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  • When Worlds Collide: The Theory of Real-World Evidence Meets Reality – Part II

    We recently blogged about the Center for Devices and Radiological Health’s (CDRH) reluctance to make full use of real-world data (RWD) and real-world evidence (RWE) to support marketing applications.  In response to the post, we did receive feedback from a company that had had the good fortune to have very positive experiences with RWD/RWE.  In the interest of fairness, we want to report that FDA was very receptive to the use of that information in several different applications.  (In the interest of fairness, we also heard from others who had the opposite experience.)

    On the one hand, it is good to know that CDRH is capable of taking full advantage of RWD/RWE and using it to meet the data requirements.  This company’s positive experience was with a particular Division, with which one of us also had a positive experience with RWD/RWE.

    On the other hand, it is frustrating to know that while CDRH is capable of utilizing RWD/RWE to meet data requirements, it does so sporadically and inconsistently.  It is not clear why one company’s experiences with a Division have not been consistently replicated across the Center.  And it is even more concerning that in the recent proposed ban of electrical stimulation devices, CDRH has publicly taken such a negative stance towards RWD/RWE, applying criteria that RWD/RWE will never be able to satisfy.

    So, we appreciate the feedback from the reader that had such favorable outcomes with its RWD/RWE.  Perhaps someday that will be the norm, rather than the exception, and therefore not newsworthy.

    Categories: Medical Devices

    Buckle Up: DOJ Initiates Rulemaking to Reschedule Marijuana

    Last August Health and Human Services (“HHS”) recommended rescheduling marijuana from schedule I under the federal Controlled Substances Act (“CSA”) to schedule III.  We wondered how given that HHS and the Drug Enforcement Administration (“DEA”) conducted eight-factor scheduling analyses in 2016, concluding that there was “no substantial evidence that marijuana should be removed from Schedule I.”  Denial of Petition to Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,688 (Aug. 12, 2016); Denial of Petition to Initiate Proceedings to reschedule Marijuana, 81 Fed. Reg. 53,767 (Aug. 12, 2016).  By recommending rescheduling to schedule III seven years later, HHS determined that marijuana no longer meets schedule I nor schedule II criteria.

    The 2016 reviews concluded that marijuana continued to meet schedule I criteria for having a high potential for abuse, no currently accepted medical use in treatment in the U.S., and lacked accepted safety for use under medical supervision.  21 U.S.C. § 812(b)(1).  For HHS to recommend rescheduling marijuana to schedule III, it must find that marijuana has a potential for abuse less than substances in schedules I and II, has a currently accepted medical use in treatment in the U.S., and its abuse may lead to only moderate or low physical dependence or high psychological dependence.  21 U.S.C. § 812(b)(3).

    Even though President Joe Biden had asked the Secretary of HHS and the Attorney General to “initiate the administrative process to review expeditiously how marijuana is scheduled under federal law” in October 2022, we also wondered how the Department of Justice (“DOJ”) and DEA would receive the HHS recommendation.  On Thursday, May 16, 2024, the Attorney General issued a Notice of Proposed Rulemaking (“NPRM”) to initiate rulemaking proceedings to reschedule marijuana.  The NPRM was signed by the Attorney General but published by DEA in the Federal Register on May 21, 2024.  Schedules of Controlled Substances: Rescheduling of Marijuana, 89 Fed. Reg. 44,597 (May 21, 2024).  The Attorney General also released DOJ’s Office of Legal Counsel (“OLC”) opinions providing the rationale and support for the NPRM.

    The Attorney General, after considering HHS’ recommendations, “concludes that there is, at present, substantial evidence that marijuana does not warrant control under schedule I.”  NPRM at 44,619.  The Attorney General further determined “at this initial stage” of rulemaking that marijuana also does not meet schedule II criteria but its lower degree of abuse potential and moderate to low level of physical dependence weighs in favor of rescheduling to schedule III.  Id. at 44,620.

    Public comments must be submitted electronically or postmarked on or before July 22, 2024, 60 days after publication in the Federal Register.


    The CSA requires analysis of eight statutory factors for scheduling, rescheduling, or descheduling substances of abuse.  21 U.S.C. § 811(c).  DOJ reviewed HHS’ scientific and medical evaluation and scheduling recommendation and conducted a separate review of the eight factors.  NPRM at 44,601.  The NPRM noted that DEA “has not yet made a determination as to its views of the appropriate schedule for marijuana.”  Id.  For each factor, the NPRM noted that DEA’s position is that additional information during the rulemaking will further inform about the appropriate schedule for marijuana.  DEA further believes that factual evidence (including scientific data) and expert opinions with additional data on different forms, formulations, delivery methods, dosages, and concentrations “may be relevant.”  Id.

    The eight factors with a summary of relevant findings follow.

    1. Marijuana’s Actual or Relative Potential for Abuse

    HHS determined that although epidemiological data indicate that marijuana has the potential for creating health hazards for the user and the community, its abuse liability compared with heroin (schedule I); oxycodone, hydrocodone, fentanyl, cocaine (schedule II); ketamine (schedule III), benzodiazepines, zolpidem, tramadol (schedule IV) and alcohol, marijuana does not produce the most frequent incidence of adverse outcomes.  Memorandum for DEA, from HHS, Re: Basis for the Recommendation to Reschedule Marijuana to Schedule III of the Controlled Substances Act, at 9 (Aug. 29, 2023) (“Basis”); NPRM at 44,603.

    1. Scientific Evidence of Marijuana’s Pharmacological Effects, If Known

    HHS found that marijuana abuse can lead to negative consequences that include addiction and the need for medical attention through poison center calls or emergency room visits.  Basis at 18; NPRM at 44,605.

    1. The State of Current Scientific Knowledge Regarding Marijuana

    HHS found that marijuana’s pharmacokinetic profile varies depending on the route of administration.  Basis at 24.  DEA noted that “there is considerable variability in the cannabinoid concentrations and chemical constituency among marijuana samples and that the interpretation of clinical data related to marijuana is complicated.”  NPRM at 44,607.  DEA explained that “the lack of consistent concentrations” of delta-9-THC and other substances in marijuana complicates the effects of different constituents within marijuana.  Id.

    1. Marijuana’s History and Current Pattern of Abuse

    HHS found that marijuana used for medical and nonmedical purposes in the U.S. is extensive but its use prevalence is less than for alcohol but “significantly more” than any other controlled substances.  Basis at 37; NPRM at 44,610.

    1. The Scope, Duration, and Significance of Abuse

    HHS’ evaluation of epidemiological databases related to medical outcomes from drug abuse placed marijuana in a lower position than alcohol, heroin, and cocaine.  Basis at 45; NPRM at 44,613.

    1. What, if Any, Risk There Is to the Public Health

    HHS found based on an evaluation of various epidemiological databases for emergency department visits, hospitalizations, unintentional exposures, and overdose deaths that public health risks posed by marijuana are low compared to other drugs of abuse.  Basis at 7-8; NPRM at 44,614.

    1. Marijuana’s Psychic or Physiological Dependence Liability

    HHS concluded that “experimental data and clinical reports demonstrate that chronic, but not acute, use of marijuana can produce both psychic and physical dependence in humans.”  Basis at 61; NPRM at 44,615.

    1. Whether Marijuana Is an Immediate Precursor of a Substance Already Controlled Under the CSA

    HHS concluded that marijuana is not an immediate precursor of another controlled substance.  Basis at 61; NPRM at 44,615.


    In addition to the eight factors, HHS provided three additional findings for determining the scheduling placement of marijuana:

    1. Potential for Abuse

    HHS conducted epidemiological analyses of marijuana abuse and its associated harms by comparison with heroin, fentanyl, oxycodone, hydrocodone, cocaine; ketamine, benzodiazepines, zolpidem, tramadol, and alcohol.  Basis at 62-63; NPRM at 44,616.  HHS found that while marijuana is associated with a high prevalence of abuse of nonmedical use, epidemiological indicators suggest that the drug does not produce negative outcomes as serious as those compared with schedule I or II drugs.  Basis at 62.  HHS concluded that marijuana is most appropriately controlled in schedule III.  Id. at 63.

    The Attorney General considered HHS’ recommendations and conclusions and gave HHS’ scientific and medical determinations binding weight at this early stage in the rescheduling process.  NPRM at 44,616.  The Attorney General concurs for purposes of the initiation of rulemaking proceedings that marijuana has less potential for abuse than schedule I and II drugs.  Id.

    1. Currently Accepted Medical Use in Treatment in the U.S.

    In 2016, HHS and DEA determined that marijuana did not have a currently accepted medical use (“CAMU”) in treatment in the U.S. because it was not the subject of an approved new drug application (“NDA”) nor an abbreviated new drug application (“ANDA”) under the Federal Food, Drug, and Cosmetic Act.  Lacking an NDA or ANDA, DEA applied a five-part test established in 1992 and found that marijuana did not meet that alternative test either so therefore lacked a CAMU.  Denial of Petition at 53,700-02; Denial of Petition at 53,779-81.

    In 2023, HHS conducted a different approach, a two-part test, to determine whether marijuana has a CAMU.  The Office of the Assistant Secretary for Health (“OASH”) found that more than 30,000 healthcare professionals “are authorized to recommend the use of marijuana for more than six million registered patients, constituting widespread clinical experience associated with various medical conditions recognized by a substantial number of jurisdictions across the United States.”  Basis at 24; NPRM at 44,617.  (Thirty-eight states authorize marijuana for specific qualifying medical conditions.)  OASH concluded “there is widespread current experience with medical use of marijuana in the United States” by licensed healthcare providers “operating in accordance with implemented state-authorized programs, where such medical use is recognized by entities that regulate the practice of medicine under these state jurisdictions.”  Basis at 63; NPRM at 44,617.  For OASH, the findings warranted a Food and Drug Administration (“FDA”) assessment under a second part to determine if credible scientific evidence supports at least one of the medical conditions.

    The FDA reviewed studies investigating the safety and efficacy/effectiveness of marijuana, professional societies’ position statements, data from state medical marijuana programs and national surveys, and FDA-approved products’ labeling.  Basis at 63-64.  FDA analyzed anorexia related to a medical condition, anxiety, epilepsy, inflammatory bowel disease, chemotherapy-induced nausea and vomiting, pain, and post-traumatic stress disorder.  Basis at 63; NPRM at 44,617.  HHS concluded that “there exists some credible scientific support for the medical use of marijuana in at least one” of the following indications: the treatment of anorexia related to a medical condition, nausea and vomiting (e.g., chemotherapy-induced), and pain for which there is a widespread current experience in the U.S.  Basis at 64; NPRM at 44,619.

    HHS noted that lack of accepted safety for the use of a drug under medical supervision is among schedule I criteria but concluded that there is accepted safety for the use of marijuana under medical supervision for the treatment of anorexia related to a medical condition, nausea, and vomiting (e.g., chemotherapy-induced), and pain.  Basis at 64.  HHS concluded that marijuana does not meet schedule I criteria.  Id. at 64.

    The Attorney General asked OLC to advise whether HHS’ test and findings established a CAMU if a drug has not been approved FDAFDA nor meets DEA’s five-part test.  NPRM at 44,617.  OLC advised that DEA’s determination of whether a drug has a CAMU is “impermissibly narrow, because it ‘ignor[es] widespread clinical experience with a drug that is sanctioned by state medical licensing regulators.’”  Id.  OLC opined that satisfying HHS’ two-part inquiry is sufficient to establish a CAMU and that while HHS’ recommendation is not binding on DEA, the medical and scientific determinations are binding until initiation of formal rulemaking proceedings, and DEA must accord those determinations “significant deference” throughout rulemaking.  Id.

    The Attorney General agreed that there is widespread clinical experience with marijuana for at least one medical condition and concurred with HHS that for purposes of initiating rulemaking, marijuana has a CAMU.  Id. at 44,617, 44,619.

    1. Level of Physical or Psychological Dependence

    HHS conceded that clinical studies demonstrate that marijuana produces physical and psychological dependence, and abuse may lead to moderate or low physical dependence depending on the frequency and degree of marijuana exposure.  Basis at 64-65.  But while exposure can produce psychic dependence, HHS noted that the likelihood of serious outcomes is low.  Basis at 65; NPRM at 44,619.  The Attorney General considered HHS’ conclusions and gave HHS’ scientific and medical determinations binding weight at the initial rulemaking stage, and concurred with HHS’ conclusion that the abuse of marijuana may lead to moderate or low physical dependence depending on frequency and degree of exposure.  NPRM at 44,619.

    “Marijuana” Subject to Rescheduling

    The proposed rescheduling would only apply to marijuana (drug code 7360) defined under the CSA (21 U.S.C. § 802(16)) and regulated by 21 C.F.R. §1308.11(d)(23) and marijuana extracts (drug code 7350) regulated by 21 C.F.R. §1308.11(d)(58).  Id. at 44,620, 44,622.  Rescheduling would also apply to delta-9-tetrahydrocannabinol (“THC”) derived from the marijuana plant (not from the mature stalks and seeds) that falls outside the definition of hemp.  Id.

    The proposed rescheduling would not apply to synthetically derived THC outside of the CSA definition of marijuana, which would remain in schedule I.  Id.  HHS’ recommendation related only to marijuana as defined in the CSA.  Rescheduling would also not apply to unscheduled hemp or any previously schedule synthetic cannabinoids.  Id.

    International Treaty Obligations

    Prior rescheduling proceedings established that marijuana could not be rescheduled in any less restrictive schedule than schedule II for the U.S. to comply with its treaty obligations.  The United States is a signatory to the Single Convention on Narcotic Drugs, 1961, and the Convention on Psychotropic Substances, 1971.  Marijuana is a schedule I substance under the Single Convention and delta-9-THC is a schedule II substance under the Convention on Psychotropic Substances. Id. at 44,620-21

    The Attorney General, based on OLC advice, concluded that marijuana could be rescheduled to schedule III, and that DEA would consider supplementing schedule III requirements with additional marijuana-specific controls such as manufacturing quotas and import and export authorizations to satisfy treaty obligations.  Id.

    Upcoming EveryLife Foundation Scientific Workshop on May 21, 2024 will Address Challenges in Developing Therapies for Ultra-Rare Diseases

    On May 21, 2024, the EveryLife Foundation for Rare Diseases (ELF) will host a Scientific Workshop at the National Press Club in Washington, D.C. aimed at identifying and characterizing the challenges in developing therapies for ultra-rare diseases and conditions that affect exceedingly small populations.

    The workshop will drive in-depth discussions from leaders across federal agencies, the patient advocacy community, industry, academia and policy to examine the current state of drug development for patients with ultra-rare diseases and identify the considerations and implications of establishing a formal statutory definition and framework for “ultra-rare.”

    Speakers at the Scientific Workshop will include Dr. Peter Marks, Director of FDA’s Center for Biologics Evaluation and Research, Dr. Janet Woodcock, former Principal Deputy Commissioner of the FDA, Dr. Janet Maynard, Director of the FDA’s Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicines, and Dr. Joni Rutter, Director of the National Center for Advancing Translational Sciences, and Hyman, Phelps & McNamara’s own Frank Sasinowski who also serves as the Vice Chair of the Board for ELF.

    The workshop is free to attend and available to all.  Due to limited spacing, new registrants must attend virtually.  More information on the Scientific Workshop can be found here and registration for the live-stream can be found here.

    Hospitals: Do You Know Where Your Controlled Substances Are?

    Employee diversion of controlled substances from hospitals has been an issue since at least 1986 when I became a diversion investigator with the Drug Enforcement Administration (“DEA”).  But there has been a recent string of large civil monetary settlements, some in the millions of dollars, to resolve allegations that hospitals’ non-compliance with the federal Controlled Substances Act (“CSA”) and DEA regulations allowed employees to divert staggering quantities of controlled substances.  These recent monetary settlements and diverted quantities are eye-opening; in some instances they are staggering.  It is unclear whether such large employee diversion has always occurred but was unreported or if there has been an actual dramatic increase of large incidents.

    Numerous recent examples of large monetary settlements and significant controlled substance doses illustrating the following:

    • Press Release– DEA investigated the University of Michigan Health System (“UMHS”) after a nurse and an anesthesiology resident overdosed, the nurse fatally. DEA alleged that UMHS failed to maintain complete and accurate records and failed to timely notify DEA of controlled substance thefts.  DEA concluded that UMHS’ deficient recordkeeping impacted its ability to guard against theft and diversion.  UMHS agreed to resolve the allegations in August 2018 for $4,300,000 and compliance with a three-year Memorandum of Agreement (“MOA”).
    • Press Release– DEA alleged that McLaren Health Care Corporation (“MHCC”), also in Michigan, dispensed schedule II drugs without prescriptions despite red flags, violated recordkeeping requirements, and failed to timely report employee thefts to DEA. In January 2021, MHCC agreed to pay $7,750,000 and comply with a comprehensive three-year MOA.
    • Press Release– Sovah Health (“Sovah”), a hospital system in Virginia, agreed to pay $4,360,000 and entered into a Non-Prosecution Agreement in June 2022 after a pharmacy tech diverted more than 11,000 schedule II doses and another 1,900 schedule III-V doses. A registered nurse also admitted she replaced fentanyl and hydromorphone with saline solution for administration to patients.  DEA alleged that Sovah failed to provide effective controls and procedures to guard against diversion, filled controlled substance orders without a system to disclose suspicious orders, and failed to maintain readily retrievable records.  Sovah also agreed to four years of increased controlled substance compliance and oversight.
    • Press Release– DEA alleged that Pikeville Medical Center (“PMC”) failed to maintain complete and accurate schedule II inventories and dispensing records that allowed a pharmacy tech to divert 62,780 schedule II doses. The tech’s husband distributed the drugs in the community..  The Kentucky hospital resolved the allegations for $4,394,600 and entered into a three-year MOA in November 2021.
    • Press Release– DEA began investigating Cheshire Medical Center (“CMC”) in New Hampshire in February 2022 after it reported that a nurse stole twenty-three fentanyl intravenous solutions (“IV”) bags. CMC later reported an additional 634 fentanyl IV bags were unaccounted for and an audit revealed an additional 17,961 controlled substance doses missing.  The nurse who allegedly stole the drugs died in March 2022.  CMC resolved the allegations by agreeing to pay $2,000,000 and implement a corrective action plan.

    Controlled substances are a necessary component in hospitals providing needed medical care to patients.  However, these recent employee diversion incidents cases illustrate the vulnerability of hospitals.  Even trusted employees are capable of bad behavior.  Hospitals that are non-compliant and fail to fulfill their controlled substance obligations pose serious health risks to patients for undertreatment, and to employees for overdose and death.  Hospitals can face potentially multi-million-dollar settlements and significant long-term compliance costs.  Employee diversion can result in unwanted local and national publicity leading to erosion of public trust and confidence.

    Ownership and management would do well to ensure that their hospitals’ comply with controlled substance recordkeeping, reporting and security requirements under the CSA and DEA regulations.

    Join Us for an HPM/Lighthouse Labs Webinar: What the FDA’s Final Rule Means for the Future of Laboratory Developed Tests; Thursday, May 16, 2024: 12:00-1:00 PM EDT

    On April 29, the FDA issued their long-awaited, controversial Final Rule governing the oversight of laboratory developed tests (LDTs). This new rule will dramatically alter the LDT regulatory landscape, while at the same time requiring significant operational changes and posing strategic challenges for many LDTs. The final rule also created exemptions for some other LDTs.

    Join us at 12:00 p.m. EDT, Thursday, May 16, as Hyman, Phelps & McNamara, P.C. attorneys Gail H. Javitt and Jeffrey N. Gibbs—in conjunction with Jon Harol of Lighthouse Labs—dive into details of the final rule and its timeline for implementation. Don’t miss this chance to get a breakdown of this significant regulatory shift and its implications.

    In this webinar you’ll learn:

    • Significant changes between the proposed and final rule
    • How the current enforcement discretion approach for LDTs will affect you
    • A timeline for the rollout of the rule’s five phases
    • Get your questions answered by the experts during the live Q&A

    Don’t delay, click here to register today!

    When Worlds Collide: The Theory of Real-World Evidence Meets Reality

    FDA has long touted the use of real-world evidence (RWE).  Extolling RWE, FDA has said “RWE can be leveraged to bring new products to market, evaluate the safety and effectiveness of existing products for new uses, and assess the continued performance and safety of products once on the market.”  FDA recognizes the potential of RWE to support regulatory submissions of medical devices and to inform benefit-risk analysis of such products, while assuring patients have timely access to devices.  FDA has even gone so far as to maintain that the “real-life clinical performance of a medical product might be more clearly demonstrated through RWD/RWE because a controlled clinical trial often cannot evaluate all applications of a product in clinical practice across the full range of potential users.”  However, in our experience, there is a large gap between FDA’s lauding the value of RWE and practice.

    FDA defines real-world data (RWD) as “data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources.”  RWE is “the clinical evidence regarding the usage, and potential benefits or risks, of a medical product derived from analysis of RWD.” RWD can be collected from a wide range of sources, such as electronic health records, registries, administrative claims, pharmacy data, and feedback from wearables and mobile technology.

    FDA acknowledges that such data offer opportunities to generate evidence and better understand clinical outcomes.  In fact, in 2018, FDA emphasized that leveraging the use of RWD and RWE in regulatory decision-making is “a top strategic priority for the FDA.”  FDA believes that RWE has the power to “accelerate medical product development and bring new innovations and advances faster and more efficiently to the patients who need them, without compromising patient safety.”  Further, FDA has stated that enabling advanced data analytics, including RWD, is one of the objectives incorporated in the FDA’s Information Technology Strategy for FY 2024-2027.

    We, and many stakeholders, agree that RWD and RWE can play an invaluable role.  However, based on our experience reviewing device premarket submissions and engaging with FDA, we have found that reviewers have not embraced it in practice.  Rather than looking at how RWD/RWE provide meaningful information on safety and effectiveness, reviewers often focus on perceived gaps.  But by their very nature, RWD/RWE will have some gaps compared to randomized controlled trials.

    Congress has recognized the challenges with FDA’s acceptance of RWD and RWE.  It was Congress that intervened in 2022, to mandate FDA to issue or revise its 2017 guidance on considerations for the use of RWD and RWE to support regulatory decision-making for devices to clarify its regulatory expectations.  Also, under the MDUFA V commitment letter, FDA was directed to continue development of RWD and RWE methods and policies to advance regulatory acceptance for premarket submissions by updating and clarifying the recommendations in the 2017 guidance, and providing RWD/RWE training for FDA review teams, among other things.

    In December 2023, FDA issued a new draft guidance on RWE, which updates and clarifies how FDA evaluates RWD to determine if it is sufficient to be used in regulatory decision-making for devices and provides updated recommendations for sponsors collecting RWD.  This guidance, when finalized, will replace the original version of this document finalized in 2017.

    Of course, as FDA has itself acknowledged, RWE can offer some significant compensatory advantages.

    FDA states it has a long history of using RWD and RWE in its regulatory decision-making for devices and conducted a sample analysis of the range of RWE that have been used in regulatory decisions in premarket submissions.  Based on a review of premarket submissions made in 2012 through 2019, FDA identified 90 examples of 510(k)s, De Novos, HDEs, and PMAs approved/cleared which utilized RWE in support of regulatory decision-making.  During this period the estimated total number of such submissions was approximately 26,121.  Based on this data set, RWD/RWE were identified by FDA as being used in a trivial 0.34 percent of examples.

    This statistic is consistent with our experience.  Similar to FDA’s assessment, we have found very few examples where FDA has used RWE as the basis for making a positive regulatory decision in a premarket submission.  Not only has FDA not accepted RWD in some cases, it has even raised the evidentiary bar by requiring a clinical study as the only adequate means.

    FDA’s proposed ban of electrical stimulation devices (ESD) is a case in point. FDA is proposing to ban the device, citing the absence of “large, randomized, and controlled trials, or even any large or randomized trials.”  (89 FR 20882 at 20889, March 26, 2024).  In taking this approach, FDA expressly rejected the adequacy of the substantial amount of RWD available.  Patients that use ESD undergo continuous 24/7 monitoring.  There is ample data collected on them during this 24/7 monitoring period such as case notes, contemporaneous patient medical records, and patient tapes.  Every use of ESD is recorded, as is every behavior that falls within the intended use.  Patients are continually monitored for safety.  Far more data are collected at the site than would ever be available in a registry or other source of RWD.  Nonetheless, FDA entirely discounted this information and has concluded that the available evidence is not enough to establish ESDs are effective and that instead “randomization, control, [and] large numbers of subjects” should be relied on for understanding the benefit-risk profile of ESDs (89 FR 20882 at 20890).  FDA’s rejection of all RWD supporting GED in favor of randomized controlled trials cannot be squared with its broader policies.  Device stakeholders would be right to be troubled by the inconsistency between FDA’s professed support for RWE and its very public rejection of it in the proposed ban.

    We recognize that there can be challenges with using RWD/RWE in regulatory decision-making.  However, despite FDA leadership’s efforts to recognize and encourage use of RWD and RWE, reviewers have not fully embraced RWD/RWE.  FDA’s brusque rejection of data obtained from 24/7 monitoring of patients, as set forth in its recent proposed ban, will do nothing to encourage reviewers to embrace RWD/RWE.

    As FDA has noted, RWD/RWE has the potential to be relied on to evaluate the safety and effectiveness of products.  Yet that potential will never be realized unless reviewers are willing to accept RWD/RWE despite their limitations.  FDA’s recent public dismissal of the use of medical information obtained from continuous, 24/7 monitoring of patients does nothing to encourage reviewers to rely upon RWD/RWE when reviewing marketing submissions.

    Categories: Medical Devices

    Can a Device Be Found Not Substantially Equivalent Because of Cybersecurity Risks? A Review of FDA’s Draft Guidance on Cybersecurity in Medical Devices

    FDA recently issued a draft guidance which would update the agency’s Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions guidance.  The draft guidance provides recommendations on what is required to meet cybersecurity obligations under section 524B of the Food, Drug and Cosmetic Act (FD&C). Once finalized, the content from the draft guidance will be included within the existing cybersecurity premarket guidance.

    Cyber devices as defined in Section 524B(c) of the FD&C Act are devices that “(1) include[] software validated, installed, or authorized by the sponsor as a device or in a device; (2) [have] the ability to connect to the internet; and (3) contain[] any such technological characteristics validated, installed, or authorized by the sponsor that could be vulnerable to cybersecurity threats.”  FDA interprets the “software” definition to include software that is firmware or programmable logic in addition to software in a medical device (SiMD) or software as a medical device (SaMD). FDA interprets the “ability to connect to the internet” to include devices that can connect to the internet by any means whether the sponsor intends the device to be connected or not.

    For medical devices that meet the definition of a cyber device, manufacturers are required to submit specific information in premarket submissions.  Manufacturers are required to design, develop, and provide a “reasonable assurance” that both the cyber device and related systems (e.g., update servers, network connections, cloud, etc.) are cybersecure. In addition, manufacturers need to submit plans for monitoring, identifying, and addressing post market cybersecurity vulnerabilities.  Consistent with the existing premarket cybersecurity guidance, FDA recommends submitting a Cybersecurity Management Plan that should also include disclosing vulnerabilities to device users and other relevant stakeholders “in a reasonable time”.  The plan should include the frequency at which cybersecurity will be re-evaluated and the frequency at which the manufacturer will deploy patches and updates to the end users. Section 524B(b)(2) requires manufacturers of cyber devices to make updates and patches for known unacceptable vulnerabilities “on a reasonably justified regular cycle” and to make updates and patches to address out of cycle, critical vulnerabilities that could cause uncontrolled risks “as soon as possible”. The guidance does not define “on a reasonably justified regular cycle” or “as soon as possible” but instead recommends manufacturers should “update appropriate cybersecurity documentation (e.g., threat modeling)” throughout the device lifecycle as a way to “quickly identify” vulnerabilities and satisfy the patching requirements in the FD&C Act.

    Manufacturers that make modifications to an existing device will also need to submit the required information in a premarket submission. In determining what information to submit, the manufacturer should assess whether the change impacts the cybersecurity of the device. FDA provides examples of changes that are likely and unlikely to impact cybersecurity of an existing device.  Even for changes that are unlikely to impact the cybersecurity of the device, such as material changes, sterilization method changes, or changes to an algorithm without changing the architecture/software structure or connectivity, FDA recommends that the following information be submitted:

    • Software Bill of Materials (SBOM),
    • Summary of any cybersecurity impact since the last authorization,
    • Summary of any vulnerabilities identified since the last authorization,
    • Description of any limitations to updating the cybersecurity of the device and related systems which should include an assessment of residual cybersecurity risks and benefit risk analysis, and
    • Cybersecurity Management Plan or if one was previously submitted, a summary of any changes to the plan and summary of patches or updates made to the device since the last authorization to increase cybersecurity.

    As part of the premarket submission review, FDA will assess whether there is a “reasonable assurance of cybersecurity.”  In making this determination, FDA will consider changes in the environment of use, new risks or vulnerabilities in technological characteristics as compared to the predicate device, and how the performance testing submitted addresses new risks and vulnerabilities. Although a “reasonable assurance of cybersecurity” is not explicitly defined, FDA points manufacturers back to the existing cybersecurity guidance (i.e., Appendix 4) for the documentation requirements to “demonstrate reasonable assurance that the device and related systems are cybersecure”.

    The draft guidance also notes that FDA may find a proposed device “not substantially equivalent (NSE)” to a predicate device if the proposed device has increased cybersecurity risks that “could negatively impact the safety and effectiveness of the device.”  In the example provided in the draft guidance, the increased cybersecurity risk could be related to a lack of “necessary encryption to protect against a recently identified cyber threat” for which the proposed device is not protected.  The sponsor of the proposed device will be expected to provide performance data to support the cybersecurity of the device against the newly identified threat, and if the data are inadequate, FDA could find the device NSE.

    The problem with this expectation, however, is that it is possible, and even likely, that the predicate device, especially as it was cleared, is also not protected against this newly identified threat.  As is often the case when there are advances in technology and understanding of risks, new devices may be held to a higher standard than those to which they are claiming equivalence.  Particularly in the context of a 510(k), it may be difficult for FDA to enforce this expectation if it is not also required of the predicate if there was no public notice to industry of the newly identified threat.  Doing so may be inconsistent with the least burdensome requirement as well as the concept of substantial equivalence.

    Given the implications of receiving an NSE for cybersecurity alone, manufacturers and interested parties can still provide comments online regarding the draft guidance until May 13, 2024.

    Categories: Medical Devices

    DEA Concurs: Marijuana Meets Schedule III Criteria

    The Associated Press reported on Tuesday following confirmation by five anonymous individuals with knowledge that the Drug Enforcement Administration (“DEA”) is moving to reschedule marijuana from schedule I to the less stringently controlled schedule III.  US poised to ease restrictions on marijuana in historic shift, but it’ll remain controlled substance (Apr. 30, 2024).  Xochitl Hinosa, Justice Department Director of Public Affairs, confirmed that Attorney General Merrick Garland signed off on DEA’s proposal stating, “Today, the Attorney General circulated a proposal to reclassify marijuana from Schedule I to Schedule III.”  Quoted in Id.  The White House Office of Management and Budget will review the rescheduling proposal.  Afterwards DEA will publish a notice of proposed rulemaking for public comment in the Federal Register.  After the public comment period closes, DEA will review comments and issue a final rule.


    In October 2022, President Biden directed the Health and Human Services (“HHS”) Secretary and the Attorney General to “initiate the administrative process to review expeditiously how marijuana is scheduled under federal law.”  Statement from President Biden on Marijuana Reform, White House (Oct. 6, 2022).  Biden also pardoned prior federal simple possession offenses and encouraged governors to do the same.  Last August, the Food and Drug Administration (“FDA”) and HHS, after considering the eight-factor analysis required by the Controlled Substances Act (“CSA”) for scheduling substances of abuse, recommended DEA reschedule marijuana from schedule I to schedule III.  Letter to DEA Administrator Anne Milgram, from Assistant Secretary for Health Rachel Levine (Aug. 29, 2023).  By recommending rescheduling to schedule III, FDA/HHS determined that marijuana no longer meets schedule I criteria under the CSA and that it does not meet schedule II criteria either.

    Since August the Attorney General and the DEA Administrator have been pressed by high profile politicians and others ranging from no rescheduling to total decontrol.  Former DEA Administrators and National Drug Policy Directors asserted that the science demonstrating marijuana’s high addictive potential, its lack of accepted medical use, and rescheduling impact on prosecuting drug trafficking organizations required marijuana to remain in schedule I.  Letter to U.S. Attorney General Merrick and DEA Administrator Anne Milgram, from Michele Leonhart, et al. (Oct. 2023).  The Democratic governors of Colorado, Illinois, Louisiana, Maryland, New Jersey and New York advocated for rescheduling to schedule III to protect the public against more dangerous drug use asserting that legal marijuana products sold in states where they are legal “are significantly safer than myriad alternatives, including opioids.”  Letter to President Joseph R. Biden, Jr., from Governor Jared Polis et al. (Dec. 5, 2023).  Democratic state attorneys general viewed rescheduling “as a public safety imperative” and also encouraged rescheduling to schedule III based on FDA’s “scientific and medical conclusions.”  Letter to DEA Administrator Anne Milgram, from Phil Weaver, et al. (Jan. 12, 2024).  Three Republican senators on the Foreign Relations Committee advised to consider U.S. treaty obligations in rescheduling.  Letter to Administrator Anne Milgram, from Mitt Romney, Pete Ricketts and James Risch (Mar. 27, 2024).  And twenty-one Democratic senators and members of Congress pushed not only “to promptly remove marijuana from Schedule I,” but to deschedule it altogether.  Letter to Attorney General Merrick Garland and Administrator Anne Milgram, from Senator Elizabeth Warren, et al. (Apr. 24, 2024).

    Scheduling Under the CSA

    Substances in schedule I of the CSA have a high potential for abuse, no currently accepted medical use in treatment in the U.S., and lack accepted safety for use under medical supervision.  21 U.S.C. § 812(b)(1).  Those in schedule III have a potential for abuse less than schedule I or II substances, have a currently accepted use in treatment in the U.S., and their abuse may lead to moderate or low physical dependence or high psychological dependence.  21 U.S.C. § 812(b)(3).

    The CSA requires analysis of eight statutory factors for scheduling actions of substances of abuse:

    1. The drug’s actual or relative potential for abuse.
    2. The drug’s scientific evidence of its pharmacological effect, if known.
    3. The state of current scientific knowledge regarding the substance.
    4. The drug’s history and current pattern of abuse.
    5. The drug’s scope, duration, and significance of abuse.
    6. The risk to public health.
    7. The drug’s psychic or physiological dependence liability.
    8. Whether the drug is an immediate precursor of a substance already controlled.

    21 U.S.C. § 811(c).

    FDA/HHS Analysis, 2023

    FDA/HHS last conducted an eight-factor analysis of marijuana in 2016 and concluded that marijuana continued to meet schedule I criteria.  Denial of Petition to Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,688 (Aug. 12, 2016); Denial of Petition to Initiate Proceedings to Reschedule Marijuana, 81 Fed. Reg. 53,767 (Aug. 12, 2016).  FDA/HHS found that marijuana continued to have high potential for abuse and lacked accepted safety for use under medical supervision but, perhaps most important, had no currently accepted medical use in treatment in the U.S.  The scientific and medical finding was binding on DEA and, without a finding that marijuana had a currently accepted medical use in treatment, DEA denied the petitions to reschedule.

    Unlike its 2016 analysis, FDA’s/HHS’ 2023 analysis considers marijuana to have a currently accepted medical use in treatment in the U.S.  The 2023 analysis “largely focused on modern scientific considerations on whether marijuana has a CAMU [currently accepted medical use] and on new epidemiological data related to abuse of marijuana” since 2016.  FDA, Basis for the Recommendation to Reschedule Marijuana Into Schedule III of the Controlled Substances Act, 5.  FDA conducted epidemiological analyses of marijuana abuse and its associated harms through comparisons with heroin (schedule I); fentanyl, oxycodone, and hydrocodone (schedule II); ketamine (schedule III); benzodiazepines, zolpidem, and tramadol (schedule IV); and alcohol.  Id.  FDA/HHS concluded that marijuana should be rescheduled to schedule III.  FDA/HHS found that even with a high prevalence of nonmedical use, epidemiological indicators suggest that marijuana does not produce outcomes as serious as those of schedule I or II drugs.  Id. at 62.

    FDA/HHS conducted a two-part test to determine whether marijuana has a currently accepted medical use in treatment in the U.S.  The Office of the Assistant Secretary (“OASH”) found that more than 30,000 healthcare professionals “are authorized to recommend the use of marijuana for more than six million registered patients, constituting widespread clinical experience associated with various medical conditions recognized by a substantial number of jurisdictions across the United States.”  Id. at 24.  (Thirty-eight states currently authorize marijuana in different formulations for specific qualifying medical conditions).  OASH concluded “there is widespread current experience with medical use in the United States” by licensed healthcare providers for which “such medical use is recognized by entities that regulate the practice of medicine in these states.”  Id.

    FDA/HHS next reviewed studies investigating safety and efficacy/effectiveness of marijuana, professional societies’ position statements, data from state medical marijuana programs and national surveys, and labeling of relevant FDA-approved products.  Id. at 63.  FDA analyzed anorexia related to a medical condition, anxiety, epilepsy, inflammatory bowel disease, nausea and chemotherapy-induced vomiting, pain, and post-traumatic stress disorder.  FDA/HHS concluded that “some creditable scientific support” exists for the medical use of marijuana for the treatment of anorexia related to a medical condition, chemotherapy-induced nausea and vomiting and pain.  Id. at 63-64.  HHS/FDA also concluded that there is accepted safety for using marijuana under medical supervision for treatment of these conditions.  FDA/HHS concluded that marijuana does not meet schedule I criteria.  Id. at 64.

    FDA further noted that clinical studies demonstrate that marijuana produces physical and psychological dependence, and abuse may lead to moderate or low physical dependence depending on frequency and degree of marijuana exposure.  Id. at 64-65.

    U.S. Treaty Obligations

    As a signatory to the Single Convention on Narcotic Drugs, 1961, the U.S. is obligated to maintain certain provisions related to drugs controlled under that treaty.  Congress has enacted a number of CSA provisions to ensure compliance.  The CSA requires the Attorney General, by delegation the DEA Administrator, to carry out treaty obligations without regard to findings required by 21 U.S.C. §§ 811(a) or 812(b), and without regard to procedures required by 21 U.S.C. §§ 811(a) and (b).  21 U.S.C. § 811(d)(1).  The Administrator must control marijuana in the schedule she deems most appropriate to comply with U.S. treaty obligations under the Single Convention.

    Cannabis and cannabis resin are schedule I substances under the Single Convention.  United Nations, International Drug Control Conventions, Schedules of the Single Convention on Narcotic Drugs of 1961 as amended by the 1972 Protocol, as of May 17, 2023 (2023).  The Single Convention requires manufacturing quotas and import/export permits for schedule I substances.  Single Convention, Arts. 19, Par 1(a)-(d); 31, Par. 4(a).  Under the CSA, import and export permits are required only for schedule I and II substances and schedule III narcotics, but not for non-narcotic schedule III substances.  Schedule III substances do not require manufacturing quotas.  To comply with the treaty obligations as a schedule III substance, DEA may have to require marijuana import/export permits and manufacturing quotas.

    Federal CSA Implications

    Rescheduling marijuana to schedule III would have significant implications for growers, processors, and dispensaries.  Those entities will likely need to obtain and maintain a DEA registration.  They will likely need to take initial and biennial inventories, maintain transaction records, file suspicious order and theft/loss reports, and maintain adequate security.  Will dispensing marijuana, as with other schedule III substances, require a prescription issued for legitimate medical purpose by a DEA-registered, state-licensed practitioner?

    State Implications

    In addition to DEA, the states, commonwealths, and territories also regulate controlled substances within their jurisdictions.  Most states’ controlled substance regulatory regimes mirror the federal CSA and DEA regulations, but most vary on how they regulate marijuana:

    • 38 states authorize different dosage formulations for specific medical conditions
    • 24 states including DC authorize adult recreational use
    • 5 states criminalize all marijuana use

    Depending upon the jurisdiction, substances of abuse are regulated as controlled substances if, as with the federal CSA, they meet certain criteria.  At least half the states require the same eight-factor analysis as the feds, but some (New Mexico and Oregon) have fewer criteria while others (Illinois and Wyoming) consider additional factors.  Any federal scheduling action will require a handful of states to automatically regulate the substance consistent with the federal action.  This will likely prove inconsistent with a state’s authorization of marijuana for medical or recreational purposes.  Federal scheduling actions automatically require about sixteen states to control with the CSA unless there is an objection, a public hearing, and state authority decision.  Other states have discretionary scheduling authority not tied to federal scheduling.

    For states that authorize marijuana for medical or recreational use, this may represent a sea change and potential culture shift.  State authorities should begin to take stock of potential federal marijuana rescheduling by assessing and understanding how it will impact their state.  Were DEA to reschedule marijuana to schedule III, and states regulate in a less restrictive schedule or allow continued recreational use, how will DEA and DOJ respond?

    The End* of a Long and Winding Road: FDA Publishes Final LDT Rule (*Or Is It?)

    On April 29, 2024, FDA announced its finalization of the laboratory developed test (LDT) rule.  The final rule will be published in the Federal Register on Monday May 6, 2024 (here).  The final rule marks another milestone in the more than three decades long battle over LDTs.  FDA notes that it received over 6,500 comments on the proposed rule.  Showing how motivated FDA was to quickly finalize the rule, the Agency claims to have reviewed and addressed all major issues they raised in less than 5 months.

    As regular readers of the blog know, we have written about LDTs many times before.  In this post, we focus on the final rule.

    Overview of the Rule

    In short, the Final Rule makes explicit that LDTs are, in FDA’s view in vitro diagnostic devices subject to FDA regulatory oversight, and always have been.  With the Final Rule’s publication on Monday, May 6, 2024, it will start the countdown to a four-year, 5-phase transition away from what FDA deems to have been its exercise of enforcement discretion for LDTs.  (The rule’s effective date is 60 days after publication.)  Below we provide a brief summary table of the phases and timeline.  These did not materially change from before.

    Table 1: Phase-Out Policy Stages, Timeline, and Requirements

    StageEffective DateRequirements to be met unless otherwise exempt


    Stage 1May 6, 2025Labs must have procedures in place to comply with the following:


    ·        Medical Device Reporting (21 C.F.R. Part 803)


    ·        Corrections & Removals (21 C.F.R. Part 806)


    ·        Complaint Handling (21 C.F.R. § 820.198)


    Stage 2May 6, 2026Labs must register their establishment (i.e., facility) with FDA and list each individual LDT (21 C.F.R. Part 807)


    LDTs much comply with FDA labeling requirements (e.g., 21 C.F.R. Part 801 and 809)


    Labs conducting LDTs for clinical investigations must comply with applicable investigational device requirements (e.g., 21 C.F.R. Part 812)


    Stage 3May 6, 2027Compliance with the Quality System (QS) requirements in 21 C.F.R. Part 820


    For LDTs performed in a single CLIA certified, high complexity laboratory, CLIA regulations will account for some but not all QS requirements. These labs will need to comply with:

    ·        Design controls under 21 C.F.R. § 820.30;

    ·        Purchasing controls (including supplier controls) under 21 C.F.R. § 820.50;

    ·        Acceptance activities (receiving, in-process, and finished device acceptance) under 21 C.F.R. § 820.80 and 21 C.F.R. § 820.86;

    ·        Corrective and preventative actions (CAPA) under 21 C.F.R. § 820.100; and

    ·        Records requirements under 21 C.F.R. Part 820, subpart M.


    Stage 4November 6, 2027High-risk LDTs requiring premarket approval (PMA) applications, humanitarian device exemption (HDE), or biologics license application (BLA) must comply with the PMA requirements


    To continue marketing after this date – applicable LDTs must be the subject of a PMA application, HDE, or BLA received by FDA, unless otherwise exempt


    Stage 5May 6, 2028Low and moderate-risk LDTs requiring premarket notification (510(k) notification) or de novo submission must comply with the 510(k) or de novo requirements


    To continue marketing after this date – applicable LDTs must be the subject of a 510(k) or de novo received by FDA, unless otherwise exempt


    Not all LDTs will be required to comply with all aspects of the phases above.  One of the most interesting aspects of the final rule is the exemptions that FDA established.    FDA has created a number of categories of tests for which FDA intends to exercise enforcement discretion.  These largely did not appear in the proposed rule.  In the table below, we summarize the types of devices for which FDA intends to exercise varying levels of enforcement discretion.

    LDT CategoryRequirements from Phase-Out Stages
    Stage 1

    [post-market requirements]

    Stage 2

    [reg/list and labeling]

    Stage 3


    Stages 4/5

    [premarket review]


    1976-Type LDTs


    Human Leukocyte Antigen (HLA) LDTs for transplantation


    Forensic Use LDTs


    LDTs performed within the VHA or DoD


    LDTs Approved by the NYS CLEP


    LDTs for unmet needs used in an integrated healthcare system




    Currently marketed LDTs (i.e., prior to May 6, 2024)




    Non-molecular antisera LDTs for rare red blood cell antigens when such tests are manufactured and performed by blood establishments and when there is no alternative IVD available to meet the patient’s need for a compatible blood transfusion





    1 In addition to standard registration and listing information, FDA is requiring the submission of labeling pursuant to 21 C.F.R. § 807.26(e) to obtain “information on test performance and a summary of the supporting validation, among other things.”  Public Inspection version p. 47, 58, 59.

    2 While required, FDA explains that compliance with NYS CLEP clinical laboratory standards could satisfy the required portions of the QS Regulation with the exception of the design control requirements in 21 C.F.R. § 820.30.

    3 This exemption is limited to the portions of the QS Regulation other than the Records requirements in 21 C.F.R. Part 820, subpart M.

    Things People Aren’t Talking About But Should Be

    While significant focus on the nuts and bolts of the final rule has been paid by the press and others, including the phase out periods and enforcement discretion carve outs, there is a lot more in this final rule, which comes in at 528 pages (in the Public Inspection version).  Below we discuss some of the notable points from the rule.  Note: there are no shortage of interesting points in this Final Rule and these are just a select few.

    Revisionist History.  FDA claims that it has exercised enforcement discretion since 1976 over LDTs.  That would be rather shocking considering that the concept was only first introduced publicly by the Agency in 1992 (see earlier post here).  (Back then, LDTs were called “home brews.”  While FDA repeatedly disparages LDTs as unsafe, it has at least dropped this disparaging term.)  This revisionist history appears to be part of the Agency’s attempt to claim jurisdiction over LDTs dating back to the enactment of the Medical Device Amendments.  (This is roughly analogous to the statement that “Oceania had always been at war with Eurasia” in 1984.)

    LDTs are Illegal.  Almost as disturbing as FDA’s revised history is its bald statements that LDTs are, and always have been, illegal.  FDA states, “Although FDA is phasing out its current general enforcement discretion approach over a period of years, the phaseout policy does not in any way alter the fact that it is illegal to offer IVDs without complying with applicable requirements.”  Of course, the natural consequence of saying that LDTs are allowed only on sufferance through FDA’s exercise of discretion means that every LDT is illegal, but FDA here is blunter in its language.

    FDA’s Claims Regarding NY State Experience.  FDA notes as evidence of LDTs lacking appropriate analytical and clinical validity that New York State Department of Health Clinical Laboratory Evaluation Program (NYS CLEP) couldn’t approve more than half of initial applications because of deficiencies such as, including inadequate validation data.  Only needing to ask questions regarding deficiencies in approximately half of submissions actually sounds like the lab industry submitting to NYS CLEP is doing quite well in these authors’ opinion.  By FDA’s logic, the entire medical device industry must be in total shambles because in the last 10 fiscal years (FY14-24) in the first cycle review, between 63 and 78% of 510(k) submissions receive a request for additional information meaning that it could not be initially cleared without addressing various deficiencies. See page 107 of FDA’s 1st Quarter FY2024 MDUVA V Report (here).  The real issue is how many tests were ultimately approved, not how many raised questions in the initial submission.

    FDA’s Stance on Collection Devices.  While some of the enforcement discretion carve outs may be modestly helpful, even labs that enjoy certain enforcement discretion may not be free from regulatory oversight.  Footnote 21 states, “We note that “IVDs offered as LDTs” does not include IVDs manufactured or used outside of a laboratory, including collection devices.”  In recent years, we have seen FDA challenging use of common collection device materials in LDTs.  Thus, labs will need to ensure that the collection materials they employ are being used for their on-label purpose.  If not, FDA may claim that the lab needs to seek clearance/approval for the collection device.  FDA’s attacks on collection devices can provide a backdoor route to challenge LDTs that enjoy continuing enforcement discretion.

    FDA Collection and Review of Labeling.  As noted above in Table 2, FDA is requiring that certain LDTs submit, as part of its device listing process, copies of a to‑be‑listed LDT’s labeling. FDA notes that it views the labeling requirements of 21 C.F.R. Parts 801 and 809 as potentially being “encompassed in more than one document, such as the test protocol, test report template, and test menu.”  See response to Comment 176.  Thus, affected labs will be required to submit to FDA significant amounts of information as part of the device listing.  What will FDA do with this information?  The Final Rule states, “This labeling will facilitate FDA surveillance for potentially poor performing LDTs that should otherwise be addressed.”  Public Inspection version p. 58.  What is a “poor performing LDT?”  How will FDA assess performance?  Will FDA give a lab the opportunity to address any claims of poor performance or will such tests be required to exist the market?  Bottom line – while these tests are “exempt” from the premarket approval/clearance process, FDA appears to still be reviewing them and perhaps with less transparency than would otherwise occur in the ordinary course.

    What Happens Next

    The Final Rule will become effective in 60 days, on Friday July 5, 2024.  In a sort of reverse Independence Day for labs, all labs offering LDTs will be on a ticking clock to begin efforts to comply with the various stages of the phase out plan, as applicable.  One looming question for many in this space is – what happens to new tests?  While the preamble to the rule is not expressly clear, it appears that new LDTs can continue to enter the market so long as they comply with the requirements at the time (i.e., per the Phase Out Policy Stages, see Table 1 above).  Of course, as time goes by, some labs will not be able to meet these timelines, and so some tests will not be introduced or their introduction will be delayed.

    While there will almost certainly be a legal challenge to the final rule, how such a challenge could affect the timeline for implementation is not clear.  It took 32 years from the first challenge to FDA regulation of LDTs to today.  If there is litigation, this next phase will be resolved far faster.

    Sarah Wicks Returns to HPM to Elevate Drug Development and Regulatory Practice

    Hyman, Phelps & McNamara, P.C. proudly announces the return of attorney Sarah Wicks to its drug development and compliance group. Sarah brings a wealth of experience and a proven track record of advising innovative drug and biologics companies through the intricate landscape of product development and commercialization. Her expertise spans a range of critical areas including: human subject protections, clinical trial conduct, development strategies, FDA interactions, and enforcement action responses.

    “Sarah’s a tremendous attorney who always understood HPM’s culture and commitment to client service.  Her additional professional experiences have only made her better and enhanced her contributions to the firm.  We couldn’t be happier that she’s back in the fold,” said J.P. Ellison, Managing Partner at HPM.

    During her previous stint with HPM, Ms. Wicks was instrumental in the firm’s approach to client-centric solutions and innovative compliance strategies. Her background also includes significant roles such as serving as an adjunct professor at the George Washington University Law School, where she coaches health law moot court teams, and engaging actively with key industry groups like the Society for Clinical Research Associates and the Food and Drug Law Institute.

    Ms. Wicks’ extensive experience also includes her time at the FDA’s Office of Generic Drugs Policy and the Office of Legislation, providing her with insider insights that greatly benefit her clients.

    “I am very excited to have Sarah rejoin HPM.  Her extensive knowledge of, and insights into, preapproval drug development and approval strategy will benefit the patients, researchers, and sponsors we serve.  We look forward to working with Sarah as she also further enhances HPM’s capacity to assist companies with clinical trial operations and compliance, human subjects research protections, product promotion, and business transactions.  Most of all, we are excited to be working alongside someone who shares our passion to bring new therapies to those in need,” notes James E. Valentine, HPM Director.

    Sarah’s expertise will contribute to our mission of helping drug and biologic companies navigate the pathways from discovery to commercialization.

    Sarah graduated with a cum laude degree in Cell and Molecular Biology from Towson University, a M.P.H. from Johns Hopkins Bloomberg School of Public Health, and a J.D. from the University of Maryland School of Law.

    Categories: Drug Development

    FDA’s Draft Guidance on the Q-Submission Program – A Step in the Wrong Direction

    FDA recently issued a draft guidance on Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program, which included some changes over the existing guidance which could have a negative impact on future pre-submissions.

    The draft guidance attempted to clarify when a Sponsor’s question may be more appropriate for more informal communication.  The guidance recommends that questions “that can be readily answered” based on the FDA reviewers “experience or knowledge” and that “do not require additional background information, an in-depth review, or other FDA staff involvement” can be done outside of the Q-Submission process.  This hardly provides clarification and seems to limit the topics that could utilize this method of feedback.

    In addition, the draft guidance, incorporated the 1998 guidance on PMA Day 100 Meetings.  The PMA Day 100 meeting may be used to discuss clarifying questions about Major Deficiencies and preliminary approaches for a response.   However, instead of committing to continued communication with the applicant every 4 weeks until the review is complete, FDA recommends the applicant submit a Submission Issue Request (SIR) to enable further discussion of a detailed  approach to addressing major deficiencies. It is not clear from the draft guidance how the timetables noted in Table 1 for an SIR would relate to an SIR submitted after the PMA Day 100 meeting.  However, Table 1 states that if the SIR request is received within 60 days of the FDA “marketing submission letter” FDA would, resources permitting, have the meeting or provide written feedback within 21 days.  It’s not clear, though, how SIR’s submitted after 60 days would be handled in the context of a post-100-day meeting interaction because some of those interactions would exceed 60 days, and per Table 1, FDA wouldn’t hold a meeting for 70 days after receiving such a request.  If this is FDA’s intent, it would be a major change to the process as set out in the 1998 Guidance allowing for monthly interactions.  In addition, the draft guidance indicates that “relevant review team members and management will attend the meeting with the applicant as well as other FDA staff as appropriate,” whereas the 1998 guidance states in addition to the relevant core review team, the Branch Chief, Division Director, or Deputy Director will attend the meeting with the applicant.

    The draft guidance also provides additional detail on the number of questions that can be addressed within one pre-submission. FDA indicates that a pre-submission with too many topics does not result in productive discussions or feedback. The draft guidance echoes the existing guidance in that the pre-submission should be limited to 3-4 topics; however, the draft guidance goes further and recommends a limit of 7-10 questions across those topics.  In addition, the draft guidance offers some considerations regarding the types of questions and information necessary for FDA to provide feedback.  If the Sponsor submits an “excessive number of topics”, FDA may contact the Sponsor to discuss which topics should be prioritized and which topics can be delayed in a subsequent pre-submission.

    The draft guidance further provides considerations for the type of questions to ask in a pre-submission.  For example, if the questions are related to regulatory pathway or indications for use, it may be too early to ask questions about performance data.  This seems misguided, as feedback on required performance data may shape the Sponsor’s decision on the final indications for use and claims for the device.  Similarly, if the design is not frozen and the Sponsor expects to make “technological changes” to the device, according to the draft guidance, it may be “premature” to ask questions about performance data. However, getting input on the design and performance testing plan at the time of the pre-submission can provide valuable insights to a Sponsor and may even direct changes to the design that were not anticipated. Conversely, waiting until the device is out of the design stage may be too late to first get input and alignment on required performance testing. Once the final device has been designed, Sponsors typically move quickly into executing performance testing (e.g., design verification and validation). For questions related to clinical study protocol, the draft guidance recommends that Sponsors provide the planned indications for use and describe the non-clinical data that will be included in a subsequent marketing application. With the increasing number of pre-submissions submitted to the Agency, it is not surprising that FDA added even more language restricting the scope and review of a pre-submission.

    This draft guidance is open for comments through May 14, 2024, which can be submitted online.  We hope the final guidance provides more clarity on use of informal interactions with the Agency as a method of getting feedback.  We consider the focus on limiting the number of questions that can be addressed in any one pre-submission and the impact that will have on development timelines to be a step in the wrong direction.  The approach to submitting a pre-submission with a limited number of questions and following with additional pre-submission supplements to get feedback and alignment with the agency on a variety of topics does not align with helping ensure timely access to new medical devices. This approach, further, seems outdated given many Sponsors utilize agile-like approaches to medical device development focusing on flexibility, rapid iterations based on customer-centric feedback (including regulator feedback), and speed to market.  The pre-submission process is a useful tool for Sponsors to gain alignment on expectations upfront and early in the development process.  We hope FDA does not limit the utility of this valuable resource and instead considers how it can continue to collaborate early and often with industry to streamline and not prolong the development process.

    Categories: Medical Devices

    Democratic Lawmakers Advocate for Prompt Decontrol of Marijuana

    On April 23, 2024 we blogged about Republican Senators Mitt Romney, Pete Ricketts and James Risch advising Drug Enforcement Administration (“DEA”) Administrator Anne Milgram to consider U.S. treaty obligations under the Single Convention, 1961, when rescheduling marijuana.  Later Democratic lawmakers, eleven senators and ten members of Congress, also penned a letter to Administrator Milgram and Attorney General Merrick Garland imploring DEA to not only “promptly remove marijuana” from schedule I of the Controlled Substances Act (“CSA”), but to deschedule it altogether.  Letter to Attorney General Merrick and Administrator Anne Milgram, from Senator Elizabeth Warren, Senator John Fetterman, et al., April 24, 2024.

    This is the third letter from some of the same Democratic lawmakers to the Attorney General and DEA Administrator on marijuana rescheduling since the Food and Drug Administration (“FDA”) and Health and Human Services (“HHS”) recommended rescheduling in schedule III last August.  The current letter conveys impatience and frustration with the time DEA is taking to conduct its review, noting that it has been eight months since FDA/HHS recommended rescheduling and eighteen months since President Joe Biden directed HHS and the Department of Justice to “initiate the administrative process to review expeditiously how marijuana is scheduled under federal law.”  Statement from President Biden on Marijuana Reform, White House, October 6, 2022.  The lawmakers assert that “[i]t is time” for DEA “to act.”

    The Dems note that marijuana’s continued schedule I placement “produces a cascade of severe penalties for marijuana users and businesses, including for criminal records, immigration statuses, employment, taxation, health care, public housing, social services, and more.”  While recognizing that rescheduling to schedule III “would be a meaningful improvement,” they assert that only descheduling, that is decontrolling altogether, would remedy the serious consequences associated with marijuana’s total prohibition.  DEA, they note, “now has the power to determine whether it will continue the failed approach of keeping marijuana in Schedule I.”

    The lawmakers recognize that while there may be internal disagreements within DEA about rescheduling, they implore the agency to move “swiftly” because “[t]he longer marijuana remains scheduled in the CSA, the longer our communities face senselessly severe penalties and the longer the marijuana laws of the majority of U.S. states must remain in conflict with federal law.”  And further that “[r]ight now, the Administration has the opportunity to resolve more than 50 years of failed, racially discriminatory marijuana policy.”

    At the same time, the lawmakers “trust that the DEA is working as quickly as possible toward a decision on how marijuana is scheduled” as noted by Vice President Kamala Harris in March.  (During a roundtable discussion about marijuana and criminal justice reform, the Vice President characterized marijuana’s schedule I classification as “absurd” but noted “I’m sure DEA is working as quickly as possible and will continue to do so, and we look forward to their work product.”  Vice president criticizes federal cannabis restrictions during White House weed event, March 15, 2024.)

    The Dems conclude by walking back their demand somewhat that DEA deschedule marijuana altogether by expressing hope only that “DEA will not make the unprecedented choice to disagree with HHS’s medical finding that a drug does not belong in Schedule I.”

    In response to the several of the senators’ earlier January 29, 2024 letter, DEA’s chief of DEA’s Office of Congressional Affairs wrote on April 16th to each that for DOJ, and by delegation DEA, to undertake administrative scheduling action on marijuana, it must follow the procedures established by Congress in the CSA that which includes opportunity for public comments and a hearing.  Letters to Elizabeth Warren, et al., from Michael Miller, April 16, 2024.  The DEA letter notes that DOJ “is carefully following those procedures as it conducts an administrative review of the scheduling of marijuana.”  DEA states that it has the final authority to reschedule a under the CSA “after considering relevant statutory and regulatory criteria and HHS’ scientific and medical evaluation.”

    While the Democratic lawmakers advocate for descheduling to remedy the “cascade of severe penalties for marijuana users and businesses” and “more than 50 years of failed, racially discriminatory marijuana policy,” the CSA requires analysis of eight specific factors (“the eight-factor analysis”) for scheduling, rescheduling or descheduling substances of abuse.  Those eight statutory factors are:

    1. The drug’s actual or relative potential for abuse.
    2. The drug’s scientific evidence of its pharmacological effect, if known.
    3. The state of current scientific knowledge regarding the substance.
    4. The drug’s history and current pattern of abuse.
    5. The drug’s scope, duration, and significance of abuse.
    6. The risk to the public health.
    7. The drug’s psychic or physiological dependence liability.
    8. Whether the drug is an immediate precursor of a substance already controlled. 21 U.S.C. § 811(c).

    Albeit the lawmakers’ reasons for quickly decontrolling marijuana are important, compelling and not without merit, but they are not among the eight factors the CSA mandates that DEA consider.

    FDA’s Revised Draft Guidance on Biological Product Promotion Provides Additional Recommendations/Clarifications

    On April 24, 2024, the FDA issued a revised draft guidance, Promotional Labeling and Advertising Considerations for Prescription Biological Reference Products, Biosimilar Products, and Interchangeable Biosimilar Products – Questions and Answers, (the “Revised Draft Guidance”) which replaces the Agency’s initial draft guidance issued in February 2020 (the “Initial Draft Guidance”).

    This Revised Draft Guidance provides considerations for manufacturers, packers or distributors (dubbed “firms”) of prescription biological reference products, biosimilar products, and interchangeable biosimilar products presenting data and information about such products in promotional materials in a truthful and non-misleading way.  Promotional labeling is generally any labeling other than FDA-required labeling that is devised for the promotion of a product, as well as other functions, and can include printed, audio, or visual matter that describes the product. While the Federal Food, Drug & Cosmetic Act does not explicitly define “advertisement,” FDA provides several examples in its regulations at 21 CFR § 201.1(l)(1) (e.g., “advertisements in published journals, magazines, other periodicals, and newspapers, and advertisements broadcast through media such as radio, television, and telephone communication systems”).

    Major differences between the Revised Draft Guidance and the Initial Draft Guidance include additional recommendations, an example of a misleading promotional communication for interchangeable biosimilar products, and clarifications on postmarketing reporting requirements.

    The Revised Draft Guidance emphasizes that where multiple products are licensed as biosimilar to and interchangeable with or biosimilar to but not interchangeable with the same reference product, promotional communications should avoid suggesting that any of the products are less safe or effective than each other for their approved uses. To emphasize this point, the Agency provides one new example of a promotional communication for interchangeable biosimilar products where it would consider the presentations described to be misleading (see Example 4 in Q7). In the example, it would be misleading for a product that is an interchangeable biosimilar to suggest superior safety and efficacy to a  non-interchangeable biosimilar product solely based on the product’s status as an interchangeable biosimilar product. Relatedly, promotional communications for a biosimilar product that suggest that a finding of biosimilarity means that the FDA determined the reference product and biosimilar product are identical to each other would not be accurate, and therefore misleading, because “biologics generally cannot be copied exactly” and typically have even minor differences between batches of the same product.

    The Revised Draft Guidance also further clarifies postmarketing reporting requirements for submitting promotional communications to the FDA do apply to promotional communications for biological reference products, biosimilar products, and interchangeable products under 21 CFR § 601.12(f)(4). The FDA specifically notes that “specimens of mailing pieces and any other labeling or advertising devised for promotion of the reference product or biosimilar product [including an interchangeable biosimilar product] must be submitted to FDA at the time of initial dissemination of the labeling or at the time of initial publication of the advertisement, as applicable” and be accompanied by a completed Form FDA 2253 (emphasis added). We note this clarification is helpful given the modification to the definition of “promotional labeling” in the Revised Draft Guidance as part of footnote 4.  In the new definition, FDA removed the phrase, “that is devised for the promotion of a product,” broadening the definition of “promotional labeling” to potentially encompass any labeling other than the FDA-required labeling.  The restatement in text that postmarketing reporting requirements apply to labeling devised for promotion is supportive of our original understanding.

    As a reminder, manufacturers, packers or distributors of prescription biological reference products, biosimilar products, and interchangeable biosimilar products may voluntarily seek FDA feedback on their proposed promotional communications before dissemination by following the current process outlined in FDA’s draft guidance Providing Regulatory Submissions in Electronic and Non-Electronic Format – Promotional Labeling and Advertising Materials for Human Prescription Drugs (April 2022).

    Comments to the revised draft guidance are due to the docket by June 25, 2024.

    OMB Completes its Review of the Final LDT Rule—A Final Rule Coming Anytime Now

    We’ve been hearing for quite some time that a Final LDT Rule would likely be coming this spring, before May 1.  This timing has been attributed to FDA’s desire to avoid having the rule being overturned by Congress under the Congressional Review Act.  Of course, if a new administration takes over next year, the rule’s future would be questionable, even without congressional action.

    As of Monday, April 22, FDA appears to be one step closer to achieving that timing goal with Office of Management and Budget (OMB) having completed its review of the final rule (see here). Our readers will recall that the rule went to OMB on March 1 for its review. OMB completed its review by concluding the final rule is “Consistent with Change.”  This conclusion means that OMB has returned the final rule to FDA with changes.  There is no way to know from this coding the source or extent of the changes as even editorial changes can cause a rule to be coded “Consistent with Change.”  Regardless of the changes, however, OMB has concluded that the final rule is consistent with its mandate to review final rules.  Bottom line – OMB did not object and FDA just cleared one more hurdle on its way to issuing the final rule.

    The final rule was identified by OMB as Section 3(f)(1) significant meaning that the rule “may have an annual effect on the economy of $200 million or more . . . ; or adversely affect in a material way the economy, a sector of the economy, productivity, competition, jobs, the environment, public health or safety, or State, local, territorial, or tribal governments or communities.”  (see here) With much at stake, OMB has held over two dozen meetings regarding the proposed rule (see here) with approximately half of those occurring since the final rule went to OMB for review.  The meetings have presented a mix of views with some organizations meeting with OMB being in favor of FDA regulation and others being very much opposed.

    With a final rule now nearly a certainty, a legal challenge seems likely to follow.  As we have previously noted, there are plenty of grounds for challenging any final rule that is released (see our prior post here).

    We will, of course, keep our readers up to date on the final rule.

    Senators to DEA: Consider Treaty Obligations In Marijuana Rescheduling

    Administrator Anne Milgram has been on the receiving end of high-level support for and against rescheduling marijuana since the Food and Drug Administration (“FDA”) and Health and Human Services (“HHS”) recommended the Drug Enforcement Administration (“DEA”) reschedule from schedule I to schedule III last August.  We blogged in February about the October 2023 letter from former DEA Administrators, Ms. Milgram’s predecessors, and Directors of National Drug Policy urging not to reschedule; the January 2004 letter Democratic state attorneys general pushing for rescheduling to schedule III; and the January 2024 letter from Democratic senators requesting descheduling altogether.  Democratic senators also weighed in, supporting rescheduling to schedule III in December 2023.

    Administrator Milgram received another letter last month from Republican senators Mitt Romney (Utah), Pete Ricketts (Nebraska), and James Risch (Idaho), who sit on the Senate Foreign Relations Committee.  The Senators implore efforts to reschedule marijuana be driven by facts, “not the administration’s favored policy,” and question whether rescheduling would violate the Controlled Substances Act (“CSA”) and U.S. treaty obligations under the Single Convention on Narcotic Drugs, 1961.  Letter to Administrator Anne Milgram, from Mitt Romney, Pete Ricketts and James Risch, March 27, 2024.

    The senators write that the U.S. ratified the Single Convention in 1967 and must impose certain domestic controls on marijuana and other drugs controlled by the treaty.  Marijuana is a schedule I drug under the Convention.  They write that the CSA implements treaty obligations in U.S. domestic law and that 21 U.S.C. § 811(d) specifically requires the Attorney General to control marijuana in the schedule he deems most appropriate for carrying out U.S. obligations under the Single Convention.

    The senators note that DEA determined in prior rescheduling proceedings that 21 U.S.C. § 811(d) required classification of marijuana as a schedule I or II substance to comply with U.S. treaty obligations under the Single Convention, opining that it is important that DEA continue “to follow the law and abide by our treaty commitments.”

    When DEA denied marijuana rescheduling petitions in August 2016, cannabis was listed as a schedule I and schedule IV substance under the Single Convention.  Schedule IV substances are highly addictive and rarely used in medical practice while schedule I substances are also highly addictive, liable to abuse or convertible to drugs similarly addictive and liable to abuse.  The Single Convention imposes more stringent controls on schedule IV substances than on schedule I substances.  The UN Commission on Narcotic Drugs removed cannabis and cannabis resin from schedule IV of the Single Convention in December 2020.  While FDA recommended rescheduling to schedule III, we think it more likely that if DEA reschedules marijuana it would be to schedule II because the Single Convention still requires manufacturing quotas for cannabis (which are not required for schedule III substances under the CSA).  In addition, the Single Convention requires import and export permits for international transactions involving cannabis, while the CSA requires permits for schedule I and II substances and schedule III narcotic substances.  The CSA does not require permits for non-narcotic schedule III substances.  Were DEA to reschedule marijuana in schedule III, the agency and registrants would have to straddle the requirements of two schedules by requiring manufacturing quotas and import/export permits.  On a final note, as a signatory to the Single Convention, U.S. marijuana manufacturers, importers, exporters, and distributors will be required to obtain DEA registrations, and prescriptions will be required for dispensing marijuana to individuals.

    In response to their letter, the senators asked DEA:

    • Whether DEA still holds the position as it did in 2016, when it declined to remove marijuana from schedule I, that marijuana must be a schedule I or II substance to comply with 21 U.S.C. § 811(d) and U.S. treaty obligations, and, if not, why has DEA’s position changed?
    • Whether DEA believes the U.S. can meet its treaty obligations under the Single Convention if marijuana is rescheduled to schedule III?
    • Whether DEA is consulting the Department of State about treaty obligations regarding marijuana and diplomatic implications of rescheduling?
    • Whether DEA consulted “with key counterdrug partner nations about our shared obligations under the Single Convention and their views regarding a potential rescheduling” by the U.S.?
    • What impact a potential failure by the U.S. to uphold its treaty obligations would have on our ability to ensure other countries enforce their drug controls under the Single Convention, including fentanyl?

    The senators requested responses to their questions by April 12th.  The senators’ position through their statements and questions makes clear to DEA that U.S. treaty obligations under the Single Treaty must be part of the agency’s rescheduling considerations.