A year ago, we blogged about a proposed rule that would replace the Quality System Regulation (QSR) at 21 C.F.R. Part 820 with a newly named Quality Management System Regulation (QMSR) (see here). The proposed rule was published on February 23, 2022 and was first heralded by FDA in 2018 and introduced in the Spring 2018 regulatory agenda. In the proposed rule, FDA stated that any final rule would become effective one year after the date of publication of the final rule in the Federal Register.

It is noteworthy that the one-year anniversary of the proposed rule has come and gone.

Keen observers may have noticed that in the most recent semiannual regulatory agenda, neither the Quality System Regulation nor the Quality Management System Regulation is referenced. This suggests that it is unlikely we will see harmonization of the QSR with ISO 13485 in 2023.

From a historical perspective, FDA issued a final rule in the Federal Register of July 21, 1978, outlining the current good manufacturing practice (CGMP) requirements for medical devices. The regulation became effective on December 18, 1978 and was codified under part 820. In the intervening years between 1978 and 1996, editorial changes were made to update organizational references and revise the list of critical devices included in the preamble.

The Safe Medical Devices Act of 1990 provided FDA with the authority to include design controls in the regulation. FDA also took steps to ensure, to the extent possible, that the CGMP regulation would be consistent with the quality system requirements in applicable international standards. FDA published a proposed rule with revisions to part 820 on November 23, 1993. Nearly three years later, the rule was finalized on October 7, 1996 with the regulation becoming effective June 1, 1997.

This is all to say we recognize the tremendous efforts underway to harmonize the QSR with ISO 13485. We hope to see the topic back on the agenda in the fall and will post an update when the rule is eventually finalized or if anything noteworthy happens before then.

FDA uses its Product Specific Guidance documents (“PSGs”) to provide recommendations as to the bioequivalence testing necessary for approval of a generic drug.  As the Office of Generic Drugs (“OGD”)  has stated, “[t]he clarity and transparency provided by PSGs help streamline generic drug product development, promote timely approval of Abbreviated New Drug Application (ANDA) submissions and increased drug competition, improving patient access to high quality and affordable medicines.”  Indeed, PSGs help facilitate generic competition, and to date, OGD has published more than 2,000 PSGs.

As part of its Generic Drug User Fee Amendments of 2022 (“GDUFA III”) Commitment, FDA agreed to expedited development of PSGs.  Specifically, FDA agreed to issue PSGs for 90 percent of new, non-complex New Chemical Entities within 2 years of reference product approval and 75 percent of complex New Chemical Entities within 3 years of approval.  FDA also agreed, for the first time, to host PSG teleconferences and meetings with applicants to provide feedback on the potential impact of a new or revised PSG on an applicant’s development program.  Pre- and post-submission meetings to discuss alternative approaches than that recommended in PSGs may also be available.

While PSGs are not new—OGD has published them for many years—a new Draft Guidance was released earlier this month covering “Product-Specific Guidance Meetings Between FDA and ANDA Applicants Under GDUFA.”  This new Guidance outlines procedures for requesting and conducting PSG meetings with OGD, including PSG-specific teleconferences, as well as pre- and post-submission PSG meetings.

According to the Guidance, the PSG-specific teleconference—also categorized as pre- or post-submission—is a prerequisite to a pre- or post-submission PSG meeting, and such teleconferences and meetings are available only after the publication of a PSG.  Like the name implies, the pre-submission teleconference or meeting would be held prior to submission of the ANDA while the post-submission teleconference or meeting occurs after submission.  A post-submission PSG teleconference and meeting should occur before responding to a possible bioequivalence deficiency identified during review or in a Complete Response Letter.

The Guidance distinguishes between the PSG teleconference and the PSG meeting.  A PSG teleconference is a forum for applicants to obtain feedback on the impact of a new or revised PSG on an in-progress development program for which in vivo bioequivalence studies have either commenced or completed.  Discussions during these teleconferences are limited to feedback on the potential impact of the PSG recommendations on an existing development program; FDA will not discuss the applicant’s questions regarding an approach other than the approach recommended in the PSG.  Applicants should submit a request for a PSG teleconference within 60 days after publication of the new or revised PSG so that FDA can provide timely feedback to applicants.  FDA may deny a PSG if the applicant’s bioequivalence testing started after the PSG publication.

If OGD indicates in the PSG teleconference that the PSG would impact an applicant’s development program, the Guidance explains that this indicates that the ongoing or completed study alone is unlikely to be sufficient to establish bioequivalence.  Any subsequent changes to the development plan resulting from the recommended PSG can be discussed with FDA in a pre- or post-submission meeting during which the Agency will discuss with the applicant the scientific rationale for an approach other than that recommended in the new or revised PSG.  These pre- or post-submissions meetings (as opposed to teleconferences) are intended to discuss scientific rationale for an alternative to the PSG and address applicant’s questions related to their own proposed bioequivalence approaches.  OGD will deny a pre-submission PSG meeting request if the applicant did not have a pre-submission PSG teleconference or if the applicant has already submitted the ANDA after the pre-submission teleconference.  Similarly, OGD intends to deny a post-submission PSG meeting request if the ANDA applicant did not have a post-submission PSG teleconference or if the ANDA applicant had a pre-submission PSG teleconference and then submitted the ANDA.  OGD may also deny the request if it determines that the questions in the meeting package have been addressed during the ANDA assessment or the ANDA applicant has already responded to the possible deficiencies to be discussed.

Specific timing goals, as well as procedures for requests, apply to each type of PSG meeting.  Meeting package content, timing of submission, and directions for submission are also covered by this Guidance.

And, of course, the Controlled Correspondence process remains an option as an alternative to a pre- or post-submission PSG meeting.

As of the morning of March 1, the hotly anticipated Joint Meeting of the Nonprescription Drugs Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee originally scheduled for March 20 has been cancelled.  The March 20 Joint Meeting concerned the NDA for naloxone hydrochloride nasal spray for nonprescription use as an opioid reversal agent in the emergency treatment of opioid overdose which was submitted by Harm Reduction Therapeutics under the trade name RiVive.  RiVive would be a direct-to-OTC approval and would represent a potential first in class product in a new therapeutic category for nonprescription drugs.  The issues for discussion at the March 20 Joint Meeting were intended to cover the adequacy of the data supporting the nonprescription application for the product.  The reason for the cancellation—scheduled to be published in the Federal Register on March 2—is that “the meeting is no longer needed.”  No further information concerning the cancellation has been made available at this time.

We previously blogged on the February 15, 2023 Joint Meeting of the same advisory committees concerning the rx-to-OTC switch application for Narcan Nasal Spray (NNS).  All 19 members of the joint Advisory Committee agreed that the benefit-risk profile of NNS is “supportive of its use as a nonprescription opioid overdose reversal agent.”  FDA has not yet taken action on the NNS application, but the Prescription Drug User Fee Act (PDUFA) goal date by which a decision is expected is March 29, 2023.

In January 2023, FDA published a paper summarizing its lessons learned from two pilot Quality Management Maturity (QMM) Pilot Programs, such as best practices for conducting QMM assessments and developing the QMM scoring system.  The lessons learned were also discussed during a November 2022 workshop hosted by the FDA.  The purpose of these two pilot programs was initially to inform development of a FDA rating system to characterize the QMM of a facility.  FDA published two Federal Register Notices in October 2020 to recruit domestic drug product manufacturers of finished dosage forms and foreign manufacturers of active pharmaceutical ingredients to participate in the QMM Pilot Programs.

Before discussing the 2023 paper, it’s important to know that the QMM Program is separate from the Quality Metrics Program, which we previously blogged about here, here, and here.  QMM is an umbrella program that includes quality metrics as well as quality culture, risk management, continual improvement, etc.  FDA describes the QMM as “above-the-bar behaviors” that exceed good manufacturing practices (GMPs).  The QMM rating is based on an evaluation of a facility’s quality practices and it is meant to be a leading indicator for detecting problems before they occur, such as a drug shortage.  By way of background, FDA first proposed using a QMM rating in its 2019 Report on Drug Shortages and Potential Solutions.  In this report, it’s stated that 62% of drug shortages reported between 2012 and 2017 were due to quality issues which is attributed in part to a lack of recognition or reward for manufacturers with mature quality management systems that focus on continuous improvement and early detection of supply chain issues.  The report recommends using a QMM rating that is shared throughout the market (purchasers, consumers, competing manufacturers) to provide manufacturers committed to QMM with a competitive advantage.  FDA intends to provide regulatory incentives to manufacturers with robust QMM systems, such as reduced inspection frequency and increased regulatory flexibility in making post-approval changes.  FDA proposed using QMM ratings as part of its decision in selecting sites for surveillance and preapproval inspections.

On November 2, 2022, the FDA’s Pharmaceutical Science and Clinical Pharmacology Advisory Committee held a meeting on CDER’s QMM Program.  In addition to providing some background on QMM, the FDA presented lessons learned from the QMM Program Pilots.  During the workshop, FDA stated that the QMM Pilot Programs will be used to develop a suitable assessment tool to identify indicators of mature quality systems to build a framework to evaluate QMM best practices and identify areas for continual improvement.  Development of this framework to measure a facility’s QMM was included in the July 2021 White House’s 100 Day Report.

The QMM Pilot Programs were conducted using two contractors who developed the QMM assessment protocol questions and the scoring system.  The contractors also conducted the QMM assessment of seven domestic manufacturers of finished dosage form and eight foreign manufacturers of active pharmaceutical ingredient.  FDA staff served as pilot program observers, but also met with the contractors to provide feedback.  The paper discusses lessons learned about the QMM assessment process, scoring approach, assessor behaviors, and perceptions of the assessment questions, reports, and ratings.  A brief discussion on the scoring approach is provided below.

FDA’s 2022 presentation and the information in the FDA’s 2023 paper on the QMM Pilot Programs are similar, but the paper provides more detail on what general aspects were assessed (referred to as practice areas) and the topics within those practice areas.  For example, domestic establishments that manufacture finished dosage forms were evaluated for the following practice areas: 1) leadership and governance, 2) continual improvement, 3) stakeholder engagement and satisfaction, 4) knowledge management, 5) workforce engagement, and 6) operations.  Topics within the practice areas were assigned scores between 1 and 5 with one representing the lowest quality maturity level and five the highest quality maturity level.  FDA provided teasers in Figure 2, showing that topics under leadership and governance may include management commitment, management reviews, oversight, and monitoring, business excellence and societal contribution, and topics under continual improvement may include customer/patient focus and stakeholder feedback and engagement.  The paper did not provide any detail into how the practice areas and topics were developed, but FDA referenced a number of organizations involved in researching and developing measures of QMM, including the University of St. Gallen and the Parenteral Drug Association (PDA).  A recent 2022 study funded by the FDA was intended to study how QMM characterizes quality and may include potential practice areas and topics for future QMM rating development.  Figure 2 of the 2023 paper showed facility and assessor scores, but it did not describe how assessors and the facilities determined the scores.  There also was not a lot of discussion on how often the scores between the assessors and the facilities aligned or not and what this meant, if anything.  FDA recognized in the paper that multiple assessors may be needed per assessment to minimize bias and to maximize inter-rater reliability.

We will continue to monitor the QMM program’s development and will post further information as it becomes available.

Since 2005, 510(k) submissions have been formatted according to FDA guidance Format for Traditional and Abbreviated 510(k)s.  The guidance describes twenty sections to be included in a Traditional or Abbreviated 510(k).  With 18 years’ experience, we have developed a pretty good system for preparing 510(k) submissions in this format.  The general structure of our submissions, and of many others that we have seen, is to have a document for each of the twenty sections and then to refer to other files, such as labeling and test reports, as attachments.  We have made improvements to the content of each of these sections over the years and have included additional information to address other guidance documents and the refuse to accept (RTA) checklist, but the general structure has been constant.  This method of submission development allows for efficient development of each section and collaboration across numerous subject matter experts and internal reviewers.

FDA announced on October 3, 2022 that the voluntary electronic Submission Template And Resource (eSTAR) templates would be required beginning October 1, 2023, as we blogged about here.  The eSTAR templates are interactive PDF forms used to develop and submit 510(k)s (Traditional, Special, or Abbreviated) or De Novo applications, or to submit additional information to these submission types.  There are two forms:  one for non-IVD devices and one for IVD devices.  The same forms are used for both 510(k)s and De Novo submissions.  It appears that use of eSTAR for PMAs may be in the future as it is seen on the templates in the selection for application purpose but is not currently able to be selected.

In order to start learning the format, and also because some submissions can take more than a year for everything to come together and we do not want to switch formats should this occur, we have decided to start some of our newest submissions using the eSTAR non-IVD and IVD templates.  While it may have to do with old dogs learning new tricks, our initial experience suggests that there is a bit of a learning curve and that it might be easier to teach Fido to roll over than it is to figure out a good process for developing 510(k)s in the new format, especially when collaborating with multiple subject matter experts and reviewers, and using cloud-based file sharing.

This post shares some our early learning on how the template works (the good and the bad).  We hope it may be of help to those embarking on an eSTAR submission for the first time.  In a second post, we will cover some of the process challenges that industry may face when using eSTAR.

By way of background, the eSTAR template is a structured form that takes a user section-by-section and question-by-question through the content of the 510(k).  The questions are generally targeted on determining what information needs to be included in the 510(k).  For example, in the Device Description section of the eSTAR template you are asked questions related to, among other things, tissue contact, software/firmware, sterility, device environment, and electrical power.  Based on responses, additional sections, questions, data fields, and places to link files, called attachments, are added.  For example, answering “yes” to the question related to use of software/firmware opens new fields for selecting related technology, including use of cloud communication, network connection, wireless communication, USB/serial ports, and software upgrades.  The selections made here impact the content that will be required later in the section of the templates related to software.

In some sections, there is a field within the template that can be used to enter the requested information or to justify why the information is not needed, or why an alternative approach was used.  In other sections of the template, attachments will be needed to include this type of information.  The text boxes also cannot accommodate tables or figures, which are often helpful particularly in comparing to a predicate device and/or explaining technological features of a device.

While this sounds like a helpful, step-wise process, it is not as easy as it may sound.

Learnings on how eSTAR works

• Starting Too Early. We all know sponsors are eager to get to clearance and sometimes even start working on their 510(k) submissions while still in development/before the device is finalized.  This could be done with the old format because the sections were fixed at the outset and could be iterated on.  In the eSTAR template, because answers to early questions cause various sections to appear in the template or not (e.g., if a user answers no to a device being sterile, the sterility sections does not present for population), a user may not know answers to all of the questions when they want to start preparing the information and/or they may miss a section depending on how they answer.
• Know Your Guidances. Several sections of the eSTAR templates have questions that walk through related guidance documents.  For example, the template asks for the number of reprocessing instructions, sterile methods, tissue contact materials, and electronic interfaces and then requests information related to the reprocessing instructions and validation, sterilization validation, biocompatibility, and interoperability in line with relevant guidance documents.  It is important to be familiar with the relevant guidance documents to answer the questions in an appropriate manner.  There are additionally places to provide attachments for test reports and other supporting documents.
• Performance Testing Summaries No Longer Needed? Maybe.  The required content related to performance testing seems to be a bit light in comparison to other sections.  The RTA checklist for eCopy 510(k) submissions requires a summary of bench performance testing formatted per FDA guidance Recommended Content and Format of Non-Clinical Bench Performance Testing Information in Premarket Submissions.  In the eSTAR template, the only requirements are a complete test reports for the testing.  This omission is quite surprising given that we have recently seen some RTA deficiencies related to lack of this summary.
• Performance Testing Comparator versus Predicate. Also, in the performance testing section of  the eSTAR template, the sponsor must identify the 510(k) number for a device “that is the best comparator for the testing.”  We find it interesting that the template calls for a predicate device that may not be the same as the predicate device used to support substantial equivalence.
• Missing Human Factors. We also note that there is no specific section of the eSTAR templates for human factors documentation to be included. We find this omission somewhat ironic seeing that this template was clearly not prepared using a human factors approach.  We plan to provide the performance test summary and human factors documentation as attachments to the bench performance testing section of the templates.
• New Labeling Requirements. As we navigate the questions throughout the template, we find that there seem to be some embedded labeling requirements that we have not previously seen.  For example, in the section for EMC, Wireless, Electrical, Mechanical and Thermal Safety there is a requirement to provide testing to support use in an aircraft or a reference to a specific attachment and page where a labeling mitigation that cautions against the use of the device in an aircraft is located.  So even if it is completely obvious that a device would not ever be used in an aircraft, sponsors will need to make sure labeling covers this issue.  Submitters should be sure to review all questions of the template carefully early in development to ensure specific labeling information is incorporated (although not too early in development – see our first point above).
• Option to Automate the 510(k) Summary. There is an option to provide a 510(k) summary as an attachment or you can enter summary information in fields throughout the template that will be used to auto generate a 510(k) summary.  We will be opting for the attachment as we often use tables or other formatting in 510(k) summaries that are not possible in the eSTAR template fields.
• Unnecessary Sections Cannot Be Omitted. For submissions of a modification to an existing device, the template requires information for all sections, even if the content of the section is not affected by the change.  In eCopy submissions, a single paragraph could often be used to make statements regarding the nature of the change and explain why new information or testing was not required compared to the previous clearance.  In eSTAR, these statements require repetition in multiple fields and attachments – making it anything but least burdensome.  For example, for a patient contacting device, the number of tissue contacting materials are identified in the template and then, for each material, the contact type and duration are filled in.  The template uses this information to generate tabs for each biocompatibility endpoint that should be evaluated per the relevant guidance.  For a modification to a patient contacting device that does not affect materials or biocompatibility, each tab for each material will require the justification for why that test was not repeated.   The situation is similar for submissions where software is not changing.  The eSTAR template will require a separate attachment for each document type (e.g., SDS, architecture document, software verification and validation) even if the same justification and reference to the prior clearance can be used across all required documents.

But, it is not all doom and gloom when it comes to eSTAR—a few things will remain unchanged (thank goodness!). First, in the eSTAR template, the sections for the Device Description, Substantial Equivalence, and Executive Summary require attachments.  This means the attachments can be formatted and organized in whatever way the sponsor prefers.  Based on our work to date, we have needed to make only a few updates to the format we used for eCopy submissions.  Given that these are some of the most critical sections in the 510(k), it is a great relief to know their structure and organization can largely remain the same.

Second, there is an option to continue to submit responses to additional information (AI) requests in an eCopy format. The eSTAR templates can also be used to respond to requests for additional information.  When entering the template, the user can select “additional information” as the submission type.  When doing so, a pop-up window provides two options.  The options are (1) to provide responses and attachments as an eCopy without an updated eSTAR template, or (2) to provide an updated eSTAR template (using the same version used for the original submission).  In this case, a section of the eSTAR template will be completed by copying the deficiency into one field and providing the response in another field.  New attachments are then included in the relevant section of the eSTAR template itself.  Depending on the nature of the deficiency, the fields in the template may not be sufficient for providing lengthy explanations that require tables, figures, or formatting to keep the response clear and organized so we are glad the eCopy option will still be available.  As anyone who has ever worked on a lengthy and/or complicated AI response knows, these responses do not always fit neatly in a text box.

Transitioning to the eSTAR template will taking some getting used to.  In both the form, as discussed above, and in process—which we will cover in Part 2 of our post.

The Drug Enforcement Administration’s (“DEA’s”) February 13th determination that THC acetate ester (“THCO”) is a schedule I controlled substance under the federal Controlled Substances Act (“CSA”) has received a good amount of attention in the cannabis press.  That determination, however, was neither a stretch nor a surprise to Rod Kight, the North Carolina attorney who posed the question to DEA, and to those who have recently analyzed whether certain cannabinoids are controlled, and if so, how.

THC acetate esters are different than delta-9-THC, the psychoactive compound found naturally in the cannabis plant.  Terrence L. Boos, Ph.D., Chief of the DEA Diversion Control Division’s Drug and Chemical Evaluation Section, responding to Kight, observed that the only THC acetate esters his agency is aware of are delta-9-THCO (“delta-9-THC acetate ester”) and delta-8-THCO (“delta-8-THC acetate ester”).  Letter from Terrence L. Boos, DEA, to Rod Kight (Feb. 13, 2023).  Dr. Boos noted that under 21 C.F.R. § 1308.11(d)(31) tetrahydrocannabinols (“THC”), controlled as schedule I substances, are “naturally contained” in the cannabis plant, but include “synthetic equivalents of the substances contained in the cannabis plant and/or synthetic substances, derivatives, and their isomers with similar chemical structure and pharmacological activity” to substances in the plant.

Dr. Boos explained that delta-9-THCO and delta-8-THCO have similar chemical structures and pharmacological activities as compounds in the cannabis plant so they fall within the definition of THC.  But, he noted, because neither delta-9-THCO nor delta-8-THCO occur naturally in the cannabis plant, they can only be obtained synthetically.  And because they do not occur naturally within the cannabis plant, they are not hemp and not excluded from control by the Agricultural Improvement Act of 2018 (“the Farm Bill”).  Dr. Boos’ determination is consistent with DEA’s August 21, 2020, interim final rule implementing the Farm Bill, noting that statute limited non-controlled THC to compounds within the statutory definition of “hemp,” that is only materials derived from the cannabis plant and did not impact the schedule I control of synthetically-derived THC.  Implementation of the Agriculture Improvement Act of 2018, 85 Fed. Reg. 51639, 51641 (Aug. 21, 2020).  (He also noted that because delta-9-THCO and delta-8-THCO are controlled substances, they do not meet the CSA’s definition of a “controlled substance analogue.”)

DEA’s determination that delta-9-THCO and delta-8-THCO are schedule I controlled substances reaffirms that any synthetic compound that does not occur naturally within the cannabis plant but which has similar chemical structure and pharmacological activities as THC, is a schedule I controlled substance.

The FDA Alumni Association (FDAAA) named Hyman, Phelps & McNamara, P.C.’s Director Deb Livornese as its 2022 Volunteer of the Year for her remarkable leadership steering its Activities Committee through COVID and many new challenges.

The FDAAA, whose members are FDA alumni and current employees, helps alumni stay in touch with the issues of the day facing FDA and supports the Agency’s public health mission.  The award was given at the association’s well-attended Winter Celebration on February 21, 2023.

“Having top-notch lawyers like Deb who have experience at the Agency is part of what contributes to our success as a firm.  We’re thrilled for Deb and pleased that her excellent work has been recognized,” said JP Ellison, HPM’s Managing Director.

The 2008 Ryan Haight Online Pharmacy Consumer Protection Act placed strict limits on online prescribing or the use of telemedicine encounters to prescribe controlled substances. The Ryan Haight Act was enacted to address the legal “grey area” in which prescribers and pharmacies operated via the creation of two new statutory requirements: 1) the at least one “in-person” medical evaluation requirement for prescribing practitioners, 21 U.S.C. § 829(e); and 2) the modified registration requirement for online pharmacies. 21 U.S.C. § 823(f).  The Act also established new definitions for “Internet,” “online pharmacy,” “practice of telemedicine,” among others. Notably, the Ryan Haight Act (and the later SUPPORT Act of 2018) also required DEA to promulgate regulations related to a “special registration” to engage in the practice of telemedicine, which now 15 years since the 2008 Act’s passage, DEA announced on February 24th – likely as a result of the relaxation of telemedicine requirements during the COVID-19 public health emergency.  21 U.S.C. § 802(54)(D)(i). That emergency declaration is set to expire on May 11, 2023. While no “special registration” will yet be required to engage in telemedicine prescribing of controlled substances, DEA is proposing parameters to guide the practice of telemedicine encounters in a post-COVID world.

The Ryan Haight Act did not limit the ability to prescribe controlled substance medications by telemedicine so long as the patient and prescriber had a least one in-person visit.  DEA’s proposed rule when finalized would authorize telemedicine pursuant to the Controlled Substances Act, 21 U.S.C. § 802(54)(G), where: 1) the prescribing practitioner has not conducted an in-person medical evaluation with the patient; 2) the prescription was issued pursuant to a telemedicine encounter; and, 3) the telemedicine encounter results in a prescription for a controlled substance medication. Section 502(54)(G), unlike the other six “permissible” telemedicine encounters in the Ryan Haight Act, permits DEA to pass regulations to expand the use of telemedicine.  See 21 U.S.C. § 503(54)(G) (specifically, telemedicine “being conducted under any other circumstances that the Attorney General and the Secretary have jointly, by regulation, determined to be consistent with effective controls against diversion and otherwise consistent with the public health and safety.”) The rule would require that the prescriptions be issued consistent with both state and federal law, and the practitioner to maintain an active DEA registration in the state in which the practitioner is located.

General Telemedicine Proposed Rule

One of the proposed rules, titled “Telemedicine prescribing of controlled substances when the practitioner and the patient have not had a prior in-person medical evaluation,” linked here, addresses a practitioner’s use of a defined “telemedicine encounter” to prescribe schedule III-V non-narcotic controlled substances and related parameters surrounding such prescribing when the patient and prescriber have not had a prior in-person evaluation.

The rule would permit a practitioner using a telemedicine encounter to prescribe controlled substances without an in-person visit under various situations involving both an audio-visual telehealth evaluation, or an in-person evaluation performed by a “referring” provider.  Notably, for services furnished for purposes of diagnosis, evaluation, or treatment of a mental health disorder to a patient generally in their home, interactive telecommunications may include two-way, real-time audio­only communication technology, if the “distant site” physician or practitioner is technically capable to use an interactive telecommunications system, but the patient is not capable of, or does not consent to, the use of video technology.  These audio-only encounters would seem to be an exception to DEA’s stated preference for use of audio-video telemedicine encounters.  The rule would also require enhanced recordkeeping requirements for both the referring practitioner (i.e., a prescriber that conducts an in-person visit) and prescribing practitioner (i.e., a prescriber that engages in telemedicine with the patient), including a review of PDMP data for the past year.

Importantly, if relying on a telemedicine visit, the prescription must be for an initial 30-day period, and only for schedule III-V non-narcotic controlled substances. If the patient seeks greater than the initial 30-day supply, then the telemedicine prescriber or referring prescriber must perform an in-person evaluation prior to prescribing additional controlled medications beyond the 30-day period. The visit may, however, include a patient’s in-person visit with another practitioner while on an interactive video link with the prescribing practitioner.

If an in-person evaluation is performed by either a referring provider or the prescribing provider, the patient may also receive schedule II controlled substances, consistent with Ryan Haight requirements already in place.

Lastly, the proposal permits continued prescribing of controlled substances (schedules II-V) for a period of 180 days following the end of the COVID-19 emergency declaration (i.e., 180 days past May 11, 2023) for those telemedicine relationships established during the COVID-19 emergency.

DEA is Seeking Comments, But on a Short Fuse

The proposal lastly notes that DEA is seeking public comments on various topics, but on a short, 30-day timeline given the looming end of the pandemic emergency.  Comment topics suggested by DEA include the following:

• Whether the rule should limit the issuance of prescriptions for controlled medications to FDA-approved indications contained in the labeling for those medications.
• Proposed practitioner recordkeeping obligations.
• Comments, including data from research and clinical practice, that provides evidence that an alternate maximum day supply (other than the proposed 30-day supply).
• Additional safeguards or flexibilities that should be considered with respect to the rule.
• Whether the proposed rule concerning the induction of buprenorphine via telemedicine (see below) should be combined with the general telemedicine rulemaking.

Telemedicine Prescribing of Buprenorphine for the Treatment of Opioid Use Disorder

DEA is also proposing regulations, linked here titled, “Expansion of induction of buprenorphine via a telemedicine encounter,” which would expand the circumstances under which practitioners are authorized to prescribe any schedule III, IV, or V narcotic controlled substance — approved by FDA specifically for use in the maintenance or detoxification treatment of OUD — via a telemedicine encounter.  The encounter may include an audio-only telemedicine encounter that meets the standards for the same set forth in CMS’s telehealth services regulations at 42 C.F.R. § 410.78(a)(3), provided certain requirements, including requirements under state laws and conditions are met. \

Specifically, DEA notes that in those states where state law prohibits the prescription of a controlled substance based solely on an audio-only evaluation, the proposed regulation would not authorize the audio-only prescription of buprenorphine for opioid-use disorder (OUD). Thus, the  authorization of audio-only OUD telemedicine prescribing, and audio-video prescribing, would only apply in those states where such prescriptions are consistent with state law. The same is true with the general telemedicine proposed rule, above.

The only schedule III-V narcotic drug that is currently approved by the FDA for OUD treatment is buprenorphine. DEA notes that expanding a registered practitioner’s authority to prescribe buprenorphine for the treatment for OUD via telemedicine, including an audio-only telemedicine encounter, would expand access to needed medical treatment. Relatedly, DEA states:

Recent studies have revealed that, in some populations, upward of 94 percent of the unhoused community had a cell phone, while a limited amount owned or had access to computers, tablets, or internet access. Not only would this rulemaking make it easier for patients to obtain treatment, many practitioners have shown a willingness to treat patients using an audio-only telecommunications system.

The rule would require the practitioner to check and maintain PDMP data for patients prior to issuing the prescription, which DEA asserts will assist the practitioner in making clinical decisions.

The authority to prescribe buprenorphine by telemedicine is not unlimited, however.  Not only must prescribing be consistent with state laws addressing use of telemedicine, but the patient must also receive a medical evaluation meeting certain requirements within 30 days of being prescribed buprenorphine via telemedicine for the induction of OUD treatment in order to obtain an additional supply of buprenorphine.  Thus, the regulations would require that, within 30 days, the patient must either be examined in person by the prescribing practitioner or practice, or the prescribing practitioner would have to examine the patient remotely while the patient is in the physical presence of another DEA­ registered practitioner that is participating in an audio-video telemedicine encounter with the prescribing practitioner.

Alternatively, the requirement of a medical evaluation is satisfied when the prescribing practitioner receives a qualifying telemedicine referral for medication assisted treatment for OUD from a DEA-registered practitioner prior to issuing a prescription for controlled substances.  Under this scenario, DEA notes the patient has already received the in-person medical evaluation from the referring practitioner, and thus the prescribing practitioner is authorized to prescribe beyond the 30-day limit.

***

For both proposed rules, the bottom line is that, while telemedicine is here to stay, circumstances permitting it are indeed not limitless. Remaining at the heart of any telemedicine encounter and controlled substances prescription is the need for an in-person medical examination – at some relatively early point (i.e. within 30 days) in the doctor-patient relationship.

And, as one who loves easy-to-follow charts… DEA has published one here, setting forth the various general parameters for prescribing via both telemedicine and in-person visits – and covering both the general and buprenorphine telemedicine proposed rules. Helpful practitioner prescribing guidance is set forth in a simplified document here.  We will release exciting details of our upcoming webinar addressing telemedicine soon.  Stay tuned.

One misnomer that has been repeated over the years has been the reference to the “Drug Enforcement Administration” (“DEA”) as the “Drug Enforcement Agency.”  This error has appeared not just in articles and other news publications but in some court documents as well.  The DEA has even made the same mistake.  Default Provisions for Hearing Proceedings Relating to the Revocation, Suspension, or Denial of a Registration; Correction, 87 Fed. Reg. 73246 (Nov. 29, 2022).  Interestingly, this same issue does not appear to have occurred with the Food and Drug Administration, in that, I am not aware of erroneous public references to the “Food and Drug Agency.”

This faux pas may take on new meaning given that recently the Department of Justice (“DOJ”) and DEA have argued that DEA is not an “agency” after all.  In a case involving a challenge to a Freedom of Information Request (“FOIA”) submitted to DEA, the DOJ and DEA appear to now argue that DEA is a “component” of the DOJ and not an agency.  Aims Institute, PLLC, v. Merrick Garland, et. al, Case No. 4:2022-cv-02396 S.D. Tex. (2023).  In an erratum filed to the deposition of an official previously self-identified as the Chief FOIA Officer, the government stated that the individual was in fact, not the Chief FOIA Officer for DEA but Chief of the FOIA/PA Unit at DEA.  The errata further stated that the Chief FOIA Officer was Vanita Gupta, Associate Attorney General of DOJ.  Also, the errata stated that DEA is a “component” of DOJ not an agency.

I refer you to the pleadings in the case and the recent motion filed by the Plaintiff that discusses the merits of the argument as to why DEA is an “agency” and should be held to statutory and regulatory requirements of any administrative agency.  The arguments in this case also highlight a longstanding frustration with obtaining FOIA information from the DEA.  In many cases, it appears DEA does not have the resources or infrastructure to maintain and produce the information to respond to FOIA requests as do other administrative agencies such as FDA.  DEA has always been somewhat unique in that arguably it is primarily a law enforcement agency that has been “burdened” with serving as an administrative agency tasked with regulating manufacturers, distributors, pharmacies and practitioners.

This case may have deeper ramifications on many of DEA’s administrative functions if there is a finding that DEA is not an agency.

More than a decade ago, FDA began systematically to incorporate review of human factors (HF) design validation within 510(k) reviews.  In 2016, the agency issued its definitive HF guidance to guide manufacturers through human factors engineering processes during the development of new medical devices, focusing specifically on the user interface.   All this time, FDA has applied the requirement for HF data to a subset of device types that pose the highest usability‑relate risks, e.g., software controlled devices, some hospital devices, and home use devices.  Accordingly, only a subset of 510(k) submissions have historically included HF validation data.

Now FDA has issued a draft guidance, Content of Human Factors Information in Medical Device Marketing Submissions (Dec. 9, 2022).  This guidance is intended as a complement to the earlier one, focusing on the type of HF data manufacturers should supply in a marketing submission.

In one way, this is good news.  The generation of HF data is a detailed and fairly burdensome process, although certainly short of a full-blown clinical study.  Furthermore, FDA’s HF reviews tend to generate a good percentage of the burdensome additional information (AI) requests in 510(k) reviews.  Many of these AI requests arise because of manufacturer unfamiliarity with the peculiarities in vocabulary and requirements current among FDA’s HF review staff.  And HF‑related AI requests are especially nerve‑racking to manage, because of the ever‑present threat that the study must be repeated to adequately respond.  Industry would certainly welcome guidance intended to smooth the HF aspects of 510(k) reviews.

But there is a very big fly in this ointment.  At least as currently drafted, it appears that the draft HF guidance dramatically expands the number of 510(k) submissions that require HF data.  The threshold is set extremely low:  if there is one “critical task” identified for a new or modified device, HF data must be addressed in some fashion.  (A “critical task” is a “user task which, if performed incorrectly or not performed at all, would or could cause serious harm to the patient or user, where harm is defined to include compromised medical care.”)

To put it another way, according to the draft guidance, the only valid justification for not including human factors data for a new device is that there are no critical tasks.  In the past, FDA made relatively specific determinations as to the HF data requirements (or lack thereof) for various types of device.  This approach is one-size-fits-all.  It will dramatically increases the burden and uncertainty associated with every submission across many device types.

If a single critical task is identified, then human factors validation must be included, regardless of whether such testing was required for the identified predicate.

If the submission is for a modified device which involves a new critical task or which impacts an existing critical task, then a human factors engineering report is required even if usability data were not required for clearance of the original unmodified device/predicate.

The only exception for a modified device is when there were no changes to: the user interface; intended device users; intended device uses; intended use environment(s); training or labeling.  Even in those cases, a high-level summary of the HF evaluation must be included.  FDA could challenge a company’s rationale for concluding that a change did not impact “human factors considerations” and thereby request HF data.  Once again, the uncertainty associated with the submission process will increase.

The draft guidance is at odds with the fundamental purpose of the 510(k) program, to enable an efficient risk-based process for FDA review and clearance of low to moderate risk devices.  A fundamental tenet of the program is that the same testing required for the predicate is generally required for the subject device.  Typically, only changes in technological characteristics from the predicate require use of test methods not required for the predicate.

Consider this scenario:

• A manufacturer files a 510(k) for a Class II device, a surgical mask.
• The subject device is identical to the predicate in all respects.
• Both devices have a single critical task (they must be correctly fitted by the user).
• FDA did not require HF data as a basis for clearance of the predicate.
• The device-specific guidance for surgical masks does not require HF data Surgical Masks – Premarket Notification [510(k)] Submissions | FDA.
• Per this new HF draft guidance FDA would require the highest level, tier 3 HF usability data for 510(k) clearance of the new surgical mask.

As the example shows, this draft guidance departs from the long-standing approach and introduces a new requirement for HF testing, regardless of whether such testing was required for the predicate and regardless of whether alternative methods of addressing differences in technological characteristics are available and less burdensome.  The new policy needs to be justified on a cost/benefit basis, which has not been done, at least as far as can be discerned from the draft guidance.  For example, the agency has not offered how many 510(k) submissions currently require HF data, the adverse effects of not applying an HF requirement more widely, and how many submissions would now present HF validation data after the change goes into effect.

At least to our knowledge, it appears that currently a relatively focused subset of all 510(k)s currently require HF validation.  If so, implementation of the draft guidance will likely cause in dramatic increase in burden on applicants and FDA.  For example, there could be a significant increase in Q‑Subs in order to work out the HF validation protocol or ensure that the agency agrees that HF data is not required.  This issue will increase uncertainty in the 510(k) modification decision making process. For example, if a critical task is introduced or impacted does that trigger the need for a new 510(k)?

The draft guidance can be fixed by simply deferring to existing requirements as to when HF data are required (e.g., as a de novo special control or in a guidance document for a specific device type).  To justify an expansion of the 510(k) burden of this magnitude, FDA needs to provide a clear and detailed accounting of what the problem is, the cost of this change, and why it will improve safety without hindering the development of better devices.

FDA says the primary purpose of this draft guidance is to smooth 510(k) reviews by providing more granular information about how to address the requirement.  It seems like mission creep for FDA to go beyond this primary purpose to impose a dramatic expansion of the requirement.

In short, this draft guidance imposes a major policy change with far-reaching implications.  Simply saying that the approach is “risk-based” is not adequate justification.  The costs and uncertainty of this expansion to HF requirements are significant.  The countervailing need for the change, however, is not well‑documented.  FDA should be careful not to upset the balance inherent in the current 510(k) system, which is used to bring the majority of medical device to market.

Comments on the draft guidance are due on or about March 8, 2023.

Last October, President Joe Biden directed the Secretary of Health and Human Services (“HHS”) and the Attorney General to begin the administrative process of reviewing current marijuana scheduling under federal law.  Then, Congress passed and the President signed the Medical Marijuana and Cannabidiol Research Expansion Act into law in December.  Last month, the Food and Drug Administration (“FDA”) announced in a release that it would not conduct rulemaking that would allow cannabidiol (“CBD”) to be marketed in dietary supplements or conventional foods because “a new regulatory pathway for CBD is needed that balances individuals’ desire for access to CBD products with the regulatory oversight needed to manage risks.”  FDA Statement, FDA Concludes that Existing Regulatory Frameworks for Foods and Supplements are Not Appropriate for Cannabidiol, Will Work with Congress on a New Way Forward.

FDA Principal Deputy Commissioner Janet Woodcock, M.D. issued the release on January 26th stating that she had chaired an FDA “high-level internal working group to explore potential regulatory pathways for CBD products.”  Dr. Woodcock announced that a new regulatory pathway is needed, noting that FDA is prepared to work with Congress on the matter.  She also announced denial of three citizen petitions asking FDA to conduct rulemaking to allow CBD products marketed as dietary supplements.

The release explained that studies have suggested that CBD can potentially harm the liver and male reproductive system and can interact with certain medications.  Exposure to vulnerable populations including children and pregnant women is also a safety concern.

A new regulatory pathway, the statement opines, would provide safeguards and oversight, managing and minimizing risks related to CBD products.  But what would an adequate regulatory pathway require?  What safeguards would it employ?  The statement explains that risk management tools could include clear labeling, prevention of contaminants, CBD content limits, and age restrictions to mitigate the risk of ingestion by children.  A new pathway could also provide access and oversight for animal CBD-containing products.

FDA’s current food and dietary supplement authorities provide limited tools for managing the risks associated with CBD products.  Under current law, the statement warns, any substance, including CBD, must meet specific safety standards to be lawfully marketed as a dietary supplement or food additive.

The working group reviewed studies related to CBD-based Epidiolex, published scientific literature, information submitted to a public docket, and studies conducted and commissioned by FDA.  The working group determined it is not apparent how CBD in dietary supplements and foods could meet safety standards because FDA has “not found adequate evidence to determine how much CBD can be consumed, and for how long, before causing harm.”

The release further noted that CBD also poses risks to animals and humans who could unknowingly be exposed to CBD by consuming meat, milk, and eggs from animals that ingest CBD.  For that reason, FDA also does not intend to pursue rulemaking that would allow CBD in animal food because it is not apparent how CBD products could meet the safety standards for animal food.  As with CBD in dietary supplements and human food, a new regulatory pathway could provide access and oversight for CBD-containing animal products.

The release warned that FDA would continue to take enforcement action, in coordination with state regulators, to protect the public against CBD and other cannabis-derived products.  FDA promised to remain diligent in monitoring the marketplace, identifying products that pose risks and acting within its authorities.  The statement observed that FDA looks forward to working with Congress to develop a cross-agency strategy to regulate CBD-containing products to protect public health and safety.

Meanwhile, dietary supplements and foods containing CBD continue to be marketed and consumed.  Key among questions raised by the release are:

1. What will the new regulatory pathway look like?
2. How will FDA work with Congress on CBD in dietary supplements and foods?
3. Will Congressional Democrats and Republicans work together on these issues or will such efforts be hindered by partisan deadlock?
4. How long will it take to agree upon and establish an acceptable regulatory pathway?

Inquiring minds are waiting.

GoodRx is a digital health platform familiar to many, and a prime example of a single player that operates in several different realms of the evolving and growing digital health marketplace. Among its services are prescription drug discounts, telehealth visits, and other health services.

The Federal Trade Commission (FTC) and its partners at DOJ’s Consumer Protection Branch recently filed a civil complaint against GoodRx for data privacy breaches. The case includes a proposed order that may sharply narrow the company’s ability to traffic in consumer data, often a key part of any digital health company’s business model.

This case was the latest example of government regulators punishing a company that refused to live up to its promises of consumer data protection. It’s also the first enforcement action under the 14-year-old FTC Health Breach Notification Rule. That Rule requires data companies to notify consumers and regulators of unauthorized disclosures of consumers’ personal health information. Unauthorized disclosures can occur either through external hacks or, as we see here, as part of a digital health company’s own internal policies.

FTC and DOJ have for years developed cases under the legal theory that lax data privacy policies amount to unfair and deceptive acts and practices and thus are violations of the FTC Act. Companies holding sensitive data must act as both the Key Masters and the Gate Keepers. Here, the FTC and DOJ allege that GoodRx committed the same sin as many other tech firms before it: the company promised users that their data was safe and inviolate, but according to the complaint, it was not.

GoodRx is alleged to have shared ostensibly protected personal health information with other tech companies, used the data for ad targeting, allowed third-party use of the data, used a HIPAA seal on its site that misrepresented its compliance status, and failed to put other policies in place to protect the data. That’s a good list of the kinds of things that most consumers really do not want their digital medical services provider to do with their sensitive personal information.

The proposed order that resolves the case may take away some of GoodRx’s tools of profitability. It permanently bans the company from trafficking-in patient data on several fronts. These measures include a prohibition on sharing health data for ads, requiring user consent to share data, and implementing a privacy program that a lot of its users probably thought it already had in place.

Perhaps these terms are severe to GoodRx, but the civil penalty was noticeably small compared to other FTC data privacy cases. GoodRx has an estimated market capitalization of over $2 billion dollars. The penalty of $1.5 million is, well, not a lot. Other notable data privacy cases that weren’t first of their kind or that did not include sensitive personal health information include, among many others, Facebook ($90m, $725m and $5b), YouTube ($170m), Capital One ($190m), and Twitter ($150m).

Through our FDA-focused lens, we see a possible roadmap as FDA’s Center for Devices and Radiological Health (CDRH) increases its resources, guidances, and enforcement emphases in the connected digital device space. It may be that cases like this one may affect future FDA data cases.

FDA is building its Digital Health Center of Excellence (DHCE). The catalogue of resources, guidances, and other regulatory materials for the DHCE is growing, as we have noted in prior blog posts. Cybersecurity for connected devices is of key importance to DCHE, as medical devices connected to apps and other portals to the internet offer hackers potential openings to exploit. And, like GoodRx, they may also offer device companies potential profitability through the sharing of valuable data. It’s not a huge leap to imagine a case where hackers get through a connected device’s cybersecurity shields. That kind of event probably triggers the Health Breach Notification Rule, and a civil action against the victim company for poor data privacy practices may not be far behind. And as we see with GoodRx, intentional sharing of data that is advertised as protected may trigger enforcement as well.

But the connected device space must also beware of FDA enforcement under the same scenarios of either voluntary or involuntary breach, and device makers can’t just try to empty their minds and wish for seemingly harmless outcomes that would be, in fact, terrifying. The new Section 3305 of FDORA adds a prohibited Act to Section 331 of the FDCA that relates to this. Failure to comply with new cybersecurity requirements is now a violation that applies to devices that include software, can connect to the internet, and may be vulnerable to cybersecurity threats. Device makers that do not monitor, update, and generally guard against post-market cybersecurity vulnerabilities seemingly face a dual threat of FTC and now, FDA enforcement action, all taken through DOJ.

FDA enforcement might take any number of forms, from a simple inspection, to Form 483, to Warning Letter, to consent decree. But whatever an FDA action might look like, we know that FTC, FDA, and DOJ will view a compromised device as a potentially unsafe device. In one form or another, exposure of consumer patient data may very well have significant regulatory consequences, where the agency streams may all cross to push violators back into a more compliant dimension.

See you on the other side.

Hyman, Phelps & McNamara (“HPM”) Director Larry Houck will present “Prescribing Red Flags, Corresponding Responsibility and DEA Investigations: What’s a Pharmacist To Do?” at this year’s American Pharmacists Association’s (“APhA’s”) Annual Meeting in Phoenix, March 24-27.  Mr. Houck was a diversion investigator with the Drug Enforcement Administration (“DEA”) in the field and at agency headquarters for 15 years before joining HPM in 2001.  Mr. Houck’s session will address pharmacists’ corresponding responsibility to identify and resolve controlled substance prescribing red flags and how to prepare for and manage DEA inspections.

The session will occur Friday, March 24th.  Pharmacists can earn 1 continuing practice education credit for attending this session.

Some of the additional APhA meeting sessions will include:

• Patient counseling
• Veterinary Basics for Community Pharmacists
• The ABCs of 340B
• Federal Regulation Affecting the Practice of Nuclear Pharmacy
• Pharmacy’s Impact on Disparities in Research
• Pharmacists and Patient-Centered Diabetes Care
• Updates in Alzheimer’s Disease
• Unique Patient Case Studies
• Taking the Sick Out of Sickle Cell Disease
• 2023 Immunization Update

Further meeting information, including registration, can be found here.

On February 15, 2023, the Nonprescription Drugs Advisory Committee (NDAC) and the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) held a joint meeting to discuss an application pending before FDA that would switch Narcan (naloxone) Nasal Spray from prescription to over-the-counter (OTC) status.  All 19 members of the joint Advisory Committee agreed that the benefit-risk profile of Narcan Nasal Spray (NNS) is “supportive of its use as a nonprescription opioid overdose reversal agent.”  While this outcome is non-binding, an Advisory Committee’s recommendation—particularly a unanimous recommendation from a joint Advisory Committee meeting—does hold significant weight with FDA.

Background

FDA has faced mounting pressure in recent years to take meaningful action in response to the ongoing opioid crisis.  For the 12-month period ending September 2022, over 100,000 drug overdose deaths were reported.  In August 2022, FDA announced the creation of the Overdose Prevention Framework with the vision to “undertake impactful, creative actions to prevent drug overdoses and reduce deaths.”  We previously blogged on FDA’s September 2022 guidance exempting and excluding specific naloxone transactions (e.g., sales of naloxone from a wholesale distributor to a harm reduction program) from certain requirements under the Drug Supply Chain Security Act.  The Framework also includes an action to support the goal of encouraging harm reduction as expanding availability and access to overdose reversal products, including naloxone, by supporting accelerated product review and “exploring over-the-counter access.”

Many states already have standing orders that allow for the dispensing of naloxone without an individual prescription and other public health initiatives to increase naloxone access.  For example, here in the District of Columbia, residents can access naloxone (free of charge with no identification requirements) at designated pharmacies throughout the District or have naloxone shipped to their address.  While laypeople are already using NNS in a number of states, FDA has cautioned that the current community use differs from OTC use because many of these programs provide patient counseling and instructions for use that go beyond what is included in the current NNS labeling.

The scope of the standing orders varies significantly state-by-state and both harm reduction experts and FDA agree that the prescription status for naloxone continues to pose a barrier to wider access.  However, FDA cannot unilaterally switch a product from prescription to OTC status.  A sponsor must submit a new application or efficacy supplement to an existing application for an Rx-to-OTC switch that includes both efficacy and safety data demonstrating that the drug is safe to use in the nonprescription setting, as well as data that demonstrate consumers can use the drug safely and effectively without the supervision of a healthcare professional.

With the Rx-to-OTC switch objective in mind, FDA took the “unprecedented” step of developing and testing a model drug facts label (DFL) for OTC naloxone and published a label comprehension study and model DFLs for naloxone administered via nasal spray and auto-injector in 2019.  In November 2022, FDA published a preliminary assessment that certain types of naloxone products (nasal spray up to 4 mg, autoinjector up to 2 mg) “may be approvable as safe and effective for nonprescription use.”  Essentially, FDA already prepared a sample DFL and made the preliminary determination that there are sufficient safety and efficacy data to support an Rx-to-OTC switch, but still needed product-specific data on the nonprescription user interface design, including packaging and labeling, to make a conclusive determination.

February 2023 Advisory Committee for NNS Rx-to-OTC Switch

Narcan Nasal Spray was originally approved by FDA in November 2015 (NDA 208411).  In September 2022, the sponsor, Emergent BioSolutions, submitted an efficacy supplement for a full Rx-to-OTC switch of NNS which was the subject of this week’s joint Advisory Committee meeting.  To support their application, the sponsor conducted a human factors validation study (HFVS) designed to verify that participants from all representative user groups could use the proposed DFL to appropriately administer NNS in a simulated overdose setting.  Other than the product-specific administration directions in Step 2, the sponsor’s proposed DFL is adopted verbatim from the FDA model DFL.  The primary endpoints of the HFVS were to evaluate if participants could successfully perform the following product-specific dosing tasks using only the proposed DFL as guidance:

Step 2: Give 1st dose of Narcan OTC Nasal Spray

1. HOLD the Narcan OTC Nasal Spray with your thumb on the bottom of the plunger
2. INSERT the tip of the nozzle into either NOSTRIL
3. PRESS the plunger firmly to give the 1st

The HFVS enrolled a total of 71 participants with an age range of 15-76.  The study results exceeded the pre-defined performance thresholds for Steps 2a and 2b.  Five participants did not adequately demonstrate Step 2c and the lower limit of the 95% confidence interval fell just short of the target, but with an observed proportion of 94.4% of participants with acceptable performance of this step.  As a result of the HFVS, the sponsor changed the layout of the carton panels, and increased the font size, color, and background of the text above the pictograms.

As discussed extensively in the briefing materials and presentation, the sponsor conducted the HFVS without requesting comment and guidance from FDA regarding the methodology or protocol.  FDA flagged five study limitations for the Advisory Committee’s consideration:

1. The HFVS did not include participants in the 10-14 age group.
2. Two user groups did not include at least 30% limited literacy participants.
3. Participants were allowed to review the DFL and packaging for an “unlimited” period which is not representative of a high-risk scenario.
4. Moderators encouraged participants to “think aloud” which is also not reflective of an actual use scenario and may have influenced participant behavior/performance.
5. The “mock” carton labeling tested in the HFVS differs from the intend-to-market carton labeling.

The inclusion of the first limitation was particularly interesting given that FDA’s own label comprehension study also did not include the 10-14 age group.  FDA explained that their Institutional Review Board objected to including children under 15 because participating in response to a simulated overdose situation would potentially be “traumatic” to younger children.  However, as noted by NDAC member Dr. Walker-Harding, seeing a loved one die from an overdose and not being able to do anything is not just potentially traumatic to younger children, but is an unfortunate reality in the current opioid crisis.  Younger children will, tragically, be in situations where they may be the only person available to administer naloxone.

The joint Advisory Committee didn’t disagree that there were certain limitations to the methodology of the HFVS and that the DFL and packaging could be better designed and some members offered suggestions for consideration in making improvements (e.g., including a QR code that links to additional training).  In fact, the DFL and packaging has been redesigned, but the redesign has not been studied in another HFVS.  However, in reaching their unanimous decision, committee members emphasized that (1) naloxone is effective in treating opioid overdoses, (2) there are extensive data that demonstrate naloxone is safe, even when administered in the absence of opioids (i.e., mistakenly administered to a patient who is not experiencing an overdose), and (3) an Rx-to-OTC switch for NNS will save lives.  Several committee members noted that the urgency in increasing access to naloxone—a drug with a well established safety and efficacy profile—is far more significant than perfecting the label.

What’s next?

As noted, the Advisory Committee’s recommendation is important, but is not determinative of FDA’s ultimate decision of whether or not to approve Emergent’s application for an Rx-to-OTC switch.  After completing its review of the application, FDA will approve the drug or may issue a complete response letter outlining the deficiencies that preclude approval.  As was briefly discussed during the Advisory Committee meeting, FDA has no statutory or regulatory mechanism to impose a postmarketing requirement on NNS in this particular context.  FDA could not, for example, approve the NNS Rx-to-OTC switch and also require that the sponsor conduct a new HFVS with the updated DFL and packaging.  The Prescription Drug User Fee Act (PDUFA) goal date by which a decision is expected is March 29, 2023.

FDA is also reviewing an application for OTC naloxone under the trade name RiVive submitted by Harm Reduction Therapeutics last year.  Harm Reduction Therapeutics’ application differs slightly in that it is a new application for a direct-to-OTC approval, rather than an Rx-to-OTC switch of an existing approved application.  The joint NDAC and AADPAC will meet again on March 20 to discuss RiVive and the PDUFA date for that application is April 28, 2023.  FDA could theoretically act on Emergent’s application at any time—before or after the Advisory Committee meets to discuss RiVive.

Sections of the radiological health regulations have been updated with the goal of lessening regulatory burdens. The regulations contain many requirements that are over 30 years old. These regulations apply to radiation emitting products, including not just medical devices but all other radiation emitting products as well.  Thus, these regulations apply to a huge variety of products.

FDA is making these updates in part due to recognition that some of the records and reporting requirements are unnecessary to comply with the Electronic Product Radiation Control (EPRC) program (sections 532, 534(a)(1), and 537(b) of the FD&C Act (21 U.S.C. 360ii, 360kk(a)(1), and 360nn(b))). FDA also noted that some of the recommended protections are outdated and redundant to Federal and State requirements, such as professional guidelines, current radiation guidance documents and industry standards that practitioners and industry rely on to ensure public health and safety.

By amending and repealing certain parts of the regulation, FDA believes that compliance to standards adequately protect public health and provide a reasonable assurance of safety and effectiveness when appropriately used by trained personnel.  Further, radiation emitting products are used in limited circumstances, such as to answer a clinical question or guide disease treatment. It is expected that, during these instances, patient risk from radiation exposure can be mitigated and minimized.

The amendments were announced in the Federal Register last month (here).  As anyone who has submitted a laser report knows, the regulations are not always clear.  It appears that some of the changes may enhance clarity and simplicity while others are more administrative in nature.

One of the most notable changes is that 21 C.F.R. § 1002.1 has been modified so that manufacturers of diagnostic x-ray products no longer need to submit initial (§ 1002.10), supplemental (§§ 1002.11), abbreviated (§ 1002.12) and annual reports (§ 1002.13).  This means that manufacturers of diagnostic x-ray systems no longer need to submit an accession number when importing products.  This should come as a relief to diagnostic x-ray manufacturers which have had to comply with both the device regulatory requirements of submitting 510(k)s, complying with the quality system regulation, and filing MDRs, among other things, as well as the radiation emitting product regulations.

The final rule will be effective February 21, 2023.  This is an ideal time for FDA to make these changes as annual reporting for radiation emitting products are not due until September 1.  Manufacturers, therefore, have ample time to familiarize themselves with the changes.