FDA Response Letter to Senator Johnson

January 15, 2021

The Honorable Ron Johnson

United States Senate

Washington, DC 20510

Dear Senator Johnson:

Thank you for your letter of November 23, 2020, cosigned by two of your colleagues and following up your letter of August 18, 2020, regarding the efforts by the Food and Drug Administration (FDA or the Agency) to address the COVID-19 public health emergency. FDA continues to balance the urgent need for safe and effective therapies while providing oversight that ensures that patients can depend on the products being deployed. The Agency also continues to utilize the full breadth of its available resources and authorities, including its emergency authorities, to evaluate emerging scientific information on potential therapeutics for the treatment of COVID-19, and make available medical products as soon as scientifically supportable in the current public health emergency.

Notably, since FDA’s previous response to you dated October 6, 2020, the Agency has authorized two neutralizing antibody therapies for emergency use for the treatment of mild to moderate COVID-19 in certain adult and pediatric patients. Specifically, FDA has authorized Eli Lilly’s bamlanivimab and Regeneron Pharmaceuticals’ casirivimab and imdevimab, administered together, for the treatment of mild to moderate COVID-19 in adult and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization.1 These products give healthcare providers options to use in treating certain patients with confirmed COVID-19 and may help those patients avoid hospitalization, and thus, potentially reduce the overall burden on our healthcare system. FDA remains committed to continuing to work with sponsors to develop additional therapeutics in this area.

Your November 23 letter requests that FDA provide any updated guidance that FDA has provided to physicians and the public regarding early-onset at-home treatments for COVID-19. We note that FDA does not generate clinical practice guidelines for the treatment of specific diseases. For COVID-19, such guidelines for the U.S. are developed by the National Institutes of Health2 and the Infectious Diseases Society of America.3 However, FDA requires that sponsors develop documents referred to as “Fact Sheets” when authorizing a particular product under an emergency use authorization (EUA). These documents provide, for example, important scientific information to healthcare providers regarding the population for which the drug may be effective and how to safely administer the product to patients for its authorized use.4 These documents generally also provide healthcare providers with a summary of the underlying clinical data and other scientific evidence that supported FDA’s authorization.

As you are aware, in issuing an EUA under the current public health emergency, FDA must determine, among other things, that based on the totality of scientific evidence available, including data from adequate and well-controlled clinical trials, if available, that it is reasonable to believe that the product may be effective in diagnosing, treating, or preventing COVID-19; that the known and potential benefits of the product, when used to diagnose, treat or prevent COVID-19, outweigh the known and potential risks for the product; and that there are no adequate, approved, and available alternatives.5 While the statutory criteria for issuance of an EUA do not specifically require data from adequate and well-controlled trials, they do recognize the inherent reliability of such clinical trials in assessing the potential safety and efficacy of a medical product for a particular use.

Importantly, FDA must have confidence in the scientific evidence that supports the clinical use of a particular medical product under an EUA. As stated in our October 6 response, there is scientific consensus that, when available, randomized controlled trials (RCTs) are the most reliable mechanism for assessing the potential safety and efficacy of a drug. Given the existing data from RCTs on the effectiveness of hydroxychloroquine (HCQ) in the early ambulatory treatment of COVID-19, the uncertainty of the relationship between underlying risk factors and clinical outcomes, and the evolving standard of care in such clinical settings, RCTs may be the only design that is able to generate reliable data on the effectiveness of HCQ in treating COVID- 19 in this setting.

In response to your request for a review of the data regarding the use of HCQ in early treatment of COVID-19, we are providing a summary of the relevant clinical trial evidence from RCTs on the use of HCQ in the early ambulatory treatment of SARS-CoV-2 infection that was publicly available at the time FDA reviewed the EUA for HCQ submitted by doctors affiliated with the Henry Ford Health System. FDA is not aware of any new data from RCTs that contradict the results of the trials FDA reviewed, which include the following:

  • A randomized placebo-controlled trial of over 400 outpatients with either 1) laboratory- confirmed COVID-19 or 2) symptoms compatible with COVID-19 and a recent COVID- 19 exposure, showed no difference in mean change in symptom severity (using a 10-point analog scale) from baseline to day 14 (2.55 and 2.29-point reduction in patients given HCQ compared to those given placebo, respectively (absolute difference -0.27 [95 percent CI, -0.61 to 0.07] P=0.117).6 This trial was limited by a lack of available PCR testing and unconfirmed SARS-CoV-2 infection in a large portion of participants.
  • An open-label randomized controlled trial conducted in Spain that enrolled 293 symptomatic outpatients with COVID-19 showed that those who received HCQ compared to those who received “usual care,” showed no difference in the mean change in SARS-CoV-2 viral load from baseline to Day 3 or Day 7.7 The rate of hospitalization was numerically similar in both groups (7.1 percent and 5.9 percent in the usual care and HCQ arms, respectively). The trial did not enroll a large enough number of patients to evaluate the statistical significance of this difference in hospitalization rates (i.e., it was not adequately powered for rate of hospitalization). No subjects in this trial required mechanical ventilation and there were no deaths. The median time from randomization to the resolution of symptoms was not statistically significantly different between the usual care and HCQ arms (12.0 days and 10.0 days, in the usual care and HCQ arms, respectively) (p = 0.38).8

Regarding the request in your letter for “all documents and communications between or among employees, agents, or contractors of the FDA and employees from January 1, 2020 to the present referring or relating to treatment of COVID-19…,” FDA staff have been in contact with your staff to explain how this request would involve an extraordinarily large volume of documents that would need to be collected, reviewed, and potentially redacted per applicable disclosure laws, and would require diverting personnel essential to FDA’s response to the COVID-19 public health emergency. Additionally, the documents you request are the subject of document requests in pending litigation in the Southern District of New York involving FDA and other federal agencies (Open Society Justice Initiative v. Department of Defense, et al.). In connection with that litigation, FDA is collecting, reviewing, and redacting as appropriate, responsive documents and posting documents relating to COVID-19 therapeutics on FDA’s website.9 FDA is actively working on processing responsive documents in this litigation and expects to process roughly 2,000 pages per month beginning March 2021. Therefore, documents responsive to your request are already publicly posted, and we expect that many more will be posted this year with appropriate redactions for information protected from disclosure under the law.

Thank you again for contacting us regarding this matter. The same letter has been sent to your cosigners.

Andrew Tantillo
Acting Associate Commissioner For lEgislative Affairs


The Honorable Alex M. Azar II

Secretary, Department of Health and Human Services

1 Information on FDA’s authorizations, including their respective Fact Sheets and product-specific responses to frequently asked questions, is located on the Agency’s website at: https://www.fda.gov/emergency-preparedness- and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs.

2 https://www.covid19treatmentguidelines.nih.gov/

3 https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

4 While products authorized (under EUA requirements) by FDA have not yet been demonstrated to be safe and effective for their uses, the Fact Sheets do provide the necessary scientific information, based on the totality of scientific information available for the product, to facilitate its appropriate authorized use as part of the response to a public health emergency.

5 See section 564(c) of the Federal Food, Drug and Cosmetic Act.

6 Skipper CP, Pastick KA, Engen NW. et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: A randomized trial. Ann Intern Med. Published July 16, 2020.

7 At day 3, the difference was -1.41 and -1.41 log10 copies/mL in the usual care and HCQ arm, respectively [95% CI –0.28; 0.29]), and, at Day 7, it was –3.37 and –3.44 log10 copies/mL in the usual care and HCQ arm, respectively [95% CI –0.44; 0.29]).

8 Mitjà O, Corbacho-Monné M, Ubals M. et al. Hydroxychloroquine for early treatment of adults with mild covid- 19: A randomized-controlled trial. Clin Infect Dis. Published online July 16, 2020.

9 https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/covid19records.cfm