COVID Weekly Recap: The need for transparency in COVID development. International COVID test standard on its way. COVID shows the need for a quality rating system.

Top stories:
· Development secrecy vs. a public’s right to know: An argument erupts
· IVD Chief: International COVID test standard likely available by end of year
· FDA issues report on comparative performance of certain COVID-19 diagnostics
· Hahn: COVID shows need for US manufacturing and a quality rating system
· FDA Device leadership lays out wish list for future pandemic preparedness

Welcome to our COVID Weekly Recap, AgencyIQ’s weekly wrap-up of the top regulatory developments related to COVID-19. The following analysis was available to AgencyIQ subscribers earlier this week as part of our daily regulatory intelligence briefings, as well as dozens of other pieces of analysis. Contact us to find out how you can become a subscriber to AgencyIQ.

Development secrecy vs. a public’s right to know: An argument erupts

By Alexander Gaffney, MS, RAC

September 14, 2020


What obligation do drugmakers have to publicize information about their investigational treatments and vaccines for COVID-19 while they remain in clinical testing? That’s the question being raised this week after reports that some vaccine developers were withholding certain information from the general public while making some of that same information available to key members of the investor community.

  • Typically, information about a product’s development is tightly held as commercially confidential. As a result, the FDA is not able to even acknowledge the existence of a particular company’s application. Any information about a company’s development of a drug candidate comes from three main sources: The company itself (such as through public notices), required disclosure statements to investors (such as those required by the SEC), and information in public databases (like and patent filings).
  • That information, though, has significant shortcomings. For example, companies may be required to inform investors that a trial is subject to a clinical hold, but would not be required to describe in depth the reason for the hold. The also might not be required to disclose certain actions determined to be “routine” in the course of a development program.
  • That may be normal, but it’s raising eyebrows in the context of COVID-19. It would be difficult for us to summarize the issue better than the New York Times’ Katie Thomas did this weekend: “It’s standard for drug companies to withhold details of clinical trials until after they are completed, tenaciously guarding their intellectual property and competitive edge. But these are extraordinary times, and now there is a growing outcry among independent scientists and public health experts who are pushing the companies to be far more open with the public in the midst of a pandemic that has already killed more than 193,000 people in the United States.”
  • One argument: If US taxpayers are primarily funding the research and development of the vaccines, then they deserve to know how their investments are faring in real-time.
  • Another argument: If this is a race to the finish line to get new therapeutics and vaccines to market, then companies have a moral obligation to let researchers, public health officials and other companies know about the successes they might be having as well as the setbacks they’re encountering. If a company is developing a drug that leverages a similar biological pathway and mechanism of action as another therapeutic, that first company could benefit from knowing the dose levels that might have resulted in adverse side effects in trial participants, for example.
  • Sharing information could also help build trust, since an absence of information could give the impression that companies are hiding unfavorable details about their products.
  • This issue is likely to continue to escalate. As AgencyIQ has previously written, the FDA does not make public information about its rejection of applications for approval, known as Complete Response Letters (CRLs). If a much-anticipated product is rejected by the FDA, the public is likely to demand to know why. If the FDA is unable to tell its side of the story, that could further erode public confidence in the agency.

IVD Chief: International COVID test standard likely available by end of year

By Laura DiAngelo, MPH

September 16, 2020


On his weekly call with diagnostic developers, Office of In Vitro Diagnostics and Radiological Health (OHT7) Director Tim Stenzel re-upped his call for more antigen test emergency use authorization (EUA) submissions, as well as at-home tests, and discussed challenges faced by developers given a limited understanding of the novel coronavirus.

  • Stenzel’s town halls with developers have become a staple for diagnostic developers during the pandemic. During the calls, Stenzel gives updates on emerging policy, outlines best practices for developers working through EUA submissions and clarifies requirements and recommendations as they rapidly evolve.
  • Limits of detection (LoD) and information. Typically, diagnostic performance is measured in terms of LOD, which is the lowest analyte concentration at which detection is feasible (i.e., what is the lowest amount of the virus in a sample that the test can detect). However, given the novelty of SARS-CoV2, there is not yet a good understanding of what the LOD should be for COVID-19 diagnostics. “There’s no international standard, so it’s hard,” Stenzel acknowledged in response to questions about test validation specifics. However, the FDA has been working to identify the LODs of the tests already on the market.
  • Identifying what it means to be infectious with COVID-19, then, “is the $100,000 question,” noted Stenzel. “There are a lot of different ways to try to get to that, but none are ideal,” he said, given that “we have seen variable information and data” researching LOD and infectiousness for diagnostic development. “We have clearly seen different levels of virus in asymptomatic populations to symptomatic populations,” he explained, but went on to say that “we don’t understand” the specifics of symptomatic versus asymptomatic transmission quite yet. “As soon as the international standard for molecular [LOD] is available, and we’re looking at potentially year end, we’ll anchor to that,” according to Stenzel. This could mean another change in standards for diagnostic developers—but also that manufacturers of serological and antigen tests will have to wait even longer to understand the LOD for their tests. Nevertheless, “we think that will be a huge advancement.”
  • In lieu of better understanding, Stenzel’s recent priority has been to focus on tests that can catch individuals who may be infectious—that is, individuals within 5-7 days of symptom onset, according to literature. Without looking for a specific LOD, the agency is focusing on authorizing tests that will be able to be widely used in populations to identify who may be passing on the virus. Stenzel continues to call on industry to develop tests that can be used in at-home in a sequence, or “serial testing,” even if those tests are not as specific as the FDA typically requires—in a Hill op-ed published last week (and reiterated during the call today), Stenzel noted that such a test could be authorized with a sensitivity down to 70%.
  • None have yet been authorized—or even submitted. “We haven’t received a single EUA [submission] for an at-home test. Not one,” said Stenzel. “We’re open, and we’re very eager, to authorize home diagnostic tests. Either [over the counter] OTC or by prescription.” The first such test received by CDRH is likely to be a priority for the agency, and if authorized will be widely announced through HHS.
  • Antigen tests remain a significant priority for the agency during the pandemic. These diagnostics, which are less complex than molecular tests but more accurate in diagnosing infections than serological tests, are intended to detect the presence of SARS-nCOV2 and can be run fairly quickly, reducing turnaround times. The FDA has authorized four direct antigen tests so far, although Stenzel once again called for developers to submit these tests for FDA authorization. “We certainly want to have more antigen tests on the market as soon as possible,” Stenzel noted, urging developers to develop and submit their tests.

FDA issues report on comparative performance of certain COVID-19 diagnostics

By Laura DiAngelo, MPH

September 16, 2020


The FDA published the comparative performance data on the Limits of Detection (LOD) of almost 60 molecular diagnostics on September 15, comparing their performance against a standardized sample panel.

  • Molecular diagnostics, also known as polymerase chain reaction (PCR) tests, are intended to detect nucleic acid from a virus in order to diagnose an individual. For COVID-19, these tests detect nucleic acid of the virus SARS-CoV-2. Molecular diagnostics are considered to be the most accurate—albeit most complicated—test type.
  • In the early days of COVID, patient samples were difficult to come by, creating challenges for developers trying to validate their tests. Until May 2020, the FDA allowed test developers to use “contrived samples,” or specimens spiked with virus RNA. While the policy was in place, the FDA authorized 59 assays based on validation data generated using contrived samples.
  • To identify the performance of these tests, the FDA had developers test their assay using a reference panel of SARS-CoV2 samples developed by the FDA. Developers were able to identify provisional LOD for their diagnostics in several ways: using viral transport media (VTM) and extraction chemistry; from a liquid source; and from dry swabs. Tests authorized with saliva as a sample matrix are also presented in a table. This is intended to demonstrate the test’s performance in a variety of real-world use-cases. These date, published by the FDA, are presented in three tables. “We think we have a pretty good rank” of the tests, noted OIVD Chief Stenzel at a town hall with diagnostic developers, but went on to caution that comparison between the tables is difficult, “because the method assessing LOD was not the same.” LODs were measured in Nucleic Acid Amplification Test (NAAT) Detectible Units (NDU) per mL. The lower the number, the lower concentration of virus a test could detect, meaning the more sensitive it is.
  • For tests using Viral Transport Media (the most common procedure and populated table), performance varies widely, from 180,000 NDU/mL by QIAGEN GmbH’s QIAstat-Dx Respiratory SARS-CoV-2 Panel to 180 NDU/mL for PerkinElmer Inc.’s PerklinElmer New Coronavirus Nucleic Acid Detection Kit. No test for use with dry swabs had an LOD of lower than 300,000 NDU/mL (Abbott ID NOW COVID-19), while the one test for use with saliva had an LOD of 54,000 NDU/mL (Fluidigm Corporation Advanta Dx SARS-CoV-2 RT-PCR Assay).
  • As previously noted, there is no international standard for acceptable LOD for COVID-19 diagnostics, although one is expected by the end of the year. At that time, certain tests may be pulled from the market if they are above the sensitivity threshold.
  • What’s next? The data available now is intended to help providers and laboratories choose appropriate tests—or avoid certain tests—when making health care decisions. The FDA is working to make the reference panel available to more developers for comparative analyses of their tests.

Hahn: COVID shows need for US manufacturing and a quality rating system

By Alexander Gaffney, MS, RAC

September 10, 2020


FDA leaders took to the opinion pages of CNBC today to argue that one of the enduring lessons of the COVID-19 pandemic is that drug manufacturing needs to return to the US in order to secure the country’s supply chain for critical drugs. But among the “enduring solutions” proposed by FDA Commissioner Stephen Hahn and Deputy Commissioner for Medical and Scientific Affairs Anand Shah is one that may impact a wide array of life sciences companies: A quality rating system.

  • Hahn and Shah: “Action to onshore America’s critical medical supply chain and modernize infrastructure for life sciences manufacturing is long overdue.” The pair went on to say that the country needs “enduring solutions that address the root causes of America’s medical manufacturing crisis,” including the “creation of a quality rating system” and investment into continuous manufacturing.
  • The idea for a quality rating system isn’t new, but it has experienced more than a few setbacks at the FDA. Under the FDA Safety and Innovation Act of 2012, the FDA was given the authority (Section 706) to inspect certain records from drug manufacturing facilities, including manufacturing quality metrics. The ability to collect real-time data and quality metrics would in theory allow the FDA to better allocate on-site inspection resources, while also providing the tools to enhance surveillance of offshore manufacturers. FDA used this authority to develop its proposed voluntary Quality Metrics Reporting Program (QMRP) and the issuance of a guidance document.
  • The problem with quality metrics: Industry was generally opposed to the FDA’s proposed collection of quality metrics for a few different reasons. First, the guidance was initially framed as a mandatory reporting program, rather than a voluntary one. But even after the guidance was revised in November 2016 to make it voluntary, industry took aim at the three metrics that the FDA proposed to collect: Lot Acceptance Rate, Product Quality Complaint Rate and Invalidated Out-of-Specification Rate. These metrics, industry said, are difficult to acquire and provide little insight into actual issues related to quality manufacturing. For example, a low Lot Acceptance Rate could indicate that a company has major quality problems or indicate that the company has exacting quality standards and errs on the side of rejecting anything that doesn’t meet those standards. In other words: Quality is difficult to objectively define and measure.
  • With COVID disrupting the FDA’s ability to inspect facilities, the FDA has been hinting at the possibility of using quality metrics to augment its existing quality surveillance activities. FDA spokesperson Jeremy Kahn told AgencyIQ earlier this year that the FDA would be “utilizing additional tools and approaches to ensure the quality of products imported into the U.S. which have proved effective in the past,” including the specific authority given to the FDA under FDASIA Section 706 that allow it to request records from sites “in lieu of” an inspection.
  • But the idea of using quality metrics to help build a more resilient supply chain has been talked about for FDA officials long before the emergence of COVID. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research (CDER), has made repeated calls for standards beyond baseline CGMP adherence and FDA inspections. At a December 2019 Congressional hearing, Woodcock advocated for incentives for drugmakers to invest in “mature quality management systems” that would support the generation of real-time metrics. Woodcock suggested he development of “a rating system that could be used to inform purchasers, group purchasing organizations (GPOs) for health care systems, and even consumers, about the quality management maturity of the facilities making the drugs.” Such a system could help alleviate drug shortages and promote drug availability. [Read our analysis on this here.]
  • In fact, the FDA already has a quality rating system—just not a public one. A substantial report issued by the FDA’s Office of Pharmaceutical Quality in June 2020 on the state of pharmaceutical quality in the life sciences industry indicated that the FDA generates “site inspection scores” for facilities. Those scores are not publicly available. The FDA has also used other metrics in its public-facing research. In August 2020 FDA quality officials published a study on the quality of difficult-to-make prescription pharmaceutical products marketed in the US. For that study, the FDA developed a metric called Process Performance Index based on dosage unit uniformity and dissolution.
  • FDA is also working on several projects related to quality metrics and quality management. For example, in August 2020, the FDA issued a contract notice indicating that it is looking to fund quality management maturity assessments at several US-based pharmaceutical manufacturers, and wants to use the experience to help train its staff and help develop a “rating system to measure and rate quality management maturity.” The FDA has also been working with the University of St. Gallen’s Institute of Technology Management to conduct a benchmarking analysis of the quality performance of drug manufacturing organizations. The goal of that survey is to identify relevant pharmaceutical manufacturing performance metrics to assess the current state of quality.
  • Michael Kopcha, Director of FDA’s OPQ, has also recently taken to Twitter to comment on news that Mylan had received a Warning Letter regarding quality issues. “If there were public ratings of a manufacturing facility’s quality management maturity that patients and purchasers could consider when making buying decisions about medicines, would things like this even happen?” Kopcha asked, referring to the company’s alleged lack of controls over impurities. “Asking for a friend…”
  • What’s next? The FDA’s years-long effort to move toward the use of quality metrics and a publicly available rating system has been tumultuous and at times controversial. Hahn and Shah’s public efforts to outline the FDA’s approach may be an effort to build political support and consensus for the move, which could be further supported by a legislative mandate.

FDA Device leadership lays out wish list for future pandemic preparedness

By Laura DiAngelo, MPH
September 9, 2020


new piece published in the New England Journal of Medicine, authored by CDRH Director Jeff Shuren and OIVD Director Tim Stenzel, provides an accounting of the FDA’s actions on COVID-19 diagnostic response and outlines a series of regulatory and legislative actions to better prepare for future threats.

  • The COVID-19 diagnostic response has been shaky. This is acknowledged in the Perspective piece, and Shuren and Stenzel identify patient access concerns as the impetus for a widely-panned February 29 policy allowing certain diagnostics to be marketed without the submission of an Emergency Use Authorization (EUA) application to the FDA—and then test accuracy concerns as the reason for reversing the policy. They also pointed to challenges with the CDC’s test in February (identified by the FDA) which resulted in significant unmet need.
  • The pandemic as a pressure test. According to Shuren and Stenzel, the COVID-19 pandemic has highlighted what has and hasn’t worked within the medical device framework in emergent situations. “We have learned lessons that should inform our response to future outbreaks,” they note, offering four suggestions.
  • #1: International cooperation. “We believe that the U.S. government should work with international partners to establish a plan for sharing clinical specimens as soon as a public health threat emerges,” they wrote. Early on in the US COVID-19 response, the lack of standard patient samples that test developers could use to demonstrate the performance and validity of their tests was a huge barrier to market authorizations. Without access to patient samples, developers were driven to use “contrived” samples (e.g., sputum samples spiked with SARS-CoV-2). While the FDA now has a standard reference panel available to developers, Shuren and Stenzel indicate that having an international agreement in place in advance of an emergency could help streamline access to clinical specimens for diagnostic development and validation.
  • #2: Large-scale testing lessons. “When a public health threat warrants large-scale testing, it would be more effective to authorize a small number of well-designed, well-developed, and validated tests run on common high-throughput platforms, followed by a few point-of-care tests, all of which are manufactured in large quantities.” The current variety of tests (almost 250 from almost as many individual manufacturers/laboratories) is “an inefficient use of resources” according to the Perspective. Under Shuren and Stenzel’s recommendations, only “a handful of test designs” would be manufactured either by the CDC or preset contract manufacturers following FDA’s “proactively create[d] validation protocols” for “anticipated pathogen and sample types” that would be modified to react once a threat emerged.
  • #3: Regulation parity. “We need common approaches to validating test design and performance, regardless of whether there is an emergency.” As Shuren and Stenzel noted in the piece, laboratory developed tests (LDTs) are generally exempt from pre-market review requirements in non-emergent situations, which led to confusion among lab-based developers during the pandemic. While the FDA typically exerts regulatory authority over these products during times of heightened risk—such as a global pandemic—the Department of Health and Human Services recently issued a policy prohibiting the FDA from requiring Emergency Use Authorizations (EUAs) for LDTs. However, Shuren and Stenzel state that “our experience with Covid-19 highlights the need for a common legislative framework to ensure that all clinical tests are accurate and reliable.”
  • Incidentally, such a legislative framework was introduced in February. The VALID Act of 2020 is a bipartisan, bicameral bill that would create a new regulatory classification for in vitro clinical tests (IVCTs), separate from the medical devices pathways, and enforce regulation of LDTs as IVCTs under the regulatory authority of the FDA. No FDA officials have specifically spoken out on HHS’ unexpected policy change, which reversed decades of administration precedent maintaining that LDTs are devices under FDA’s authority. However, this piece from CDRH leadership makes the case there is a need for more enforcement of LDTs, not less, as a lesson of the pandemic.
  • #4: Better clinical training. “The clinical community should understand test performance and how to use that information in patient care.” According to Stenzel and Shuren, the pandemic “revealed that some clinicians have a limited understanding of test performance,” including the ideas of positive and negative predictive values. They recommend increased training and continuing education to better inform clinicians when choosing, performing and interpreting diagnostics.
  • Up next: Going forward, the FDA is likely to be called to account for its actions during COVID-19 before Congress over the next few years. The lessons learned during the pandemic may foment significant regulatory change, although it’s not clear how many of the suggestions from Stenzel and Shuren will be considered by legislators. For now, Stenzel and Shuren maintain that the FDA’s policies will continue to evolve with the needs of the current pandemic, including the impending development of non-prescription tests.

What we’re watching

This week we’ll be watching closely for a new FDA guidance on the use of Emergency Use Authorization (EUA) for COVID-19 vaccines. On a call last week, CBER Director Peter Marks hinted at the possibility that the guidance would be available very soon, and today CBER published an updated guidance agenda containing the title of the guidance: Emergency Use Authorization for Vaccines to Prevent COVID-19; Guidance for Industry.


Marks also provided extensive remarks about an “EUA-Plus” approach for vaccine authorization, in which the FDA might only grant an EUA if the sponsor had effectively met all the criteria for the approval of a Biologics License Application (BLA) except for providing certain quality data, secondary analyses and long-term safety data. Our POLITICO colleague Zach Brennan has the details for AgencyIQ here.


. . .


Get ready for the Groundhog Day Advisory Committee. That’s according to Bloomberg, which is reporting that the FDA is getting ready to potentially have scheduled advisory committee meetings every week from October through potentially December. The topic of all of the meeting meetings: The safety and efficacy of vaccines for COVID-19.

Our initial thought: This is a sea change for the FDA, which as recently as several weeks ago refused to even commit to a single advisory committee meeting.

Data points: 


The number of drug development programs in the planning stages for COVID-19 (excluding vaccines) as of August 2020. More than 310 of these have initiated trials that have been reviewed by the FDA.


“While the FDA has not yet authorized tests that can be performed entirely at home, we recognize that expanded access to testing outside of a health care setting is crucial to supporting the efforts to address the pandemic. As part of our ongoing effort to encourage the development of these tests, we currently recommend diagnostics for COVID-19 used at home should perform with at least 80 percent sensitivity if ordered by a health care professional, and at least 90 percent sensitivity if purchased over-the-counter for one-time testing. When consumers take the test over-the-counter at home, the consumers wouldn’t be advised by a health care professional on what to do or if they need a second test. Americans will use those results and make decisions about quarantining further, or returning to work, school and their community. Therefore, accurate results are particularly important.”


Jeffrey Shuren and Timothy Stenzel, respectively the Director of FDA’s Center for Devices and Radiological Health and the Director of the FDA’s Office of In Vitro Diagnostics and Radiological Health, writing today in The Hill in defense of their approach to diagnostic regulation. “FDA performance recommendations in our existing templates try to strike the right balance for public health for the respective scenarios,” they added.

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