On October 21, 2022, FDA published a draft guidance document titled Select Updates for the Breakthrough Devices Program Guidance: Reducing Disparities in Health and Health Care.  This draft guidance proposes updates to FDA’s Breakthrough Devices Program, which is outlined in a separate December 2018 guidance document.

FDA intends to incorporate these updates into the December 2018 Breakthrough Devices Program guidance after considering public comment.  The proposed updates are designed to clarify how the Breakthrough Devices Program may be applicable to devices “that benefit populations impacted by health and/or health care disparities.”

First, FDA is proposing to add a statement to the introduction section of the 2018 guidance that certain “non-addictive medical products to treat pain or addiction” may be eligible for breakthrough designation.  The draft guidance states that this addition is consistent with FDA’s obligations under the Substance Use-Disorder Prevention That Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act, which required FDA to update existing guidance documents to address how the Agency may apply breakthrough criteria to such products.

FDA is also proposing updates to Section III of the 2018 Breakthrough Devices Program guidance to clarify the designation considerations for the first breakthrough criterion—whether a device provides for “more effective” treatment or diagnosis.

Specifically, FDA proposes to add language stating that the level of evidence required to demonstrate “more effective” treatment or diagnosis may vary depending on the intended use of the device, its technology and features, and the available standard of care alternatives.  For this reason, FDA intends to consider the totality of the information about the proposed device, its function, potential for technical success, potential for clinical success, potential for a clinically meaningful impact, and its potential benefits and risks.

This first criterion, requiring a demonstration of “a reasonable expectation that the device may provide for more effective treatment or diagnosis as compared to the current standard of care” is often cited in decisions denying breakthrough designation.  It is not always clear to sponsors of breakthrough designation requests the level of evidence required to meet this standard.  For some devices, preclinical data may be sufficient, while for other devices, FDA may request a clinical study validating the technology.  The language that FDA is proposing to add to the 2018 guidance seems to further reinforce that the level of evidence require will vary widely, and therefore may be difficult to predict, though the new language does not appear to change the “reasonable expectation” standard.

The most significant proposed update is the addition of a new section to the 2018 guidance on reducing disparities in health and health care.  This section notes that, when FDA assesses the statutory eligibility criteria for breakthrough designation, it intends to consider technologies and device features that may help to address health and/or health care disparities and promote health equity by providing for more effective treatment or diagnosis in populations that exhibit health and health care disparities.

Such technologies and features may include those tailored to better address characteristic differences (e.g., those arising from social factors, phenotypic variations, pathophysiology, and/or response to treatment) compared to standard of care.  FDA also intends to consider devices that address disparities that arise in populations impacted by rare diseases or conditions with limited diagnostic and treatment options.

Additionally, FDA plans to consider “accessibility” to health care, which is described as an individual’s or group’s capacity to benefit from a medical device.  Features that may improve accessibility include user features that make a device more adaptable or easily used by diverse populations or in diverse settings.  However, increased “accessibility,” as that term is described in the draft guidance, does not appear to include cost-related considerations.

These examples of technologies and features that may lead to more effective treatment or diagnosis through their ability to address health and health care disparities may open the door for companies that may not have otherwise considered their device to be a breakthrough device.  It appears that demonstrating an advantage over standard of care with regard to a device’s ability to address a health disparity could help support a finding that the device would lead to “more effective” treatment, satisfying the first breakthrough criterion.

Finally, FDA is proposing to add language to the 2018 guidance regarding the confidentiality of breakthrough requests.  The proposed update clarifies that FDA will not disclose the existence of requests for breakthrough designation or the Agency’s decision on the breakthrough request (e.g., in response to a FOIA request), unless the designation was previously publicly disclosed or acknowledged by the sponsor.  Additionally, once a breakthrough device receives marketing authorization, FDA intends to disclose its breakthrough status for that indication for use in a list on the FDA website.  FDA recently updated this list on October 28^th, announcing that there has been a total of 56 breakthrough devices that FDA has authorized for marketing (see Breakthrough Devices Program metrics here).

FDA is accepting comments on these proposed updates until December 20, 2022 via a docket established on Regulations.gov.

FDA recently published the final guidance document “Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA.”  This final guidance provides recommendations to original applicants and holders of approved applications for human drugs and certain biological products on implementing chemistry, manufacturing, and controls (CMC) postapproval changes(s) through the use of a Comparability Protocol (CP).

According to the FDA, the draft guidance was published in 2016 in order to update the 2003 guidance by including current pharmaceutical quality concepts, providing more flexibility regarding filing procedures for notification of modifications to an approved CP in less burdensome reporting categories than a prior approval supplement, and adding an appendix to address commonly asked questions.  The updated final guidance now also incorporates ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product lifecycle Management.  The final guidance includes several changes that are summarized below.

Section D: Comparability Protocol for the Proposed CMC Change(s) was largely rewritten to add more detail on what the CP should describe as well as recommendations for designing the CP.  For example, the guidance now includes that the design of the CP should take into account your understanding of the product, manufacturing process, risks, control strategy that are relevant to the proposed change(s), and the intended use of the product.

To address industry comments regarding the requirement to perform tests and studies or collect and analyze data for the proposed change(s) at commercial manufacturing scale, the guidance now includes “…except where less than commercial scale is justified.”  According to the updated final guidance, it might be possible to design a CP to compare the post-change product to established quality reference standards and/or comparator products, but that it recommends reaching out to the Agency for complex products that are difficult to characterize.

FDA added examples in Section V of the guidance of modifications to an approved CP that must be submitted as an annual report.  Additional examples of modifications to an approved CP that must be submitted as either a CBE-30 or CBE-0 were also provided in the updated guidance.  In the updated guidance FDA’s clarifies that it is acceptable to submit a CBE-0 to replace or modify a characterization test or study as specified in an approved CP that provides increased assurance of the product quality.  FDA also provided additional examples as to what changes would be considered “annual reportable.”  While the clarifications appear to be minor, they can save companies significant time in the preparation of materials for FDA review.

The FDA added in Section VI that if the data does not demonstrate that the approved acceptance criteria in the CP have not been achieved or there is some other impact on product quality, applicants have a few options, including 1) withdrawal of the approved CP in a CBE-0 supplement, 2) pursue change without using a CP using applicable reporting categories established in 21 CFR 314.70 or 601.12, or 3) pursue a change using a CP by contacting FDA to discuss an appropriate course of action.

When you are ready to notify the FDA of the change(s) in the approved CP, the FDA states that you should include all of the information agreed upon in the approved CP and that the submission should update, using the ICH CTD-Q format (where applicable), the appropriate section(s) of the application to which the CMC change(s) applies.

Based on comments from Industry, the updated guidance now includes questions and answers for Manufacturing Equipment Changes, Drug-Device or Biologic-Device Combination Products, and Master Files.  The Manufacturing Process Changes section of the Appendix now includes two questions on process scale changes and a change from batch to continuous manufacturing.  FDA states that a CP can be useful for changes in manufacturing process scale (scale-up, scale-down, scale-out), and that FDA recommends including information on potential effects of changes in manufacturing scale on product quality.  Regarding a change from batch to continuous manufacturing process, the FDA states that a reporting category other than a PAS would generally not be justified.

The question of whether FDA has authority to take pictures during an inspection of a facility has bounced around the food and drug bar for many years. FDA’s view is stated in the agency’s Investigation Operations Manual, and it is one with which a number of practitioners disagree. To date, neither side has sought to take the issue to the mat in a way that would definitively resolve the dispute. In the interim, the issue has reared its head again in FDA’s recently issued guidance for industry, titled Refusal of Inspection by a Foreign Food Establishment or Foreign Government. 

As the name suggests, the guidance explains the circumstances under which FDA will conclude that a foreign food establishment or foreign government has refused inspection, and the consequences that could flow from that refusal. In part, the guidance states:

In the domestic context, FDA has authority to compel inspection, namely, when a domestic firm refuses inspection completely or refuses to permit us to fully conduct an inspection (e.g., refuses to provide access to applicable records, refuses to permit the investigator to take photographs as necessary or refuses to permit sample collection), FDA may seek an inspection warrant to compel the inspection.

*            *            *

We consider an owner, operator, or agent in charge of a foreign food establishment to have refused an inspection when an owner, operator, or agent in charge prevents the FDA investigator from fully conducting an inspection of the establishment, by establishing unreasonable preconditions to allowing the inspection or by preventing or interfering with completion of some aspect of the inspection. Examples of where we would generally consider preventing the FDA investigator from fully conducting an inspection include… [t]he owner, operator, or agent in charge refuses to allow the FDA investigator to collect evidence to document potential violations (e.g., to take photographs as necessary; to collect samples; talk to pertinent staff; or to collect food labels and labeling).

Absent extraordinary circumstances, it seems unlikely that FDA would seek a warrant to compel a domestic firm to allow the taking of photographs. However, in the context of imports, FDA can more easily wield a much bigger cudgel.

As explained in the guidance, “[u]nder section 807(b) of the FD&C Act, FDA shall refuse admission into the United States of a food from a foreign food establishment of which the owner, operator, or agent in charge or the foreign government refuses to permit an inspection.” That refusal is executed administratively, with no need to involve lawyers or judges, and the results can be highly disruptive. The refusal likely would land the foreign food establishment on the Red List of Import Alert 99-32, Detention Without Physical Examination of Products From Foreign Establishments Refusing FDA Inspection. Once on the Red List, an establishment can try to get off by contesting FDA’s decision – likely an uphill battle – or can ask FDA to schedule an inspection. However, as pointed out in the guidance, it could take at least a year before FDA returns to the establishment for the inspection. That’s a long time to potentially lose access to the U.S. market.

The unfortunate scenario painted above is more than theoretical. As we’ve discussed in prior blog postings, FDA has already trod this path with respect to foreign drug establishments that allegedly prevented the taking of photographs. See here and here. Even though CDRH has not yet issued its own guidance about inspection refusals like the drugs, biologics, and food centers, it is likely that CDRH would take the same position about taking photographs during device inspections.

As an aside, a number of establishments from a handful of countries are already on the Red List in Import Alert 99-32. The vast majority of those establishments appear to be located in China, notwithstanding the fact that country purportedly accounts for a relatively small proportion of food imported to the U.S.

During last year’s 2021 Pharmaceutical Quality Symposium, CDER described the development of a regulatory framework called FRAME –Framework for Regulatory Advanced Manufacturing Evaluation, to accommodate innovation expected in the next 5-10 years with a focus on 4 technologies: End to End Manufacturing, Distributed Manufacturing, Point-Of-Care, and Artificial Intelligence.  On October 17, 2022, FDA finally published a webpage officially describing FRAME.  In addition to describing FRAME’s technology focus, the webpage includes descriptions of its priorities to develop a regulatory framework for advanced manufacturing technologies:

• Seek and Analyze Input: CDER plans to solicit stakeholder feedback by releasing discussion papers and holding a public workshop on regulatory areas of consideration for advanced manufacturing technologies.
• Address Risks: Through FRAME, CDER is evaluating our existing risk-based regulatory framework as it applies to these technologies to enable timely adoption of advanced manufacturing technologies.
• Clarify Expectations: As a result of FRAME, CDER may issue new or updated guidance to explain the current thinking on a regulatory issue.
• Harmonize: The FRAME initiative is aligned with FDA’s efforts to work through the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) to develop international guidelines related to advanced manufacturing technologies, such as continuous manufacturing, the subject of a new ICH Q13 guideline.

For the Seek and Analyze Input priority, CDER is seeking input from stakeholders on its recently published a discussion paper on Distributed Manufacturing and Point-of-Care Manufacturing of Drugs.  For the purposes of the discussion paper, CDER and CBER define Distributed Manufacturing (DM) to be a decentralized manufacturing strategy consisting of a manufacturing platform of manufacturing units deployed to multiple locations; Point-of-Care (POC) manufacturing is defined as a subset of DM that uses manufacturing units distributed to host sites in proximity to patient care ( e.g., healthcare facilities).  The discussion paper describes regulatory areas of consideration for an applicant’s ability (human drugs and biologics) to comply with the current regulatory framework or FDA’s assessment of a marketing application when using distributed manufacturing (DM) and point-of-care manufacturing (POC).  FDA included questions for each technology (DM and POC) to facilitate public comment.  For example, are there additional aspects of the current regulatory framework that may affect DM or POC that should be considered by the FDA; are there new regulations or guidances that should be considered; what are the necessary steps for demonstrating quality or comparability of product quality, etc.  The commenting period for this discussion paper ends December 13, 2022 (FDA docket FDA-2022-N-2316).  Interested stakeholders may also provide input at the FDA/PQRI Workshop on the Regulatory Framework for Distributed and Point of Care Pharmaceutical Manufacturing:  An Opportunity for DM/POC Stakeholder Engagement on November 14-16, 2022.  According to the website, the Workshop aims to facilitate interaction among DM/POC stakeholders on critical areas for development and implementation of these technologies including terminology, technical challenges to adoption, operation of Pharmaceutical Quality Systems, good manufacturing practice expectations, and the unique challenges and considerations that apply to complex biologics.

Making use of real-world data has long been of interest to stakeholders as having tremendous potential value.  These data are routinely collected from a variety of sources, such as electronic health records, providing information on health and healthcare in actual patients, rather than in the controlled environment of a clinical trial.  This value is potentially even greater for rare diseases, where there are limited sources of data.  These data exist and are being collected – it is up to the stakeholders to figure out how to leverage them to realize this potential.

However, translating real-world data into real-world evidence (“RWE”) has proved to be a challenge.  While some sponsors have succeeded in using RWE, typically as external controls, few have been able to use RWE as even supportive evidence of effectiveness for approvals (FDA’s 2021 approval of Prograf (tacrolimus) for a new indication based on a non-interventional study using real-world data from a registry of transplant recipients appears to be the largest role for RWE thus far).

To encourage efforts in this arena, Congress, in the 21st Century Cures Act’s Section 3022, codified at 21 U.S.C. § 355g(a), directed FDA to “establish a program to evaluate the potential use of real world evidence” both “to help to support the approval of a new indication” and “to help to support or satisfy postapproval study requirements.”  FDA announced its intentions to do just that in its PDUFA VII Goals Letter, which described a commitment to establish this pilot program by December 31, 2022.  On October 20, 2022, FDA issued a Federal Register notice announcing the establishment of the “Advancing Real-World Evidence (RWE) Program” as the culmination of this commitment.

The Federal Register notice states that the Advancing RWE Program “seeks to identify approaches for generating RWE that meet the regulatory requirements in support of labeling for effectiveness (e.g., new indications, populations, dosing information) or for meeting post-approval study requirements.”  The notice makes clear that this is an optional pathway for sponsors submitting RWE proposals; established procedures will continue to be available for non-participants.

Applicants accepted into the program will have the opportunity to meet with Agency staff prior to protocol development or study initiation to discuss the use of RWE in development.  Such sponsors will be granted up to four meetings to “discuss approaches for generating RWE that can meet regulatory requirements.”

The Federal Register notice also announced a new website for the program with additional details.  The website describes three eligibility criteria:

• The sponsor has an IND or pre-IND number for the medical product;
• The proposed RWE is intended to meet regulatory requirements in support of labeling for effectiveness or to meet post-approval study requirements; and
• The sponsor and FDA reach agreement on the study design information to be publicly disclosed.

FDA will select submissions meeting these criteria “based on their potential regarding fit-for-use data, adequate study design, and appropriate regulatory conduct.”  Other considerations include “promoting diversity of data sources, study designs, analytical methodologies, and regulatory indications, as well as to diversity of diseases.”

However, as an important goal of the program is “[t]o promote awareness of characteristics of RWE that can support regulatory decisions,” sponsors should be aware that “study designs discussed through the program may be presented by FDA in a public forum.”  An agreement between FDA and the sponsor on the information FDA may disclose publicly is a prerequisite to participation in the program.  However, certain specifics are excluded from disclosure, including the sponsor’s name, product name/molecular structure, a complete description of study eligibility criteria, and patient-level data.

There will be two submission deadlines per year on March 31 and September 30, through March 31, 2027.  The website describes the required content and format of the initial request for a meeting under the Advancing RWE Program.  The scope of the requested information is aligned with the goal of soliciting proposals before the sponsor makes final decisions on study design.  The request should also specify elements of the study design the sponsor considers non-disclosable along with a rationale for exclusion.  For follow-up meetings, the request should include any major changes, new information, or decisions made since the preceding meeting.

FDA will review all initial meeting requests received in the preceding 6-month cycle following each submission deadline.  Based on the criteria above, FDA will accept one to two primary meeting requests and up to two alternates per submission cycle in FY 2023-2024, and one to four primary meeting requests and up to four alternates per submission cycle in FY 2025-2027.  Sponsors who submit requests will be notified of the determination approximately 45 days after the submission deadline.  For each meeting request granted, FDA will conduct an initial meeting, and, as mentioned above, up to three follow-up meetings, as requested.

The initial meeting is intended to be held 30 days following FDA’s notification of acceptance (and 75 days following the preceding submission deadline) and follow-up meetings 45 days following requests.  After each meeting, a meeting summary will be sent to the requester within 30 days.

The website notes that any public presentations based on study designs developed through the program will “focus on those elements relevant to the understanding of the RWE and its potential use,” but may be presented prior to approval or completion of the post-marketing study.  “When feasible,” FDA intends to notify a sponsor in advance of such disclosure.

If you have purchased anything in recent months or kept up with economic reports, you are familiar with the unwelcome observation: “Prices have gone up!” That could not be more true than in the area of medical device user fees.

Medical Device User Fees

After the Congressional passage of Medical Device User Fee Amendments of 2022 (MDUFA V), which was signed into law by President Biden, FDA posted medical device user fees for Fiscal Year 2023 (i.e., October 1, 2022 through September 30, 2023). See here for the medical device user fees for FY2023. We produced a table below using the medical device user fee information for FY2022 and for FY2023 to show year over year changes.

As you can see, the percent changes for medical device user fees from FY2022 to FY2023 ranged from 18% to a whopping 56%!

The eye-catching 56% increase for a 510(k) submission could be burdensome to many device manufacturers given that the 510(k) premarket notification is the most frequently used regulatory pathway for medical devices.  In terms of the percent change, the increase in medical device user fees from FY2022 to FY2023 is much higher than the increases in previous years (7% increase from FY2020 to FY2021; 3% increase from FY2021 to FY2022; these percentages were across the board and did not vary according to submission type). The same is true when the range of the percent change in the medical device user fees from FY2022 to FY2023 is compared to other FDA programs (e.g., prescription drug user fees, generic drug user fees, and biosimilar user fees).

Suggestion for Industry

Given the substantial increase in the medical device user fees for FY2023 and the likelihood of further increases in FY 2024 − FY 2026, device manufacturers should take advantage of reduced fees if they qualify as a small business. In our next blog post, we will provide practical guidance on applying as such through FDA’s Small Business Determination Program.

If, as Albert Einstein supposedly quipped, a cluttered desk is the sign of a cluttered mind, what then does a cluttered medicine cabinet signify?  More than a mere sign, a cluttered medicine cabinet can be hazardous if it contains unneeded and expired prescription medication susceptible to theft, misuse and abuse.  If you need more motivation to clean out your cluttered medicine cabinet, the Drug Enforcement Administration (“DEA”) and its law enforcement partners are hosting thousands of local drop-off locations nationwide for proper disposal of unneeded medication on Saturday, October 29, 2022, from 10 am to 2 pm local time.

DEA hosts National Prescription Drug Take Back Days each spring and autumn.  DEA’s Take Back Day in April collected more than 720,000 pounds of unneeded medication at 5,144 collection sites and has collected nearly 16 million pounds of medication since 2010.  More information about DEA’s National Prescription Drug Take Back Day, including disposal locations, can be found here.

DEA’s website also lists permanent, year-round disposal locations.  It may not be a bad idea to tidy up your desk as well.

Last week, our blog post advised planning a transition strategy in advance of the news of the termination of the Covid-19 public health emergency. On October 17, 2022, FDA published the list of CDRH proposed guidances for FY 2023 (see here). Amongst CDRH’s highest prioritized device guidance documents are final versions of the transition plans for medical devices that fall within enforcement policies or that were issued emergency use authorizations (EUAs) during Covid-19 public health emergency (PHE). These are documents on the A-list, a list of prioritized documents that FDA intends to publish during FY2023. FDA published draft guidances for these topics in December 2021 (here and here). This prioritization suggests that the transition guidances will very likely be published this fiscal year. Some other final guidance documents on this A-list include 1) cybersecurity in medical devices: quality system considerations and content of premarket submissions and 2) breakthrough devices program (revised).

On the FDA’s B-list, a list of documents that FDA intends to publish as resources permit during FY2023, are final guidance on peroxide-based contact lens care products and draft guidances on 1) chemical analysis for biocompatibility assessment of medical devices and 2) marketing submission recommendations for a change control plan for artificial intelligence/machine learning (AI/ML)-enabled device software functions. This AI/ML guidance is much needed, particularly as the use of AI/ML in medical devices continues to expand (see FDA’s recent list of AI/ML-enabled devices published earlier this month, here).

Also part of FDA’s FY2023 guidance document plan is a retrospective review of guidance documents issued in 1993, 2003, and 2013. The 1993 guidance documents largely pertain to 510(k) submissions for various device types (e.g., electronic thermometers, single lumen needles, piston syringes). FDA’s retrospective review of the 2003 guidance documents will include user labeling for devices that contain natural rubber and premarket approval application modular review. The 2013 guidance documents include, but are not limited to, in vitro diagnostic and clinical trial considerations.

CDRH is open to feedback on the relative priority of those documents identified on the A-list and B-list. They are also open to information to include in these guidance documents. If you would like to provide suggestions in the transition plan for Covid-19 related products or any other guidance documents, comments may be submitted to www.regulations.gov by December 26, 2022.

As we emphasized in our previous blog post, the termination of COVID-19 PHE could complicate the business plan for some medical product companies. If you are currently marketing your products via EUA or COVID‑related enforcement discretion, we suggest you start to develop a transition strategy to be able to continue to market such products after the EUA termination date. If you are currently considering drafting an EUA application for your product, remember that the time you could enjoy the EUA authorization may not last long. Such companies should at least consider a “hybrid” approach to bring the products to the market via an EUA for the time being, but at the same time, prepare for a traditional regulatory submission (e.g., 510(k) premarket notification, de novo request, or PMA).

Hyman, Phelps & McNamara, P.C. (HP&M) is pleased to announce that James E. Valentine will become the firm’s newest Director beginning on January 1, 2023.  James’s practice focuses on regulatory considerations for developing new drug and biologic products and FDA regulatory requirements for approval/licensure.  James has been involved with the approval of many new molecular entities, often for serious and rare diseases, several which utilized the accelerated approval pathway (see examples discussed here and here).  A unique aspect of his practice has been to ensure that patient stakeholders have a voice in drug development and approval decision-making, having helped to organize nearly 75% of the over 65 externally-led Patient-Focused Drug Development meetings held since the initiation of the program in 2015.  James’s work to advocate for the needs of rare disease patients was recognized by Global Genes, when in 2019 the organization named him a RARE Champion of Hope.

“James’s commitment to tackling the most challenging drug development scenarios, bringing a depth of technical expertise and a breadth of experiences that stem from nearly weekly meetings with FDA, offer our clients paths forward to develop important new drugs that may help to relieve the suffering of our brothers and sisters living with a wide range of devastating conditions,” said Frank Sasinowski, HP&M Director. “He brings compassion and hope to those very patients and their caregivers, ensuring they have a seat at the table with FDA officials and industry executives, a model of drug development that James has helped to pioneer.”

James joined the firm from the FDA, where he facilitated patient input into regulatory decision-making and, among other things, helped develop and launch the Patient-Focused Drug Development program.

His full bio can be found here.

“We still have a problem with COVID. We’re still doing a lot of work on it. But the pandemic is over. If you notice, no one is wearing masks. Everybody seems to be in pretty good shape. And so I think it’s changing.”

President Biden made this comment in a “60 Minutes” interview on September 18, 2022.  The President’s comments caused us, who work in the medical product industry, to wonder how the federal government officially declares an end to the Covid-19 public health emergency.

Before we talk about the future, let’s briefly review the history.  It was January 31, 2020 when the Secretary of the Department of Health and Human Services (HHS) first declared the 2019 Novel Coronavirus (2019-nCoV) outbreak a public health emergency (PHE), pursuant to Section 319 of the Public Health Service Act (see here).  Two separate emergency declarations were then made—one pursuant to section 564 of the Federal Food, Drug, and Cosmetic (FD&C) Act by the Secretary of HHS on February 4, 2020 (see here), and the other under the Public Readiness and Emergency Preparedness (PREP) Act by the Secretary of HHS on March 17, 2020 (see here). Shortly thereafter, then-President Trump made a national emergency declaration on March 18, 2020, pursuant to Section 201 of the National Emergencies Act (see here).  If you haven’t checked out the CDC Museum COVID-19 Timeline, please check it out here.

Among these many declarations, which declaration is pertinent to FDA’s issuance of an emergency use authorization (EUA)?  It is the one that is issued pursuant to section 564 of the FD&C Act.  In other words, even if the Secretary of HHS declares that the public health emergency is over, under section 319 of the Public Health Service Act, an EUA that was granted under section 564 of the FD&C Act will continue to remain in effect.

Under section 564(b) of the FD&C Act, the Secretary of HHS must publish advanced notice in the Federal Register that an EUA declaration will be terminated.  For medical devices, FDA noted in the 2021 December draft guidance (see here) that it will provide 180 days advanced notice before terminating the EUA declaration.  Once the Secretary terminates an EUA declaration, then any EUAs issued based on that declaration will no longer be in effect. (The exception being instances where under section 564(f)(2), an unapproved product continues to be effective to provide for continued use with respect to a patient to whom it was administered while the declaration remains effective, to the extent found necessary by such patient’s attending physician.)

This advanced notice allows for an effective transition period.  For unapproved products with EUAs, the transition period allows time for proper product disposition.  For unapproved uses of approved products, the transition period allows time for companies to update labeling or other associated materials. The December 2021 draft guidance document sets forth a pathway for unapproved medical devices to obtain permanent marketing authorization.  We previously blogged on this guidance document here.

“The advance notice of termination of each EUA declaration pertaining to devices will be published in the Federal Register 180 days before the day on which the EUA declaration is terminated.”

FDA provides FAQs about what happens to EUAs when a public health emergency ends (see here).  We all look forward to the end of the COVID-19 pandemic.  But if you are a medical product manufacturer, the news of the termination of COVID-19 PHE could complicate your business plan.  Therefore, plan your transition strategy in advance and be on the lookout for the 180-day advance notice!

While COVID-19 and monkeypox may be the public health emergencies garnering much of our current attention, we have been in the midst of another declared public health emergency for nearly 5 years: the opioid crisis.  FDA recently issued a Guidance (Exemption and Exclusion From Certain Requirements of the Drug Supply Chain Security Act for the Distribution of FDA-Approved Naloxone Products During the Opioid Public Health Emergency) that is narrowly tailored, but it is intended to increase access to naloxone—a prescription drug critical in the rapid treatment of opioid overdoses—by harm reduction programs that often serve the most at-risk populations.  In light of the urgent public health need to facilitate and expedite access to naloxone, FDA is implementing this Guidance immediately without prior public comment.

As background, naloxone hydrochloride (“naloxone”) is an opioid antagonist indicated for the emergency treatment of known or suspected opioid overdoses and is available in three FDA-approved forms (injectable, auto-injector, and nasal spray).  Naloxone is a prescription drug, but unlike some other prescription drugs used in the treatment of opioid addiction such as buprenorphine, it is not a controlled substance.  Most states have some form of naloxone standing order that allows a healthcare provider to write a prescription that covers a large group of people rather than just an individual patient.  For example, the Maryland standing order allows all Maryland licensed pharmacists to dispense naloxone, including any necessary sup​​plies for administration (e.g., syringes), to any individual without a patient-specific prescription.

Despite the state standing orders, “harm reduction programs” that provide products and services to individuals at risk of experiencing an opioid overdose or those who might respond to an overdose, still face logistical difficulties in acquiring naloxone, as was the subject of a March 2022 workshop on Naloxone Access hosted by the Reagan-Udall Foundation for the FDA.  Because naloxone is a prescription drug, its distribution is subject to the requirements of the Drug Supply Chain Security Act (DSCSA).  One of the DSCSA requirements is that the trading partners of a manufacturer, wholesale distributor, repackager, or dispenser must be “authorized,” which generally requires they hold a valid FDA registration or applicable state license.  Harm reduction programs typically aren’t medical clinics or pharmacies and would not hold any state licenses that would allow them to purchase prescription drugs; although, at least one state (Rhode Island) has created a licensure category for harm reduction centers.   As described by Dr. Nabarun Dasgupta in the Naloxone Access workshop, wholesale distributors often treat harm reduction programs like pharmacies because naloxone is a prescription drug.  Because many harm reduction programs don’t have a pharmacy or medical license, wholesale distributors may determine that they are ineligible to purchase prescription drugs.

By statute, certain activities are automatically excluded from particular DSCSA requirements upon the declaration of a public health emergency under section 319 of the PHS Act.  Specifically, the distribution of a product for emergency medical reasons (including a public health emergency declaration), is exempted from the definition of a “transaction” and excluded from the definition of “wholesale distribution” under the DSCSA.  The purpose of the recent Guidance is to clarify FDA’s interpretation that the exemption and exclusion apply to the distribution of FDA-approved naloxone products to harm reduction programs and to harm reduction suppliers.  The Guidance is intentionally narrow and only remains in effect for the duration of the declared public health emergency which currently must be renewed by the HHS Secretary every 90 days.

During the declared opioid public health emergency, trading partners engaged in the distribution of FDA-approved naloxone products to harm reduction programs and harm reduction suppliers, and the harm reduction programs and harm reduction suppliers obtaining naloxone through such distribution, are not required to comply with the DSCSA product tracing and product identification requirements that are triggered by a “transaction.”  Additionally, FDA does not intend to take enforcement action against trading partners for the distribution of naloxone to harm reduction suppliers and harm reduction programs that are not “authorized trading partners.”

While it is clear that FDA intends to provide clarity and increase access to naloxone for harm reduction programs in particular, we see two potential impediments that can hopefully be easily resolved:

1. Wholesale distributors that sell naloxone to harm reduction programs—particularly the individuals responsible for onboarding new customers—need to be aware of the DSCSA exemption and exclusion provided by the Guidance or else the administrative roadblocks described by Dr. Dasgupta will persist.
2. It may not be clear to supply chain stakeholders which entities may be considered “harm reduction programs” for the purposes of this Guidance. While certain states do define “harm reduction programs” (e.g., West Virginia), there is no such definition in FDA regulations or in the DSCSA.  When ordering from a new supplier, harm reduction programs should be prepared to provide an explanation of how then intend to dispense or otherwise use the products.

We note that the clearest (but certainly not fastest) way to reduce barriers to naloxone access for harm reduction programs and other stakeholders is for naloxone to be available as an OTC drug, which remains an ongoing effort and is well beyond the scope of the particular Guidance.  If naloxone were available for OTC use, the patchwork of state standing orders would no longer be necessary and the transactions would not be within the scope of the DSCSA, which only applies to the distribution of prescription drug products.

As we begin the final quarter of 2022 and the leaves here on the east coast begin to turn and fall, it seems the clock may be running out on FDA and the Center for Drug Evaluation and Research (CDER) to meet its goal of publishing a draft guidance on confirmatory evidence this year.  For the past two years, CDER’s Guidance Agenda has included a spot for this eagerly anticipated guidance, tentatively titled ‘Meeting the Substantial Evidence Standard Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence’.  To be fair, the annual guidance agenda consistently presents a lengthy and somewhat aspirational to do list, and it is not surprising when one slips through the cracks.  However, we wonder whether recent and ongoing approval decisions are shaping FDA’s thinking, possibly pushing back issuance of a draft.

The two previous FDA guidance documents on meeting the patient benefit part of the statutory standard for drug approval – substantial evidence of effectiveness – were released in May 1998 (Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, available here) and December 2019 (Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products, available here), just over two decades apart!  Additional guidance on confirmatory evidence is sorely needed as the December 2019 draft guidance spends just two of its 18 pages telling us what FDA thinks of such a key piece of statutory language.  Moreover, the draft guidance is the first time FDA tried to explicitly describe its position on such a key phrase (“confirmatory evidence”) that was made a part of the plain language of the statutory standard for drug approval in 1997, a 22-year interval of near public silence.

Even in the absence of a guidance document dedicated to explaining FDA’s views on interpreting the statutory construct of “confirmatory evidence,” a number of drug approvals over the past few years give us a great deal of insight into FDA’s current thinking and how FDA is applying this standard.  These illuminating drug approvals include FDA’s September 29th approval of Amylyx Pharmaceutical’s therapy for amyotrophic lateral sclerosis (ALS), Relyvrio (see additional recent coverage from HPM’s FDA Law Blog, here, and the Pink Sheet, here).  While Relyvrio’s approval is just the most recent and perhaps high-profile application of this single study approval standard, we think confirmatory evidence is having a moment all its own through such FDA actions.

We use the term “confirmatory evidence” as short-hand for one of the two ways explicitly defined in the Federal Food Drug & Cosmetic Act (“FD&C Act”) for demonstrating substantial evidence of effectiveness.  Since 1962, the Act has given FDA authority to reject a drug application that fails to provide substantial evidence of effectiveness.  The Act defines substantial evidence as that consisting of “adequate and well-controlled [clinical] investigations” upon which qualified scientific experts could conclude that a drug will have its purported effect.  In 1997, the Food and Drug Administration Modernization Act (“FDAMA”) amended the definition to make clear that substantial evidence could alternatively be demonstrated by “one adequate and well-controlled clinical investigation plus confirmatory evidence” (emphasis added).  However, the Act does not define what may constitute such confirmatory evidence other than to say FDA’s interpretation is to be “based on relevant science.”

In the December 2019 draft guidance, FDA describes the rationale behind confirmatory evidence by drawing an analogy to its interpretation of the original 1962 evidentiary bar.  In prevalent conditions, FDA nearly universally requires that substantial evidence be demonstrated via two adequate and well-controlled clinical investigations, for example, two Phase 2 or 3 trials (as long as they have the characteristics delineated at 21 CFR § 314.126).  Some may confuse this requirement for two studies as a need for replication.  Those who do should be forgiven as we often think of replication as the appropriate means to demonstrate that the results of a scientific study are not due to chance.  But replication implies identical repetition of the first study and thus may be prone to any flaws inherent to the first study.  More importantly, replication is but one means to substantiate the results of a clinical investigation or scientific study.

Conducting a second investigation that tests the same fundamental principles (e.g., that drug A can treat disease X) but with some variation in its design (e.g., different endpoints, populations, or durations) may provide more compelling substantiation that a drug has the effect it purports to have.  Showing that the drug has consistent effects across two slightly different patient populations with the same disease reinforces the evidence that the drug has a beneficial effect.  However, both the FD&C Act and FDA acknowledge that running two adequate and well-controlled investigations may not be necessary to provide assurance that the drug will have the effect it is purported to have.  Rather, confirmatory evidence can be a means to substantiate the effects observed in a single pivotal trial.

Even so, FDA does not make the decision to rely upon a single adequate and well-controlled trial plus confirmatory evidence lightly.  Several factors may influence FDA’s determination, such as the persuasiveness of the single trial, the robustness of the confirmatory evidence, and the public health need due to the seriousness of the disease, an unmet medical need, or a combination of both, and the feasibility of enrolling two clinical trials.  The infeasibility of a second clinical trial more commonly manifests in orphan conditions because they offer limited pools for recruiting patients.  Therefore, we have more commonly encountered use of the confirmatory evidence pathway in rare disease drug approvals.  However, this statutory standard is not restricted to use in rare disease settings.  The confirmatory evidence standard is applicable in any condition, especially in those where the clinical context warrants expedited development as a result of having a serious or life-threatening unmet medical need.

Notably, the single study approval pathway using the “confirmatory evidence” standard is just one approach that allows FDA to use its expert judgment to determine that an application meets the substantial evidence of effectiveness standard.  FDA’s Subpart E regulations and the December 2019 draft guidance also provide for broader application of scientific judgement in review of new drugs, mainly through the acceptance of greater uncertainty based on what can constitute an adequate and well-controlled trial (e.g., a study designed to be externally-controlled).  Such expert judgment should be considered on top of use of the “confirmatory evidence” standard in rare, serious diseases with an unmet medical need.

All of this brings us back to where we started – FDA’s interpretation of “confirmatory evidence.”  In the December 2019 draft guidance, FDA provides four examples of what may constitute such evidence – (1) supportive evidence from existing adequate and well-controlled clinical investigation(s) in a closely related approved indication, (2) evidence from data that provide strong mechanistic support, (3) compelling results from the single adequate and well-controlled clinical investigation supported by additional data from the natural history of the disease, and (4) support from scientific knowledge about the effectiveness of other drugs in the same pharmacological class.  While the guidance clearly describes these as just four illustrations of confirmatory evidence, it has been our experience that individual review divisions within FDA have not always shared this view.  We have at times encountered not only a reluctance to apply the “confirmatory evidence” standard but even experienced refusal to recognize other sources of evidence not explicitly mentioned in the guidance (but equally capable of substantiating a single pivotal trial’s results).

Despite these experiences, we have been involved with several “confirmatory evidence” approvals, especially for rare serious conditions, in the past few years that suggest that the FDA may be taking confirmatory evidence more seriously.  Many of these approvals have been variations of the guidance’s mechanistic confirmatory evidence example.  These examples have often taken a similar form whereby the positive findings on a clinical endpoint in the single adequate and well-controlled trial are supported by an effect on a biomarker, another pharmacodynamic endpoint, or even a drug mechanism of action that fits squarely within the disease’s pathogenic pathway(s).  In these examples, we have seen everything from data from the same clinical trial to data collected during in vitro and in vivo experiments cited as confirmatory evidence.  These variations on the mechanistic confirmatory evidence example provide some indication that the December 2019 draft guidance’s language is intended to illustrate just a portion of what may be possible sources of confirmatory evidence rather than provide a rigid framework to be followed.

In other precedents, we have seen FDA cite to consistent clinical findings in earlier phase (i.e., phase 1 and 2) studies, randomized trials of higher or lower doses of the same drug, and data from the open-label cross-over portion of a single pivotal trial.  Notably, none of these latter examples are mentioned in the December 2019 draft guidance.  Further, FDA notes in that draft guidance that the strength of evidence from the clinical trial and the robustness of the confirmatory evidence are two additional factors to consider when deciding whether a single adequate and well-controlled trial plus confirmatory evidence demonstrates substantial evidence of effectiveness.

All of this is why we find FDA’s application of the “confirmatory evidence” standard in the case of Relyvrio so interesting.  In this example, FDA explained that Relyvrio’s primary finding, a slowing of disease progression as measured by the ALSFRS-R clinical rating scale, was supported by long-term survival benefit observed in the open-label extension and by vital status census of all those originally randomized in the clinical trial.  Here, FDA cited to survival data from the same clinical trial population as confirmatory evidence.  The FDA noted that the ALS functional rating scale and survival were distinct aspects of the disease.  In other words, these two types of data represented phenomena that were sufficiently distinct that a survival effect could substantiate, or confirm, a functional one.

Relyvrio may be just the latest and perhaps most high-profile confirmatory evidence approval precedent to date, but it reinforces the interpretation that FDA’s discussion of confirmatory evidence in the December 2019 draft guidance was meant to illustrate what is possible and was not intended to set rigid bounds or limitations on the nature or scope of types of confirmatory evidence.  We would be remiss not to mention that our extensive analyses of FDA’s rare disease approvals lead us to believe that a substantial number of FDA’s orphan drug approvals have been based on this “confirmatory evidence” standard since its enactment in 1997 even when FDA has not explicitly cited to this part of the law.

However, we also see Relyvrio and other confirmatory evidence approvals as indicia of FDA’s emerging, explicit interest in this 25-year old portion of the FD&C Act.  Even in the absence of a stand-alone guidance, we sense that confirmatory evidence may be having a moment all its own.

On September 28, 2022, the FDA issued the long anticipated final Clinical Decision Support Software Guidance (CDS Guidance), which replaces the revised draft guidance document from 2019.  The CDS Guidance interprets the “medical software” carve-out of the 21st Century Cures Act (2016) as it pertains to Clinical Decision Support (CDS) software functions.  Specifically, the guidance interprets the Cures Act’s four criteria for exclusion of CDS software functions from FDA’s medical device jurisdiction (so-called “Non-Device CDS”).  You can find our preliminary blog post on the release of this guidance here, and our blog posts on the draft CDS guidances here and here.

The final CDS Guidance represents a marked change in approach from prior drafts and foreseeably will result in the regulation of many types of CDS that were previously considered to be Non-Device CDS or low-risk Device CDS under enforcement discretion.  The final guidance therefore may have significant implications for a wide range of stakeholders, including not only software developers but also health care providers, hospitals, patients and payors.

Interpretation of Statutory Criteria Under the Final Guidance

The CDS Guidance interprets the Cures Act’s definition of “medical software” that is excluded from the statutory “device” definition, as it relates to CDS software.  As a refresher, the Cures Act established the following four criteria for Non-Device CDS software:

• Criterion 1: Non-Device CDS software functions do not acquire, process, or analyze medical images, signals from an in vitro diagnostic (IVD) device, or patterns or signals from a signal acquisition system.
• Criterion 2: Non-Device CDS software functions display, analyze or print medical information about a patient or other medical information.
• Criterion 3: Non-Device CDS software functions are intended for the purpose of supporting or providing recommendations about a patient’s care to a health care professional (HCP) user.
• Criterion 4: Non-Device CDS software functions provide sufficient information about the basis for the recommendations to the HCP user, so that the HCP user does not rely primarily on any of the recommendations to make a clinical decision about an individual patient.

Criterion 1: The first criterion describes the type of data inputs that are not permissible for Non-Device CDS (inputs that would render CDS software ineligible for the statutory medical software exclusion).  While the final guidance includes the same definition of “signal” as that used in the draft guidance—i.e., signals that typically require the use of either an IVD or a signal acquisition system—it revises the definition for “medical image” and provides a definition for “pattern” for the first time.  As newly defined, the terms “medical image” and “pattern” would appear to narrow the scope of Non-Device CDS.

“Medical image” is defined as including “those images generated by the use of medical imaging systems to view any parts of the body or images acquired for a medical purpose,” even if the images were not “originally acquired for a medical purpose but are being processed or analyzed for a medical purpose.” FDA interprets the term “pattern” to mean “multiple, sequential, or repeated measurements of a signal or from a signal acquisition system.”  As these definitions were not proposed in the draft guidance, stakeholders have not previously had an opportunity to weigh in on the impact of these changes.  Furthermore, the examples of software functions that fail Criterion 1 that are included in the final guidance do little to illustrate the application of these new definitions in practice, as the examples are limited to software products that have been regulated as medical devices for years.

Criterion 2: The second criterion describes the type of data inputs that are permissible for use in Non-Device CDS.  Here again, FDA’s novel interpretation of statutory terms effectively narrows the scope of information that a software product can display, analyze, or print and still be considered Non-Device CDS.  FDA gives no rationale for interpreting the apparently broad statutory term “medical information” in such a restrictive manner.

Medical information about a patient

The 2019 draft guidance interpreted “medical information about a patient” to mean the “kind of information used by the intended user to make decisions.”  In contrast, the final guidance interprets this phrase to mean the “type of information that normally is, and generally can be, communicated between HCPs in a clinical conversation or between HCPs and the patient in the context of a clinical decision, meaning that the relevance of the information to the clinical decision being made is well understood and accepted.”

The CDS Guidance lists four general types of medical information that would meet the definition of “medical information about a patient”—a radiology study report, an ECG report, a blood pressure result, and a lab test result—but these examples shed little insight on how to apply the interpretation in practice.  Furthermore, the subjective terminology in the revised definition gives rise to many questions, including what other types of information “normally” are or “generally can be” exchanged during a clinical conversation, who can determine that the relevance of the information is “well understood and accepted,” and what kind of objective documentation a software developer must collect to document that software inputs meet these conditions.

The CDS Guidance also adds a novel limitation to patient-specific medical information that may be used under Criterion 2, stating that the information must be a “single discrete test or measurement result.”  In contrast, a “continuous sampling” of the same information would constitute a “pattern” or “signal” and therefore fail Criterion 1. The guidance provides no rationale for hinging the device status of CDS software on the frequency with which medical information is collected.  Certainly we would expect clinical communications, as well as HCP-patient communications, to include discussions of test results over time as these would seem highly relevant to clinical decision making.

Other medical information

FDA interprets “other medical information” to include items such as “peer-reviewed clinical studies, clinical practice guidelines, and information that is similarly independently verified and validated as accurate, reliable, not omitting material information, and supported by evidence.”  Consistent with the 2019 draft guidance, the final guidance also includes textbooks, approved drug or medical device labeling, and government agency recommendations as other permissible types of medical information.  The final guidance does not provide further insight as to what other types of information would be considered “similar” in their level of independent verification and validation, but could be read to exclude any reports, such as sponsor white papers, that have not undergone third-party peer review.

Criterion 3: The third criterion defines the scope of permissible intended uses for Non-Device CDS; namely, to support or provide recommendations about a patient’s care to the HCP.  FDA’s 2019 draft guidance explicitly tied its interpretation of Criterion 3 to the International Medical Device Regulators Forum (IMDRF) risk-based categorization scheme, such that Non-Device CDS could only “inform” but not “drive” clinical management.  While the final guidance continues to borrow some IMDRF concepts, it no longer limits Non-Device CDS to software that informs clinical management (per the IMDRF guidelines).  Instead, the final guidance states that, to satisfy Criterion 3, Non-Device CDS must satisfy the following four conditions:

1. Provide condition-, disease-, and/or patient-specific information and options to an HCP to enhance, inform, and/or influence a health care decision;
2. Not provide a specific preventive, diagnostic, or treatment output or directive;
3. Not be intended to support time-critical decision-making; and
4. Not be intended to replace or direct the HCP’s judgment.

FDA justifies these new conditions as intended to prevent clinical errors caused by “automation bias,” i.e., the human propensity to over-rely on a suggestion from an automated system.  The final guidance raises the concern that software that provides single, specific outputs or that is intended to support time-critical decisions will tend to replace or direct HCP judgment even if the software is not explicitly intended to do so.  Thus, to meet Criterion 3 software functions must be designed to prevent automation bias by providing lists of options or follow up for the HCP to consider, and must not be intended to support time-critical decision making.

While the four new conditions on their face would appear to provide more flexibility than the 2019 draft guidance’s binary “inform vs. drive” standard, as interpreted by FDA these conditions appear to limit the scope of Non-Device CDS functions to an even greater extent, as the examples below illustrate.

Risk Scores Off the Table

The final guidance takes the position that software that informs an HCP that a patient “may exhibit signs” of a disease or condition, or that identifies a “risk probability or risk score” for a specific disease or condition, necessarily provides a “specific preventive, diagnostic or treatment output” and therefore is inconsistent with condition 2 and categorically excluded under Criterion 3.  This interpretation of Criterion 3 does not clearly align with the statutory language and could cause more software to be regulated as a device than Congress intended in the Cures Act.  Software providing a risk score for a specific disease could, plausibly, be intended to “support or provide recommendations” to HCPs and it therefore seems a stretch for the agency to categorically determine that such software, just because its output includes a risk probability or risk score, could never meet Criterion 3.  FDA’s novel reading of Criterion 3 may dramatically affect the regulatory status of CDS software that includes risk probabilities or risk scores as outputs.

Criterion 4: The fourth criterion seeks to ensure that Non-Device CDS does not supplant an HCP’s independent clinical judgment.  The statute achieves this through disclosure of information by the software manufacturer about the “basis for” the recommendations made by the software.  The final guidance focuses on labeling as a means to effectuate Criterion 4.  To that end, FDA recommends that:

• software output explains how the logic was applied to the patient and identify other variables to consider when interpreting the recommendation; and that
• software or labeling
  • include the intended use, user, and intended patient population,
  • a summary of the algorithm’s logic or methods (e.g., AI/ML techniques), a description of the datasets used, and clinical studies conducted to validate the algorithm/recommendations, and
  • identification of required inputs, how the inputs are obtained and quality of inputs.

The final guidance stresses the importance of ensuring that an HCP can understand the “strength/limitations of the CDS software recommendations.”

A focus on information disclosure through labeling is generally consistent with the 2019 draft guidance and appears, at least on paper, a reasonable approach to interpreting Criterion 4.  Software developers will need to carefully review their current software and labeling to ensure they provide adequate and understandable information concerning the intended use, inputs, algorithms, datasets and validation.

In addition to labeling, the final guidance adds that software developers “may need to perform usability testing to evaluate if their implementation meets Criterion 4.”  Although not phrased as a requirement for demonstrating compliance with Criterion 4, it is possible that FDA in practice may expect software developers to perform usability studies to demonstrate HCP comprehension, which would add new burdens not clearly supported by the statute.

The Demise of Enforcement Discretion

The final guidance notably eliminates the category of low risk “Device CDS” subject to enforcement discretion that had been included in draft guidance.  Under the draft guidance documents, FDA had provided numerous examples of HCP- and patient-directed CDS software that the agency did not intend to regulate as matter of policy.  The final guidance instead suggests that the regulatory status of such software should be evaluated under FDA’s Policy for Device Software Functions and Mobile Medical Applications and Software as a Medical Device (SaMD): Clinical Evaluation; Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices—revised versions of which were released concurrently with the CDS Guidance—as well as under the 2019 General Wellness: Policy for Low Risk Devices.

Takeaways for Stakeholders:

Overall, this long-anticipated CDS Guidance includes a number of dramatic changes from past iterations, many of which would appear to limit the statutory exclusions for CDS software provided under the Cures Act.  The final guidance foreseeably will lead to more CDS software needing to comply with FDA medical device requirements, including in some cases the requirement for premarket authorization, i.e., 510(k) clearance, de novo classification, or Premarket Approval.  Developers and users of CDS software currently in distribution should carefully evaluate the effect of this guidance on their continued distribution and use of such software, respectively, as well as the impact on regulatory strategy for and timeline for availability of software currently in development.  We expect this guidance will generate concerns not only from software developers but also from HCPs, health care institutions, payors, and patients.  Stakeholders with such concerns may consider expressing them through the submission of public comments to the guidance document’s docket at regulations.gov, filing of Citizen Petitions, or legislative engagement.

On October 6, President Joe Biden issued a brief but sweeping three-step statement towards reforming Federal marijuana law.  The president’s first step was a pardon of all prior federal offenses of simple marijuana possession and a direction to the Attorney General to develop an administrative process to issue certificates of pardon to eligible individuals.  Possession by an individual of a small amount of a drug for personal use without intent to distribute constitutes “simple possession.”  It is important to note that the president’s pardon is limited to simple possession and he made clear that “important limitations on [marijuana] trafficking, marketing and underage-sales should stay in place.”  The president’s pardon is estimated to affect over 6,500 persons with prior federal convictions and thousands of others convicted under District of Columbia law.

Because the vast majority of marijuana-related convictions are at the state level, President Biden’s second step encouraged governors to follow his lead and issue similar pardons.  The President cannot compel governors to act, but their issuing such pardons would be largely consistent with the wave of decriminalization and authorized use of marijuana that has occurred across the country in recent years.  As of earlier this year, 37 states and the District of Columbia have legalized marijuana for medical use and 19 states and the District of Columbia have legalized cannabis for adult recreational use.  Additionally, marijuana legalization measures are on the ballots for the upcoming midterm elections in Arkansas, Maryland, Missouri,  North Dakota, and South Dakota.  We also note there are states where marijuana remains the equivalent of a schedule I controlled substance.

Separate and apart from the loosening of marijuana restrictions by these states, marijuana remains a schedule I controlled substance under federal law.  In his third step, President Biden asked Secretary of Health and Human Services (“HHS”) Xavier Becerra and Attorney General Merrick Garland to “initiate the administrative process to review expeditiously how marijuana is scheduled under federal law.”  The Controlled Substance Act (“CSA”) authorizes the Attorney General to reschedule (or deschedule) substances of abuse after consideration of the drug’s potential for abuse and dependence as well as its acceptance for medical use for treatment in the United States.  Before the Attorney General and the Drug Enforcement Administration (“DEA”) can initiate proceedings to reschedule a substance, they must request a scientific and medical evaluation of the substance from HHS.  HHS has undertaken scientific and medical evaluations of marijuana in recent years.  In 2016, DEA denied two petitions — originally filed in 2011 and 2009— after HHS concluded that marijuana continued to meet schedule I criteria by having a high potential for abuse, no accepted medical use in the United States, and lacking an acceptable level of safety for use even under medical supervision.

The CSA requires DEA to seek an opinion from HHS and determine whether the “scheduling recommendation, scientific and medical evaluation, and ‘all other relevant data’ constitute substantial evidence that the drug should be rescheduled as proposed.”  HHS’ recommendations are binding on DEA as to scientific and medical matters.  This “eight factor analysis” requires consideration of:

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

Again, HHS concluded in 2016 upon considering the eight factors, that marijuana met the scheduling criteria for remaining in schedule I because marijuana does not have a currently accepted medical use in the United States.  While DEA also made specific findings relative to these factors, in effect, DEA’s hands were tied because without a finding from HHS that marijuana has an accepted medical use, DEA had to deny any petition to reschedule the drug.  In summary, the key to any future rescheduling of marijuana remains a finding, specifically by HHS, and supported by DEA, that marijuana does have an accepted medical use in the United States.

President Biden’s statement and requests are no doubt significant.  The federal pardon will have a near-term effect on the lives of those who have been charged and convicted with simple possession of marijuana.  However, only time will tell whether governors will follow President Biden’s lead and issue similar pardons for offenses under state law.  The rescheduling or descheduling of marijuana would be the most monumental and President Biden has clearly signaled his support of this goal.  This is not something we expect will occur quickly.

On September 29, 2022, FDA’s Center for Biologics Evaluation and Research (CBER) and the Office of Tissues and Advanced Therapies (OTAT) held a town hall to answer questions related to gene therapy chemistry, manufacturing, and controls.  Wilson Bryan opened this new forum for direct agency feedback by describing the transformation of OTAT into the Office of Therapeutic Products (OTP).  The restructuring of OTAT into a “super-office” will increase its review capabilities, and enhance expertise on new cell and gene therapies.

When on the bleeding edge of new product development, it can be hard to know ahead of time what the agency is looking for in terms of CMC information.  The standard practice is for FDA to engage with companies on an individual basis through formal meetings and deliver directed feedback to specific sponsor questions.  With the explosion of new gene therapy investigations in recent years, these meetings with industry have become a proverbial black-hole of OTP’s time, energy, and reviewer resources.  OTP has spent years communicating industry-wide problems on an individual basis.

The solution that OTP has reached is to address what are very likely to be common industry problems in a public setting. This move is likely to ease the pressure on their overburdened review staff by creating an organic reference Q&A for industry without having to create and iterate a new series of guidance documents.  Town Hall forums have been used to great success since the start of the pandemic in CDRH to accelerate the development of new IVD products.  Sponsors can interact with FDA in the town hall by submitting questions in advance or by asking a question live during the meeting.  It is important to keep in mind that this meeting is for general CMC feedback and sponsors are informed that “FDA is not able to comment on or answer questions regarding specific investigational products or drug applications during the town hall.”

The major theme underpinning their commentary for this first meeting was the need for cell and gene therapy product developers to think ahead to the long term and plan accordingly.  While the transcript of the town hall will be posted for a healthy dose of science-filled pleasure reading, we highlight a few key points that hopefully set the tone for what to expect from future meetings:

Comparability

OTP acknowledged the elephant in the room that their expectations for comparability assessment is a “hot topic”, and that to address this complex question, they are developing a specific guidance document (i.e., “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products”) that should be released “sometime in the near future.”  At this time, they recommend developers follow ICH Q5e when assessing comparability.  The Agency’s recommendation is that developers implement changes in product manufacturing as early as possible to reduce the risk in the development program.  Depending on the change (e.g., change from an adherent to a suspension cell product system), the Agency might expect both comparability assessments and developmental studies to support that the change does not adversely affect product quality.  The Agency emphasized that release testing alone is not sufficient to assess comparability and that additional characterization testing or in process testing be conducted based on risk assessment and developmental studies.  In some cases, the effect on the final drug product should also be assessed (e.g., vector manufacturing for a transgene vector).

Process Control and Potency

The Agency recommends determining the process requirements early in the development process because late changes in the development program will introduce uncertainty later that may result in a clinical hold.  Product developers should have a robust understanding of their process and process controls. In addition, they should know how to control for analytical method variability prior to starting the clinical trial.  The Agency recognized that sponsors may have difficulties establishing a single suitable test for products with complex mechanisms of action, which is why they recommend developers think about characterizing the product and potency assay development during pre-clinical development.  The Agency expects that the quantitative test to measure biological function of the product is expected prior to initiating clinical studies.  As the product advances in clinical development, expectations are that the potency test be refined to measure biological activity of the product.  If developers want to use a surrogate test(s) for function they must comply with product specific considerations, such as whether the test(s) is specific to the product, provides meaningful measure of activity, and contributes to the overall potency assessment.  The Agency considers early qualification of assays to characterize the product as critical to the success of the program.  The Agency stressed to “think in advance and work hard to getting the data you need to support whatever potency test you submit” as many comments in pre-INDs are regarding inadequate potency tests.

Release Criteria

To determine lot release criteria and to ensure product consistency and quality, OTP recommended that gene therapy product developers use multiple lots during the clinical study, even if one lot is enough to treat everyone in the pivotal study.  Use of multiple lots will help developers set commercial specifications and understand the variability in the product and how it affects the clinical trial results.  One way to facilitate this strategy would be to conduct PPQ runs and use those few runs during the pivotal study.  OTP recognized that this strategy may not be possible for all products (e.g., rare diseases) and recommended developers either leverage data they have from similar products they’ve manufactured from pre-clinical lots, engineering lots, and small-scale development studies, or to design the manufacturing process to allow for more drug product to be used during the clinical study.  They recommended product developers to meet the OTP review team if there are still concerns that there will not be enough data to set the commercial lot release criteria.

We look forward to the next town hall and will be sitting in the virtual front-row.