Similar to what was done with COVID-19, the National Institute for Health (NIH) Rapid Acceleration of Diagnostics (RADx) initiative has established a Monkeypox Independent Test Assessment Program (ITAP) and it currently accepting new proposals on a rolling basis to address the outbreak.  The program began accepting proposals on September 7, 2022, from manufacturers that have existing technologies and can scale production, while meeting FDA quality requirements.

The focus of the program is for both molecular and antigen tests that can be used in either point-of-care settings or home use. The program is currently not accepting applications for antibody tests (HPM has blogged previously about FDA’s Monkeypox Policy here).  The program provides support to manufacturers by providing both analytical and clinical testing that meets FDA requirements for an EUA submission.

Manufacturers can apply if they meet the following criteria:

• Demonstrated capacity for manufacturing and distributing high-quality in vitro diagnostics, AND at least one of the following:
  • An existing technology adapted for POC or home detection of monkeypox virus, at design lock, with performance data
  • An existing monkeypox virus test kit available for POC or home diagnostic use in international markets
  • A self-collection kit for monkeypox virus samples which can be modified and optimized for at-home use

Getting accepted into the ITAP program may be your best bet in getting a subsequent EUA for your Monkeypox test, because (as of right now) there is only one cleared comparator to use for your clinical testing, CDC’s non-variola orthopoxvirus test.  It may be difficult to set up a clinical study on your own as use of the CDC’s assay is limited to Laboratory Response Network (LRN) designated laboratories. In addition, the ITAP program provides the manufacturer an entire project team and necessary resources to ensure the analytical testing is completed quickly and meets FDA requirements.

In addition to filling out the application for the ITAP program, manufacturers will still need to submit their intent to file an EUA with the FDA within 30 days of the FDA Monkeypox policy being announced in the Federal Register.  This means you should complete both your ITAP submission and your intent to submit an EUA to the FDA now — or you may miss being considered for priority review.

FDA recently published Alternative or Streamlined Mechanisms for Complying with the Current Good Manufacturing Practice Requirements for Combination Products; List under the 21st Century Cures Act in the Federal Register (FR Notice).  By way of background, 21 C.F.R. § 4.3 requires generally that manufacturing of a combination product (CP) must comply with the applicable current Good Manufacturing Practice regulations (cGMPs) for all of its components (i.e., a drug/device CP must follow the cGMPs for drugs as well as those for medical devices).  21 C.F.R. § 4.4 provides an optional alternative streamlined approach for current good manufacturing practices (cGMPs) for manufacturers of drug-device combination products (CPs).  The 21st Century Cures Act required FDA to publish in the Federal Register a list identifying types of CPs and manufacturing processes that may vary from the requirements of § 4.4, or that FDA proposes can satisfy the requirements in § 4.4 through alternative or streamlined mechanisms.  FDA must also review the list periodically.  FDA published a proposed list on June 13, 2018 (83 FR 27609), which we blogged about here.

The recent FR Notice does not modify § 4.4, but instead describes FDA policy on applying § 4.4, much like an FDA guidance document.  The FR Notice also emphasizes in several places that interaction with the Agency may be needed when applying alternative or streamlined mechanisms for complying with cGMP requirements for CPs.

For manufacturers of CPs that have established a quality system that complies with the full requirements of 21 C.F.R. Part 820 Quality System Regulation and additional provisions from 21 C.F.R. Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals, the list describes alternative mechanisms for complying with the requirements in § 211.165 Testing and Release for Distribution, § 211.166 Stability Testing, § 211.167 Special Testing Requirements, and § 211.170 Reserve Samples.

The list of alternative mechanisms for complying with Part 211 in this FR Notice is not different from what was proposed in the 2018 FR Notice.  Of the six comments FDA received on the 2018 FR Notice (five were published), only one raised Part 211. FDA added some clarifying language or examples (shown below in italics) to the Part 211 list:

• Section 21 C.F.R 211.165 – Testing and Release for Distribution: Manufacturers may be able to use product samples that are not finished combination products when performing the required testing, but they would need to establish that any differences in the manufacturing process for the sample used, as compared to the finished combination product, do not affect the drug constituent part (i.e., there is no difference in the quality attributes related to the drug constituent part in the representative sample as compared to the attributes related to the drug constituent part in the finished combination product).

• Section 21 C.F.R 211.166 – Stability Testing: Manufacturers may be able to leverage stability knowledge, data, or information for an already marketed combination product, for example, when the new combination product is a modification of an already marketed product and the modification does not impact the stability of the drug constituent part.
• Section 21 C.F.R 211.167 – Special Testing Requirements: Manufacturers may be able to define “batch” based on the drug constituent part rather than the finished combination product for purposes of special testing requirements involving pyrogens and endotoxins. This mechanism would only potentially be available if there would be no impact on the endotoxin and pyrogen levels for the finished combination product from subsequent manufacturing processes, including when the constituent parts are combined to produce the final combination product (e.g., there are no statistically significant differences in pyrogen or endotoxin test results for the combination product immediately following a drug coating process step as compared to the finished combination product).
• Section 21 C.F.R 211.170 – Reserve Samples: Manufacturers may be able to use validated surrogates as representative samples to meet the requirements of this regulation, provided the surrogate is appropriate, both in terms of the manufacturing process and the characteristics of the container closure. It may be permissible to maintain as a reserve sample only the drug-containing subassembly of a single-entity combination product, such as only the distal tip subassembly (with drug-containing collar) of a pacemaker lead without the associated internal electronic components, or the drug constituent part of a co-packaged combination product, such as the prefilled cartridge of a combination product that is distributed as a prefilled cartridge with an injector system.

For manufacturers of CPs that have established a quality system that complies with the full requirements of 21 C.F.R. Part 211 and additional provisions from 21 C.F.R. Part 820, the list provides information on integration of the design control requirements within a pharmaceutical development program and discussion of exemption from cGMP requirements for applicable device constituents.

The FR Notice notes that many design control requirements may be addressed by a robust pharmaceutical development program, but adds that it is important to align terminology with design control principles and ensure that any design control elements not covered by pharmaceutical development procedures are documented.  Emphasis is placed on ensuring that management of postmarket design changes to the CP follows the requirements of § 820.30.

Some low-risk devices  are exempt from cGMPs except for complaint handling and record keeping requirements, e.g., a liquid medication dispenser (21 C.F.R. § 880.6430).  The FR Notice clarifies that these devices may also be exempt from the provisions of Part 820 called out in §4.4.  For determining if the device constituent of a CP is GMP exempt, the FR Notice references the .9 regulations (e.g. § 880.9).  Although the .9 regulations describe limitations for 510(k) exemption and not GMP exemption, FDA intends to apply the same exemptions for purposes of determining if the device constituent of a CP is GMP exempt.

For any specific CP there can be nuances, so interaction with the Agency may be warranted to obtain FDA feedback prior to making a premarket submission or submitting a postmarket supplement.  The FR Notice provides guidelines on types of interactions and information to provide in a request.

Overall, the FR Notice provides additional options for CP manufacturers to reduce burdens by streamlining their approach to cGMPs, but FDA wants to be involved in decisions to use these approaches.

On September 14, 2022, FDA/CDER/Office of New Drugs, in collaboration with the Duke-Margolis Center for Health Policy, hosted a virtual meeting on advancing premarket safety analytics, including sessions on new FDA Medical Queries and standardized presentations of safety data. For a number of years, FDA has been including groups of related preferred terms in tables in the Adverse Reactions Section of drug labeling (Section 6), generally describing such groupings with the use of footnotes. For example, Table 20 in Section 6 of the current Latuda labeling includes the term “somnolence” with the footnote “Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence.” Such groupings have generally seemed to appear in labeling on an ad hoc basis, without standardization. At the September 14 virtual meeting, FDA demystified these groupings by announcing the FDA Medical Queries (FMQs), followed by an open discussion. The FMQs include some 100 standardized groups of related MedDRA preferred terms to be used in the identification and labeling of adverse drug reactions.

Typically, clinical trial subjects are questioned regarding adverse events, and investigators record them in their own words. Such descriptions are called ‘verbatim terms,’ and may include medical shorthand. For example, ‘Hip Fx after fall’ might be recorded for a patient who fell and sustained a hip fracture. A verbatim term cannot be analyzed, however, until it is translated into its corresponding standard ‘preferred term,’ or in this case, two preferred terms: ‘Fall’ and ‘Hip Fracture.’ There are over 24,000 preferred terms, each serving essentially as a standard safety outcome that can be tabulated for a clinical trial(s). For example, one could calculate the percentages of patients in the drug and control groups with a hip fracture. The problem is that adverse reactions are generally broader than a single preferred term. In this case, for example, it seems likely that if a drug predisposes patients to hip fractures, it would predispose to other fractures. Thus, one would like to quantify all fractures—not only hip fractures. Thus, as illustrated by this example, the objective of a query is to combine similar terms to create meaningful analyses of adverse drug reactions, e.g., fractures, pneumonias, seizures.

FDA shared the following example to show how the use of queries can lead to a more accurate characterization of adverse drug reactions. In this example, only adverse events with a frequency >2% in the drug group were to be included as adverse drug reactions. When assessing anxiety as a single preferred term, the frequency in the drug group was slightly less than 2%; therefore, anxiety was not classified as an adverse drug reaction. When related preferred terms were included in an anxiety query, e.g., ‘nervousness,’ ‘general anxiety disorder,’ the frequency exceeded 2% and was included as an adverse reaction in the drug labeling. This example represents a situation where the existence of the adverse drug reaction depends on whether it is based on a single preferred term (‘anxiety’), or a grouping of anxiety-related preferred terms.

MedDRA, the Medical Dictionary for Regulatory Activities, maintains the list of preferred terms used internationally, and provides a large number of Standard MedDRA Queries (SMQs), which are used routinely by many companies. As I pointed out at the meeting however, as noted on the MedDRA web site, “SMQs are tools developed to facilitate retrieval of MedDRA-coded data as a first step in investigating drug safety issues in pharmacovigilance and clinical development.” Conversely, the FMQs have been developed specifically for use in assessing the safety of new drugs and biologics in clinical development. Dozens of FDA medical experts contributed to the development of the FMQs, all with longstanding interest in drug safety, which makes them fit-for-purpose. FDA is also beginning the development of “algorithmic” FMQs that combine preferred terms with laboratory data and temporal information.

The discussion on FMQs was followed by an introduction to FDA’s new “Standard Safety Tables and Figures: Integrated Guide.” FDA provided presentations on standard safety tables and figures, tabulation of adverse events, statistical considerations in the analyses of adverse events, discussion of relative risk vs. risk differences, and advice on pooling trials (including Simpson’s Paradox), ascertainment windows, standard laboratory analyses, and drug-induced liver injury.

It seems likely that FDA will encourage use of FMQs and these analytical methods and presentations for premarket safety data, but will not mandate these activities at this time. It also seems likely that FDA will be running these FMQs on many NDAs and BLAs under their review, and will be incorporating the results in labeling. Running FMQs on clinical datasets prior to, or during, NDA review could shed important light on FDA’s safety concerns and may become an industry best practice. Because we believe such information is highly important, HPM has developed the capacity to run the FMQs for our clients with a rapid turn-around time.

In a recent JAMA editorial (unfortunately behind a paywall), three authors called for increased use of the Park Responsible Corporate Officer doctrine, under which senior level officials at a company can be held liable under a strict liability theory even if they were not involved in, or even knew about, the alleged violations of the Federal Food, Drug, and Cosmetic Act (United States v. Park, 421 U.S. 658 (1975)).  While the authors did a yeoman’s job of combing through the criminal cases to identify what they view as a “handful” of cases and call for increased use of the Park doctrine, we at the FDA Law Blog respectfully disagree.  We note our prior writings on the subject, which extend to five pages of posts,.  We note further that the JAMA editorial cites our own John Fleder, which makes sense since John is one of the foremost experts on Park liability from his time at the Department of Justice’s Office of Consumer Litigation as well as private practice with our firm.  An interesting historical sidenote is that if one looks at the official Park decision from the Supreme Court, one will find our own Paul Hyman who was one co-author of the amicus curiae briefs.  Our own reactions to the decision when it came out was somewhat muted, given that we were in our low single digits at the time of the decision.

The JAMA editorial notes that there are few Park cases for two primary reasons:

[The government] may lead . . . favor cases of clear intentional wrongdoing over cases of mere negligent oversight. Others may be uncomfortable with the strict liability premise of the Park doctrine, adhering to the value that punishment should not be inflicted without proof that the defendant intended to commit wrongdoing. The public may harbor similar doubts, leading prosecutors to avoid putting Park cases before juries.

These intuitions about fairness weigh against policy interests designed to protect the public health. The logic of the Park doctrine in its special applicability to medical products is to bring special legal vulnerability for problematic products to the executives who participate in the lucrative marketplaces of human health and illness, rather than have that risk borne by the patients who depend on the products or only by impersonal corporate entities less responsive to sanctions. The drug and medical device industries present particularly compelling arenas in which to pursue deterrence through such prosecution because misconduct can carry high levels of public risk.

The editorial conflates a number of distinct but related principles of law and federal prosecution.  First, regardless of Park, under the FDC Act, any individual who commits an FDC Act violation can be held liable for a strict liability misdemeanor, regardless of whether the individual is a responsible corporate officer.   Second, because of this strict liability exposure, an individual can be charged with an FDC Act misdemeanor as a lesser included offense any time DOJ charges an FDC Act felony.  Therefore, as a matter of proof, DOJ can obtain a misdemeanor conviction even when a jury acquits on a felony.  Third, while the sanction in the original Park case was a $50 fine, DOJ can seek terms of imprisonment for misdemeanor violations and when multiple counts are involved, seek consecutive sentences.  Last, because of the tremendous power given government prosecutors under this strict liability misdemeanor statutory framework, it is critical that those prosecutors exercise prosecutorial discretion, which is why the Justice Manual identifies a host of factors that prosecutors should consider before bringing any criminal charge.  A Park case should be no different.  It’s one thing to prosecute a corporation for the actions of employees since a corporation, while a legal entity, can only act through the individuals that make up that entity.  And if the corporation lacks the regulatory and compliance functions necessary to ensure safe products, then it makes sense to punish that corporation.  It’s another thing entirely to prosecute individuals who were not involved in the misfeasance and were unaware of the alleged violations.  It’s a bedrock principle of criminal law that crimes require an actus reus (the prohibited act) and the requisite mens rea (mental state).  While strict liability criminal statutory schemes are an exception to that rule, we don’t agree that the government should bring a Park case just because it can.

On August 9, 2022, the Secretary of the Department of Health and Human Services (HHS) declared the outbreak of monkeypox virus a public health emergency (see announcement here).  On September 7, 2022, the Secretary of HHS declared that “circumstances exist justifying the authorization of emergency use of in vitro diagnostics for detection and/or diagnosis of infection with the monkeypox virus, including in vitro diagnostics that detect and/or diagnose infection with non-variola Orthopoxvirus,” thereby opening the door for submission of requests for emergency use authorization (EUAs) of monkeypox tests.

On the same day, September 7, CDRH published a policy for monkeypox tests.  CDRH has also published templates for EUA requests.

This policy and the EUA templates mirror the approach taken by FDA for COVID-19.  With COVID-19, CDRH was forced to “build the plane while flying it,” in that it had to create the administrative infrastructure and related guidance and templates while simultaneously issuing the first round of EUAs.  This led to delays in releasing a uniform policy and templates for COVID-19, as well as many other problems (see blog post chronicling some of the challenges here).  Now that FDA has worked out an approach to EUAs through COVID-19, it seems the agency has more easily launched a similar framework for monkeypox on the same day as the HHS declaration permitting EUAs for IVDs.

The monkeypox test policy describes how FDA will prioritize review of EUA requests for monkeypox tests, stating that FDA intends to focus on requests for high-throughput tests, tests with home specimen collection, or rapid diagnostic tests, all from experienced developers with high manufacturing capacity.

We note that this policy defines an “experienced developer” more narrowly than the COVID-19 policy.  For monkeypox, an experienced developer is one who has “successfully been issued an EUA” or received approval or clearance for a diagnostic test.  For COVID-19, an experienced developer is one who has only “interacted with FDA through an EUA request or pre-EUA submission,” regardless of success.  This narrower definition of experienced developer may make it more difficult for new companies to break in compared to COVID-19, where many novice companies submitted EUAs.

Additionally, to be subject to prioritized review, test developers are advised to send preliminary information to FDA by email within 30 days after publication of this policy to indicate their intent to submit an EUA request for a monkeypox test.  The preliminary information should include a description of the test technology; manufacturing capacity; test throughput; expected timeline for development, validation, and submission of an EUA request; and any available validation data.  FDA intends to respond to developers by email to indicate whether they intend to prioritize the proposed test.  As with COVID-19, “prioritization” simply means that FDA will review the EUA; if the test is not a priority, FDA will decline to review.

This process for submitting preliminary information to FDA appears to be one area where CDRH is applying a lesson-learned from its approach to COVID-19.  With COVID-19, CDRH has similar criteria for priority review.  However, it was not always clear to developers, prior to submission of an EUA request, whether their test would satisfy the priority criteria.  This led to many developers spending the time and money to validate a test and prepare an EUA request, only for it to be rejected – or languish in regulatory limbo – as a non-priority.  With this new monkeypox policy, it appears test developers will have the opportunity to learn prior to completion of validation whether their test will be granted to priority review.

The policy states that FDA, at this time, does not intend to object to monkeypox tests developed and performed in a high-complexity, CLIA-certified laboratory “to address immediate capacity needs.”  Additionally, if a high-complexity, CLIA-certified laboratory modifies a cleared or authorized monkeypox test, and the modifications do not change the indications for use or change the analyte specific reagents, FDA does not intend to object to implementation of the modification without a new 510(k) or EUA.

The policy also addresses serology tests.  Incorporating some insights gained from its initial policy for COVID-19 serology tests, FDA is approaching monkeypox serology tests in a more restrictive manner.  The policy cautions that serology tests “can provide information that may further our understanding of the disease process,” but cannot diagnose infection and “are not tests of immunity.”  FDA does not intend to object to the use of monkeypox serology tests that are developed and performed by high-complexity, CLIA-certified laboratories that are “part of an entity that conducts research on diseases and is integrated into the direct medical care of the patient” (i.e., academic medical center laboratories).  Such laboratories are not required to submit an EUA, so long as they submit a notification to FDA and include disclaimer statements in test reports (exact language in the policy), which clarify that the test results are not for diagnosis.

Finally, the policy emphasizes the importance of validation data, and states that FDA is providing EUA templates.  While the policy notes that “recommendations in the templates are voluntary,” we have learned from experience with COVID-19 EUAs that CDRH will likely adhere closely to the template guidelines and will be resistant to deviate from the FDA-recommended approach to validation.  Compared to the COVID-19 templates, the monkeypox EUA template appears to include more detail about what is expected, and includes many check-the-box responses from lists of options (e.g., for interfering substances) rather than open-ended prompts in which developers can draft descriptive summaries.  This format may lead to more uniformity in initial EUA submissions, which may cut down on interactive requests from EUA reviewers for clarifying information.

As we have learned from COVID-19, CDRH’s monkeypox policy and EUA templates will likely evolve over time as CDRH begins to receive EUAs and learns more about the unique validation issues that may arise with monkeypox tests.  That said, monkeypox test developers are starting with much more guidance from CDRH compared to COVID-19, which will hopefully lead to submission of EUAs that are more likely to meet CDRH’s expectations, and in turn, lead to faster roll-out of high-quality tests.

In a speech last week, Deputy Attorney General Lisa Monaco touched on a number of topics that should interest readers of this blog.  First, although the topic of her speech was corporate criminal enforcement, DAG Monaco stressed that DOJ’s “number one priority is individual accountability.”  While individual accountability is not a new theme, the speech suggested that companies may see a new level of urgency to government investigations. DAG Monaco stated, “In individual prosecutions, speed is of the essence.”  For companies (who routinely control the documents and information relevant to the government’s investigation of individuals), she warned “undue or intentional delay in producing information or documents—particularly those that show individual culpability—will result in the reduction or denial of cooperation credit” for the company.

The next topic that DAG Monaco addressed was corporate recidivism.  The speech explained how DOJ will look at that issue. Of particular interest to readers of this blog, she noted “if a corporation operates in a highly regulated industry, its history should be compared to others similarly situated, to determine if the company is an outlier.”  She also explained that while the evaluation of prior misconduct is a multi-factor analysis, “dated” misconduct is given less weight, defining dated as “[c]riminal resolutions that occurred more than 10 years before the conduct currently under investigation, and civil or regulatory resolutions that took place more than five years before the current conduct.”  Of further interest to those considering acquisition of a company with a troubled past, DAG Monaco explained “We will not treat as recidivists companies with a proven track record of compliance that acquire companies with a history of compliance problems, so long as those problems are promptly and properly addressed post-acquisition.”

The speech’s third topic, voluntary self-disclosure is potentially the most significant. DAG Monaco announced that “every Department component that prosecutes corporate crime will have a program that incentivizes voluntary self-disclosure.” While programs may vary in some respects, “Absent aggravating factors, the Department will not seek a guilty plea when a company has voluntarily self-disclosed, cooperated, and remediated misconduct.”  Whether programs will offer any guidance on what constitutes “aggravating factors”—an exception that could swallow the rule—remains to be seen.

DAG Monaco closed her speech by discussing how DOJ views corporate compensation. She explained “when prosecutors evaluate the strength of a company’s compliance program, they will consider whether its compensation systems reward compliance and impose financial sanctions on employees, executives, or directors whose direct or supervisory actions or omissions contributed to criminal conduct.”  While the speech did not identify any examples of compliance bonuses, it did note compensation clawbacks as one example of a compensation policy to deter misconduct.

We expect further guidance documents on these topics in the coming days and will continue to follow how these changes play out both on paper and in practice.

Earlier this week, President Biden signed Executive Order 14081, titled “Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and Secure American Bioeconomy.”  The Executive Order was spurred in part by the COVID-19 pandemic, but it points out that biotechnology and biomanufacturing—defined as use of biological systems to develop products, tools, and processes at commercial scale—has other uses outside of human health, including securing supply chains and growing the American economy.   Efforts to further policies outlined in the order are referred to as the National Biotechnology and Biomanufacturing Initiative (NBBI).

The Executive Order includes objectives to bolster and coordinate Federal investment in biotechnology and biomanufacturing, and to improve and expand on domestic biomanufacturing production capacity and processes while also accelerating the translation of basic research results into practice (section 1).  It also includes a Section on improving the clarity and efficiency of the regulatory process for agricultural biotechnology products (section 8).   The Executive Order also mentions the need to develop genetic engineering technologies and techniques and advance the science of scale-up production so that innovative technologies and products can reach markets faster.  We’ve only touched on a few of the objectives identified in this ambitious and all-encompassing order.

To achieve the objectives outlined in section 1, several heads of agencies, including the Health and Human Services (HHS) are to submit reports to the President through the Assistant to the President for National Security Affairs (APNSA), in consultation with the Assistant to the President for Economic Policy (APEP) and the Director of the Office of Science and Technology Policy (OSTP) within 180 days of the order.  Each report is to identify high-priority basic research and technology development, opportunities for public-private collaboration, and actions to enhance biosafety and biosecurity.  These reports will be used to develop an implementation plan and by September 2024, HHS and other heads of agencies will report on measures taken and resources allocated to enhance biotechnology and biomanufacturing per the plan.

HHS published a press-release in response to the Executive Order, stating that it will support development of 1) FDA research programs for advanced manufacturing technologies, 2) Advanced Manufacturing Innovation Hub in the FDA’s Office of Counterterrorism and Emerging Threats, 3) FDA Center for Advancement of Manufacturing Pharmaceuticals and Biopharmaceuticals, etc.  While it is not clear what HHS will discuss in its report, the FDA/CDER Emerging Technology Program and FDA/CBER Advanced Technologies Program are collaborative programs where industry, innovators/developers, and the FDA can discuss advanced technologies, including advanced manufacturing.  However, the Committee on Identify Innovative Technologies to Advance Pharmaceutical Manufacturing, indicated industry is still hesitate to implement innovative technologies due to inconsistent feedback from the FDA during these meetings.  In addition to holding meetings, FDA also solicits applications for extramural funding to support advanced manufacturing and other innovative technologies through the FDA Broad Agency Announcement and the NIH Grants and Funding portal.  While HHS mentions the FDA’s Center for Advancement of Manufacturing Pharmaceuticals and Biopharmaceuticals, there is little information on this center aside what the FDA stated in October 2021 and January 2021.  The HHS’s report may consider incorporating some of the FDA’s efforts (Framework for Regulatory Advanced Manufacturing Evaluation) to identify and implement changes in the regulatory structure to enable new technologies, including advanced manufacturing mentioned very, briefly, here.

On September 9, 2022, FDA published two notices regarding draft guidance related to labeling of drug products: a notice on the publication of a draft guidance on the Statement of Identity and Strength — Content and Format of Labeling for Human Nonprescription Drug Products and a notice on the publication of a draft guidance on the Quantitative Labeling of Sodium, Potassium, and Phosphorus for Human Over-the-Counter and Prescription Drug Products.  For both draft guidances, it is unclear what induced FDA to publish these draft guidances now.

Draft Guidance Regarding the Statement of Identity and Strength for Human Nonprescription Drug Products

FDA indicates that this guidance is intended to help manufacturers ensure consistent content and format of the statement of identity and strength for all nonprescription drug products, which then will allow consumers to compare products.  FDA’s thinking on the format to be used is quite specific.

The guidance applies to all non-prescription drugs available in the United States, including products approved by FDA and monograph drug products.  It details FDA’s interpretation of the regulation 21 C.F.R. § 201.61 regarding the statement of identity.  FDA interprets the regulation for drug products without an established name (generally monograph drug products do not have an established name) as requiring the name of the active ingredient, the pharmacological category, and strength.  (The regulation does not include a specific requirement to identify the strength of the active ingredient).  In addition, unless it is obvious, the route of administration (ROA) should be included.  For products that include more than one active ingredient, FDA recommends that this information for each active ingredient is vertically aligned.

The regulation requires that the statement of identity must be in “a font reasonably related to the most prominent printed matter on the principal display panel” (PDP).  Consistent with FDA comments in a few Warning Letters,  FDA asserts that this means that the statement of identify must be 50% or more of the size of the most prominent printed matter.  FDA does not explain how it arrived at 50% or more.  (Interestingly, in the 2019 proposal for sunscreen labeling, FDA proposed to require a size at least one quarter the size of the most prominent printed matter).

Without further discussion or explanation, FDA asserts that the requirement for the placement of the statement of identity “in direct conjunction” with the brand or proprietary name “implies that the proprietary name and the statement of identity should not be separated by any intervening matter.” (underline added).

If a monograph includes requirements for the statement of identity that are inconsistent with this guidance, FDA does not intend to take action against companies who follow the guidance.

Draft Guidance on the Quantitative Labeling of Sodium, Potassium, and Phosphorus for Human Over-the-Counter and Prescription Drug Products

For OTC drug products, this guidance (simply) restates the legal requirements included in regulations regarding the quantitative information for sodium and potassium in labeling of OTC products intended for oral ingestion. Interestingly, it provides information for manufacturers who want to include (voluntarily) the phosphorus level in the drug product.

The amount of phosphorus would be the calculated equivalent amount of elemental phosphorus from all the phosphorus-containing components. (FDA stresses that it should not be the amount of phosphate).  As is the case for sodium and potassium, the amount of phosphorus should not be declared if it is less than 5 mg per single dose because that amount is not expected to be clinically relevant.  Also, amounts should be rounded to the nearest 5 mg.  FDA recommends including this information in the Drug Facts under the heading Other information, i.e., in the same sections as where sodium and potassium (if present) will be declared.   If the product contains sodium, potassium, and phosphorus in amounts of 5 mg per single dose, phosphorus must be listed after potassium (which is listed after sodium).  However, if a voluntary statement about the absence of sodium, potassium, or phosphorus is included, it should be the last statement in the “Other Information” section.  The guidance includes several examples of the labeling.

Patients with certain conditions, such as heart failure, hypertension, or chronic kidney disease, are advised to restrict their dietary intake of sodium, potassium and/or phosphorus. Thus, inclusion of information on sodium, potassium, and phosphorus content in a drug may help healthcare providers and patients to select drug products with lower amounts of sodium, potassium, or phosphorus.

For both guidances, comments must be submitted by November 8, 2022, to be considered by FDA.

As promised in our posts from earlier this summer (here and here), we are back to report on our assessment of CDRH’s electronic submission process through its Customer Collaboration Portal (CCP).  In short, the process is FANTASTIC!  Say goodbye to your thumb drives and CDs – the CCP electronic submission process couldn’t be easier.  FDA’s CCP allows for a simple drag and drop to upload of a zip file containing your full eCopy directly to the Center.  The site, alternatively, allows for uploading of an eSTAR formatted submission.  The upload process really couldn’t be easier.  The instructions are simple and the site is user friendly and intuitive.

This author has now submitted two 510(k)s using the system.  It has been seamless.  In both cases, the 510(k)s were submitted in the afternoon/early evening.  We immediately received an automated confirmation through the website after each was submitted.  Then, the following business day, we received the confirmation email from the Document Control Center identifying the submission number.

The CCP also tracks your sent submissions as well as your Traditional 510(k)s currently under review.  In our view, this submission functionality is a great technological step forward for CDRH.  We look forward to the application being opened up to allow additional users to submit electronically and for the tracking function to be expanded to other submission types (e.g., pre-submissions, IDEs, Special 510(k)s).

It’s been almost 11 years since FDA first clarified use of multiple predicate devices and introduced the concept of Reference Devices in the draft guidance titled The 510(k) Program:  Evaluating Substantial Equivalence in Premarket Notifications [510(k)], which we blogged about here.  The final guidance with the same title (Guidance), which we blogged about here at the time of release in 2014, provided additional clarity, but we find that, even with years of experience, it is still a challenge in many cases to decide how best to bring a second device into a substantial equivalence discussion.  One frequent issue that arises is whether to designate that second device as a secondary predicate device or so‑called reference device.

A little history may be helpful.  Prior to the Guidance, FDA had sometimes allowed so‑called split predicates in 510(k)s.  A split predicate was one “using one legally marketed device for intended use and a different legally marketed device for technological characteristics to demonstrate substantial equivalence.”  Guidance at 39.  In the Guidance, FDA took the position that “the use of a ‘split predicate’ is inconsistent with the 510(k) regulatory standard.” Id.  Since that time, this practice has essentially been taken off the table for 510(k) submissions.

Even as the Guidance ruled out the use of split predicates, it acknowledged that the practice of relying on multiple predicates in a submission can be valid.  However, the Guidance recommended designating a single device as the “primary predicate device” while citing additional devices as either “secondary predicate devices” or “reference devices.”  The Guidance defined a secondary predicate as one used when “combining features from two or more predicate devices with the same intended use into a single new device, when seeking to market a device with more than one intended use, or when seeking more than one indication for use under the same intended use.” Id. At 11.

Things are a bit clearer with reference devices.  The Guidance defines a reference device as a device that is used to “support scientific methodology or standard reference values.” Id. at 13.  This device explicitly does not need to satisfy each step in the SE flow chart.  Rather, it aids with respect to step 5a related to acceptability of methods for performance testing.

When combining features from two or more devices with the same intended use, the determination of whether to consider the second device a secondary predicate or reference device is not always obvious.  Based on the guidance, the second device would be identified as a secondary predicate device.  However, as the primary predicate is sufficient to reach a determination of substantial equivalence, one may also consider an argument that the second device is merely referenced for support of test methods or standard reference values for specifications related to the features not present in the primary predicate device.

Given FDA concerns over split predicates, it seems that most applicants lean towards use of a reference device, even when identifying the device as a secondary predicate may be more appropriate.  As long as the primary predicate device is appropriate, we have not seen FDA raising concerns during review over whether a second device is a secondary predicate or a reference device.  However, given the drift towards considering any second device a reference device, it is important to review the definitions and descriptions of both secondary predicates and reference devices so that the most appropriate choice can be made in the preparation of 510(k) submissions.

Hyman, Phelps & McNamara, P.C.’s Deborah Livornese will be a panelist for FDAnews’ September 15, 2022 webinar titled “Califf’s Post-PDUFA, Post-COVID FDA Agenda: Key Developments, Insights and Analysis”.  Aspirational only title notwithstanding, you can find more information about the webinar and registration at FDAnews and use code VIP20 for a 20% discount.

Three patient advocate groups have sued the Department of Health and Human Services (HHS) and the Centers for Medicare and Medicaid Services (CMS), challenging HHS’s 2020 Notice of Benefits and Payment Parameters (NBPP) rule.  As it stands, the rule allows insurers and pharmacy benefit managers (PBMs) to broadly use copay accumulator programs, which have long been criticized by patient advocacy groups as padding insurers’ pockets while leaving patients high and dry.

Recognizing the problems that high prescription drug costs pose to patient access to medications, many drug manufacturers have created copay assistance programs to help patients afford the copays and deductibles for their medications.  In a common example of this practice, the drug manufacturer issues a coupon to an insured individual to present at the pharmacy.  The pharmacy bills all or most of the individual’s copayment or coinsurance—which the patient would otherwise pay the pharmacy directly—to the manufacturer.

Insurance companies and PBMs, on the other hand, have largely resisted these programs to shift drug costs away from patients and have instead found ways to shift the cost of drugs back to the patient and away from the insurer.  By prohibiting patients from counting manufacturer-provided assistance as part of the patient’s copay obligation, insurers can collect from both the patient and the manufacturer.  These prohibitions are often referred to as copay accumulator adjustment programs.  Under a copayment accumulator adjustment program, if a patient pays the $300 copay for a one-month supply of medication using a $300 manufacturer copay card or coupon, the insurer accepts the payment but does not count any manufacturer-provided copay assistance against the insured individual’s deductible or out-of-pocket maximum in the insurer’s internal accounting systems.  The insurer receives a windfall by being able to collect payments from the manufacturer and then still collect the full deductible and copayment amounts from the patient.

The patient, on the other hand, is no closer to meeting their deductible than before.  Despite securing funds to satisfy the copay obligation, the insurer’s disregard of that payment leaves full benefits and more affordable drugs for the rest of the year the same distance out of reach.  Patients who exhaust any available copay assistance program benefits will then return to square one, facing the same, limited choice: go into debt to acquire needed medications or forgo sometimes life-saving or life-extending treatment.

During the Trump administration, HHS and CMS issued the 2020 NBPP rule, revising 45 C.F.R. § 156.130(h) to explicitly allow insurers to broadly use copay accumulator programs.  The 2019 rule allowed the use of copay accumulator programs, but only with respect to drugs for which a generic alternative was available.  The complaint alleges that “copay accumulator adjustment policies have grown in the wake of HHS’s changing policy” (internal quotations omitted).

We have blogged before on Trump-era drug pricing and payment regulations, most of which have been struck down by the courts (see here and here), including another accumulator adjustment rule (see here).  The HIV and Hepatitis Policy Institute, the Diabetes Patient Advocacy Coalition, and the Diabetes Leadership Council have similarly filed suit in the U.S. District Court for the District of Columbia, challenging the 2020 NBPP rule as plainly unlawful on the grounds that it conflicts with the plain language of the Affordable Care Act (ACA) and the agencies’ existing regulations, and is arbitrary and capricious.

Among other arguments, the complaint asserts that the NBPP rule violates the ACA’s cost-sharing cap, which mandates that cost-sharing, i.e., the part of an insured patient’s annual healthcare costs for which the patient is responsible, “shall not exceed” the result of a statutory formula.  The ACA defines “cost-sharing” to include “deductibles, coinsurance, copayments, or similar charges” and “any other expenditure required of an insured individual…”  The statute sets an annual cap on the “expenditure[s] required of an insured individual” by their health insurance plan.  The complaint argues that the rule must be set aside as contrary to the ACA because the statutory text “looks not to where the money used for a copay originates,” yet the rule permits insurers to exclude payments from the annual statutory cap on cost-sharing “just because the insured obtains assistance from the drug manufacturer in satisfying that obligation.”

The complaint further argues that the rule contradicts the statute because the ACA defines the maximum amount of funds that an insurer may receive as compensation beyond premiums, yet the rule allows insurers to collect more money than the statute authorizes by collecting the ACA out-of-pocket maximum and any manufacturer-provided copay assistance.

The patient advocate groups are requesting that the court declare unlawful and set aside the rule.  An opinion that is favorable to the patient groups would mark another defeat of Trump-era drug pricing regulations.  As it stands, 14 states and Puerto Rico have passed laws outlawing copay accumulator programs.  It remains to be seen whether copay accumulator programs will be banned throughout the nation.

Last month FDA published its 4th annual report on the state of pharmaceutical quality and, needless to say, there were some interesting statistics, particularly for us FDA nerds.

Number of Manufacturing Sites and Registered Products

The report states that for fiscal year 2021, there were 4,451 CDER drug manufacturing sites, which is a 3% increase over fiscal year 2018, the only comparison year provided.  39% of these manufacturing sites are what is referred to as “no application” sites, meaning that the products manufactured there are without an approved FDA application, which includes over-the-counter (OTC)  products, unapproved prescription drug products and homeopathic products.  The remaining 61% of the sites manufacture at least one application product, meaning either a product resulting from a Biologics License Application (BLA), a New Drug Application (NDA), or an Abbreviated New Drug Application (ANDA).

The countries with the five most manufacturing sites, namely, the United States, India, China, Germany and Canada, all saw net increases in the number of manufacturing sites in inventory over the past three years.

For fiscal year 2021, CDER oversaw 12,428 ANDAs, 3,537 NDAs and 315 BLAs. CDER also oversaw more than 140,000 non-application products, including 75,300 OTC products, and 15,640 homeopathic products.  Presumably the balance of non-application products are unapproved prescription drug products, though that was not specified in the report.

Quality Surveillance with Foreign Regulatory Authority Inspection Reports and Record Requests

Given the problems with performing on-site inspections during COVID over the last year, alternative inspection tools were used by FDA to a greater degree during fiscal years 2021, including review of foreign regulatory authority inspection reports and records requests of the facility at issue.  During fiscal year 2021, FDA reviewed and classified 139 site inspections in 18 Mutual Recognition Agreement (MRA) countries, as we as six other countries.  The latter point about six other countries is particularly interesting because FDA does not appear to have previously acknowledged accepting for review and classification site inspections from non MRA countries.  In addition, during the same period FDA conducted 288 surveillance-based assessments using information from section 704(a)(4)(A) (record review) requests, which resulted in 21 import alerts.

Product Quality Defect Reports

The so-called product quality defect (PQD) reports includes Field Alert Reports (FARs), Biological Product Deviation Reports (BPDRs), MedWatch Reports (MWs) and Consumer Complaints (CCs). During fiscal year 2021, CDER received  4,115 FARs, 205 BPDRs, 11,512 quality related MWs and 273 CCs, which appear to be similar to the number of such product quality defects reported in fiscal year 2020.  According to FDA, in the coming years, the CARES Act will enable FDA to normalize product quality defect reports by the amount of each product manufactured, thereby allowing for a more thorough evaluation of the impact and magnitude of PQDs.

Import Alerts and Recalls

During fiscal year 2021, FDA placed 49 sites on import alert for, among other things, non-compliant laboratory testing, non-compliant findings from inspections, refusing inspections, and refusing 704(a)(4)(A) records requests.  The largest number of import alerts were from sites in China and Latin America, the latter owing to the large number of facilities that manufactured hand sanitizer that were detained at the border.

For the second consecutive year, the total number of recalls increased, from a near historic low in fiscal year 2019 of around 300 (my estimate, based on a review of figure 3 in the report), to around 700 in fiscal year 2020 and around 800 in fiscal year 2021 (the report doesn’t provide precise numbers).  In addition, the number of Class I recalls appears to have nearly doubled in fiscal year 2021 from the prior year, due in large measure to the recalls associated with hand sanitizer products that contained methanol, and the sunscreen products that contained benzene.

In my next blog post, I will summarize FDA’s views from the report on their research into the general state of quality in the pharmaceutical industry, as well as detail the agency’s progress with respect to two initiatives, the New Inspection Protocol Project (NIPP), and the Quality Management Maturity Project (QMM). So stay tuned!

FDA recently published a Draft Guidance entitled “Charging for Investigational Drugs under an Investigational New Drug Application: Questions and Answers” (the Draft Guidance). This Draft Guidance, when finalized, will replace the Final Guidance issued just six years ago (the 2016 Guidance). As the new Federal Register notice explains, FDA issued the 2016 Guidance in question and answer format to respond to the most frequently asked questions about charging for investigational drugs provided under an IND for either clinical trials or expanded access for treatment use under 21 CFR section 312.8

Changes from the 2016 Guidance

What’s new in the new Draft Guidance? Not all that much.  The 2022 Draft Guidance keeps all the same 20 questions with minimal tweaks to wording and added just three new questions and answers.  The new Q & As (Q21, Q22, and Q23) all concern charging in the context of expanded access.  Below we outline the Draft Guidance and highlight the new information in the 2022 Draft Guidance.

The Draft Guidance covers charging in a clinical trial or in one of the expanded access settings and the differences between them. However, many provisions are broadly applicable in both settings. For example, the Draft Guidance includes answers to general questions about the intended timeframe for response to charging requests (30 days), who should request FDA’s authorization to charge (the IND sponsor), and whom the sponsor may charge with this authorization (not FDA’s business). For this last question, FDA explains that it anticipates the sponsor would charge the patient directly or would charge a payor if reimbursement were available, but clearly states that FDA has no authority in this arena.  FDA has added language to the Answer that covers this topic (A3), stating that sponsors should ensure that charging for drugs in a clinical trial or through expanded access does not create barriers to access “that may exacerbate disparities in clinical trial participants or expanded use patients.”

Authorization for Charging in the Clinical Trial Context

The Draft Guidance continues to list the regulatory requirements to obtain authorization for charging in a clinical trial setting: (1) evidence that the drug has a potential clinical benefit that would provide a significant advantage over available products; (2) the data to be obtained from the trial would be essential to establishing that the drug is safe or effective for the purpose of initial approval or a significant change in labeling; and, (3) the trial could not be conducted without charging because the cost of the drug is “extraordinary” to that particular sponsor.

The Draft Guidance also notes that if the sponsor is evaluating an unapproved use of its approved drug, it is still required to obtain authorization; however, if a sponsor is not the marketing entity and must purchase an approved drug, it is not required to obtain authorization to charge for the drug (limitations on the amount that can be charged still apply even when authorization is not required). Additionally, authorization is not required for a sponsor to charge for the use of its own approved drug as concomitant therapy in a clinical trial intended to evaluate another drug when the concomitant therapy is not part of the clinical trial evaluation, as this is not an investigational use of the approved drug. Finally, the Draft Guidance notes that charging may continue for the duration of the clinical trial unless FDA specifies otherwise.

Authorization for Charging in the Expanded Access Context

The requirements described in the Draft Guidance for authorization to charge in an expanded access setting reflect the particular concerns that arise in the expanded access context.  Specifically, reasonable assurance that charging will not interfere with drug development is needed, and for a treatment IND or treatment protocol under 21 CFR § 320. The reasonable assurance must include (1) evidence of sufficient enrollment in ongoing clinical trials (to reasonably assure FDA that those trials will be completed as planned); (2) evidence of “adequate progress” in the development of the drug for marketing approval; and, (3) information about drug development milestones the sponsor plans to meet in the next year.

Charging may continue for 1 year from authorization unless FDA specifies a shorter period. The Agency may reauthorize upon request for additional periods if the requirements continue to be satisfied.

Cost Calculations

The Draft Guidance explains that the regulation is intended to allow a sponsor to recover direct costs specifically and exclusively incurred in making a drug available. The cost calculation submitted in the request must be accompanied by a statement that an independent certified public accountant (CPA) has reviewed and approved the calculations. The Draft Guidance adds a clarification that the independent CPA “must be qualified to make the required determinations”.

When the amount to be charged is simply the amount charged to the expanded access sponsor by a third party such that there is no calculation to be made, the sponsor does not need to submit the CPA statement, but should submit a copy of the receipt or invoice from the source to justify the amount to be charged.

Although a sponsor of an individual patient expanded access trial may only recover direct costs associated with making the drug available, a sponsor of an intermediate-size patient population expanded access IND, or a treatment IND may also recover administrative costs directly associated with the expanded access use. These additional costs may include fees paid to a third party for administration, including any profit that may be included in the fees.

Two of the new questions added in the Draft Guidance (Q22 and Q23) address the fact that monitoring and other administrative “startup” costs, and manufacturing costs are often higher in the first year compared to subsequent years. These new Q & As explain that some sponsors may amortize costs.  Specifically, sponsors of an intermediate or treatment IND or protocol  can take this approach for monitoring and other administrative startup costs, and sponsors of an expanded access IND or protocol may do so for the costs of manufacturing. In these cases, the sponsor can distribute the additional costs to reduce the per patient cost difference between patients treated earlier and patients treated later. Such a cost amortization plan should be done in accordance with standard accounting practices and this must be reviewed and approved by an independent CPA. In these situations, sponsors must still submit requests to reauthorize charging to continue after the expiration of the initial authorization period.

Finally, the Draft Guidance adds the new recommendation that if a sponsor of an intermediate-size patient population expanded access IND or treatment IND seeks to recover fees paid to a third party, it should disclose the relationship with the third party to patients, and notes that under the regulations governing informed consent, this information  also must be included in the informed consent document.

We are almost three years into the public health emergency as a result of the COVID-19 pandemic, and still only have 19 rapid antigen tests authorized for at-home use in the United States. The primary barrier to bringing new antigen tests to market has been FDA’s minimum requirement of 80% sensitivity for authorization. The 80% sensitivity requirement for antigen tests has yet to be explained either scientifically or clinically by the Agency.

It is clearly rooted in fear that less sensitive tests may have too many false negatives. But the question is, is 80% sensitivity the right place to set the bar? By doing so, FDA has limited the number of tests that have reached the market, thereby reducing available supply and increasing prices. Right now, the demand is not particularly high, but last winter had a severe shortage in which it was hard to find antigen tests at any price. That could happen again.

As FDA would acknowledge, the antigen tests are the fastest and most practical method for distributing testing in the general population. These practical benefits are in marked contrast to molecular COVID-19 tests that are used for definitive diagnosis and are generally expected to detect the SARS-CoV-2 virus at least 95% of the time when someone is infected. The molecular tests must be run in a laboratory and usually take several days due to the need to ship the sample and the constraints on laboratory availability and supplies.

Everyone understands that antigen tests are less sensitive and could miss someone who is asymptomatic with an early infection or a low viral load. But on the flip side, they are very specific, i.e., if a positive result is obtained, the result is typically very accurate in the range of 95% of the time or better.  The question is whether requiring 80% sensitivity is too high for this tool and keeping too many of them from the market.

Ironically, a recent FDA safety communication points to a potential way out of this dilemma.  In this safety communication, FDA advises the public as follows:  If you test negative and have COVID-19 symptoms, you test again 48 hours later for a total of two tests. After two negative tests, you should consider a molecular test, or call your healthcare provider. If you test negative and do not have COVID-19 symptoms, you should test again 48 hours later. If the second test is negative, you should test again 48 hours after the second test. If the third test is negative, you should test again with an antigen test, or get a laboratory molecular-based test, or call your healthcare provider. If you get a positive result on any repeat test with an at-home COVID-19 antigen test, you most likely have COVID-19.

These recommendations come based on the latest National Institutes for Health (NIH) and University of Massachusetts Chan Medical School study which was funded by the NIH Rapid Acceleration of Diagnostics (RADx) program.  This prospective cohort study recruited participants who were asymptomatic to investigate the performance of serial testing using COVID-19 rapid antigen tests compared to molecular tests. The study represents the most robust attempt at understanding the performance of serial use of rapid antigen tests for SARS-CoV-2 detection among asymptomatic individuals in the U.S. The study demonstrates that serial testing does optimize the ability to detect SARS-CoV-2 infections when using at-home rapid antigen tests.

This testing scheme calls into question whether it is really necessary to require at least 80% sensitivity when comparing an initial at-home antigen test result to the more sensitive molecular tests. One can use serial testing to make up for the sensitivity shortfall in most antigen tests.

In fact, FDA recently authorized several antigen tests that did not meet the sensitivity threshold of 80% for symptomatic individuals when the study population had more than 20% of individuals with low viral loads. The low viral loads were most likely due to individuals infected with the Omicron variant. Instead of simply denying authorization, FDA responded by authorizing these tests with a requirement in the labeling for serial testing. For example, labeling stated: This test is authorized “when tested twice over three days with at least 24 hours (and no more than 48 hours) between tests.”

While this was a step in the right direction, only the tests whose clinical studies occurred during the Omicron surge had this stipulation included in their labeling. Low viral loads within the population will impact all authorized tests, not just the ones that have been authorized since the emergence of the Omicron variant. However, we have not observed any action on the part of FDA to revise the labeling of products that were authorized in 2020 or 2021 to make the labeling consistent across all tests. Nor has FDA required additional warnings highlighting, to the user, that the clinical performance data on the currently authorized tests were generated primarily on a variant that is no longer circulating in the U.S. This lack of uniformity across manufacturers may place an unfair stigma on the newest entrants to the market as being fundamentally less accurate when that may not be the case.

The NIH RADx-sponsored study mentioned in the safety communication addresses a data gap in FDA’s review of antigen tests. FDA permitted the authorization of tests with at least 80% sensitivity in symptomatic individuals and allowed claims regarding serial screening of asymptomatic individuals without submitting performance data on this population. While companies were required to commit to conducting such studies post-authorization, none have been completed to date based on our knowledge. (This nebulous post-authorization study is not well defined in the public templates. See our previous post on the topic here.) The NIH RADx-funded study is a long-awaited dataset finally made public addressing the question of performance in asymptomatic individuals but also includes performance against the Omicron variant for tests authorized without this challenge.

The study results are not surprising, excluding singleton RT-PCR positives, the first-week sensitivity was only 79.2% (71.0-85.9%) after testing three times with a rapid antigen test at 48-hour intervals. Meaning the tests currently on the market and evaluated in the study do not appear to meet FDA’s minimum requirement of 80% sensitivity, even when tested three times in a serial fashion.

The results of this study referenced in the safety communication could be a signal of a new requirement for antigen test developers to add to their labeling, essentially requiring testing at least 3 times with 48 hours between tests if you are asymptomatic and get a negative test result. Adding this new testing scheme to labeling may provide flexibility to the 80% sensitivity requirement but may also require new clinical study designs from sponsors still vying for EUA authorization.

FDA said they are committed to appropriately accurate and reliable at-home COVID-19 tests. The recent safety communication may be a model for how FDA can more broadly authorize tests that do not meet the 80% sensitivity requirement and in addition level the playing field through consistent labeling of the testing scheme for all EUA holders.