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  It finalized a draft guidance published in 2022.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.

The Wall Street Journal (WSJ) recently published a series of articles as part of its special report “What’s Ahead for Artificial Intelligence.” Three of these articles focus on medical applications of Artificial Intelligence and Machine Learning (AI/ML) and explore FDA’s role in regulating such products.

• The first article—“Is the Eye the Window to Alzheimer’s?”—discusses several approaches that companies are exploring for use of AI in the diagnosis of Alzheimer’s Disease, including AI-enabled software for retinal scans and identification of genetic triggers.
• In the second article—“Why AI is Medicine’s Biggest Moment Since Antibiotics”—Dr. Lloyd Minor, Dean of the Stanford University School of Medicine discusses both the potential promise of increasing use of AI in healthcare settings (e.g., increased access to care in rural areas) and its potential risks (e.g., demographic bias of data fed to algorithms).
• The third article—“Your Medical Devices are Getting Smarter. Can the FDA Keep them Safe”—focuses on FDA’s role in regulating clinical applications of AI/ML technologies and the impact of FDA’s regulatory requirements on the type of products developers choose to bring to market and how quickly they can be improved once there. In particular, the article discusses FDA’s April 2023 draft guidance on pre-determined change control plans (which we previously blogged on here) and whether such plans afford sufficient flexibility for AI/ML developers to innovate and improve products based on new data while also providing sufficient guardrails to ensure patient safety.

Meanwhile, FDA’s AI/ML-focused initiatives continue to expand.  On October 11, 2023 FDA announced the establishment of a new Advisory Committee on Digital Health Technologies that is tasked with, among other responsibilities, helping the Agency navigate complex scientific and technical issues related to AI/ML-enabled devices. Just a day earlier, FDA’s Center for Devices and Radiological Health (CDRH) released a list of the guidance documents the Center intends to publish in the upcoming 2024 fiscal year. Among these are plans to finalize FDA’s guidance on predetermined change control plans for AI/ML-enabled devices and a draft guidance on lifecycle management considerations and premarket submission recommendations for such devices.

With more than 500 devices currently on FDA’s list of cleared AI/ML-enabled devices, these initiatives signal FDA’s recognition that these devices will continue to play a significant and increasing role in the delivery of healthcare in the years to come. We will continue to monitor ongoing developments in this field and are available to assist product developers with their development and regulatory strategies.

For years, submitting a Suitability Petition has been like screaming into a void: You’d be lucky if FDA ever responds.  This has been a big problem because FDA’s inattentiveness can delay entry of certain types of ANDAs for years—often resulting in the ANDA applicant’s abandonment of the Suitability Petition.  Industry has been asking for Suitability Petition reform for years, either by FDA or mandated by Congress, but, other than a few rejected bills, such requests have basically gone nowhere.

Taking a step back, a Suitability Petition is used when an ANDA applicant wants to submit an ANDA that differs from its Reference Listed Drug in strength, dosage form, route of administration, or, in the case of a combination drug, active ingredient.  Under 21 C.F.R. § 314.93, an applicant that wants to submit such an ANDA “must first obtain permission from FDA to submit such an ANDA.”  Such an ANDA therefore can be submitted only upon the submission and approval of a special Citizen Petition, called a Suitability Petition.  Technically, FDA is supposed to review and approve Suitability Petitions within 90 days, but the reality is that it can take years for FDA to respond—if the Agency ever responds at all.

FDA now has committed under GDUFA III to actually reviewing Suitability Petitions.  Like with other types of Reviews, FDA will assign a “goal date” to any Suitability Petition submitted after October 2, 2023.  FDA has contacted applicants with pending Suitability Petitions to confirm continued interest in a response and invited those Petitioners to resubmit Petitions after October 2, 2023 to be assigned a goal date.  For context, before GDUFA III, FDA received 20-30 Suitability Petitions per year and had approximately 170 pending as of July 2021.  To address this backlog and any forthcoming Suitability Petitions, FDA’s GDUFA III commitment letter states that the Agency will review 50% of Suitability Petitions—up to 50 Suitability Petitions—within 6 months after a 21 day completeness review in FY 2024; 70%, or up to 70 Suitability Petitions, in FY 2025; 80%, up to 80 Suitability Petitions, in FY 2026; and 90%, or up to 90 Suitability Petitions, in FY 2027.  Priority is given to Suitability Petitions that could mitigate or resolve a drug shortage; address a public health emergency declared by HHS; mitigate waste by way of new strengths for parenteral products; or subject to special review under the President’s Emergency Plan for Aids Relief.  If FDA misses goal dates, it will prioritize review of those Suitability Petitions with missed goal dates prior to reviewing newly-submitted Suitability Petitions.

In late September 2023, presumably in light of the upcoming goal date assignments, FDA revised MAPP 5240.5 covering ANDA Suitability Petitions.  In the newly-revised MAPP, FDA fully integrates its GDUFA III commitments, including the goal date commitments and the priority list.  FDA also commits to conducting completeness assessments of all submitted Suitability Petitions within 21 days or issue an Information Request as necessary.  All in all, goal dates will be approximately 7 months after submission, or 6 months after completeness assessment.  But we’ll have to wait quite a few years until almost all Suitability Petitions are reviewed within their assigned goal date period.

The MAPP itself adds little new that’s interesting for industry (assuming you’ve read the GDUFA III Commitment Letter), but it reflects that FDA now may be taking seriously its commitment to reforming the Suitability Petition process.  Such a change is welcome, as it not only accelerates and facilitates competition, but it should greatly reduce industry frustration.  It’s too early to tell what kind of traction this effort will get and if FDA will be able to meet its commitments, but it’s promising that FDA has, for the first time, made an actual commitment to trying.  Those of us that have submitted Suitability Petitions after October 2 are waiting with bated breath for FDA’s completeness review and assignment of a Goal Date and to see whether FDA can meet its targets.

On September 18, 2023, FDA published an updated, final iteration of guidance for immediate implementation entitled, “Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions Due to Disasters and Public Health Emergencies.”  This final guidance replaces and supersedes the March 2020 guidance entitled, “Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency.”  The new guidance is meant to expand the earlier’s scope to emergencies outside of the COVID-19 pandemic including but not limited to disasters and public health emergencies such as hurricanes, earthquakes, military conflicts, infectious disease outbreaks, or bioterrorist attacks.

In general, both of these guidances provide recommendations for sponsors to consider and analyze when a disaster (e.g., hurricane) or public health emergency (e.g., pandemic) strikes, causing a major disruption to the conduct of a clinical trial.  For example, a disaster or public health emergency may lead to clinical trial disruptions via population quarantines, travel restrictions, various interruptions to the supply chain, and other logistical issues.  The recommendations provided by the final guidance, and largely included in its previous iteration, center around ensuring the safety of the clinical trial subjects, maintaining adherence with good clinical practice, and limiting the risk to the integrity of the clinical trial (i.e., protecting the clinical trial’s goal of continuing to produce valid data to support eventual regulatory decision-making).

The final guidance largely subsumes the COVID-19-specific guidance with a handful of updates.  First, as previously discussed, FDA broadened the ambit of the final guidance to apply to disasters and public health emergencies generally.  The other major changes come in the appendix which provides a series of questions and answers, including the removal or update of outdated questions (i.e., those specifically related to the COVID-19 public health emergency).  In addition, the final guidance clarifies and expounds upon its previous recommendations, including several potential logistical concerns (e.g., shipment of and charging for investigational product) and a risk-based evaluation for monitoring clinical trial sites and subjects.

While it makes sense for FDA to apply its learnings and considerations to other public health emergencies beyond COVID-19, the shift in focus comes at a time when many medical product programs are still reeling from the effects of the pandemic on their previous or even still-ongoing clinical trials.  Trials that were adapting (or not) in real time due to the emergent nature of the pandemic experienced real, lasting COVID-19 disruptions affecting everything from adherence to study protocols, impacts confounding safety and efficacy evaluation to different degrees at different periods, and less-than-ideal fixes to ongoing protocols and statistical analysis plans in an attempt to protect participants and study personnel.  In our experience, these programs are the ones that seem to be left behind, as FDA has been uncertain of how to handle the results from these COVID-19 era studies.

In the case of trials for orphan drugs, this is particularly concerning because there is often already difficulty in interpreting clinical trial results to establish effectiveness due to the common challenges inherent in rare disease drug development.  Layering on COVID-19 impacts, and the added uncertainty they impart, many of those trials were deemed uninterpretable or negative conclusions of effectiveness were drawn.  This can be the death knell for some rare diseases, as over 95% do not have even a single FDA-approved therapy, so a failure of one program can result in a departure of investment interest by other companies.  While individual sponsors continue to discuss these COVID-19 impacts on orphan drugs in development with FDA, we hope that the Agency will consider the specific impacts on rare disease drug development in future public health emergencies.  There are already enough unique challenges these rare disease drug development programs face, and every patient that participates in clinical trials is precious, so we owe it to them to find a more holistic approach to salvaging clinical trials that are impacted by public health emergencies.

Hyman, Phelps & McNamara, P.C. (“HP&M”), the largest FDA-dedicated law firm, is pleased to announce that Julie Beitz, M.D. has joined the firm as a Principal Drug Regulatory Expert.

Dr. Beitz served in leadership positions in FDA’s Center for Drug Evaluation and Research for nearly three decades.  She is an oncologist/hematologist and at the time she retired from FDA on July 29, 2023, she was the Director of the CDER Office of Immunology and Inflammation (OII) in the Office of New Drugs (OND).

Dr. Beitz was selected by FDA to be the inaugural Director of OII in March 2020 as part of the CDER OND reorganization.  In this position, she had primary oversight for actions taken by the following review divisions:

• Division of Dermatology and Dentistry
• Division of Gastroenterology
• Division of Hepatology and Nutrition
• Division of Rheumatology and Transplant Medicine
• Division of Pulmonology, Allergy and Critical Care
• Division of Pharmacology/Toxicology – Immunology and Inflammation

Prior to the March 2020 creation of OII, Dr. Beitz for 14 years was Director of the Office of Drug Evaluation III (ODE 3) in OND where she oversaw the Division of Gastroenterology and Inborn Errors of Metabolism, the Division of Dermatology and Dental Products, and the Division of Bone, Reproductive and Urology Products.

Other key drug leadership positions that Dr. Beitz served in at FDA include Acting Deputy Director for Clinical Sciences of OND, Director of the Division of Drug Risk Evaluation in the Office of Surveillance and Epidemiology and Acting Deputy Director and Clinical Team Leader in the Division of Oncology Drug Products.

Dr. Beitz earned a Bachelor of Arts (summa cum laude and honors in chemistry) from Barnard College, Columbia University, and a Doctor of Medicine from the College of Physicians and Surgeons, Columbia University.  She completed her residency and a fellowship in medical oncology/hematology at Brown University, Roger Williams Medical Center, and Brown University Affiliated Hospitals.

As a Principal Drug Regulatory Expert, Dr. Beitz joins HP&M’s Drug Development Team, which is comprised of attorneys and regulatory experts who assist companies on a range of drug and biological product legal, regulatory, and policy issues.  Dr. Beitz will be joining fellow former FDA Office Director Dr. Ellis Unger who joined HP&M in February 2022.  “I know Dr. Beitz well from our days as Office Directors at FDA, and I am delighted she is joining Hyman Phelps & McNamara! She made major, and lasting, contributions to public health at FDA. I always found her to be immensely thoughtful, knowledgeable, and insightful, and I am confident our clients will appreciate her approach,” said Dr. Unger.

“HP&M has long respected Dr. Beitz and enjoyed a professional working relationship with her during her distinguished FDA career.  We are thrilled that she is joining the firm and will add her expertise to our already exceptional Drug Development Team,” said JP Ellison, HP&M’s Managing Director.

Drug development attorney Frank Sasinowski commented: “For 20 years I have brought therapies that were needed by patients before Dr. Beitz and her colleagues in OII and ODE 3 and for that long I have admired and respected her sound scientific judgment and regulatory acumen.  Consequently, you can imagine how honored I am that Dr. Beitz would join her former OND Office Director Dr. Ellis Unger and our long-established HP&M drug development regulatory team to assist sponsors and patients in collaboratively working with FDA to bring critical new therapies to those in need.”

As we recently blogged, FDA released three draft guidance documents to help enhance the predictability, consistency, and transparency of the 510(k) program.  One of these documents focuses on “Evidentiary Expectations for 510(k) Implant Devices.”  Implant devices are used in a range of settings such as dental and orthopedic procedures.  Having a clear understanding of FDA’s data expectations for 510(k) applications related to implants is crucial for successful marketing clearance.  In this blog post, we highlight the distinctive data expectations recommended for implant devices in the draft guidance.

Background

The draft guidance addresses the review considerations applicable to all implanted devices undergoing evaluation within the 510(k) program, referred to as “510(k) Implants” in the draft guidance.  Implants subject to premarket approval (PMA), those eligible for the De Novo classification process, or those exempt from the 510(k) requirements fall outside the scope of this draft guidance.  The objectives of the draft guidance are as follows:

• “Serve as a primary resource on expectations for all 510(k) implant devices, generally, while device-specific guidances provide further specificity for a given device type
• Assist industry in design and execution of appropriate performance testing to support 510(k) submissions for implant devices
• Provide recommendations for content and labeling to include in 510(k) submissions for implant devices, and
• Convey that the FDA considers the patient experience to be paramount in improving implant device safety, and encourages the collection, analysis, and integration of patient experience data for implants to support 510(k) submissions for those devices.”

General Considerations: What Makes Implants Unique Compared to Other Device Types?

Implant devices are unique because they are designed for continuous implantation for a period of 30 days or more, as per 21 C.F.R. § 860.3.  This distinct use scenario, combined with new features of such devices, may increase the risks compared to other device types or predicate devices.  For instance, FDA highlights risks associated with everyday activities (e.g., airport security screening), or surgical procedures, as well as the potential for reoperation or revision of the implant.

FDA recommends that applicants of 510(k) devices that are intended to be implanted for fewer than 30 days also consider the recommendations outlined in the draft guidance.

Performance data should be customized to the indications for use, including the specific intended patient population (adult vs. pediatric), disease state, conditions of use, and the target anatomical location.  In the case of 510(k) Implants indicated for use in pediatric patients, FDA recommends consulting two other guidance documents: Pediatrics Guidance and Extrapolation Guidance.

The intended duration of implantation is another crucial factor in performance testing.  Testing should be in line with the device’s intended duration of implantation, but FDA may consider whether testing results for a shorter duration can be extrapolated to provide information about long-term performance.  In cases where devices are expected to be frequently replaced, testing should be guided by the aggregate patient exposure.  Safety and effectiveness evaluations should encompass wear and degradation, taking into account the worst-case implantation conditions.

Non-Clinical Recommendations

The draft guidance highlights non-clinical review areas that are generally relevant across 510(k) Implants and offers recommendations for performance data to include in a 510(k) submission.  It is important to note that the type and amount of performance data required may vary based on the device, device type, and differences from the predicate device.  If a submitter believes that certain testing described in the draft guidance does not apply to their device, they should provide a rationale in the 510(k) submission.

The draft guidance provides an overview of various standard testing areas such as biocompatibility, sterility and shelf life, reprocessing and cleaning, software and cybersecurity, electrical safety and electromagnetic compatibility (EMC), and magnetic resonance (MR) compatibility.  Information about these typical non-clinical tests is generally based on previously released guidance documents for each topic, as linked above.

The draft guidance places emphasis on specific tests, such as acute systematic toxicity and material-mediated pyrogenicity for biocompatibility, pyrogenicity testing for sterility, and the applicability of ISO 14708 for the EMC of certain active implantable medical devices.  For example, the draft guidance outlines a minimum five endpoints for biocompatibility testing (cytotoxicity, sensitization, irritation or intracutaneous reactivity, acute systemic toxicity, and material-mediated pyrogenicity) that should be assessed for 510(k) Implants, plus eight additional endpoints for biocompatibility (e.g., subacute/subchronic toxicity, genotoxicity, implantation, hemocompatibility, chronic toxicity, carcinogenicity, reproductive/developmental toxicity and degradation).  It would be beneficial for the industry to have a clear understanding of which endpoints should be evaluated for specific types of implants and their respective implant locations.

Additionally, FDA has identified eight additional non-clinical performance testing areas unique to 510(k) Implants, as summarized in the table below.  We find that this information is noteworthy for manufacturers to consider.

Animal Testing

When engineering analyses and mechanical tests may not comprehensively address the complexities associated with the clinical use of an implant, the draft guidance suggests that an animal study may be necessary to support SE to the predicate device.  We suggest consulting the draft guidance for a few representative examples of situations in which FDA may recommend animal testing.  FDA encourages manufacturers to submit a pre-submission to discuss the animal study protocol with the Agency before submitting a 510(k) application.

Implant Device Design Considerations

Information regarding raw materials and manufacturing processes can be crucial for certain implants, such as those made of nitinol, implants with unique in vivo wear characteristics, implants composed of degradable materials or biologically-derived materials, and implants manufactured using additive manufacturing processes.  In these cases, it is recommended that a 510(k) submission include details about materials, specifications, design and critical processing information, including reaction parameters and solvents used in processing or cleaning to allow FDA to better understand the final, finished form of the implant and how it compares to the predicate device in evaluating substantial equivalence.

Human Factors/Usability (HF/U) and Clinical Performance Testing

The draft guidance offers general information about HF/U and clinical performance testing.  FDA acknowledges the particular importance of HF/U testing for implant devices with complex interfaces intended for implantation by healthcare practitioners (HCPs) and implants that involve post-implantation management by either the patient or HCP (e.g., programming, monitoring, maintenance).

The FDA notes that, in most 510(k) submissions, clinical data is not typically required to establish SE.  However, there are specific scenarios where clinical data may become necessary to support an SE determination, as explained in another recent draft guidance on clinical data in 510(k), which we will discuss separately in a forthcoming blog post.

Patient Experience Information

As CDRH administers the Patient Science and Engagement Program, the draft guidance includes a separate section to encourage, rather than mandate, submitters to include patient experience data (such as patient preference information and patient-reported outcomes) for implants in a 510(k) submission, if it is relevant to the determination of SE.  Regarding this aspect, FDA refers to three guidance documents: Patient-Reported Outcome Measures, Patient-Reported Outcome Instruments, and Patient Preference Information.

In evaluating substantial equivalence, FDA may consider patient preference information in conjunction with non-clinical and clinical testing.  The totality of information helps inform FDA’s decision when it considers the overall benefit-risk profile of the implant device.  Note that FDA performs a benefit-risk assessment in the 510(k) context when it determines whether the new device is “as safe and effective” as the predicate device after the Agency finds that the intended use of the new device and predicate device are the same and have different technological characteristics that do not raise different questions of safety and effectiveness if there are different technological characteristics.

Labeling and Implant ID Card

Lastly, it is critical that patients are provided with implant information as it pertains to their devices. Manufacturers should create user-friendly instructions for use that facilitate patient understanding of potential risks over the expected lifespan of the implant.  FDA offers a flexible approach to achieve this goal, suggesting that some information may be suitable for inclusion on an implant ID card for the patient or caregiver, while other information may be better communicated in a different format (e.g., separate patient labeling).  Concerning the implant ID card, FDA recommends including basic information such as model name and manufacturer and important details concerning patient contacting materials, including those that may be associated with allergic reactions.  FDA also recommends the implant ID card provide contact information in the event of malfunctions or adverse events.  Finally, for magnetic resonance (MR) conditional implants, FDA recommends identifying those conditions for safe MR use.

Closing Remarks

We encourage sponsors of implant devices to carefully review the draft guidance, participate in the FDA’s webinar scheduled for October 26, 2023, and consider submitting comments on this draft guidance by December 6, 2023, through the provided link.