It was some time ago that we posted on what we though was “the Good” in an avalanche of FDA-related legislation that we sorted into three categories: the Good, the Bad, and the Ugly.  Our prior post took a look at a couple of bills that we thought fit Clint Eastwood’s role as “the Good” in the 1966 Italian epic spaghetti Western film, “The Good, the Bad and the Ugly”: the “Modernizing Therapeutic Equivalence Rating Determination Act” (S. 1463) and the “Simplifying the Generic Drug Application Process Act” (S. 1462).

We intended to quickly follow up that post with another post addressing a couple of bills that we thought fit the role of Lee Van Cleef as “the Bad,” and Eli Wallach as “the Ugly”: the “Prompt Approval of Safe Generic Drugs Act” (H.R. 2831) and the “Bringing Low-cost Options and Competition while Keeping Incentives for New Generics Act of 2021” (H.R. 2853), which is better known as the “BLOCKING Act of 2021.”  The BLOCKING Act in particular has drawn this blogger’s ire in prior blog posts (here, here, and here) and in Congressional testimony as antithetical to a primary goal of the Hatch-Waxman Amendments: getting high quality, low-cost generic drugs into the hands of consumers—fast.

Well, things got away from us due to other intervening priorities at the time and we never quite got to finishing up that post.  But Good things—and in this case Bad and Ugly (and we mean really Bad and really Ugly!) things too—come to those who wait!  But before we get back to “the Good” again, let’s take a look at “the Bad” and “the Ugly” . . . .

Earlier this week, FDA issued its Fiscal Year 2023 Budget Justification and related documents.  Among the various documents, a document titled “Executive Summary of FY 2023 Legislative Proposals” caught our attention.  It’s a list of 14 legislative proposals that FDA says would “better support Agency efforts to protect American consumers and patients, particularly during public health emergencies like the COVID-19 pandemic.”  The first of such legislative proposals targets 180-day generic drug exclusivity.  It says:

Amend the 180-Day Exclusivity Provisions to Encourage Timely Marketing of First Generics

In practice, 180-day patent challenge exclusivity is not operating as expected to encourage early generic entry, because this exclusivity is often “parked” by first applicants who either receive approval but do not begin marketing for extended periods of time following approval, or by first applicants who delay receiving final approval of their ANDAs for extended periods of time.  This proposal would substantially increase the likelihood that generic versions of patent-protected drugs will come into the market in a timely fashion, and that multiple versions of generic products will be approved quickly (leading to significant cost savings).  FDA is proposing to amend sections 505(j)(5)(B)(iv) and (D)(i)-(iii) of the FD&C Act, which govern the 180-day patent challenge exclusivity provisions, to specify that FDA can approve subsequent applications unless a first applicant begins commercial marketing of the drug, at which point approval of subsequent applications would be blocked by 180 days, ensuring that the exclusivity actually lasts 180 days (i.e., from the date of first commercial marketing by a first applicant until 180 days later) rather than for multiple years, as can occur under current law.

If the scent of this proposal smells vaguely familiar, it is.  It’s regime change!  It’s an effort to rework the current and longstanding ANDA Paragraph IV 180-day exclusivity incentive regime by replacing it with a new 180-day exclusivity regime modeled after the Competitive Generic Therapy (“CGT”) 180-day exclusivity regime created with the passage of the FDA Reauthorization Act of 2017 for drugs for which there is inadequate generic competition and for which there are no unexpired patents or exclusivities listed in the Orange Book at the time of original submission of an ANDA.

But before we delve into how a CGT-like exclusivity model would be misplaced and disastrous for a generic drug approval system based on patent challenges, it’s worth taking a quick look at the (false) premise of the proposal: “180-day patent challenge exclusivity is not operating as expected to encourage early generic entry, because this exclusivity is often ‘parked’ by first applicants who either receive approval but do not begin marketing for extended periods of time following approval, or by first applicants who delay receiving final approval of their ANDAs for extended periods of time.”  This sounds a bit dramatic . . . and it is.  It’s overly dramatic.

This blogger would expect FDA to point to the Agency’s findings in a November 2021 research report, titled “Marketing of First Generic Drugs Approved by U.S. FDA from January 2010 to June 2017” as evidence to support the premise above.  But that report—a not-too-thinly-veiled promotion piece for the BLOCKING Act and other legislation—is flawed.  In addition to stale data, data sets that may count the same product multiple times across different first applicants, and some selective data omissions, the report looks at the incorrect endpoint for its analysis: the time from ANDA approval to product launch.  However, the more accurate, reasonable, and meaningful endpoint for an analysis of the success of the current Paragraph IV 180-day exclusivity regime is the time between product launch and patent expiry.  That is, how much sooner does a generic drug come to market than it otherwise would without a patent challenge.  In other words, FDA’s analysis looks at the wrong end of the equation.  It’s not the time from ANDA approval to launch that is meaningful, but the time taken off of patent life allowing for an early launch that is meaningful.

Turning back to the legislative proposal, it says that FDA is proposing to amend FDC Act §§ 505(j)(5)(B)(iv) and (D)(i)-(iii)—the statutory provisions currently governing the qualification for and forfeiture of 180-day patent challenge exclusivity eligibility—“to specify that FDA can approve subsequent applications unless a first applicant begins commercial marketing of the drug, at which point approval of subsequent applications would be blocked by 180 days, ensuring that the exclusivity actually lasts 180 days (i.e., from the date of first commercial marketing by a first applicant until 180 days later) rather than for multiple years, as can occur under current law.”

That’s exactly how CGT 180-day exclusivity operates.  Indeed, here’s how FDA explains that exclusivity in guidance:

The 180-day CGT exclusivity period described under section 505(j)(5)(B)(v) of the FD&C Act is triggered by the “first commercial marketing of the competitive generic therapy (including the commercial marketing of the listed drug) by any first approved applicant.”  After this exclusivity is triggered, the 180-day period runs without interruption.

The FD&C Act also specifies that only an ANDA “for a drug that is the same as a competitive generic therapy for which any first approved applicant has commenced commercial marketing” can have its approval blocked until the 180-day CGT exclusivity period has been extinguished.  As such, once the first approved applicant has commenced commercial marketing, FDA is restricted from approving ANDAs for a drug that is the same as a CGT approved in the first approved applicant’s ANDA.  Therefore, FDA would not be restricted from approving other ANDAs covering a drug that is the same as the CGT prior to or after the approval of a first approved applicant’s ANDA for the CGT unless and until the first approved applicant has commenced commercial marketing and triggered the exclusivity period.  Likewise, the triggering of the CGT exclusivity period by the first approved applicant would not restrict other ANDA applicants that were approved prior to the trigger of such exclusivity from commercially marketing their products.

While the CGT 180-day exclusivity regime has operated quite well for drugs with inadequate generic competition and for which there are no unexpired patents or exclusivities listed in the Orange Book (as evidenced by the 130 CGT approvals thus far), using it as a blueprint for the approval of generic versions of brand-name drugs with dense patent thickets makes no sense.  What generic drug companies would be willing to invest millions of dollars in generic drug development and patent challenges for the potential of a hollow exclusivity incentive?  That is, because patent challenges often result in patent settlements that allow for generic competition (i.e., launch) prior to patent expiration, a CGT-like exclusivity regime that triggers the exclusivity only upon launch—which may occur years after ANDA approval—means that by the time launch occurs and exclusivity is triggered there will be no further approvals to which the exclusivity would apply.

Perhaps this is FDA’s way of trying to limit patent settlements.  But if you limit a generic drug manufacturer’s ability to settle cases, that manufacturer does not settle fewer cases, it submits fewer Paragraph IV ANDAs.  And fewer ANDAs means less, not more, generic drug competition.

The problem here, as with FDA’s November 2021 research report, is that the Agency is focused on the wrong endpoint.  FDA focuses on ANDA approvals instead of launches.  But more approvals does not necessarily translate into more launches.  Indeed, over time, a CGT-like exclusivity regime for Paragraph IV ANDAs may mean fewer ANDA approvals and launches.  And that ultimately means fewer choices for consumers and higher costs to the U.S. healthcare system.

If FDA and Congress were to focus on addressing the launch issue and not approvals alone, then a simple proposal that addresses this issue may be something along the lines of the following, which we call the “First Applicant Prime” exclusivity approach:

• If a “first applicant,” as currently defined under the statute, receives final approval within 45 months of ANDA submission or commercially markets more than 5 years before the expiration of the latest exclusivity-qualifying Paragraph IV Orange Book-listed patent, then that applicant would be eligible for 270 days of exclusivity rather than the current 180 days of exclusivity.
• If there is a group of first applicants and only a single first applicant meets the 45-month/5-year criteria above, then that applicant would be eligible for the first 90 days of exclusivity alone and other first applicants would get approval on day 91 of the 270-day exclusivity period.

This “First Applicant Prime” approach has several advantages, and is Clint Eastwood’s “the Good” in this post.  It incentivizes the submission of high-quality applications, which is what FDA wants.  There would be a competition to see who the “true” first applicant would be, meaning the first applicant who can both submit first and get approved first.  It could also address FDA’s concern about companies submitting ANDAs with non-compliant manufacturing facilities identified.  Separately, such a proposal could address the “25-tied ANDA first applicant situation” that is a problem with all New Chemical Entities.  That is, it would restore true generic drug exclusivity (to a one ANDA applicant for 90 days).  This approach could also help play a role in patent settlement agreements by potentially allowing companies to negotiate better agreements that fit into the 5-year criterion above.

Legislation has been proposed in Congress that would require FDA to regulate all contrast agents as drugs even though two courts determined that doing so clearly contradicts the plain language of the Federal Food Drug and Cosmetic Act (“FDC Act”).  Unless amended, the proposed legislation would reverse a Court determination that FDA had erroneously classified a frequently used contrast agent, barium sulfate, as a drug.  Our client Genus Medical Technologies, plaintiff in the cases decided by the courts and one of two distributors of barium sulfate in the United States, is seeking a revision to the proposed legislation.

By way of background, barium sulfate is ingested before some radiographic procedures studying the gastrointestinal tract. In 2017, FDA issued a warning letter to our client, Genus Medical Technologies, for distributing barium sulfate, which FDA characterized as an unapproved drug. After years of regulatory procedures and litigation in two federal courts (the District Court for the District of Columbia and the U.S. Court of Appeals for the D.C. Circuit), Genus’s position was vindicated: barium sulfate must be regulated as a medical device, not a drug, because the product achieves its primary intended purposes through its physical characteristics rather than through biological or metabolic action. The court decisions were subjects of prior blogposts (link here and here). After the government decided not to challenge the appellate court decision, FDA acceded to the decision and issued a Federal Register Notice discussing about how products would be transitioned if they had been classified as drugs inconsistent with the court decision (the Federal Register Notice was the subject of a blogpost linked here).

Congress is currently considering legislation that would revise statutes governing User Fees for drugs and medical devices, and a rider to that legislation has been proposed that would lump all contrast agents into the drug classification, resulting in huge expenses for Genus and other companies to market barium sulfate, which has been used safely and effectively for more than 120 years. The regulatory fees associated with introducing a drug, even a generic drug, to market, are around $400,000 in the first year (and $150,000 annually thereafter). By contrast, applications for marketing authorization for medical devices cost tens of thousands of dollars, followed by much more limited costs once the device is marketed.

Unless amended, the proposed legislation would isolate all contrast agents – including barium sulfate – from the well‐settled statutory and regulatory scheme that has, as the courts decided, dictated that products meeting the statutory definition of medical devices be classified and regulated as medical devices. Specifically, the FDC Act defines medical products by excluding from the definition of devices any products that achieve their primary intended purposes through chemical action in or on the body or through metabolic action, and has done so for about 50 years.

In initially trying to shoehorn barium sulfate into the drug category, FDA insisted that it needed to regulate all contrast agents as drugs based on a prior District Court decision (an argument the Courts rejected), and claimed that the change would be administratively convenient. Citing a case that says that FDA cannot regulate similar products differently, FDA decided to regulate all contrast agents as drugs while ignoring the fact that not all contrast agents are similar. Yet FDA insisted that all contrast agents needed to be regulated as drugs with no credible explanation for treating products that work differently as if they are the same. FDA appeared to be saying that its administrative convenience trumps the disparate safety and effectiveness concerns that arise in the context of drugs and devices.

While Genus would raise no objection to regulating the other products addressed by the legislation – radioactive drugs and OTC monograph drugs – as drugs, a simple amendment to the proposed legislation (linked to here) would limit the legislation’s effect on contrast agents to injectable contrast agents (this would cover, for example, iodine‐based solutions that are injected for computer tomography scans). Other contrast agents, like barium sulfate, which may have an oral, rectal, or dermal route of administration, would be classified and regulated as drugs or devices depending on the long‐standing statutory distinction: as drugs, if they achieve their primary intended purposes through chemical action in or on the body or through metabolic action.

While FDA argued in court that all contrast agents should be classified and regulated as drugs, there are important distinctions between those that achieve their primary intended effects through chemical or metabolic action, and those that do not. Radioactive drugs, and intravenously administered contrast agents, are capable of perfusing through or transforming tissues or cells. Consistent with an FDA Guidance, linked here, that elaborates on what chemical action means, these types of products are much more likely to be systemically distributed through the body, and could have results that are like those of pharmaceutical products. But, as FDA conceded, barium sulfate is not one of those products: the compound does not pass through tissue or transform cells. Instead, it absorbs X‐rays during radiographic procedures, resulting in contrast enhancement, which improves visualization of tissues.

Indeed, studies show that, under physiological conditions, barium sulfate passes through the gastrointestinal tract in an unchanged form.

We will keep you posted on the progress of Genus’s proposed amendment, and this legislation.

It’s not often that FDA issues an “Immediately in Effect Guidance,” but it’s not often that a case like Genus v. FDA comes along and upends twenty years of FDA practice.  Almost a year after the D.C. Circuit held that products that simultaneously meet both the FD&C Act’s general “drug” definition and its more-restrictive “device” definition must be classified and regulated as “devices,” FDA issued an “Immediately in Effect Guidance” to implement the decision as applied to ophthalmic products.  In the Guidance, entitled Certain Ophthalmic Products: Policy Regarding Compliance With 21 CFR Part 4, FDA explains that it can no longer regulate eye cups, eye droppers, and other dispensers intended for ophthalmic use as drugs when packaged with the ophthalmic drug with which they are intended to be used as a result of the Genus decision.  This is because the Genus decision no longer allows FDA to regulate devices as drugs, and, if the dispensers provided with the drug are devices, then the entire product as supplied must be considered a combination product.  Consequently, the Guidance announces that FDA will now “regulate these products as drug-led combination products composed of a drug constituent part that provides the primary mode of action and a device constituent part (an ophthalmic dispenser).

With the drug as the primary mode of action, the product will stay in the Center for Drug Evaluation and Research, but as a combination product, different requirements apply.  Manufacturing practices for combination drug-device products, as the relevant ophthalmic products will now be regulated, must consider both the cGMP requirements and QSRs, which may require additional steps or documentation.  Manufacturers may continue to use a cGMP-based operating system, but it must integrate each applicable provision of the device QSRs.

For the next 12 months, FDA will exercise enforcement discretion while impacted sponsors develop a Quality System that complies with 21 C.F.R. § 820.  Products subject to pending applications will be required to submit additional documentation for the combination product, including all facilities involved in the manufacturing of the device element.  Depending on the risk profile of the product, FDA may decide to evaluate new QS regulation requirements only during inspection following approval, may require a Pre-Approval Inspection, or may review quality information as part of the quality assessment of the combination product application.  However, “FDA anticipates that pre-approval assessment of [sponsor] compliance with any applicable QS regulation requirements generally will not need to include facility inspection against these requirements.”

As FDA attempts to implement Genus, industry should expect to see more products transitioning from drug to device and more guidances like this one to facilitate those transitions.  If you’re the sponsor of one of the products that Genus likely affects, be on the lookout for your own Immediately in Effect Guidance.

All companies dread the logistics, cost, and reputational harm associated with conducting a recall when necessary to remove or correct products in the field.  But the more prepared a company is for a potential recall, the less pressure it will feel when a situation necessitates taking action.  To clarify what preparations companies should take to more seamlessly manage a recall, on March 2, 2022, FDA published its Final Guidance Document on Initiation of Voluntary Recalls Under 21 CFR Part 7, Subpart C.

The Guidance provides detail on a recalling firm’s responsibilities, preparations, and communications and how the Agency can assist a firm with carrying out its recall responsibilities.  The Guidance applies to voluntary recalls of any food, drug intended for human and animal use, any cosmetic, biological, and tobacco product intended for human use, and any item subject to a quarantine regulation under 21 CFR part 1240.

What is a recall?  The guidance defines a recall as a firm’s removal or correction of a marketed product that the FDA considers to be in violation of the laws it administers and against which the Agency would initiate legal action, e.g., seizure.  But FDA notes that the same principles could apply to a company’s action even if it does not rise to the level of a recall, e.g., market withdrawals.  Almost all recalls are conducted on a voluntary basis by the manufacturer.  FDA maintains a database for recalls of FDA-regulated products based on information gathered from press releases and other public notices.

“It is critical for firms in a product distribution chain to be “recall ready.””

The Guidance emphasizes that firms need to be “recall ready.”  The Guidance provides practical guidelines for both firms and direct accounts.  For example, firms should identify and train appropriate personnel with recall-related responsibilities and establish a recall communications plan.  In recognition that hard copy communications are slower and more cumbersome, FDA recommends that firms use electronic communications, as they lay out the details of the electronic means here, to notify the public about recalls.  The Guidance highlights that the firm should identify specific points of contact for internal communications, communications with FDA, and communications to direct accounts or the public ahead of time and maintain draft templates for prompt communication.  FDA has model recall communication templates available here that firms can utilize.

Firms should identify any reporting requirements for distributed products and know in advance whether their product is associated with any legal or regulatory requirements to make a report to FDA.  Firms also need to maintain distribution records to facilitate identifying the direct accounts that received the recalled product by name, physical address where the product was delivered, and contact information.  Whether required or not, distribution records should be maintained by the recalling firm to locate the products being recalled.  Distribution records should be retained for a time period that exceeds the shelf life or expected life of the product and at least the length of time specified in applicable record retention regulations.  Product coding (e.g., unique device identifier for devices, product identifier for drug products) is helpful for the identification of the recalled products, but it may also help a recalling firm accurately limit the scope of recall.

The Guidance also provides recommended procedures for initiating a recall and performing actions related to initiating a recall.  For instance, the Agency recommends that firms prepare, maintain, and document written procedures for initiating a recall and performing actions related to initiating a recall.  This effort could help minimize delays created by uncertainty about what actions to take when a firm decides to initiate a recall, thereby reducing the amount of time a violative product is on the market.  An effective written procedure should carefully delineate (i) the plans of ceasing distribution, shipment, and/or sales of the affected product, (ii) a recall strategy, (iii) communication strategies to notify direct accounts about the product being recalled, including what should be done with respect to the recalled product, and (iv) a communication plan to notify the public about a product that presents a health hazard, when appropriate.

If there is an indication of a problem with a distributed product, FDA recommends that all firms should implement procedures to (i) identify indicators that there may be a problem with a distributed product, (ii) investigate the problem, (iii) make decisions and take action, and (iv) consult with FDA about the problem.  Of note, FDA emphasizes that the recalling firm does not need to wait for the completion of an investigation before it initiates a voluntary recall.  In addition, if a firm identifies any problem with a distributed product, it should not delay initiation of a voluntary recall pending FDA’s review of its recall strategy or recall communications.  The recalling firm should promptly issue a press release or other public notice.  The details of the procedural guidance regarding press releases and written recall notification letters can be found here.

Finally, the Guidance notes that FDA’s recall coordinators can work cooperatively with a recalling firm to facilitate the orderly and prompt removal of, or correction to, a violative product in the marketplace.  If a recalling firm is located in the United States, it can contact a Division Recall Coordinator within the FDA Office of Regulatory Affairs (ORA).  Note that for recalls of CBER-regulated products, firms should contact the CBER’s Direct Recall Classification (DRC) Program.  If a recalling firm is located outside of the United States and is recalling a product exported to the United States, then the recalling firm should contact ORA Headquarters.

Most FDA-regulated entities have an established SOP that governs the evaluation, decision, notification, and process for conducting a recall.  Although the guidance does not impose new requirements, it provides detail on what these SOPs should address and encourages companies to begin the recall process even if FDA has not agreed with the recall plan:

“A recalling firm need not delay initiation of a voluntary recall pending FDA’s review of its recall strategy or recall communications.”

We recommend companies take another look at their existing SOPs to ensure they would satisfy FDA’s expectations set forth in this guidance.

The saying “Hope for the best, prepare for the worst” applies to recalls.  Manufacturers hope for the best that their products are going to be used safely and effectively for patients and consumers.  At the same time, they should prepare for the worst by being “recall ready.”

The Centers for Disease Control and Prevention (“CDC”) issued a voluntary practice guideline on opioid prescribing for clinicians treating chronic pain five years ago.  (We blogged on the final 2016 guideline here on March 17, 2016).  On February 10th, the agency published a comprehensive proposal to update the guideline.  Proposed 2022 CDC Clinical Practice Guideline for Prescribing Opioids, 87 Fed. Reg. 7,838 (Feb. 10, 2022); Dowell, Deborah, MD., et al, CDC Clinical Practice Guideline for Prescribing Opioids-United States, 2022, CDC.  As explained more fully below, CDC concedes that states, insurers, pharmacies and pharmacy benefit managers have implemented laws, regulations and policies that have misapplied the 2016 guideline.  Some have interpreted the 2016 guideline as requiring a hard, daily opioid dosage of 50-90 morphine milligram equivalent (“MMEs”) and opioid treatment duration of three to seven days.  CDC’s proposed 2022 practice guideline takes a more flexible, patient-specific approach relying on clinicians’ judgment rather than applying “inflexible standards of care across patient populations.”  Proposed 2022 CDC Practice Guideline, 7,839.

We believe the proposed 2022 guideline provides much needed clarification of CDC’s recommendations for both practitioners and regulators.  We remain concerned, however, that the “misapplication” of the 2016 guideline and the same risk for the 2022 proposed guideline, may continue to adversely affect patient care.

Purpose of the Proposed Guideline

CDC intends the proposed guideline to improve communication between clinicians and patients about the risks and benefits of pain treatment that includes opioid therapy; improve the safety and effectiveness of pain treatment with an eye towards improved function and patient quality of life; and reduce opioid use disorder, overdose and death associated with long-term opioid therapy.  Id.

2016 Guideline

As CDC notes in the 2022 proposed guideline, the 2016 guideline provided twelve recommendations for primary care clinicians who prescribe opioids for chronic pain in outpatient settings.  CDC Clinical Practice Guideline, 10.  The 2016 guideline recommendations were based on systematic review of the best available evidence with input from experts, the public and an advisory committee, noting that the goals were to ensure clinicians and patients consider safer, more effective pain treatment, improve patient outcomes with reduced pain and improved function and reduce opioid use disorder, overdose, or other adverse events.  Id. at 11.  The guideline impacted the continuing decline of total numbers of opioid prescriptions issued in the U.S., and although not an intention, also impacted laws, regulations and policies.  Id.  Over half the states enacted legislation limiting initial opioid prescriptions for acute pain to seven days or less while insurers, pharmacy benefit managers and pharmacies enacted similar policies.  Id.  CDC emphasizes that while some of the initiatives had positive results for some patients, guideline “recommendations are voluntary and intended to be flexible in support, not supplant, individualized, patient-centered care.”  Id. at 12.  CDC notes with “particular concern” that some policies purportedly from the 2016 guideline “have, in fact, been notably inconsistent” with the guideline “and have gone well beyond its clinical recommendations.”  Id.  CDC notes that misapplication of recommendations have even extended to cancer and palliative patients, opioid tapering and abrupt discontinuation without patient collaboration, rigid application of opioid dosage thresholds, duration limits, and patient dismissals.  Id.  Misapplication of the guideline has “contributed to patient harm, including untreated and undertreatment of pain, serious withdrawal symptoms, worsening pain outcomes, psychological distress, overdose, and suicidal ideation and behavior.”  Id.

The Proposed Guideline

From our perspective, given misapplication of the 2016 guideline, we begin with what the proposed guideline is not rather than what it is.  The proposed guideline is not “[a] replacement for clinical judgment or individualized, person-centered care” and its recommendations are not inflexible standards of patient care.  Id. at 2.  The guideline is neither law, regulation nor policy.  The guideline is not applicable to the treatment of pain related to sickle cell disease, or palliative or end-of-life care.  Id.

According to the CDC, the proposed guideline is a clinical tool meant “to improve communication between clinicians and patients, empowering them to make more informed, person-centered decisions related to pain care together.”  Id.  It is intended for clinicians (primary care, physicians, nurse practitioners, physician assistants, and oral health practitioners) who provide pain care to outpatients aged 18 years or older with acute pain (lasting less than a month), subacute pain (lasting 1-3 months) or chronic pain (lasting more than 3 months) in outpatient settings.  Recommendations do not apply to inpatient care during hospitalization, emergency department or other observed settings, but do apply to prescribing for pain management upon discharge.  Id. at 3.

Methodology

CDC developed the proposed practice guideline using Grading of Recommendations Assessment, Development, and Evaluation (“GRADE”) framework.  Id.  Recommendations are based on a review of available scientific evidence; benefits and harms; patients’, caregivers’, and clinicians’ values and preferences; and resource allocation (such as costs to patients or health systems, including clinician time).  CDC also obtained input from conversations with patients, caregivers, and clinicians, through Federal Register notices and comments from the public, peer reviewers, and an advisory committee.  Id.

Recommendations

The proposed guideline generally follows the organization of the 2016 guideline, listing recommendations within four general areas: (1) determining whether to initiate opioids for pain; (2) opioid selection and dosage; (3) opioid duration and follow-up; and (4) assessing risk and addressing potential harms of opioid use. Id. at 31.

Note:  Given nuances in language, we quote each recommendation verbatim in bold text below and include certain implementation considerations for each recommendation though not verbatim.  To fully understand and benefit from the proposed rationale and explanation of the guideline, clinicians and others should read the proposed recommendations and implementation considerations in their entirety.

 (a)  Determining Whether to Initiate Opioids for Pain

Recommendation 1.

Nonopioid therapies are effective for many common types of acute pain.  Clinicians should only consider opioid therapy for acute pain if benefits are anticipated to outweigh risks to the patient.  Id. at 64.

• Opioid therapy plays an important role in treating acute pain related to severe traumatic injuries such as crush injuries and burns, invasive surgeries with moderate to severe postoperative pain, and other severe acute pain when non-steroidal anti-inflammatory drugs (“NSAIDs”) and other therapies are contraindicated or ineffective. Opioids should not be first-line therapy for acute pain conditions, like low back and neck pain, pain related to musculoskeletal injuries including sprains, strains, tendonitis and bursitis, pain related to minor surgeries associated with minimal tissue injury and mild postoperative pain (for example, dental extraction), dental pain, kidney stones, and headaches including episodic migraines.
• Clinicians should maximize use of nonopioid pharmacologic therapies such as NSAIDs or acetaminophen and nonpharmacologic therapies that include ice, heat, elevation, rest, immobilization and exercise for specific conditions. They should continue such therapies as needed after opioid therapy is discontinued.
• Clinicians should prescribe opioids on an “as needed” basis rather than on a scheduled basis (e.g., “one tablet every 4 hours”) and encourage tapering if opioids are to be taken around the clock for more than a few days.

Recommendation 2.  

Nonopioid therapies are preferred for subacute and chronic pain.  Clinicians should only consider initiating opioid therapy if expected benefits for pain and function are anticipated to outweigh risks to the patient.  Before starting opioid therapy for subacute or chronic pain, clinicians should discuss with patients the known risks and realistic benefits of opioid therapy, should work with patients to establish treatment goals for pain and function, and should consider how opioid therapy will be discontinued if benefits do not outweigh risks.  Id. at 75.

• Clinicians should use noninvasive, nonpharmacologic approaches to help manage chronic pain.

(b)  Opioid Selection and Dosage

Recommendation 3.  

When starting opioid therapy for acute, subacute, or chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long-acting (“ER/LA”) opioids.  Id. at 91.

• ER/LA opioids should be “reserved for severe, continuous pain.”

Recommendation 4.  

When opioids are initiated for opioid-naïve patients with acute, subacute, or chronic pain, clinicians should prescribe the lowest dosage to achieve expected effects.  If opioids are continued for subacute or chronic pain, clinicians should use caution when prescribing opioids at any dosage, should carefully evaluate individual benefits and risks when considering increasing dosage, and should avoid increasing dosage above levels likely to yield diminishing returns in benefits relative to risks to patients.  Id. at 95-96.

• “[B]efore increasing total opioid dosage to ≥ 50 MME/day, clinicians should pause and carefully reassess evidence of individual benefits and risks. If a decision is made to increase dosage, clinicians should use caution and increase dosage by the smallest practical amount.”
• “The recommendations related to opioid dosages are not intended to be used as an inflexible, rigid standard of care; rather, they are intended to be guideposts to help inform clinician-patient decision making. Further, these recommendations apply specifically to starting opioids or to increasing opioid dosages, and a different set of benefits and risks applies to reducing opioid dosages.”

Recommendation 5.

For patients already receiving higher opioid dosages, clinicians should carefully weigh benefits and risks and exercise care when reducing or continuing opioid dosage.  If risks outweigh benefits of continued opioid therapy, clinicians should optimize other therapies and work closely with patients to gradually taper to lower dosages or, if warranted based on the individual clinical circumstances of the patient, to appropriately taper and discontinue opioids.  Unless there are indications of a life-threatening issue, such as warning signs of impending overdose, e.g., confusion, sedation, or slurred speech, opioid therapy should not be discontinued abruptly, and clinicians should not abruptly or rapidly reduce opioid dosages from higher dosages.  Id. at 101. 

• When risks outweigh benefits of continued opioid therapy, clinicians should consider reducing opioid dosage, or tapering and discontinuing opioid therapy, collaborate with patients prior to initiating changes, how quickly tapering will occur and when tapering pauses may be warranted.
• Clinicians should follow up at least monthly with patients engaged in opioid tapering.
• Payers, health systems, and state medical boards should not set rigid standards related to opioid dose or opioid therapy duration, and should ensure that policies not result in rapid tapers or abrupt discontinuation of opioids and do not penalize clinicians for accepting chronic pain patients using prescribed opioids, including high doses. Id. at 103.

(c)  Opioid Duration and Follow-Up

Recommendation 6.

When opioids are needed for acute pain, clinicians should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids.  Id. at 115.

• Clinicians can often manage nontraumatic, nonsurgical acute pain without opioids.
• A few days or less are often sufficient when opioids are needed for nontraumatic, nonsurgical pain. “However, durations should be individualized based on the clinical circumstances of the specific patient.”
• Clinicians should evaluate patients continuing to receive opioids for acute pain at least every 2 weeks.
• Clinicians should refer to recommendations on subacute and chronic pain for follow-up (Recommendation 7) and tapering (Recommendation 5) for treating patients receiving opioids for a month or longer.

Recommendation 7.  

Clinicians should evaluate benefits and risks with patients within 1 to 4 weeks of starting opioid therapy for subacute or chronic pain or of dose escalation.  Clinicians should evaluate benefits and risks of continued therapy with patients every 3 months or more frequently.  Id. at 120.

(d)  Assessing Risk and Addressing Potential Harms of Opioid Use

Recommendation 8.  

Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk for opioid-related harms and discuss with patients.  Clinicians should work with patients to incorporate into the management plan strategies to mitigate risk, including offering naloxone when factors that increase risk for opioid overdose are present.  Id. at 125.

• Clinicians should offer naloxone when prescribing opioids to patients at increased risk for overdose including patients with a history of overdose, substance use disorder or sleep-disordered breathing. It also includes patients who take higher dosages of opioids, for example 50 MME/day or more, patients taking benzodiazepines with opioids and patients at risk for returning to a high dose who have lost tolerance.

Recommendation 9.  

When prescribing initial opioid therapy for acute, subacute, or chronic pain, and periodically during opioid therapy for chronic pain, clinicians should review the patient’s history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or combinations that put the patient at high risk for overdose.  Id. at 135.

• Clinicians ideally should review PDMP data before every opioid prescription for acute, subacute, or chronic pain in all jurisdictions where available and practicable.
• For long-term opioid therapy, clinicians should review PDMP data before an initial opioid prescription and at least every 3 months thereafter.
• Clinicians should not dismiss patients on the basis of PDMP information.

Recommendation 10.

When prescribing opioids for subacute or chronic pain, clinicians should consider toxicology testing to assess for prescribed medications as well as other prescribed and non-prescribed controlled substances.  Id. at 139.

• Clinicians should not dismiss patients based on toxicology test results.

Recommendation 11.

Clinicians should use extreme caution when prescribing opioid pain medication and benzodiazepines concurrently and consider whether benefits outweigh risks of concurrent prescribing of opioids and other central nervous system depressants.  Id. at 145.

• There are circumstances when it is appropriate to prescribe opioids to a patient who is prescribed benzodiazepines, for example a patient in acute pain who is taking long-term, low-dose benzodiazepines. Clinicians should consider whether benefits outweigh risks of concurrent use of opioids with other central nervous system depressants such as muscle relaxants, non-benzodiazepine sedative hypnotics and potentially sedating anticonvulsant medications like gabapentin and pregabalin.

Recommendation 12.

Clinicians should offer or arrange treatment with medication for patients with opioid use disorder.  Id. at 149. 

• Clinicians should not dismiss patients due to opioid use disorder.

CDC’s Conclusion

CDC observes that “[a] central tenet of the clinical practice guideline is that acute, subacute, and chronic pain needs to be appropriately and effectively treated independent of whether opioids are part of a treatment regimen.”  Id. at 162.  CDC notes that this is achieved by nonpharmacologic or pharmacologic treatments that “maximize patient safety and optimize outcomes in pain, function, and quality of life.”  Id.  CDC emphasizes the need for care “to be individualized and person-centered.”  Id.  CDC warns that the guideline not be misapplied beyond its intended use, and policies derived from it not result in unintended consequences for patients, warning that inflexibility on opioid dose and duration, discontinuing or dismissing patients, rapidly tapering patients who may be stable on higher doses without collaboration, and applying to cancer, sickle cell, or end receiving end-of-life patients.  Id. at 164.

HPM Comment

Clinicians face difficult decisions in deciding whether to prescribe opioids, the dosage to prescribe and duration of treatment for acute, subacute and chronic pain patients.  As we stated at the time, we found the 2016 guideline to be reasonable.  Its recommendations constituted sound medical practice applicable to prescribing opioids, and non-opioid controlled and non-controlled medication.  However, while the 2016 guideline helped clarify legitimate medical purpose standards for prescribing and dispensing controlled substances for clinicians, pharmacies and regulators, we cautioned that legitimate medical treatment may conflict with strict adherence opioid therapy of more than seven days or in excess of 50-90 MMEs daily.  We remain concerned.

CDC stressed that the 2016 guideline was “voluntary, rather than prescriptive” and advised clinicians to “consider the circumstances and unique needs of each patient when providing care.”  CDC Guideline for Prescribing Opioids for Chronic Pain-United States, 2016, 2.  CDC now  acknowledges that states, insurers, pharmacies and pharmacy benefit managers implemented laws, regulations and policies that have misapplied the 2016 guideline.  They misapplied the recommendations as inflexible CDC mandates to the chronic pain patient population and inappropriately applied them to cancer, palliative and end-of-life patients.

We questioned then as we question now whether the Drug Enforcement Administration and state regulators will similarly “misapply” the proposed guideline and pursue enforcement action against practitioners who do not strictly comply with the proposed guideline.  Clinicians and regulators must strive to apply the 2016 and proposed guideline in the manner in which CDC intended so that patients receive the appropriate opioid treatment their legitimate condition requires.  So both the regulators and the regulated industry must recognize the intent of the 2022 proposed  guideline and apply the recommendations appropriately.  Otherwise, legitimate patients will remain at risk for nontreatment or undertreatment of acute, subacute or chronic pain.

Public Comments

The public can comment on the proposed guideline and recommendations until April 11, 2022.  We urge all interested parties to weigh in.

Hyman, Phelps & McNamara, P.C. is pleased to announce that Sophia Gaulkin will be presenting and speaking on an expert panel at Informa Connect’s Drug Pricing Transparency Congress, which is being held virtually and in-person in Philadelphia on March 28-29, 2022.

Ms. Gaulkin’s presentation on Changes for 2022 Drug Price Transparency Reporting will outline new state drug pricing transparency reporting requirements that have taken effect in 2022, examine updated laws in Maine, Nevada, and Texas, and consider trends and what to expect in state-level legislative efforts regarding drug pricing going forward.

In a later session, she will join a panel of experts to answer questions about developments in drug pricing transparency requirements and provide practical advice to implementing the state requirements.

This hybrid event brings together experts working in or with the pharmaceutical and biotechnology industries to share best practices and discuss how current and future drug pricing transparency regulations will impact commercialization, reimbursement, pricing, and compliance practices.

FDA Law Blog readers are offered a discount of 10% off the registration price.  The discount code is 22HYMAN10.  You can access conference information and register for the event here.

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

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

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

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

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

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

Devices Marketed Under an Enforcement Policy

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

The Transition Period will consist of three phases:

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

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

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

Devices Marketed Under an EUA

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

To this end, this Guidance is intended to:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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