In May 2023, CDER and CBER published a draft guidance titled “Pediatric Drug Development: Regulatory Considerations – Complying with the Pediatric Research Equity Act [“PREA”] and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act [“BPCA”]” (the “Draft Guidance”).  This Draft Guidance, in part, replaces a 2005 guidance titled “How to Comply with the Pediatric Research Equity Act.”  The Federal Register notice notes that “[c]ombining discussion of PREA and the BPCA together in regulatory guidance emphasizes the sponsor’s need to consider both laws when developing pediatric drugs and biological products.”

The Draft Guidance covers the legal requirements of PREA and the voluntary incentive  mechanisms of the BPCA in a comprehensive fashion.  However, one piece, excerpted below, stood out to us:

Historically, FDA has at times issued WRs solely for studies required under PREA, even if there were no other indications that may produce health benefits in the pediatric population.  However, over time, data on pediatric labeling changes pursuant to BPCA and/or PREA have been collected.  Between 2002 and 2019, there were 768 products with pediatric labeling changes under BPCA and/or PREA.  Sixty-three percent of these labeling changes were based on studies conducted under PREA/Pediatric Rule alone; 21 percent were based on studies conducted under BPCA alone; 16 percent were based on studies conducted under both the BPCA and PREA.  These data suggest that studies required under PREA are successfully completed, and that PREA requirements have resulted in an increase in pediatric labeling, even without the added incentive of the BPCA.

The BPCA provides FDA with discretion to determine whether to issue, and the appropriate scope of, WRs based on the information that “may produce health benefits” in the pediatric population.  In light of the data on pediatric labeling changes pursuant to the BPCA and/or PREA, FDA believes WRs should be reserved for those sponsors who conduct additional pediatric studies — beyond what is required under PREA — that may produce health benefits in children.  Thus, upon finalization of this guidance, FDA does not expect to issue WRs solely for studies or planned studies that are required under PREA.  In general, FDA expects that a WR that includes studies or planned studies required under PREA will also include additional indications or populations.  If there are no additional studies for indications or populations that may produce health benefits in the pediatric population beyond the studies or planned studies required under PREA, then FDA does not expect to issue a WR for that drug.

This represents a significant policy change from the 2005 guidance, wherein the Agency stated: “It is the Agency’s policy to offer applicants the opportunity to qualify for pediatric exclusivity under section 505A of the Act for studies required and conducted under PREA.”

It is perhaps not surprising that the statutory requirement of PREA, with accompanying enforcement tools, is responsible for such a large percentage of relevant pediatric labeling changes as compared to BPCA’s voluntary incentive.  Moreover, it is not surprising that such a small percentage of relevant pediatric labeling changes are due to the BPCA alone, as one might speculate these largely to be studies outside the scope of PREA – that is, studies for uses unapproved in adults.  However, given FDA’s prior announced policy, it is somewhat surprising that only 16% of pediatric labeling changes pursuant to BPCA and/or PREA between 2002 and 2019 were conducted under both the BPCA and PREA.

Still, however, it appears FDA has had enough of these 16%.  Instead, the Draft Guidance expresses an intention to limit pediatric exclusivity to the 21% of relevant pediatric labeling changes based on studies conducted under the BPCA alone.

It is not clear if any or all of the 16% of pediatric labeling changes based on studies conducted under both BPCA and PREA would have been conducted if BPCA exclusivity was not an option, but the Agency appears ready to test the theory that PREA is all it needs, when applicable.  BPCA exclusivity, consequently, appears likely to now be limited to studies outside the scope of PREA, such as studies in indications or populations unapproved in adults.

On May 11, 2023, the U.S. Department of Health and Human Services declared the long-awaited end of the federal COVID-19 Public Health Emergency.  The pandemic had changed the way people live, work and communicate.  Such changes are not limited to personal circumstances.  The pandemic also deeply impacted how industry and the government conduct their operations.  One distinct change has been the rise of conducting meetings over digital platforms.  However, not all changes are forever. FDA has begun to reintroduce in-person meetings.

CDER and CBER

CDER and CBER announced they would resume in-person face-to-face (FTF) industry meetings on February 13, 2023.  Soon after, the Agency announced beginning on March 27, 2023, the FDA generic drug program would resume in-person FTF meetings, but caveated that the in-person FTF meeting option would only be available for pre-ANDA product development meetings and pre-submission meetings for which the applicant requests this in-person FTF meeting format.

It is also noteworthy that in the March 27 announcement, FDA distinguished between teleconferences and videoconferences despite using the same online platform (e.g., Zoom).  A teleconference will be conducted by voice only with no projection of presentations or use of video/camera; a videoconference would involve sharing a screen so that a presentation can be viewed by all participants and/or involve the use of video.  Therefore, for planning purposes, applicants should clearly indicate the type of meeting they are requesting.  Applicants should also be aware that FDA has the discretion to decide the format of the meeting (e.g., videoconference, teleconference, or an in-person meeting).

On May 31, 2023, FDA announced that beginning on June 12, 2023, CDER and CBER will expand in-person FTF industry meetings (with a hybrid component), to include requests for Type B End-of-Phase 2 (EOP2), along with the previously announced Type A, BPD Type 1, and Type X meeting requests.  In this announcement, FDA clarified that an FTF meeting “includes in-person meetings and virtual meetings on IT platforms that allow for both audio and visual communication” per the PDUFA VII and BsUFA III commitment letters (see footnote 9 in PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2023 Through 2027, and footnote 2 in Biosimilar Biological Product Reauthorization Performance Goals and Procedures Fiscal Years 2023 Through 2027).

FDA notes that all in-person FTF formal meetings at CDER and CBER will have a hybrid component (virtual attendees in addition to in-person attendees).  Participants with a primary speaking role from FDA and the sponsor side are encouraged to attend meetings in-person while others join virtually.  FDA posted the recommendations for ZoomGov audio and video settings for in-person participants during the hybrid meetings.  FDA also notes that the number of approved in-person meeting requests is limited due to the availability of hybrid conference rooms.  Any meeting requests received before June 12, 2023, or meetings already scheduled, will not be converted to in-person format.

CDRH

As of this blog post, CDRH has not made any official announcements regarding the resumption of in-person meetings.  An estimated timeline for the return of in-person meetings has not been provided by CDRH.

That said, the availability of in-person meetings may differ among the Offices of Health Technology (OHTs).  Based on our experience, some OHTs may offer a meeting where certain members of the review team attend the meeting in person, while others may join the meeting online; others may be entirely online.  However, to the best of our knowledge, CDRH has not granted a meeting where sponsor participants are permitted to join a meeting in-person.

Advisory Committee Meetings

As of this blog post, all Advisory Committee Meetings that FDA has announced will be conducted via an online platform.

Tips for Successful FDA Meetings

Irrespective of the meeting type, it is essential for sponsors to be well-prepared in advance of meeting with FDA.  A successful meeting with FDA hinges on several key factors, including a comprehension of the meeting purpose, an understanding of FDA’s expectations regarding the matters at hand (often conveyed through written feedback before the meeting), the anticipation of and preparation for potential challenges from the review team, and the ability to communicate clearly and effectively.  It is also crucial to maintain a respectful and cooperative demeanor, document the meeting discussion and action items, and promptly address follow-up actions.  By following these tips, industry may be able to foster a productive and constructive engagement with FDA, leading to favorable outcomes for the development of new medical products and a strengthened relationship going forward.

As we move into the heat of the summer, we can look forward to the annual June deluge of opinions coming from the Supreme Court.  Last week, the Court ruled on a pair of combined cases that potentially impacts many of our blog readers in the pharmaceutical, device, and biologics space that benefit from reimbursements from Federal health care programs.

The court handed down its decision in cases colloquially referred to as SuperValu, which readers may recall from our coverage of another, related circuit court decision and the Supreme Court oral arguments.  The case pitted whistleblowers against chain pharmacies SuperValu and Safeway, both accused of overbilling Federal programs for reimbursements on prescription drugs.  The cases were both brought under the False Claims Act (FCA), the Civil War-era law that the government uses to claw back funds it pays out to parties that overbill federal programs.

The False Claims Act is an important tool for the Federal government to recoup misspent taxpayer dollars, used across numerous agencies to recapture billions of dollars each year.  Doing business with the federal government comes with numerous restrictions and special provisions in exchange for the benefit of having access to Federal reimbursements.  When recipients of federal funds violate those terms, whistleblowers can file a suit that the Department of Justice can take up to reclaim some of those lost taxpayer dollars.

The FCA incentivizes whistleblowers to come forward by awarding them a cut of any recovery.  They are entitled to receive one third of any claw back, which can result in multi-million-dollar awards.  Additionally, the FCA explicitly allows for treble damages, meaning that companies that overbill the federal government may be liable for up to three times the amount of their disallowed reimbursements.

What was SuperValu all about?

The FCA also has a scienter requirement, that is, a requirement to show intent to defraud.  It’s not a often viewed as a high evidentiary bar, as the FCA is a civil statute written and interpreted to sweep in a wide range of fraudulent intent in order to protect Federal funds.  The scienter requirement stated in the statute includes proof of actual knowledge, deliberate ignorance, or recklessness.  In this case, the Supreme Court provided greater clarity on how to interpret that requirement.

In SuperValu, whistleblowers accused the two nationally known retail pharmacies of overbilling the Centers for Medicaid and Medicare Services (CMS) for reimbursements for prescription drugs.  According to the suit, the pharmacies improperly collected the full price for drugs from CMS that they dispensed to consumers under a discounted pricing plan.  The whistleblowers alleged that the pharmacies were entitled only to claims for the discounted prices, and the full claims were therefore improper.

This case made it to the Supreme Court because the pharmacies defended the whistleblower claims by arguing that their practices amounted to an “objectively reasonable interpretation” of one of those aforementioned restrictions on doing business with the Federal government.  CMS requires payees to bill only for “usual and customary” prices of drugs.  Borrowing from a scienter standard set in the Fair Credit Reporting Act (FCRA), the chain pharmacies asserted that was exactly what they were doing.

According to their defense, CMS had not made clear that they had to discount their reimbursement claims to the same degree that they discounted prices to patients. Under their argument, billing the full price was objectively reasonable in the face of lacking guidance from CMS.  The Seventh Circuit accepted the pharmacies’ take in a 2-1 vote that resulted in a summary judgment victory for the pharmacies, and the dismissal of the whistleblowers’ suits.

The Supreme Court Decision

The unanimous Supreme Court was having none of it.  Justice Clarence Thomas authored the court opinion, which promptly dismissed the pharmacies’ strategy and the use of the FCRA’s “objectively reasonable” standard in FCA cases.  The FCA rises and falls on subjective intent of the overbilling party, the Court ruled, an idea now enshrined in the Supreme Court ruling in addition to the words of the statute.  Thomas wrote:

Based on the FCA’s statutory text and its common-law roots, the answer to the question presented is straightforward: The FCA’s scienter element refers to respondents’ knowledge and subjective beliefs—not to what an objectively reasonable person may have known or believed. And, even though the phrase “usual and customary” may be ambiguous on its face, such facial ambiguity alone is not sufficient to preclude a finding that respondents knew their claims were false.

This was the long-predicted outcome, as the pharmacies received a frosty reception at the oral argument earlier in the term.  SuperValu will now go back down to the Seventh Circuit for reconsideration, where the evidence of the pharmacies’ intent will presumably face a less forgiving re-evaluation.

The “objectively reasonable” standard was a potential boon for companies overbilling the government, as it would have allowed them to produce any sort of reasonable excuse well after the billings took place and use that as a shield against enforcement.  But the real loss here is for companies that, on a daily basis and with the blessing of CMS (see, e.g., footnote 16 of this guidance), are required to make reasonable assumptions in the hugely complex and often ambiguous rules for reporting average sales price, average manufacturer price, and best price.

This ruling tells these companies that an objectively reasonable interpretation of an ambiguous requirement may not always protect them from whistleblower and government scrutiny.  SuperValu is undoubtedly a victory for whistleblowers, and a shot over the bow for recipients of government reimbursements.

The Inflation Reduction Act’s price negotiation program for drugs covered under Medicare Parts B and D (“Negotiation Program”) has been challenged in federal court.  Yesterday, Merck filed a complaint in the D.C. District Court challenging the Negotiation Program as a “sham,” an “extortion,” and a violation of the First and Fifth Amendments to the Constitution.

We described the Negotiation Program in our summary of the IRA here.  Recall that CMS will require manufacturers of selected drugs to negotiate a maximum fair price (“MFP”) with the agency according to the following timeline (the dates apply from applicable year 2027 onwards).  Note, in particular, the array of severe penalties with which manufacturers are threatened for non-compliance at the various stages:

*unless manufacturer withdraws all its drugs from Medicare and Medicaid.

In its complaint, Merck characterizes the Negotiation Program as coercive and draconian. According to the company, neither the negotiations nor the agreements are genuine: the government unilaterally selects drugs for inclusion into the program, compels the manufacturer to sign an agreement to sell the drug at whatever price the negotiation will produce, and then requires the company to agree to the price—all under threat of enormous taxes or penalties.

Merck challenges the program on two constitutional grounds.  First, Merck characterizes the program as a “per se taking” without just compensation under the Fifth Amendment, because manufacturers are “force[d] . . . to transfer their patented pharmaceutical products to Medicare beneficiaries, for public use” at a government-dictated price that is a fraction of the drug’s value.  Complaint at 2.  Although the Act does allow manufacturers to avoid the tax penalty by terminating its agreements for all of its drugs under Medicaid and Medicare (i.e., the Medicaid Drug Rebate Agreement and the Medicare Part D Coverage Gap Discount Agreement or the agreement under the successor Part D discount program that begins in 2025), Merck characterizes that as a coercive penalty for the refusal to forfeit its First and Fifth amendment rights.  Merck also points out that it takes between 11 and 23 months for a manufacturer’s termination of the Part D agreement to take effect, during which it is subject to the tax.  Merck asks the Court to declare that the Negotiations Program is a taking without just compensation and to enjoin the government’s agreements under the Fifth Amendment.

Second, Merck argues that the parody of a negotiation and a fair price compels speech in violation of the First Amendment.  The “façade of ‘negotiations’ and ‘agreements’” require Merck to communicate that it has “agreed” to an HHS-mandated price, and to endorse the viewpoint that the price is ‘fair’”, when in fact there has been neither a real agreement nor a fair price.  The complaint characterizes this as political deception that conscripts companies to legitimize government extortion. Complaint at 3.

In a prior post, we commented that, in enacting previous government discount programs in the early 1990s (the Medicaid Drug Rebate Program, the 340B drug discount program, and the VA federal ceiling price requirements), and even the Medicare Part D Coverage Gap Discount Program in 2003, Congress was careful to found the programs on voluntary agreements, in part to avoid Takings Clause and other Constitutional challenges.  With the IRA Negotiation Program, Congress jettisoned the voluntary agreement approach in all but name.  Constitutional challenges by Merck, and probably other manufacturers, are the predictable result.

The Academy of Managed Care Pharmacy (AMCP)’s Format Executive Committee is excited to let you know that after two years of work, version 5.0 of the Format for Formulary Submissions (also known as dossiers) is on the horizon.  And we need your feedback!  We’ve included revisions to the Format in key areas related to digital therapeutics, health disparities, streamlining dossiers, as well as AMCP guidance on Pre-Approval Information Exchange (PIE) decks.

We want to hear from you!  The evidentiary recommendations and guidelines outlined in the Format  are used by manufacturers and health care decisions-makers to inform coverage, policy, and reimbursement decisions for medical products.  The Format was last updated to version 4.1 in 2020.  Please review the proposed revisions to the Format and provide your comments in this form by June 30.

FDA recently released further updates to the Customer Collaboration Portal (“CCP”).  Readers of the blog will know that I am a HUGE fan of the CCP (see our earlier posts here and here).  It has made filing of all premarket submissions much easier by facilitating a direct upload of the submission to FDA.

The CCP has also allowed industry the ability to track the status of 510(k) submissions.  The CCP identifies the 510(k) date of receipt, and the number of days until a decision/response is due.  It also lists all major 510(k) submission milestones and when they are complete.

The most recent updates to the CCP allow sponsors of Pre-submissions to track their status just as they are able to do for 510(k)s.  Just like the 510(k) tracker, the pre‑submission tracker shows the official correspondent the date on which the submission was received and the major milestones.  As shown in the screenshot below, the milestones include (i) acceptance decision, (ii) setting the meeting date, (iii) providing written feedback, and (iv) holding the meeting.  Sometimes pre-submissions do not follow as predictable a path as 510(k)s.  By providing standard pre-submission timelines, we hope it will provide greater transparency to sponsors as to the status of their pre‑submission review.

We look forward to continuing to see the expansion of the CCP.

Last Friday, May 26, CMS published in the Federal Register an assortment of proposals to change the regulations governing the Medicaid Drug Rebate Program.  Most are new or revised definitions and administrative changes, but several proposals represent new policies that should be of concern to drug manufacturers.  It is not our purpose to describe all of the nearly 20 changes proposed in this regulation, but the most noteworthy are described below, roughly in order of importance.

1. Price Transparency Surveys

The MDRP statute requires manufacturers to submit only three prices: average manufacturer price (AMP), best price, and nominal prices.  Absent from the statute is any requirement to report information on manufacturer costs and price setting.  Nevertheless, riding on the wave of drug price transparency legislation in several states and similar legislative proposals in Congress, CMS is proposing to expand the MDRP into the realm of drug price transparency reporting.  For 10 high-cost single source covered outpatient drugs selected annually by CMS, manufacturers would be required to respond to a so-called “price verification survey” by providing not only clinical and utilization information about the drug, but also costs of production, distribution, research, and marketing; revenue and profit; and ex-U.S. pricing.  Non-proprietary information disclosed in the survey would be posted on a public web site.

To select drugs for the annual survey, CMS would identify single source covered outpatient drugs that have the highest (top 5^th percentile) Medicaid drug spend per claim; the highest (top 0.5%) total Medicaid drug spend; the highest (top 1%) WAC increase over 12 months; or the highest (top 5^th percentile) launch price where the annual treatment price exceeds $500,000.  From this list would be removed drugs of manufacturers that have participated in a program of price negotiation with CMS, and those that have negotiated supplemental rebates with at least half the states totaling a specified aggregate amount.  If the resulting list exceeded 10 covered outpatient drugs, CMS would narrow the list by eliminating drugs subject to manufacturer price reduction programs offered to states, such as value-based purchasing arrangements or subscription models, and/or by considering cost.  A manufacturer that refused to respond to a survey would be subject to civil monetary penalties.

As authority for this dramatic expansion of manufacturer reporting requirements under the MDRP, CMS cites its authority to survey “manufacturers that directly distribute their covered outpatient drugs, when necessary, to verify manufacturer prices and manufacturers’ average sales prices (including wholesale acquisition cost) ….”  42 U.S.C. § 1396r-8(b)(3)(B).  However, the survey is not limited to manufacturers that directly distribute their drugs and its purpose goes well beyond verifying prices.

2. Best Price Stacking

We previously blogged about the 4^th Circuit Court of Appeals decision in United States Ex Rel. Sheldon, v. Allergan Sales, which affirmed a lower court decision in a Federal False Claims case involving best price stacking.  “Stacking” refers to aggregating discounts provided by a manufacturer to different customers on the same unit of drug – for example a discount to a pharmacy and a rebate to a third-party payor – when determining best price.  In the Allergan case, the relator claimed that Allergan knowingly failed to stack discounts on the same drug unit to two different customers when determining best price.  The Maryland Federal District Court found for Allergan, holding that the government could not establish the requisite intent because Allergan had not been warned by authoritative guidance from CMS and CMS had failed to clarify the stacking issue.  Now CMS proposes to rectify this shortcoming, and short-circuit any similar lawsuits in the future, by unambiguously requiring the stacking of discounts on the same unit of drug to different best-price eligible entities – regardless of whether the entities are affiliated or not.

3. “All In” Manufacturer Definition

CMS believes that the National Rebate Agreement (NRA) requires a “manufacturer” to report to Medicaid all of its covered outpatient drugs, under all of its labeler codes.  Some multi-affiliate manufacturers have withheld the drugs of a corporate affiliate from the MDRP on the ground that the affiliate is a different manufacturer with a different labeler code and does not have an NRA.  CMS proposes to eliminate this practice by reviving the substance of a 1995 proposed rule that was never finalized: CMS would add to the definition of “manufacturer” a requirement that “all associated entities of the manufacturer that sell prescription drugs, including but not limited to, owned, acquired,  affiliates, brother or sister corporations, operating subsidiaries, franchises, business segments, part of holding companies, divisions, or entities under common corporate ownership or control, must each maintain an effectuated rebate agreement.”  This includes newly acquired labeler codes and newly formed subsidiaries.  In CMS’s terms, manufacturers must be “all in” for all of its drugs or “all out.”  If a manufacturer terminates the NRA for one of its labeler codes, CMS will terminate all of the manufacturer’s NRAs for all labeler codes.

4. Penalties for “Misclassification”

The Medicaid Services Investment and Accountability Act of 2019 added new penalties to the Medicaid rebate statute for knowingly misclassifying a covered outpatient drug.  See 42 U.S.C. § 1396r-8(b)(3)(C)(iii).  The CMS regulation (unlike the statute) would expansively define a “misclassification” to include, not only misclassifying the drug category (e.g., misclassifying a single source drug or innovator multiple source drug as a non-innovator multiple source drug), but also reporting other “drug product information . . . that is not supported by the statute and applicable regulations.”  The preamble provides an example of reporting an incorrect baseline AMP, which reduces the unit rebate amount.  Under this contrived definition, an error in reporting any of the numerous drug and pricing data fields in the Medicaid Drug Programs reporting system would potentially be considered a “misclassification” subject to the new penalties – even if it did not result in any financial harm to Medicaid.  The new penalties (over and above the payment of any underpaid rebates) include a civil monetary penalty of 23.1% of the AMP of the drug multiplied by the number of misclassified units paid for under Medicaid, and suspension of the drug from federal payment under Medicaid.

5. Best Price Exemptions for Patient Savings Programs Restored

Under CMS regulations before December 2020, best price and AMP excluded patient savings programs in the form of manufacturer discount cards, coupons, copayment assistance, patient rebates, and free product vouchers, provided that the full value of the benefit provided is received by the consumer.  As we previously blogged, a final CMS regulation issued on New Year’s Eve 2020 added that the manufacturer must “ensure that” the full value is received by the patient, effectively requiring manufacturers to verify for each individual patient whether the patient’s health plan had an accumulator adjustment program, which would effectively prevent the patient from receiving the full value of the benefit.  PhRMA successfully challenged that amendment, and on May 17, 2022, the United States District Court for the District of Columbia ordered that the 2020 rule be vacated and set aside.  To implement the court order, CMS now proposes to eliminate the offending text and revert to the original exclusions.

6. Suspension of NRA for late submissions

The MDRP statute imposes per-day penalties for late pricing submissions, and also provides for suspension of the manufacturer’s NRA if the submission is over 90 days late.  42 U.S.C. § 1396r-8(b)(3)(C)(i).  CMS proposes a suspension procedure under which CMS would provide written notice to the manufacturer of a failure to submit a timely report.  If the information were not reported within 90 calendar days after the notice, the manufacturer’s NRA would be suspended for all of its covered outpatient drugs after the 90-day period, and federal payment would be unavailable for the drugs.  The NRA could be reinstated when the information is ultimately reported, but not until at least 30 days after the date of suspension.  The preamble clarifies that a suspension of the NRA would not affect the manufacturer’s obligations under the 340B drug discount program or reimbursement under Medicare Part B.

7. Internal Investigations

Under the MDRP, manufacturers must restate incorrect AMPs and best prices and may do so without CMS involvement going back three years from the current quarter.  Restatements of periods before the three-year window require CMS approval of a request, and one of the grounds for such a request is to address specific rebate adjustments as required “under an internal investigation.”  CMS now proposes to define an “internal investigation” as a manufacturer’s investigation of its AMP, best price, customary prompt pay discounts, or nominal prices previously certified to CMS that results in a finding of fraud, abuse, or a violation of law or regulation.  What is noteworthy about this proposed definition is that it adds a new requirement that “[a] manufacturer must make data available to CMS to support its finding.”  Presumably, the data referred to are the support for the recalculated values, which CMS heretofore has not required in the typical recalculation submission.  There is no limitation on the amount of detail CMS may require under this definition.

8. Diagnosis in prescriptions

The statutory definition of a “covered outpatient drug” excludes a drug used for an indication that is not a “medically accepted indication,” which is in turn defined as an indication that is approved by FDA or that is favorably noted in specified drug compendia.  42 U.S.C. §§ 1396r-8(k)(3) and 1396r-8(g)(1)(B)(i).  This limitation is virtually unenforceable because prescriptions and Medicaid claims for drugs do not identify the patient’s diagnosis or condition.  For this reason, CMS requests information (but proposes no rule yet) on whether prescriptions should be required to identify the diagnosis.  The preamble notes that this information would help ensure that drugs are being used for approved or otherwise medically accepted indications.

9. Definitions

Apart from the definitions of “manufacturer” and “internal investigation” discussed above, CMS proposes to add other definitions:

• “Market Date”: Largely consistent with the definition in existing subregulatory guidance, this term would be defined as the date on which the drug was first sold by any manufacturer.
• “Vaccine”: Because vaccines are excluded from the MDRP, CMS proposes to define them solely for purposes of the MDRP.  Vaccines would be defined as a product that is administered prophylactically to induce active, antigen-specific immunity for the prevention of one or more specific infectious diseases and that is licensed by FDA.  The preamble clarifies that the definition does not include a therapeutic vaccine.

*    *    *

Several of the changes described above – most notably the price transparency surveys, the best price stacking policy, the control group definition of “manufacturer”, and the expansive definition of a “misclassification” warranting penalties – represent substantial but questionable expansions of CMS authority under the Medicaid rebate statute.  These, at least, are deserving of comments, which are due by July 25, 2023.

CBS News caused a bit of commotion last week in reporting that after a four-year delay, DEA issued a final order revoking Morris & Dickson’s DEA registration.  However, until today there had been no public information about this decision. This morning, the Federal Register published two DEA notices on the Morris & Dickson matter (here and here).

The first notice is a Final Decision and Order revoking the Morris & Dickson registration, but not effective until 90 days after publication. Usually, a Final Decision and Order is effective 30 days from publication. The second notice solved that mystery. In the second notice the DEA Administrator is issuing an Order granting the 90-day effective date from publication of the Final Decision. According to that Order, Morris & Dickson had requested a stay of the Final Decision to renew settlement negotiations. The government, while opposing the stay, stated it was willing to enter settlement discussions.  Thus, the DEA Administrator has given the parties 90 days to work something out.

Those of us tracking DEA matters had wondered about the long delay in publication of a Final Decision in this matter. On May 24, 2019, Morris & Dickson paid a $22 million civil penalty related to the failure to report suspicious orders and ignoring certain red flags in the distribution of controlled substances.  However, at the time the parties were unable to settle the pending administrative show cause action based on the same violations.  DEA held an administrative hearing on the alleged violations in May 2019 and, according to the proposed Final Decision and Order, the DEA Administrative Law Judge transmitted his Recommended Decision to revoke the DEA registration to the DEA Administrator on November 26, 2019.

The Recommended Decision has sat through three (3) DEA Administrators and more than 3 (three) years before notice of the current proposed actions. There have been other cases where Final Decisions and Orders have taken more than a year, but 3 ½ years is as long as we can remember. It also highlights how such delays are a disservice to the industry and public interest.

While this decision was pending, Morris & Dickson remained an authorized DEA registrant to continue to handle controlled substances.  It has continued to serve customers who have relied on the distributor to supply controlled substances and other medicine. But such activity has operated under a cloud which affected both suppliers and customers of Morris & Dickson given that the DEA registration was not issued a new registration but nor was it revoked. Except in the case of an immediate suspension, a DEA registrant remains authorized to handle controlled substances during the course of a show cause proceeding.  We also speculate that if DEA had any new evidence that Morris & Dickson was not otherwise complying with its regulatory responsibilities it would/should have taken further action during this time, otherwise the delay in issuing the Final Order would have been contrary to the public interest. For its part, during these four years, Morris & Dickson has had the opportunity to demonstrate the effectiveness of its remedial measures.

Neither the CSA nor regulations promulgated by DEA provide any deadline for issuing a Final Order and Decision.  But given that the issue for granting or revoking a DEA registration is whether the registration is in the “public interest” the delay does raise issues about the reasonableness of revoking a DEA registration more than 3 years later, having let Morris & Dickson continue to actively handle controlled substances during that time.

The resolution to the conundrum appears to be a potential settlement that could result in Morris & Dickson obtaining a new DEA registration, likely subject to a Memorandum of Agreement.  DEA was unwilling to settle the matter four years ago, so the Agency’s willingness to discuss a settlement now would have to be based on findings that Morris & Dickson’s recent compliance efforts justify granting a new registration at this time.

ONE WEEK AWAY! Join attendees from around the globe at the IBA’s World Life Sciences Conference in Washington, DC.  We are honored to have keynote addresses from DOJ and FDA officials.  The conference will highlight hot topics affecting the healthcare and life sciences industries.

Hyman Phelps & McNamara, P.C. Director, Anne Walsh, will moderate a panel that addresses what companies should consider when in the crosshairs of a government investigation.  She will bring together speakers to discuss the wide variability in the penalties that can be brought against a company and any responsible individuals, particularly in light of the different frameworks available globally for making prosecutorial decisions.  Register here.

On May 16, the U.S. Food and Drug Administration (FDA) released a draft update to its Compliance Policy Guide (CPG) for FDA staff on the Agency’s enforcement of major food allergen labeling and cross-contact.  The draft CPG reflects the three major laws and regulations that form the foundation of FDA’s regulatory framework for major food allergens and which became effective since the issuance of the current CPG, CPG Sec 555.250 Statement of Policy for Labeling and Preventing Cross-contact of Common Food Allergens, which was first issued in 2001 and last revised in 2005.  Since then, the science and legal and regulatory framework for food allergens have evolved considerably:  Congress enacted the Food Allergen Labeling and Consumer Protection Act (2004) and the Food Safety Modernization Act (2011), and FDA implemented the regulatory requirements set forth in 21 C.F.R. Part 117, and the Food Allergy Safety, Treatment, Education and Research Act (2021).

The draft CPG describes FDA’s enforcement policy and cross-contact controls for major food allergens, including:

• The labeling requirements for major food allergens identified in the Federal Food, Drug and Cosmetic Act;
• FDA’s position on the proper use of the ingredient list and “Contains” statement for major food allergen declarations:
  • Major food allergens unintentionally incorporated into a food may not be declared in the ingredient list or the “Contains” statement;
  • When a “Contains” statement is used on a food label, then the food source of all major food allergens present in the food must be declared in the “Contains” statement, even if they are also declared in the ingredient list;
• Requirements for firms to implement controls that prevent or significantly minimize allergen cross-contact and a note that the allergen advisory statement does not relieve the manufacture from the obligation to minimize or prevent allergen cross contamination; and
• Additional allergen labeling violations (e.g., the product label declares “tree nut” or “fish” but fails to declare the type of tree nut or species of fish in either the ingredient list or in a separate “Contains” statement).

The draft CPG directs FDA field staff to examine possible food product adulteration due to labeling related to allergen cross-contact.  Specifically, field staff are advised to pay close attention to situations where allergen cross-contact may occur because of poor current good manufacturing practices (cGMPs), inadequate preventive controls, or inadequate controls under the juice or seafood HACCP regulations.

In the announcement of the release of the draft CPG, FDA acknowledged that “some manufacturers are intentionally adding sesame to products that previously did not contain sesame and are labeling the products to indicate its presence” to avoid implementing difficult and costly practices to prevent cross-contamination.  FDA noted that it “does not support” intentionally adding sesame as a regulatory compliance strategy, because it “may make it more difficult for sesame-allergic consumers to find foods that are safe for them to consume.”  Although the draft CPG does not address this industry practice, FDA commented that it is engaged with stakeholders on this issue.

The Center for Science in the Public Interest publicly condemned FDA’s “tepid” and “not adequate” statements regarding this practice—a practice which began shortly after the addition of sesame to the major food allergen list, and which has faced mounting criticism from other consumer advocacy groups and lawmakers.

To be considered, comments to the draft CPG must be submitted to the docket by July 17, 2023.  We expect to see comments urging FDA to act against the industry practice of intentionally adding sesame to foods, but it is unclear what actions FDA could take without interfering with manufacturers’ choice over the ingredients in their products.  We will have to wait and see whether FDA will add sesame-specific guidance addressing this issue (which seems to be limited to sesame) to its CPG for major food allergens.

Well, it’s official: The Federal Circuit decision in GSK v. Teva stands, as the Supreme Court has decided not to hear the case on appeal.  While the statistics were against the Supreme Court taking up the case given the limited number of cases heard per year, it’s definitely disappointing for those of us who have been watching the case for the last 7 years.  And, for generics, the Federal Circuit decision will be looming large behind any carve-out proposals, keeping open the possibility of liability for induced infringement even if compliant with the statutory scheme permitting such carve-outs.

We previously noted that “the skinny label may be dead” and, while we still can’t be sure if it’s truly gone (but not forgotten), we now know that the Supreme Court won’t hear this case at this time.  As a result, the case goes back to the Delaware District Court where additional issues not decided in the original 2017 trial will be presented to the court.  Among the issues to be presented in a bench trial is whether GSK should be prevented from asserting its patent on the use of carvedilol to treat congestive heart failure because of representations it made to the FDA as to which uses of the drug that patent covers.  So GSK may not see any money yet, but the Federal Circuit’s position on induced infringement—that a carve-out, even if legally permissible under the FDCA, can still be the basis of an induced infringement claim— stands firm.  In the Federal Circuit rehearing decision, the Court did state that “[w]e do not hold that an AB rating in a true section viii carve-out (one in which a label was produced that had no infringing indications) would be evidence of inducement,” but whether a carve-out is a “true carve-out” may be unclear and may only be clear once a carve-out is challenged in patent litigation.  Each patent carve-out, therefore, will be subject to a fact-specific inquiry as to infringement.

Due to the subjectivity of a fact-specific inquiry, whether in the hands of a jury or a District Court judge, the carve-out is now, from a practical perspective, fraught with peril.  If the sufficiency of a carve-out can be assessed only by a court, there is a risk that any carve-out could be the subject of litigation.  Indeed, we’ve already seen some of these cases being brought.  The subjectivity of that assessment makes all carve-outs liable for litigation, which significantly increases the risk of a tool that’s supposed to be used precisely to avoid litigation.  This leaves generic manufacturers with a real concern that any carve-out will be brought to court, which may significantly reduce the number of carve-outs by risk-averse generic companies.

Further, FDA, in its ministerial role, only looks at the use code and approves a carve-out based on the use code.  But the decision here suggests that the use code really doesn’t do enough.  Generic manufacturers, as they always have before, must review the patents and carve-out information in accordance with that patent.  But generic manufacturers are hamstrung because FDA will only permit them to carve-out the use code.  Consequently, RLD sponsors now have an incentive to include a narrower use code, walking a potential carve-out into an induced infringement claim.  In other words, where before there was incentive to have use codes that were too broad to prevent carve-outs in the first place, now there are incentives to have use codes that are too narrow to permit an induced infringement claim.  And the only practical way to address an overly broad or overly narrow use code is in the throes of patent litigation!

So, while the skinny label may not actually be dead, there will certainly be a reluctance to use it.  Perhaps Congress will weigh in, but until then, we’ll say that the skinny label is on life-support.

Accounting for controlled substances, maintaining complete and accurate records/reports and employing effective, compliant security do not alone guarantee a successful Drug Enforcement Administration (“DEA”) inspection.  A negative DEA inspection can plague registrants for years.

Hyman, Phelps & McNamara, P.C. (“HP&M”) invites you to join Director Larry Houck for a free webinar demystifying DEA inspections by providing an understanding of controlled substance accountability audits, the importance of conducting mirror reviews, and mock DEA-style internal inspections.  The webinar, scheduled for Wednesday, May 24, 2023 from 12:00-12:45 (Eastern), will share additional valuable inspection tips.

Registrants are far from powerless when DEA investigators inspect their controlled substance operations.  This webinar will provide insight on how to prepare for and manage inevitable DEA inspections to help ensure favorable results.

Before joining HP&M in 2001, Mr. Houck conducted numerous scheduled cyclic and targeted inspections and investigations as a DEA Diversion Investigator in the field for ten years.  He later served as Staff Coordinator in Diversion Control’s Liaison and Policy Section at DEA headquarters.

We hope that you will be able to join us!  Please see the attached flyer that includes a link to register for the webinar.

In a dense, multi-part opinion, the Supreme Court affirmed 5-4 the lower courts’ dismissal of a challenge to California’s Proposition 12. That law bans the knowing sale of eggs, uncooked pork, or veal derived from farm animals that are housed under conditions that do not meet certain minimum requirements – regardless of whether the animals are raised in California or out-of-state. Our colleagues at SCOTUSblog have penned a helpful analysis that examines the basis for the Court’s opinion, as well as its multiple parts and concurring opinions. Our focus is on the decision’s practical impact, which could be felt almost immediately.

The California Department of Food and Agriculture (CDFA) issued regulations implementing Proposition 12 on September 1, 2022, but their implementation was enjoined until July 1, 2023, pending the Supreme Court’s decision. With that out of the way, implementation of CDFA’s regulations can be expected to go forward, barring any further judicial or legislative intervention. CDFA has established a web page with multiple resources for producers and distributors, including links to the regulations and guidance documents.

California is not the only state to have established animal welfare requirements affected by the Supreme Court’s decision. Voters in Massachusetts approved a ballot initiative (Question 3) in 2016 that imposed requirements similar to those imposed under Proposition 12. The Massachusetts Department of Agricultural Resources (MDAR) subsequently issued implementing regulations that were partly enjoined pending the Supreme Court’s decision. Those regulations are now expected to take effect on June 10, 2023, barring any further judicial or legislative intervention.

Given consumer interest in farm animal welfare generally, it seems certain that additional states will seek to establish their own requirements similar to those in California and Massachusetts. To the extent that those requirements differ from one another, pressure may build for federal legislation to establish uniform national standards.

As we noted in our previous blog post available here, Quidel’s Sofia 2 SARS Antigen+ FIA, Sofia 2 SARS Antigen+ FIA Control Swab Set’s De Novo, now opens the door for follow-on 510(k) submissions that declare this product as their predicate, if the product meets the established Special Controls as noted in the reclassification order.  In this blog we examine the Special Controls put in place to mitigate false results, incorrect interpretation of results, and incorrect operation of the device.

Design Verification and Validation Special Controls

Analytical testing includes many of the same tests already required for an EUA:

• Limit of Detection (LoD)
• Inclusivity, including relevant variants
• Cross-reactivity
• Microbial interference
• Interfering substances
• Hook effect
• Inclusivity of relevant circulating variants
• Specimen stability
• Reagent stability
• Flex studies

However, there are some additional studies noted, specifically site-to-site reproducibility, within-lab precision, carryover and cross contamination, and competitive inhibition.  Previously, the EUA template only required these studies for Multiplex Respiratory panels in which a new instrument was used with the proposed device; however this De Novo was for a simple point-of-care device to detect SARS-CoV-2 viral targets only.

Final Release Criteria Special Controls

Sponsors will need to provide the final manufacturing release criterion with evidence that lots released at the extremes of the specification will still meet the claimed device performance (i.e., analytical, clinical and stability).  The Special Controls are silent on what would constitute appropriate levels of evidence necessary to satisfy this criterion.

Collection Device Special Controls

Sponsor will need to select a collection device that is either FDA-cleared, -approved, or -classified as 510(k) exempt (either as a standalone collection device or as part of a system) or alternatively the collection device can be cleared within the premarket submission for the POC test.

Clinical Testing Special Controls

In the Special Controls, there are two different criteria a sponsor can meet for their clinical study, each resulting in different indications for use:

Serial testing was defined as testing symptomatic individuals twice over three days with at least 48 hours between tests, which is in accordance with study findings from the National Institute of Health referenced here and current EUA labeling for serial testing.

The other requirements, listed below, for the clinical study are similar to previous recommendations included in the Antigen EUA template with some important subtle nuances to consider:

• prospective multi-site clinical study,
• geographically diverse intended use population,
• consistent with the intended use population and intended operators,
• conducted in a representative intended use setting,
• performance estimates derived for each claimed specimen, and
• compare results of the candidate device to an” FDA accepted” molecular comparator method.

For EUAs, FDA recommended the clinical evaluation be done at one to two sites; however, the Special Controls explicitly states the testing should be done in geographically diverse intended use populations, to ensure the device results represent “all present, circulating strains of the SARS-CoV-2.” It is not clear how sponsors are to meet this special control as prospective studies are executed in the months prior to the FDA review, given the time necessary to prepare for and submit a 510(k) in addition to the FDA’s premarket review timelines.  Even though only two sites are required, sponsors should consider including a sufficient number of sites to ensure geographic diversity and ability to capture all circulating strains in the study.

The selection of operators is another critical component of the study design and should be operators that would be typically expected to run simple tests in a POC environment and are not hired just to execute a clinical study.  We note the Special Controls indicated that the POC study needs to be conducted in the representative intended use setting so consider incorporating the testing into the operator’s existing workload.

Notably absent are details regarding what is considered an “FDA accepted” molecular method.  In the EUA template the FDA indicated sponsors should use a “RT-PCR which used chemical lysis step followed by phase extraction of nucleic acid (e.g., silica bead extraction) and reports cycle threshold values and be one of the more sensitive RT-PCR assays.”  We note the FDA has granted a De Novo and subsequent clearance for SARS-CoV-2 RT-PCR test which would seem to be the logical comparator of choice, however discussing the proposed comparator or even the use of a composite comparator with the FDA prior to initiating a clinical study is highly recommended.  Sequencing can be an important tool to understand the distribution of variants in the clinical study especially given the fact sponsors will be required to include a statement in their labeling regarding the predominant strain in the study.

Software Special Controls

If the device includes software or is an instrument with software, the software required under the special controls is consistent with the typical software documentation provided in 510(k) submissions.  In addition, similar to what was required for an EUA, sponsors should evaluate cybersecurity of their system to ensure user and patient safety in the intended use environment.

Continuous Monitoring and Post Market Reporting Special Controls

Within the Special Control for Risk Analysis are details regarding continuous monitoring.  The submission will need to include a “detailed description of a protocol for continuous monitoring, identification, and handling of genetic mutations and/or novel isolates or strains.”  The Special Controls provides the examples on what sponsors might do to monitor:

• regular review of published literature, and
• periodic in silico analysis of target sequences to detect possible mismatches.

Is this really as straightforward as reviewing literature and doing periodic in silico analysis? When reviewing FDA’s Policy for Evaluating Impact of Viral Mutations on COVID-19 Tests (Revised) dated January 12, 2023, the agency previously stated monitoring the impact on antigen tests is not as straightforward as monitoring the impact on molecular tests because antigen tests do not directly target the genetic sequence.  The Special Controls seem to leave it up the sponsor to determine if monitoring is required for all new circulating variants or only if they reach a threshold level of prevalence in the United States.  It is unclear what specific testing would be done to demonstrate the impact on established performance.  We know that FDA has asked sponsors to conduct Limit of Detection Studies with specific variants, but it is not clear what FDA’s expectations are for demonstrating equivalence.

The monitoring protocol also needs to include plans to update labeling with the additional performance data.  This data and any additional FDA-directed data analysis must be provided to the FDA, when requested or be made available during a routine evaluation.  FDA can request that sponsors provide this data within 48 hours of the Agency making said request.  While it is true sponsors will have the data on file, responding and providing the data within a 48-hour time-period can create stress in any organization.  And if you think a 48-hour turn-around time is fast, if novel respiratory pathogen strains or isolates impact the stated performance of the device, the data needs to be sent to the FDA immediately (although the specific trigger for such “immediate” notification is “unclear”).  While immediately is not defined, it could suggest a shorter turnaround time than the previously stated 48 hours.  The Special Controls is silent on defining to what extent a reduction in performance would require immediate reporting to the FDA.  In the prior FDA EUA guidance, a reduction of test performance of 5% or more from the established performance or a drop below the stated performance recommendation in the EUA templates were identified as thresholds for impact on performance, however it is unclear if this same threshold would be applied.

Emergency Analytical Reactivity Post Market Obligations Special Controls

Interestingly the Special Controls also add details regarding post market obligations if a new public health emergency is declared for the analyte detected and if FDA has characterized samples available for testing.  In this case, sponsors will have 30 days to complete testing in accordance with an FDA protocol.  Within 60 days and continuing for 3 years, sponsors will be required to include the results of that testing in the device’s labeling along with details about the samples used for the testing.

Labeling Special Controls

The labeling may seem like the easiest Special Control for demonstrating compliance.  Here we have broken out the requirements for the Indications for Use, Quick Reference Instructional Sheet, and Device Labeling.

Indications for Use

The indications for use should include the following:

• analytes detected,
• specimen types tested,
• indication for testing of respiratory specimens,
• clinical indications for which the test is used,
• specific intended population(s),
• intended use locations including testing location(s),
• statement regarding positive results,
• for symptomatic, number of days of symptom onset,
• statement regarding negative results,
• statement regarding the predominant strain during performance testing, and
• depending on the results of the clinical study serial testing requirement.

Quick Reference Instruction

The Quick Reference Instructions (QRI) should include, at a minimum, the following:

• name of the test,
• intended use of the test,
• easy to follow step-by-step instruction for controls,
• easy to follow step-by-step instructions for each sample type,
• graphic illustrations of each step,
• results interpretation guidance,
• warning and limitations,
• toxicology information and safety considerations for any hazardous materials,
• troubleshooting or frequently asked questions, and
• how to get technical assistance (e.g., Customer Support Help line).

Labeling Instructions for Use

The labeling should include the following:

• detailed device description,
• detailed description of performance characteristics,
• detailed descriptions of the test procedure(s), interpretation of results, and acceptance criteria for QC testing,
• statement regarding positive results and patient management decisions,
• detailed instructions on how to minimize exposure to infectious reagents included in the device,
• detailed instructions on how to minimize false positive results, and
• limiting statements regarding results and performance characteristics with the predominant strain.

As we stated previously, this submission took well over nine (9) months to review and develop the Special Controls.  After reviewing the Special Controls, we understand what took so long.  Unlike like the definition of “simple test,” the Special Controls are anything but simple.  Since the De Novo reclassification order on March 8, 2023, the FDA has recently posted the Quidel’s decision summary, which happed at warp speed as compared to this De Novo from July 2022, which still has yet to have its decision summary posted.  Stay tuned for a future post evaluating the details of the Quidel’s decision summary.

For those readers unfamiliar with the regulation of animal food ingredients in the United States, below is a brief background.

In the United States, animal food (feed) regulations are enforced by state and federal regulatory officials.  At the federal level, the Center of Veterinary Medicine (CVM) of FDA regulates food for animals, including livestock and pets.  As part of its regulatory responsibilities, CVM reviews the safety of new or modified animal food ingredients.  Such reviews may be in response to food additive or color additive petitions, or notifications that a substance is generally recognized as safe (GRAS).  In addition, CVM, on its own initiative, may propose an animal food additive or color additive regulation.

States frequently review labels (and labeling) for animal food products.  Part of this review involves the status of the ingredients included in the product.

The Association of the American Feed Control Officials (AAFCO) is a group of state, federal, and international regulatory officials that partner to support uniform animal food regulatory systems.  AAFCO develops model regulations, that serve as model for the states.  The goal is to create uniformity to facilitate interstate commerce.

A major component of AAFCO is its work on ingredient definitions, specifying what ingredients may be use in animal feed under what conditions.  AAFCO’s ingredient definitions are not federal regulations and do not have the force or effect of federal law. However, most states incorporate the ingredients listed in the AAFCO Official Publication (OP) into their state laws, so the AAFCO feed ingredient definitions facilitate the interstate marketing of animal food ingredients.  The AAFCO OP includes FDA approved feed and color additives, substances that are subject to GRAS notifications (AGRNs), etc.  Most states treat the OP as a “positive list” of ingredients that may be included in animal foods.  The absence of “common foods” in the OP has resulted in uncertainty as to whether such common foods can be used in animal foods.

On May 2, AAFCO announced that it had published its first installment of a common food index (CFI).  AAFCO defines “common food” as a food item “commercially available and suitable for use in animal food but [which is] not defined by AAFCO, including but not limited to certain whole seeds, vegetables, or fruits.” The CFI includes a list of common foods that “may be appropriate for use in animal food and serve as a tool for use during review of ingredients on an animal food label.”  The goal of this positive list is to provide harmonization, consistency, and transparency.

The first installment includes 72 foods. AAFCO is requesting stakeholders, such as veterinarians, animal nutritionists, consumer groups, and the public, to provide feedback on the initial CFI by June 2, 2023.  Comments may be submitted using a virtual form.  AAFCO has developed procedures for further review and determination as to what products will be included or removed from the CFI.  This document also describes an appeal procedure.

This by no means constitutes the complete list of common foods.  AAFCO has developed a process for submitting applications to add additional products to the CFI.  However, while AAFCO is receiving feedback on this first proposed list of products, applications for additional common foods are not accepted.

Inclusion on the CFI does not mean that the common food is safe.  Manufacturers are responsible for determining that the common food is safe and has utility for its intended use prior to commercial distribution as animal food.