Last week the U.S. Attorney’s Office for the Western District of Texas announced that People’s Rx, a local chain operating five retail pharmacies and a compounding laboratory in the Austin area, agreed to pay $200,000 to settle allegations that it violated the Controlled Substances Act (“CSA”).  Austin Pharmacy to Pay $200,000 in Civil Penalties for Alleged Violations of the Controlled Substances Act, Aug. 16, 2023 (DOJ Press Release).  During a routine inspection in June 2022, Drug Enforcement Administration (“DEA”) diversion investigators determined that People’s Rx pharmacy violated recordkeeping requirements, improperly dispensed controlled substances to practitioners for office stock and issued prescriptions without authorization.  Id.  Investigators also found that the pharmacy sold pseudoephedrine (“PSE”) products but failed to self-certify in violation of the Combat Methamphetamine Act of 2005 (“CMEA”).  Id.

We note that in December 2020, the same U.S. Attorney’s Office announced that another pharmacy paid $320,000 to resolve allegations that in addition to violating recordkeeping provisions, it had also sold PSE and ephedrine products without self-certifying with DEA.  Odessa Pharmacy and Owner to Pay $320,000 in Civil Penalties for Alleged Violations of the Controlled Substances Act and the Combat Methamphetamine Epidemic Act of 2005, Dec. 2, 2020 (DOJ Press Release).

These settlements provide powerful reminders for “regulated sellers” of PSE, ephedrine and phenylpropanolamine.  “Regulated sellers” (retail distributors including pharmacies, grocery stores, general merchandise stores and mobile vendors) selling “scheduled listed chemical products” (“SCLPs”) (products containing ephedrine, PSE and phenylpropanolamine that may be marketed in the U.S. as non-prescription drugs) directly to walk-in customers or in face-to-face transactions by direct sales must self-certify with DEA that their employees have been trained on SCLP sales requirements.  21 U.S.C. § 830(e)(1)(B)(i).  Regulated sellers must renew their self-certification annually for each place of business where they sell SCLPs.  21 C.F.R. § 1314.40(b).  Mail-order distributors of SCLPs must also self-certify.  21 C.F.R. § 1314.102(a).

Regulated sellers must train employees responsible for delivering SCLPs into the custody of purchasers or who deal directly with purchasers by obtaining payment for the SCLPs then self-certify that they have done so.  21 U.S.C. § 830(e)(1)(A)(vii).

Regulated sellers must limit daily sales of SCLPs to 3.6 grams and 30-day limits to 9 grams, verify each customer’s identification, maintain records of each sale and keep products behind the counter or in a locked cabinet away from customer access.  Before they can sell SCLPs, regulated sellers must certify their employees have been trained on these requirements.  21 C.F.R. § 1314.35(a).  Certification must also include a statement that the regulated seller understands the requirements for selling SCLPs and will comply with those requirements.  21 C.F.R. § 1314.40(a).

Regulated sellers must train employees on SCLP sales requirement content developed by DEA and listed on the DEA website provided at the Diversion Control Division Retail Training Page.  DEA has developed two sets of training materials: one for regulated sellers who are not mobile retail vendors, and a second set for mobile retail vendors.

After employees have been trained, regulated sellers must self-certify through the DEA website provided at the Diversion Control Division Self-Certification Page.  Regulated sellers must print out and maintain a copy of their self-certification certificate.  In the unlikely event a regulated seller cannot recall whether they have self-certified, they can consult DEA’s monthly self-certification list of all who have current self-certifications found at the Diversion Control Division CMEA Monthly List.

Self-certification fees are waived for DEA-registered regulated sellers but the fee for initial self-certification and renewal for regulated sellers who are not DEA registrants is $21.00.  Id. at 21 C.F.R. §1314.42(a), (b).

I saw the sign…and the answer is no—FDA-approved labeling apparently is not enough under state failure-to-warn laws, according to certain courts.  While it has been long established that FDA-approved or mandated labeling preempts state failure-to-warn claims, some courts have decided that sometimes labeling just isn’t enough, never mind what FDA thinks.  FDA approves (or sometimes dictates depending on the product and regulatory pathway to market) the content of drug product labeling to set forth the conditions of use for which the benefits of the product outweigh the risks.  While the approval of that labeling is squarely on the shoulders of FDA, state failure-to-warn laws are used by plaintiffs to ask courts to pass judgment on the adequacy of labeling notwithstanding the fact that the scientific experts at the FDA have signed off on the labeling.  This begs the question of whether these courts, and other courts looking at other state law claims, are actually undermining FDA’s authority to determine whether a drug can be used safely and effectively under its proposed conditions of use.  After all, the labeling is intended to do exactly that: it informs patients and prescribers of the risks to ensure the product is used effectively and in a manner that mitigates risks, according to FDA’s understanding of the relevant science.

Brand drugs, generic drugs, and medical devices alike have all been the target of state failure-to-warn litigation; in a recent case, OTC acetaminophen is the target.  For OTC products, two pathways to marketing exist: through a full New Drug Application or Abbreviated New Drug Application, requiring FDA approval (including the approval of the label), or under an OTC monograph, which basically serves as an instruction manual for making and labeling certain OTC drugs.  Relevant to our conversation, OTC monographs establish conditions—such as active ingredients and indications for use, and product labeling—under which an OTC drug is generally recognized as safe and effective and does not require a product-specific approval.  Most OTC drugs, particularly drugs that have been around for a while, are primarily marketed pursuant to OTC monographs.  As explained in a 2020 CRS Report and a 2020 GAO Report, until the 2020 passage of the CARES Act (see our blog post here), amending a monograph was challenging because “the agency’s ability to update and finalize monographs in response to safety issues and to reflect new scientific information was limited by the rulemaking process the agency was required to follow, as well as insufficient resources. Agency officials estimated that it took at least 6 years to complete the required rulemaking process.”  More than a few have taken far longer—literally decades.  The GAO Report further explained that the agency did not have the resources to regulate the estimated 100,000 OTC drugs marketed through the monograph process.  (Recall that the funds provided under the Prescription Drug User Fee Acts (PDUFA) are not available to support the agency’s efforts related to monograph drugs.)  FDA did, however, try to identify safety issues through the medical literature and (after 2007 when mandatory safety reporting for OTC human drug products marketed without an approved application became effective) through the adverse event reporting system.  Further, FDA has utilized a variety of strategies to call attention to safety issues through Dear Doctor letters or other forms of communication, even if directing changes to labeling is difficult.  The passage of the OTC monograph provisions of the 2020 CARES Act was intended to address the lack of resources, and user fees are being collected, but, as expected, implementing all the other aspects of the new law is a long process.

FDA’s jurisdiction over OTC monograph drug labels is clear, but some courts seem to believe that compliance with the label requirements set forth in the relevant monograph is not only not sufficient, but also is discretionary, implicitly chipping away at the authority of the agency.  A recent state law failure-to-warn case in the SDNY makes that very point.  There, Plaintiffs (a mother individually and on behalf of her child) alleged that Defendants Johnson & Johnson and Walmart failed to include a warning on acetaminophen products they sold pursuant to the relevant OTC monograph, as well as under NDAs, that use of acetaminophen while pregnant causes children to be born with autism spectrum disorder and ADHD.  Plaintiffs also alleged strict liability for design defect due to inadequate warnings and precautions and negligence and breach of consumer protection laws.  Plaintiffs alleged that Defendants had a duty under state law to warn consumers of a (potential) risk of prenatal exposure to acetaminophen.  Interestingly, the Plaintiffs alleged that this duty existed when the mother was pregnant in 2015 even though the studies relied upon in the litigation are from 2021.  But we digress.

Defendants moved to dismiss on grounds that state failure-to-warn claims are preempted, as FDA approved the NDA-product labeling and dictated the labeling for OTC monograph products, but the Court disagreed.  It’s important to note here that the warnings and precautions listed in the acetaminophen labeling complied with FDA’s Pregnancy Rule (which applies to all OTC systemic products), stating “if pregnant or breast-feeding ask a health professional before use,” and with the acetaminophen OTC Monograph and the relevant NDAs.  Thus, Defendants argued that FDA already required the warning for pregnancy, rendering the decision to use it during pregnancy to a healthcare professional, and that FDA had considered the risks of in utero exposure and rejected the addition of those risks to the labeling.  Nevertheless, despite the immense hurdles to changing a warning in a monograph (as specifically noted in the GAO Report), despite that FDA expressly rejected the change to the monograph at the time the Plaintiff-mother was pregnant in 2015, and despite the clear and specific language of the Pregnancy Warning Rule, the Court denied the Motion to Dismiss, holding that the failure-to-warn claims were not preempted.

Though the case addressed both NDA and monograph OTC products, it is notable as one of the first to address the issue of preemption with respect to the Pregnancy Warning Rule or to OTC Monographs.  On these issues, the Court took the position that neither expressly forbade including additional labeling, and thus, under both of these FDA schemes, the presumption is that sponsors can add stronger warnings to product labeling without FDA concurrence; consequently, the Court concluded it was not impossible to follow federal law and provide appropriate warnings under state protection laws.  Specifically, the Court explained, because “[t]he Pregnancy Warning Regulation simply does not speak to whether a further warning related to a drug’s use during pregnancy can be added to the general Pregnancy Warning on a drug label, whether added by the FDA or added by a manufacturer,” the ”regulation does not, therefore, preempt state law . . . .”  Similarly, the Court stated, “FDA’s silence regarding acetaminophen-specific warning does not preempt state law.”  Thus, the Court presumed, there is no reason that the sponsors could not add stronger pregnancy warnings.

And, as the Supreme Court previously explained, the Court noted, if the Defendants could have unilaterally strengthened warnings on labeling without prior approval from FDA, state failure-to-warn claims are not preempted.  Here, the Court presumed that Defendants could do just that: absent an attempt by Defendants to change the labeling and subsequent FDA rejection, the Court decided that Defendants could have added truthful warnings about the risk of in utero exposure without violating federal law.  Indeed, the Court explained, it could hardly be otherwise, because if a sponsor is “not free to add truthful warnings related to the use of acetaminophen during pregnancy, then that would mean that all manufacturers of OTC monograph-approved drugs intended for systemic absorption would be similarly barred from adding to their labels truthful warnings about the use of their own drugs during pregnancy.”  But what the Court didn’t consider is that, if sponsors of OTC Monograph drugs could change their labeling to include more warnings without FDA buy-in, identical products could have very different labeling, which is not contemplated under the OTC Monograph scheme.  While OTC Monographs may no longer include exact wording requirements for some information, this is only because, as the Court reminds us, “there can be various ways of accurately stating the same thing;” the problem arises when there are substantive changes to the labeling, like the addition of new warnings, such that all OTC Monograph products for a given drug don’t actually state the same thing even when there is no actual difference in risk between the products.  This can lead to consumer confusion with consumers believing that there are actual differences.  This is precisely the type of confusion FDA strives to avoid.

The Court’s determination that, even though FDA fully dictated the labeling for OTC Monograph products, Defendants could lawfully change the labeling undermines both FDA’s attempt to ensure consistency in the OTC drug market, as well as FDA’s decision that a healthcare professional should be consulted before use of acetaminophen in pregnancy; instead, it places the onus on manufacturers to basically beg FDA to modify monographs.  This is because the presumption that manufacturers can unilaterally make substantive changes to the labeling of an OTC Monograph drug product is false.  Just like it was over a decade ago in Pliva v. Mensing in the case of generic drugs, where the Supreme Court held that failure-to-warn claims for generic drugs were preempted precisely because the Reference Listed Drug holder—and FDA—controlled whether the generic sponsors could add new warnings to the labeling; in other words, generic drug sponsors could not just change labeling to add new safety warnings.  And like the Court said in Pliva v. Mensing, “even if [the sponsors] had fulfilled [a] federal duty to ask for FDA assistance, they would not have satisfied the requirements of state law.”  That requirement would only be fulfilled if FDA agreed to such a change.  And indeed, after Pliva v. Mensing, there was much discussion about adding authority to the FDC Act to allow generics to make safety changes to product labeling without FDA approval.  FDA went so far as to issue a proposed rule (see our blog post here), that ultimately went nowhere.  And that such a proposal ultimately fizzled out is not surprising considering the issues with overwarning and the relatively limited profits made by generic companies when compared to the additional liability burden created by the obligation to make safety changes separately from the Reference Listed Drug product.  The same considerations ring true for OTC drugs.

FDA, for years, has been concerned with overwarning.  As FDA explained in a 2008 Rulemaking, FDA’s existing policies are “intended to ensure that scientifically valid and appropriately worded warnings will be provided in the approved labeling for medical products, and to prevent overwarning, which may deter appropriate use of medical products, or overshadow more important warnings.”  In the Proposed Rule, FDA explained further that “[e]xaggeration of risk, or inclusion of speculative or hypothetical risks, could discourage appropriate use of a beneficial drug, biologic, or medical device or decrease the usefulness and accessibility of important information by diluting or obscuring it. As FDA has stated, labeling that includes theoretical hazards not well-grounded in scientific evidence can cause meaningful risk information to lose its significance.”  In a 2017 Request for Information, the agency similarly noted that overwarning, or the concept that “individuals are exposed to so many warnings in the course of daily life that they are less likely to pay attention to any one particular warning,” “may lead consumers to discount all risks, or miss the most important risk information.”  OPDP therefore initiated a study of “how repetition and overwarning apply to the presentation of risks in promotional prescription drug print pieces.”

If those marketing OTC drugs under the monograph were required to add new warnings because some literature noted a risk, the chances of overwarning are high, rendering the existing risk information potentially less impactful. It also raises questions about how much medical literature is required before a new warning is required, does it matter where it comes from (reddit or NEJM), or what types or quality of evidence are presented, and what if other medical literature disagrees?  And, as in the acetaminophen case, what if FDA has already considered and rejected the need for a specific warning?

Notably, FDA had even addressed the strength of the evidence for acetaminophen warnings.  Rather than adding in every potential risk in the case of acetaminophen, in that 2015 Drug Safety Communication, FDA specifically recommended that pregnant women consult their doctors before taking acetaminophen:

Pregnant women should always consult with their health care professional before taking any prescription or OTC medicine.  Women taking pain medicines who are considering becoming pregnant should also consult with their health care professionals to discuss the risks and benefits of pain medicine use.  Health care professionals should continue to follow the recommendations in the drug labels when prescribing pain medicines to pregnant patients.

FDA, in other words, directed, and continues to direct, pregnant women to a learned intermediary.  According to FDA, therefore, use in pregnant women is neither condoned nor directed by the labeling—that’s a question for them to discuss with their doctors.  The Court acknowledged all this, but nonetheless found that the failure-to-warn claims were not preempted because, essentially, the Defendants should have at least tried to change the labeling.

Unlike prescription drugs with approved NDAs, OTC monograph drugs generally are not blockbuster drugs protected by patents for which sponsors expect huge returns.  FDA has estimated that there are more than 100,000 OTC drugs marketed through the monograph process, with 800 active ingredients for over 1,400 uses as of December 2019.  With all that competition, particularly with respect to drugs as well-known as acetaminophen, it’s unlikely that there’s a lot of money to be made by an individual company; while the acetaminophen market may be large, there are just so many market participants.  If every company that brings an OTC Monograph drug to market is hit with state failure-to-warn claims and forced to litigate such claims to completion, the market is sure to shrink.  For many brands, the potential return is too small when compared to the potential for immense products liability claims for labeling that the sponsor cannot even control.  Liability is precisely why the vaccine market shrunk so significantly in the 1980s, going from 26 manufacturers to 4, after lawsuits claiming $3.5 billion in damages were brought between 1980 and 1986.  Things got so bad that Congress acted to shield vaccine manufacturers from liability in order to ensure sufficient availability of vaccines.  There’s no reason to believe that continued state liability for FDA-mandated labeling would result in any different outcome where there is unfettered opportunity to bring state law claims against OTC monograph sponsors for labeling products in accordance with FDA requirements.

Nevertheless, court decisions that contrast with FDA’s positions are imposed on drug manufacturers of all sizes and types.  Take, for example, sunscreens.  In 2023, a Northern District of California Court determined that state law claims alleging violations of unfair competition and other consumer protection provisions could stand notwithstanding the fact that cosmetic foundation with sunscreen complied with FDA’s labeling requirements for sunscreens.  There, the Court let proceed Plaintiffs’ suit alleging that foundation including sunscreen, advertised with a 24- or 25-hour duration, misleadingly suggested that sun protection could last for 24 or 25 hours, even though the directions stated clearly and unambiguously—and compliant with FDA’s sunscreen labeling rules—that the product must be reapplied every 2 hours for sunscreen coverage.  Similarly, the District Court of Connecticut found that allegations of various state consumer protection laws for failure to list benzene as an ingredient in Banana Boat sunscreen were not preempted when nothing in FDA regulations suggests that benzene, as an impurity, is an “ingredient;” additional consumer protection claims about benzene also were not preempted because the Court found that nothing in the OTC sunscreen monograph precluded a warning about benzene.

To be fair, we note the many examples of cases where courts have found such claims preempted.  But cases like the ones described here create precedent for the next OTC monograph case.  In turn, each of these cases triggers concerns about how far courts are willing to go.

In January 2023, Vanda Pharmaceuticals, Inc. (Vanda) submitted two interesting and substantially similar citizen petitions (Docket Nos. FDA-2023-P-0313 and FDA-2023-P-0344) regarding its product Hetlioz (tasimelteon).  Vanda requested that FDA revoke the approval of Apotex’s and Teva’s generic versions of Hetlioz on the grounds that the generic tasimelteon products did not meet the statutory “same labeling” requirement for generic drugs found in 21 U.S.C. § 355(j)(2)(A)(v).  This statutory provision requires generic drugs to have the same labeling as that approved for the listed drug “except for changes required because of differences approved under a [suitability petition, allowing for certain differences] or because the new drug and the listed drug are produced or distributed by different manufacturers.”  FDA regulations, at 21 C.F.R. § 314.94(a)(8)(iv), interpret these provisions to also allow changes due to an aspect of labeling protected by patent or exclusivity.

The difference at issue here is the fact that Vanda’s Hetlioz product includes braille writing on its packaging, with some accompanying language (“Do not cover Braille”), and the generic products’ labeling does not.  This matters particularly strongly in this case, Vanda argued, because the generic products are approved for only one indication, a sleep disorder that disproportionately occurs in blind individuals.  Vanda’s Hetlioz was, in fact, the first FDA-approved drug product to include braille labeling.  Nor did this difference meet any of the statutory or regulatory exceptions to the “same labeling” requirement, Vanda argued.  As such, Vanda’s citizen petition stated that these approvals are “clearly erroneous under the FDCA and agency regulations and will put . . . patients in harm’s way.”  The citizen petition requested FDA revoke the approvals and recall the product in the marketplace.

FDA responded in late July, denying Vanda’s petitions.  FDA’s response stated that the two generic sponsors had submitted side-by-side comparisons of the labeling for their products as compared to the reference listed drug (RLD) Hetlioz, noting the differences Vanda raised in its petition.  FDA concluded at that time that these differences still met the “same labeling” requirement due to the “different manufacturer” exception.

FDA’s petition response included several grounds on which it based its decision to deny Vanda’s citizen petitions.  First, FDA noted that the Agency has interpreted the “different manufacturer” exception broadly, on a case-by-case basis, and listed various examples of when they have done this in the past.  Such differences have included different disposal methods in the labeling, a different ingredient safety warning, and a situation where a generic did not include halal and kosher certifications in its labeling where the RLD labeling did.  Other differences have included differences in font, color, trade name, and other trade dress.  Thus, FDA’s response argued that Vanda’s interpretation of the exception is inconsistent with FDA’s.

Secondly, FDA’s response stated that the only pieces of information that were repeated in braille in Vanda’s container labeling were the proprietary name and the strength of the drug product.  As the proprietary name is not generally included in generic drug labeling, which is interpreted as an acceptable difference, this leaves only the strength as the information that would be expected to appear in generic labeling.  FDA also disagreed that the inclusion of the strength or a product name was necessary for the safe and effective use of the drug product, noting that this was a voluntary addition to the labeling by Vanda, not required by the Agency during review.  FDA did request a Label Comprehension Study during Hetlioz’s review to evaluate whether the braille might introduce a new risk of medication errors, which Vanda conducted, but, the response stated that this does not establish that the braille is necessary for the safe and effective use of the product.

Moreover, other information, such as dosing instructions and warnings, were not presented in braille.  FDA argued that this rebutted Vanda’s argument regarding the necessity of the braille to the safe and effective use of the product.  FDA stated in its response that there is not sufficient support for a claim that the absence of braille will lead to medication errors for the patients at issue, nor have there been any such reported to date.

Finally, FDA’s response stated that the accompanying language (“Do not cover Braille”) would be acceptable to omit, given that it might cause confusion where there is no braille on the generic product labeling, and this would not violate the “same labeling” requirement.

Vanda has a history of challenging FDA statutory interpretations in court, so it’s possible this is not the last we hear of this issue.  However, we will have to wait and see what happens.

Well, if you, like many within industry, felt emboldened to disseminate promotional materials that may push the envelope on efficacy (so long as your risk information was tight) think again!  OPDP is back in the game, letting all the people know that they are back to run the show.

In what may be the surprise “Warning Letter of the Year” (can you tell this blogger was pretty shocked?) OPDP took issue with AstraZeneca’s professional sales aid for Breztri Aerosphere (budesonide, glycopyrrolate, and formoterol fumarate) inhalation aerosol for oral inhalation use.  Why is this Warning Letter so shocking?  Let’s take a walk down OPDP Warning Letter memory lane . . .

• The last Warning Letter OPDP issued was in early 2022 to CytoDyn for promoting its investigational drug as an effective treatment for COVID-19 despite a failed study (and despite an FDA release issued a year prior about the same failed study – but that’s another story).
• Prior to the CytoDyn letter in 2022, OPDP issued a Warning Letter in 2021 to CooperSurgical for a DTC video entitled “Paragard: Family Planning During the Pandemic” which failed to communicate ANY risk information.
• And before CooperSurgical, another 2021 Warning Letter was issued to AcelRx for the infamous “Tongue and Done” tagline used to promote a Schedule II controlled substance subject to a REMS program that requires a healthcare professional’s precise placement of the drug using a single-dose applicator into the patient’s sublingual space.

Whew!  Pretty egregious stuff, right?

In this most recent Warning Letter, however, OPDP did not take issue with ANY of the safety information presented about Breztri in the sales aid; rather, objections were focused solely on false or misleading claims related to efficacy.  And those efficacy presentations included disclaimers and context, yet FDA found they were insufficient to “mitigate the misleading impression” caused.  Sheesh!

Let’s go over some background information relating to Breztri and the OPDP Warning Letter.

Breztri was approved just over 3 years ago in July 2020 for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).  The indication includes a limitation of use that Breztri is not indicated for the relief of acute bronchospasm or for the treatment of asthma.  The drug does not have a Boxed Warning, but has an extensive list of Warnings (17 in total).  The promotional piece at issue is a 12-page brochure intended for healthcare professionals, with the offending presentations appearing on pages 6 and 7.

OPDP first took issue with a headline and graph presented on page 7 of the 12-page brochure.  The headline, “Difference Observed in Time to All-Cause Mortality (Over 52 Weeks)” appears above a graph titled “Secondary Endpoint Study 1:  Time to all-cause mortality in the ITT population” and includes claims that there is an observed relative difference between Breztri v. LAMA/LABA.  The Kaplan Meier graph closely resembles one appearing in the American Journal of Respiratory and Critical Care Medicine Journal, a bi-weekly peer-reviewed medical journal published by the American Thoracic Society.  The page in the brochure calls out that the data were also included in the New England Journal of Medicine.  FDA took issue with the representation that there was a 49% observed relative difference in all cause mortality with Breztri v. LAMA/LABA because the results intended to support that claim come from a study with multiple secondary endpoints and there was a failure to show significance on endpoints ranked higher in the analysis hierarchy.  Despite AstraZeneca’s inclusion of the statement “These results are observational in nature, and any comparisons between treatment arms should be interpreted with caution,” FDA provided its typical response re disclaimer statements – that they do not “mitigate the misleading impression” of the presentation.

The second issue raised by OPDP was that the inclusion of a p value in conjunction with a claim suggested statistical significance when the results were not, in fact, statistically significant.  OPDP states that a p-value is generally understood to indicate statistical significance if it is less than 0.05.  However, in the testing strategy from the trial,

the raw p-value of each hypothesis test was compared to the corresponding critical value to determine whether the test was statistically significant.  As the p-value for the Breztri to ICS/LABA comparison (p=0.02) was greater than the critical value (0.008) for that hypothesis test, the result, per the threshold set by the testing strategy, is not statistically significant.  Therefore, the presentation of these claims (i.e., with a p-value of 0.02) creates the misleading impression that Breztri provides a statistically significant reduction in severe exacerbations compared to ICS/LABA by 20% when this has not been demonstrated.

FDA acknowledged a footnote that explained that the analysis was based on predefined Type-1 error control plan however, as above, FDA stated “this does not mitigate the misleading impression.”

What does this mean?

While one could argue that these presentations are misleading because they overstate the efficacy of Breztri, the presentations are limited to the middle of a 12-page brochure intended for healthcare professionals and the brochure otherwise describes the studies discussed and includes relevant safety information.  The claims are (presumably) not made to patients and each had context that described how the data was interpreted.  This certainly doesn’t seem like promotion that is prioritized for OPDP enforcement– while the drug has many warnings, it is not a Boxed Warning drug or an opioid, it is not subject to a REMS, nor is it used for COVID-19.  As Breztri has been approved for just over 3 years, this is not launch material for a newly approved drug, nor is it a product that has been the subject of previous compliance letters and the promotion is not a “far-reaching” campaign.

In a post-CFL world, these claims walk the line in that they could be “consistent” with the FDA-required labeling in accordance with FDA’s stated 3-factor analysis.  Clearly, OPDP thinks differently.  As part of the Warning Letter, OPDP states, “To date, no drug has been shown to improve ACM in COPD” and includes a footnote that states, “Through the issuance of this letter, FDA does not intend to convey any views on whether data that did show that Breztri improved ACM in COPD would support a change to the FDA-approved labeling for Breztri.”  This seems to suggest that FDA expects this type of outcome claim to be included in labeling.

Enforcement may also have been triggered by the manner of the presentation.  If AstraZeneca wanted to present this data in text form as opposed to colorful graphics, careful to equally present context with a description of the findings, this may not have resulted in a Warning Letter.

But a Warning Letter?  This blogger is curious to see what else OPDP has up its sleeve for 2023.  At a minimum, this letter gives industry a lot to think about as it considers Rx drug promotional materials.

Francis Godwin, Director of the Office of Manufacturing Quality of the Office of Compliance at FDA’s Center for Drug Evaluation and Research provided useful information (presentation attached here) Tuesday at the GMP by the Sea Conference.  He talked about regulatory discretion being exercised for drug manufacturing facilities with serious compliance problems, about how firms should respond to FDA inspectional observations, and about an upcoming guidance that will be of interest to generic drug manufacturing firms that have received Warning Letters.

First, Mr. Godwin provided updated information on the presentation made the day before by another CDER official, Jennifer Maguire, the Director of the Office of Quality Surveillance within the Office of Pharmaceutical Quality at CDER,.  We summarized in a blog post yesterday  her comments about facilities with FDA inspections that had been classified as Official Action Indicated, the most serious classification for FDA inspections relating to current Good Manufacturing Practice compliance.  Mr. Godwin’s presentation made the same point, although with more data to back it up: so far this fiscal year (since October 1, 2022), the number of OAI inspections resulting in the exercise of regulatory discretion is unusually high.  Regulatory discretion, in this context, means basically that FDA has decided not to issue a Warning Letter, request a Regulatory Meeting, impose an Import Alert, or to take a more serious enforcement action.  There were 286 FDA GMP-related inspections of drug manufacturing facilities in this period with OAI classifications.  Of that number, 80 of the facilities were graced with FDA’s regulatory discretion (28%), 75 resulted in imposition of an import alert (26%), 66 resulted in Warning Letters (23%), and 62 prompted Regulatory Meetings (22%).

Mr. Godwin confirmed that the percentage of OAI facilities receiving regulatory discretion was unusually high, and stated that he believes (as we posited in the blogpost yesterday) that the higher percentage was due to COVID-related causes: there were more facilities making critically needed drugs, and the drug supply chain has not recovered from COVID shutdowns and delays, making shortages of important drugs much more likely.  FDA would not want to curtail supplies of vitally needed drugs by, for example, imposing an Import Alert.

Second, Mr. Godwin said he reads numerous responses to FDA Forms 483, the report that FDA issues at the end of a GMP inspection, and that it is critically important that the responses include a narrative summary of the major remedial actions that a company has made or intends to make, and discuss if a company contests a finding.  “Document dumps,” he said, are not helpful without the assistance of a narrative placing the documents in context.

Third, Mr. Godwin said that he expects FDA to issue soon a Guidance document that will address how generic drug manufacturers should request, and what they should present, at meetings with his office that will be held after the company receives a Warning Letter.  After his remarks, Mr. Godwin stated that the Guidance, and the necessity of FDA providing such a meeting is one of the commitments in the GDUFA III  Commitment Letter.

At the GMP by the Sea Conference ongoing in Cambridge, Maryland, a presentation was made by a representative of FDA’s Center for Drug Evaluation and Research that shows some interesting trends in enforcement.

Jennifer Maguire, the Director of the Office of Quality Surveillance within the Office of Pharmaceutical Quality at CDER, told attendees that there were 163 FDA inspections from the beginning of October 2022 to the end of March 2023 conducted at drug manufacturing facilities (excluding drug compounding facilities) that were classified as Official Action Indicated (OAI).  OAI is FDA’s classification for facilities it deems to be in an unacceptable state of compliance.

Of those, only about a quarter (26%) resulted in Warning Letters, less than a quarter (19%) resulted in imposition of import alerts (restricting or prohibiting imports into the United States of drugs from a specified facility), slightly more (24%) resulted in regulatory meetings with the agency, and the plurality (29%) resulted in FDA exercising “regulatory discretion,” which means a decision not to take enforcement action.  One inspection resulted in FDA’s securing a consent decree to restrict or shut down operations, and two resulted in an “untitled letter,” which is not available to the public on FDA’s website.

The large percentage of OAI inspections resulting in the exercise of regulatory discretion is unusually high.  Lest we grow too optimistic, though, industry should be aware that this-larger-than-historical number of what is a favorable disposition may not be a trend that will continue.  It is believed that many of the inspections conducted during this period were of facilities producing essential medicines, such as COVID-related medications, for which FDA did not want to create or exacerbate product shortages.

Other interesting datapoints from her presentation:

For the period from FY2000 to May of 2023, the percentages of drug manufacturing inspections with OAI classifications was lower in China (about 5% of inspections) than in the United States (8%).  Again, this is a trend that may not continue: not many FDA inspections were conducted in China during this period due to COVID travel restrictions, whereas U.S. facility inspections are approaching traditional levels.

FDA has created a list of essential medicines, and provided calculations of how many of the drugs were totally or partially manufactured in countries other than the United States.  FDA also looked at how may of the Active Pharmaceutical Ingredients for those drugs were manufactured overseas.

• Remarkably, only 11% of the finished drug products were totally manufactured overseas, although 92% of the API for those drugs was either totally or partially manufactured in foreign countries.
• Of those facilities manufacturing essential medicines deemed to be the product of complex manufacturing processes, 68% were located in the U.S., the European Union, or the United Kingdom. For those facilities manufacturing essential medicines deemed to be non-complex, 60% were located in these countries.

These figures confirm that, although the vast percentage of active ingredients of important pharmaceuticals comes from overseas, the actual manufacturing of finished dosage form drugs occurs in the United States or Europe (broadly defined to include the UK).

The GMP by the Sea conference, an annual conference sponsored by PharmaConference.com, is an annual event in Cambridge, Maryland, linked here.

On August 7, 2023, a little less than five months before the registration and listing of cosmetic product facilities and products becomes mandatory, FDA announced the availability of a draft guidance regarding the new facility registration and product listing requirements under the Modernization of Cosmetic Regulations Act of 2022 (MOCRA).  The information is presented in a Q&A format.

As reported previously, MOCRA includes a requirement for facility registration and listing of cosmetic products.  Specifically, with some exceptions, parties that own or operate a facility engaged in the manufacturing or processing of a cosmetic product for distribution in the United States must list their facilities.  In the case of contract manufacturers, either the contract manufacturer or the person whose name appears on the label (i.e., the “responsible person”) must register (only one single registration per facility is required, even if the same facility contract manufactures products for more than one responsible person).   As discussed in the draft guidance, before registration, a facility must have a facility registration number which will be the facility establishment identifier (FEI).  Companies that do not have a FEI can request one.

MOCRA also requires that the responsible person for each cosmetic product submit a product listing. A single listing submission may include multiple cosmetics with identical formulations or formulations that differ only in respect to colors, fragrances or flavors, or quantity of contents.   The cosmetic product listing information must include the facility registration number of each facility where the cosmetic product is manufactured or processed.  For facilities that are small businesses that may not have a facility registration number, the facility name/address may be submitted.  In addition to the mandatory information to be submitted (i.e., the facility registration number of each facility where the product is manufactured or processed, name and contact number of the responsible person, name of the cosmetic product, cosmetic category, ingredient listing, product listing number (if any) and type of submission), FDA requests submission of a list of optional information, including but not limited to parent company name (if applicable); type of business (manufacturer, packer, or distributor); image of the label; product webpage link.

The draft guidance describes the mandatory elements that must be included in the registration and listing.  For both the registration and listing, FDA describes optional information that FDA would like to get.  In addition, FDA requests that a party submitting the information, attest to the accuracy and veracity of the information submitted.”

FDA is developing an electronic portal for registration and listing submissions that will be available in October 2023.  On the same day that FDA issued the draft guidance, the Agency issued a request for (nine) volunteers to participate in a pilot program on the electronic registration and listing program.  Although FDA strongly encourages electronic registration, it is developing a paper form as an alternative to electronic registration.

FDA states that is intends to make relevant information from cosmetic product facility registration and listing available to the public to the extent permitted by law.  Under the law, FDA may not disclose the product listing number, registration number, and brand names under which cosmetic products are sold.

Comments on the draft guidance may be submitted until Sept. 7, 2023. (Instructions for submission of electronic and paper comments are included here).

On August 3rd, FDA issued 11 warning letters to foreign facilities registered as OTC drug manufacturers.  For each of these facilities, FDA did not conduct an on-site inspection of the facility prior to issuing the warning letter.  Instead, FDA issued a request for records pursuant to Section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FDCA).

Section 704(a)(4) was added to the FDCA by the Food and Drug Administration Safety and Innovation Action (FDASIA) in July 2012.  This section grants FDA the authority to request records regarding drug products remotely, without an on-site inspection:

Any records or other information that the Secretary may inspect under this section from a person that owns or operates an establishment that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug shall, upon the request of the Secretary, be provided to the Secretary by such person, in advance of or in lieu of an inspection, within a reasonable timeframe, within reasonable limits, and in a reasonable manner, and in either electronic or physical form, at the expense of such person. The Secretary’s request shall include a sufficient description of the records requested.

Remote review of records in lieu of an inspection is known as a “paper inspection” or, in FDA guidance, a “remote regulatory assessment.”

Of the 11 warning letters, 6 of the warning letters identified cGMP issues in the records reviewed (see, e.g., Warning Letter to Suhan Aerosol).  As a result of the cGMP issues identified, the 6 firms were placed on Import Alert 66-40, which requires detention of products from “a firm that is not operating in conformity with [cGMP].”  The other 5 warning letters identify the firm’s failure to furnish records after multiple records requests from FDA (see, e.g., Warning Letter to Daxal Cosmetics Private Limited).  These firms were placed on Import Alert 66-79, which applies to “foreign establishments refusing FDA inspection.”

Despite FDA having the authority to conduct paper inspections since the statutory provision was added to the FDCA by FDASIA in 2012, FDA did not issue a warning letter citing Section 704(a)(4) until January 2021.  FDA’s new use of Section 704(a)(4) starting in early 2021 was the result of FDA’s inability to conduct on-site inspections of foreign facilities during the height of the COVID-19 pandemic.  FDA has resumed on-site inspections of foreign facilities focused on current Good Manufacturing Practices (cGMP) but has continued issuing records requests under Section 704(a)(4), which spurred this latest round of warning letters.

In July 2022, FDA issued a draft guidance titled Conducting Remote Regulatory Assessments, which explains that FDA adapted its field operations to continue to provide regulatory oversight of manufacturing facilities during COVID-19, through the use of remote regulatory assessments (RRAs).  The draft guidance defines RRAs to include records requests under Section 704(a)(4).  As described in the draft guidance, FDA learned through its experience during the COVID-19 pandemic that there are “significant benefits in using RRAs” and FDA intends to continue to use RRAs “to assist FDA during and beyond the COVID-19 pandemic.”

The warning letters issued on August 3^rd demonstrate that FDA is indeed continuing to take advantage of its authority to conduct paper inspections, even when an on-site inspection may be feasible.  There are obvious efficiencies with remote review of records in conserving agency resources.  It allows FDA to identify manufacturing facilities with flawed cGMP procedures without traveling to a facility for a multi-day inspection.  It may also allow FDA to review the cGMP practices of more facilities than it would otherwise.

However, there is of course the possibility that a firm may have adequate procedures, but is not following those procedures at the facility, which could only be discovered in person.  As FDA continues to issue records requests under Section 704(a)(4) it will be interesting to see if FDA will allow remote records review to replace a routine on-site inspection, or if FDA will follow up on an adequate records review through an on-site inspection.

If a patient presents a paper prescription for a controlled substance to a pharmacy and the pharmacy cannot fill it, the patient can take that prescription to another pharmacy.  However, electronic prescriptions for controlled substances (“EPCS”), which a practitioner transmits directly to a pharmacy, do not allow the patient such an option.  Instead, the patient must request that the prescriber send a new prescription to a different pharmacy.  That is until August 28th when DEA’s final rule becomes effective.  DEA explained its chief reasons for amending its regulations to allow the transfer of EPCS for initial filling are to provide patients with the option of transferring to prevent treatment delays, reducing patient burden and stress, as well as minimizing opportunities for diversion.  Transfer of Electronic Prescriptions for Schedule II-V Controlled Substances Between Pharmacies for Initial Filling, 88 Fed. Reg. 48365, 48369 (July 27, 2023).  DEA also recognized the potential diversion if the prescriber transmits a new prescription to a different pharmacy and fails to cancel or void the original prescription.  Id. at 48366.

DEA has amended its regulations to allow, upon request from a patient, the transfer of an EPCS between retail pharmacies for initial filling on a one-time basis only.  Id. at 48379 (to be codified at 21 C.F.R. § 1306.08(e)).  Any authorized refills included on schedule III-V prescriptions transfer with the original prescription.  The pharmacy must transfer the EPCS in its electronic form and cannot convert it to another form (such as paper or facsimile) for transmission.  Id. (to be codified at 21 C.F.R. § 1306.08(f)(1)).  The content and prescription information elements required by 21 C.F.R. § 1306.06 cannot be altered during the transmission.  Id. (to be codified at 21 C.F.R. § 1306.08(f)(2)).  Two licensed pharmacists must directly communicate the transfer.  Id. (to be codified at 21 C.F.R. § 1306.08(f)(3)).  The transfer of EPCS for initial dispensing is permissible only if allowable under existing State or other applicable law.  Id. (to be codified at 21 C.F.R. § 1306.08(g)).

Patients wishing to transfer EPCS to another pharmacy should confirm that the receiving pharmacy has the ability to fill the prescriptions before requesting the transfer.

The transferring pharmacist must update the EPCS prescription record to note the transfer.  That pharmacist must also update the prescription record with:

• Name, address, and DEA registration number of the pharmacy to which the prescription was transferred;
• Name of the pharmacist receiving the transfer;
• Name of the transferring pharmacist; and
• Date of the transfer. Id. (to be codified at 21 C.F.R. § 1306.08(f)(4)).

The receiving pharmacist must document:

• The word “transfer” to the electronic prescription record;
• Transferring pharmacy’s name, address, and DEA registration number;
• Name of the transferring pharmacist;
• Date of the transfer; and
• Name of the pharmacist receiving the transfer.  Id. (to be codified at 21 C.F.R. § 1306.08(f)(5)).

The transferring or receiving pharmacy’s prescription processing software may, if capable, capture the required information from the EPCS and automatically populate the corresponding data fields documenting the transfer.  Id. (to be codified at 21 C.F.R. § 1306.08(f)(6)).  The transferring or receiving pharmacist must ensure that the populated information is complete and accurate.  Id.

As with other required controlled substance records, electronic records documenting EPCS transfers must be maintained for two years from the transfer date by both the transferring and receiving pharmacies.  Id. at 48379-80 (to be codified at 21 C.F.R. § 1306.08(h)).  DEA’s final rule does not alter or revise any other prescription or electronic prescription requirements.

DEA’s allowing patients to request a pharmacy to transfer an EPCS for initial filling to another pharmacy not only provides flexibility when medication may be needed most, but it actually reduces the potential for diversion by a prescriber duplicating the prescription without canceling or voiding the original prescription.

Please sing to the tune of “Honesty,” by Billy Joel:

Nitrosamines, it’s such an ugly word,

In pharmaceuticals’ impurity.

Nitrosamines are hardly ever good,

Now FDA has issued policy.

Failure to detect nitrosamines, failure to notify FDA when nitrosamines appear in finished drug products, failure to identify impurities in drugs that may be nitrosamines, even having a deviation in pH of an Active Pharmaceutical Ingredient that might conceivably contribute to the formation of nitrosamines in a finished drug product.  All of these deviations discussed in FDA inspectional observations and Warning Letters have caused serious issues for manufacturers of APIs or finished drug products.

Now, just two weeks after we blogged on nitrosamines, and a week before a PharmaConference where we will talk about the importance of impurities in FDA enforcement, FDA has issued a final guidance, entitled, “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance Related Impurities (NDSRIs).”  NDSRIs are a particular focus for FDA, because they are a nitrosamine subcategory that share structural similarity to drug API.

The Guidance, which provides details about nitrosamines and FDA’s experience regulating them, explicitly applies to all finished drug products (including Rx, OTC, and unauthorized drugs), to “prescription and OTC drug products in clinical development,” and to both API and drug manufacturers.  In other words, it’s a sweeping application across the industry.  An earlier FDA guidance, revised in 2021. urged manufacturers to conduct risk assessments for nitrosamines in APIs and drug products; (2) conduct confirmatory testing if risks are identified; and (3) report changes in formulation or manufacturing as required in approved and pending NDAs and ANDAs.  There were tables in each guidance that appear to be consistent where they overlap, but also include different nitrosamines/NDSRIs (FDA guidances are not generally binding law, but, rather, express FDA policy.)

The new final guidance, by its own terms, establishes “a recommended framework for predicting the mutagenic and carcinogenic potential of nitrosamine drug substance-related impurities (NDSRIs) that could be present in drug products and recommends acceptable intake (AI) limits for NDSRIs.”  It further defines the AI as being “a level that approximates an increased cancer risk of one additional case in 100,000 people based on a conservative assumption of daily exposure to the impurity over a lifetime (70 years).”

The Guidance then goes on to categorize the types of NDRSIs and to suggest the appropriate acceptable intake limits for drugs, and sets a timetable for manufacturers – or those with pending applications – to review their drug products and take appropriate action.

This second half of this guidance beginning with the “Flowchart to Predict the Carcinogenic Potency Category of an NDSRI and Identify an Associated Recommended AI Limit” takes one back to basic organic chemistry and breaks down the key structural and electronic considerations into a step-by-step guide.  The substitution of the α-carbons and the electronic effects of the “Deactivating” or “Activating” groups yield tangible scores that one can apply to determine a “Potency Score” and therefore the recommended acceptable intake.  Perhaps most importantly, the guidance concludes with examples of how manufacturers would apply this framework to Nitroso compounds.

All drug manufacturers and API manufacturers would be well served to examine the guidance, and perform analysis suitable for their products, to determine whether further assessment is necessary.

The Center for Devices and Radiological Health (CDRH) offers learning opportunities for new and experienced CDRH staff through the Experiential Learning Program (ELP). Through ELP, CDRH staff visit sites that provide formal training and enhance understanding on topics such as how products are developed and how they fit into the larger healthcare system. Site visits can also provide the opportunity to engage with patients on various topics, such as prototyping, trial design and conduct, and product launch and understand the challenges related to quality systems development and management in the product life cycle.

The visits are intended purely to provide a training perspective, and not for CDRH staff to opine on any regulatory functions.

Participation is encouraged from:

• Companies
• Academia
• Clinical facilities
• Medical device incubators and accelerators
• Health insurers
• Health technology assessment groups
• Others, including previous participants in the ELP or the FDA’s other site visit programs.

One noticeable difference from years past is the option for virtual site visits. These allow CDRH to participate during times when the ability to travel is limited while expanding participation from CDRH staff.

Those interested in submitting a proposal to host CDRH staff should:

1.  Complete a Site Visit Request (Sample Site Visit Request).

a.  Ensure that proposals have only one Training Area of Interest.

b.  Include the Identifier Code with the Area of Interest.

2.  Complete a Site Visit Agenda (Sample Site Visit Agenda).

a.  Identify the site visit duration. (Most common are one- or two-day site visits.)

b.  Indicate ability to host a virtual site visit.

3.  Submit proposal documents by email to ELP Proposal Submissions by September 5, 2023 at 12 PM ET.

ELP Proposals will be selected based on a variety of factors such as applicable areas of interest, CDRH resource availability, and logistical considerations.

As a former participant, it was beneficial to me to engage with companies in person at their place of business and see the equipment used in manufacturing the medical devices that are reviewed by FDA. It was also helpful to hear first-hand the practical challenges companies navigate in bringing products to market. Companies may want to consider submitting a proposal so they can meet the CDRH staff who will be working with them on the review of their regulatory submissions. On the other hand, companies may not want to participate if they are not prepared to host FDA and answer questions, or do not meet one of the areas of interest identified on FDA’s webpage.

Anabolic steroids that include testosterone, methyltestosterone, nandrolone decanoate and oxandrolone are schedule III controlled substances with currently accepted medical uses in the U.S.  Other anabolic steroids are approved only for use in veterinary medicine.  Because anabolic steroids are also abused to enhance athletic performance and increase muscle strength, Congress has enacted three laws regulating anabolic steroids: the Anabolic Steroid Control Acts of 1990 and 2004, and the Designer Anabolic Steroid Control Act of 2014 (“DASCA”).  Congress felt that the laws prior to DASCA failed to sufficiently curtail the misuse of anabolic steroids.  So, through DASCA, Congress targeted those who would circumvent the Controlled Substances Act (“CSA”) by manufacturing anabolic steroids with slightly different chemical structures from those expressly controlled by the CSA but which are intended to cause the same potentially harmful effects.  Implementation of the Designer Anabolic Steroid Control Act of 2014, 88 Fed. Reg. 50,036 (Aug. 1, 2023).

DASCA amended the CSA by revising and adding specified substances to the definition of “anabolic steroid,” providing for the temporary and permanent scheduling of anabolic steroids and adding labeling requirements for products containing anabolic steroids.  DASCA became law, amending the CSA, on December 18, 2014.  The Drug Enforcement Administration (“DEA”) issued a final rule on August 1st whose sole purpose is to codify DASCA’s CSA amendments in DEA’s regulations, taking effect immediately and not requiring public comment because it “merely conforms the DEA’s regulations to the statutory amendments to the CSA that have already taken effect, and does not add additional requirements.”  Id.

Definition of “Anabolic Steroid”

To address exploitation of the earlier narrow statutory definition of “anabolic steroid,” DASCA controlled anabolic steroids by name that had emerged after 2004 under the CSA and expanded the definition of “anabolic steroid” to control such steroids that would emerge in the future.  Id. DASCA amended the CSA definition of “anabolic steroid” by adding 22 new substances to the prior list.  Id. at 50,037 codified at 21 C.F.R. § 1308.13(f).

DASCA expanded the definition of “anabolic steroid” to include a drug or hormonal substance chemically and pharmacologically related to testosterone (other than estrogens, progestins, corticosteroids and dehydroepiandrosterone) that brings to 86 substances now listed in 21 C.F.R. § 1308.13(f).  Id. at 50,039 codified at 21 C.F.R. § 1300.01(b).

A drug or hormonal substance, other than estrogens, progestins, corticosteroids, and dehydroepiandrosterone not listed in 21 C.F.R. § 1308.13(f) and “is derived from, or has a chemical structure substantially similar” to an anabolic steroid in that provision is considered an anabolic steroid if:

• The drug or substance has been created or manufactured with the intent of producing a drug or other substance that either promotes muscle growth, or otherwise causes a pharmacological effect similar to that of testosterone; or
• The drug or substance has been, or is intended to be, marketed or otherwise promoted in any manner suggesting that consuming it will promote muscle growth or any other pharmacological effect similar to that of testosterone. Id. at 50,040 codified at 21 C.F.R. § 1300.01(b)(2)(i).

The definition excludes anabolic steroids intended for administration through implants to cattle or other nonhuman species that have been approved by the Secretary of Health and Human Services (“HHS”) for such administration.  Id. at 50,039-40 codified at 21 C.F.R. § 1300.01(b)(1)(i).  Also not considered to be a drug or hormonal substance for purposes of the new definition is an herb or other botanical; a concentrate, metabolite, or extract of, or a constituent isolated directly from an herb or other botanical that is a dietary supplement for purposes of the Federal Food, Drug, and Cosmetic Act (“FDCA”).  Id. at 50,040 codified at 21 C.F.R. § 1300.01(b)(2)(ii).

Administrative Scheduling

DASCA authorizes DEA to issue a temporary scheduling order adding a drug or substance to the list of anabolic steroids in schedule III for up to two years that can be extended six additional months if the agency finds that the drug or substance satisfies criteria as an anabolic steroid and will assist in preventing abuse or misuse of the substance.  Id. at 50,041 codified at 21 C.F.R. §§ 1308.50(a)-(b).  The temporary scheduling cannot take effect until 30 days after publication in the Federal Register.  Id. at 50,041 codified at 21 C.F.R. § 1308.50(b).  DEA must also transmit the notice of a proposed order to HHS and take into consideration comments from that agency.  Id. at 50,041 codified at 21 C.F.R. § 1308.50(c).  In addition, DASCA gave DEA authority to issue a permanent order adding a drug or substance to the definition of “anabolic steroid” if it satisfies the criteria for being considered an anabolic steroid.  Id. at 50,041 codified at 21 C.F.R. § 1308.50(f).

Labeling Requirements

DASCA also added a labeling requirement in the CSA to identify products containing anabolic steroids.  It is now unlawful to import, export, manufacture, distribute, dispense, or possess with intent to manufacture, distribute, or dispense an anabolic steroid or product containing an anabolic steroid, unless the product bears a label clearly identifying it as such by International Union of Pure and Applied Chemistry (“IUPAC”) nomenclature.  Id. at 50,040 codified at 21 C.F.R. § 1302.08(a).

DASCA exempts IUPAC labeling if the product is labeled under the FDCA or is the subject of an approved new drug application under 505(b) or (j) of the FDAC or is exempt as a new drug intended solely for investigational use and is being used solely for purposes of a clinical trial subject to a new drug application.  Id. at 50,040 codified at 21 C.F.R. § 1302.08(b).

Civil Fine Provisions

In addition, DASCA added civil fine provisions to the CSA of up to $500,000 for each instance an importer, exporter, manufacturer, or distributor, and up to $1,000 for each violation at the retail level, that fails to comply with labeling requirements.  21 U.S.C. §§ 842(c)(1)(C) and (D).  DEA may take failure to comply with labeling requirements into consideration when issuing or revoking a DEA registration.  Id. at 50,038.

****

Again, the anabolic steroid requirements have been in effect in the CSA since December 2014.  The final rule does not change the legal status of the anabolic steroids.  It amends and merely updates DEA regulations for consistency with DASCA’s amendments to the CSA.

President Barack Obama signed the Comprehensive Addiction and Recovery Act of 2016 (“CARA”) intended to reverse serious prescription drug abuse trend in the United States on July 22, 2016.  CARA amended the Controlled Substances Act (“CSA”) to enable physicians or patients to request pharmacists to partially fill prescriptions for schedule II substances including opioids and to allow remaining quantities to be filled up to 30 days after issuance of the prescription (up to 72 hours for emergency oral prescriptions).  With the amendment by CARA, the CSA allows for partial dispensing of schedule II prescriptions if not prohibited by state law, is requested by the patient or prescriber and the total quantity dispensed in partial fillings does not exceed the total quantity prescribed.  21 U.S.C. § 829(f)(1).

Over a year later in a December 22, 2017, Congress in a bipartisan letter noting that “[l]arge amounts of unused medications are a key contributor” to the nationwide opioid crisis and that between 67% and 92% of surgery patients “reported they had unused opioids remaining after the procedures,” urged the Drug Enforcement Administration (“DEA”) to quickly update its regulations on the partial filling of schedule II prescriptions.  Letter from Congress of the United States, to Robert Patterson, Acting Administrator, DEA (Dec. 21, 2017).  Three years after that letter, DEA proposed a rule to amend its regulations consistent with CARA on December 20, 2020.  Partial Filling of Prescriptions for Schedule II Controlled Substances, 85 Fed. Reg. 78,282 (Dec. 4, 2020).

Now, in July 2023, DEA has finally issued its final rule amending its regulations for partial filling of prescriptions for schedule II substances.  Partial Filling of Prescriptions for Schedule II Controlled Substances, 88 Fed. Reg. 46,983 (July 21, 2023).

Partial Filling of Schedule II Prescriptions Historically

Pharmacists generally have been able to partially fill prescriptions for most schedule III-V controlled substances and non-controlled substances but have been permitted to partially fill prescriptions for II substances only in very limited circumstances.  Pharmacists could partially fill a schedule II prescription if the pharmacy is unable to supply the full quantity of a written or emergency oral prescription.  21 C.F.R. § 1306.13(a).  In addition, a pharmacist could partially fill a schedule II prescription issued to patients in a Long Term Care Facility or who have a terminal medical illness diagnosis.  21 C.F.R. § 1306.13(b).

The Final Rule

a.  General Requirements

DEA’s final rule allows the partial filling of a prescription for a schedule II substance at the request of either the prescribing practitioner or a patient.  Consistent with CARA, a pharmacist may partially fill a prescription for a schedule II controlled substance if:

(1) Not prohibited by state law;

(2) The prescription is written and filled in accordance with the CSA, DEA regulations, and state law;

(3) Partial filling is requested by the patient, by a person acting on behalf of the patient (a caregiver of an adult patient authorized in a medical power of attorney or a parent or legal guardian of a minor patient), or by the practitioner who wrote the prescription; and

(4) The total quantity dispensed in all partial fillings does not exceed the total quantity prescribed.  Id. at 47,001-02 (codified at 21 C.F.R. § 1306.13(b)(1)).

b.  Time Limits

If all of these conditions are met, remaining portions of a partially filled schedule II prescription, if filled, must be filled not later than 30 days after the date the prescription is written.  However, the remaining portions of a partially filled emergency oral prescription for a schedule II controlled substance, if filled, must be filled not later than 72 hours after the prescription is issued.  Id. at 47,002 (codified at 21 C.F.R. § 1306.13(b)(2)).

c.  Practitioner’s Partial Fill Request

A practitioner issuing a schedule II prescription who wants it to be partially filled must specify the quantity to be dispensed in each partial filling on the face of a written prescription, in the written record of an emergency oral prescription, or in the record of an electronic prescription.  After consulting with a pharmacist, a practitioner may also authorize a partial fill after the date the prescription was initially issued but the prescription cannot be filled later than 30 days after it was written.  The pharmacist must note the subsequent request.  All required information, except authorization for partial filling at a later date, must be included on the prescription with all other required elements at the time the practitioner signs the prescription.  For an emergency oral prescription, the prescribing practitioner must communicate the information to the pharmacist during the oral communication.  Id. (codified at 21 C.F.R. § 1306.13(b)(3)).

d.  Patient Request

A patient may also request that their prescription for a schedule II substance be partially filled.  A caregiver named in an adult patient’s medical power of attorney or a parent/legal guardian of a patient who is a minor under age 18, may also request that a prescription be partially filled.  If a practitioner has requested partial filling of a prescription, neither the patient nor one acting on behalf of a patient may request partial filling in an amount greater than what has been requested by the practitioner.  A request by or on behalf of a patient may be made in person; in writing if signed by the patient, caregiver, or parent/legal guardian; or by a phone call to the pharmacist from the patient, caregiver, or the parent/legal guardian.  Id. (codified at 21 C.F.R. § 1306.13(b)(4)).

e.  Recording Required Information

(1)  At the Request of a Prescriber

The pharmacist, upon partially filling a prescription at the request of the prescribing practitioner when the prescriber issued the prescription, must note the quantity dispensed on the face of the written prescription or in the pharmacy’s electronic records, in the written record or the pharmacy’s electronic records of the emergency oral prescription, or in the record of the electronic prescription.  When the pharmacist partially fills a prescription, after the prescriber has conveyed the request during consultation with a pharmacist, the pharmacist must note: “Authorized by Practitioner to Partial Fill,” practitioner’s name, discussion date and time, with the pharmacist’s initials.

In addition, for each partial filling whether requested by the prescriber on the prescription or during consultation with the pharmacist, the pharmacy must maintain a dispensing record of each dispensing date, name or initials of the individual dispensing, controlled substance name and dosage form, date filled, and quantity dispensed.  For electronic prescriptions, the quantity dispensed, date dispensed, and the dispenser must be linked to each electronic prescription record.  Id. (codified at 21 C.F.R. § 1306.13(b)(5)(i)).

(2)  Record at the Request of a Patient

For partially filling a prescription at the request of a patient or by a caregiver or parent/legal guardian, the pharmacist must note on the face of the written prescription or in the pharmacy’s electronic records, in the written record or the pharmacy’s electronic records of the emergency oral prescription, or in the record of the electronic prescription: “The [patient, parent or legal guardian of a minor patient, or caregiver of an adult patient named in a medical power of attorney] requested partial fill on [date such request was made]” and the quantity dispensed.

In addition, for each partial filling, the pharmacy must maintain a record that includes the date of each dispensing, the name or initials of the individual who dispensed the substance, controlled substance name and dosage form and date filled.  For electronic prescriptions, the quantity dispensed, date dispensed, and the dispenser must be linked to each electronic prescription record.  Id. (codified at 21 C.F.R. § 1306.13(b)(5)(ii)).

Effective Date

The final rule is effective on August 21, 2023, over seven years after CARA became law, five and a half years after the congressional letter urging DEA to quickly update its regulations and more than two and a half years after the proposed rule.

We need to talk about nitrosamines.  Recent industry comments submitted to FDA and new, international efforts against these nefarious, potentially carcinogenic organic compounds have the shifting state of regulation here back in the news.

What are nitrosamines?

Nitrosamines are chemicals that can form during drug manufacturing, known by their scientific names as N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), and N-Nitroso-N-methyl-4-aminobutyric acid (NMBA).  N-nitrosamine drug substance-related impurities (NDSRIs) are a pernicious form of nitrosamines that possess structural similarity to active pharmaceutical ingredients (API).

In addition to human drugs, processed foods that contain nitrates and nitrites such as cured meats and alcoholic beverages may contain nitrosamines.  OTC products are also susceptible; testing has revealed nitrosamines in heartburn remedies containing ranitidine.

The evolving upswing in NDSRI regulation is due to their link to cancer.  According to several studies, nitrosamines are a potentially potent carcinogen, depending on the length and depth of exposure.

What is FDA doing about NDRSIs?

The canary in the coal mine for nitrosamines was their 2018 appearance in blood pressure medications called sartans.  That discovery set off a global response, that included a series of recalls, a number of FDA-issued guidances, public advisements, mitigation strategies, and warnings, and generally created the current regulatory focus that CDER Director Patricia Cavazzoni has recently called a priority for CDER.

Aside from its publications, FDA is continuing to investigate the presence of NDSRIs in drug products, which may lead to more inspections or, at least, heightened expectations for industry.  The Agency is trying to meet manufacturers a point where testing standards on how to identify and control NDSRIs become more standardized.  Yet, currently, how the Agency plans to handle nitrosamines is unclear, which has led to the delay in approval of many drugs with no path forward for many of these companies.

As FDA and industry continue to grow their respective understandings about NDSRIs, more of them are turning up.  In May, FDA published a Federal Register request for “collaborative efforts to develop NDSRI data,” and said that as companies are implementing risk assessments recommended in FDA’s 2020 Nitrosamine Guidance, the Agency has unsurprisingly “received an increasing number of reports of NDSRIs that had formed in drug products across multiple drug classes.”  And FDA has had numerous with meetings with individual stakeholders seeking a better understanding of their approach to nitrosamines.  Seek, and ye shall find, so FDA hopes.

Upcoming Deadlines and New International Guidances

Responses to the May 2023 request for comments were due to FDA in early July, as FDA originally hoped that industry would collectively detail its best practices by October 1, 2023.  However, discovering NDSRI-producing gaps in manufacture is so tricky, FDA is considering giving industry an extension on its homework project.  When asked in the Federal Register Notice if a one-year extension would be useful, the response was a resounding “yes!”  Respondents also asked FDA to align its standards to the emerging new guidances and ongoing global efforts to root out NDSRIs.  In addition to the FDA’s efforts, agencies in the E.U., Canada, Australia, and Malaysia have also recently updated their policies and recommendations.

The global search for nitrosamines is rapidly becoming a complex game of Three-Dimensional Chess, as international regulators try to work together to find solutions, walking hand-in-hand with the industry they must all oversee.  Meanwhile, manufacturers are on the hunt to find their quarry before their customers do it for them.  We’ll report back as this complex regulatory structure continues to take shape.

Neither Jazz Pharmaceuticals nor Avadel CNS Pharmaceuticals has taken the battle of sodium oxybate—a drug approved to treat narcolepsy—lying down.  After suing each other in patent litigation and Avadel’s suit against FDA challenging the Agency’s authority to compel patent certifications, it’s Jazz’s turn to sue FDA.  This time, rather than use codes and patent certifications, the fight is over orphan drug exclusivity (“ODE”), with Jazz challenging FDA’s clinical superiority decision concerning sodium oxybate in the treatment of narcolepsy.  Specifically, FDA determined that Avadel’s Lumryz can “break” Jazz’s ODE because it is “clinically superior” based on Lumryz’s “major contribution to patient care,” rendering it not “the same drug” under the Orphan Drug Act.  With that decision, Jazz lost its ODE, allowing Avadel’s sodium oxybate product to compete with Jazz’s long before the expiration of the ODE covering Jazz’s most recent product, Xywav, in 2027.

Approximately six weeks after FDA approved Lumryz and issued its clinical superiority decision, Jazz filed a Complaint against FDA in the District Court of D.C. asking the Court to set aside FDA’s approval of Lumryz, alleging that FDA did not have statutory authority to use clinical superiority to break ODE and that FDA’s approval of Lumryz was arbitrary and capricious.  Like in the multitude of Orphan Drug Act cases preceding this one, Jazz alleges that FDA’s authority under the Orphan Drug Act was limited by the statutory language.  Its main argument is that Congress included only two exceptions to FDA’s restriction barring FDA from granting new approvals during the ODE period: the inability to provide sufficient quantities of a drug and consent from the ODE holder.  Though the Orphan Drug Act (now) includes a clinical superiority clause, Jazz argues that it is not a third exception to ODE.  Jazz also argues that, notwithstanding the language that instructs FDA to promulgate regulations implementing the clinical superiority provisions at 21 U.S.C. § 360cc(c), the statute does not permit FDA to promulgate regulations to use clinical superiority to break ODE.

Taking another stab at the plain language of the statute, Jazz argues that FDA does not have the authority to interpret the term “same drug” in its implementing regulations, as the term is not ambiguous.  Specifically, Jazz notes that the clinical superiority provisions in the Orphan Drug Act “does not authorize FDA to use a determination of clinical superiority as a basis to find that two drugs are not ‘the same drug’ for purposes of [ODE].”   In other words, Jazz states, the “‘different drug’ fiction is the linchpin of OOPD’s [ODE] analysis,” but the distinction between “same drug” based on clinical superiority is “inconsistent with the statute. . . .”

More specific to the facts of this case than the governing statute, Jazz argues that OOPD’s determination that Lumryz is clinically superior to Xywav is inconsistent with FDA’s regulations.  Essentially, Jazz argues that FDA’s determination is based on “greater efficacy,” which is not supported by the types of evidence FDA requires for such a determination—namely, head-to-head comparative studies.  Though FDA framed its clinical superiority decision as a Major Contribution to Patient Care (“MC-to-PC”) superiority finding, Jazz believes that it is actually a greater efficacy argument in disguise.  Because the premise of FDA’s determination—that not needing to awaken to take a second dose will provide medical benefits to narcolepsy patients by improving their sleep architecture and reducing disrupted or fragmented sleep—it must be a comparative effectiveness finding.  And, because comparative effectiveness claims must be supported by substantial evidence—one or more adequate and well-controlled clinical trials—FDA’s decision cannot stand as Avadel never conducted a comparative clinical trial of Xywav and Lumryz.  Thus, Jazz argues, there is no evidence that Lumryz is more effective than Xywav.

Perhaps the most notable assertion is that FDA deviated from Agency policy with respect to clinical superiority in determining that a drug need not be comparable in safety to break ODE on efficacy or MC-to-PC grounds.  In the ODE determination, FDA explained that “one drug can demonstrate a [MC-to-PC] over a previously approved drug even if the drug is not as effective or safe in every respect as the previously approved drug.”  Jazz believes that FDA precedent precludes that position and thus FDA departed from established policy, which FDA denied ever existed.  Jazz, however, cites to the preamble to the 2011 revised implementing regulations for the Orphan Drug Act, which states that MC-to-PC is a narrow category that is applicable and “meaningful only when the subsequent drug [product] provides safety or effectiveness comparable to the approved drug.”  Thus, Jazz contends that FDA has had a longstanding policy that comparable safety is necessary for an MC-to-PC clinical superiority finding.  Jazz points to several other examples of such a requirement, including Procysbi (the brief states that OOPD “observed that an ‘[i]nherent’ part of a major contribution to patient care finding was a threshold requirement that the new drug ‘would maintain a similar or improved adverse event profile and similar efficacy’”) and Ravicti (which, the brief states, FDA rejected the MC-to-PC request “because there was ‘a lack of objective evidence to support [the sponsor’s] claim that [Ravicti] would have comparable safety and effectiveness profiles as those of [the existing phenylbutyrate products].’”

Jazz also asserts that FDA failed to disclose or explain three prior memos in the Lumryz administrative record that found that Lumryz does not provide a MC-to-PC.  In rejecting Avadel’s argument for Priority Review, Jazz explains that FDA must have determined that Lumryz did not represent a “significant improvement” over existing therapies, including Xywav, and thus the clinical superiority determination conflicts with the Priority Review determination.  Jazz argues, essentially, that the change in position was the product of a pressure campaign within the Agency.  But rather than disclose these conflicting analyses, Jazz contends that FDA “conceal[ed] the existence” of these prior determinations.

Finally, Jazz argues that the ODE determination was arbitrary and capricious and an abuse of discretion because FDA ignored relevant scientific considerations.  FDA did not seek input from Jazz or Avadel, and neither had an opportunity to “comment on FDA’s thinking because FDA did not share it.”  Consequently, FDA made its determination without informed comments from the affected stakeholder, which Jazz says is “an indispensable feature of well-reasoned agency decisionmaking.”  The record also does not reflect consultation with the requisite experts, and FDA ignored some of the risks associated with elevated sodium intake, which is precisely the benefit provided by Xywav.  Additionally, Jazz says, FDA exaggerated the importance of once-nightly dosing because the idea that Lumryz allows narcolepsy patients to achieve “normal” sleep is scientifically baseless and unsupported.

Avadel has intervened as a Defendant, and neither FDA nor Avadel has yet to respond to the Complaint.  Our best guess is that FDA will argue that it has broad authority to interpret the provisions of the Orphan Drug Act and interpret “clinical superiority” and “same drug” as it sees fit.  Though FDA has a losing streak when it comes to the Orphan Drug Act, this case is a bit of an uphill battle for Jazz because Congress did include a clinical superiority provision in the Orphan Drug Act as of 2017, and FDA has broad discretion to categorize the basis of its clinical superiority decisions (i.e. greater efficacy, greater safety, or MC-to-PC), and even wider discretion to make MC-to-PC determinations, “which are evaluated on a case-by-case basis for each drug product.”  Such discretion is typically carte blanche for FDA in these types of cases, but again FDA’s track record with the Orphan Drug Act is pretty bleak.  We will keep on watching, as this case is one that might keep us up at night.