On Friday, November 4, CMS finalized a rule to implement mandatory rebates (called “refunds”) for discarded amounts of separately paid Medicare Part B single-source drugs packaged in single-dose or single-use containers.  For a summary of the rule, we refer readers to our July 2022 post on the proposed rule (click here), since he substance of the final rule has not changed from the proposal.  The only differences relate to timing.  Refunds will still be owed for quarters beginning with 1Q 2023, and CMS will still send annual reports to manufacturers containing the number of discarded units and the refunds owed for four quarters.  However, whereas the proposed rule provided that CMS would send the first annual report by October 1, 2023 and manufacturers would have to pay undisputed refunds by December 31, 2023, CMS has now decided to postpone establishing a timeline for the reports and payment.  The preamble explains that CMS wants to coordinate the collection of these refunds with the collection of Part B and D inflation rebates imposed under the Inflation Reduction Act (see our summary of those requirements here).  CMS will address the timing of reports and payment deadlines in a future rulemaking.  A preliminary report on discarded amounts during the first two quarters of 2023 will be issued by December 31, 2023, but the report will not be final and will not require payment of refunds.

Other clarifications in the preamble include the following:

• Part B refunds on discarded amounts will be excluded from average sales price (ASP) and Medicaid rebate average manufacturer price (AMP) and best price because CMS deems them to be refunds for “otherwise unsaleable return goods,” which are excluded from those prices.
• The requirement to use a JZ modifier where there were no discarded amounts has been delayed for six months until July 1, 2023. The requirement to use a JW modifier for discarded amounts beginning on January 1, 2023 remains in place.
• CMS clarifies that units of drugs packaged under the end-stage renal disease (ESRD) prospective payment system, like other packaged drugs, are not subject to the discarded drug refund.

The refunds for discarded drugs seem a relatively benign and narrowly focused government discount in comparison to the Part B and D inflation rebates and negotiated prices imposed under the Inflation Reduction Act.  CMS notes that Medicare Part B spending on discarded drugs is weighted heavily toward a small number of drugs.  However, even assuming CMS is correct, manufacturers of drugs in single-use containers will still be faced with decisions about whether to spend resources introducing smaller container sizes, or risk ongoing liability for discarded drug refunds.

We previously blogged about Pfizer’s copay assistance lawsuit, which sought to challenge HHS’s interpretation of the Federal health care program anti-kickback statute (AKS) and position that the company’s proposed copay assistance program would violate the AKS.  Now, after an unfavorable HHS Office of the Inspector General (OIG) advisory opinion and two defeats in court, Pfizer has appealed the Second Circuit’s decision to the Supreme Court.

In its petition filed earlier this month, Pfizer challenges HHS’s interpretation of the AKS as “staggeringly overbroad,” contrary to the congressional intent behind the AKS, and a threat to “almost any activity that facilitates patient access to federally funded healthcare.”  At the center of Pfizer’s argument is whether an AKS violation requires corrupt intent.  If SCOTUS takes up this case, it could have significant and far-reaching implications across the healthcare fraud and abuse landscape.

Background

Pfizer manufactures tafamidis (sold under brand names Vyndaqel and Vyndamax), a breakthrough treatment for a rare, progressive heart condition called transthyretin amyloid cardiomyopathy (ATTR-CM).  Pfizer set the price of tafamidis at $225,000 for each one-year course of treatment.  Under Medicare’s payment formula, Part D plan enrollees who take tafamidis are responsible for a copay of approximately $13,000 per year.  Recognizing that this out-of-pocket cost represents a significant financial barrier for many patients, Pfizer proposed a Direct Copay Assistance Program for Medicare Part D enrollees using tafamidis.  Under the proposed program, Pfizer would directly cover nearly all of a Medicare Part D enrollee’s copay for tafamidis, subject to certain eligibility criteria, including financial need.  Eligible patients would be responsible for only $35 per month, and Pfizer would cover the rest of the approximately $13,000 annual copay.  The Medicare program would pay most of the remaining $225,000 in annual cost.  In June 2019, Pfizer sought an OIG advisory opinion to ensure that its proposal would not run afoul of federal law.

In September 2020, the OIG issued an unfavorable advisory opinion to Pfizer, concluding that the proposal was “highly suspect” under the AKS because one purpose of the program, and perhaps the primary purpose, would be to induce Medicare beneficiaries to purchase Pfizer’s federally reimbursable medication.   Federal courts, too, have broadly interpreted the AKS to cover any arrangement where “one purpose” of the remuneration is to induce referrals, purchases, or orders of federally reimbursable items or services, even if the arrangement has other, legitimate purposes (see, e.g., United States v. Borrasi, 639 F.3d 774 (7th Cir. 2011), here, and United States v. Greber, 760 F.2d 68, 71 (3d Cir.), cert. denied, 474 U.S. 988 (1985), here).

Pfizer challenged the OIG’s interpretation as contrary to law in a lawsuit brought in the Southern District of New York (SDNY).  The district court sided with OIG, rejecting Pfizer’s narrower reading of the AKS, which would require an element of “corrupt” intent to impose AKS liability.  Pfizer appealed to the Second Circuit, which again ruled against Pfizer.

The Second Circuit’s Interpretation of the AKS and its Mens Rea Element

The AKS makes it a criminal felony to knowingly and willfully offer or pay any remuneration (including a kickback, bribe, or rebate) directly or indirectly, overtly or covertly, in cash or in kind, to induce a person to, inter alia, purchase, order, or arrange for the purchase or order of, a drug reimbursed in whole or in part by a federal healthcare program, such as Medicare Part D.

In affirming the district court’s decision, the Second Circuit held that Pfizer’s proposed program falls squarely within the AKS’s prohibitions because it is specifically designed to induce Medicare beneficiaries to purchase Pfizer’s federally reimbursable drug, tafamidis.

In relying on the plain meaning of the term “induce,” as the district court had done, the Second Circuit clarified the definition as:  to entice or persuade another person to take a certain action.  Contrary to Pfizer’s contention that the term implies a corrupt intent, the Court found it to have neutral intent, as one can persuade another to take an action with good or bad motives.

Similarly, the Court drew on the plain meaning of “willfully” to reject Pfizer’s argument that the term suggests “an element of corruption.”  The Court instead interpreted the term, as used in the AKS, to mean an intentional violation of a known legal duty, but concluded that “the mens rea element goes no further.”  Consistent with the district court, the Second Circuit likewise found nothing in the statutory text that would indicate that corrupt intent is a required element of an AKS violation.  On the contrary, referring to the statement in the statute itself that a person need not have actual knowledge of the AKS or specific intent to commit a violation of it, the Court concluded that a person can willfully violate the AKS, even without knowledge of the exact statutory provision that her conduct violates, as long as she knows her conduct is illegal.

In addition, the Second Circuit rejected Pfizer’s argument that the AKS should be read more narrowly than the beneficiary inducement statute (BIS), a civil statute that prohibits a person from offering to a Medicare or Medicaid beneficiary any remuneration that the person knows or should know is likely to influence such individual to order or receive from a particular provider, practitioner, or supplier any item or service for which payment may be made, in whole or in part, under Medicare or Medicaid.  According to Pfizer, Congress intended that the BIS be the AKS’s broader, civil counterpart, meaning that the Court should interpret the term “induce” in the AKS more narrowly than the term “influence” in the BIS.   The Second Circuit found that, although the two statutes have some subject matter overlap, they prohibit different activities—the AKS is not simply a narrower or criminal version of the BIS.  The Court found that there is at best little utility in interpreting the AKS by reference to the BIS.

Pfizer’s Petition to SCOTUS

Pfizer is now asking SCOTUS to reject these earlier interpretations of the AKS.  As Pfizer has argued throughout this legal battle, its proposed copay assistance program “poses no risk of corrupting independent decision making” or of inducing improper utilization of tafamidis.  According to Pfizer, this is because tafamidis is the only FDA-approved drug to treat ATTR-CM.  Because no approved alternative exists, its proposed copay assistance program would not influence treatment decisions away from other drugs.  However, HHS, SDNY, and the Second Circuit have each concluded that corrupt intent is not required for an AKS violation—copay assistance “induces” a beneficiary to purchase a medication when the assistance removes a financial barrier, even if the medication is one that the beneficiary needs and would have purchased if they had the financial means to do so.  Pfizer’s case therefore turns on whether it can convince the Court to adopt a narrower reading of the AKS.

Pfizer’s arguments for a narrower reading of the AKS in its petition are consistent with its arguments inSDNY and the Second Circuit.  Pfizer contends that these earlier interpretations of the AKS are not supported in the statute’s text, structure, or legislative history.  Rather, Pfizer argues, the AKS focuses on “corrupt transactions,” such as the specific examples of “kickback, bribe, or rebate” that Congress provided.  To Pfizer, HHS’s interpretation is “out of step” with the Supreme Court’s “longstanding efforts to ensure that criminal laws do not sweep more broadly than Congress intended.”

If SCOTUS takes up this case, we will expect to see HHS make familiar responses to Pfizer’s AKS interpretation arguments as explained above, relying on the plain meaning of “induce” and “willfully” and declining to interpret the AKS by distinguishing it from the BIS.

It remains to be seen how the justices will respond to Pfizer’s petition, but without a circuit split on this issue, it is less likely that they will take up the case.  SCOTUS has until Dec. 14, 2022 to decide whether to grant certiorari.  For now, the Second Circuit decision still stands: however serious the disease, however beneficial a copay assistance program might be to patient access to treatment, and however well-intentioned the manufacturer may be, manufacturer copay programs that include government beneficiaries are at high risk under the AKS.

On October 26, 2022, US Pharmacopeia (USP) Biologics Stakeholder Forum held a workshop on “Collaborating to solve CMC challenges and support efficient development of lentiviral-mediated CART cell therapies.”  Panelists discussed CMC challenges for CART therapies, including potency assay development, analytical method transfer, and demonstrating comparability.  Panelists also provided advice and recommendations on how they approach potential these challenges as well as potential areas for standards development.  USP aims to identify tools and solutions that may facilitate CART therapy development and mentioned potentially writing an information chapter on developing assays for CART therapies based on the workshop’s panel discussion.

The workshop included presentations by USP on its available standards for advanced therapies, FDA/CBER on CMC challenges for CART cell therapies, and industry approaches to potency testing during CART development, and using Analytical Quality by Design (AQbD) principles in potency assay development.   The majority of the workshop was spent on Q&A and included discussions on too many topics to write about in this blog.

USP opened the workshop with a description of its organization, each of its applicable standards for advanced therapies, including its standards (general chapters) <1046> Cell and Tissue Based Products and <1047> Gene Therapy Products, and its microbial related chapters open for comment: <74> Solid Phase Cytometry-Based Rapid Microbial Methods for Detection of Contamination in Short Shelf-Life Products, <77> Mycoplasma Nucleic Acid Amplification Tests, and <1114> Microbial Control Strategies for Cell Therapy Products.

FDA/CBER (the Agency) provided an overview of CMC challenges for CART development (e.g., limited manufacturing experience, in-process testing, product characterization, product stability data, assay development and qualification), CMC expectations for late-stage CART cell development (have a controlled manufacturing process, well developed and qualified analytical methods, and sufficient manufacturing experience), and regulatory considerations for potency assay development.  Some key points the Agency shared included the following:

• Your product is only as good as the process-demonstrate your manufacturing process consistently produces drug product as per your critical process parameters (CPPs)
• Have qualified potency assay(s) prior to conducting your pivotal study
• Agency often sees issues when the drug product is put on an expedited manufacturing or an expedited clinical program
  • As the clinical program for the drug product matures, the CMC information should mature hand in hand
• Early product characterization and concurrent matrix-based assay development are often seen as a key for product development and licensure success
  • Helps you move forward in drug development and quicker later in development (i.e., avoid CMC bottleneck prior to initiating pivotal study)
  • You’ll have the data to support comparability for when changes are made
  • May help you avoid analytical bridging studies
  • Allows you to determine which potency assay(s) are most relevant for your product
• Don’t assume that product characterization is not needed when using an automated piece of equipment that is generating CART products. Use of automation does not allow for bypassing FDA requirements with respect to method transfer comparability.
• Although not expected at the pivotal study stage, successful sponsors validate early
  • Opportunity for feedback from FDA if provided pre-BLA
• Avoid running Process Performance Qualification (PPQ) prior to validating your methods
• A replication competent lentivirus (RCL) testing exemption can be requested after you’ve obtained several lots showing that you can repeatedly generate RCL negative drug product
• It is less likely for a company to be granted a RCL testing exemption if IND B vector uses a different length of viral vector backbone or is manufactured in a different way than the IND A vector
• The ultimate goal of a comparability study is not to demonstrate that the products are identical, but to demonstrate you can consolidate clinical data from these lots
  • Release testing alone is not sufficient
  • The bar for demonstrating comparability is high if a manufacturing change is introduced in the middle of a Phase 2 pivotal study versus if a sponsor introduces a process improvement between Phase 1 and before starting the Phase 2 pivotal study

Panelists stated that a reference standard should be incorporated into your strategy for method monitoring, which then informs how your methods may change over time.  You also want your reference standard to reflect the manufacturing process.  Overall, it appeared from the workshop discussions that potential standards relevant to CART cell therapies include particle size, particle number, for the cell line, and infectious titers.

Stay tuned for USP white paper(s) on the workshop’s discussion as well as USP information chapters on lenti-viral vector cell therapies.  USP is currently looking for volunteers to serve as scientific experts on the Lentivirus Cell Therapy Expert Panel who will develop lenti-viral vector standards.

FDA began the Software Precertification (Pre-Cert) pilot program in 2017 to evaluate an alternative approach to regulation of software as a medical device (SaMD) over the total product lifecycle (TPLC).  We have followed it over the last five years, with blog posts here, here, here, here, here, here, and here.  The Pre-Cert pilot program, as described in the Working Model, included an Excellence Appraisal (pre‑certification) to demonstrate a culture of quality and organizational excellence, a review determination to evaluate whether a pre-market review would be required for the particular SaMD, a streamlined premarket review, when required, and evaluation of real-world performance to verify the product’s continued safety, effectiveness, and performance.  As part of the pilot program, FDA included a Test Plan.

As of September 2022, FDA has now announced the conclusion of the pilot program.  It also has released a report summarizing the findings from the pilot program.  The Software Precertification (Pre-Cert) Pilot Program: Tailored Total Product Lifecycle Approaches and Key Findings (“Key Findings”).  The Key Findings are summarized below, along with our thoughts on the lessons learned in the pilot and how some of the pilot’s findings may be useful to industry while we wait to see if there will be a sequel.

Excellence Appraisals

FDA found that further development would be needed before they would be comfortable identifying low-risk devices where the Excellence Appraisal alone could be relied upon without further premarket review.   The basis of this conclusion relates to the large range of device indications and technology and nuances of testing to support them. It seems that FDA may have validated that, even with an Excellence Appraisal above and beyond standard compliance with good manufacturing practices, there is a need for pre-market review for Class 2 devices.  FDA notes that “a future approach could build on features of the current regulatory system, where a Quality Management System and other general and, in some cases, special controls provide a reasonable assurance of safety and effectiveness for certain low to moderate risk devices.” Key Findings at 12.

Streamlined Review

In their evaluation of the Streamlined Review process, FDA identified an issue that industry has complained about for years – that there is variability in how information is used in making regulatory decisions.  FDA proposes that “modern mechanisms that support clear and consistent communication of device information could facilitate efficient device review activities” and notes that they “consistently observed the need for structured data . . . .” Id.  One struggle that many companies face is the need to generate data in compliance with their quality system and then reformat or restructure it for review in a premarket application.  We hope that any regulatory tools proposed by the Agency to support premarket review are developed in conjunction with FDA’s post-market reviewers and inspectors so that changes are helpful across the TPLC and do not introduce new burdens.

Test Plan

As discussed in our previous posts, we were concerned that the Agency may not be able to adequately validate the program.  FDA did find that their ability to fully test the program was limited.  Challenges to a successful test program included there being only nine companies in the pilot program and the need to limit formal implementation to the De Novo classifications.  It was noted that authorizing a device through a De Novo would create pilot specific special controls that other companies would need to follow, even if not participating in the pilot program.

Despite the limitations in testing, some of the findings were noteworthy.  As part of the testing, FDA retrospectively reviewed applications to determine if the Excellence Appraisal could be used in lieu of certain other premarket software documents.  They found that either a “concise statement of precertification without the expectation of further premarket review of the Excellence Appraisal information, or a detailed report of the Excellence Appraisal process and results to be reviewed in-depth in the context of the device subject to review” would be useful, but a summary that fell in between these two approaches was least valuable.  Id. at 8.  While the former approach would likely be welcome by sponsors, the need to write a detailed report of the Excellence Appraisal as it applies to the device may be equally burdensome to the software document it is intended to replace.

Key Performance Indicators

The pilot resulted in many findings related to excellence principles and key performance indicators (KPIs) that may be useful to manufacturers of SaMD, as well as other device types, both with and without software.  Within the current legislative framework, the efficiency of the premarket review process will be best when device information is clearly presented and answers key questions related to review of the device’s safety and effectiveness.

Implementing some or all of the KPI objectives presented in Appendix List A of the Key Findings document may, therefore, improve efficiency of the regulatory process regardless of whether there is a new regulatory framework for software devices.  You may also note that many of these key findings can be considered best practices for implementation of a quality management system in compliance with the Quality System Regulation, 21 C.F.R. Part 820.  The Descriptive KPI Objectives include:

1. Processes engage the right people, at the right times, to the right degree: “We use knowledgeable, qualified, and multidisciplinary teams throughout the TPLC.”
2. Development process results in well-characterized software: “Our software behaves as expected.”
3. Deployment and monitoring process confirms well-characterized software in context of use: “Our software behaves as expected in the real-world.”
4. Patching process ensures timely resolution of issues across the entire installed base: “We can fix our software when it doesn’t behave as expected.”
5. Update process ensures modifications meet user needs identified through real-world use: “We can identify and implement improvements to the expected behavior of our software.”

Key Findings at 18.

Statutory Authority

Finally, FDA concluded that there were challenges with implementing the Pre-Cert approach under the current statutory authorities.  While there is a need for new statutory authority, the Key Findings report does not provide any details as to what type of regulatory framework would be useful to achieve the goals of the Pre-Cert program.  FDA provides only high-level information on the need for a “flexible, risk-based approach to regulation” that “could allow FDA to tailor regulatory requirements more efficiently for devices based on the latest science, the benefits and risks posed by devices, their real-world performance, and their contribution to promoting health equity.” Id. at 13.

While it is not clear if there will be a sequel to the Pre-Cert pilot program, we look forward to seeing what new ideas FDA’s Digital Health Center of Excellence will bring to reducing regulatory burdens to allow software devices to be developed and iterated efficiently, while ensuring safety and effectiveness.

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.