Companies often use rebranding to reposition and refocus their business.  Sometimes they do it with great fanfare; sometimes it is done quietly and incrementally.  The federal government does its own version of rebranding with each change in administration.  Just before the July 4 holiday weekend, DOJ quietly rebranded the role of guidance documents, reversing two distinct but related policies regarding such documents.  The first policy it reversed, originally announced in 2017 by Attorney General Sessions, prohibited all DOJ components from “issu[ing] guidance documents that purport to create rights or obligations binding on persons or entities outside the Executive Branch (including state, local, and tribal governments).”  The second, and arguably more significant, policy prohibited its lawyers from civilly prosecuting companies for violating “requirements” set forth in agency guidance documents.  This policy, announced by then Associate Attorney General Rachel Brand in 2018 was referred to as the Brand Memo.  As a matter of administrative law, the Brand Memo made good sense from the perspective of FDA-regulated industry, as we described here.  Because guidance documents have not undergone the notice-and-comment rulemaking process required under the Administrative Procedure Act, these documents should not be used to bind the public or coerce regulated parties into acting beyond what is required by law and regulation.  DOJ’s policy (ironically issued via guidance document, but later memorialized in the Justice Manual) stated that DOJ would not use noncompliance with guidance documents as the sole basis for an affirmative civil enforcement case.

The July 1, 2021 Memo signed by Attorney General Garland describes the earlier policies as “overly restrictive,” and claims it has “discouraged the development of valuable guidance” and “hampered [DOJ] attorneys when litigating cases where there is relevant agency guidance.”  The Attorney General now instructs DOJ lawyers handling an enforcement action that they “may rely on relevant guidance documents” in instances when a guidance document “may be entitled to deference or otherwise carry persuasive weight with respect to the meaning of the applicable legal requirements.”  The memorandum cites the 2019 Supreme Court decision, Kisor v. Wilkie, 139 S. Ct. 2400, 2420 (2019), which recognized that agencies can issue interpretive rules without notice-and-comment as long as they are meant only to advise the public of how the agency understands, and is likely to apply, the binding laws and regulations.

FDA’s database contains 2,623 guidance documents that address a plethora of topics, ranging from the mundane (e.g., electronic formatting for regulatory submissions), scientific (e.g., clinical testing of implanted brain computer interface devices for patients with paralysis or amputation), enforcement (e.g., recalls), and the COVID-19 emergency.  The top of each document includes the following disclaimer:

Even though these guidance documents explicitly are “not binding on FDA or the public,” companies rarely divert from terms within a guidance document because disagreement with FDA could result in costly delays in regulatory approval or administrative sanctions.  Nevertheless, the Brand Memo gave companies some solace that a failure to “dot all the I’s and cross all the T’s” within a guidance document would not be the basis for a government prosecution.  Rather, companies that met the legal and regulatory standards could defend their conduct even if they did not do so exactly as FDA proposed in guidance.

In light of the seemingly renewed general focus on enforcement activities after a COVID-19 lull, regulated companies should anticipate the resumption of FDA inspections.  In preparation, companies should consider whether new guidance documents have been issued that “require” changes in business practices and documentation.

Additionally, on the government investigation front, companies should expect that DOJ lawyers assessing potential False Claims Act cases based on alleged FDC Act violations, are reading FDA guidance documents with renewed vigor and contemplating how to use those guidance documents in their cases, which routinely result in multi-million dollar settlement demands.  Companies should be prepared to vigorously defend themselves, starting with Attorney General Garland’s own reminder: “By definition, guidance documents ‘do not have the force and effect of law.’”

It is a well-accepted fact that even well run ethical and compliant organizations can have serious problems.  The Sentencing Guidelines, the DOJ Manual, and the HHHS OIG–among others–all recognize that reality.  In its Compliance Guidance for Pharmaceutical Manufacturers, the HHS OIG notes:

The OIG recognizes that the implementation of a compliance program may not entirely eliminate improper conduct from the operations of a pharmaceutical manufacturer. However, a good faith effort by the company to comply with applicable statutes and regulations as well as federal health care program requirements, demonstrated by an effective compliance program, significantly reduces the risk of unlawful conduct and any penalties that result from such behavior.

Generally speaking, that recognition has limits, however.  While the Organizational  Sentencing Guidelines provide for a sentencing reduction for companies with an effective compliance and ethics program, that reduction is presumptively not available “if an individual— within high-level personnel of a small organization; or within substantial authority personnel, but not within high-level personnel, of any organization, participated in, condoned, or was willfully ignorant of, the offense.”  The Guidelines rationale is that “[o]rganizations can act only through agents and, under federal criminal law, generally are vicariously liable for offenses committed by their agents.”  The Justice Manual on the Principles of Federal Prosecution of Business Organizations further expounds on this notion:

Under the doctrine of respondeat superior, a corporation may be held criminally liable for the illegal acts of its directors, officers, employees, and agents. To hold a corporation liable for these actions, the government must establish that the corporate agent’s actions (i) were within the scope of his duties and (ii) were intended, at least in part, to benefit the corporation . . . .

Agents may act for mixed reasons—both for self-aggrandizement (direct and indirect) and for the benefit of the corporation, and a corporation may be held liable as long as one motivation of its agent is to benefit the corporation. . . . . Moreover, the corporation need not even necessarily profit from its agent’s actions for it to be held liable.

In light of the above, the government generally resists the notion that an organization is a victim of its own employees.  Earlier this year, in denying a restitution request from a company, Judge Rakoff in the Southern District of New York wrote that a company’s “efforts to root out misconduct, however extensive, do not ‘immunize the corporation from liability when its employees, acting within the scope of their authority, fail to comply with the law.’” He further noted that “the mere fact that the defendants may have misled other employees or agents of [the company does not relieve [the company of its criminal liability under the principle of respondeat superior, especially where, as here, the wrongdoing was committed by company’s highest officers.

In sum, a company seeking to show that it is not responsible for the bad acts of its employees faces an uphill fight. Which brings us to the FIFA prosecutions, a topic that would not typically be blogworthy for the FDA law blog.

At a very general level, starting in 2015, in a high profile series of prosecutions, the DOJ accused a number of top FIFA officials of widespread criminal conduct.    At that time, DOJ noted that “[t]he defendants charged in the indictment include high-ranking officials of the Fédération Internationale de Football Association (FIFA), the organization responsible for the regulation and promotion of soccer worldwide.”  That type of headline typically signals that the organization is going to be a defendant, not a victim, but earlier this week, DOJ announced that FIFA would be receiving victim compensation in the form of remission.  In that same announcement, DOJ noted that:  “To date, the prosecutions have resulted in charges against more than 50 individual and corporate defendants from more than 20 countries, primarily in connection with the offer and receipt of bribes and kickbacks paid by sports marketing companies to soccer officials in exchange for the media and marketing rights to various soccer tournaments and events.”  In other words, despite a widespread and seemingly systemic fraud, the organization was a victim.  These types of resolutions are intensely fact-specific, and for all the reasons noted above a company that simply claims that it’s a victim without laying the factual and legal basis for such a claim is unlikely to get very far, but nevertheless, this case is relevant precedent for companies who find themselves investigating employee misconduct and navigating government investigations.

On August 6, 2021, the Pharmaceutical Research and Manufacturers of America (PhRMA) announced the release of a revised PhRMA Code on Interactions with Health Care Professionals, which takes effect on January 1, 2022.  The PhRMA Code is a voluntary code of conduct focusing on the pharmaceutical industry’s interactions with health care professionals as they relate to the marketing of products.  The PhRMA Code is updated periodically to reflect changes in industry norms or, as is likely the case with the latest revision, in response to political pressure or increased scrutiny from the federal government.

The latest changes to the PhRMA Code are primarily focused on speaker programs, including meals and drinks offered, the venue used, and attendance at such programs.  These revisions appear to be responsive to a November 16, 2020 Special Fraud Alert issued by the Office of Inspector General at the U.S. Department of Health and Human Services (OIG) (see our blog post on this Special Fraud Alert here).

While PhRMA does not reference the OIG Special Fraud Alert in its announcement of the revised code or its summary of revisions to the code, the substantive updates to the code are directly traceable to OIG’s critiques of speaker programs.  OIG provided examples of practices that are common in violative speaker programs that are conducted with the intent to induce health care professionals (HCPs) to prescribe or order products paid for by Federal health care programs:  holding programs at non-conducive venues or events; providing expensive meals; repeat attendance by HCPs at substantially similar trainings; and attendance by the HCP’s friends or families.

PhRMA has updated its guidance regarding speaker programs through the following additions to the Code:

• The purpose of a speaker program should be to present substantive educational information to address a bona fide educational need, and only those with a bona fide educational need for the information should be invited (i.e., not friends, significant others, or family members of a speaker or invitee). Repeat attendance at a program on the same topic is generally not appropriate, unless there is a bona fide educational need for repeat attendance.
• The speaker program should occur in a venue that is conducive to the informational communication. If held in a third-party venue, the venue “should not be extravagant or the main attraction of the event” (e.g., the venue should not be a luxury resort, high-end restaurant, or other entertainment, sporting, or recreational venue).  The new Code continues to permit incidental meals that are modest by local standards (still without defining “modest”), but adds a prohibition on providing alcohol.
• It continues to be appropriate for companies to offer HCP speakers reasonable compensation for their time, travel, lodging, and meal expenses. However, the revised Code clarifies that an HCP should not be selected to serve as a speaker based on past revenue that the speaker has generated or potential future revenue that the speaker could generate by prescribing or ordering a company’s products.

Other, less extensive changes have been made to Code sections on topics other than speaker programs.  The section on informational presentations by company representatives continues to permit modest meals to be provided during such presentations, but a requirement has been added that there must be a reasonable expectation, and reasonable steps taken to confirm, that each attendee has a substantive interaction or discussion with a company representative.  “Grab-and-go” meals and alcohol are not appropriate.

The current Code discourages the use of resort venues for several types of meetings, including consultant meetings, speaker programs, and speaker training meetings.  Wherever a “resort” venue is discouraged in the current Code, the revised Code substitutes “luxury resort.”  In other words, under the revised Code, a resort may be an appropriate venue as long as it is not a “luxury resort.”  This change probably reflects the trend since the Code was last revised for relatively modest hotels to include “resort” in their names.

It is timely to remind our readers that, although the PhRMA Code remains a voluntary industry code, its important function in risk reduction cannot be overstated.  The OIG long ago recommended that drug manufacturers adopt the Code, explaining in the Compliance Program Guidance for Pharmaceutical Manufacturers that, “[a]lthough compliance with the PhRMA Code will not protect a manufacturer as a matter of law under the anti-kickback statute, it will substantially reduce the risk of fraud and abuse and help demonstrate a good faith effort to comply with the applicable federal health care program requirements.”  Moreover, three states — California, Connecticut, and Nevada – have essentially incorporated the Code into state law by requiring pharmaceutical companies to develop and maintain compliance programs that include, or are consistent with, the PhRMA Code.

In a repeat of 2013, 2015 and 2018, Rep. Frank Pallone (D-N.J.) has yet again introduced the Food Labeling Modernization Act (FLMA).  As in the past, there are a few new things of note, and a few other things have been removed (e.g., requirements for sesame allergen labeling, which was accomplished earlier this year).

The latest version of the bill again directs FDA to establish a standard symbol system for front-of-package labeling for conventional foods.  A food would be misbranded unless its principal display panel bears “summary nutrition information that reflects the overall nutritional value of the food or specified ingredients” as required in regulations that would be issued by FDA.

As noted in the previous iterations, the 2021 FLMA focuses on nutrients.  As FDA has recognized, modern nutrition science no longer focuses on nutrients, but instead focuses on certain foods and dietary patterns

The FMLA seems to be a compilation of items that have been subject to petitions by various NGOs and others covering a wide range of topics, as well as a few things already in process as part of FDA’s Nutrition Innovation Strategy, including:

• Amending the Food Drug and Cosmetic Act to address the amount of wheat and grains in grain-based products, and real fruit, vegetable, and yogurt required in products bearing fruit, vegetable and yogurt claims. Interestingly, this provision also applies to the terms “froot” and “frooty.”
• Revising the term “healthy” and addressing nutrient content claims that “may not be compatible with maintaining healthy dietary practices” and how those claims should be qualified. Defining the term “natural.”
• The addition of “gluten-containing grain” when referencing food allergens, and the addition of “gluten-containing grain” to FSMA’s Hazard Analysis and Preventive Controls, as well as to food allergen inspections language.
• A review of Standards of Identity, as well as amendments to existing standards to allow for the use of salt substitutes where appropriate. The bill includes a specific provision related to a minimum level of live and active cultures per gram – an issue that has been addressed already in FDA’s June 2021 final rule to amend the standard of identity for yogurt.
• A study on the fortification of corn masa flour.
• Regulation to establish levels of allulose, polydextrose, sugar alcohols or isolated fibers above which require a warning that the food contains levels that cause “deleterious health effects.”
• A provision setting forth requirements for infant and toddler beverages.
• A study on text size and color contrast that make food labeling information visually accessible to most consumers.
• Regulations to establish requirements for the sale of food online, including access to label or labeling information prior to purchase

The bill does not include any provisions to fund the work to conduct the studies and establish the required regulations, and includes a provision requiring the issuance or proposed regulations within one year of passage (shortened from two years in the last iteration), and two years to finalize the regulations (shortened from three years) – and if final regulations are not issued within that timeframe, the proposed regulations become final on that deadline. This is an incredibly short timeframe, and would seemingly make final regulations that do not have the benefit of any incorporation of comments.  As to whether this version will eventually become a law, it is doubtful given that this is the fourth iteration and a partisan bill, but we will alert you if things change.

Meet the newest category of drug applications: the PANDA.  A PANDA, or the Pre-Hatch-Waxman Abbreviated New Drug Application, refers to abbreviated drug applications submitted and approved under sections 505(b) and 505(c) of the Federal Food, Drug, and Cosmetic Act (FDCA) prior to the enactment of the Hatch-Waxman Amendments in 1984, as FDA announced in the Federal Register last week.  Drugs approved as PANDAs are, for all intents and purposes, follow-on drugs approved based on FDA’s previous findings of safety and efficacy for a given drug, but, because they were not submitted under section 505(j) of the FDCA, they are not technically “Abbreviated New Drug Applications (ANDAs).”  Nonetheless, FDA has been calling them ANDAs and listing them in the Orange Book as ANDAs for years, but recent changes to the Orange Book have spurred some confusion.  Thus, FDA divided them into their own category and is now seeking Comments on whether the 505(b) or the 505(j) regulatory scheme should apply.

While generic drugs as we know them are a creation of the 1984 Hatch-Waxman Amendments, the Federal Register Notice explains that FDA first introduced the concept of an ANDA in 1968 to facilitate approval of Drug Efficacy Study Implementation (DESI) drugs.  By 1970, products evaluated as DESI drugs ultimately determined to be effective for one or more indications could be eligible for approval as ANDAs if they were similar or related to DESI drugs even if the drug products had not been marketed under a 505(b) New Drug Application (NDA).  However, because they are not necessarily the same as any previously approved drugs, the title “ANDA” is a bit of a misnomer.  Yet some of these ANDAs, which FDA is now calling PANDAs, still are marketed today, and, despite the misnomer, are listed in the Orange Book as ANDAs.

Because PANDAs are listed in the Orange Book as ANDAs but are not duplicates of any FDA-approved 505(b) drugs, there has been confusion about whether they can serve as Reference Listed Drugs (RLDs) for new ANDAs or 505(b)(2) NDAs.  As ANDAs, the PANDAs are not listed RLDs in the Orange Book; they are only Reference Standards (RS) and therefore cannot be relied on for FDA’s findings of safety and effectiveness.  While this was not an issue when FDA did not distinguish RLDs from its associated RS in the Orange Book (and therefore these PANDAs were listed as RLDs), it became confusing when FDA revised the Orange Book in 2017 to separately identify a RLD and a RS.  To address this confusion, FDA has decided to designate PANDA products as RLDs in an effort to provide “clarity both to prospective 505(j) ANDA applicants seeking to make generic versions of these products, and to applicants of 505(b)(2) applications that there is a finding of safety and effectiveness for these products that may be relied upon for approval.”  This approach, FDA explains, is consistent with its efforts to “advance competition and increase patient access to more affordable medicines.”

FDA already has started adding RLD designations for PANDAs to the Orange Book and will continue to do so “as expeditiously as resources permit.”  In the interim, ANDA applicants may also submit Controlled Correspondence to FDA seeking to designate a PANDA as a RLD.  FDA also provided a list of PANDA products currently identified as an ANDA in the Orange Book for reference.  FDA emphasizes, however, that this effort expressly excludes antibiotic drug products originally submitted under FDCA § 507.

The Federal Register Notice also solicits input from PANDA holders or other interested stakeholders related to FDA’s post-approval regulation of PANDAs.  Because PANDAs were submitted to FDA under section 505(b) and approved under 505(c)—which typically apply to NDAs—but are nonetheless treated as ANDAs, FDA recognizes ongoing confusion as to which regulatory scheme might apply for purposes of postmarketing reporting requirements, labeling updates, patent listing, exclusivity eligibility, and drug-safety related requirements or procedures; indeed, PANDA holders have typically elected which regulatory scheme to follow.  FDA therefore seeks industry comment on whether “there are regulatory or policy reasons for treating PANDAs differently from other 505(b) Application.”  Specifically, FDA asks for Comments on regulatory or policy rationales for treating PANDAs differently from other 505(b) applications in certain respects, in particular with respect to:

• Labeling requirements and updates, including safety-related information;
• Patent listing requirements;
• Eligibility for exclusivity; and
• Certain safety-related requirements, such as the postmarket studies and clinical trials, safety-labeling change requirements, and REMS requirements.

Further, FDA requests Comment on:

• Factors FDA should consider in determining a reasonable amount of time for PANDA holders to make changes to their practices, if applicable;
• Any additional steps FDA should take to highlight for PANDA holders that their ANDA is a PANDA;
• Any additional steps, beyond the Orange Book, that FDA should take to aid other interested persons in identifying PANDAs;
• Any necessary modifications to the PANDA list for accuracy; and
• Any other issues FDA should consider in assessing the regulatory framework for PANDAs under the FDCA.

FDA will accept Comments on its PANDA proposal—submitted to the docket in black and white (see what I did there?)—until December 13, 2021.

A determination of “intended use” is fundamental to FDA’s regulation of drugs and medical devices.  It is a primary basis for determining if an article is regulated by FDA at all, and if so, what regulatory requirements apply.  It is embodied in parallel drug and device regulatory definitions of intended use (21 C.F.R. §§ 201.128 (drugs), 801.4 (devices)).

FDA has now issued a final rule governing how intended use of a distributed product is to be determined.  Thus ends a saga that began with a proposal in 2015 to amend the “intended use” regulation.  The proposal was to remove the “knowledge provision,” which had always seemed to problematically suggest that a manufacturer could be held responsible for off‑label use if the manufacturer knew about it.

This provision stated (as of April 2021):

But if a manufacturer knows, or has knowledge of facts that would give him notice that a device introduced into interstate commerce by him is to be used for conditions, purposes, or uses other than the ones for which he offers it, he is required to provide adequate labeling for such a device which accords with such other uses to which the article is to be put.

The proposal to delete this provision made sense, because the off‑label uses under consideration are entirely lawful.  It is contrary to the statutory scheme to require a manufacturer to obtain cleared or approved labeling for an off-label label use simply based on knowledge that physicians were choosing to use the device off‑label.  It is especially problematic to criminalize these otherwise lawful sales until such clearance or approval can be obtained.

In 2017, however, FDA shockingly finalized this proposed rule without deleting the knowledge provision.  Indeed, FDA arguably strengthened it.  This set off a firestorm, eventually leading to a new proposed rule in 2020, which was much closer to the one in 2015.  We were generally in favor of it, although not without some criticisms.

FDA has now finalized the rule roughly as proposed last year.  On the whole, the amended intended use regulation is a modest improvement over the one in place for many decades.  (It could have been made much better; our more comprehensive proposal is here.)

The entire modified rule (device version) can be found here.  It states:

The words intended uses or words of similar import in §§  801.5, 801.119, 801.122, and 1100.5 of this chapter refer to the objective intent of the persons legally responsible for the labeling of an article (or their representatives). The intent may be shown by such persons’ expressions, the design or composition of the article, or by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. Objective intent may be shown, for example, by circumstances in which the article is, with the knowledge of such persons or their representatives, offered or used for a purpose for which it is neither labeled nor advertised; provided, however, that a firm would not be regarded as intending an unapproved new use for a device approved, cleared, granted marketing authorization, or exempted from premarket notification based solely on that firm’s knowledge that such device was being prescribed or used by health care providers for such use. The intended uses of an article may change after it has been introduced into interstate commerce by its manufacturer. If, for example, a packer, distributor, or seller intends an article for different uses than those intended by the person from whom he or she received the article, such packer, distributor, or seller is required to supply adequate labeling in accordance with the new intended uses.  (Italics supplied.)

We have three quick comments on the revised regulation:

First, the removal of the problematic knowledge provision is a significant victory for regulatory clarity and brings the regulation more in line with the statutory scheme.  This was the core of the 2015 proposal and it is amazing that it took six years to get back to that proposal.  Still, it is a welcome outcome.

Second, the new italicized proviso introduced in this rulemaking is important.  It further prevents FDA from inferring off-label intent based merely on knowledge that an otherwise lawfully marketed device is being used off-label.  We had suggested striking the word “solely” to clarify further that a manufacturer’s knowledge of off-label use should never enter into a FDA’s determination of intended use.  Nonetheless, although FDA did retain “solely,” it seems unlikely that mere knowledge of lawful off-label use could be used to bring a case against a manufacturer without significant unlawful promotion being involved as well.

Finally, as discussed here, this revised provision gives FDA the right to consider “design and composition” in determining intended use.  To the extent that FDA infers an unapproved new intended use based upon the design and composition of a device as it has been cleared or approved, then it may conflict with Section 513(i)(1)(E) of the FDCA.

That provision requires FDA limit the determination of intended use in premarket review to the proposed labeling.  If FDA believes based upon a device’s design (which includes composition) that an off-label use is possible and could cause harm, it may do no more than require certain cautionary labeling statements.  The agency may not require that the manufacturer obtain clearance or approval of the off‑label use implied by the design or composition.

It would contradict this statutory scheme for FDA to clear or approve a device with a particular design or composition and then turn around and seek to hold the manufacturer liable for an off-label intended use based upon the same design or composition.  That would be an inappropriate end run around Section 513(i)(1)(E).

About two weeks ago, FDA made an exciting announcement (and it remains exciting even if we’re late posting about it): FDA approved the first interchangeable biosimilar.  On July 30, 2021, FDA approved Semglee (insulin glargine-yfgn), an insulin product that relies on Lantus (insulin glargine) as its reference product.  In its Press Release, FDA explains that Mylan, the Semglee sponsor, submitted evidence that showed that “there are no clinically meaningful differences” between Semglee and Lantus “in terms of safety, purity, and potency (safety and effectiveness)” and that Semglee “can be expected to produce the same clinical result as Lantus” in any given patient.  As a result of this decision, Semglee can now be substituted for Lantus prescriptions without the intervention of a health care provider in accordance with state substitution regulations.  While Semglee was previously approved as a 505(b)(2) NDA referencing Lantus in June 2020, it was not rated as therapeutically equivalent (and therefore substitutable) to Lantus, and it immediately transitioned to a BLA upon approval as a result of the BPCIA (more on that below).  Thus, though Semglee is not new to the market, it is for the first time substitutable for Lantus without intervention of a health care provider.

Though Congress enacted the pathway for approval of interchangeable biosimilars in 2010 in an effort to incentivize competition to address the high prices of biologics, no sponsor had yet to crack the code to interchangeable approval until now.  In the past eleven years, we have seen a plethora of biosimilar approvals—which, like their name implies, are “similar” but not quite the “same” as and therefore substitutable for approved biologics—but substitutable biologics remained a pipe dream due to the difficulty of replicating a large molecule.  Biosimilars do provide a more affordable way for sponsors to get products onto the market—by referencing the clinical studies performed by the reference product sponsor—which, in theory, allows for the introduction of lower cost versions of expensive biologics.  But because these biosimilars cannot be substituted for their reference products—requiring health care professional brand awareness for both the brand name and the biosimilar—biosimilars have not quite made the dent in the market that Congress had hoped.  The expectation is that interchangeable biologics would make all the difference.

Yet, even with the first interchangeable biosimilar approval, it’s not quite clear when patients will see those savings.  Though no exclusivity is listed in the Purple Book yet, Semglee should be eligible for 12 months of exclusivity, which would block FDA licensure of any subsequent interchangeable biosimilars starting from its first commercial launch.  Even though Semglee has been approved and marketed as a biologic for a little over a year already and therefore first commercial marketing already has occurred, it’s interchangeable biosimilar is approved under a new BLA.  Interchangeable exclusivity, assuming it’s awarded, likely will be triggered at launch of the product under the new BLA, which, according to the NDC Code database, has not yet occurred.

Regardless of exclusivity, with no interchangeable competition as of yet, Mylan can price Semglee only slightly less than Lantus and still take market share, only marginally reducing costs to consumers.  As FDA states in its Press Release, “Biosimilars marketed in the U.S. typically have launched with initial list prices 15% to 35% lower than comparative list prices of the reference products,” but this 15 to 35% is not a huge relief for patients given the high cost of biologics.  For that reason, FDA merely states that biosimilars have the “potential to reduce health care costs.”  It’s not clear how much interchangeable approval will affect these health care cost reductions or how much competition is needed for prices to come down.  So, it remains to be seen if and when interchangeable Semglee will have any meaningful effect on insulin prices in the near future.

And it’s no surprise that the first interchangeable biosimilar is insulin.  FDA has long encouraged generic competition for insulin but developing a generic under an ANDA was very difficult “due to the complexities of these products”.  As part of the BPCIA, Congress amended the definition of “biologic” so that it included proteins, and protein products previously approved as drugs transitioned to biologics in March 2020, and, also under the BPCIA, became eligible for use as a reference product for biosimilar approval.  This transition eased the way for the development of insulin follow-on products because they no longer needed to be identical to their reference products for generic approval.  In 2019, Commissioner Gottlieb even noted: “The transition is particularly important for insulin” and that “FDA is dedicated to facilitating access to insulin.”  FDA further held a public hearing specific to insulin interchangeable biosimilar, and, in November 2019, issued a guidance on clinical immunogenicity specifically for insulin products.  To say that access to lower cost insulin products has been a priority for the Agency may be an understatement.

In tandem with its approval of Semglee, FDA issued a Consumer Update, as well as Fact Sheets and Stakeholder Toolkits, explaining the “treatment choices” arising from biosimilar and interchangeable approvals.  In contrast to claims made by certain reference product sponsors (which Pfizer took issue with back in 2018), FDA states in the Update that “Biosimilars are as safe and effective as the original biologic” and that consumers “can expect the same safety and effectiveness from the biosimilar over the course of treatment as you would from the original product.”  An interchangeable “meets additional requirements” for substitution, and “health care providers and patients can be confident in the safety and effectiveness of a biosimilar or an interchangeable biosimilar product, just as they would be for the FDA-approved original product.”  Even before this approval and Update, health insurers heard this message loud and clear and have taken to paying patients to switch to biosimilar versions of medications to encourage widespread use in an effort to address costs.

FDA, in its Consumer Updates, states that it “expects to approve more interchangeable products in the future.”  Now that FDA has hit this milestone and mapped a blueprint for its interchangeable expectations, hopefully we won’t have to wait too much longer for the flurry of interchangeable approvals needed to add some meaningful competition in the biologics market and presumably address biologic prices.

The Department of Health and Human Services (HHS) is proposing to rescind a Trump era rule that would have established a “most favored nation” (MFN) model to base Medicare Part B drug payment on international prices.  The Trump Administration rule had a troubled history.  The idea of basing Medicare drug reimbursement on prices in foreign countries was first proposed during the Obama Administration in 2016.  That proposal was withdrawn by the Trump HHS, but the notion of international reference pricing was subsequently incorporated in an October 2018 HHS Advance Notice of Proposed Rulemaking (ANPR) (see our post here).  HHS took no further action on the ANPR, but two years later, in the waning days of the Trump Administration, HHS issued a final rule with comment period establishing a MFN model for Part B rate setting methodology, circumventing the usual proposed regulation stage.  The MFN rule, which we summarized here, called for Part B payment for at least 50 high-expenditure drugs selected by HHS to be based on the lowest payment rate in 22 specified foreign countries, with a fixed add-on payment for drug administration.  Predictably, PhRMA, BIO, and numerous provider organizations took advantage of the procedural irregularity to challenge the rule on APA grounds in three separate lawsuits, and succeeded in obtaining injunctions blocking the rule from taking effect on January 1, 2021 (as we reported here and here).

Finally, CMS released a proposed rule on August 6 seeking to rescind the interim final rule.  According to CMS, the agency considered the nationwide preliminary injunction and multiple court challenges based on the rule’s procedural deficiencies, and stakeholder concerns about its start date and its far-reaching impact.  According to the proposal, CMS will review the issues identified by commenters and continue to explore opportunities to address high drug costs based on stakeholder comments to the interim final rule.  The proposed rule to rescind will be published in the August 10 Federal Register and comments will be due on October 9.

It is possible that CMS will issue a new proposed rule to impose international reference pricing in the future, but it is far more likely that the initiative will move to Congress.  Use of international reference pricing as a target for Medicare to negotiate prices with drug manufacturers appears in H.R. 3, the “Elijah E. Cummings Lower Drug Costs Now Act,” introduced by Representative Pallone on April 22.  This bill is the slightly revised and re-introduced version of the comprehensive drug pricing bill that passed the House during the last Congress, and represents the House Democrats’ drug pricing proposal.  On the Senate side, a drug pricing bill being developed by Ron Wyden, Chairman of the Senate Finance Committee, has been reported by the trade press to include the use of either international or domestic prices as reference benchmarks for setting payment rates under Medicare, and perhaps  even commercial insurance markets.

As always, we are following drug payment and price reduction initiatives in the Administration and Congress with great interest, and will be reporting on important developments as they occur.

On the heels of Genus Medical Technologies’ successful lawsuit against FDA—Genus was represented by Hyman, Phelps & McNamara PC—in both the District Court of D.C. and the Court of Appeals for the D.C. Circuit, FDA published a Federal Register Notice today (August 9) soliciting comments on its proposed approach to implementing the Court’s interpretation of the Federal Food, Drug, and Cosmetic Act (FDCA) distinction between drugs and devices.  As you may remember, Genus sued FDA back in 2019, alleging that FDA’s classification of, and putative regulation of, its barium sulfate products as drug products violated the FDCA because barium sulfate meets the statutory definition of medical device and therefore must be regulated as a device.  The FDCA definition hinges on the mechanism by which a product meets its primary intended purposes.  FDA claimed that Congress afforded FDA the discretion to regulate devices as drugs based an overlap in the statutory definitions of “drug” and “device” and chose to do so in the case of contrast agents in response to a 1997 court decision and related Citizen Petition.  Both courts disagreed with FDA’s broad assertion of discretion, as neither the statutory construction nor the legislative history supported such discretion.  Ultimately, FDA decided not to request a hearing en banc nor to seek review of the decision in the Supreme Court.

In light of this decision, FDA has acquiesced to regulating barium sulfate as a device, and is now exploring the application of this decision beyond the Genus products at issue in the litigation.   To that end, FDA’s Federal Register Notice explained that “FDA intends to regulate products that meet both the device and drug definition as devices, except where the statute indicates that Congress intended a different classification . . . .”  Further, FDA will comb through its previous classifications to “bring previously classified products into line with the Genus decision.”  Products—not just barium sulfate products or contrast agents—that satisfy the device definition will hereafter be regulated as devices regardless of previous classification.

FDA stated that it will now use as the determining factor, in accordance with the definitions in the FDCA, “whether the product achieves its primary intended purposes through chemical action within or on the body or is dependent upon being metabolized for the achievement of its primary intended purposes.”  While FDA previously stated in guidance that these factors typically determine how to regulate medical products, the Federal Register Notice admits that “FDA has not always examined these factors”—the exact problem that led to the Genus litigation in the first place—due to its presumed discretion.  Now, however, the courts have made clear that FDA must regulate devices as devices unless other provisions of the FDCA say otherwise.  Thus, FDA will evaluate the primary intended purposes and mechanism of action for all products, and then comb the statute for any language suggesting otherwise.  Previously, FDA applied that analysis only to those products that FDA decided merited such an analysis.

The Federal Register Notice specifically addresses medical imaging products, like those at issue in the Genus case.  While FDA previously regulated all imaging agents as drugs regardless of how they achieve their primary intended purposes, FDA will now “reexamine whether individual imaging agents meet the device definition.”  Existing approved imaging agents will transition from drug status to device status where applicable, and the Agency will aim to transition products in a way that does not disrupt supply.  FDA will publish a Federal Register Notice with a tentative list of approved products that will transition from drug to device and will provide an opportunity for industry to comment on the specific product’s classification.  Recognizing that the transition will require sponsors to shift from compliance with the drug regulatory scheme to the device scheme, FDA requests that stakeholders provide comments on the timeline for implicated products to come into compliance with device regulations, such as updating labeling, establishing procedures that comply with FDA’s Quality System Regulations, and preparing for device inspections.  FDA also seeks industry suggestions to facilitate the transition without disrupting supply.

FDA explains that the transition will take some time and consequently products previously regulated as drugs will still be subject to drug approval user fees (PDUFA and GDUFA user fees) until they transition: The Federal Register Notice explains that FDA “does not anticipate that the identification and transitioning of products from drug status to device status pursuant to the Genus decision will be completed before October 1, 2021.”  Thus, FDA suggests that sponsors of implicated products pay the drug user fees to avoid placement on the arrears list and any associated penalties.  Sponsors can then request a refund.  This could get complicated though, as FDA explains that the transition may affect program fee tier assessments for ANDA holders or facility fees.  And it is unclear how the excess user fees collected for devices would factor into the estimates to set the next year’s user fee rates.

FDA encourages all sponsors of implicated products to submit comments on this notice.  Until FDA takes action, there is nothing else for sponsors to do but to sit tight, but FDA includes no anticipated timeline for taking action.  However, for all “time-sensitive” inquiries, questions can be directed to a Genus-transition-specific email address at Drug_Device_Transition_Inquiry@fda.hhs.gov.  FDA also requests comments on “statutory provisions other than the drug and device definitions that may indicate Congressional intention regarding the appropriate regulatory pathway (i.e., drug or device) for certain types of products.”

Interestingly, throughout Genus’s dealings with FDA, the Agency insisted that very few products had been subject to its “discretion” to regulate devices as drugs, but the Federal Register Notice implies that the transition will affect more than a handful of stakeholders.  It’s unclear at this time how many products have been erroneously classified due to FDA’s purported discretion, and its request for comments on other statutory provisions that may direct the appropriate regulatory pathway suggests that application of this discretion may not have been limited to devices.  In that case, it’s not entirely clear how far FDA believed its discretion extended, and on what basis that discretion was predicated.  It definitely seems possible that FDA’s exercise of discretion went farther than the Agency represented.  We look forward to seeing the tentative list of products that need to transition, and reading industry comments.

Comments are due on October 8, 2021.

We are old enough to remember the “poke” function on Facebook, and too old to remember what purpose it served.  We are similarly at a loss to understand the purpose of Facebook’s new policy requiring that pharmaceutical manufacturers, telehealth companies, and online pharmacies apply for permission to advertise on Facebook.  This new policy goes into effect on August 25, 2021.

The new policy restricts advertising prescription drugs to the three types of entities mentioned above.  Prior to advertising prescription drugs, these entities must apply for permission to do so.  The application form is fairly basic and seems designed to ensure that the advertiser is a legitimate business. Telehealth companies and online pharmacies must submit certification from LegitScript, an organization that provides certification for online health entities, primarily in the addiction treatment space.  Pharmaceutical companies do not need to do this.

Advertisers are limited to promoting prescription drugs in the US, Canada, and New Zealand, and only to people over the age of 18.

So far, so good.  This is pretty basic, although other than ensuring that the entities are real and not scammers or selling illicit drugs, we’re not sure what purpose this serves.  For example, while pharmaceutical companies do submit paid advertisements, much of their Facebook and social media activity is on their own pages, whether corporate, product, or disease state (or, in many cases, all three).  This policy doesn’t seem to restrict those activities.  While those pages require activity by the user to view them, as opposed to ads which are proactively put in the Facebook user’s feed, it still seems to be inconsistent.  And what about influencer marketing?  It is unlikely that this policy impacts sponcon – an increasingly popular means to deliver messaging to a particular demographic.

Nor does the policy apply to prescription medical devices which we’ve also seen advertised endlessly on Facebook.  (Hey, as we opened with, we’re “of a certain age”.  And Facebook is good at targeting our demographic.  They don’t advertise video games and acne products to us.)

Facebook has stated that it can take up to four to six business days to validate information provided and to approve the application.  Since the policy goes into effect on August 25th, advertisers should postpone those summer vacations and “poke” Facebook.  (Seriously, can someone explain the poke function?)

On Monday August 2, 2021, the Senate took up for review H.R. 3684, the Infrastructure Investment and Jobs Act, following House passage of its version last month. Although the bipartisan bill largely deals with the nation’s transportation infrastructure, Section 90006 delays the so-called “rebate rule,” a Trump-era rule finalized by the Office of the Inspector General (OIG) of the U.S. Department of Health and Human Services in December 2020 to prevent Medicare Part D and Medicaid Managed Care plans from receiving rebates from manufacturers unless the rebates are passed through to pharmacies to reduce patient out-of-pocket expenses.

We previously explained the rebate rule and its likely impact on patients and payors here. The rebate rule significantly narrows the anti-kickback statute (AKS) safe harbor for discounts, so that it excludes manufacturer rebates to Medicare Part D plans (or their pharmacy benefits managers (PBMs)). See 42 C.F.R. § 1001.952(h). At the same time, the rule establishes a new safe harbor protecting rebates paid by manufacturers to Part D plans, Medicaid Managed Care plans, or their respective PBMs if the rebates are passed through to the dispensing pharmacy.  OIG argued that confidential manufacturer rebates to Medicare Part D plan sponsors and PBMs generally do not reduce patient out-of-pocket costs but act as kickbacks to these “middlemen.” CMS estimated that the rule would result in savings in individual out-of-pocket costs but such savings would be more than offset by increased premiums. The rule was estimated to cost the federal government around $196 billion over ten years.

The new safe harbor was originally effective on January 29, 2021 and the new discount safe harbor exclusion on January 1, 2022, but these effective dates were delayed until January 1, 2023 pursuant to court orders in a lawsuit brought by the PBM industry association.  Section 90006 of the proposed infrastructure bill would further delay implementation of the rebate rule until January 1, 2026, providing the government with an estimated savings of $49 billion. See bipartisan bill summary at 5. If the infrastructure bill passes the Senate, the rebate rule delay would still have to survive reconciliation with the House version of the infrastructure bill, which did not contain the delay provision.

Last week the Drug Enforcement Administration (“DEA”) issued a direct final rule clarifying requirements about who may record the supplier’s DEA registration number on a single-sheet DEA Form 222 (“single-sheet form”).  Clarification Regarding the Supplier’s DEA Registration Number on the Single-Sheet DEA Form 222, 86 Fed. Reg. 38230 (July 20, 2021).  DEA issued a final rule in September 2019 implementing a new single-sheet form to replace triplicate carbon copy DEA Form 222s (“triplicate forms”).  New Single-Sheet Format for U.S. Official Order Form for Schedule I and II Controlled Substances (DEA Form 222), 84 Fed. Reg. 51368 (Sept. 30, 2019).

DEA requires registrants use DEA-222s to transfer schedule I and II controlled substances.  (Registrants may also use DEA’s electronic Controlled Substance Ordering System (“CSOS”)).  Both the single-sheet and triplicate forms require information about the supplier, including their name, address and DEA registration number.  21 C.F.R § 1305.12(c).  DEA explained, consistent with the triplicate form, that the final rule requires the supplier when filling the order to record their DEA registration number on the DEA-222.  DEA notes that the field on the triplicate form for the supplier’s registration number is in the section marked “To Be Filled in By Supplier” while the field on the single-sheet form for the supplier’s registration is in the section titled “To Be Filled In By the Purchaser.”  Needless to say, the inconsistency has caused some confusion for DEA registrants.

The final rule clarifies that either the purchaser or, if not entered by the purchaser, the supplier, may record the supplier’s DEA number on a single-sheet form.  Allowing the purchaser to omit a supplier’s DEA registration number for the supplier to add later provides flexibility for when a supplier may have to fill an order from a different registered location than the one contemplated by a purchaser.

As a reminder, registrants may only use their triplicate forms until they exhaust their supply, after which they must use single-sheet forms.  But in any case, registrants must cease using triplicate forms as of October 30, 2021, after which time they must use single-sheet forms.  21 C.F.R. § 1305.20.

As a direct final rule, the rule becomes effective October 18, 2021, unless DEA receives significant adverse comment.  DEA will withdraw the rule by September 20, 2021, if it receives significant adverse comment.  Electronic comments must be submitted, and written comments postmarked, on or before August 19, 2021.

Maine and Nevada previously enacted laws requiring drug manufacturers to report information about the pricing of their products. (See our coverage here and here). As summarized below, each state has recently updated their reporting requirements.  Both states’ new requirements will become effective in October 2021 and should be considered as manufacturers prepare for state drug price transparency reporting in 2022.

Maine

LD 686 provides the Maine Health Data Organization with new authority to publish a list of the prescription drugs for which the manufacturer has: (A) increased the wholesale acquisition cost (WAC) of a brand-name drug by more than 20% per pricing unit; (B) increased the WAC of a generic drug that costs at least $10 per pricing unit more than 20% per pricing unit; or (C) introduced a new drug with a WAC that exceeds the threshold for a specialty drug under the Medicare Part D Program (currently $670). This list will be posted on a publicly accessible website no later than January 30, 2022 and updated annually thereafter.

LD 686 also revises the process for disclosures by manufacturers, wholesale drug distributors and pharmacy benefits managers (PBMs). Previously, manufacturers, wholesale drug distributors and PBMs were required to provide “pricing component data” within 60 days of a request from the state. Now, the state will post a list of drug product families for which it intends to request pricing component data from manufacturers, wholesale drug distributors, and PBMs on a publicly available website on or before February 15th each year. No sooner than 30 days after the posting of the list, the state shall provide notice via email to manufacturers, wholesale drug distributors, and PBMs of its request for pricing component data. These entities will then have 60 days to provide the pricing component data to the state. “Drug product family” is defined as “a group of one or more prescription drugs that share a unique generic drug description and drug form.” In determining which drug product families are included on the list, the state intends to consider prescription drugs included on the public notice list described above, as well as the 25 costliest drugs, the 25 most frequently prescribed drugs, and the 25 drugs with the highest year-over-year cost increases.

The definition of “manufacturer” has also been updated to specify that a manufacturer is an entity that manufactures or repackages, and sets the WAC for, prescription drugs.

Finally, LD 686 updates the confidentiality provisions that apply to information disclosed to the state by manufacturers, wholesale drug distributors and PBMs. While information could previously be shared in the aggregate if it did not allow for the identification of an individual drug, the state may now share information in the aggregate “as long as it is not released in a manner that allows the determination of individual prescription drug pricing contract terms covering a manufacturer, wholesale drug distributor or [PBM].” In addition, the state may share information that is publicly available.

Nevada

Nevada’s reporting requirements have previously been primarily focused on drugs deemed to be essential for treating asthma and diabetes and included on an annual list published by the state (the “Essential Drug List”). SB 380 removes asthma from the Essential Drug List, and provides the state with authority to compile an additional new list of drugs for which manufacturers will need to report information. The latter list, which will be published at the same time as the Essential Diabetes Drug list, will consist of prescription drugs with a WAC exceeding $40 for a course of therapy that have been subject to an increase in WAC of 10% or greater during the immediately preceding calendar year or 20% or greater during the immediately preceding two calendar years (the “WAC Increase List”). A “course of therapy” is defined as the recommended daily dosage as set forth on the FDA-approved label for 30 days, or, if the normal course of treatment is less than 30 days, the recommended daily dosage set forth on the FDA-approved label for the duration of the recommended course of treatment. Manufacturers of drugs that appear on either or both of the current Essential Drug List or WAC Increase List must submit reports to the state by April 1 of each year. The elements of the manufacturer’s reports remain substantially the same, however SB 380 adds new reporting elements if the manufacturer acquired the intellectual property for the drug within the immediately preceding five years.

SB 380 also updates the reporting requirements for PBMs and adds a new reporting requirement for wholesalers that sell prescription drugs included on either or both of the lists compiled by the state. By April 1 of each year, wholesalers that sell these products must report information regarding WAC and rebates with manufacturers, pharmacies, PBMs, and other entities. Wholesalers that do not comply with the reporting requirements are subject to the same penalties that can be assessed against manufacturers and PBMs – i.e., up to $5,000 per day of violation.

On July 1, 2021, the Federal Trade Commission (FTC) announced the availability of the pre-publication of the final rule on “Made in USA” (MUSA) claims in the Federal Register. The final rule was published on July 14, 2021.  We previously reported on events that resulted in this rule.

FTC received more than 700 comments in response to the notice of proposed rulemaking from individuals, industry groups, consumer organizations, and members of Congress. FTC concluded that none of the comments provided a compelling basis to change the substantive requirements of the proposed rule.

The rule does not set a new standard for MUSA claims.  Instead, it authorizes FTC to seek not only an injunction but also civil penalties of up to $43,280 per violation of the final rule.

The new rule applies not only to product labeling, but to any “mail order catalog” or “mail order promotional material” that includes a seal, mark, tag, or stamp that labels a product as having been made in the United States.  Mail order catalogs and promotional material are defined as “any materials, used in the direct sale or direct offering for sale of any product or service, that are disseminated in print or by electronic means, and that solicit the purchase of such product or service by mail, telephone, electronic mail, or some other method without examining the actual product purchased.”

As we previously reported, two Commissioners did not support the proposed rule and questioned FTC’s application of the rule to materials that did not appear to constitute labels, such as mail order catalogs.  In the preamble to the final rule, FTC concludes that the final rule does not cover MUSA claims in all advertising.  Instead, it covers labels appearing in all contexts, whether, for example, they appear on product packaging or online.  FTC does not clarify the definition of labels and we anticipate that the meaning of that term will become a topic of discussion when FTC asserts that a Company is liable under the new rule for a claim appearing in a context that arguably does not constitute a “label.”

Some notes about the final rule:

• It applies only to unqualified MUSA label claims.  For false or misleading qualified MUSA claims, FTC authority remains limited to injunctive relief.
• It includes a list of equivalents to “Made in USA” in 16 C.F.R. § 323.1 (listing “made,” “manufactured,” “built,” “produced,” “created,” or “crafted” in the United States or in America).  However, this list is not exhaustive.
• The final rule does not supersede, alter, or affect the application of any other federal statute or regulation relating to country-of-origin labeling requirements, including but not limited to regulations issued under the Federal Meat Inspection Act, the Poultry Products Inspection Act.; or the Egg Products Inspection Act.  As readers of our blog know, “Product of USA” and other country of origin labeling issues on meat and poultry products have been an issue of discussion in recent years.  Last year, in response to a Petition regarding such claims, USDA committed to  rulemaking to address the voluntary use of “Product of USA” claims on meat and poultry.  On July 1, 2021, USDA announced its plan to initiate a top-to-bottom review of “Product of USA” claims.  (Incidentally, earlier in June, the National Cattlemen’s Beef Association submitted a Petition to USDA requesting notice and comment rulemaking regarding “Product of USA” claims on beef products).
• The effective date of the rule is Aug. 13, 2021.