On Dec. 20, 2022, FTC announced the publication of its Health Products Compliance Guidance (“new Guidance”). FTC staff  prepared the new Guidance to update and replace Dietary Supplements:  An Advertising Guide for Industry, issued in 1998 (“1998 Guidance”).  The new Guidance provides the first update in 25 years on FTC’s thinking regarding substantiation and disclosures for health-related claims.

An accompanying blog post touts the new Guidance as potentially “one of the most important documents you’ll read in 2022.” We are inclined to agree, given that the new Guidance applies to all products making health-related claims, including food, over-the-counter drugs, homeopathic products, health equipment, diagnostic tests, and health-related apps.

The FTC maintains that the legal fundamentals of its guidance on substantiation remain unchanged, but a close reading indicates otherwise.  For example, the substantiation standard remains competent and reliable evidence.  However, the 1998 Guidance was equivocal with respect to the number or type of studies required to substantiate advertising claims.  It focused on the totality of the evidence and considered all types of evidence, including animal, in vitro, and epidemiological evidence.  While recognizing that well-controlled human clinical studies are the “most reliable,” the 1998 Guidance did not claim that such studies are the only form of acceptable substantiation, and acknowledged that animal and in vitro studies could be acceptable in some circumstances.  In contrast, the new Guidance states that “[a]s a general matter, substantiation of health-related benefits will need to be in the form of randomized, controlled human clinical testing (RCTs) to meet the competent and reliable scientific standard. . . . Animal and in vitro studies may provide useful supporting or background information, but, without confirmation by human RCTs, they aren’t sufficient to substantiate health-related claims.”

As an additional example, the 1998 Guidance stated that the FTC would accept epidemiologic evidence when supported by other evidence, such as research explaining the biological mechanism underlying the claimed effect.  In contrast, the new Guidance suggests that FTC only will accept “high-quality” epidemiologic evidence in “limited cases where (1) it is considered an acceptable substitute for RCTs by experts in the field; and (2) RCTs aren’t otherwise feasible.”

The new Guidance includes 23 new examples (among a total of 53) of FTC’s thinking applied to advertising of supplements and other products, such as a children’s nutrition drink, an infant formula, nasal strips, and a smartphone app for treating acne.

The new Guidance also provides more detail on “clear and conspicuous disclosure,” noting that disclosures must be unavoidable.  Hyperlink disclosures do not meet the clear and conspicuous standard because they are avoidable. The new Guidance emphasizes the need for disclosures made both visually and audibly when claims are made in both formats, and also addresses specific groups of targeted consumers. For example, “[w]hen an endorsement targets a specific audience, such as older adults or children, the effectiveness of the disclosure will be judged from the perspective of a member of that group.”

The FTC’s new Guidance does not have the force and effect of law. Rather, it is “intended to help advertisers comply with the basic tenets of FTC law,” and as stated in FTC’s blog post, “it offers practical perspectives from FTC staff.” The FTC did not seek public comment prior to issuing the new Guidance.

In October, when pardoning those federally convicted of cannabis possession, President Joe Biden directed the Secretary of Health and Human Services (“HHS”) and the Attorney General “to initiate the administrative process to review expeditiously how marijuana is scheduled under federal law.”  See President Biden Gives the Green Light for Significant Marijuana Reform, October 10, 2022.  The enactment of the Medical Marijuana and Cannabidiol Research Expansion Act (“the Act”) into law (Public Law 117-215) last month is a step in that direction.  The legislation passed in the House by a 325 to 95 vote last July and by Voice Vote in the Senate in mid-November.  President Biden signed the law on December 2nd.

As Congressman Earl Blumenauer (D-Oregon), founder and co-chair of the Congressional Cannabis Caucus and a sponsor of the bill observed, “Research is foundational for the path forward on cannabis policy. Research is essential to better understand the therapeutic benefits of cannabis that have the potential to help millions of Americans struggling with chronic pain, PTSD, multiple sclerosis, anxiety disorders and more.”  Earl Blumenauer, Press Release, Dec. 2, 2022.

We discuss the statute’s major provisions summarized below.

A.  Federal Research

As discussed in more detail below, the Act facilitates research of cannabis and its derivatives including cannabidiol (“CBD”), extracts, preparations and compounds, and the development of approved medications.  However, its most significant and enduring impact on federal cannabis regulation may be the mandate that HHS assess the compound’s therapeutic potential.  Within a year, HHS in coordination with the National Institutes of Health (“NIH”) must report to the Caucus on International Narcotics Control and responsible congressional committees on:

1. The potential therapeutic effects of cannabis on serious medical conditions including intractable epilepsy; and
2. The potential effects of cannabis, including the increase of delta-9-tetrahydrocannabinol (“THC”) levels on the human body, adolescent brains and the cognitive abilities to operate motor vehicles or heavy equipment.

The report must also discuss the barriers associated with conducting research with cannabis and CBD in states that have legalized their use, how barriers might be overcome and whether public-private partnerships or federal-state partnerships can or should provide researchers with additional cannabis and CBD strains.  HHS, in addition, must, “[t]o the extent practicable, the Secretary of Health and Human Services, either directly or through awarding grants, contacts [sic] , or cooperative agreements, shall expand and coordinate the activities of the NIH and other relevant federal agencies to better determine the effects of cannabis outlined in the report.”

To date 39 states and the District of Columbia have legalized cannabis for medical use (and 21 for adult recreational use), mainly through ballot initiatives.  The Act requires that HHS provide a scientific analysis on whether cannabis and its derivatives are safe and effective treatments for different medical ailments and their other effects on the human body.  A positive finding in this regard is critical to any potential that cannabis would be approved for medical use under federal law.

B.  Doctor-Patient Relationship

Also of great importance is the Act’s authorizing state-licensed physicians to advise patients or their legal guardians of the potential harms and benefits of cannabis derivatives as a medical treatment.  As a federally-controlled schedule I substance, cannabis by definition has no currently accepted medical use in treatment in the U.S.  21 U.S.C. § 812(b)(1)(B).  The Act is silent as to whether those physicians must hold a Drug Enforcement Administration (“DEA”) registration but significantly does not authorize physicians to administer, dispense nor prescribe cannabis.  There is no explicit federal prohibition against DEA-registered physicians advising patients on cannabis as a medical treatment, but to do so could subject a physician to DEA scrutiny.

C.  Adequate and Uninterrupted Supply of Cannabis

The Act places the onus on DEA to ensure an adequate, uninterrupted supply of cannabis for research.  The Act requires DEA, in consultation with HHS, to assess annually whether an adequate and uninterrupted supply, down to specific strains, exists and to establish sufficient quotas to ensure an uninterrupted supply.  Should DEA and HHS determine cannabis, even specific strains, to be inadequate or interrupted, DEA must report to Congress within 60 days on:

• The contributing factors;
  • Expected impacts on approved ongoing research protocols; and
  • Specific steps the agency will take to restore an adequate, uninterrupted supply.

It is unclear whether DEA, FDA or both will make the determination whether a shortage exists.

D.  Cannabis Researcher Registrations

1.  Application Process

The Act mandates that DEA streamline and accelerate registration application procedures for cannabis researchers and manufacturers of cannabis for research.  DEA must register practitioners to conduct cannabis research if (i) their protocol has been approved by HHS or NIH, and (ii) they have effective procedures to safeguard the compound in the quantities they seek to use in research against diversion.  DEA may deny an application if it determines the registration would be inconsistent with the public interest by considering:

• Recommendations of the appropriate state licensing board or professional disciplinary authority;
• The applicant’s experience in dispensing or conducting research with controlled substances;
• The applicant’s conviction record under federal or state laws relating to the manufacture, distribution or dispensing of controlled substances;
• Compliance with applicable state, federal or local laws relating to controlled substances; and
• Such other conduct which may threaten the public health and safety. 21 U.S.C. § 823(g)(1).

With respect to timing, DEA must issue a registration or request supplemental information within 60 days after receiving a complete application.  DEA then has 30 days after receiving supplemental information to issue or deny a registration.  DEA must provide a written explanation of the basis for denying a registration.  The Act authorizes DEA to deny registrations only if approved protocols lack adequate security.

2.  Research Protocols

As a reminder, the Controlled Substances Act (“CSA”) and DEA regulations require that research with cannabis and other schedule I drugs can only be conducted with a protocol approved by DEA and FDA.  21 C.F.R. §§ 1301.13(e), 1301.18, 1301.32.  The Act allows researchers to amend or supplement their research protocol without notifying DEA if there is no change to cannabis quantity or type, its source, or to its storage, tracking or administration.  If a researcher wishes to change those research elements, they must notify DEA via registered mail or electronically within 30 days before implementation.  Researchers may proceed if DEA does not explicitly object within 30 days, and the agency can only object if additional security is required.

If a change of cannabis quantity does not impact other factors, researchers must notify DEA by registered mail or electronically and the agency must respond within 3 days.  Notifications are deemed approved unless DEA explicitly objects within 10 days if it finds that a change in quantity impacts the cannabis source or how it is stored, tracked, administered or requires additional security measures.

Although the Act limits DEA’s authority over cannabis research protocols, it does not limit HHS’ authority, including over changes in the method of administration, dosing and the number of individuals involved in research

DEA must promulgate regulations implementing these application process changes within one year.

3.  Security

Researchers must store cannabis in a securely locked, substantially constructed cabinet.  21 C.F.R. § 1301.75(a).  The Act restricts DEA from mandating more stringent security requirements for cannabis researchers than those imposed on other schedule I and II researchers.

E.  Cannabis Manufacturer Registration for Research

As with cannabis researcher registrations, the Act requires DEA to approve an application for a cannabis manufacturer registration or request supplemental information within 60 days after receiving complete applications.  Manufacturer applications are complete when the applicant has demonstrated that they:

• Have satisfied requirements designated in the Federal Register notice;
• Have satisfied statutory and regulatory requirements;
• Will transfer or sell cannabis only to DEA-registered researchers for preclinical research or clinical investigation pursuant to a New Drug Exemption;
• Will transfer or sell cannabis only with prior, written DEA consent;
• Has completed the application and review process for bulk manufacture of schedule I
  substances;
• Has established and begun a process for storing and handling schedule I substances including inventory control and security; and
• Is licensed by each state in which it will conduct operations.

Also like researcher applications, DEA must approve or deny issuing a registration within 30 days after receiving requested supplemental information and must provide written explanation of the basis of a denial.

F.  Commercial Production and Distribution of FDA-Approved Cannabis Drugs

Consistent with the Controlled Substances Act, DEA cannot deny a manufacturer registration solely on the basis that the applicants wants to manufacture an FDA-approved product containing cannabis.

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Other cannabis-related bills that were not acted upon in the waning days of the 117th Congress include the Secure and Fair Enforcement Banking Act of 2021 (“SAFE Banking Act”), Veterans Equal Access Act, the Preparing Regulators Effectively for a Post-Prohibition Adult-Use Regulated Environment Act of 2022 (“PREPARE Act”) and the Veterans Medical Marijuana Safe Harbor Act.

As we turn into the New Year, we offer a few items of interest in digital and telehealth regulation, enforcement, and compliance that may provide some helpful guideposts for stakeholders.

In 2022, the chief regulating entities—FDA, FTC, and DOJ—all continued to forge policies to help bridge the rapidly moving waters between traditional regulatory concerns about safety and effectiveness on one side and cybersecurity, data privacy, and identity integrity on the other. To date, regulatory enforcement litigation focused on actual or imminent patient harm has taken a backseat to cybersecurity as FDA continues to update and implement its oversight framework. But a compromised device is a threat to patient safety, so that timeline could change in the event of an adverse event that imperils consumer health. Until that happens, interested parties in this space continue to face many of the same cybersecurity threats as other data-tech entities.

In mid-November, FDA collaborated with the MITRE Corporation to publish an update to the Medical Device Cybersecurity Regional Incident Preparedness and Response Playbook. The Playbook is a guide for healthcare delivery organizations to respond to cybersecurity incidents that threaten device function and, potentially, patient safety. It emphasizes building partnerships with local health and law enforcement authorities, so organizations can mitigate any breaches, especially those that can potentially cripple smaller, less resourced providers.

Among other things, the Playbook encourages preparedness, provides some considerations for impacts and downtime, and adds a resource appendix to give users more tools and resources. It is another effort from CDRH’s Digital Health Center of Excellence to provide structure and guidance to participants across the connected device playing field, including both delivery organizations as well as manufacturers. CDRH is building an extensive library of similar reports and white papers as it prepares its final guidance for medical device cybersecurity, scheduled to come out next Fall.

Combination products are sharing the digital moment with those classified solely as medical devices. Combination products might be part drug, part device, or part software or hardware. Those different pieces create a complex regulatory puzzle, and cybersecurity failings in them can quickly descend into the same depths of functionality and threats to patient safety.

Remarks at the November AFDO/RAPS Combination Products Summit highlight the complexities of connected combination products. The current Team Lead for Injection Devices in CDRH’s Division of Drug Delivery and General Hospital Devices and Human Factors noted that depending on the product, the pre-market path for a connected combination product might require an IND, IDE, or a determination that it is a medical device data system, which are not regulated as devices. Post-market, combination products potentially face the same enforcement scrutiny as single-entity medical devices. FDA counsels that, as is the case with any other electronic device, seemingly small, routine steps like software maintenance and updates are ways companies can address possible vulnerabilities that could lead to adverse events.

FDA has shown a willingness to intervene in this space. One example is the Warning Letter FDA sent to Medtronic in late 2021 concerning a vulnerability in insulin infusion pumps. Another is the June 2022 Letter to Health Care Providers about a cybersecurity vulnerability affecting Illumina medical devices for clinical diagnostic use in sequencing a person’s DNA or testing for various genetic conditions.

Digital providers and manufacturers not only have the concerns of the FDA to consider, but those of the FTC as well. Where evidence supports, the FTC views data security breaches as violations of the FTC Act as unfair and deceptive advertising practices. The theory here is that if digital device makers tell customers their data is safe, but in fact it is not, and if a breach occurs, those makers may face liability.

This was a topic at the December Food and Drug Law Institute conference on Current Developments in Digital Health Technology and Regulation. Speakers from both the FTC’s Division of Privacy and Identity Protection and DOJ’s Consumer Protection Branch expressed a continued willingness to bring suits against firms that fall short in their data integrity efforts, citing cases against SkyMed and Flo Health as examples of their work that also touch upon FDCA concerns. Another takeaway from this conference was that CDRH received high marks from commentators across many panels about both the quality and quantity of the Agency’s efforts to develop and align regulatory expectations in this area.

Healthcare delivery organizations are facing increasing pressure from cyberattacks due to the sector’s profitability and the increasing number of accessible endpoints that advancing technology provide. Thus, cybersecurity is tightly intertwined with safety and effectiveness, and government regulators seem willing to invest in the resources to detect cybersecurity problems that affect the regulatory landscape. Moving forward, it seems likely that those issues will become even more prominent during both the pre-market process as well as in post-market monitoring and use to guard against data breaches and adverse events. More updates will follow here as trends develop in 2023.

A win for patient access!   Prescription drug and medical device Pre-Approval Information Exchange (PIE) now has specific legal protection allowing for sponsors to proactively communicate to payors certain information about products in development to help expedite patient access upon product approval.

The PIE Act, otherwise known as section 3630, “Facilitating Exchange of Product Information Prior to Approval” of H.R. 2617, the “Consolidated Appropriations Act, 2023,” was signed into law by President Biden on December 29.   The provision amends the Federal Food, Drug, and Cosmetic Act section 502 to provide explicit protection for conveying certain information about products in development to payors, including unapproved uses of approved products.

While pre-approval payor communications are not entirely new, the legal protection now afforded to them will help (hopefully) expedite the creation and reviews of such communications that, have to date, been often fraught with internal company debate.  As background, 21 C.F.R. §312.7 explicitly prohibits the “promotion” of investigational drugs:

A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug.  This provision is not intended to restrict full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media.  Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution.

While the focus of the regulation seems to be a sponsor’s suggestion that its investigational drug is safe or effective, the language of the regulation more broadly states that a sponsor shall not “otherwise promote the drug” and that its intent is “to preclude commercialization of the drug before it is approved.”  Industry has grappled with interpreting this regulation – what is promotion? what is commercialization? We know that, in the context of payor communications, the Office of Prescription Drug Promotion (and before it, the Division of Drug Marketing, Advertising and Communications – DDMAC) has long considered the provision of healthcare economic information about drugs to payors to be “promotional,” requiring this content to be submitted to FDA on Form 2253 as promotional labeling.

When FDA published its draft guidance on payor communications in 2017, it seemed revolutionary – introducing the concept of pre-approval information exchange for wholly unapproved products. Upon finalization of the guidance a year and a half later in June 2018 (which gave those who follow ad/promo guidance documents whiplash given the number of still-in-draft guidances) FDA expanded its enforcement discretion to include communications about unapproved uses of approved products.  Per the final guidance, sponsors could provide payors with information about unapproved products and unapproved uses of approved products including information about indications sought, descriptions of clinical studies, anticipated timeline for possible FDA approval/clearance, product pricing, patient utilization projections, and product related programs or services.  FDA recommended that communications include a clear statement that the product or use is not FDA-approved and that safety or effectiveness of the product or use has not been established.

As we noted back in our 2018 blogpost , the expanded scope of the final guidance – covering unapproved uses of approved products – was significant, as these discussions are tantamount to off-label discussions and discussions with Medicare and Medicaid providers could raise False Claims Act questions.  While helpful to have an FDA guidance, there was nothing specifically in the law or regulations that would otherwise protect these communications (other than the First Amendment which, let’s face it, is always a bit risky when litigating).  Reconciling the guidance with 21 C.F.R. §312.7’s prohibition on promoting investigational drugs was difficult.  We had stated, at that time, that “[r]egardless of these new, more permissive guidelines, industry should be careful of suggesting an unapproved use for an approved product.”  FDA had put industry in a quandary.

The PIE Act largely adopts the language from FDA’s guidance and provides the legal protection for these communications desperately sought by sponsors, payors, and patients.  Until now, since the publication of the final guidance, we have witnessed internal company struggles regarding whether and how to provide this important information to payors.  We are hopeful that this critical information will facilitate earlier patient access to needed treatments once they are approved.

On December 7, 2022, FDA’s Center for Biologics Evaluation and Research (CBER) and the Office of Tissues and Advanced Therapies (OTAT) held a town hall to answer questions related to cell therapy and tissue-engineered products chemistry, manufacturing, and contr­­ols (CMC).  The purpose of these town halls are to discuss topics related to OTAT-regulated products, engage with product development stakeholders, and to provide information to help stakeholders to help advance drug development.  The next town hall will focus on the clinical development of gene therapy products for rare diseases in February 2023.

As previously mentioned, sponsors can interact with FDA in the town hall by submitting questions in advance or by asking a question live during the meeting.  It is important to keep in mind that this meeting is for general CMC feedback and sponsors are informed that “FDA is not able to comment on or answer questions regarding specific investigational products or drug applications during the town hall.”

In case you do not have time to watch the town hall, we provided a summary of select topics that are discussed below.  There was a lot of information on CMC regulatory requirements and pitfalls for cellular therapies and tissue engineered products discussed during the OTAT town hall that are not included in this blog.  These topics included the requirements for using irradiated murine cell lines, core blood as a starting material, and fetal bovine serum, FDA’s standards for the development of cell and gene therapies and tissue products, testing requirements for stability, donor eligibility, delivery devices, and for a scaffolding component of a tissue-engineered product.

Common CMC Issues for Phase 1 IND Study

The Agency stated that the most common reason for a clinical hold of a Phase 1 study under an investigational new drug (IND) is related to safety.  The reasons for these holds might include not providing sufficient information to describe the manufacturing process, using reagents which are not demonstrated to be of sufficient safety or quality, not conducting donor eligibility or appropriate cell bank testing, insufficient safety testing of the product, insufficient information on the assays to conduct the safety testing, insufficient safety information on delivery device and data demonstrating that the device does not impact the safety or quality of the drug product.  The Agency repeatedly stated and strongly recommends sponsors engage with FDA prior to submitting the IND.

Potency

Similar to the OTAT town hall meeting in September, potency assay requirements and pitfalls were discussed.  The Agency referred to its 2011 FDA Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products during the town hall.  As you may know, there are challenges related to developing potency assay(s), and the Alliance for Regenerative Medicine and the American Society of Gene and Cell Therapy recently published a white paper on a workshop held to discuss these challenges.  The workshop is also discussed in Cell & Gene here and here.

The Agency recommended that product developers begin designing potency assay(s) early, and developing and evaluating multiple potency assays since not all potency assays can be validated and some potency assays may not fully reflect the biological activity.  The Agency stressed that because the ability to measure potency is fundamentally related to product characterization, developers should initiate potency assay development by the way of product characterization during preclinical and early clinical investigation.  The potency assay may not be completely defined early in the development, but should become progressively more comprehensive as developers accumulate manufacturing experience, product characterization data and clinical data.  For first in human studies, developers need to provide plans for characterization, including a description of the initial critical quality attributes, potency assay development plans during clinical development, and a quality target profile.  As the product advances in clinical development, expectations are that the potency test be refined to measure a relevant biological activity of the product.  The Agency directly quoted the 2011 FDA Guidance, “if one assay is not sufficient to measure the product attribute(s) that indicates potency, then an alternative approach could be used, such as developing multiple complementary assays that measure different product attributes associated with quality, consistency and stability.”  The Agency stated because cellular and tissue-engineered products usually have multiple potentially related critical quality attributes (CQAs), the potency assay strategy could include multiple assays, each of which quantitates a potency-related CQA.

The Agency pointed out that a qualitative potency assay should be accompanied by one or more quantitative assays and cannot be used without a quantitative assay.  Although demonstrating accuracy and precision for a qualitative assay could be challenging, the Agency stated that with proper assay design (e.g., sufficient replicates), developers should be able to demonstrate adequate assay consistency.  Per the 2011 FDA Guidance, developers should validate the assay prior to conducting a clinical study that will investigate the efficacy for licensure.

Comparability

For any change, the Agency recommended that developers conduct a risk assessment per ICH Q5E to determine whether there is a potential to affect product quality.  This would include an evaluation of the potential for product attributes and process parameters to affect the product quality as they relate to the product safety and efficacy.  The goal of the comparability study is to demonstrate a lack of adverse effect on the product quality.  The Agency recommended changes in product manufacturing are implemented in the earlier phases of the clinical study to reduce risk to the development program (i.e., before evaluating clinical effectiveness).  Depending on the change and at what phase of the clinical study it is made, the Agency expects that a comparability assessment, developmental studies, and risk assessment be conducted to support the change.  The developmental studies and the risk assessment should allow sponsors to rank the different product characteristics to determine the type of evaluation that should be performed such that a study can be designed to address the risk(s) identified. The Agency emphasized that release testing alone is not sufficient to assess comparability and that additional characterization testing or in process testing be conducted to demonstrate that there is not adverse effect on product quality.

The extent of analytical evaluation needed in comparability studies generally increases with the stage of clinical and product development and should be supported by knowledge of CQA, accumulated manufacturing experience, and further understanding of the mechanism of action.  Understanding the impact of manufacturing changes on product quality is essential to determine the risks to product quality and to design the comparability study.  It is important to use analytical methods that could detect meaningful differences in product quality.  The Agency recommended developers determine the most appropriate process time points to detect the change in the quality attributes, which could entail evaluating the product at multiple stages of manufacturing.  It is possible that the comparability study results may not be sufficient to establish product comparability.  The sufficiency of comparability evaluation depends on the type of change and a developer’s level of understanding of product quality attributes as predictors of clinical safety and efficacy.  The inclusion of additional characterization tests or preclinical studies may be necessary to support comparability.  For some products, animal models may be used to demonstrate that the product has the desired biological effect and provide supportive evidence for comparable biological activity of the pre-change and post change product.

Release Criteria

The Agency acknowledged that early in development, a complete understanding of appropriate process controls may be limited and that specific controls may be added or refined during the life cycle.  However, the initial IND submission should describe and justify the controls that are implemented to ensure adequate quality and manufacturing consistency.  The Agency recommended that product be as fully tested as feasible in early stages of development and that specifications should be appropriate to the stage of product development.  For example, for early phase clinical studies, assays should be in place to access identity, quality, strength, and purity.  In later stages, more detailed product characterization and potency should be provided.  The acceptance criteria for release testing should be established and justified based on data from lots used in preclinical or early clinical studies, lots used in demonstration of manufacturing consistency, and stability studies, and relevant product studies.  The Agency recognizes few specifications will be finalized and some tests may still be under development; however, for any given stage of the development, the testing plan submitted should be adequate to describe the physical, chemical, or biological characteristics of the drug product necessary to ensure quality and safety.  Specifications should be further refined as product development and tightened based on manufacturing experience as clinical development moves forward.

Other Questions

At what point does manufacturing at the clinical site become manufacturing that requires additional final product release testing?

The Agency stated that manufacturing steps conducted at a clinical site considered to be substantial manipulations (e.g., those used to prepare final drug product after its been released) are subject to manufacturing controls and good manufacturing practices. The Agency also recommended that sponsors work to eliminate additional manipulation steps at the clinical site after the product is released and distributed from the manufacturing site.

How should sponsors handle manufacturing deviations, including product lots that do not meet lot release specifications?

Manufacturing deviations should be investigated to identify the root cause and appropriate  corrective actions should be taken to avoid repeat occurrences in the future.  The Agency expects that sponsors provide their risk management approach and change control procedures for how to address the risk manufacturing deviations in their IND.  Manufacturers who hold a biological license should report manufacturing deviations to the FDA per 21 CFR 600.14.  Product should not be released if it does not meet lot release specifications due to the manufacturing deviations.  Sponsors may consult with the Agency to release out of specification product if a patient is at significant risk and is conditioned to receive the product.

Is it acceptable to use products manufactured from engineering runs in clinical studies?

The Agency stated that this may be permissible if adequate justification on safety and quality of the batch and whether or not there are differences in the manufacturing process for that engineering run versus the intended clinical run.

If I use GMP grade reagents, isn’t that sufficient to support their safety?  What are the general expectations on reagents used to manufacture products under an IND?

The Agency pointed out that just because a reagent is labeled “GMP grade” does not necessarily mean that the reagent was manufactured using good manufacturing practices (GMP).  In some cases, a certificate of analysis from the supplier may be sufficient and FDA would not require additional information regarding the reagent.  In other cases, the Agency would require additional testing to ensure safety and quality of the GMP grade reagent. The Agency recommended that sponsors follow the requirements under 21 CFR 211.84(d)(2) and conduct an identity test on at least one lot of reagent in addition to maintaining a supplier qualification program that evaluates reagent suppliers.  The Agency stated sponsors could qualify use of research grade reagents in an IND, but that sponsors should progress towards using reagents that have been manufactured under GMP conditions.  During the town hall on gene therapy CMC, the Agency noted that it does not recommend the use of research use reagents or materials, but that it could be flexible (minute 42 of the recording here).

Hosted by American Conference Institute, the FDA Boot Camp returns for its 40th iteration with the continued intent of providing an essential working knowledge of core FDA concepts, and real-world examples that will help you to excel in your everyday practices.

This year’s conference co-chairs include Stacy Cline Amin (Partner, Morrison Forester) and Kurt R. Karst (Director, Hyman, Phelps & McNamara P.C.). Comprehend the structure of FDA and the roles of the three major agency centers: CDER, CBER and CDRH, master the basics of the application and approval processes for drugs and biologics, gain a practical working knowledge of clinical trial process for pharmaceutical products and much more! The distinguished speaker faculty includes Jennifer Bragg (Partner, Skadden Arps Slate Meagher & Flom LLP), Seth Mailhot (Partner, Husch Blackwell), Cathy L. Burgess (Partner, Alston & Bird LLP) and many, many more!

The speaker faculty of top FDA regulatory authorities will share critical insights on:

• The organization, jurisdiction, functions, and operations of FDA
• The essentials of the approval process for drugs and biologics
• The role of the Hatch-Waxman Act in the patenting of drugs and biologics
• Clinical trials for drugs and biologics
• Labeling in the drug and biologics approval process
• cGMPs and other manufacturing concerns relative to products liability
• Proactive adverse events monitoring and signal detection
• Recalls, product withdrawals, and FDA oversight authority

FDA Boot Camp is taking place virtually from March 22-23, 2023, visit http://bit.ly/3WxcEHs to learn more!

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On December 23, 2022, when many of us were distracted by the cold weather, Congress passed the Food and Drug Omnibus Reform Act of 2022 (“FDORA”) as part of the Consolidated Appropriations Act of 2023. FDORA includes, as subtitle E, the Modernization of Cosmetics Regulation Act of 2022!

As discussed here, the Modernization of Cosmetics Regulation Act of 2022 (“MOCRA”) originally was included in the Senate version of the FDA Safety and Landmark Advancements (FDASLA) Act (S.4348).  However, the House’s version of this bill did not include cosmetics regulation reform, and the final  version of the FDA user fee legislation, which was enacted and signed into law on September 30,  did not include the cosmetics regulation language.

MOCRA amendments to the Federal Food, Drug, and Cosmetic Act constitute the first statutory change to FDA’s authorities over cosmetics since 1938.  As described in our previous blog post, MOCRA focuses on safety of cosmetics.  Among other things, FDA is to develop and issue good manufacturing practice regulations, develop tests for asbestos and address PFAs in cosmetics.  Industry will become subject to registration and listing requirements (one year after enactment of MOCRA), must have records to substantiate safety of its products, and must report serious side effects to FDA.  MOCRA gives FDA mandatory recall authority (when it determines that there is a reasonable probability that a cosmetic is adulterated or misbranded and the use or exposure to the cosmetic will cause serious adverse health consequences or death) and expands FDA’s access to certain records.

MOCRA  preempts state law requirements differing from, or in addition to, those relating to registration and product listing, good manufacturing practice, recordkeeping, recalls, adverse event reporting, and safety substantiation.  However, other prohibitions and limitations on the use or amount of an ingredient in a cosmetic product, state tort laws, and state laws and referendums, such as California’s Proposition 65, are carved out from preemption.  Although the preemption provision certainly is not as strong as industry would prefer, industry has generally supported modernization of cosmetic regulation as it will advance innovation, modernize oversight and (presumably) bolster consumer confidence. At least for now, industry has been successful in preventing user fees for cosmetic companies. Congress appropriated $14,200,000 for fiscal year 2023, $25,960,000 for fiscal year 2024, and $41,890,000 for each of fiscal years 2025 through 2027 to FDA for developing regulations and performing the other activities under MOCRA.

The passing of MOCRA does not change matters for industry overnight.  The requirements for registration and listing and new enforcement provisions become effective one year after enactment of the legislation.  A client memo prepared in early 2023 will address MOCRA and other major provisions of FDORA in further detail.

Back in June, when Congress was negotiating the User Fee Acts, FDA asked Congress to add in some provisions reversing several lawsuits that it had just lost.  Ultimately, FDA lost that fight, and a slimmed down version of the FDA Safety and Landmark Advancements (“FDASLA”) passed without those sections.  That fight has now been moved to the Appropriations Bill, where Congress is trying to integrate certain provisions that would reverse—at least in part—some of those litigation losses with little scrutiny, either by Congress or other stakeholders.

One of the more concerning provisions in the Appropriations Bill can be found in section 3306, which addresses “Bans of Devices for One or More Intended Uses.”  This section is directly in response to the 2022 D.C. Circuit decision in Judge Rotenberg Educ. Ctr., Inc. v. FDA, which held that that banning a single intended use of a specific device was inconsistent with the Federal Food, Drug, and Cosmetic Act’s (“FDC Act”) clear pronouncement that FDA cannot regulate the practice of medicine.  (Hyman, Phelps & McNamara, P.C., was co-counsel for the Judge Rotenberg Center in this litigation.)  In brief, that case involved the appeal of a 2020 Final Rule in which FDA banned the use of an Electrical Stimulation Device (“ESD”) only in the treatment of self-injurious behavior or aggressive behavior.

The site offering the treatment, the Judge Rotenberg Educational Center, and parents of patients that were treated with an ESD for self-injurious or aggressive behavior filed a Petition for Review in the D.C. Circuit of FDA’s Final Rule banning the ESD specifically for those purposes.  The Petitioners alleged multiple violations of the Administrative Procedure Act, as well as alleged that FDA violated the FDC Act itself by banning a particular use of a device rather than the device itself.  The Court agreed with the Petitioners, holding that banning the use of the device would regulate the practice of medicine or prohibit the off-label use of a device.  Now, Congress seeks to overturn that decision by amending the FDC Act to permit FDA to ban a specific intended use.

In the Appropriations Bill, the proposed provision amends section 516(a) of the FDC Act (21 U.S.C. § 360f(a)) to allow FDA to ban a device “for one or more intended uses” and states that “A device that is banned for one or more intended uses is not a legally marketed device under section 1006 when intended for such use or uses.”  Section 1006 refers to the “Practice of Medicine” provision of the FDC Act (21 U.S.C. § 396), which prohibits FDA from limiting or interfering “with the authority of a health care practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease . . . .”  In other words, Congress is proposing to let FDA ban devices for particular uses, including off-label uses.

This provision represents a complete shift in the way FDA is allowed to regulate products.  Previously, FDA determined whether a product was safe and effective for its intended use but could not dictate the way a practitioner used that product.  That, of course, is reserved for the practice of medicine, and FDA does not govern the practice of medicine.  This proposed revision turns that premise on its head: If FDA can say that a given device can’t be used for a specific treatment, then the practice of medicine is inherently subject to FDA discretion, regardless of the provisions in section 1006.   Congress has effectively narrowed Section 1006 by giving FDA the authority to ban off-label uses of devices.

At first blush, this might not seem like such a big deal.  After all, FDA has only used its banning authority 3 times since 1976.  Yet this provision would have serious implications.  Firstly, the proposed provision, should it pass, would allow FDA to ban a device in a way it has never been allowed to, ultimately giving the Agency authority to dictate the practice of medicine.  Secondly, the proposed provision would be implemented with no scrutiny, public input, or public hearing.  Yet this provision could potentially have far-reaching consequences.  Even if FDA has infrequently used its banning authority, nothing would stop FDA from seeking to use this power much more extensively in the future.  Giving FDA the power to ban off-label uses could preclude patient access to off-label therapies that FDA objects to even though their physicians deem the treatment essential.  Thirdly, this provision erodes a bedrock principle: FDA does not have the power to regulate the practice of medicine.  This particular provision may seem like a small exception, but small holes in the fabric of the law can grow into gaping holes over time.

In our previous blog post, we provided a flowchart for the Digital Health Policy Navigator’s process so that our blog readers can quickly review the seven steps in determining whether their product’s software functions may be potentially the focus of FDA oversight. Two days after the blog post, FDA updated the Digital Health Policy Navigator to improve access to the tool through the webpage and add examples to the clinical decision support software policy considerations in Step 6.  These include the following examples of software functions that meet Criterion 3 of clinical decision support software (section 520(o)(1)(E)(ii) of the Federal Food, Drug, and Cosmetic Act):

• Evidence-based clinician order sets for an HCP to choose from, tailored for a particular condition, disease, or clinician preference;
• Matching patient-specific medical information from records or reports to reference information (e.g., clinical guidelines);
• Contextually relevant reference information about a disease or condition;
• Drug-drug interaction and drug-allergy contraindication notifications to avert adverse drug events;
• Drug formulary guidelines;
• Duplicate testing or prescription production prevention notification (e.g., medication reconciliations and test reconciliations);
• Reminders for preventive care or clinician’s orders; and
• Patient data reports and summaries (e.g., discharge papers).

Besides the newly included examples above, no other changes were made to the Digital Health Policy Navigator. As a result, the flowchart we created is still current and can be downloaded here.

On December 9, 2022, FDA issued a draft guidance document on the Voluntary Malfunction Summary Reporting (VMSR) Program for medical devices.

Generally, FDA’s MDR regulations require device manufacturers to submit Medical Device Reports (MDRs) for individual reportable malfunctions within 30 calendar days of the manufacturer becoming aware of the malfunction.  The VMSR Program allows manufacturers to bundle malfunction reports of “like events” together in a single summary report.  The purpose of this program is to reduce the volume of reports that a manufacturer needs to submit to FDA and to “make malfunction event trends more readily apparent.”

FDA began an initial VMSR pilot program in 2015.  Then, in 2016, FDA noted its goal to streamline MDR requirements in the Medical Device User Fee Amendments of 2017 (MDUFA IV) commitment letter.  In that letter, FDA stated that it would “permit manufacturers . . . to report malfunctions on a quarterly basis and in a summary MDR format” for devices in certain product codes that the Agency would publish in a list.

In August 2018, FDA published a notice in the Federal Register granting an alternative under 21 C.F.R. § 803.19 permitting manufacturers of devices in eligible product codes to submit certain device malfunction MDRs in summary form on a quarterly basis (see our blog post on this notice here).

The draft guidance provides information about the VMSR Program eligibility and scope, reporting conditions, and the reporting process.

When FDA initially implemented the VMSR Program, in 2018, the Agency reviewed all product codes to determine eligibility for the program.  Product codes that had been in existence for less than two years were generally not eligible for the program, because FDA wanted more timely and detailed malfunction information from newer product codes.  The draft guidance states that FDA intends to periodically reassess product codes to update eligibility for the VMSR Program, but does not provide details on the frequency, timeline, or process for reassessment.

Each product code’s eligibility for the program is noted for that product code in FDA’s Product Classification database.  In assessing eligibility, FDA intends to consider the frequency of reported serious injuries and deaths, the number of 5-day reports (for events that require remedial action to prevent an unreasonable risk of substantial harm to the public health), and whether any devices in the product code have had any class I or class II recalls.  Manufacturers can also submit a request to FDA for a product code to be considered for eligibility in the VMSR Program.  The draft guidance sets forth a process for doing so.

As described in the draft guidance, there are certain conditions for participation in the VMSR Program.  Specifically, manufacturers that participate in the VMSR Program must submit individual reports, rather than summary reports, for (1) malfunctions associated with a 5-day report, (2) malfunctions that are the subject of certain device recalls, (3) when FDA has determined that individual MDR reporting is necessary to address a public health issue, (4) when FDA has determined that a manufacturer may no longer report in a summary reporting fashion (e.g., due to failure to comply with MDR reporting requirements), and (5) when a new type of reportable malfunction occurs for a device.

Summary malfunction reports should be submitted electronically on Form FDA 3500A.  The draft guidance provides instructions for completion of this form, including an appendix with a sample report.  Additionally, the draft guidance restates the VMSR reporting schedule set forth in the regulations:

In short, the guidance provides little detail beyond what was in the final rule and regulation.  But what it does provide may be of some practical use to manufacturers.  Interested parties can submit comments on the draft guidance to FDA until February 7, 2023 via Regulations.gov.

On December 7, 2022, FDA announced the availability of the final guidance regarding the enforcement policy for homeopathic drug products.  This concludes FDA’s reevaluation of the regulation of homeopathic drugs which it started in 2015.

As we reported previously, here, and here, as a result of the growth of the industry and safety issues, in 2015 FDA started the reevaluation of its regulatory framework for homeopathic products.  In 2017, it decided to withdraw the compliance policy guide (CPG; from 1988) under which, for decades, the Agency essentially had permitted the marketing of over-the-counter homeopathic drug products. FDA concluded that the CPG limited its ability to act against unsafe homeopathic drug products and decided to develop a risk-based enforcement policy.  It issued a draft guidance in 2017 which was subsequently revised in 2019.

The final guidance issued last week is the same as the 2019 draft guidance except that the final guidance includes a paragraph in which FDA mentions that the provisions of the CARES Act regarding OTC monograph reform do not apply to homeopathic drug products.

As we previously reported, the 2017 draft guidance generated many comments including a citizen petition by  Americans for Homeopathy Choice.  FDA denied that petition in 2019.  Not deterred by this denial, Americans for Homeopathy Choice submitted another citizen petition in 2020.  The 2020 petition requested that FDA issue a proposed regulation for homeopathic drugs.  As described in the executive summary of the petition:

Petitioners [sought] to have FDA establish regulations that would assure consumers: that drug products labeled “homeopathic” are either included in the HPUS or can be reasonably expected to be accepted for inclusion in the HPUS because they meet eligibility thresholds, as determined by relevant third-party review; that products that do not meet the foregoing criteria are not permitted to be labeled “homeopathic;” that homeopathic drugs are free of adulteration and properly labeled; and that FDA applies standards appropriate for low-risk products when evaluating the risks of homeopathic drugs. Further, petitioners [sought] recognition by FDA that homeopathic drugs, properly manufactured and labeled, and evaluated by appropriate standards, do not meet the legal definition of “new drugs,” and therefore are not subject to premarket review other than satisfying the requirements of current or likely inclusion in the HPUS

FDA issued its denial of this second petition a day before the final guidance became available.  Consistent with its prior thinking,  FDA’s response lays out FDA’s conclusion (consistent with its prior thinking) that homeopathic drug products are new drugs; they are not eligible for any exception and may legally be marketed only if they are approved by FDA.

FDA’s actions and statements leave no uncertainty that FDA has concluded that homeopathic drug products are unapproved drugs.  That said, the Agency acknowledges that many homeopathic drug products will fall outside the categories of drug products for which FDA intends to prioritize enforcement and regulatory action as described in its final guidance.  Although FDA is authorized to take action against those products, any enforcement action is not likely in the absence of evidence that a product poses a risk described in the guidance.

In the wake of President Biden’s July 2021 Executive Order—Promoting Competition in the American Economy—and the exchange of letters between the Patent and Trademark Office (USPTO) and FDA, the USPTO announced recently a “public listening session” in collaboration with FDA to seek comments on how the agencies can work together to promote greater access to medicines.  That session will be held on January 19, 2023, and the agencies have opened a docket to receive comments on effective collaboration.  Registration to speak at the conference closes on January 5, 2023.  Written comments will be accepted until February 6, 2023.

As a brief reminder, the July 9, 2021 Executive Order directed FDA to write a letter to the USPTO describing concerns about uses of the patent system to delay generic and biosimilar competition.  FDA’s September 2021 letter explains the issues raised by patent thickets, patent evergreening, and product-hopping—all of which, FDA explains, are used to delay approval of less expensive, generic versions of branded products.  The USPTO responded to FDA’s letter on July 6, 2022, citing its intent to enhance collaboration with other agencies; improve procedures for obtaining a patent; improve the PTAB challenge practice; and improve public participation.  Both letters recognized the need for “robust and reliable patents” to “incentivize and protect” the research and development investment made to bring new drug products to market, but they also cite the importance of increased competition.  More information about these letters can be found in our July 21, 2022 blog post.

The intent of the “listening session” is to obtain input on additional areas for USPTO and FDA collaboration.  The agencies are seeking broad feedback from patients, healthcare providers, and industry alike.   The PTO asks stakeholders to consider several questions (while emphasizing that this list is not all-inclusive).  Specifically, the PTO seeks feedback on:

• Publicly available FDA resources that should be included when training USPTO patent examiners to assess the patentability of claimed inventions;
• Mechanisms to assist patent examiners in determining whether patent applicants have submitted inconsistent statements to the USPTO and the FDA;
• Opportunities and challenges related to the use of AIA proceedings to address the patentability of claims in pharmaceutical and biotechnological patents;
• Collaboration and information exchange between the USPTO and the FDA with respect to patent term extensions;
• Additional information to provide the public regarding patent term extensions;
• Policy considerations the USPTO and FDA should explore related to method of use patents and associated FDA use codes;
• Policy considerations the USPTO and FDA should explore in relation to the patenting of risk evaluation and mitigation strategies (REMS) associated with FDA-approved products;
• Steps, other than those set forth in the USPTO letter, the USPTO and FDA could take to collaboratively address concerns about potential misuse of patents to improperly delay competition or to promote greater availability of generic versions of scarce drugs that are no longer covered by patents;
• Any additional input on any of the initiatives listed in the USPTO Letter.

The USPTO, in collaboration with FDA, is waiting to hear from you, so provide your comments before the docket closes in February.  In the words of the esteemed Dr. Frasier Crane, the USPTO says: “I’m listening.”

It is widely expected that the fate of the VALID Act – and therefore the world of diagnostic regulation – will be determined in the next two weeks (see our previous post here).  While the potential mitigating impact of the “grandfathering” clause on laboratories currently offering LDTs has been the focus of much attention, many of the numerous other provisions have received little attention.  One example is a short provision that could have a large adverse effect on telehealth-based laboratory testing by sharply restricting grandfathering.

This is not a trivial matter.  Telehealth has become increasing important to the health care system.  It has undergone dramatic recent growth, due in part to COVID-19.  Telehealth can address significant issues with access and convenience.

In response to concerns that VALID would harm health care by blocking currently available tests, the grandfathering provision has been expanded.  However, not all LDTs currently on the market would qualify for grandfathering.  One significant limitation is that VALID would prohibit laboratories from performing LDTs on specimens collected at home unless the specimen collection devices used for such collection are FDA authorized for the specific type of testing performed by the laboratory.  While there are numerous commercial products labeled for sample collection by health care professionals, there are very few collection devices explicitly “authorized” for at-home collection.  Thus, this condition could force laboratories to reduce – or even discontinue — home collection-based testing. (FDA has, in fact, been very resistant to allowing home collection devices on the market, but that’s another story for another day.)  Although on its face the restriction applies to LDTs, collection device manufacturers could, as a consequence, effectively be precluded from continuing to market their specimen collection devices to labs offering LDTs which enable home collection unless they first obtain authorization specifically for home collection.

The latest draft of the VALID Act being circulated states (Section 587G) that “in vitro clinical tests” (a term that encompasses tests now offered as LDTs) will be exempt from the new statutory requirements if they were “first offered for clinical use … not later than 45 days after the date of enactment” of the legislation, as long as they meet certain conditions.

Of relevance here, the grandfathering provision applies to an LDT only if:

• The test is not for use with home specimen collection, unless the specimen is collected with a collection container, receptacle, or kit that—
  1. has been approved, cleared, or authorized by the Secretary for home specimen collection and the collection is performed pursuant to the approved, cleared, or authorized labeling, including any indication for use as prescription use or over-the-counter use, or
  2. is exempt from premarket review and its use is consistent with applicable limitations on the exemption. (Emphasis added)

This provision could upend longstanding laboratory practice.  Laboratories routinely test specimens collected in a wide range of specimen types (e.g., blood, urine, saliva) that have been collected using a variety of specimen collection devices.  Laboratories also routinely supply third-party sourced collection devices from IVD manufacturers and distribute them to end users, which may include blood collection stations, physician offices, or – increasingly – individuals at home.  Laboratories are responsible under CLIA to ensure that the specimen collection and transport method adequately maintains sample integrity.

Many of these collection devices are classified as Class I, 510(k)-exempt (e.g., capillary blood collection tube) while some are Class II and require 510(k) clearance (e.g., blood specimen collection device).   The classification regulations typically are worded generically, i.e., they do not specify the type of test that can be performed on the specimen or the setting in which specimen collection must be performed.  Collection device manufacturers routinely sell these devices to laboratories for general specimen collection purposes, without labeling or promoting them for a specific type of test or the setting of collection.  Laboratories take these collection devices, which are lawfully in distribution, and then send them to consumers.

The clause stating that the use of the collection container must be “consistent with applicable limitations on the exemption” could (and we believe in some circumstances likely would) be interpreted by FDA to prohibit home collection unless the collection device was specifically authorized for the type of test being performed by the laboratory.  FDA has in fact asserted this position in the past: CRL v. Sullivan involved an effort by FDA to prohibit a clinical laboratory from offering LDT-based HIV antibody testing on urine and saliva specimens on the basis that the specimen collection devices did not have FDA premarket approval for such testing.  While the appellate court in that case disagreed, based on the “common sense” proposition that the “function of generic . . . specimen containers does not vary with the protocols later executed upon the samples they hold” – the VALID Act’s provision could provide renewed support for FDA’s position.  FDA could also argue that products that are otherwise exempt lose that exemption if they are intended to be used by patients for home collection.The specimen collection provision could therefore limit consumer access to a wide range of laboratory testing via “telehealth.”  Home specimen collection is a linchpin of remote laboratory testing, which has grown in popularity because of the pandemic but is expected to continue to grow significantly even in a post-COVID environment (see here).  The inability to offer existing LDTs via telehealth could create substantial barriers to consumer access to home tests.

In summary, under the VALID Act’s “grandfathering” provision, laboratories may continue performing their LDTs on home-collected specimens only if the specimen collection devices have been specifically authorized for such use or, for devices that are otherwise exempt from FDA review, the device’s use is deemed consistent with the limitations on that exemption.  Since very few specimen collection devices include home use indications and FDA could take the view that an otherwise exempt device forfeits the exemption if intended for home use, the VALID Act may effectively limit the performance of LDTs to specimens collected in a healthcare setting.  Telehealth-based laboratory services providers may well find it much harder to source LDTs, which are critical to caring for their patients.

As far as we can tell, inhibiting telehealth-based laboratory services is not a goal of the legislation, but an inadvertent side effect. Indeed, creating barriers to telehealth-based laboratory testing would appear contrary to bipartisan Congressional efforts to foster telehealth flexibility during the pandemic (see here) which stakeholders have overwhelmingly urged Congressional leaders to extend (see here).  It similarly is out of step with HHS initiatives aimed at expanding telehealth to enable direct to consumer care (see here).

Thus, this seemingly insignificant clause in VALID could have far reaching, unintended consequences.  This makes us wonder what else is lurking in this is nearly 250-page, 43,000-word bill that could have far-reaching – and unintended – consequences. The legislation never received any consideration by a House committee.  And it has never been reviewed as a standalone bill by either chamber.  The seemingly inadvertent limitation on home testing for telehealth stands as a warning sign that the effects of the bill should be better understood by Congress before the bill is enacted.

Last summer, FDA published a draft guidance, Laser-Assisted In Situ Keratomileusis (LASIK) Lasers – Patient Labeling Recommendations (July 29, 2022) setting forth a proposal for new recommended patient‑directed labeling.  It is focused on excimer lasers with premarket application (PMA) approval for LASIK  in product code LZS.  This proposal is not, however, simply advice for preparation of an application for a new device.  The draft guidance purports to apply to current PMA holders.  This broad scope is curious.  The approved devices already have patient‑directed labeling that FDA has approved.  Why would it be necessary for FDA to issue a new set of patient labeling recommendations in a non‑binding guidance?  How could the manufacturers even follow this guidance without illegally departing from their previously approved labeling?  What is going on here?

Draft Guidance

In the draft LASIK guidance, FDA has a 15‑page outline of recommended patient labeling, broken into 10 subsections that would address things like the risks, benefits, and possible alternatives to LASIK.  In an appendix, FDA provides a model “decision check list” for patients.  It looks similar to the type of procedural informed consent a surgeon ordinarily would present to a patient.  The introductory paragraph states:

The review and understanding of this document is a critical step in making the decision whether you should choose LASIK surgery.  This form lists important risks, including those known or reported to be associated with the use of the LASIK laser devices based on information from clinical trials, scientific literature, and reports from patients who have undergone LASIK.  After reviewing the information . . . please read and discuss the items in this checklist with your doctor. You should place your initials in the location provided next to each item to indicate that you have read and understood the item. Your full signature at the end of this document means that you have read and understood the materials and that your physician has answered all questions to your satisfaction.  [Draft LASIK Guidance at 22.]

Public Comments

It was this apparent foray into the realm of informed consent that appears to have provoked considerable backlash in the public comments on the draft guidance.  The Refractive Surgery Council (RSC) and Society for Excellence in Eyecare (SEE), the Medical Device Manufacturers Association (MDMA), and even the Commonwealth of Kentucky’s attorney general (AG) all requested the draft guidance be withdrawn.  All of them stated some version of an argument that this guidance requires labeling that will overlap and potentially clash with the informed consent process.  MDMA, for example, states:

The patient labeling recommendations in the Draft Guidance inappropriately require manufacturers, rather than surgeons, to provide information to patients regarding the risks of LASIK as a procedure, as distinct from the risks of the approved device (i.e. excimer laser systems) used to perform the procedure. The Draft Guidance incorporates a Patient Decision Checklist Example (the “Checklist”) at Appendix A, which would become part of the device’s labeling.  There appears to be significant overlap in content between the Checklist and informed consent forms and processes routinely provided by healthcare providers to their patients. MDMA is concerned this Checklist will not assist patients in their decision regarding whether to undergo surgery, but rather do the opposite by presenting potentially conflicting informed consent information. In addition, the Checklist is not device-specific and may not reflect the data contained in the manufacturer’s premarket approval application (PMA). This proposal is a[n] . . . intrusion [into] the doctor-patient relationship.

The Kentucky AG uniquely adds that FDA’s proposal improperly interferes with the Commonwealth’s exercise of supervisory authority over its physicians, including statutes addressed to obtaining informed consent.

There was also controversy in the comments over how to characterize LASIK’s risks, underscoring how far FDA seems to have strayed from its statutory mandate.  The argument was not about evaluating the performance of a particular device, which is FDA’s bread and butter.  Rather, it was about the assimilation of the full range of available medical data and information to assess how procedural risk generally should be conveyed to patients, regardless of the specific LASIK device being used.

More than one commenter on the draft guidance was troubled that FDA’s proposed labeling fails to incorporate most recent data bearing on LASIK’s risks.  Additionally, several of the commenters pointed out apparent errors in FDA’s characterization of risk.  We are not equipped to say who is right about the data, but this dialogue seems to be playing out on the medical professionals’ home turf.

Regulatory Analysis

We return now to the puzzle of how these new draft recommendations relate to the previously approved labeling for these devices.  FDA describes the legal effect of the draft guidance as follows:  “The contents of this document do not have the force and effect of law and are not meant to bind the public in any way. . . .  This document is intended only to provide clarity to the public regarding existing requirements under the law.”  In this context, this statement is absurd.  FDA has already approved the patient labeling in connection with each individual manufacturer’s PMA approval.  None of the manufacturers require any clarification, since FDA has already specifically reviewed and approved the labeling.

At the end of this discussion, we learn what the game is.  The draft guidance states (p. 4):  “FDA intends to work with manufacturers of new LASIK devices through the premarket approval application (PMA) process, and manufacturers of currently marketed LASIK devices through the PMA supplement process, to integrate these important labeling recommendations.”

FDA’s statement tacitly concedes that current PMA holders have a limitation on their ability to adopt the recommendations in this guidance.  As a legal matter, they would need to first obtain supplemental approval from FDA granting them permission to do so.  It appears that the purpose of the guidance is really to induce manufacturer’s to seek approval of a labeling change, and to direct them as to what changes they should request.  As FDA points out, the agency can readily impose this labeling for new devices during an original PMA process, but they need existing PMA holders to “voluntarily” file supplements to make these changes.

The draft guidance is directed at devices in the LZS product code, most of which originally gained approval in the mid‑1990s to early 2000s.  While there are PMA supplements steadily filed in this product code until the present, it appears from FDA’s database that the last original PMA approval was in 2006.  Therefore, it is likely that this guidance is really directed at existing PMA holders.

It would seem that these targeted PMA holders would be on rock solid legal ground to ignore the guidance.  They may legally continue to use their existing PMA‑approved labeling.  No doubt, if FDA persists, some manufacturers may be unable to resist the pressure.  That does not speak to the propriety of this maneuver.

A final word about the limits of FDA’s authority.  FDA is not categorically barred from requiring manufacturers to provide patient information.  These lasers were previously approved with patient information booklets.

The problem here is that FDA seeks to substitute new patient labeling based on a generalized assessment of procedural outcomes obtained via a wide range of medical information, not device‑specific evaluations.  And, perhaps more important, FDA is requesting that the labeling convey risk information to patients that clearly overlaps with routine surgical informed consent.  FDA’s mandate, however, is to supervise the safety and effectiveness of specific devices used in LASIK procedures.  FDA is not authorized to impinge on the informed consent process.  It is a subtle distinction, but it is well established and is usually honored by the agency.  In this case, it appears that FDA has crossed over the line.

With the explosion of health‑related software, many software developers are generating products with functionality that is subject to regulation by the Food and Drug Administration (FDA).  If you are a manufacturer of implants that go into the human body for the treatment of disease, it’s an easy yes that you are a manufacturer of a medical device. But, for software products, it is often not straightforward to address this question by simply referring to the statutory definition of a device. Determining whether your product meets the definition of a medical device has significant implications, such as whether you need to comply with the Federal Food, Drug, and Cosmetic Act (FD&C Act).

This blog post describes the medical device determination process and a way of assessing software functions to determine if your software product is subject to FDA regulations.  While the methodology for determining if your product is a medical device has not changed, FDA’s Digital Health Policy Navigator (“Navigator”) provides a convenient and efficient framework for developers to assess software functions.  This interactive 7-step process guides developers in assessing each discrete software function in a product.  It identifies key questions to consider that originate from a variety of FDA guidance documents and aggregates the information into a one-stop shop. While the Navigator should not be used in place of seeking regulatory advice, it is a helpful tool to review when determining what features of a software product may be subject to FDA oversight.

Medical Device Determination Process

The first step of the device determination process is to compare the intended use and indications for use of your product against the above statutory definition of a device (see here).  Section 201(h)(1) of the FD&C Act defines a medical device, in pertinent part, as an “instrument, apparatus, implement . . . or other similar or related article” which is “intended for use in the diagnosis of disease or other conditions.”  Note that section 201(h)(1) of the FD&C Act ends with the sentence “[t]he term “device” does not include software functions excluded pursuant to section 520(o).”

Thus, the second step is to determine if an appropriate product classification exists for your product. This can be done by either searching the FDA Product Classification Database or searching for similar devices. Please check out FDA’s presentation on this very topic – Is My Product a Medical Device? (See here for the slides, here for the recording of the presentation, and here for the transcript.)

In case your product meets the definition of a device but an appropriate product classification is not identified, you may need to submit a de novo classification request to FDA. Also, even if your software product meets the definition of a device, there is a chance that your product meets one of the five carve-outs described below.

Section 3060(a) of the 21st Century Cures Act amended the FD&C Act to add section 520(o), which provides carve-outs from the definition of device in section 201(h)(1) of the FD&C Act.  These are functions that are intended for (1) administrative support of a health care facility, (2) maintaining or encouraging a healthy lifestyle, (3) serving as electronic patient records, (4) transferring, storing, converting formats, or displaying data and results, and/or (5) providing clinical decision support. Manufacturers of software products should determine whether their software functions are excluded from the definition of a device.  If the software functions do not meet the definition of a device under section 201(h)(1) of the FD&C Act or are excluded from the device definition by section 520(o) of the FD&C Act, FDA does not regulate them as devices.

There are multiple resources that FDA provides to facilitate the understanding of the Agency’s thinking regarding the amended device definition and the interpretation of section 3060(a) of the Cures Act, including sections 520(o)(1)(A)-(D) of the FD&C Act.  The following Guidance documents are critical to understanding the FDA’s policy for software products:

• Changes to Existing Medical Software Policies
• General Wellness: Policy for Low Risk Devices
• Policy for Device Software Functions and Mobile Medical Applications
• Clinical Decision Support Software
• Off-The-Shelf Software Use in Medical Devices
• Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices
• Multiple Function Device Products: Policy and Considerations

Digital Health Policy Navigator Tool

FDA  developed the Digital Health Policy Navigator (Navigator) to aggregate the FDA’s digital health guidance documents into one user-friendly resource.  The Navigator guides manufacturers in their assessment of whether a particular software function meets the device definition and if so, whether it is the focus of FDA’s regulatory oversight. A software function is the distinct purpose of the product which could be the intended use or subset of the intended use of the product.  The Navigator is designed as an interactive overview with seven simple steps, each with a set of questions that should be answered for each software function.  It then identifies the applicable laws, guidances, and policies that may apply.

• Step 1: Is the software function intended for a medical purpose?
• Step 2: Is the software function intended for administrative support of a health care family?
• Step 3: Is the software function intended for maintaining or encouraging a healthy lifestyle?
• Step 4: Is the software function intended to serve as electronic patient records?
• Step 5: Is the software intended for transferring, storing, converting formats, or displaying data and results?
• Step 6: Is the software function intended to provide clinical decision support?
• Step 7: Does the Device Software Functions and Mobile Medical Applications Guidance apply?

The possible outcomes from the Navigator are:

• Likely not a device
• Likely FDA intends to exercise enforcement discretion
• Likely the focus of FDA’s regulatory oversight
• Your product may be a device

Below, we reproduced the Navigator’s process in a flowchart format so that our blog readers can quickly arrive at an outcome and its implications for their software product. The flowchart can be downloaded here. For detailed explanations for each step, please refer to the Digital Health Policy Navigator. We appreciate FDA’s efforts to aggregate relevant resources so that manufacturers can more easily identify whether their software products are subject to regulation.