The first anniversary is always special.  Janus-like, it offers the opportunity to simultaneously reflect on hitting a milestone and projecting the future.  The first anniversary can also prompt a taking of stock: how well did the first year go?

Recently, the over-the-counter (OTC) hearing aid rule, which went into effect on October 17, 2022, celebrated its first anniversary.  The rule established a new category of OTC hearing aids for individuals with mild to moderate hearing loss, allowing them to purchase hearing aids directly from stores or online retailers without the need for a medical examination, prescription, or fitting adjustment by an audiologist.

When FDA released the final rule, it outlined its ambitious goals.  The Agency stated that the rule was “designed to assure the safety and effectiveness of OTC hearing aids, while fostering innovation and competition in the hearing aid technology marketplace.”  The rule also aimed to provide “consumers with perceived mild to moderate hearing loss with improved access to devices that meet their needs and are less expensive than current options.”  There was widespread agreement among stakeholders that utilization of hearing aids by people with hearing loss was far too low, although there was substantial disagreement as to causes for the underutilization.  Proponents of OTC hearing aids had long claimed that these products would sharply reduce price, expand options, reduce barriers to purchase, and thereby increase usage.  One year later the question begging to be answered is: have these goals been met?

For those who are unfamiliar with the rule, let us briefly explore its history across three different administrations (see our previous blogs: here, here, and here).  The journey began in October 2015 when the President’s Council of Advisors on Science and Technology (PCAST) during the Obama Administration recommended the creation of a class of hearing aids for OTC sale.  Following this, in June 2016, the National Academies of Sciences, Engineering, and Medicine (NASEM) made a similar recommendation of creating a new category of OTC “wearable hearing devices.”  Under the Trump Administration, Congress directed FDA to establish a new category of OTC hearing aids in the FDA Reauthorization Act and publish proposed OTC hearing aid rules by August 2020.  However, FDA missed that deadline.  Almost a year later, in July 2021 President Biden issued an Executive Order mandating publication.  FDA issued a proposed rule in 2021 and the final rule in August 2022, culminating a seven-year effort involving three Administrations, Congress, FDA, and various stakeholders.  That rule went into effect on October 17, 2022, leading us to this blog post about the one-year anniversary.

In some measurable ways, the rule has been a success.  Access has expanded.  Over the past year, many retailers—including some very large ones—started offering OTC hearing aids in their stores or on their websites, and some are available at audiology clinics.  And the number of companies selling OTC hearing aids is impressive: as of this blog post, 54 companies list OTC hearing aids with FDA under the product code QUF while 18 companies list OTC self-fitting hearing aids under the product code QUH.  However, estimating the number of entirely new OTC hearing aids spurred by the rule over the past year is not straightforward given that many of these OTC devices were previously accessible as “direct-to-consumer” (DTC) devices without FDA oversight.  Nevertheless, the presence of over 70 companies currently listing OTC hearing aids with FDA signifies a positive trajectory for further improving accessibility, at least for this first year.

By one measure, affordability has improved.  There are now more cheap OTC hearing aids available.  Price has been seen as a barrier for some consumers.  (By law, Medicare is barred from paying for hearing aids.)  As expressed in the NASEM report, and the price of hearing aids has often been cited as a deterrent to their purchase.  At the 67^th International EUHA Congress in October in Nuremberg, Germany, Hearing Industries Association (HIA) reported a wide price range for OTC hearing aids, spanning from $89.97 to $5,500.00.  Such a wide price range has allowed for more customers to dive into the market, but the technological differences between lower and higher cost products are often confusing, leading to questions about the distinction between the higher and lower end devices—and even more questions about whether the higher priced devices are worth the premium or whether the low cost products really work.  And the lack of third party coverage is still a problem such that OTC hearing aids—at least for higher priced versions—may still be unaffordable for many potential customers.

As far as we know, there are no definitive data on the volume of OTC sales.  According to HIA, OTC hearing aid sales are estimated from 100,000 to one million units.  It is unknown how many of these sales are ones that would not have occurred but for the existence of OTC products.  Reportedly, buyers of OTC hearing aids tend to be younger and seek a simple process without appointments or prescriptions.  Notably, some hearing aid companies have partnered with consumer brands (e.g., GN and Jabra, Nuheara and HP, WSAudiology and Sony, Sonova and Sennheiser), and, because these consumers frequently prefer purchasing from recognized brands, these brands apparently have had some traction.

Nevertheless, it’s not quite clear how well these OTC hearing aids are working.  Anecdotal data suggests that some OTC devices sufficiently meet the hearing aid fitting algorithm targets—called the NAL-N2 targets—which aim to make speech intelligible and overall loudness comfortable; some, however, reportedly do not.  The New York Times recently pointed out a considerable range of quality among OTC hearing aids that are currently on the market.  This poses a problem because if bad quality products fail to satisfy the user, the user might assume that OTC devices do not work and give up entirely, rather than trying another device or hearing care program.  (Data have shown that once dissatisfied consumers stow away their hearing aids, it can take years before they try buying a new set.)  This is reflected by return rates: One publicly traded company reports a sales return rate of 34 to 36% and notes that unsatisfactory fit and insufficient audio amplification are the most commonly cited reasons for product returns.  Further public information reveals sales with returns of more than 30% for OTC devices.  According to HIA, OTC buyers receiving some assistance from a hearing care professional or from customer service representations may have higher rates of satisfaction and lower returns to the company than those buyers who receive no assistance at all, suggesting that a hybrid OTC model is working for some customers.  This is not entirely a surprise, since people who were skeptical of the pure OTC model said that, unlike with eyeglasses, use of hearing aids was a process that required some professional help.

One of the ostensible advantages of the implementation of OTC hearing aid rules is FDA oversight.  “DTC” hearing aids had become notorious for exaggerated claims and misleading statements.  Even with the advent of OTC hearing aids and FDA oversight, however, there are still concerns about bad actors making unsubstantiated claims, engaging in misleading advertising, and failing to conform to FDA regulations.  Examples of misleading advertising include claims of “Restore Your Natural Hearing” or recommending an OTC hearing aid for those who “Suffer from mild to severe hearing loss.”  Given that OTC hearing aids are only for mild or moderate hearing loss and cannot “restore” natural hearing, this kind of claim is plainly impermissible.  And then there is a personal favorite: using “CIA technology” for invisible hearing aids.  Most of the time, these bad actors are not registered with FDA.

Previously, we emphasized that the success of OTC hearing aids is contingent on robust FDA enforcement, but despite this abundance of improper claims, FDA has yet to take public enforcement action to address bad actors within the hearing aid industry.  To its credit, FDA did post notices on its website including information about OTC hearing aids for both companies and consumers, but it is doubtful that these kinds of statements on an FDA website will have much effect on bad actors.  This absence of public enforcement, such as warning letters, may only serve to embolden these companies. Strengthened enforcement is crucial to protect the public health and facilitate the success of OTC hearing aids.  Bogus claims for OTC hearing aids will hurt consumers and may lead to public skepticism that OTC hearing aids are useful products.

The one-year anniversary is a good point for reflection, but it is also early to assess the ultimate success of OTC hearing aids.  Yet the milestone should not pass without recognition, and it provides a great opportunity for objective evaluation.  It seems that results thus far have been mixed: we may have made some progress, but there’s still a ways to go.  It does seem likely that without FDA intervention, bad claims will proliferate, devaluing the entire OTC hearing aid market.

There is one other point worth making.  Proponents of OTC hearing aids had long predicted that the adoption of the model would almost instantly lead to a blossoming of high-quality, low-cost hearing aids and a dramatic uptick in utilization.  It seemed simple: allowing consumers to by-pass costly hearing professionals would save money, make sales more “frictionless,” and lead to much greater product use.  While the advent of OTC hearing aids has had an impact, those lofty goals have not been met, at least yet.  As FDA embarks upon much more far-reaching and consequential rulemaking, such as the complete overhaul of regulation of laboratory developed tests, it is important to keep in mind that marketplaces are complex and messy, and the Law of Unintended Consequences should never be ignored.

“Human sacrifice! Dogs and cats living together! Mass hysteria!”  At least that’s this blogger’s reaction to the recent news that FTC sent out Notice letters to 10 different drug companies about the patent information they list in the Orange Book.  It’s so exciting that we might actually have an answer to some lingering questions about listability!  Maybe I’m overreacting, but it’s been almost 20 years since industry first asked FDA if it could list device patents in the Orange Book, and FTC’s intervention here is the closest thing we’ve seen to an answer to that question.  This is only by implication though: FTC did not provide an explanation as to why it thinks the patents listed are improperly listed—at least in the Notice letters made publicly available.  While I’m not a patent lawyer, these patents appear to be mostly device patents, which signals that FTC not only thinks REMS patent-listings are anti-competitive, but it also thinks device patents are.  My rudimentary and cursory review of some of these patents (NB: I’m not a patent lawyer) suggest that they aren’t all device component patents but are patents that cover entire devices in some cases.

As FTC explains in a Press Release, the Agency “challenged more than 100 patents” that it believes are improperly or inaccurately listed in the Orange Book.  Using FDA’s process for such disputes, codified at 21 C.F.R. § 314.53(f)(1), FTC notified FDA that it disputes “the accuracy or relevance of patent information submitted to . . . and published by FDA.”  As part of that requirement, FTC must have described the specific grounds for disagreement for each patent, which FDA will send to the NDA holder.  The NDA holder then must confirm the correctness of the patent and sign a verification of accuracy, or the NDA holder must amend the patent information within 30 days of FDA’s dissemination of the statement of dispute.  So ultimately whether the patent is delisted is up to the applicant, and we should know more in about 30 days, but it’s really not the effect of the activity that’s so notable—it’s that it happened at all.

As we have recounted a number of times, most recently here, FDA has been reluctant to comment on the types of patents that should be listed in the Orange Book.  FDA has asked for comments and published a report, but really nothing has come of that other than repeated requests from industry for guidance in this space.  As noted, the statute says that only drug formulation, composition, or method of use patents are listable, but FDA has said that patents that claim finished dosage forms, which can include “metered aerosols, capsules, metered sprays, gels, and pre-filled drug delivery systems,” should be listed in the Orange Book, suggesting that a patent that claims both the drug substance and the delivery device must be listed.  But whether a patent that only claims a device constituent of a combination product has been unclear.  And there have been no signs that FDA is planning to opine on that issue.

So instead of FDA getting involved, FTC has taken a vested interest and issued a Policy Statement lamenting the anticompetitive listing of patents in the Orange Book.  But FTC failed to explain exactly what type of patents are anticompetitive, leaving the industry waiting with bated breath to find out what exactly FTC would do, to whom, and for what—and of course whether FTC would actually do anything or leave it to FDA, who has statutory authority over the List (AKA the Orange Book).

Well, what FTC apparently did was review hundreds of patents in the Orange Book and utilize FDA’s regulatory processes.  But there’s no telling what the implicated manufacturers will do, because again, it is legally unclear whether the listing of the device patents is actually anticompetitive.  And this is the first inkling we have about the government’s position.  And we still haven’t heard anything substantive from FDA.

It also is notable that FTC reserved the right to take further action, including under Section 5 of the FTC Act, which suggests that FTC is ready to take further enforcement action against companies that don’t de-list.  Indeed, that one line in the Notice letters FTC sent may end up being really critical if companies don’t willingly de-list.  But if FTC takes this further, it’s going to be interesting from a legal perspective to see how this will be handled given that neither FTC nor FDA has given a clear answer about whether device patents are listable in the Orange Book.  Requests for delisting likely don’t count as Notice and Comment…

Anyway, it’s going to be some time before there’s any movement here.  The companies who received the Notices will need some time to assess, and FTC will need time to review the resulting activity.  But, given how quickly FTC moved after issuing its Policy Statement, it seems like there’s a big appetite for this issue at FTC.  I’m guessing that FTC is going to continue to cross FDA’s streams, and that really raises the risk of gooey marshmallow everywhere.

We were preparing this blogpost about FDA’s draft guidance on “Remote Interactive Evaluations” when we learned something.  A phone call to FDA requested information about the number of Remote Interactive Evaluations (RIEs) that FDA has performed at drug manufacturing facilities since it announced in April 2021 that it would start using them as an alternative to on-site inspections.  In response, we learned that only about seven – and certainly less than 10 – RIEs for manufacturing compliance have been performed at drug facilities in the last 30 months.  This stands in stark contrast to FDA on-site drug manufacturing inspections, which have resumed in the wake of the easing of COVID-related restrictions, totaling more than 1,800 during the same period.  To accomplish so few RIEs, especially when on-site inspections dropped off dramatically about three and a half years ago, is certainly a missed opportunity, in our view.  The number of RIEs also stands in stark contrast to the number of RIEs – more than 100 – that the Bioresearch Monitoring (BiMo) Program has performed.  Admittedly, BiMo inspections (into items like adequacy of bioequivalence data, consistency of clinical trial data with medical records, and compliance with clinical trial protocols) lend themselves better to an RIE than assessing manufacturing compliance with regulatory requirements.

Not having much more to say about the paucity of the use of this alternative method of reviewing a manufacturing site’s regulatory compliance, let us turn to the recent draft guidance about RIEs.  Compared with the COVID-centered version of the document released in April 2021, there is very little that is new or different.

We should explain what RIEs are.  Early in the COVID epidemic, many other regulatory agencies worldwide – but not FDA – launched virtual inspections (also referred to as “remote inspections”) of drug and medical device manufacturing facilities when COVID restricted travel and on-site inspections.  FDA, late to the game, published a guidance about its substitute for virtual inspections, making clear it doesn’t want to call RIEs “inspections,” for reasons that are somewhat obscure but are discussed in the guidances.  Significantly, FDA agrees that the RIEs may be conducted in lieu of an inspection.

Under the new guidance, many of the same conditions apply as under the one that was issued 30 months ago:

• The guidance notes that requests for documents under the governing statutes and virtual inspections (inspectors are in a remote location, and tour the facility using equipment that can furnish an audio and video feed, with the inspectors directing where the video camera should venture and asking the questions) are both considered “Remote Regulatory Assessments.”
• The guidance states that FDA does “not intend to accept requests from applicants or facilities for FDA to perform a remote interactive evaluation,” because decisions to perform an RIE “depend on many factors and information not always known to applicants or facilities, and it would be unduly burdensome on all parties to establish a request-based program.” Raising the question: how does FDA define “all parties?”  Many of our clients wouldn’t consider it a burden to request an RIE to try to resolve a Warning Letter, an Import Alert, or a suspension of review of a new drug application because an earlier inspection resulted in a manufacturing facility being classified as Official Action Indicated.  Contrariwise, FDA states in the draft guidance that RIEs may be used to “rank or prioritize a facility for an inspection, particularly a surveillance CGMP inspection.”  This implies that FDA may engage with companies on a more frequent basis than the standard (although unobserved, in practice) 2-year cycle.
• FDA specifically states that RIEs may be utilized to conduct Preapproval Inspections, which are conducted at manufacturing facilities prior to approval of a new drug application.
• RIEs will require the facility to accommodate the “use of teleconference, livestream video, and screen sharing of data and documents.”
• The guidance applies to facilities manufacturing human drugs, biologics, and veterinary medications, and to clinical trial sites for drugs.
• Responses to written observations made as a result of an RIE will not be made in a Form 483 (issued at the conclusion of about half of FDA’s on-site drug inspections), but facilities are still “encouraged” to file responses within 15 business days.

What was added in the new draft guidance?

• Facilities where FDA requests that an RIE be performed will need to consent, in writing, to the performance of the RIE (the earlier guidance did not require consent in writing). It is unclear what would happen if the facility refuses: probably, a refusal would be foolhardy, for a number of reasons. The current and earlier guidances note that declining an RIE may delay regulatory decisions, such as approvals of applications for marketing authorization.  Likewise, a refusal to permit an RIE may well trigger an on-site inspection.  The answer to which type of inspection industry would prefer is probably self-evident.
• Comments on the guidance are invited. In contrast, the April 2021 guidance noted that it was being “implemented immediately,” without “public participation” in the drafting of a final guidance.

WASHINGTON, DC — Hyman, Phelps & McNamara, P.C. is pleased to announce it took top honors in two categories in the 2023 LMG Life Sciences Awards, which recognize the best life science practitioners and firms over the past 12 months from the United States, Canada, and Europe.

Hyman Phelps & McNamara received the following honors:

• Tier 1 FDA: Pharmaceutical
• Tier 1 FDA: Medical Device

Additionally, eight professionals are included in LMG’s coverage:  Robert A. Dormer (Hall of Fame), Jeffrey N. Gibbs (Hall of Fame), John A. Gilbert, Gail H. Javitt, Kurt R. Karst, Alan M. Kirschenbaum, Frank J. Sasinowski, and Josephine M. Torrente.

“While our attorneys don’t do this work for the recognition, it is gratifying to see their excellent work recognized.  The LMG awards are reflective of HPM’s excellence across several of our core life sciences practices, from controlled substances work to drug development, to Hatch-Waxman, to drug pricing, to medical device regulation. That combined depth and breadth of experience is why clients come to us.  The excellent work of these and other professionals at HPM is why we’ve maintained a high level of client service for 43 years,” said JP Ellison, HPM’s managing director.

The LMG Life Sciences awards are based on case evidence and feedback from clients and peers and selected by the editors to provide attorneys and law firms with information on the legal market and the U.S. life sciences industry. Research for the guide was based on 1,000s of interviews and surveys completed by law firm partners active in the market.

About Hyman, Phelps & McNamara

Hyman, Phelps & McNamara, P.C. is the largest dedicated food and drug law firm in the country. Niche practices in new drug development, controlled substances, advertising, and health care law complement our core FDA practice. Our knowledge of the laws and regulations governing drugs, medical devices, foods, dietary supplements, and cosmetics is unparalleled in breadth and depth. Due to our broad bench of expertise, the firm is well equipped to defend companies against government enforcement actions and advise clients on necessary compliance efforts. The firm’s clients are as diverse as the regulatory issues they face. They range from individuals and start-up companies with no in-house legal staff to large multinational corporations. In addition, other law firms retain HPM to provide targeted expertise in food and drug law to assist their clients. HPM works to avoid legal problems when possible, and to help solve them when necessary. The firm helps companies conduct business as efficiently and profitably as possible by providing advice and counsel on meeting current and future regulatory requirements.

Contact:

Jeff Grizzel, Chief Marketing Officer

Hyman, Phelps & McNamara, P.C.

700 13th Street, N.W., Suite 1200

Washington, DC 20005

(202) 999-0302 cell

(202) 800-6116 direct

jgrizzel@hpm.com

The 14th Asia Pacific Symposium on Cochlear Implant and Related Sciences is poised to captivate the global scientific community from November 8-11, 2023, as it convenes in Seoul, Korea.  This prestigious four-day conference promises to deliver a wealth of cutting-edge insights, featuring presentations by eminent scientists and clinicians, all unified under the thought-provoking theme, “Towards Better Speech Perception and Beyond.”

A standout highlight of the symposium is the anticipated presentation by Dr. Philip Won, of Hyman, Phelps & McNamara, P.C.  Dr. Won will share his expertise and insights on the intricacies of the United States Food and Drug Administration (FDA) regulations pertaining to medical devices, with a special focus on class II and class III hearing devices.  Notably, Dr. Won’s career path included a tenure at FDA’s Center for Devices and Radiological Health (CDRH), Division of Dental and ENT Devices within the Office of Product Evaluation and Quality.  During this time, he deftly led multi-disciplinary teams, comprised of engineers, scientists, and clinicians, in the review of intricate submissions that left an indelible mark on the industry.

Beyond his regulatory acumen, Dr. Won is an accomplished author, boasting a portfolio of more than 40 peer-reviewed journal articles, spanning various aspects of hearing devices (see his Google Scholar page). His unique background underscores his remarkable expertise as a cochlear implant researcher, a former FDA regulator, and his current role as a device attorney.  During his presentation at the symposium, Dr. Won will share invaluable insights into effective regulatory strategies that empower companies to navigate the intricate FDA approval process for cochlear implants.

The comprehensive agenda for the symposium can be accessed in its entirety here.

On October 20, 2023, FDA announced the availability of the final guidance authored by CBER titled “Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies.”  It finalized a draft guidance published in 2022.  Although fairly short and light on substance, it has the potential to reshape the industry in ways that are sorely needed.

In short, Voluntary Consensus Standards (VCS) are intended to be exactly what the name conveys – standards that are adopted by consensus and are not mandatory (not legal or regulatory requirements).  These standards would be developed outside the Federal government, leveraging the expertise of the private sector.  This program is modeled after a similar program in place for medical devices, the formal standards and conformity assessment program (S-CAP).  In the device world, the benefits of voluntary consensus standards are two-fold: (1) sponsors are able to refer to standards for protocol design, generating a potentially massive time saving in development, and (2) if a sponsor provides a study report that conforms to a consensus standard, FDA does not need to spend time reviewing the details of the protocol and can focus reviewer resources on the results and their meaning for an application.  The hope with this new program is that it can similarly benefit the development and review of regenerative medicine therapies.  It is not especially novel even within CBER, as previous publications had encouraged the use of standards in product development.  However, in creating a standards recognition program (the “standards recognition program for regenerative medicine therapies”, or “SRP-RMT”), this guidance has the potential to get regenerative medicine to a place where it has struggled to reach: standardization.

We have heard clients and other stakeholders repeatedly express frustration with the absence of standards in regenerative medicine.  We are also aware that FDA spends a tremendous amount of time and resources answering the same questions for sponsors.  For example, CBER’s Office of Therapeutic Products (and its predecessor the Office of Tissues and Advanced Therapies) has held six Town Hall meetings in the past 13 months (by our count) on the following topics: gene therapy CMC, cell therapy CMC, clinical development of gene therapy products for rare diseases, gene therapy CMC (again), cell therapy CMC (again), and nonclinical assessment of cell and gene therapy products.  These meetings have a question-and-answer format to provide clarity to sponsors about the particular topics at hand.  The Town Hall meetings are initial steps toward both standardization and efficiency that the new program seeks to advance.

FDA needs assurances regarding the safety, purity, and potency of regenerative medicine products to approve them.  Because this is a relatively new field that has exploded in recent years in terms of the diversity of medical products, there are a lot of unanswered questions as to how this can be demonstrated.  A considerable roadblock in the development of RMT products is a lack of regulatory predictability. Voluntary consensus standards will not design the measuring tools, but they will help companies validate these tools and define acceptable results.  While on the surface this may not seem like major advance for the field, this could be a game changer for the gene therapy space.  While the diseases and conditions being investigated are very diverse, the treatments, delivery systems, and measuring tools have a high degree of overlap across this entire sector.  The implementation of voluntary consensus standards to methodologies that assess potency or safety could yield a profound acceleration in new treatments.

The absence of standards was a focal point of the Cellular, Tissue and Gene Therapies Advisory Committee Meeting in September 2021 that was convened to discuss the toxicity risks of AAV vector-based gene therapy products.  The minutes from that meeting reflect the discussion on that topic well in a wide variety of areas:

• Regarding the merits and limitations of animal studies to characterize risks and recommendations on specific preclinical study design elements: “Current scientific gaps/limitations, emerging technologies for integration analysis, and the value of developing and standardizing methods were discussed.”
• Regarding the risk of oncogenesis: “Monitoring for signs of hepatocellular carcinogenicity could be done by adopting standard approaches.”
• Regarding screening for risk of liver injury: “Total and/or neutralizing antibody titers are screened in many clinical studies, but how such testing is performed, the cut-offs, and the acceptance criteria are all variables that may need standardization.”
• Regarding the risk of hepatotoxicity with high doses: “An arbitrary upper limit of the total vector genome dose or total capsid dose is not recommended, as it is hard to standardize vector measurements across studies or to determine if there is an appropriate upper limit…Assays for empty capsids need better standardization.”
• Regarding the risk of thrombotic microangiopathy with high doses: “One challenge for recommendation of an upper limit on vector dose per subject is the lack of reference standards, limiting the comparison of critical quality attributes across sponsors and/or products.”

And here we stand today, on the brink of potentially transformational change to the industries affected – in theory.  The new guidance notes that “[i]ncreased development and use of standards has the potential to contribute to regulatory predictability and facilitate the overall development of safe and effective [regenerative medicine therapy] products.”  The guidance describes the following as potentially being suitable for the VCS recognition program:

• Common rules, conditions, guidelines, or characteristics for products or related processes and production methods;
• Definition of terms; classification of components; delineation of procedures; specification of dimensions, materials, performance, designs, or operations; measurement of quality or quantity in describing materials, processes, products, systems, services, or practices; test methods and sampling procedures; formats for information and communication exchange; or descriptions of fit and measurements of size or strength;
• Terminology, symbols, packaging, marking or labeling requirements as they apply to a product, process or production method.

The guidance describes elements that would be required of VCS bodies for recognition of standards they adopt: openness (with meaningful opportunities to participate), balance (broad range of stakeholders), due process, an appeals process, and consensus.  Consensus does not require unanimity, but a general agreement.  The standards would, as stated previously, be voluntary, unless mandated by statute or regulation, and they cannot conflict with existing law or regulation.

Existing published VCS may be identified internally by FDA or externally by stakeholders.  CBER would receive a candidate VCS from FDA staff or external stakeholders (the guidance includes a specific email address for this purpose), determine within 180 days (as resources permit) whether to recognize it in whole or in part, and then list recognized standards on its website along with summaries for future use.

As previously stated, the novelty of this guidance and the SRP-RMT program is not the use of standards, but rather the publication of standards publicly acknowledged by FDA to be generally appropriate.  CBER may still request additional information when deemed appropriate, but the stated hope is that increased use of VCS can facilitate product development by reducing the need to develop unique methods for individual products and that they will typically reduce the amount of necessary documentation “and may reduce FDA review time.”

Only time will tell how successful this program will be, but there is certainly the potential for order to come to the field of regenerative medicine, where there is currently a frustrating amount of variability and uncertainty.  Perhaps even more encouraging is the fact that FDA is deferring to the expertise of the private sector that struggles intimately with this variability and uncertainty in their efforts to meet FDA’s standards and get regenerative medicine therapies to patients.  By collaborating with the private sector, the hope is that FDA can leverage the expertise that such close familiarity engenders and can provide sponsors with some level of clarity and consistency for their development programs.  Not only does this provide an opportunity for sponsors and other stakeholders to shape FDA policy and to provide leadership on crucial unanswered development questions, we can only hope it will deliver answers (or at least options) for sponsors dealing with these challenges where there are currently few certainties.

For more than three decades, FDA has claimed that the Federal Food, Drug, and Cosmetic Act (FD&C Act) gives the agency legal authority to regulate laboratory developed tests (LDTs) as medical devices (see our prior post here).  In this post, we summarize the purported basis for this claim as described in the proposed rule (PR) and assess the strength of potential legal challenges should a final rule be issued (see our prior posts on the proposed rule here and here).

Regulating LDTs: A Long and Winding Road

In what might sound to some like protesting too much, the PR invokes FDA’s longstanding assertion that IVDs “manufactured” by laboratories are medical devices and that clinical laboratories that develop tests are acting as manufacturers.  Indeed, FDA’s claim of jurisdiction is not new, nor is this the first time FDA has tried to regulate LDTs, directly, or indirectly. We recount a few milestones along the road here:

FDA’s Legal Basis for Regulating LDTs

Despite the Agency’s putative concerns with LDTs, it is far from clear that the Agency has legal authority to regulate these products. In fact, stakeholders have repeatedly challenged FDA’s assertions of authority in Citizen Petitions, public comments, and other forums.  FDA-supported legislative efforts to amend the FD&C Act to give FDA new regulatory authority over LDTs have failed to gain traction over successive sessions of Congress.

Anticipating such objections, the PR spends considerable ink rebutting potential arguments that the Agency lacks the legal authority to regulate LDTs.  Close followers of the LDT saga in recent years may notice that these rebuttals attempt to address several of the issues raised in a June 22, 2020 memo from the HHS General Counsel to the FDA Commissioner that questioned FDA’s authority to regulate LDTs and supported HHS’s (since rescinded) announcement that FDA would no longer require premarket review for LDTs absent notice-and-comment rulemaking.

FDA sets forth three main arguments in support of its jurisdiction:

1. IVD test systems are devices;
2. Test systems manufactured by laboratories are devices; and
3. FDA’s jurisdiction over IVDs manufactured by laboratories is not altered by the FD&C Act’s provisions related to “interstate commerce” and “commercial distribution.”

The PR first sets out to establish that it has authority to regulate in vitro diagnostic “test systems” as devices, and not just the system’s individual components, such as reagents, instruments, specimen collection devices, and software.  FDA supports its argument with what it calls a straightforward reading of section 201(h)(1) of the FD&C Act, as well as references to “test systems” in FDA regulation and legislative history dating back to the 1970s.

The PR goes on to state that the FD&C Act definition of a device does not turn on where or by whom a test system is “manufactured.”  FDA recognizes that the FD&C Act exempts licensed healthcare practitioners from certain device regulations if they manufacture devices solely for use in the course of their professional practice.  However, FDA states that this exemption does not apply to corporate or hospital laboratories that employ licensed practitioners, and the agency says FD&C Act otherwise contains no exception or limitation for devices manufactured by laboratories.

The PR states that LDTs are not the “practice of medicine,” with which FDA generally may not interfere.  Instead, FDA states that LDTs are the devices that are prescribed or administered as part of the practice of medicine, and FDA regulates the manufacture of devices such as LDTs.

Addressing the arguably preemptive effect of CLIA, the PR argues that CLIA neither expressly nor impliedly repealed FDA’s authority over IVDs manufactured by laboratories.  Rather, FDA describes CLIA as a complementary regulatory framework with an independent purpose and that does not address a wide range of activities regulated under the FD&C Act, such as clinical validation and design activities.

The PR takes on two specific statutory grounds raised by the June 22, 2020 HHS memo—the requirements for “interstate commercial” and “commercial distribution”—and argues that they are not impediments to FDA jurisdiction over LDTs.  Responding to the challenge that LDTs do not travel in interstate commerce because they are designed, manufactured, and used in a single laboratory, FDA points out that most of the “prohibited acts” in the FD&C Act applicable to devices do not contain “interstate commerce” elements and even those that do, like section 301(k), have been interpreted broadly by the courts to allow FDA jurisdiction over devices that have not been introduced in interstate commerce if the components used in manufacturing the product have traveled in interstate commerce.

FDA also notes some commentators’ argument that, if laboratories design, manufacture, and use an IVD in a single laboratory and do not introduce their IVD into interstate commerce, section 510(k) does not apply to such laboratories.  FDA asserts that such an argument does not lead to the conclusion that FDA lacks jurisdiction over LDTs, but it would simply mean that section 510(k) does not apply, and therefore the consequence would be that affected laboratories would be forced into the more rigorous review pathways (e.g., Premarket Approval or De Novo pathways).

Addressing the argument that LDTs are not introduced into “commercial distribution” because no physical test system is sold or distributed off-site to anyone,  FDA points to legislative history and (one solitary) judicial opinion in 1985 that interpreted “commercial distribution” broadly to mean “on the market,” which does not require the physical transfer of an object.

Conspicuously missing is any rebuttal to one other issue raised in the June 22, 2020 HHS memo: that laboratories based out of state universities or public health departments are not “persons” as defined in key premarket review and enforcement provisions of the FD&C Act.  If these provisions are not applicable to these laboratories, FDA may not have authority to require premarket review or bring enforcement action for LDTs manufactured by these entities.  Tellingly, the PR seeks comments on whether FDA should “continue the general enforcement discretion approach with respect to any requirements, such as premarket review requirements, for tests manufactured by [academic medical center] AMC laboratories” – suggesting FDA may not have resolved jurisdictional considerations over at least some AMC laboratories.

FDA’s position is, however, only one side of the story.  Counterarguments abound, many of which were detailed in 2015 in a publication by counsel for the American Clinical Laboratory Association (here).

Specific features of the PR will foreseeably yield new bases for challenge.  For example, FDA’s regulations have exempted from certain regulatory requirements (e.g., registration and listing and 510(k) premarket notification) healthcare practitioners who are “licensed by law to prescribe or administer a device” and who “manufacture[] that device … solely for use in the course of … professional practice.” But the PR now dramatically curtails that well-established exception: It claims that “corporate and hospital laboratories” are not eligible for this exemption because they employ, but are not themselves, licensed practitioners. In support for this position, FDA states that hospitals that reprocess single-use devices have been viewed as manufacturers and points to its own webpage for support.  This comparison is misplaced.  Unlike hospital reprocessing facilities, many clinical laboratories are overseen by laboratory directors who themselves are medical doctors.   Thus, the person ultimately responsible for laboratory operations (including development, validation, and performance of an LDT) will often be a licensed practitioner.  The PR, however, would exclude these laboratory directors, and the laboratories they oversee, from the longstanding licensed practitioner exemption, simply because they are employed by incorporated entities and/or hospital system (which, of course, can act only through their personnel.).

If finalized, the PR may also be subject to broader challenges.  In recent years, the Supreme Court repeatedly has invoked the “major questions” doctrine to invalidate agency efforts to regulate matters of substantial economic or political significance where Congress has not clearly vested the agency with authority to do so.  This increasingly robust line of cases can be traced back to the Supreme Court’s rejection of FDA’s last attempt to exert regulatory authority over an industry long considered to be outside its jurisdiction—its ill-fated effort to regulate tobacco products in the 1990’s despite Congress’s repeated rejection of legislation that would have empowered the Agency to do precisely that (See Brown & Williamson v. FDA). FDA’s attempt to exert jurisdiction over LDT’s certainly seems to fall within this line of cases.  The Agency itself has estimated that the PR could impose more than $100 billion dollars in one-time costs and up to $14 billion in annual recurring costs—demonstrating its substantial economic significance. Furthermore, as in the tobacco cases, Congress has not enacted legislation granting FDA express authority over LDTs, despite numerous opportunities to do so.

In response to past FDA efforts to regulate LDTs, some stakeholders publicly signaled their intent to sue the Agency.  No doubt the PR has sparked similar considerations, and we certainly expect an array of stakeholders to file suit and seek to stay the rule’s implementation if it is finalized.   Indeed, recent jurisdictional developments suggest that a wide of array of stakeholders could have standing to challenge the Agency’s attempt to restrict access to commonly used LDTs, including individual laboratories, hospitals, physicians and healthcare providers who routinely use these tests, and patients who depend on them. Even so, the entry of a stay pending final judgment may not be sufficient to immunize parties who rely on LDTs from the PR’s consequences. Given the time required to come into compliance with these burdensome new rules and the inherent risk that a court might uphold FDA’s new rules, many LDT users may be forced to begin preparing for regulation when a final rule is issued.

Bottom line – in the proposed rule, FDA asserts that it has clear regulatory authority over LDTs, but that’s not the full picture.  Only a court can adjudicate whether FDA’s authority under the FD&C Act extends to LDTs, and such adjudication cannot begin until a final rule is published.

The Drug Enforcement Administration (“DEA”) has issued its notice finalizing updates to its longstanding Special Surveillance List of chemicals and equipment used in the illicit manufacture of controlled substances and listed chemicals.  Special Surveillance List of Chemicals, Products, Materials and Equipment Used in the Manufacture of Controlled Substances and Listed Chemicals, 88 Fed. Reg. 73,044 (Oct. 24, 2023).  DEA’s notice of updates with the Special Surveillance List is attached here.

The Comprehensive Methamphetamine Control Act of 1996 (“MCA”) amended the Controlled Substances Act (“CSA”) and provides for the Attorney General to publish a Special Surveillance List of chemicals and other “laboratory supplies” used in the clandestine manufacture of controlled substances.  21 U.S.C. § 842(a).  A “laboratory supply,” is defined as “a listed chemical or any chemical, substance, or item on a special surveillance list published by the Attorney General, which contains chemicals, products, materials, or equipment used in the [illicit] manufacture of controlled substances and listed chemicals.”  21 U.S.C. § 842(a).

DEA published its Special Surveillance List on May 13, 1999 and has never revised it.  Special Surveillance List of Chemicals, Products, Materials and Equipment Used in the Clandestine Production of Controlled Substances or Listed Chemicals, 64 Fed. Reg. 25,910 (May 13, 1999).  Although the CSA does not require notice and comment for revisions of the Special Surveillance List, DEA provided notice and comment of the proposed changes in June.  Special Surveillance List of Chemicals, Products, Materials and Equipment Used in the Manufacture of Controlled Substances and Listed Chemicals, 88 Fed. Reg. 39,479 (June 16, 2023).   DEA’s notice of proposed updates is attached here.  Our blog post on the proposed updates is here.

The updated List, as with the original List, contains chemicals used in the manufacture of methamphetamine, PCP, and LSD, but now also includes those being used in the production of fentanyl, amphetamine, and other controlled substances and listed chemicals.  In addition to current List I and II chemicals, and the chemical mixtures and over-the-counter products and dietary supplements containing them, the updated Special Surveillance List includes 28 additional chemicals.  88 Fed. Reg. 73,045.  DEA also removed hypophosphorus acid and red phosphorus from the Special Surveillance List because as List I chemicals they are automatically included as laboratory supplies.  Id. at 73,045-46.  And while the Special Surveillance List has always included hydrogenators, tableting and encapsulating machines, and 22-liter heating mantels, DEA specifically added “tableting machines, including punches and dies.”  Id.

DEA received 29 comments to its proposed updates to the Special Surveillance List.  Commenters asserted that the proposed updates would further regulate the chemical industry by imposing “additional regulatory burdens on small businesses.”  Id. at 73,044.  DEA explained that the updates do not impose any new regulatory burden as they do not impose any recordkeeping or reporting requirements.  Id.  Commenters also objected to the addition of sodium borohydride, propiophenone and propionyl chloride to the List.  Id.  DEA replied that sodium borohydride and propionyl chloride can be used in the manufacture of fentanyl and fentanyl analogues, and propiophenone can be used in the manufacture of several schedule I substituted cathinones.  Id. at 73,045.

DEA noted that the Special Surveillance List informs about the potential illegal uses of the listed chemicals and other items.  It reminds that civil penalties of up to $250,000 (with inflation, now $470,640) may be imposed under 21 U.S.C. §§ 842(a)(11) and (c)(2)(C) on businesses who distribute or export a laboratory supply with reckless disregard for the illegal uses to which it will be put.  Id. at 73,044.

The updated Special Surveillance List became effective on October 24th, the day the notice was published in the Federal Register.

Just over two years ago, I wrote about the challenges with implementation of the contraceptive mandate in the Patient Protection and Affordable Care Act (ACA).  You will recall that, despite the ACA, a 2019 HRSA Guideline, and guidance from the federal agencies responsible for enforcing the contraceptive coverage requirement of the ACA (the Departments), women seeking contraceptives that were not specifically identified on an FDA Birth Control Guide were encountering roadblocks to accessing the contraceptive of their choice.

Since that blog post, an important step forward was the decoupling of the coverage requirement from the FDA Birth Control Guide in the guidance provided by the Department to plans and issuers.  This occurred in January 2022 when the Departments issued additional guidance, which discussed reports of denial of coverage in violation of the ACA requirement and provided a reminder to plans and issuers of their responsibilities under the statute and 2019 HRSA Guideline (FAQ Part 51, Q9).  Regarding the latter, the guidance made clear for the first time that “if an individual and their attending provider determine that a particular service or FDA-approved, cleared, or granted contraceptive product is medically appropriate for the individual (whether or not the item or service is identified in the current FDA Birth Control Guide), the plan or issuer must cover that service or product without cost sharing” (FAQ Part 51, Q9, emphasis added).  This guidance was based on stakeholder feedback that the current FDA Birth Control Guide may not identify all and/or newer contraceptive products approved, cleared, or granted by FDA.

Regarding the reports of noncompliance, the guidance provided examples, including denial of coverage for brand name contraceptives, even after the individual’s healthcare provider determines and communicates to the plan or issuer that a particular contraceptive product is medically necessary for that individual; requiring individuals to fail other numerous products within the same contraceptive method before approving coverage for the product that is medically necessary for the individual as determined by their healthcare provider; requiring individuals to fail products in other contraceptive methods before approving coverage for the product that was medically necessary for the individual as determined by their healthcare provider; and failing to provide an easily accessible, transparent, and sufficiently expedient except ion process that is not unduly burdensome.

In July 2022, the Departments issued further guidance in response to reports that individuals continued to experience difficulty in accessing contraceptive coverage without cost sharing.  With this guidance, the Departments decided to reference the 2019 HRSA Guideline rather than the FDA Birth Control Guide for the range of identified categories of contraception (FAQ Part 54, Q2), stating that plans and issuers must cover without cost sharing at least one form of contraception in each category.  The guidance also reiterated prior guidance that plans and issuers are required to “cover without cost sharing any contraceptive services and FDA-approved, cleared, or granted contraceptive products that an individual and their attending provider have determined to be medically appropriate for the individual, whether or not those services or products are specifically identified in the categories listed in the HRSA-Supported Guidelines, including contraceptive products more recently approved, cleared, or granted by FDA” (FAQ Part 54, Q2).

The Departments also reiterated that, while reasonable medical management techniques can be utilized to determine which specific products to cover without cost sharing, “[t]he plan or issuer must defer to the determination of the attending provider, and make available an easily accessible, transparent, and sufficiently expedient exceptions process that is not unduly burdensome so the individual or their provider (or other individual acting as the individual’s authorized representative) can obtain coverage for the medically necessary service or product without cost sharing” (FAQ Part 54, Q3).

While the Departments were updating their guidance, the House Committee on Oversight and Reform was investigating contraceptive coverage for individuals enrolled in private health plans by seeking information from five of the nation’s largest health insurers and four of the largest pharmacy benefit managers (PBMs) to assess how companies provided patients with access to FDA-approved birth control.  In October 2022, the Committee issued a report titled “Barriers to Birth Control: An Analysis of Contraceptive coverage and Costs for Patients with Private insurance,” which determined that:

• health plans and PBMs have coverage exclusions or cost-sharing requirements for at least 34 different contraceptive products;
• insurers and PBMs disproportionately impose cost-sharing or coverage exclusions for newer contraceptive products;
• many contraceptive products used by patients with distinct healthcare needs or disproportionately used by people with lower incomes are subject to cost-sharing or exclusions;
• health insurers and PBMs deny an average of at least 40% of exception requests with one denying up to almost 80% per year; and
• exceptions processes are inadequate.

The report recommend that Departments consider issuing further guidance to (1) clarify requirements regarding “appropriate medical management” for coverage of contraceptives, which could include providing guidance that “all FDA-approved contraceptive products that do not have a therapeutic equivalent should be covered without cost-sharing as part of every plan or formulary,” which would allow health plans and PBMs to use medical management techniques to prioritize the use of generic pharmaceuticals where possible, while ensuring that patients have access without cost-sharing to products that do not yet have a generic version; and (2) encourage exceptions processes that are automatic at the point of prescribing.

Shortly thereafter in December 2022, HRSA updated its Women’s Preventive Services Guidelines to make it more explicit that the full range of contraceptives  approved, granted, or cleared by FDA be available as part of contraceptive care.

Most recently, in June of this year, the Biden administration issued an Executive Order focused on protecting and expanding access to contraception.  Specifically, Section 2 of this executive order directs the Secretaries of the Treasury, Labor, and Health and Human Services (Secretaries) to

consider issuing guidance, consistent with applicable law, to further improve Americans’ ability to access contraception, without out-of-pocket expenses, under the Affordable Care Act.  In doing so, the Secretaries shall consider actions that would, to the greatest extent permitted by law:

• ensure coverage of comprehensive contraceptive care, including all contraceptives approved, granted, or cleared by the Food and Drug Administration, without cost sharing for enrollees, participants, and beneficiaries; and
• streamline the process for patients and healthcare providers to request coverage, without cost sharing, of medically necessary contraception.

While progress has been made in terms of the Departments’ guidance no longer depending on whether a product is identified in FDA’s Birth Control Guide, the new Executive Order makes it clear that the Biden administration believes that additional guidance is needed to ensure that full effect is given to the ACA contraceptive mandate.  It will be interesting to see what new tactics may be employed by the Departments to implement the Executive Order.

In our June blog post, we reported on FDA’s request for comments about its program to receive information from the public alleging misconduct by other companies.  FDA uses this program to help it identify risks and to determine whether further investigation is needed.  Because this program requires information collection from the public, the Paperwork Reduction Act (PRA) of 1995 (44 U.S.C. 3501) and its implementing regulations at 5 CFR 1320, requires federal agencies to minimize paperwork burden and ensure quality of information, amongst other objectives. On October 12, 2023, FDA published a notice reporting on several comments about its information collection activities under this program, and the changes FDA made to address those concerns.

One comment FDA received had noted that existing procedures do not allow for complete anonymity, specifically when requiring that attachments be sent via email. While changes have not been made to allow for attachments to the Allegations of Regulatory Misconduct Form, which would address this comment in part, FDA did acknowledge confidentiality as “an important concern” and cited that under the Freedom of Information Act (FOIA) (5 U.S.C. 552), there are exemptions from mandatory disclosure. While we would encourage providing contact information so that FDA may follow up, if need be, we appreciate the value of being able to submit information anonymously.

Another comment questioned FDA’s process to verify the accuracy and validity of the allegations. In response, FDA noted that it reviews allegations of regulatory misconduct and prioritizes taking action based on risk level, but did not address any specifics on how or whether it decides when to follow-up with subsequent questions about an allegation. We renew our comment from June that transparency on FDA’s activities in response to allegations would make the program much more meaningful to industry.

In response to comments on improving the submission form, FDA already has implemented a notable change by adding asterisks on the Allegations of Regulatory Misconduct Form, to identify the fields that are required (e.g. name and model of medical device and detailed description of the allegation with any supporting documentation) versus non-required. This will help streamline the submission for those complaints that may not have all the information to complete the fields. We also note that an assistant director for allegations has now been identified in the CDRH management directory. We hope to be surprised with more changes that result in transparency on the process and progress of all investigations FDA undertakes when reviewing allegations of regulatory misconduct.

Yesterday, FDA published a new Draft Guidance, “Communications from Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products Questions and Answers” (SIUU Guidance or Draft Guidance).  Previous iterations of this guidance from 2009 and 2014 (blogged on here and here) were known as Good Reprint Practices (GRP).  These guidances focused on the types of scientific publications (journal articles, reference texts, and in 2014, clinical practice guidelines) and necessary accompanying information that firms could proactively provide in a manner that would not, on its own, constitute evidence of a new intended use.  The SIUU Guidance, which supersedes the 2014 Draft GRP Guidance, is not substantially different in that regard and contains similar information as to the types of disclosures previously recommended.  However, there’s a clear shift in FDA’s approach that is noticeable from the title of the Draft Guidance, alone.

The SIUU Guidance introduces two new concepts that are of note to industry regarding information it may choose to disseminate under this “safe harbor:” 1) application to firm-generated presentations of scientific information; and 2) material that meets a new evidentiary standard – scientifically sound and clinically relevant.

Creation of a “Safe Harbor” for Firm-Generated Presentations of Scientific Information

FDA acknowledges that firms may develop presentations of scientific information from an accompanying reprint.  Firm-generated communications must meet the general recommendations in the Draft Guidance and “should be truthful, non-misleading, factual and unbiased and provide all information necessary for HCPs to interpret the strengths and weaknesses and validity and utility of the presented information . . .”  The presentation should be accompanied by the reprint and the reprint, itself, must meet the criteria articulated in the SIUU Guidance for reprints.  FDA recommends that firm-generated portions of an SIUU communication should use “plain language,” as despite having specialized training, “research indicates that HCPs may nonetheless have difficulty understanding some types of scientific information, including clinical trial data, and the design and methodological limitations of studies.”

Creation of a New Evidentiary Standard

FDA’s new standard, scientifically sound and clinically relevant, is a departure from its decades-long approach under GRP that articles about unapproved uses of approved products must describe adequate and well-controlled clinical investigations.  Throughout the SIUU Guidance, FDA refers to studies and analyses, suggesting that publications may cover more than a description of an adequate and well-controlled clinical trial.  FDA notes that real-world data and associated real-world evidence may be scientifically sound and clinically relevant depending on the circumstances.

Other Topics of Note

In addition to the two concepts above, FDA also discusses the use of dedicated vehicles, channels, and venues to distinguish SIUU communications from promotional communications to reduce the risk of HCPs confusing approved and unapproved use information.  FDA also addresses social media platforms, providing advice for firms seeking to communicate on platforms that may impose character-space limitations that would hinder a firm from including all recommended disclosures (hint:  keep the communication unbranded, linking out to a fully formed SIUU communication).

FDA repeatedly references that in creating the SIUU Guidance, it has sought to balance HCP interests in scientific information with mitigating the potential that government interests in motivating firms to comply with premarket requirements will be undermined.  While the information in the SIUU Guidance is a welcome departure from FDA’s more restrictive approaches under GRP, it may not go far enough.   For example, FDA’s references to firm-generated communications appear inextricably linked to an underlying reprint publication, which seems arbitrary, as firms can generate truthful and non-misleading information about studies and analyses that have not been published.  The SIUU Guidance may leave industry with the feeling that it still hasn’t found what it is looking for in terms of FDA’s attempts to strike the right balance.

As of October 1, 2023, all 510(k) submissions, unless exempted, must be submitted to FDA using the electronic Submission Template And Resource (eSTAR).  The same template can also be used for De Novo submissions.  Currently, eSTAR is voluntary for medical device De Novo submissions, but FDA has initiated the process of requiring De Novos to be submitted using eSTAR.  On September 29, 2023, FDA released a draft guidance on Electronic Submission Template for Medical Device De Novo Requests.

Recap of eSTAR

eSTAR is an interactive PDF form designed to assist users in creating a “complete” submission.  It includes questions, text, logic, and prompts, and integrates databases such as FDA product codes and FDA-recognized voluntary consensus standards.  It also presents specific questions to collect data from the submitter and provides links to relevant regulations and guidance documents.   For 510(k) and De Novo submissions, FDA’s eSTAR Program website offers two different types of eSTAR templates: Non-In Vitro Diagnostic devices and In Vitro Diagnostic devices.  There is also a third template for Pre-Submissions for Non-In Vitro and In Vitro Diagnostic devices.  Make sure you submit your application using the most up-to-date version of eSTAR, as FDA frequently updates eSTAR templates.  To learn more about our experience with the eSTAR for 510(k)s, check out our previous blogs (here, here).

Structure of the eSTAR for De Novos

The draft guidance provides a table that offers a high-level overview of the structure of the eSTAR for De Novos, including elements such as the cover letter, device description, proposed indications for use, classification, benefits, risks, mitigation measures, labeling, and supporting data.  These content elements precisely follow the De Novo request content described in 21 C.F.R. § 860.220, meaning that using eSTAR does not necessarily change the type and amount of information required in a De Novo submission.

Acceptance Review

eSTAR helps submitters prepare a “complete” 510(k) or De Novo submission.  The Refuse To Accept (RTA) process is an acceptance review of 510(k) submissions, aiming to assess whether a submission is administratively complete, and includes all the necessary information within 15 calendar days of FDA receiving a 510(k) submission.  One key benefit for the industry in using the eSTAR for 510(k)s is that 510(k) eSTAR submissions do not undergo an RTA process.  This is beneficial to industry because at times the RTA review is not purely administrative and crosses into substantive issues.  Note, however, that there is a virus scanning and technical screening process that will still happen.  During the technical review, FDA will check to ensure that the attachments to a question are relevant to the question and there are no inaccurate responses provided to any question.

In contrast, for De Novos, the equivalent of a 510(k) RTA review is an acceptance review of De Novos, codified in 21 C.F.R. § 860.230.  Unlike 510(k)s, using eSTAR for De Novos does not eliminate the acceptance review process, which must be conducted and completed within 15 calendar days of FDA receiving a De Novo request.  The draft guidance notes that “[i]f the eSTAR is not complete when submitted, FDA will notify the submitter via email and identify the incomplete information, and the De Novo will be placed on hold.”  This statement appears consistent with the technical review that is being done for the 510(k) eSTAR submissions.

Timeline

FDA notes that when this draft guidance is finalized, it will specify the corresponding timetable(s) for the implementation of De Novo electronic submissions.  The draft guidance indicates that this timetable will be announced by September 30, 2025.  There will be a transition period before requiring all De Novo requests to be submitted electronically.

We can gain insights into the potential timetable from the FDA’s process for eSTAR for 510(k) submissions.  In September 2021, FDA released a draft guidance on Electronic Submission Template for Medical Device 510(k) Submissions (see our blog).  As of October 1, 2023, approximately two years after the release of that draft guidance, all 510(k) submissions are now required to be submitted using eSTAR.  If FDA follows a similar timeline, it is possible that, in approximately two years, FDA may require that all De Novo submissions must be submitted using eSTAR.  For those with experience in using eSTAR for 510(k) submissions, we anticipate that the learning curve for eSTAR for De Novo submissions may not be as steep when FDA mandates that all De Novo submissions must be submitted using eSTAR.  But, for those who do not have any experience with eSTAR, the learning curve may be more significant.

Medicine cabinet, stuffed to the gills
Capsules, liquid, patches, and pills
Expired oxy, hydro, benzos, and more
All kind of meds flowing out the door

We will, we will, clear you
We will, we will, clear you

Were the Drug Enforcement Administration (“DEA”) a rock band, it might promote the upcoming National Prescription Drug Take Back Day by setting the lyrics above to a catchy tune.  DEA is not a band, but along with its law enforcement partners, the agency will host thousands of local drop-off locations nationwide for clearing out and proper disposal of expired and unneeded medication from medicine cabinets between 10:00 am to 2:00 p.m. local time on Saturday, October 28, 2023.

DEA has held Drug Take Back Days each spring and autumn since 2010.  The events have led to the removal of more than 17 million pounds of unwanted medication across the country.  Last April’s Drug Take Back Day alone removed 663,725 pounds (332 tons) of medication at almost 5,000 collection sites hosted by 4,500 law enforcement agencies.

Additional information about DEA’s National Prescription Drug Take Back Day, including local disposal locations, can be found here.

So, clear out that stuffed medicine cabinet.

Although it seems not widely known outside of the medical device industry, FDA can require sponsors to include clinical data as part of a 510(k) submission.  Such data may be needed to demonstrate substantial equivalence to a previously-marketed predicate device or, less frequently, to show that new or modified indications for use fall within the same intended use as the predicate device.

Despite previous efforts by FDA to shed light on this issue (see The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] (510(k) Program Guidance), sponsors still often find there is disagreement with FDA when it comes to determining if clinical data are needed, especially when the sponsor believes there is a reasonable justification that non-clinical data are sufficient to reach a substantial equivalence determination.

As part of a multipronged effort to strengthen and modernize the 510(k) program (see our recent blog post here), FDA recently issued a draft guidance, Recommendations for the Use of Clinical Data in Premarket Notification [510(k)] Submissions (Draft Guidance), describing situations in which clinical data may be necessary to demonstrate substantial equivalence in a 510(k) submission.  When necessary, data from clinical studies is submitted in addition to standard non-clinical data such as bench performance testing; sterilization and shelf-life testing; biocompatibility testing; animal studies; electrical, mechanical, and thermal safety testing; electromagnetic compatibility testing; software testing; and cybersecurity testing.

The 510(k) Program Guidance provides several scenarios that illustrate the most common situations in which clinical data may be needed to demonstrate substantial equivalence. The Draft Guidance provides additional context and clarity to these three scenarios and adds a new scenario in which clinical data may be needed.  The scenarios are intended “to provide broad considerations to be used by industry and FDA to help determine whether clinical data may be necessary to demonstrate that a new device is substantially equivalent to a predicate device.”

The four scenarios, described in the new Draft Guidance, in which clinical data may be needed in a 510(k) include:

1. There are differences between the indications for use of the new device and the predicate device;
2. There are differences between technological characteristics of the new device and the predicate device;
3. SE between the new device and the predicate device cannot be determined by non-clinical testing (analytical, bench, and/or animal); and
4. A newly identified or increased risk for the predicate device suggests clinical data may be needed for the new device.

The Draft Guidance provides specific examples illustrating the application of each scenario.  The examples include both diagnostic (including in vitro diagnostic) devices and therapeutic devices, since there are significant differences in the types of clinical data that may be needed for these two categories of devices.

While the first three scenarios, and the accompanying examples, seem fairly straightforward and reasonable, the newly-added fourth scenario is perplexing, as it describes a situation where clinical data may be needed for a new device even though no clinical data were needed for the predicate device. This situation is where most surprises arise as a sponsor reviews the 510(k) summary for the predicate device, sees that clinical data were not needed for clearance, and assumes that clinical data will not be needed for their similar device.

The Draft Guidance suggests not using predicate devices with newly identified risks but acknowledges that there may be some cases where there is not a more recently cleared predicate device that does not share the newly identified risk.  FDA’s examples for this scenario show a good faith attempt for a level playing field between new devices and existing devices by describing situations where new device submissions will require clinical data while the currently marketed devices with newly identified risks may be subject to postmarket surveillance studies or recalls with new submissions for modifications to the recalled device that include clinical data.  However, we can envision situations where clinical studies of the previously cleared devices with the new risk have not yet occurred and a sponsor with a new, similar device may be surprised at the need for clinical data.

Although there is some discussion in the examples that relates to whether the predicate device required clinical data for 510(k) clearance, we found that the Draft Guidance does not explicitly address the question of whether or not inclusion of clinical data in the predicate device 510(k) provides any bearing on whether clinical data will be needed for a new device.

The Draft Guidance also describes the types of data that may constitute clinical data supporting a 510(k), drawing on previous recommendations of the International Medical Device Regulators Forum  (see “Clinical Evidence – Key Definitions and Concepts”).  These include:  results of pre- and post-market clinical investigation(s) of the device (i.e., traditional clinical trials); results of pre- and post-market clinical investigation(s) or other studies reported in the scientific literature of a comparable device; published and/or unpublished reports on clinical experience of either the device in question or a comparable device; and other sources of clinical experience such as registries, adverse event databases, and medical records (e.g., electronic health records, claims).

When considering whether data from a comparable device can be used, the Draft Guidance indicates that “adequate justification regarding the applicability of such data should be provided demonstrating why such data would be representative of the new device.”  Given FDA’s current emphasis on data being collected on the final, finished device, it may be beneficial to use the pre-submission process to discuss the applicability of data collected with a comparable device with FDA to allow time for a new clinical study, if they do not agree that the justification is adequate.

Finally, it is not surprising that the Draft Guidance notes that there may be other scenarios not described where clinical data may be necessary and that the need for clinical data may also change as information on the device type is accrued.  We think that the Draft Guidance may prove helpful, especially in situations where the sponsor concludes that clinical data are necessary, at which time they can engage with FDA via the pre-submission process to discuss clinical study design.  However, sponsors should be cautious when review of the Draft Guidance suggests that clinical data are not necessary.  If there are differences in indications for use, novel technology, or the potential for differences in risk profile, a pre-submission may be warranted to confirm FDA agrees with the sponsor’s application of the scenario to the specific circumstances and the conclusion that no clinical data are needed to support substantial equivalence.

On September 15, 2023, FDA released a final guidance document titled “Breakthrough Devices Program.”  Compared to the previous version, the new guidance document highlights that the Breakthrough Devices Program may also be applicable to certain devices that benefit populations impacted by health and/or healthcare disparities and to certain non-addictive medical products to treat pain or addiction.  If you are developing such products, now may be the time to explore the opportunities presented by the Breakthrough Devices Program.

Background

The Breakthrough Devices Program, established under section 515B of the Federal Food, Drug, and Cosmetic Act (FD&C Act), is a voluntary program for certain medical devices and device-led combination products.  FDA previously released the final guidance document in December 2018 outlining the program’s principles, features, designation criteria, and other considerations.  The designation criteria, as defined in section 515B(b) of the FD&C Act, have remained unchanged and continue to govern the program for devices as follows:

(1) that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions; and

(2)(A) that represent breakthrough technologies;

(B) for which no approved or cleared alternatives exist;

(C) that offer significant advantages over existing approved or cleared alternatives, including the potential, compared to existing approved alternatives, to reduce or eliminate the need for hospitalization, improve patient quality of life, facilitate patients’ ability to manage their own care (such as through self-directed personal assistance), or establish long-term clinical efficiencies; or

(D) the availability of which is in the best interest of patients.

In October 2022, FDA released the draft guidance entitled “Select Updates for the Breakthrough Devices Program Guidance: Reducing Disparities in Health and Healthcare,” as previously discussed in our blog.  This 2022 draft guidance proposed that certain non-addictive medical products for pain or addiction treatment could be eligible for breakthrough designation, aligning with the Agency’s obligations under the Substance Use-Disorder Prevention That Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act.  Additionally, the 2022 draft guidance suggested the addition of a new section to the 2018 guidance on reducing disparities in health and healthcare.  The new guidance does not surprise us as the scope of the changes is limited to the select updates, but it is certainly exciting that FDA expands product areas for the Breakthrough Devices Program.

Non-Addictive Medical Products to Treat Pain or Addiction

The SUPPORT Act (Public Law 115-271) mandated that FDA issue a guidance document to provide information on how the Agency can apply section 515B of the FD&C Act to non-addictive medical products intended to treat pain or addiction.  As suggested in the 2022 draft guidance, FDA included a statement in the introduction section of the guidance, indicating that “the Breakthrough Devices Program may be available for certain non-addictive medical products to treat pain or addiction (FD&C Act section 515B (21 U.S.C. 360e-3)).”  Apart from this statement in the introduction section, the new guidance document does not offer any further guidance related to non-addictive medical products for pain or addiction treatment.  This may be because FDA has already been granting breakthrough designation to devices intended to treat pain (e.g., Wysa, see here) and addiction (e.g., reSET-O, see here, here).

The readers may be wondering what kind of devices would be able to leverage the new guidance to receive breakthrough designations.  Although not directly relevant, the FDA Innovation Challenge program called “Devices to Prevent and Treat Opioid Use Disorder” may provide you with an idea.  FDA launched this challenge in 2018 to foster the development of medical devices aimed at addressing the opioid crisis, preventing, and treating Opioid Use Disorder (OUD).  FDA selected and posted eight challenge participants, which included monitoring, OUD therapy, pain therapy, medication dispensing, overdose therapy, and diagnostic devices.  FDA notes “Breakthrough Device designation will be granted to those devices that meet the statutory criteria for designation without submission of a separate application.”  It appears that the devices selected for the challenge may align with the type of non-addictive medical products for pain or addiction treatment that the new breakthrough guidance targets.

Reducing Disparities in Health and Health Care

FDA introduced a new section in the guidance document focused on reducing disparities in health and healthcare.  In this section, FDA acknowledged that treatment outcomes might vary based on factors such as race, ethnicity, sex, age, disability, and others.  Consequently, FDA underscores the importance of considering “technologies and device features tailored to address characteristic differences” such as social factors, phenotypic variations, pathophysiology, and response to treatment when evaluating the first designation criterion.  This implies that if device technologies and features can produce a clinically meaningful impact for the treatment or diagnosis of a condition in certain populations, such data could support the case that the device satisfies the first designation criterion.

The new guidance also presents an opportunity for device manufacturers working for patient populations affected by rare life-threatening or irreversibly debilitating diseases or conditions, such as sickle cell disease.  FDA will consider if technologies and device features “address unmet needs in these populations” when evaluating criterion one.  In addition, criterion one can also apply to technologies and device features aimed at improving accessibility, defined as “an individual or group’s capacity to benefit from a medical device or procedure.”  FDA recognizes the existence of barriers that may hinder underserved populations from receiving medical treatment or diagnosis.  To address these barriers, FDA promotes the development of impactful devices that can enhance accessibility for patient populations with limited or no available options.  This might include “user features that are adaptable or more easily used by diverse populations or allow for use in more diverse settings.”  With improved accessibility, one can make the argument that there is a “reasonable expectation that the device may provide for more effective treatment or diagnosis as compared to the standard of care.”

Other Updates

With respect to the first part of the first criterion (i.e., whether a device provides for more effective treatment or diagnosis), FDA introduced a paragraph explaining that “[t]he level and type of evidence needed to determine whether a device is reasonably expected to “provide for 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.” (Emphasis added.)  While the reasonable expectation standard remains unchanged, FDA emphasizes that it will consider the totality of information regarding 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.

Remaining Questions

We perceive the new guidance as an expansion rather than a restriction of the types of products that may qualify for Breakthrough Device designation.  However, the new guidance does not address certain questions that the industry may encounter when seeking the breakthrough designation.

For example, it remains uncertain whether devices indicated for addiction or pain treatment would be considered to satisfy the second part of the first criterion (i.e., whether a disease or condition is life-threatening or irreversibly debilitating), regardless of the type or severity of the underlying diseases or conditions causing pain.  Furthermore, the new guidance does not provide any indication of the level of evidence necessary to demonstrate that a candidate device can contribute to reducing disparities in health and healthcare.  There may also be questions about the level of evidence required to demonstrate that a device can address characteristic differences arising from social factors, phenotypic variations, pathophysiology, and/or response to treatment.  Although the new guidance does not explicitly state that clinical data is a mandatory requirement for a breakthrough application, it is our experience that a review division typically expects to review some level of clinical evidence to assess the reasonable expectation of clinical success.

If FDA’s evidentiary expectations are set too high, it could undermine the intent of the new guidance.  FDA has stated that it “considers the totality of available information regarding the device, including its potential for a clinically meaningful impact and its potential benefits and risks.”  We hope that “the totality of available information” that could meet FDA’s expectations will not impose an excessive burden on companies seeking breakthrough designations.