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  • ACI’s 17th Annual Paragraph IV Disputes Conference (In-Person and Livestream)

    The American Conference Institute (“ACI”) is hosting its 17th Annual Paragraph IV Disputes Conference in New York (and livestream) from April 26-27, 2022 (Eastern Daylight Time).  Over the course of two days, this event will provide impactful and practical programming all geared towards assessing the implications and imprimaturs of court cases, legislation, and industry behaviors which affect the patent endgame and the pursuit of related profits.

    2022 agenda highlights include:

    • The Viability of Written Description as a Compelling Invalidity Defense
    • Clarity On What Satisfies Section 1400(b)’s Venue Requirements in the Hatch-Waxman Context
    • Whether a Skinny Label Alone Is Enough to Preclude Induced Infringement Allegations
    • The Latest FDA Initiatives Impacting Pharmaceutical Patents -Restrictions on Reverse-Payment Settlements

    Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will be speaking at a session titled “Brand and Generic Perspectives on the Latest FDA Initiatives Impacting Pharmaceutical Patents.”

    FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: D10-896-896EX04. You can access the conference brochure and sign up for the event here. We look forward to “seeing you at the conference.”

    More of a Bad Thing? Thoughts on FDA’s Proposal to Extend the FDR Process to Withdrawals of Accelerated Approvals

    On March 28, 2022, FDA transmitted its justification to Congress for its Fiscal Year 2023 budget.  This document contains a number of legislative proposals, including three proposed amendments to the accelerated approval statutory provisions in section 506(c) of the Federal Food, Drug, and Cosmetic Act.  The proposal to “revise 506(c)(3) so that FDA can follow its dispute resolution [(FDR)] procedures for drug applications when withdrawing a drug product’s accelerated approval” caught our attention in light of our extensive experience with the FDR process.

    Consistent with due process considerations, the administrative hearing process that is currently used for the withdrawal of a drug approved via accelerated approval requires the Agency to provide the administrative record to the applicant.  In contrast, FDA’s custom in an FDR is not to disclose the administrative record or even a review division’s underlying reviews to the applicant.  As previously noted, this lack of transparency significantly hampers an applicant’s ability to present a winning case.  Certainly FDA’s application of this unwarranted lack of transparency shouldn’t be extended to now also affect the withdrawal procedures for an accelerated approval.

    We would instead hope to see the Agency begin to provide the administrative record and/or the medical/statistical reviews (depending on the context) for all FDRs, such as those appealing complete response actions (CRs).  The importance to sponsors and applicants of obtaining the division’s reviews of their applications is underscored by the recent lawsuit filed by Vanda Pharmaceuticals, Inc. (Vanda) to obtain the medical and scientific reviews underlying a CR letter it received for a supplement to an approved NDA.  See Vanda Pharmaceuticals, Inc. v. Food and Drug Administration, No. 1:22-cv-0938 (D.D.C. Apr. 6, 2022).  As Vanda noted in its complaint, without those underlying reviews, it cannot know the detailed basis for FDA’s decision not to approve its supplement and whether FDA’s decision was the result of a factual error or whether or how Vanda should adapt its development program.

    A key to efficient drug development is transparency.  When FDA decides to take an action – be it to withdraw a drug approved via accelerated approval or to issue a CR letter – disclosure to the affected party of the detailed reasons for the decision is crucial.  If Congress were to give FDA the authority to follow its FDR procedures for the withdrawal of an accelerated approval, it is imperative that the FDR procedures specifically require that FDA provide the administrative record to the applicant.  Otherwise, the applicant will be deprived of the process it is due, the FDA deciding official will not have the benefit of a fulsome debate, and patients with serious conditions may unnecessarily lose access to a safe and effective drug when no other therapy is available.

    Estimating Risk Associated with Medical Device Malfunctions: FDA’s Warning letter to Medtronic Highlights an Under Appreciated Potential Source of Error in the Estimation

    One of the more complex areas of device regulation is the management of risks associated with malfunctions reported from the field.  A critical task in this situation is for a firm to estimate the risk posed by the issue as accurately as possible.  This estimation of risk is important because it drives both decision making and regulatory compliance.

    A December 2021 warning letter to Medtronic, Inc. (Medtronic Warning Letter) provides an important reminder from FDA as to the correct estimation of risk associated with malfunctions.  The warning letter is long and covers many issues associated with the management of risks associated with malfunctions and complying with the complex web of regulations potentially applicable when malfunctions occur.

    Our focus, however, is on FDA’s criticism of Medtronic’s calculation of risk.  As background, Medtronic manufactures the MiniMed 600 series insulin infusion pumps.   During an inspection, FDA learned that Medtronic had opened a CAPA to address complaints of damaged retainer rings in these pumps (more than 74,000 between June 2016 and November 2019, with more than 57,000 reported to FDA as MDRs).  An internal investigation apparently had determined the device failures were caused by a malfunction involving the retainer ring.  According to FDA, a “damaged retainer ring may result in the over or under-delivery of insulin, which may lead to hypoglycemia or hyperglycemia.”

    In Medtronic’s quality system, as FDA notes:  “Your CAPA System procedure (SOP114-01DOC, Effective Date 5/19/2015, Version L) requires your firm to determine whether distributed product is potentially affected by a nonconformance and to conduct additional risk assessment activities per the Product Risk Management Process (SOP104- 08, Version W).”  FDA acknowledged that Medtronic followed the procedures but disagreed with the assessment of risk.

    Specifically, FDA criticized the risk calculation formula because it used the total shipment of affected product, which “underestimates the probability of occurrence because the number of products shipped includes devices not in use by patients (e.g., devices shipped to distributors that have not yet been distributed to customers).”

    Is FDA’s criticism valid?  After all, it is fairly common for firms to use shipment (or sales) as a denominator in a risk estimate.  It would seem, though, that FDA is right that total shipments of affected product could potentially overstate the number in actual use by patients, thereby underestimating the risk.  Of course, it would not always be true that there is a significant gap between the number of medical devices shipped and the number in actual use.  Some products may move with high velocity to patient use.  Nonetheless, firms would be wise to at least consider the issue when calculating risk.

    One last nuance:  As FDA noted toward the end of the warning letter, there was such a large gap between the number shipped versus the number in use (according to Medtronic’s own calculation) that the number held by distributors might not account for the entire gap.  Whether true or not in that case, the lesson here is that an estimate of the delay in reaching the patient should consider all possibly contributing factors and not simply time in possession of distributors.  For instance, some products could remain in boxes in hospital inventory for an extended period.

    In a nutshell, when estimating risk of harm from a malfunction, be sure to consider whether the total shipments of affected product is an adequate proxy for the total number in use!  Firms should update their procedures to include this consideration.

    Categories: Medical Devices

    James R. Phelps: 1938 – 2022

    With great sadness, we announce that our firm’s co-founder, leader, colleague and friend, Jim Phelps passed away on April 2, 2022, at the age of 83. Jim is survived by Sophia, his wife of 57 years, his three sons and their wives, Evan and Nicola, Morgan and Mijiko, Michael and Kimberley, and 9 grandchildren.

    Jim established the firm with Paul Hyman and Bob Dormer on March 17, 1980. He maintained an active practice until our 30th Anniversary on March 17, 2010, when he took senior counsel status. Although he then split his time between Great Falls, VA and Fort Myers, FL, and spent as much time as he could on the golf course, he was always available to help when needed.

    Jim was an acknowledged leader of the food and drug bar, admired by his colleagues, clients, fellow practitioners and even his opponents (despite his tendency sometimes to intimidate them). Jim was an exceptional litigator, a great teacher and an inspiration to all of us in the firm. He had a great ability to identify key issues and to develop creative and effective solutions to them. He was always polite, civil and correct in his demeanor and actions no matter how tense or serious the matter. Jim was so respected as a food and drug lawyer that, for many years after he retired, he routinely was listed among the best lawyers in the field.

    A graduate of the University of Cincinnati and its law school, after service in the U.S. Army, Jim began his legal career in 1965 as a Trial Attorney with the Office of General Counsel, Food and Drug Division, of the U.S. Department of Health, Education and Welfare (now the FDA’s Office of Chief Counsel). In 1967, Jim became an Assistant U.S. Attorney for the District of Columbia. He left that office in 1969 to join Burditt, Calkins & Wiley, a leading food & drug law firm in Chicago, where he remained until 1977, when he became vice president and general counsel of the pharmaceutical company G.D. Searle, which had a particular need for Jim’s litigation and broad FDA regulatory experience. He left Searle to join the other founders of our firm.

    Jim’s practice extended to all areas of the food and drug bar. Jim also advised clients on matters involving controlled substances domestically and internationally, handling matters before the World Health Organization, the International Narcotics Control Board and the U.N. Commission on Narcotic Drugs.

    Jim was a member of the U.S. National Commission for the United Nations Educational, Scientific and Cultural Organization from 1983-1985. He also was General Counsel of the Regulatory Affairs Professionals Society from 1982 to 2002.

    Jim was a great companion and friend. He was proud of his roots in East Bernstadt, Kentucky, and liked to tease the mostly East Coast “johnnies” he worked with about their limited horizons. Jim was a great competitor in all aspects of life, from the courtroom to the squash court, the golf course and even the card table. His ability and intelligence supported his success in all these fields. He also had extraordinary eyesight, which he used to produce fantastic photographs of birds and other wildlife during his retirement. Some of these photos are proudly hung on the walls of our firm.

    It is no exaggeration to say that Jim was the soul of the firm. Those of us who were privileged to know Jim are pledged to carry forward his commitment to the law and to the firm he helped start.

    We extend our heartfelt sympathy to his wonderful wife, Sophia, and to his entire family. Jim will be greatly missed.

    Categories: Uncategorized

    Not An April Fool’s Joke: California BOP Establishes Loss Reporting Thresholds

    Effective April 1, 2022, California Board of Pharmacy (“BOP”) regulations no longer require reporting every single missing tablet or dosage form.  Instead, the amended loss regulations establish thresholds which will reduce the number of reports received by the California BOP, and in our opinion, creates a more meaningful and substantive reporting system.  The joke appeared to be on the BOP because reporting every loss has created “an administrative burden for both the licensee and the Board to prepare, review, and document the reported loss.”  Reporting Drug Loss, Cal. Regulatory Notice Register, June 4, 2021, 727.  The Board is not joking now, for several reasons, including reducing the estimated number of an estimated 10,000 loss reports per year to 6,667 per year, and more closely aligning with federal requirements, has fine-tuned its loss reporting requirements.  Id.

    The prior BOP regulations became effective April 1, 2018, requiring owners to report the loss of any controlled substance, even single doses, to the Board.  Id. § 1715.6(a)(1).  The new regulations, require reporting a loss in part if it hits one of several triggers including if it meets or exceeds established aggregate quantity thresholds within the prior year.

    1. Owners must report the following dosage units meeting or exceeding these thresholds:
    • Tablets, capsules or other medication-99 dosage units;
    • Single-dose injectables, lozenges, films such as oral, buccal and sublingual,
      suppositories or patches-10 dosage units; and
    • Injectable multidose injectables, infusion medications or unidentified other multi-dose unit-two or more multi-dose vials, infusion bags or other containers. Cal. Code Regs. § 1715.6(a)(1).
    1. Owners must also report all losses caused by employee theft, diversion or self-use within 14 days of discovery. Id. at § 1715.6(a)(2); Cal. Business and Professions Code, 4104(c).  (Federal regulations enforced by the Drug Enforcement Administration (“DEA”) require reporting all thefts, not just those by employees.  21 C.F.R. § 1301.76(b)).  Board inspectors must investigate all employee thefts “to ensure that no additional controlled substances have been diverted and that appropriate action can be taken against the subject employee’s license to restrict their access to controlled substance in the future.”  Initial Statement of Reasons, Reporting Drug Loss, California Board of Pharmacy, March 24, 2021, 3.
    2. Also similar to federal requirements, owners must report any “significant loss” determined by the Pharmacist-In-Charge (“PIC”), including though not limited to losses “deemed significant relative to the dispensing volume of the pharmacy.” Id. at § 1715.6(a)(3).
    3. Loss reports must specify loss details including controlled substance name, quantity and strength, and date of discovery. Id. at § 1715.6(b).

    No one should be surprised that requiring any controlled substance loss, including a single tablet, to be reported, has resulted in thousands of meaningless reports of de minimis losses.  The new regulations seek  “to eliminate this excessive reporting and more closely align the Board’s regulation with the federal regulation by providing increased clarity with respect to the quantities of controlled substance losses that must be reported.”  Initial Statement of Reasons, Reporting Drug Loss, California Board of Pharmacy, March 24, 2021, 1.

    That the Board has established a minimum aggregate reporting threshold quantities to resolve ambiguity is laudable.  We note that DEA has provided the following factors as to what it considers may be a significant loss:

    1. The actual quantity lost relative to the business type;
    2. The controlled substances lost;
    3. Whether the loss can be associated with access by specific individuals, or if the loss can be attributed to unique activities that take place involving the controlled substances;
    4. A pattern of losses over a specific time period, whether the losses appear to be random, and the results of efforts taken to resolve the losses; and, if known,
    5. Whether the controlled substances are likely candidates for diversion and
    6. Local trends and other indicators of the diversion potential of the controlled substances.  Id.

    Also, DEA regulations require pharmacies and other registrants to report all thefts, but only losses that are significant, in writing within one business day of discovery, and to complete and submit a DEA Form 106.  21 C.F.R. § 1301.76(b).

    One difficulty with the new Board requirements involves how pharmacies maintain a running total of losses over a year in order to report if the aggregate total hits or exceeds the quantity threshold.  In addition, the new regulation does not totally eliminate ambiguity about “significant loss” because a PIC, using their professional judgment, must report if they determine it “significant” relative to how much the pharmacy dispenses.  So even if losses do not hit a threshold, a pharmacy must report a loss deemed significant.  We wonder how often the Board is going to second-guess a PIC regarding failure to report what it considers a significant loss.

    It is noteworthy in reading the administrative record for the new regulations that the Board considered the loss of one tablet falling on the floor requiring disposal to be a reportable.  The Board presumably requires dosage units meeting the reporting threshold that fall on the floor or spilled requiring disposal to be reportable losses.  This is another area where Board requirements diverge from DEA requirements.  Unlike the Board, DEA does not require witnessed damaged, spilled or damaged controlled substances reportable because the registrant can account for them.  Reports by Registrants of Theft or Significant Loss of Controlled Substances, 68 Fed. Reg. 40,576, 40,578 (July 8, 2003).  DEA registrants, however, must maintain records if the lost controlled substances are not recoverable.

    Unlike the April 1, 1957, BBC broadcast report that a Swiss region near the Italian border was experiencing “an exceptionally heavy spaghetti crop” and showing film footage of people harvesting spaghetti off trees, the amended California controlled substance loss reporting requirement is no joke.

    CMS Releases Guidance on Multiple Best Price Reporting for Value Based Arrangements

    In January 2021, we reported on a CMS rule that, among other things, revised the Medicaid rebate best price regulation to remove impediments to value-based purchasing (VBP) arrangements in Medicaid. The rule, which will go into effect on July 1, 2022, defined a VBP is “an arrangement or agreement intended to align pricing and/or payments to an observed or expected therapeutic or clinical value in a select population . . . .”   VBP pricing may be determined by outcomes-based measures, which substantially link a drug’s cost to its actual performance or a reduction in medical expenses, or by evidence-based measures, which substantially link cost to existing evidence of effectiveness and value for a specific use.  See 42 C.F.R. 447.505(a), 85 Fed. Reg. 87000, 87102 (Dec. 31, 2020).

    Last week, CMS issued Manufacturer Release 116 to put flesh on the bones of the new multiple best price option, including details about the structure of VBP arrangements and the respective responsibilities of manufacturers, states, and CMS.  The arrangements are to be structured as a series of outcome-based tiers, each tier associated with a guaranteed net unit price (GNUP).  Each GNUP will be the ultimate cost to the state net of the Medicaid rebate and an additional VBP rebate.  CMS gives the following illustration for a drug whose list price is $2,000:

    • If a beneficiary is undergoing treatment with the drug and is hospitalized in year one, the GNUP will be $500.
    • If a beneficiary is undergoing treatment with the drug and hospitalized in year two, the GNUP will be $750.
    • If the beneficiary is undergoing treatment with the drug and is hospitalized in year three, the GNUP will be $1,000.

    The manufacturer will report a best price corresponding to each GNUP.  Since best price is determined by prices to commercial customers who will not receive the Medicaid rebate portion of the GNUP but may receive the VBP discount, the reported best price corresponding to each GNUP presumably is the GNUP plus the Medicaid unit rebate amount (URA), assuming that the commercial customer receives no other discounts.  The manufacturer will also report a non-VBP best price, which CMS will use to calculate the traditional URA, but CMS will not calculate the VBP rebates.  That will be left to the states, which will invoice the manufacturer separately for ordinary Medicaid rebates and the VBP rebates that the state has earned.

    In order to avail itself of multiple best price reporting, a manufacturer must offer the VBP arrangement to all states.  The manufacturer will upload a description of the VBP into the Medicaid Drug Programs (MDP) reporting system, which is currently used for Medicaid price reporting.  The MDP will notify states about manufacturer VBP offers along with a summary and contact information, and it is up to an interested state to contact the manufacturer.  The manufacturer will report in MDP when it has entered into a VBP arrangement with a state.  CMS will not be involved in the review of VBP programs; the various outcomes measures, the intervals and methods for measuring them, data content and format of state invoices, frequency of invoicing, and other terms and conditions will be negotiated between the manufacturer and the state.

    Ceiling prices under the 340B Drug Discount program will not be affected by VBP best prices, but instead will continue to be based on the non-VBP best price as well as average manufacturer price.  However, Medicare Part B average sales price (ASP) will include VBP discounts paid to ASP-eligible customers.

    A manufacturer who wishes to offer a VBP arrangement only to commercial customers will not be able to report multiple best prices, because that  option requires that the VBP be offered to every state Medicaid program.  As discussed in our summary of  the December 2020 CMS rule (at p. 3), a manufacturer that offers a VBP arrangement only in the commercial market may instead use a bundled sale methodology whereby a discount (or full refund) on one unit of drug that failed to achieve the outcome measure, instead of setting the best price, may be allocated among all the units sold under the VBP arrangement during the quarter, reducing the cost of each one by a small amount.  However, the bundled sale methodology does not offer much best price relief when the total number of units sold during a quarter is small, such as for an orphan drug.  For such drugs, multiple best price reporting could be an attractive option, as long as the manufacturer is willing to offer the VBP to Medicaid.

    Categories: Health Care

    The Good, the Bad and the Ugly: New FDA Legislative Proposal on 180-Day Exclusivity (Both “the Bad” and “the Ugly”)

    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.

    Proposed Legislation Would Reverse Genus Decisions

    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.

    Genus Decision Continues to Ripple Through Industry

    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.

    Are You Recall Ready? FDA Expects You to Be

    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.”

    CDC Proposes Updating Practice Guideline for Prescribing Opioids, Warning Against Continued Misapplication

    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.


    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.


    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.

    HP&M’s Sophia Gaulkin to Present on Changes to State Drug Pricing Transparency Requirements

    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.

    FDA Reports on Accomplishments for First Year of OMUFA

    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.

    CDRH Looks Towards the End of the Public Health Emergency and Transition for EUA and Devices Marketed Under Enforcement Discretion

    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.

    FDA Proposes to Harmonize the Quality System Regulation with ISO 13485

    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.

    Categories: Medical Devices