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  • FDA Publishes Discussion Paper Seeking Feedback on 3D Printing of Medical Devices at the Point of Care

    On December 10, 2021, FDA issued a discussion paper titled 3D Printing Medical Devices at the Point of Care seeking feedback on FDA regulatory oversight of various 3D-printing scenarios, in order to inform future policy development.

    This discussion paper is not the first time that FDA has grappled with the tricky regulatory questions presented by 3D printing.  In October 2014, FDA held a public workshop titled “Additive Manufacturing of Medical Devices: An Interactive Discussion on the Technical Considerations of 3D Printing.”  In May 2016, FDA released a draft guidance document titled “Technical Considerations for Additive Manufactured Devices” (see our blog post on the draft guidance here), which was finalized in 2018 (see our blog post on the final guidance here).  This guidance document is still in effect today.

    The recent discussion paper is not a guidance document and FDA says it is not intended to convey any current policy.  Rather, it is meant to present various scenarios related to use of 3D‑printed devices at the point of care, along with a series of discussion questions seeking input from industry and other stakeholders.

    The discussion paper starts with an acknowledgment of the benefits of 3D printing at the point of care.  Specifically, that it allows for fast production of “patient-matched devices” (i.e., devices that are fitted specifically to a patient’s anatomy), and anatomical models for surgical planning.  3D printing has also allowed for production of medical devices such as face shields, face mask holders, nasopharyngeal swabs, and ventilator parts during device shortages caused by the COVID-19 pandemic.

    However, the discussion paper summarizes, there are a number of regulatory challenges associated with 3D printing, including (1) ensuring devices are safe and effective; (2) ensuring appropriate controls are in place for design and manufacturing so that product specifications are met; (3) clarifying which entities are responsible for compliance with regulatory requirements; and (4) ensuring that point-of-care facilities have the necessary training and expertise to produce 3D-printed devices.

    The discussion paper provides an overview of FDA’s current approach to regulation of 3D-printed devices.  In brief, such devices can be commercially distributed to the general public for non-medical purposes without FDA regulation (e.g., use in education, construction, art, and jewelry).  Additionally, general purpose manufacturing equipment, including 3D printers and mills, are not subject to FDA regulation if not specifically intended to produce medical devices.  FDA does regulate 3D printing equipment and activities when intended to produce regulated medical devices (i.e., products intended for medical purposes).  The regulatory requirements for the devices that are 3D-printed generally govern the responsibilities of the entities that are manufacturing and distributing the 3D printing equipment for that use at the point of care.

    The proposed regulatory approach in the discussion paper incorporates several high-level concepts:

    • The extent of FDA oversight should correspond with the risks of the printed device and the 3D printing of the device at the point of care;
    • The device specifications should not change based on the location of manufacture (i.e., a traditional manufacturing site vs. the point of care);
    • The capabilities available at a point-of-care healthcare facility can help mitigate production risks;
    • Entities involved in 3D printing of devices should understand their regulatory responsibilities under the Federal Food, Drug, and Cosmetic Act; and
    • FDA intends to leverage existing regulatory controls for the regulation of 3D printing at the point of care, including existing standards and processes.

    The discussion paper outlines three illustrative scenarios, to facilitate discussion and feedback from stakeholders.

    The first scenario is a healthcare facility using a medical device 3D-printing production system.  FDA is seeking feedback on the challenges that a manufacturer of a 3D-printing system may face in being responsible for FDA regulatory requirements for devices that are 3D-printed by independent healthcare facilities, including with respect to adverse event reporting.  FDA also asks questions about the challenges related to any post-production manufacturing steps that may be undertaken by a healthcare facility after the device is printed.

    The second scenario is a traditional manufacturer that is co-located at or near the healthcare facility site, where the 3D printing is conducted by the manufacturer to supply devices to the healthcare facility.  In this scenario, FDA is interested in the possibility of frequent design changes that may occur in response to clinical feedback (e.g., requests for different sizes or geometries after a printed device is examined by a healthcare provider).  FDA also asks whether there are any specific considerations in this co-location scenario that differ from traditional non-3D printed manufacturing processes for devices.

    The third scenario is a healthcare facility that has assumed all traditional manufacturer responsibilities, including complying with all FDA regulatory requirements that apply to traditional device manufacturers.  The discussion paper notes that healthcare facilities already have internal quality systems in place that could be adapted to compliance with device regulatory requirements (e.g., complaint handling and adverse event reporting processes) and staff trained in the maintenance of equipment.  FDA is seeking feedback on which parts of FDA’s regulatory framework would be the easiest for healthcare facility’s to implement, and which would present the greatest challenges.

    Separate from these three scenarios, the discussion paper seeks feedback on considerations for “very low risk” devices.  FDA has not yet defined “very low risk,” but the discussion paper states that it is considering developing a list of characteristics that would help identify very low risk devices.  The discussion paper includes a question for stakeholders on a proposed list of considerations in identifying these devices (e.g., intended use, device class, whether the device requires sterilization).  For these devices, FDA is considering exercising “regulatory flexibility” when these devices are 3D-printed at a healthcare facility, which we assume refers to some level of enforcement discretion with regard to compliance with manufacturing regulatory requirements.

    The discussion paper states that FDA will use the feedback submitted to the public docket it has opened (Docket No. FDA-2021-N-1272) to inform future policy development.  Comments may be submitted until February 7, 2022.

    Categories: Medical Devices

    Is The Skinny Label Back From the Dead?

    Since the August 2021 decision in GSK v. Teva, the generic industry has been waiting with bated breath to see whether the section viii carve-out (and thus skinny-labeled generic drugs) will survive.  With the District Court of Delaware’s January 4 decision in a similar case (brought by GSK’s lawyers), Amarin v. Hikma, the generic industry can have some hope.  Relying heavily on the Federal Circuit’s contention that the decision in GSK v. Teva was a “narrow, case-specific review,” Judge Andrews dismissed Amarin’s suit against Hikma in which Amarin alleged that Hikma’s skinny-labeled generic icosapent ethyl induced infringement of Amarin’s method-of-use patents.  The Court, however, would not dismiss similar allegations as applied to health insurer.

    In the wake of GSK v. Teva, in which the Federal Circuit reversed the District Court of Delaware’s decision to overturn a jury verdict finding that Teva induced infringement of GSK’s method-of-use patents covering carvedilol, several Reference Listed Drug (“RLD”) sponsors sued generic manufacturers marketing skinny-labeled versions of their products under the same induced infringement theory that prevailed in GSK v. Teva.  (The Federal Circuit twice reversed the District Court decision at issue in GSK v. Teva, but Amarin v. Hikma was filed in November 2020 after the Court’s first decision issued in October 2020.)  One of those RLD sponsors, Amarin, sued generic sponsor Hikma for induced infringement of method-of-use three patents listed in the Orange Book for Amarin’s Vascepa (icosapent ethyl) after FDA approved Hikma’s product with the patented use carved out, alleging that Hikma’s approved label “is ‘not skinny-enough.’”  Amarin also sued Health Net, an insurer that provides coverage for both Vascepa and Hikma’s generic.

    The procedural background of Amarin v. Hikma (unlike that of GSK v. Teva) is simple:  Amarin received FDA approval for Vascepa as adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia in 2012 (referred to as the “SH indication”) and as an adjunct to statin therapy in patients with elevated triglyceride levels and established or risk factors for cardiovascular disease in 2019 (the “CV indication”).  Amarin listed Vascepa in the Orange Book with multiple patents, including several method-of-use patents covering only the CV indication.  In accordance with the statutory “section viii” provision, FDA approved Hikma’s generic product referencing Vascepa in May 2020 omitting information pertaining to the patented CV indication.

    Five months later, Amarin sued Hikma for induced infringement arguing, essentially, that Hikma’s labeling does not adequately carve out Amarin’s protected method of use concerning the CV indication and thus induced infringement of Amarin’s patents.  Specifically, Amarin alleged that Hikma’s label “teaches CV risk reduction” due to “a notice regarding side effects for patients with CV disease” and an absence of a statement that the generic “should not be used for the CV indication….”  Hikma countered that the notice of side effects for patients with CV disease is a warning, not an instruction to use the product in CV patients, and that Hikma has no duty to provide a statement discouraging an infringing use.  The Court agreed with Hikma, finding that a warning “is hardly instruction or encouragement.”  The Court also explained that the Federal Circuit has already rejected Amarin’s argument that generic labels must contain a clear statement discouraging use of the patented indication.  Further, the Court noted, Amarin did not sufficiently plead that Hikma, “took affirmative steps to induce” infringement in its labeling.

    Amarin also argued that Hikma’s non-label claims—public statements, including press releases and its website—induced infringement by stating that Hikma’s product is the “generic equivalent to Vascepa” and that Vascepa “is indicated, in partfor the SH indication while citing to sales numbers for Vascepa in all indicationsAmarin also took issue with the statement on Hikma’s website that its generic icosapent ethyl isAB rated” in the “Therapeutic Category: Hypertriglyceridemia.”  Ultimately, the Court explained that the question here is whether these statements are sufficient to support inducement “without a label or other public statements instructing as to infringing use.”  The Court said that they are not, as these statements “might be relevant to intent but they do not support actual inducement.”  “Intent alone is not enough; Amarin must plead an inducing act.”

    The Court took pains to distinguish Hikma’s labeling and promotion from Teva’s in GSK v. Teva.  There, the Court explained, Teva’s promotion of carvedilol for as a cardiovascular agent that is a generic of GSK’s Coreg for the “treatment of heart failure,” as well as its direction to the partially carved-out labeling—as opposed to Hikma’s more general “AB rated” language—differentiated GSK v. Teva from this case.  The Court again made sure to emphasize language from GSK v. Teva explaining thatit is still the law that ‘generics could not be held liable for merely marketing and selling under a “skinny” label omitting all patented indications, or for merely noting (without mentioning any infringing uses) that FDA had rated a product as therapeutically equivalent to a brand-name drug.”

    Taking induced infringement for skinny labeling in a different direction, Amarin also sued health insurer Health Net.  Amarin alleged that Health Net’s formulary placement induces infringement of Amarin’s method-of-use patents covering Vascepa.  Specifically, Health Net lists Hikma’s generic in a lower tier than Amarin’s Vascepa, making the product available for a lower co-pay when the generic is dispensed.  Given state automatic substitution laws, Amarin alleges that Health Net’s placement of Hikma’s generic on the formulary “leads to substitution on ‘all VESCEPA (sic) prescriptions, not just the prescriptions directed to the’ SH indication.”

    The Court denied Health Net’s Motion Dismiss, finding that Amarin pled enough facts to allege that Health Net knew of Amarin’s CV patents, made affirmative acts to induce infringement by placement on the formulary, and had specific intent to induce based on the listing of the patented indication on the insurer’s generic icosapent ethyl capsules prior authorization form.  Thus, the court concludes, “Health Net’s placement of generic icosapent ethyl on a preferred tier encourages the substitution of the generic for the branded drug, including for the patented indication.”  The issue, explained the Court, is the incentives the formulary puts in place to prescribe the generic regardless of the indication.  Whether Health Net induced infringement is a “factual question” that cannot be resolved on a motion to dismiss.

    As we have learned from GSK v. Teva, Amarin’s case against Hikma could still end very differently if it is appealed to the Federal Circuit.  In GSK v. Teva, the District of Delaware was certain that Teva’s promotion did not induce infringement of GSK’s patent, going as far as to overturn a jury verdict, but the Federal Circuit reversed.  Amarin could appeal this dismissal, and the Federal Circuit could do the same here and reinstate the case.  So, while generic sponsors may have a brief reprieve from concerns that the skinny-label is altogether dead, the Federal Circuit could kill it once again.  Thus, until the Federal Circuit addresses this case, it’s difficult to read too much into the decision here.  Of course, if the Federal Circuit doesn’t hear this case, the Court’s fact-specific inquiry suggests that the implications of GSK v. Teva are less far-reaching than initially believed.

    The case against Health Net introduces another wrinkle to the skinny-label debate though.  That insurers may have some liability for induced infringement merely by listing a skinny-labeled generic on a formulary could dissuade health insurers from covering skinny-labeled generics.  This would either force patients to brand-name products or to pay out of pocket for generics; in either scenario, it would increase prices for patients.  But thus far Amarin’s allegations have only survived a Motion to Dismiss; it’s entirely possible that this theory of induced infringement is rejected by the Court sometime in the future.

    We still have a way to go until there’s certainty with respect to the future of the skinny label.  GSK v. Teva is still awaiting a decision from the Federal Circuit on Teva’s request for rehearing from the full panel, Amarin may appeal the Hikma decision, and the claims against Health Net must still be litigated.  So while we’re hesitant to say that the skinny-label has been resuscitated, we’re not ruling out the possibility of resurrection.

    We are hiring! HP&M Seeks Mid-Level FDA Regulatory Attorney

    Hyman, Phelps & McNamara, P.C. is the largest dedicated FDA law firm, and we need attorneys to help our clients bring pharmaceutical drugs and medical devices to market.  Our ideal candidates have experience working at FDA (CDER, CDRH, CBER, or OCC), or have at least two years working in private practice with a sophisticated FDA practice group.  Our firm culture is collaborative, the work environment is flexible, and the subject matter is intellectually stimulating.   If you want to join our team, please send your resume to Anne Walsh, awalsh@hpm.com.

    Categories: Jobs

    District Court Interprets EKRA

    “EKRA” refers to the Eliminating Kickbacks in Recovery Act, which was part of the Substance Use – Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act of 2018.  EKRA is codified at 18 U.S.C. § 220 and was described on HP&M’s blog here.  Until recently, no federal court had had occasion to interpret EKRA.  That changed on October 18, 2021 when the Federal District Court for the District of Hawaii handed down a decision that construed key terms in the statute.

    I.   The Eliminating Kickbacks in Recovery Act (“EKRA”)

    In general, EKRA prohibits, knowingly and willfully, soliciting, receiving, paying or offering kickbacks in exchange for referring to, inducing a referral to, or using the services of a recovery home, clinical treatment facility, or laboratory.

    EKRA defines “recovery home” as “a shared living environment that is, or purports to be, free from alcohol and illicit drug use and centered on peer support and connection to services that promote sustained recovery from substance use disorders.”  18 U.S.C. § 220(e)(5).  “Clinical treatment facility” is defined as “a medical setting, other than a hospital, that provides detoxification, risk reduction, outpatient treatment and care, residential treatment, or rehabilitation for substance use, pursuant to licensure or certification under State law.”  18 U.S.C. § 220(e)(2).  “Laboratory” is defined broadly as “a facility for the biological, microbiological, serological, chemical, immuno-hematological, hematological, biophysical, cytological, pathological, or other examination of materials derived from the human body for the purpose of providing information for the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health of, human beings.”  42 U.S.C. § 263a.  Note that while EKRA was passed as part of a bill to combat the opioid crisis, its definition of “laboratory” applies to lab activities far beyond those involving opioid or other drug testing.

    EKRA is also broadly written because it applies to all “health care benefit” programs.  A “health care benefit program” is defined as “any public or private plan or contract, affecting commerce, under which any medical benefit, item, or service is provided to any individual, and includes any individual or entity who is providing a medical benefit, item, or service for which payment may be made under the plan or contract.”  18 U.S.C. § 24(b) (emphasis added).  Note that EKRA’s reach is broader than the Anti-Kickback Statute, which applies only to “federal healthcare programs” — e.g., Medicare, Medicaid, Tricare, etc.

    EKRA also contains several exemptions.  18 U.S.C. § 220(b).  In particular, the employee exemption, relevant to the S&G Labs Haw., Ltd. Liab. Co. v. Graves case described below, states that it is not unlawful to pay an employee/independent contractor (as part of a bona fide employment relationship) to the extent that the employee’s payment does not vary by the following:

    (A) the number of individuals referred to a particular recovery home, clinical treatment facility, or laboratory;

    (B) the number of tests or procedures performed; or

    (C) the amount billed to or received from, in part or in whole, the health care benefit program from the individuals referred to a particular recovery home, clinical treatment facility, or laboratory.

    18 U.S.C. § 220(b)(2).

    EKRA violations constitute a criminal offense with a maximum sentence of up to 10 years imprisonment and/or a $200,000 fine for each violation of the statute.

    II.   S&G Labs Haw., Ltd. Liab. Co. v. Graves, No. 19-00310 LEK-WRP, 2021 U.S. Dist. LEXIS 200365 (D. Haw. Oct. 18, 2021)

    A.   Background Facts

    S&G Labs Hawaii, LLC (“S&G Labs”) is a Hawaiian laboratory company that performs various lab testing services including toxicology (for both legal and illicit substances) and COVID testing.  These lab tests are performed for physicians, substance abuse treatment centers and other types of organizations.

    The litigation between S&G Labs and Graves involved multiple claims and counterclaims, many of which are not related to EKRA.  This summary will focus on the EKRA issue and facts pertinent to that issue.

    S&G Labs’ pay structure was important to the Court’s decision regarding the EKRA issue.  S&G Labs alleged during the litigation that they are paid on a “per test” basis by third party insurers, government agencies under the Medicare and Medicaid programs, and direct “self-pay” by some individuals.  S&G Labs has no contractual relationships with the entities that referred clients to S&G Labs.  Specifically, S&G Labs has no contracts with any physicians, substance abuse counseling centers, or other organizations in need of having individuals tested.   S&G Labs receives no compensation from physicians, substance abuse treatment centers, or other similar types of organizations who refer individuals for testing.  Those “clients” are free to cease using the services of S&G Labs and direct their patients to other medical lab testing companies at any time.  S&G Labs Haw., Ltd. Liab. Co. v. Graves, 2021 U.S. Dist. LEXIS 29248, at *2-3 (D. Haw. Feb. 17, 2021).

    Graves was an employee of S&G Labs whose job was to oversee client accounts.  His job was governed by an employment contract that contained both salary provisions and restrictive covenants.  Graves was compensated by receiving a $50,000 salary.  Graves also received 35% of the monthly net profits generated by his client accounts and a portion of the 35% monthly net profits generated by the accounts handled by the S&G Labs’ employees who Graves managed.  Id. at *4.  Graves’s employment contract also prohibited the following:  engaging with any business competitor, making disparaging remarks about S&G Labs, soliciting current employees to resign from S&G Labs and soliciting particular clients while an employee and for two years post-employment.  Id. at *4-6.

    B.   EKRA Issue

    The EKRA issue in this case centered on how Graves was compensated.  S&G Labs received legal advice in 2018/2019 that, under EKRA, employee compensation could not vary based on the number of lab tests performed or revenue received by S&G Labs.  S&G Labs, therefore, concluded that they could not pay Graves 35% of the monthly net profits generated by his client accounts and a portion of the 35% monthly net profits generated by the accounts handled by the S&G employees who Graves managed.

    S&G Labs and Graves, however, could not reach agreement on a new compensation model.  Ultimately, Graves alleged that S&G Labs breached his employment contract.  S&G Labs argued that Graves’s employment contract became illegal and, thus, unenforceable.  The issue for the Court was, therefore, what effect did EKRA’s enactment have on Graves’s employment contract?  The district court was required to engage in statutory interpretation to answer this question.

    C.   District Court’s Holding

    The Court first held that S&G Labs is a “laboratory” as defined by EKRA.  S&G Labs Haw., Ltd. Liab. Co. v. Graves, 2021 U.S. Dist. LEXIS 200365, at *29 (D. Haw. Oct. 18, 2021).

    The Court next interpreted the statutory terms “remuneration” and “individual” as those terms are used in EKRA.

    (a) Offense.–Except as provided in subsection (b), whoever, with respect to services covered by a health care benefit program, in or affecting interstate or foreign commerce, knowingly and willfully–

    (2) pays or offers any remuneration (including any kickback, bribe, or rebate) directly or indirectly, overtly or covertly, in cash or in kind–

    (A) to induce a referral of an individual to a recovery home, clinical treatment facility, or laboratory; or

    (B) in exchange for an individual using the services of that recovery home, clinical treatment facility, or laboratory.

    18 US.C. § 220(a) (emphasis added).

    EKRA does not define these terms, so the Court looked to the Anti-Kickback Statute.  Applying the definitions in the Anti-Kickback Statute, the Court defined “individual” as “an individual, a trust or estate, a partnership, or a corporation (citing, 42 U.S.C. § 1301(a)(3)) and concluded that “for purposes of the anti-kickback statute, an “individual” is not an artificial entity.”  Id. at *31-32.

    The Court relied on Section 1301(c) to define “remuneration” as including payments from an employer to an employee.  Specifically, Section 1301(c) states:

    Whenever under this chapter or any Act of Congress, or under the law of any State, an employer is required or permitted to deduct any amount from the remuneration of an employee and to pay the amount deducted to the United States, a State, or any political subdivision thereof, then for the purposes of this chapter the amount so deducted shall be considered to have been paid to the employee at the time of such deduction.

    42 U.S.C. § 1301(c) (emphasis added).

    The Court interpreted EKRA in the same manner as the Anti-Kickback Statute because, as the Court explained, an act should “be interpreted as a symmetrical and coherent regulatory scheme, one in which the operative words have a consistent meaning throughout.”  S&G Labs Haw., Ltd. Liab. Co. v. Graves, 2021 U.S. Dist. LEXIS 200365, at *30 (D. Haw. Oct. 18, 2021), citing Gustafson v. Alloyd Co., 513 U.S. 561, 569 (1995).

    Applying the definitions of “individual” and “remuneration” the Court concluded that EKRA applied to Graves and his employment contract.  And, importantly, Graves’s salary structure constituted remuneration under EKRA.  However, because Graves was not paid for use of S&G Labs services, “[t]he critical issue is whether Graves’s remuneration was to induce a referral of an individual to S&G.”  Id. at *32, citing 18 U.S.C. § 220(a)(2)(A).

    The Court noted that Graves’s salary structure undoubtedly induced him to generate business for S&G Labs.  However, Graves’s clients were physicians/physician offices — not individual patients in need of lab services.  Moreover, S&G Labs is not directly compensated by their clients (e.g., physicians and substance abuse counseling centers).  S&G Labs is primarily compensated by patient’s insurance providers.  EKRA, however, prohibits kickback payments in exchange for inducing “individual” referrals and in exchange for “individuals” using a laboratory’s services.  18 U.S.C. § 220(a)(2).  The Court, therefore, concluded that Graves’s employment contract using commission-based incentives did not violate EKRA because his clients were not “individuals” as that term is used in EKRA.  The Court further noted that the EKRA’s exceptions were inapplicable because “Graves’s commission-based compensation from S&G [Labs] was a payment made by an employer to an employee, and it was determined based upon the number of tests that S&G performed.  Thus, the exception in § 220(b)(2) would not apply to Graves’s compensation under his Employment Agreement.”  S&G Labs Haw., Ltd. Liab. Co. v. Graves, 2021 U.S. Dist. LEXIS 200365, at *34-35 (D. Haw. Oct. 18, 2021).

    III.   Conclusion

    EKRA is a broadly written statute that applies to all lab services billed to any public or private health insurance.  EKRA also applies to lab activities beyond those involving drug testing.  All labs must be aware of EKRA to avoid paying illegal kickbacks to generate business.

    In this specific case, there was no evidence cited, and the Court did not analyze, whether or not Graves may have aided and abetted or been involved in a conspiracy with his clients.  In future cases, there will likely be a different result where a lab employee conspires with a client to refer “individuals” back to the employee’s lab in exchange for a kickback.  Moreover, other courts may decide that remuneration based on the volume of referrals induced by an employee is unlawful pursuant to EKRA, despite the fact that the employee does not personally refer or use the lab services him/herself.

    The S&G Labs case is one of the first cases that has interpreted EKRA, and it is unlikely to be the last.  This case may be appealed and there will certainly be more cases in the future to interpret the statute.  EKRA is also a new law and the U.S. Department of Justice has not, as of yet, prosecuted many cases under EKRA.  Therefore, the scope of the statute has not yet been extensively judicially tested.  Much like the Anti-Kickback Statute, we anticipate that EKRA will be tested more often over the next several years.

    HP&M Promotes Sara Koblitz to Director

    Hyman, Phelps & McNamara, P.C. (HP&M) is pleased to announce that Sara W. Koblitz has become the firm’s newest Director.  Sara’s practice covers the intersection of FDA regulatory issues and Intellectual Property, including the Hatch-Waxman Amendments, the Biologics Price Competition and Innovation Act, and the Orphan Drug Act, biosimilars, and the Orange Book.  She assists pharmaceutical drug companies of all sizes on product lifecycle management, as well as regulatory strategies related to obtaining FDA approval, exclusivity, and patent listing.  Sara also has been heavily involved in FDA-related litigation and interpretation of the Federal Food, Drug, and Cosmetic Act.

    Sara joined the firm from a well-recognized intellectual property firm in 2017.  Her full bio can be found here.

    Categories: Miscellaneous

    Congratulations to HP&M’s first Principal Medical Device Regulation Expert, Adrienne Lenz

    Hyman, Phelps & McNamara, P.C. (HP&M) is pleased to announce Adrienne R. Lenz has become its first Principal Medical Device Regulation Expert.  Adrienne joined HPM in September 2017.  In her time with HPM, she has made significant contributions to the firm and its clients.

    Prior to joining HP&M, Adrienne worked as an independent regulatory consultant and consultant with Emergo.  She has also held positions in regulatory affairs, quality assurance, and test engineering at GE Healthcare and Smiths Medical.

    As a Principal Medical Device Regulation Expert, Adrienne will continue to provide consulting to medical device and combination product manufacturers. Adrienne assists clients with a wide range of pre and postmarket regulatory topics including developing regulatory strategy, preparing regulatory submissions, drafting regulatory policies and procedures, and addressing enforcement matters.

    In the premarket area, Adrienne prepares IDEs, 510(k)s, de novos, and PMAs. She also prepares pre-submissions, and assists clients in preparing for and represents clients at pre-submission meetings with FDA. In the postmarket area, she advises clients on complaint handling, MDRs, field actions, and QSR compliance.  Adrienne’s full bio can be found here.

    Revised PhRMA Code Took Effect on January 1, 2022, and Certain State Obligations Follow

    Happy New Year!

    On January 1, 2022, the recently revised version of the PhRMA Code on Interactions with Health Care Professionals went into effect. We summarized the major revisions to the Code in a blog post when it was released in August 2021. Many of the updates relate to drug manufacturer practices with regard to speaker events, including meals, choice of venue, and attendance.

    Although the PhRMA Code is a voluntary code of conduct, drug manufacturers should consider updating their marketing policies and practices to align with the new Code. The updated Code incorporates the latest guidance from the Office of Inspector General at the U.S. Department of Health and Human Services (OIG). This includes a November 2020 Special Fraud Alert wherein OIG explained its enforcement focus regarding speaker programs. (We blogged about the Alert here).

    Another reason drug manufacturers may want to update their marketing policies are the numerous state requirements tied to the Code. Several states, including Connecticut, California, District of Columbia, Massachusetts, and Nevada, have adopted or incorporated the Code in their statutes or regulations. In some cases, a revised PhRMA Code adds obligations for manufacturers to update their practices. For example, California’s drug marketing law requires pharmaceutical companies to adopt an internal marketing compliance policy that aligns with the PhRMA Code. See Cali. Health & Safety Code § 119402(b). If the Code is revised, the California law gives companies six months to update internal policies to conform to the new version. Other jurisdictions like D.C. require sales representatives to comply with the Code “as it may be amended or republished from time to time.” See D.C. Municipal Regulation § 8305.11.

    Given these state requirements, following the PhRMA Code is not only an approach to mitigate litigation risk – it is an explicit requirement for manufacturers that interact with health care practitioners in a state that has adopted or incorporated the Code.

    All Too Few (Two Year Version) or Where Have All the COVID Tests Gone?* A Review of FDA’s Policies

    As we approach our third year of COVID, one of the major questions from March 2020 eerily echoes today: where are all the COVID tests?  The situation now, of course, is very different and much more favorable than two years ago.  Unlike March 2020, numerous tests by multiple manufacturers have been reviewed by FDA and are being distributed.  There is also a wide variety of tests, including PCR assays, antigen tests, and antibody tests, and at least 16 over-the-counter assays (4 of which were authorized in the past month).  And yet, there is still a dramatic shortfall in the number of tests available.  There are innumerable accounts of desperate scavenger hunts for a COVID assay (link), and a photograph taken by one of us (Jeff) at the local library depicts an all too common scene.

    There are multiple explanations for the current inadequate number of tests (link), including government policies on test procurement, manufacturers’ decisions to curtail production when demand fell this summer, the extraordinarily rapid spread of the omicron variant, and surges in demand brought on by the holidays.  But while the advent of omicron unquestionably precipitated the immediate critical shortage, limitations on the availability of COVID tests in the United States was a vulnerability long before the emergence of this variant (link).  As we chronicle in an article that appears in the current edition of the Food and Drug Law Journal, FDA’s policies for reviewing COVID assays, have been a contributing factor.

    Over the past two years, FDA has played a central role as gatekeeper for COVID tests.  This role is one that has sporadically received attention (link) but which has not undergone a detailed analysis.  To help fill that void, our article takes an in-depth look at FDA’s policies since the emergence of the pandemic in the United States.  This article (link), which is made available with the permission of the Food and Drug Law Institute, examines multiple facets of FDA’s regulation of COVID assays.

    The onset of COVID brought unprecedented challenges to FDA.  There is no question that the agency has devoted herculean efforts and resources to reviewing and authorizing COVID assays.  As of the latest count, FDA has granted more than 420 Emergency Use Authorizations (EUAs) for COVID In Vitro Diagnostics (IVDs) (25 of which were laboratory developed tests).  And that total understates the agency’s efforts to address the critical need for testing, which have included holding 75 Town Hall meetings and issuing eight EUA submission templates.

    At the same time, as our article discusses, the agency has taken steps that have unnecessarily impeded the introduction of assays.  For example, the agency has abruptly changed its policies, leaving numerous tests in regulatory limbo and unavailable for use.  The agency’s prioritization scheme has been opaque and confusing, and its implementation has kept COVID tests off the market and hampered decision-making by IVD companies.  The strict data requirements for tests intended to be used with asymptomatic patients led to a lack of tests available for that use.  Ultimately, FDA took the unprecedented step of affirmatively encouraging the off-label use of tests authorized for symptomatic patients to be used off-label for asymptomatic patients.  As we learned first-hand through our counseling of scores of companies, and as has been reported in the media (link), the unpredictability of FDA policies had a chilling effect on product development and submissions.

    FDA’s approach to laboratory developed tests (LDTs) has been perhaps one of the most remarkable examples of the impact of agency regulation on test development and availability).  As we’ve blogged about on many occasions (see, e.g., link, link, link, link), FDA’s LDT policy has been fraught for decades, and the consequences of unresolved jurisdictional issues were made manifest during the pandemic.

    As we describe in the article, at the outset of the pandemic FDA blocked labs from offering COVID LDTs without an EUA, choosing instead to rely solely on the CDC’s assay.  When that assay turned out to be flawed (link), there were no alternate laboratory tests available because labs had been discouraged from developing them.  Only after weeks of the country flying blind in the face of the viral onslaught did FDA permit labs to offer testing while they prepared EUA requests for submission.  In August 2020, the Department of Health and Human Services intervened, directing FDA to stop requiring EUAs for LDTs in the absence of rulemaking.  This policy was reversed in November 2021, and laboratories were given 60 days to submit EUA requests (the deadline is January 14th) (link).  Given the inadequate testing capacity and the surging demand in the United States, it is inexplicable that FDA would take any steps that could increase burdens on test developers and potentially reduce test availability without an extraordinary reason – which FDA did not offer.

    Our article closes with a strong recommendation that FDA take a close look at what has gone well with its review of COVID IVDs – and a lot has – and where improvements are needed.  Mistakes cannot be glossed over.  Under FDA’s quality system requirements, device manufacturers must review all available sources of information to identify quality problems, institute meaningful corrective and preventative actions when appropriate, and then verify effectiveness.  We should expect no less from FDA itself when it comes to self-evaluation of the impact of its testing policies on pandemic preparedness.

    In the past few decades, multiple new and deadly etiologic agents have arisen.  SARS-CoV-19 will not be the last one.  The next time, the United States – and FDA – need to be much better prepared to facilitate widespread testing.

    * In recognition of the wide and eclectic musical tastes of our HPM Blog followers, this blog post title alludes to the music of both Pete Seeger and Taylor Swift.

    The authors acknowledge and thank Charlie Snow for his assistance in preparing this blog post.

    Categories: Medical Devices

    Assessing the Credibility of Computational Modeling and Simulation in Medical Device Submissions

    On December 23, 2021, CDRH released as a draft guidance, Assessing the Credibility of Computational Modeling and Simulation in Medical Device Submissions (Draft Guidance).  Computational modeling and simulation (CM&S) can sometimes be useful to demonstrate the safety and effectiveness of medical devices or incorporated into devices.  FDA indicates that they receive regulatory submissions with such computational modeling, but the submissions “often lack a clear rationale for why models can be considered credible for the context of use.” Draft Guidance at 4.

    The Draft Guidance describes a nine-step framework for evaluating the credibility of CM&S information submitted in pre-market applications.  A computational model is “the numerical implementation of the mathematical model performed by means of a computer.” Draft Guidance at 8.  The National Institute of Biomedical Imaging and Bioengineering describes computational modeling as “the use of computers to simulate and study complex systems using mathematics, physics and computer science.” NIH, Computational Modeling (May 2020).  Weather forecasting is an example of computational modeling and simulation for which most of us are familiar.  Similar techniques can be used to model complex biological systems. The Draft Guidance applies to physics-based or mechanistic CM&S and not statistical or data-driven CM&S, such as those incorporating artificial intelligence or machine learning.

    The Draft Guidance describes four types of CM&S that can potentially be used to support a regulatory submission, by either being used to provide evidence to support a device’s safety and effectiveness or by being incorporated within the device, itself:

    • In Silico Device Testing, which are computational models that simulate medical device performance. Draft Guidance at 5.
    • CM&S used within medical device software, which is use of computational modeling within medical device software to perform device functions. at 6.
    • In Silico Clinical Trials, where “device performance is evaluated using a ‘virtual cohort’ of simulated patients with realistic anatomical and physiological variability representing the indicated patient population.”
    • CM&S-based qualified tools, which are tools for developing or evaluating a medical device that can be submitted to CDRH under the Medical Device Development Tools (MDDT) Program.

    In the Draft Guidance, credibility is defined as “trust in the predictive capability of a computational model.” Id. at 4.  The guidance assesses credibility using key concepts from FDA-recognized standard ASME V&V 40 Assessing Credibility of Computational Modeling through Verification and Validation: Application to Medical Devices.  However, where the ASME standard assumes the ability to perform traditional validation activities, the Draft Guidance provides a more general framework that additionally incorporates non-traditional validation evidence.

    A nine-step framework is presented for assessing credibility for purposes of a regulatory submission of the four types of computational modeling described above.  The first steps are to (1) describe the question of interest, (2) describe context of use and (3) model risk.  Next, (4) credibility evidence, either previously generated or planned, is identified and categorized, followed by (5) defining credibility factors and setting prospective credibility goals.  Prospective adequacy assessment is then performed (6) to answer the question, “will the credibility evidence be sufficient to support using the model for the context of use given the risk assessment?” Id. at 10.  Credibility evidence is then generated (7) by executing the proposed studies and/or analyzing previously generated data.  A post-study adequacy assessment (8) is conducted to determine if credibility goals were met, followed by preparation of a credibility report (9).

    Key concepts from the framework are then presented in detail within the Draft Guidance, including points of consideration for each type of CM&S, where applicable.  The question of interest should describe the question that is being addressed using the model and along with other sources of information.  When considering the context of use, it should be the specific role and scope of the computational model used to address the question of interest.  The Draft Guidance recommends that a model’s risk, defined as “the possibility that the computational model and the simulation results may lead to an incorrect decision that would lead to an adverse outcome” is assessed according to the ISO 14971 and ASME V&V 40 standards.  Id. at 9.

    Credibility evidence is evidence that could support the credibility of a computational model.  Id. at 8. There are three types of credibility evidence (code verification, calculation verification, validation) and ten distinct categories within these three types of credibility evidence that are discussed in the Draft Guidance.

    Code verification provides evidence demonstrating that a computational model implemented in software is an accurate implementation of the underlying mathematical model.  Calculation verification determines the solution accuracy of a calculation.  Both calculation verification and validation of the model may be provided through a number of types of evidence, including: general non-context-of-use evidence, evidence generated using bench-top conductions to support the current context of use, evidence generated using in vivo conditions to support the current context of use, evidence generated using bench-top conductions to support a different context of use, and evidence generated using in vivo conditions to support a different context of use.  Validation can additionally be provided by population-based evidence, emergent model behavior, model plausibility and model calibration evidence.  Model calibration evidence is an assessment of the fit of simulation results against the data used to develop the model; while it can support the validation of the model, it alone cannot be used to validate the model.

    Although a pre-submission is optional, the Draft Guidance suggests it may be useful to receive Agency feedback on the model risk assessment and prospective adequacy assessment.  A Credibility Assessment Plan is suggested for inclusion in pre-submissions.  For regulatory submissions, the Draft Guidance recommends inclusion of a Credibility Assessment Report.  The structure for both a Credibility Assessment Plan and Credibility Assessment Report are provided in Appendix 2 of the Draft Guidance. Id. at 34-36.

    For regulatory and legal professionals, the Draft Guidance provides information that will help ensure regulatory submissions provide appropriate documentation to support the credibility of computational modeling and simulation information provided to support the safety and effectiveness of medical devices.  As FDA indicates, it is especially important to consider these issues within the clinical context (conditions of use).  A model that is credible in one context may not be credible in another.  We are interested to hear from engineers as to whether this guidance will also prove helpful in developing and validating CM&S.

    Categories: Medical Devices

    CMS Hammers Final Nail in the Coffin of International Reference Pricing for Drugs

    We reported in August that CMS proposed to rescind the Most Favored Nation (MFN) drug pricing interim final rule issued in the latter days of the Trump regime.  Today, CMS finalized that proposal, effectively putting an end to the concept of international reference pricing as a means to limit drug prices.  The bipartisan idea of international reference pricing generated considerable controversy during its short lifetime.  The November 2020 rule was promptly challenged in four lawsuits, one of which resulted in a nationwide preliminary injunction against its implementation.  Though regulatory implementation was stymied, international reference pricing was carried over by Democrats into the drug pricing provisions of H.R. 5376, the Build Back Better Act, which passed the House on November 19.  However, the approach has been rejected in the version of the Build Back Better Act that is slowly taking shape in the Senate.  (See section 129001 of the most recent Finance Committee text.)  Rather than using foreign prices as benchmarks, that legislation would use a specified percentage of the non-federal average manufacturer price (NFAMP) reported by manufacturers to the Department of Veterans Affairs, in order to set a ceiling on Medicare Part B and D drug payment for selected high cost brand drugs.  With today’s action by CMS, the idea of international reference pricing for drugs has reached its demise in both the Congress and the Administration.

    Categories: Health Care

    California Dreaming Part 4: The Court Tells California to Keep on Dreaming

    Since California passed AB 824: Preserving Access to Affordable Drugs in September 2019, the Association for Accessible Medicines (“AAM”) has been trying to invalidate the law, which imposes a presumption of anticompetitive effect on any Paragraph IV patent settlement in which the generic sponsor receives “anything of value,” including an exclusive marketing license or promise not to launch an authorized generic, from the patent holder.  Intended to target “reverse payment” settlement agreements, in which a brand company pays a first-filer ANDA holder to delay launch, the California law shifts the burden of proof to the drug sponsors to demonstrate that any Paragraph IV settlement agreement is not an antitrust violation.  In other words, the California law assumes that every potential Paragraph IV patent settlement is anticompetitive, and the pharmaceutical manufacturers must show that the settlement is not anticompetitive to avoid upwards of $20 million in fines.  Unsurprisingly—and understandably given the evidentiary hurdle imposed, as well as the amount of proprietary information that must be disclosed for all Paragraph IV patent settlement agreements—industry was not happy.

    Thus, as soon as AB 824 went into effect in January 2020, AAM sued California alleging that AB 824 violates the dormant Commerce Clause because it extends to entities and agreements that are not located in California.  Ultimately though, the Eastern District of California denied AAM’s request for a preliminary injunction “primarily due to the nature of Plaintiff’s pre-enforcement attack on AB 824,” determining that AAM “failed to establish a likelihood of success on the merits or raise serious questions going to the merits.”   The Court also determined that AAM failed to establish an irreparable harm that was both likely and imminent.  AAM appealed, but the Ninth Circuit ultimately determined that AAM failed to demonstrate that its members had an Article III injury in fact and therefore lacked associational standing to bring claims on its members’ behalf.  The case was dismissed without prejudice.

    Litigation Take 2: AAM filed suit again in the Eastern District of California on August 25, 2020, once again seeking injunctive relief based on allegations that AB 824 is unconstitutional.  AAM argued that AB 824 violates the dormant Commerce Clause by regulating out-of-state conduct; is preempted by federal patent law in view of FTC v. Actavis, 510 U.S. 138 (2013) and the BPCIA; violates the constitutional prohibition on excessive fines under the Eighth Amendment; and violates due process by burden-shifting with no meaningful opportunity to rebut the presumption applied.  This time, in spite of California’s contention otherwise, AAM argued that it has standing because several members have suffered “concrete economic” harm from AB 824.  Because an AAM member company submitting a Declaration stating that it “decided to pull out of a settlement negotiation for a pay-for-delay settlement agreement and chose instead to continue litigating a patent-infringement lawsuit at significant cost due to concerns about enforcement of AB 824,” the Court found the claim prudentially ripe and sufficient for purposes of standing.

    With respect to the merits, the Court only addressed (here) the merits of the dormant Commerce Clause Claim because that argument alone was strong enough for the relief requested.  AAM argued that AB 824 directly regulates out-of-state commerce because it is not limited to settlements entered in California or between California entities; conversely, California argued that AB 824 does not regulate conduct occurring wholly outside of California.  The Court applied the “extraterritoriality theory” which precludes states from unduly burdening interstate commerce.  Under that theory, any statute that directly controls commerce outside the boundaries of the state exceed the limits of that state’s authority.  Recognizing that the Supreme Court rarely has held that statutes violate the extraterritoriality doctrine, the Court nevertheless explained that “AB 824 may reach the kind of settlement agreements . . . in which none of the parties, the agreement, or the pharmaceutical sales have any connection with California,” in violation of the doctrine.

    California disagreed and told the Court that AB 824 applies only to agreements in California because manufacturers could omit California sales from any agreements subject to 824, but, said the Court, nothing in AB 824 limits the statute to only California settlements.  Because, as written, AB 824 could apply to settlements in which none of the parties, the agreement, or pharmaceutical sales have any connection with California, the statute violates the dormant Commerce Clause.  Further, AB 824’s civil penalties provision is violative, as it could levy substantially significant penalties on parties with no connection to California.  Thus, AAM “is likely to succeed in showing that AB 824 violates the dormant Commerce Clause.”

    Because AAM members will be unable to recover monetary damages against the state even if AAM is successful, the Court determined that the monetary injury here constitutes irreparable harm absent a preliminary injunction.  And California could not demonstrate that the balance of equities tip in its favor due both the economic injury for pharmaceutical companies and the lost savings from slowed generic and biosimilar market entry.  As AAM explained, AB 824 will lead—and has already led—to delays in availability of generic medicines and driven manufacturers to withdraw Paragraph IV ANDAs.  This potential harm was not balanced by the need for California to have additional tools to address collusive agreements and its theory that the presumption ultimately will lower drug prices in California.

    So AAM’s suit lives to see another day, and California is enjoined from enforcing AB 824.  California has pledged to continue the fight.  For now, California will have to continue to dream.  And we imagine we’ll see you back in 2022 for California Dreaming Part 5.

    HP&M’s Adrienne Lenz to Present on Deciphering New and Proposed Regulatory Guidances for Medical Devices and Diagnostics

    Hyman, Phelps & McNamara, P.C. is  pleased to announce that Adrienne Lenz will be speaking on Deciphering New and Proposed Regulatory Guidances For Medical Devices and Diagnostics at the Q1 Productions 4th Annual Life Science Regulatory Intelligence Virtual Event being held January 24-25, 2022.  The foundation of the regulatory intelligence and strategy is to remain abreast of current regulatory and legislative guidelines.  The magnitude of guidance documents affecting a product throughout its lifecycle makes this a continual challenge for regulatory teams. This session will highlight current guidance documents that are of key importance to device and diagnostic manufacturers and regulatory intelligence executives.  This virtual event brings together global intelligence, strategy, policy and legal experts to share best practices on challenges faced by regulatory teams.

    FDA Law Blog readers are offered a discount of 15% off the registration price.  The case-sensitive discount code is Q1HPM15.  You can access conference information and register for the event here.

    Categories: Medical Devices

    NPA Files Complaint Seeking to Prevent FDA from Applying the Exclusionary Clause Retroactively

    On December 7, 2021, the Natural Products Association (NPA) filed a complaint seeking an injunction based on FDA’s actions excluding N-acetyl-L-cysteine (NAC) from the definition of dietary supplement.  At issue is FDA’s interpretation of the “exclusionary clause,” section 201(ff)(3)(B)(ii) of the FDC Act, which among other things excludes from the dietary supplement definition articles that are approved as new drugs, or authorized by FDA for investigation for therapeutic uses for which “substantial clinical investigations have been instituted and for which the existence of such investigations has been made public” and which were not “marketed as a dietary supplement or as a food” before such approval or authorization.  Specifically, the issue is whether this provision applies to bar dietary supplements, such as NAC, that were on the market before the enactment of the Dietary Supplement Health Education Act (DSHEA), in 1994, which added this exclusionary clause into the FDC Act.

    NAC is widely available as a dietary supplement and has been marketed as a dietary supplement since before the enactment of the DSHEA.  It also has been approved and is used to treat acetaminophen poisoning and some other conditions.   According to FDA, NAC is excluded from the dietary supplement definition because NAC was approved as a drug in 1963 and, as far as the Agency has been able to determine, there is no evidence that NAC was marketed as a food or supplement before the drug approval.

    In July 2020, FDA sent warning letters (WLs) to seven companies about products containing NAC.  The main reason for the WLs seemed to have been the companies’ impermissible use of drug claims that NAC was effective against hangover.  However, FDA also asserted that NAC is excluded from the dietary supplement definition because NAC has  been approved as a drug in 1963 and FDA was not aware of evidence of the marketing of NAC before that date.  FDA did not consider that NAC was legally marketed as a dietary supplement before 1994.

    Although FDA had previously questioned or suggested that NAC was excluded, FDA had not taken any enforcement action against NAC supplements during the more than 25 years that they have been marketed as a dietary supplement.

    In December 2020,  the Council for Responsible Nutrition (CRN) sent a letter asserting, among other things, that NAC had been on the market before DSHEA was enacted and, therefore, was a “grandfathered” ingredient.  CRN argued that the exclusionary clause in DSHEA was not intended to apply to such grandfathered ingredients but instead was intended to bar new dietary ingredients which would be first introduced into the US market after the enactment of DSHEA.  Absent a specific provision in DSHEA, the exclusionary clause would not apply retroactively; the passing of DSHEA did not affect the status of ingredients on the marketed prior to DSHEA.  FDA did not respond to the letter.

    Six months later, in an effort to get FDA to address the issue, CRN submitted a Citizen Petition (CP) again asking that FDA reconsider its position that NAC is excluded.   Several months later, NPA filed its own CP  making the same arguments.

    In November 2021, FDA issued tentative responses to the two CPs, here and here.  In these responses and in the Constituent Update , FDA requests information on the earliest date that NAC was marketed as a dietary supplement or as a food, the safe use of NAC in products marketed as a dietary supplement, and any safety concerns.  Much to the frustration of the industry, the tentative response did not address the legal issue crucial to the future of NAC, i.e., that NAC is a legal (grandfathered) dietary ingredient because DSHEA does not apply retroactively to exclude dietary supplements that were on the market before the enactment of the law.  FDA merely indicated that it was still considering that issue.

    As readers of this blog may know, FDA is not required to provide a substantive response to a CP within a specific time and it may take years before FDA issues a response (In fact, HPM submitted a CP in 2000 to which FDA has yet to respond).  Since FDA’s statements about NAC as dietary supplement had resulted in several retailers barring the sales of NAC supplement, getting to FDA to address this issue was an urgent matter.  Therefore, NPA filed a lawsuit.  NPA’s complaint includes essentially the same arguments and facts as the Citizen Petitions.  In addition, it points to statements by an FDA Office of Criminal Investigations agent in an application for search warrants that NAC is excluded from the definition of dietary supplement.  NPA points to these and subsequent statements by FDA in the prosecution as final agency action re NAC which can be challenged in court.

    NPA asks the court to declare that the exclusionary clause does not retroactively apply to the dietary supplement NAC and seeks a preliminary and permanent injunction prohibiting FDA from taking any regulatory action against manufacturers, sellers or distributors of NAC based on the claim that the drug exclusion prohibition is retroactive.

    There are interesting procedural and substantive issues in this case, both with respect to NAC specifically and with respect to FDA regulation generally.  First, what constitutes, reviewable agency action?  Here, FDA has not issued a rule or other formal administrative action, but it has—in what are purportedly non-final actions—pressed its interpretation.  Seemingly that should give a plaintiff standing.  Second, was DSHEA intended by Congress to apply retroactively?  As a matter of statutory construction, absent explicit language, statutes are generally intended to apply prospectively.  Third, even if Congress intended DSHEA to apply retroactively, does the Constitution permit it?  The Ex post facto clause of the Constitution generally makes it unconstitutional to have a law retroactively impose penalties. We will be monitoring developments in this litigation.

    FDA Proposes Substantial Changes to Agricultural Water Requirements

    On December 6, 2021, FDA published a proposed rule to reorganize and amend the highly criticized agricultural water provisions of the Produce Safety Rule (PSR). This marks the Agency’s latest effort to balance public health protections with covered farms’ persistent concerns that the current provisions are overly complex, difficult to implement, and ill-suited to address the diversity of water uses and sources in the produce industry.

    The proposed changes are extensive, but the three main takeaways to note are that the proposed rule:

    • will replace microbial quality and testing requirements with systems-based agricultural water assessments;
    • will enhance risk-based mitigation measures with expedited mitigation for known or reasonably foreseeable hazards from animal activity, biological soil amendments of animal origin, or improperly treated human waste associated with adjacent or nearby lands; and
    • emphasizes flexibility for covered farms to choose how to comply with the agricultural water requirements.

    These changes are described in greater detail below. We note that the proposal concerns pre-harvest activities and the existing standards for covered farms’ harvest and post-harvest activities are not affected by the proposed rule. Also, the proposal concerns all produce except for sprouts, which are subject to separate requirements.


    The PSR, finalized in 2015 under the Food Safety Modernization Act (FSMA) and codified at 21 C.F.R. Part 112, established (for the first time ever) mandatory federal science-based minimum standards for the safe production and harvesting of produce for human consumption. FDA has long recognized (in its own investigations and based on decades of scientific research) that the quality of agricultural water is an important factor in produce safety. Subpart E of the PSR was specifically developed to address agricultural water quality control.  Among other requirements, it establishes testing obligations and microbial quality criteria for agricultural water based on the water’s intended use, e.g., irrigation water, water used in preparing crop sprays, etc.). In addition, Subpart E includes measures that a covered farm must take if its agricultural water fails to meet these requirements.

    FDA quickly found itself in troubled waters with these new requirements. The regulated industry criticized the complexity and the one-size-fits-all approach of Subpart E.  In 2017, in an effort to lighten the burden for affected parties, FDA proposed to extend compliance dates until at least Jan. 26, 2022.  Despite opposition, FDA finalized the proposal to extend the compliance dates in March 2019.

    Now, six years after finalizing the PSR but before the compliance date, FDA published a proposal to address stakeholders’ concerns about the PSR’s agricultural water requirements.

    Testing the waters with a comprehensive assessment framework

    FDA proposes to replace Subpart E’s prescriptive and highly technical testing requirements and microbial water quality criteria with more flexible provisions. These provisions will instead require covered farms to perform comprehensive, systems-based, and management-reviewed agricultural water assessments to identify and address potential risks associated with pre-harvest agricultural water.

    If finalized, covered farms will be required to conduct written pre-harvest agricultural water assessments annually. The assessments must include all possible sources which are reasonably likely to introduce known or reasonably foreseeable hazards regardless of whether the farm has control over those hazards, specifically:

    • The location, nature, and current and previous use(s) of the water source;
    • The type of water distribution system;
    • The degree to which the system is protected from possible sources of contamination, such as adjacent and nearby land uses, and particularly animal impacts;
    • The type of application method (e.g., overhead sprinkler or seepage irrigation);
    • The time interval between the last direct application of agricultural water and harvest of the covered produce;
    • Crop characteristics that make covered produce vulnerable to contamination (e.g., susceptibility of the produce to surface adhesion or internalization of contaminants);
    • Environmental conditions (e.g., rainfall patterns that may impact the agricultural water system or damage produce); and
    • Other relevant factors that could inform the assessment (e.g., optional testing).

    Covered farms will also be required to conduct pre-harvest agricultural water assessments whenever a significant change occurs that may increase the likelihood that a known or reasonably foreseeable hazard will be introduced into or onto produce or food contact surfaces. In other words, any change in the factors considered in the agricultural water assessment will trigger a reassessment requirement if that change may impact hazard identification or a risk management determination. For example, a change in the manner of water application will require a farm to conduct another agricultural water assessment if that change introduces, or increases the chance of introducing, a known or foreseeable hazard into or onto produce or food contact surfaces.

    This comprehensive assessment approach is adaptable to diverse and changing circumstances.  The proposal recognizes that many interconnected factors, such as variability in agricultural water sources, systems, and practices, nearby land uses, crop characteristics, and environmental conditions, pose possible sources of contamination which differ from farm to farm. In addition, the proposed rule is designed to accommodate future improvements in agricultural water quality science. For instance, although generic E. coli is currently the preferred indicator for monitoring water quality, future scientific developments may provide for the use of viral indicators, such as coliphages, to inform water quality assessments. As FDA explains, “as new science [becomes] available in the realm of water quality monitoring, farms should have the flexibility to take those findings into account when establishing or updating their sampling programs.”

    The proposed rule further provides covered farms the flexibility to choose whether to test their pre-harvest agricultural water for generic E. coli and, as science evolves, other appropriate organisms or analytes. This option, which would be in addition to the required agricultural water assessments, includes detailed requirements for sample collection, testing frequency, and validation to ensure that the testing is adequate to supplement a farm’s agricultural water assessment. Optional testing helps alleviate the burden on produce farms that lack nearby laboratories capable of testing water samples, or that rely on water sources that are too numerous or inconsistent to provide representative water sampling.

    Finally, proposed exemption provisions add flexibility to the regulations. FDA proposes to exempt covered farms from conducting a pre-harvest agricultural water assessment if they can demonstrate that their pre-harvest agricultural water for covered produce:

    • meets the PSR requirements for harvest and post-harvest agricultural water (such as the microbial quality criterion and testing requirements for untreated ground water);
    • is received from a public water system that meets Safe Drinking Water Act or state regulations (provided that the farm has public water system results or certificates of compliance demonstrating that the water meets relevant requirements); or
    • is treated in accordance with the applicable PSR standards (i.e., the method, delivery, and monitoring of the treatment are done in a manner that is effective to make the water safe and of adequate sanitary quality for its intended use).

    Corrective and mitigation measures to keep farmers’ heads above water

    FDA proposes that covered farms use the assessments to determine whether corrective or mitigation measures will be necessary to reduce the risk of contamination of their pre-harvest agricultural water, or whether routine inspections and maintenance will suffice to ensure the water’s safety and sanitary quality. The assessments also allow covered farms to evaluate trends impacting their agricultural water systems and the effectiveness of any mitigation measures taken.

    FDA is proposing to require that corrective or mitigation measures be taken based on certain findings, displayed in the chart below.

    If the covered farm determinesThen it must
    that its agricultural water is not safe or is not of adequate sanitary quality for intended use(s)immediately discontinue use(s) and take corrective measures (e.g., re-inspecting the entire affected agricultural water system under the farm’s control to make necessary changes such as repairs, and treating the water in accordance with the PSR’s standards) before resuming use of the water for pre-harvest activities.
    there is one or more known or reasonably foreseeable hazards related to animal activity, biological soil amendments of animal origin, or improperly treated human waste for which mitigation is reasonably necessaryimplement expedited mitigation measures (e.g., changing water application methods or time intervals between the last direct application of agricultural water and harvest to allow for microbial die-off) promptly and no later than the same growing season.
    there is one or more known or reasonably foreseeable hazards not related to animal activity, biological soil amendments of animal origin, or improperly treated human waste for which mitigation is reasonably necessaryimplement mitigation measures as soon as practicable and no later than the following year, or test water as part of the assessment and implement measures, as needed, based on the outcome of the assessment.
    that there are no known or reasonably foreseeable hazards for which mitigation is reasonably necessaryinspect and adequately maintain the water system(s) regularly, and at least once annually.

    Even though the proposed rule prescribes measures that covered farms must take based on findings from their agricultural water assessments, it provides covered farms with choices of mitigation measures.  For example, they may adopt microbial die-off or removal post-harvest activities (e.g., commercial washing) as a mitigation measure.

    By providing covered farms with options rather than being prescriptive, the proposed rule helps address the root cause of covered farms’ complaints that Subpart E’s requirements are too complex and rigid to implement effectively.

    It’s Time to Sink or Swim: Proposed Effective and Compliance Dates

    As mentioned above, the earliest compliance date for Subpart E is Jan. 26, 2022 (the compliance date for small farms is Jan. 26, 2023, and the compliance date for very small farms is Jan. 26, 2024). Since the current requirements are likely to change, FDA proposes to exercise enforcement discretion for the agricultural water requirements for covered produce while it works to extend the compliance dates until after the proposed rule has been finalized.

    FDA has not identified a target date for publication of the final rule. Comments to the proposed rule may be submitted until Apr. 5, 2022 here.

    What is Going on with the Pre-Submission Program?

    It seems like every other discussion I have these days someone asks, “what is going on with the pre-submission program?”  “I heard CDRH isn’t reviewing pre-submission,” or “I heard FDA is only providing written feedback and not holding meetings.”  So, we thought it was time for a post dedicated to every device manufacturer’s favorite early interaction process – the pre-submission program.

    This spring, CDRH provided an update on how the pandemic had affected the Center’s workload (announcement here).  The announcement indicated that OHT7 (formerly OIR) has been and would continue to be declining most pre-submissions.  The only pre-submission that this Office have been and would be continuing to review are those “related to COVID-19, companion diagnostics, a breakthrough designation request, or have a significant public health impact.”  In our experience, OHT7 has been reviewing pre-submissions for these product types.  Companies with non-COVID diagnostics should carefully consider whether their tests fit within one of these categories.

    For pre-submissions in other Offices, the announcement stated that CDRH “anticipate[s] pre-submissions . . . be[ing] completed within 120 days, rather than the usual 70 days.”  In our experience, these estimates have held true.  Offices, other than OHT7, have continued to review pre-submissions and hold teleconferences, when requested.  These meetings are often taking longer than the pre-pandemic 70-day timeline, however.  In our experience, these delays, sometimes, come at the last minute just before a meeting has been scheduled.  Thus, sponsors will need to remain flexible even when a meeting has been scheduled.  We have also noticed, in some circumstances, Offices declining to answer all of a sponsor’s questions noting that, for example, a separate pre-submission was required for a question regarding study risk when the pre-submission is seeking input on the study design.  These efforts appear designed to limit the focus of pre-submissions.

    Bottom line – the pre-submission program is still running just with some minor modifications.  Meetings are being held – virtually still.  In light of Omicron, it is unclear when in-person pre-submissions will return.  We confirmed that there have been no other changes to the Center’s policies.  Sponsors should be aware that CDRH is doing its best to remain flexible with its Divisions given their workload and many Divisions are currently understaffed due in part to departures and/or resources having been pulled to other Divisions.

    Categories: Medical Devices