(c) (effective Mar. 22, 2021).

Producers are responsible for ensuring labs testing their samples report results to USDA.  (Informal testing conducted throughout the growing season monitoring THC concentration do not need to be reported to USDA).  Test result reports must contain:

1. Producer’s license or authorization identifier;
2. Producer’s name and address;
3. Lot identification number for the sample;
4. Laboratory name and, no later than December 31, 2022, laboratory’s DEA registration number;
5. Date of test and report;
6. Identification of a pre-harvest or post-harvest retest; and
7. Test results. 7 C.F.R. § 990.70(d) (effective Mar. 22, 2021).

Enforcement

State and Tribal plans must include enforcement provisions for “negligent” and “culpable” producer violations as well as felonies.  7 C.F.R. § 990.6(a)-(e).  The plans must prohibit anyone who materially falsifies any application information from program participation.  7 C.F.R. § 990.6(f).  Hemp producers cannot receive more than one negligent violation per calendar year.  7 C.F.R. § 990.6(b) (effective Mar. 22, 2021).  As with USDA requirements, negligent violations include:

• Failing to provide a legal description of land where hemp is produced;
• Producing hemp without a license; and
• Producing cannabis exceeding the acceptable hemp THC level. Id.

For each negligent violation, the State/Tribe must require a corrective action plan for a minimum of two years that includes the date by which the producer will correct negligent violations and the producer’s regular reporting on compliance.  7 C.F.R. § 990.6(c).  Producers who negligently violate their license three times within five years will have their license revoked and are ineligible to produce hemp for five years.  7 C.F.R. § 990.29(e).

State/Tribal programs must also contain provisions relating to producers who commit violations with a “culpable mental state greater than negligence.”  86 Fed. Reg. 5606.  Programs must immediately report  licensees to the U.S. Attorney General, and the chief law enforcement officer of the State or Indian territory.  7 C.F.R. § 990.6(d).  State and Tribal programs must prohibit any person with a State or Federal controlled substance-related felony conviction from participation in hemp production for ten years from the conviction date.  7 C.F.R. § 990(e).

It will be interesting to see how USDA will administer its own hemp production program while overseeing numerous State and Tribal programs.  As noted, the final rule is effective March 22, 2021.

Yesterday’s FDA Warning Letter, Press Release, and accompanying public relations campaign related to AcelRx’s promotional material for Dsuvia (sufentanil) are remarkable for exactly the reasons FDA intended them to be remarkable: these actions all signal to industry that despite anemic levels of FDA enforcement related to Rx drug promotion, when it comes to opioids, FDA is paying attention and ready to take action.  In addition to the Press Release, FDA’ers tweeted about the Warning Letter, including the following tweet (of three) by Dr. Janet Woodcock:  “False or misleading promotional communications will not be tolerated.  The agency is focused on reducing harm by decreasing exposure to opioids, while still enabling appropriate access for patients with medical need.”  FDA, in what appears to be a new approach, has already updated the OPDP 2021 Warning Letter website to include CDER’s press release, in addition to posting the Warning Letter and underlying promotional material.

It should come as no surprise that the media blitz and OPDP’s first letter of 2021 relate to opioid promotion.  Before retirement, Tom Abrams, former Director of OPDP, regularly stressed OPDP’s enforcement priorities and, included among them, was promotion for drugs that have serious risks.  Just last month, Acting Director of OPDP, Katie Gray, provided an interview where she explicitly stated, in response to a question on which promotional materials were priorities, that OPDP would focus “on promotional materials for high-risk drugs, such as opioids. We want to make sure the promotional materials accurately convey the risks associated with these drugs, convey responsible use of opioids, and do not inadvertently contribute to the opioid epidemic.”  The last time an OPDP Warning Letter was accompanied by an FDA Press Release was back in December 2019, relating to a treatment intended to prevent relapse to opioid dependence.

Back to the Dsuvia Warning Letter – there are a number of key takeaways for industry.  It is apparent that the letter was triggered, in this particular instance, by the use of the pithy tagline, “Tongue and Done” that emphasizes simplicity in administration.  Given FDA’s history with this product, and that administration was one of the issues cited as part of a complete response letter – it is not surprising that this type of promotion was likely to garner the agency’s attention.  (As an aside, knowing how much former FDA Commissioner Scott Gottlieb enjoys our song references, these bloggers spent an inordinate amount of time looking for clever references to music videos that would relate to this tagline.  Not surprisingly, after watching a few too many Kiss videos – featuring Gene Simmons – we abandoned the exercise.  Hence the name of this blogpost.)

Putting the tagline trigger aside, FDA also called out the company’s failure to include information on the maximum dosing within a 24 hour period, despite otherwise calling out the ability to re-dose Dsuvia within an hour.    This is a practical concern, not simply for opioids, as there is a safety suggestion implied with re-dosing statements.

Industry should pay close attention to other FDA comments in the Warning Letter with regard to the presentation of risk and benefit information.  The allegations relating to how the company presented the full indication and limitations for the product, as well as Important Safety Information, should be scrutinized as the techniques employed are often used by others.   From the Warning Letter:

“the full indication with the limitations of use are intermingled with risk information in a paragraph format in a much smaller font size and a plain white background, and are accessible only if viewers “scroll” down the banner. Therefore, this does not mitigate the misleading impression.”

These bloggers find it shocking that FDA would object to presenting the full indication, particularly one that is longer and includes limitations of use, with safety information and that FDA would particularly call out that it was against a plain white background.  One of the core tenets of any ad is ensuring that the full indication and safety information are legible – and FDA has a long history of calling out instances when safety information was minimized because it was presented against a colored background.   In fact, this very issue was addressed in FDA’s Draft Guidance on Presenting Risk Information, dating back to 2009, in a section on Contrast:

“Contrast between text and background should not highlight the benefit information more than the risk information. Example 18: If benefit information in a piece is presented in white letters on a black background, risk information should be presented with similar contrast. If the piece presents risk information in a way that would make it difficult to discern (e.g., using white letters on a light gray  background or gray letters on a black background), the presentation may be considered false or  misleading. Even if the background is a color designed to attract attention, the contrast influences the prominence of the words once attention has been gained. In fact, printing words in some attention-grabbing colors (e.g., red) may make the words difficult to read.  Similarly, the placement of risk information over pictures or other visual elements with multiple colors can cause this information or portions of this information to lack prominence and be difficult to read. Furthermore, a print piece that superimposes risk information over a visual image could compromise the accuracy of the piece as a whole by drawing attention away from the risk information.

While it may be fair to point out in the Warning Letter that the safety information was only visible after scrolling within the digital banner ad, it is absurd to think that by providing safety information in black font against a plain white background that the company has somehow minimized risk.

In looking at the banner ad, it looks like the company employed a “20%” approach to the inclusion of safety information.  This approach includes a scroll bar for the user to obtain additional safety information, but devotes 20% of the visual field to safety information as balance.  In this Dsuvia banner ad, that amount of space was not enough to present the full, all caps title from the Boxed Warning.  Although somewhat consistent with how industry treats digital banner ads (although arguable that 20% of an ad would be sufficient balance for an opioid with significant safety concerns and a REMS), companies should be mindful, not only of spacing, but of the substantive safety information in view.

FDA also cited both the digital banner as well as a print flyer for failing to present information relating to the Boxed Warning, Contraindications, Warnings and Precautions, and Adverse Reactions “with a prominence and readability reasonably comparable with the presentation of information relating to the benefits” of the drug.  FDA cites “typography, layout, contrast, headlines, paragraphing, white space, and other techniques” as affecting readability and emphasis. FDA also highlights that “risk information is relegated farther down in paragraph format with less prominence.”

The key takeaways here are not new:  minimizing safety, particularly for a drug with serious risks, will likely trigger FDA enforcement (no matter how sleepy OPDP may seem).  The issues cited by OPDP are those clearly outlined in its 2009 Draft Guidance – which was not exactly revolutionary at the time it was originally published and simply summarized points made in prior DDMAC Warning and Untitled Letters.  Many of the techniques utilized by AcelRx, and objected to by OPDP, are those employed across industry.  One has to question whether lack of OPDP enforcement has led, to a certain degree, to industry falling back into old habits –  with safety information “below the line,” at the end of a piece, in small font with running text.  While it may have been the nature of this promotion in the midst of the opioid crisis that stirred FDA to action, the issues OPDP called out are nevertheless ones even non-opioid manufacturers might want to reconsider in light of this letter.