Letter revoking EUA for chloroquine phosphate and

June 15, 2020

Gary L. Disbrow Ph.D.

Deputy Assistant Secretary

Director, Medical Countermeasure Programs

Biomedical Advanced Research and Development Authority (BARDA)

Office of Assistant Secretary for Preparedness and Response (ASPR)

U.S. Department of Health and Human Services (HHS)

330 Independence Ave, S.W., Room 640G

Washington, D.C. 20201

Dear Dr. Disbrow:

This letter is in response to your request, dated today, that the Food and Drug Administration

(FDA) revoke the Emergency Use Authorization (EUA) for emergency use of oral formulations

of chloroquine phosphate (CQ) and hydroxychloroquine sulfate (HCQ) to be distributed from the

Strategic National Stockpile (SNS) issued on March 28, 2020. Like BARDA’s earlier request to

FDA to issue the EUA, BARDA’s request to revoke the EUA is part of a collaborative, USG-

interagency effort to rapidly respond to this continuously evolving public health emergency.

Today’s request to revoke is based on new information, including clinical trial data results, that

have led BARDA to conclude that this drug may not be effective to treat COVID-19

[Coronavirus Disease 2019] and that the drug’s potential benefits for such use do not outweigh

its known and potential risks.

The authorization of a product for emergency use under section 564 of the Federal Food, Drug,

and Cosmetic Act (the Act) (21 U.S.C. 360bbb-3) may, pursuant to section 564(g)(2) of the Act,

be revised or revoked when the criteria under section 564(b)(1) of the Act no longer exist, the

criteria under section 564(c) of the Act for issuance of such authorization are no longer met, or

other circumstances make such revision or revocation appropriate to protect the public health or

safety.

FDA has determined that the criteria under section 564(c) of the Act for issuance of the EUA

referenced above are no longer met. Under section 564(c)(2) of the Act, an EUA may be issued

only if FDA concludes “that, based on the totality of scientific evidence available to the

Secretary, including data from adequate and well-controlled clinical trials, if available, it is

reasonable to believe that: (A) the product may be effective in diagnosing, treating, or

preventing—(i) such disease or condition [….]; and (B) the known and potential benefits of the

product, when used to diagnose, prevent, or treat such disease or condition, outweigh the known

and potential risks of the product […].”

As explained in the attached memorandum, based on a review of new information and a

reevaluation of information available at the time the EUA was issued, FDA now concludes that

these criteria are no longer met. The bases for this decision include the following:

Page 2 – BARDA

• We now believe that the suggested dosing regimens for CQ and HCQ as detailed

in the Fact Sheets are unlikely to produce an antiviral effect.

• Earlier observations of decreased viral shedding with HCQ or CQ treatment have

not been consistently replicated and recent data from a randomized controlled trial

assessing probability of negative conversion showed no difference between HCQ

and standard of care alone.

• Current U.S. treatment guidelines do not recommend the use of CQ or HCQ in

hospitalized patients with COVID-19 outside of a clinical trial, and the NIH

guidelines now recommend against such use outside of a clinical trial.

• Recent data from a large randomized controlled trial showed no evidence of

benefit for mortality or other outcomes such as hospital length of stay or need for

mechanical ventilation of HCQ treatment in hospitalized patients with COVID-

19.

FDA has concluded that, based on this new information and other information discussed in the

attached memorandum, it is no longer reasonable to believe that oral formulations of HCQ and

CQ may be effective in treating COVID-19, nor is it reasonable to believe that the known and

potential benefits of these products outweigh their known and potential risks. Accordingly, FDA

revokes the EUA for emergency use of HCQ and CQ to treat COVID-19, pursuant to section

564(g)(2) of the Act. As of the date of this letter, the oral formulations of HCQ and CQ are no

longer authorized by FDA to treat COVID-19.

While HCQ that has been distributed from SNS is no longer authorized under the EUA for the

authorized use to treat hospitalized patients for COVID-19, FDA-approved HCQ can be

distributed in interstate commerce. The CQ products covered by the EUA are not approved by

FDA for any indication and therefore cannot be legally introduced into interstate commerce. In

addition, under section 564(f)(2) of the Act, HCQ and CQ that were distributed from the SNS

under this EUA remain authorized for emergency use to continue to treat any hospitalized patient

to whom the authorized product has already been administered during the COVID-19 public

health emergency, to the extent found necessary by such patient’s attending physician.

Notice of this revocation will be published in the Federal Register, pursuant to section 564(h)(1)

of the Act.

Sincerely,

/s/

___________________________

RADM Denise M. Hinton

Chief Scientist

Food and Drug Administration

Page 3 – BARDA

Attachment: Memorandum Explaining Basis for Revocation of Emergency Use Authorization

for Emergency Use of Chloroquine Phosphate and Hydroxychloroquine Sulfate

pg. 1

Memorandum Explaining Basis for Revocation of Emergency Use Authorization for

Emergency Use of Chloroquine Phosphate and Hydroxychloroquine Sulfate

On March 28, 2020, the Biomedical Advanced Research and Development Authority (BARDA)

requested and the U.S. Food and Drug Administration (FDA or The Agency) issued an

Emergency Use Authorization (EUA) for emergency use of oral formulations of chloroquine

phosphate (CQ) and hydroxychloroquine sulfate (HCQ) for the treatment of 2019 coronavirus

disease (COVID-19). Based on information available to FDA at the time, the Agency

determined that CQ and HCQ may be effective in treating COVID-19 and that the known and

potential benefits of CQ and HCQ outweigh the known and potential risks for this use. The

Agency limited the use of the authorized products to adults and adolescents who weigh 50 kg or

more and are hospitalized with COVID-19 when participation in a clinical trial is not available,

or participation is not feasible.

Since that time, emerging data and published literature have raised new questions on whether CQ

and HCQ may be effective in treating COVID-19 and whether CQ and HCQ’s known and

potential benefits outweigh the known and potential risks associated with their authorized use.

As part of the Agency’s ongoing review of the appropriateness of the EUA, FDA scientific staff

conducted reviews of these new data and also conducted new analyses of information known at

the time of initial authorization.

A summary of this information includes the following:

• The suggested dosing regimens for CQ and HCQ as detailed in the Fact Sheets are

unlikely to produce an antiviral effect.

• Earlier reports of decreased viral shedding with CQ or HCQ treatment have not been

consistently replicated and recent data from a randomized controlled trial assessing

probability of negative conversion showed no difference between HCQ and standard of

care alone.

• Current U.S. treatment guidelines do not recommend the use of CQ or HCQ in

hospitalized patients with COVID-19 outside of a clinical trial, and the NIH guidelines

now recommend against such use outside of a clinical trial.

• Recent data from a large randomized controlled trial showed no evidence of benefit for

mortality or other outcomes such as hospital length of stay or need for mechanical

ventilation of HCQ treatment in hospitalized patients with COVID-19.

Letter of Authorization, March 28, 2020. Available at: https://www.fda.gov/media/136534/download Accessed

June 9, 2020.

pg. 2

Based on the above, the Agency has concluded that it is unlikely that CQ and HCQ may be

effective in treating COVID-19. Further, in light of ongoing reports of serious cardiac adverse

events and several newly reported cases of methemoglobinemia in COVID-19 patients, the

Agency has concluded that the known and potential benefits of CQ and HCQ do not outweigh

the known and potential risks for the authorized uses. Therefore, the Agency believes that the

criteria

for issuance of an authorization are no longer met and is revoking

EUA 039.

Authorization of EUA 039

The information available at the time the EUA was issued regarding potential benefit included

several components.

First, CQ and HCQ are antimalarial drugs that were reported to have in

vitro activity against SARS-CoV-2 at drug concentrations achievable by doses considered safe in

humans.

6,7,8

A brief clinical report on 100 COVID-19 patients in China reported clinical

improvement and superior viral clearance with CQ treatment versus an unspecified control.

Additionally, a clinical survey by French researchers involving 20 COVID-19 patients reported

that HCQ alone and in combination with azithromycin was associated with viral load reduction

over 6 days. In the French report, the viral load changes were statistically significant compared

to a nonrandomized control group and were more pronounced in patients who received the

combination.

Based on experience with other viral illnesses, it was reasonable to believe that

reduction in viral load may be predictive of clinical benefit.

At the time, a number of national treatment guidelines had been reported as incorporating

recommendations regarding the use of CQ or HCQ in the setting of COVID-19, including

guidelines used in China and Korea. Expert assessments associated with a number of U.S.

medical institutions also included discussion on the use of these drugs in clinical care. Regarding

the known and potential risks, the safety profiles of CQ and HCQ were well established as these

are approved and commonly used anti-malarial drugs and, in the case of HCQ, approved for

rheumatoid arthritis and systemic lupus erythematosus as well. The suggested dosing for CQ and

HCQ under the EUA was within the range of that recommended in the approved labeling for

these products. In general, the drugs are well-tolerated for their approved uses, though known

See Section 564(c) of the Federal Food, Drug & Cosmetic Act (FD&C Act).

FDA notes that the Agency has consulted with BARDA on this matter. On June 15, 2020, BARDA requested that

FDA revoke this EUA.

See Section 564(g)(2) of the FD&C Act.

See FDA Decision Memo for EUA 039, Submitted March 28, 2020.

Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel

coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30: 269-71.

Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting

SARS-CoV02 infection in vitro. Cell Discov 2020; doi: 10.1038/s41421-020-0156-0. [epub ahead of print]

Yao X, Ye F, Zhang M, et al. In vitro activity and projection of optimized dosing design of hydroxychloroquine for

the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020; doi:

10.1093/cid/ciaa237. [Epub ahead of print]

Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of

COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020. DOI: 10.5582/bst.2020.01047. [Epub

ahead of print]

Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results

of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020. doi:

10.1016/j.ijantimicag.2020.105949. [Epub ahead of print]

pg. 3

adverse reactions may include QTc prolongation and ocular, neuropsychiatric, cardiac, and

hematologic toxicity.

Hospitalized patients were likely to have greater prospect of benefit (compared to ambulatory

patients with mild illness) and could be more closely monitored for potential toxicity, although it

was recognized that enrollment in a clinical trial would be the best option when using these drugs

so that data on safety and effectiveness could be obtained.

FDA therefore concluded, based on the totality of scientific evidence available to FDA at the

time, that it was reasonable to believe that CQ and HCQ may be effective in treating COVID-19,

and that, when used under the conditions described in the authorization, the known and potential

benefits of CQ and HCQ when used to treat COVID-19 outweigh the known and potential risks

of such products. The EUA was authorized at a time when there was widespread use of these

drugs by physicians to treat COVID-19 patients, and when such use had presented challenges

with ensuring adequate drug availability for patients being treated with these drugs for approved

uses as well as adequate drug availability to conduct clinical trials.

Similarity of CQ and HCQ and Rationale for Inclusion of Both Products in EUA 039

CQ and HCQ belong to a class of drugs known as 4-aminoquinolines and both occur as

enantiomers (R and S isomers). Desethylchloroquine is an immediate downstream product of

CYP-mediated dealkylation of both drugs, whereas desethylhydroxychloroquine is a metabolite

of only HCQ. Bisdesethylchloroquine is a downstream metabolite of both drugs.

HCQ is

administered as a sulfate, whereas CQ is administered as a phosphate salt. Both drugs are usually

absorbed in the upper intestinal tract. Some studies have reported differences in the

pharmacokinetics of CQ and HCQ in humans; however, these differences can be explained by

differences in either the analytical methods applied, the sample source used (that is, plasma

versus whole blood), or renal clearance of these drugs.

Important to the pharmacokinetics,

pharmacodynamics, and toxic properties of these drugs is their ability to accumulate in acidic

compartments such as lysosomes, as well as inflamed (acidic) tissues. The large volume of

distribution and long half-lives of these drugs can explain some of their clinical characteristics,

such as their slow onset of action and prolonged effects after drug discontinuation. Both drugs

are approved for the treatment of malaria with similar dosing and both have similar adverse

Costedoat- Chalumeau, N., Isenberg, D. & Petri, M. Letter in response to the 2019 update of the EULAR

recommendations for the management of systemic lupus erythematosus by Fanouriakis et al. Ann. Rheum.Dis.

https://doi.org/10.1136/annrheumdis-2019- 215573 (2019).

McChesney, E. W. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am. J. Med. 75, 11–18

(1983).

Tett, S. E. et al. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br. J. Clin. Pharmacol.

27, 771–779 (1989).

Furst, D. E. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases.

Lupus 5, S11–S15 (1996).

Cutler, D. J., MacIntyre, A. C. & Tett, S. E. Pharmacokinetics and cellular uptake of

4-aminoquinoline antimalarials. Agents Actions Suppl. 24, 142–157 (1988).

McChesney, E. W. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am. J. Med. 75, 11–18

(1983).

pg. 4

effects such as QT prolongation.

While only HCQ has an approved indication for chronic

discoid lupus erythematosus and systemic lupus erythematosus in adults and the treatment of

acute and chronic rheumatoid arthritis in adults, this is based on NDA submissions to the

Agency. Both drugs have been used to treat rheumatologic diseases for many years.

Thus, for

the purposes of EUA 039 and consideration of data regarding the use of these products for

COVID-19, it is reasonable to assume that data regarding one product are applicable to the other.

Review of New Information Relevant to Assessing Whether CQ and HCQ May be Effective in

Treating COVID-19

Clinical Pharmacology Assessment Regarding Dosing

Agency clinical pharmacology reviewers have re-assessed the publications relied upon at the

time of EUA authorization regarding significantly higher lung concentration relative to the in

vitro EC

value as the rationale to support CQ and HCQ as potentially efficacious against

SARS-CoV-2 at the dosage suggested in the EUA. The FDA clinical pharmacology reviewers

cite limitations with these studies

including that the in vitro antiviral EC

values reported in

the literature were extracellular drug concentrations present in cell culture media and should be

compared with in vivo free drug concentration in the plasma (likely to be equal to free

extracellular tissue concentration). Under the assumption that in vivo cellular accumulation is

similar to that from the in vitro cell-based assays, the calculated free lung concentrations that

would result from the EUA suggested dosing regimens are well below the in vitro EC

/EC

values, making the antiviral effect against SARS-CoV-2 not likely achievable with the dosing

regimens recommended in the EUA. The substantial increase in dosing that would be needed to

increase the likelihood of an antiviral effect would not be acceptable due to toxicity concerns.

The reviewers include the caveat that if these drugs have immunomodulatory effects that could

be beneficial in patients with COVID-19, those effects would not be predicated on achieving

concentrations that exceed the EC

value.

Although many published papers predict adequate antiviral effect, the majority of these papers

refer to the methods and findings of the publication with the limitations described above. In

addition, conclusions in the most recent publication regarding in vitro activity of HCQ and

achievable concentrations at the site of action are consistent with the FDA assessment.

Results

of analyses made available since the EUA was issued lead to the conclusion that it is unlikely

that the dosing regimens in the EUA would be able to have an antiviral effect.

See FDA Decision Memo for EUA 039, Submitted March 28, 2020.

Schrezenmeir E, Dorner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for

rheumatology. Nature Reviews Rheumatology 2020. 16:155-60.

Office of Clinical Pharmacology Consult Review, EUA 039, Submitted May 15, 2020.

Maharaj AR, Wu H, Hornik CP, et al. Simulated Assessment of Pharmacokinetically Guided Dosing for

Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019. JAMA Pediatr. 2020.

doi:10.1001/jamapediatrics.2020.2422.

pg. 5

Published Literature Regarding Viral Shedding

The Agency has reviewed additional published literature becoming available since the EUA was

issued regarding the effects of CQ or HCQ on viral RNA shedding (see TABLE 1). The highest

quality data are those published by Tang et al. from a randomized open-label trial comparing

HCQ with standard of care alone in 150 hospitalized patients with COVID-19. The proportion

with conversion of RT-PCR specimens obtained from the upper or lower respiratory tract to

negative by day 28 was similar in both groups at multiple timepoints. Other published studies,

which include an extremely small randomized trial as well as several observational comparisons,

were inconsistent with respect to reporting a difference in viral RNA shedding comparing HCQ-

or CQ- treated patients with others who were not treated with either of these medications. These

publications are summarized in TABLE 1 below.

TABLE 1: Publications Relevant to Viral Shedding

Article (design)

Comparison groups (n)

Viral shedding outcomes

Tang W, et al

BMJ

(randomized,

open-label,

stopped early)

HCQ 1200 mg/day x 3 d then 800 mg/day

to complete 2-3 weeks plus standard of

care (75)

SOC alone (75)

53 HCQ and 56 SOC PCR(-) “well before”

day 28 endpoint; K-M “probability of

negative conversion” by 28 days reported

as “similar”; median time to (-) 8 and 7

days respectively; proportion (-) “similar”

at multiple time points

Huang M, et al

J Mol Cell Biol

(randomized,

2 antiviral arms)

CQ 500 mg bid x 10 d (10)

Lopinavir/ritonavir (12)

All CQ patients PCR(-) by day 13,

11 of 12 L/r patients PCR(-) by day 14;

authors say CQ PCR(-) % “slightly higher”

on some days

Chen X, et al

medRxiv preprint

(retrospective,

observational)

Retrospective analysis of multiple

interventions (CQ in 25 of 284 on page 7,

28 on page 9; also steroids, L/r, arbidol,

oseltamivir)

CQ (and other antivirals) not associated

with improvement in viral clearance;

median 6 days from admission in 121 on

no antivirals, 7 days in 17 patients

receiving CQ without other antivirals

Mallat J, et al

medRxiv preprint

(retrospective,

observational)

HCQ 400 mg/day (21)

Non-HCQ (13)

Median time to (-) PCR 17 days HCQ, 10

days non-HCQ;

14/23 HCQ, 10/11 controls (-) day 14

Huang M, et al

medRxiv preprint

(prospective,

observational)

CQ Phosphate 500 mg (300 mg base)

once or twice daily until (-) (233 but

analyzed only 197 who “completed”)

Historical controls (192 “collected”; 176

analyzed)

Median time to (-) PCR 3 days CQ, 9 days

controls; 91% and 94-96% CQ, 57% and

80% controls (-) at days 10 and 14; 3 CQ

patients “re-positive” after discharge

Citations for articles mentioned in table:

Tang W et al. BMJ. May 14, 2020;369:m1849. doi:10.1136/bmj.m1849

Huang M et al. J Mol Cell Biol. May 18, 2020;12(4):322‐325. doi:10.1093/jmcb/mjaa014

Chen X et al. medRxiv 2020.04.09.20058941; doi: https://doi.org/10.1101/2020.04.09.20058941

Mallat J et al. medRxiv 2020.04.27.20082180; doi: https://doi.org/10.1101/2020.04.27.20082180

Huang M et al. medRxiv 2020.04.26.20081059; doi: https://doi.org/10.1101/2020.04.26.20081059

Shabrawishi M et al. medRxiv 2020.05.08.20095679; doi: https://doi.org/10.1101/2020.05.08.20095679

Kim M et al. medRxiv 2020.05.13.20094193; doi: https://doi.org/10.1101/2020.05.13.20094193

Hraiech S et al. Ann Intensive Care. May 24, 2020;10(1):63. doi: https://doi.org/10.1186/s13613-020-00678-4

pg. 6

Article (design)

Comparison groups (n)

Viral shedding outcomes

Shabrawishi M, et

medRxiv preprint

(retrospective,

observational)

HCQ (any dose) ± AZI/other AV (45)

Supportive care (48)

(excluded those transferred to ICU or

isolation facility while still PCR(+))

No significant difference in time to first (-)

PCR or proportion (-) by 5 or 12 days

(median 3 days from treatment start, 33 by

5 days and 38 by 12 days in each group)

Kim M, et al

medRxiv preprint

(retrospective,

observational)

HCQ 200 mg bid + antibiotics (22)

Lopinavir/ritonavir + antibiotics (35)

Conservative treatment (40)

Hazard ratio for time to viral clearance

0.49 for HCQ/antibiotics (mean 15.3 days)

versus L/r plus antibiotics (mean 19.1

days), 0.44 for HCQ/antibiotics versus

conservative treatment (20.7 days)

Hraiech S, et al

Ann Intensive Care

(retrospective,

observational)

HCQ 600 mg/day + AZI (17)

Lopinavir/ritonavir (13)

No antivirals (15)

At day 6 of treatment, PCR(-) in 3

HCQ/AZI, 5 L/r, 2 no-antivirals

In summary, although there were two positive reports observing an impact on viral shedding

available at the time the EUA was issued, this observation has not been consistently replicated.

The largest randomized controlled trial assessing probability of negative conversion (Tang et al.)

showed no difference: the proportion of patients with detectible shedding of viral RNA was very

similar over time in the group that received HCQ when compared to the group that did not. At

the time the EUA was issued, it was reasonable to assume that an impact on viral shedding

would be associated with a clinical benefit for patients. However, neither a favorable impact of

CQ or HCQ on viral shedding nor an established clinical benefit of a decrease in viral shedding

has been borne out by data and reports available since the EUA was issued.

U.S. National Treatment Guidelines

At the time EUA 039 was authorized, a number of countries initially impacted by COVID-19

had recommended treatment of patients with COVID-19 with CQ or HCQ in their national

treatment guidelines.

However, there were no national treatment guidelines available in the

U.S. This is no longer the case. On April 11, 2020, The Infectious Diseases Society of America

Guidelines on the Treatment and Management of Patients with COVID-19 published

recommendations on CQ and HCQ in the context of a clinical trial among patients admitted to

hospital with COVID-19, describing the evidence supporting its use as “very low.”

The NIH

COVID-19 Treatment Guidelines, which were initially published on April 21, 2020, were

updated on June 11, 2020,

to recommend against the use of CQ and HCQ for the treatment of

COVID-19, except in a clinical trial. The Johns Hopkins ABX Guide updated June 3, 2020,

states,

“CQ or HCQ: the overall feeling is that safety is an issue especially in more severely ill

patients; however, it remains without high-quality data to argue for or against its use.” In

summary, U.S. treatment guidelines are now available and do not recommend the use of HCQ or

CQ in hospitalized patients with COVID-19 outside of a clinical trial.

See FDA Decision Memo for EUA 039, Submitted March 28, 2020.

Available at: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/#toc-1

Available at: https://www.covid19treatmentguidelines.nih.gov/

Available at:

https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540747/all/Coronavirus_COVID_19__

SARS_CoV_2_

pg. 7

Randomized Evaluation of COVID-19 Therapy RECOVERY Trial (NCT04381936)

The RECOVERY trial is being sponsored by Oxford University in the United Kingdom in

collaboration with several foundations and British government agencies. It is designed as an

adaptive platform trial in hospitalized patients with COVID-19 to assess the effectiveness of trial

treatments in reducing all-cause mortality within 28 days. Treatment arms include: usual care; or

usual care combined with corticosteroid therapy, lopinavir/ritonavir, azithromycin, or HCQ.

Additional randomizations are included between convalescent plasma and placebo and between

tocilizumab and placebo for eligible patients.

Over 11,000 patients have been enrolled so far, of an estimated target enrollment of 12,000. On

June 5, 2020, the chief investigators announced closure of the HCQ arm due to lack of benefit.

With 1542 patients randomized to HCQ and 3132 to the usual care comparator, mortality was

reported as 25.7% and 23.5% respectively (hazard ratio 1.11, 95% CI 0.98-1.26, p=0.10).

The

difference in mortality rates trends in favor of the usual care comparator. No evidence of benefit

was reported for other outcomes such as hospital length of stay or need for mechanical

ventilation. These were noted as preliminary results with follow-up complete for just over 80%

of participants; the investigators announced “These data convincingly rule out any meaningful

mortality benefit of hydroxychloroquine in patients hospitalised with COVID-19. Full results

will be made available as soon as possible.” While the HCQ findings in the RECOVERY trial

were based on a randomized but open label design, the endpoint of mortality is generally less

susceptible than other more subjectively assessed endpoints to biases that may be of concern

with such a design.

Only randomized controlled trials can answer the question of whether HCQ or CQ is of clinical

benefit in hospitalized patients with COVID-19, and the RECOVERY Trial results offer

persuasive evidence of a lack of benefit of HCQ in the treatment of hospitalized patients with

COVID-19.

There are additional trials ongoing in hospitalized patients.

It is important to note that the

criteria for issuance of an EUA are more stringent than the conditions justifying equipoise to

See: https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-

covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-

hydroxychloroquine-in-hospitalised-patients-with-covid-19

Preliminary results from the RECOVERY trial were provided to FDA by the chief investigators. See letter from P.

Horby and M. Landray, University of Oxford, to J. Woodcock, Director, CDER (June 10, 2020). Archived in the

Document Archiving Reporting and Regulatory Tracking System for EUA 039.

Some examples of ongoing trials include:

Outcomes Related to COVID-19 Treated with Hydroxychloroquine Among In-Patients with Symptomatic Disease

(ORCHID) Study (NCT04332991): This trial is being conducted by the Prevention and Early Treatment of Acute

Lung Injury (PETAL) Clinical Trials Network of the National Heart, Lung, and Blood Institute (NHLBI), part of the

National Institutes of Health. ORCHID is a multicenter, blinded, placebo-controlled, randomized clinical trial

evaluating HCQ for the treatment of adults hospitalized with COVID-19. The primary aim is to compare the effect

of HCQ versus placebo on clinical outcomes, measured using the COVID Ordinal Outcomes Scale at Day 15. The

current planned sample size is 510. Over 400 participants have been enrolled to date. The trial has undergone recent

DMC review and the DMC recommended continuation of the trial.

pg. 8

continue a clinical trial. In addition to trials in hospitalized patients, numerous clinical trials have

been in progress studying treatment of outpatients with COVID-19 or use of HCQ or CQ for pre-

or post-exposure prophylaxis. One such trial conducted under U.S. IND recently published

results showing no significant difference in development of symptomatic illness compatible with

COVID-19 between HCQ and placebo recipients for post-exposure prophylaxis, though with

limitations that outcomes were largely self-reported with little opportunity for laboratory

confirmation.

Review of New Information on Known and Potential Risks of the Products

Office of Surveillance and Epidemiology Review of Adverse Events Associated with CQ or

HCQ Use for COVID-19

The FAERS database and literature were searched for adverse events associated with CQ or

HCQ use for COVID-19, as well as the American Association of Poison Control Centers

(AAPCC) National Poison Data System (NPDS) for calls associated with CQ OR HCQ

exposure.

As of May 6, 2020, key findings were as follows: A total of 347 HCQ and 38 CQ cases were

identified. The majority of the cases (69%) involved males with a median age in the early 60s.

Five cases reported HCQ use through the EUA. Of all serious adverse events (cardiac and non-

cardiac), QT prolongation was the most commonly reported adverse event for both HCQ and

CQ.

There were 109 cases with serious cardiac AEs, some reporting one or more of the following: 80

(73%) reported QT prolongation, 4 (4%) reported Torsades de Pointes, 14 (13%) reported

ventricular arrhythmia, ventricular tachycardia or ventricular fibrillation, and 25 (23%) had a

fatal outcome. Among the 109 cases, 92 (84%) reported concomitant use of at least one other

medication that prolongs the QT interval and 75 (69%) reported concomitant use of

azithromycin.

There were 113 cases with serious non-cardiac AEs. Hepatitis/increased liver

enzymes/hyperbilirubinemia were the most commonly reported adverse event (59%). These are

Solidarity Clinical Trial for COVID-19 Treatments: This is a collaborative trial facilitated by the World Health

Organization enrolling adults with COVID-19 admitted to hospital. Patients are randomized to local standard of care

or local standard of care plus one of remdesivir, hydroxychloroquine, lopinavir with ritonavir, or lopinavir with

ritonavir plus interferon beta-1a. National arms of this trial, such as those from Canada (NCT04330690) and

Norway (NCT04321616), may be listed separately in ClinicalTrials.gov. The primary endpoint is in-hospital

mortality. As of 3 June 2020, more than 3500 patients have been recruited in 35 countries, with over 400 hospitals

actively recruiting patients

Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure

Prophylaxis for Covid-19 [published online ahead of print, 2020 Jun 3]. N Engl J Med.

2020;10.1056/NEJMoa2016638. doi:10.1056/NEJMoa2016638;

Cohen MS. Hydroxychloroquine for the Prevention of Covid-19 - Searching for Evidence [published online ahead

of print, 2020 Jun 3]. N Engl J Med. 2020;10.1056/NEJMe2020388. doi:10.1056/NEJMe2020388

Office of Surveillance and Epidemiology Pharmacovigilance Memorandum, EUA 039, Submitted May 19, 2020.

pg. 9

labeled events for HCQ and CQ. The most commonly reported unlabeled adverse event was

acute kidney injury/renal failure (5%). Of note, acute kidney injury has been associated with

COVID-19. Methemoglobinemia was reported in 4 cases (4%); two of these cases were fatal

(methemoglobinemia is currently not in the labels for HCQ or CQ).

The reviewers were unable to assess the rates of these AEs using FAERS data, NPDS data, and

literature alone because the total number of persons exposed to either product is unknown. The

cardiac adverse events identified are serious risks associated with death in some patients. On

April 24, 2020, FDA issued a Drug Safety Communication cautioning against the use of HCQ

and CQ for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart

rhythm problems.

The EUA 039 Health Care Provider Fact Sheets recommend use with

caution in patients at increased risk for ventricular arrhythmia, performing a baseline

electrocardiogram, and monitoring the electrocardiogram during treatment. While this

monitoring can reduce the risk of harm, the risk of cardiac adverse events under the EUA 039

authorized use remains. Methemoglobinemia is an adverse event which was not included in

labeling for either products and is now reported in the setting of COVID-19. A recent case series

described 3 cases of methemoglobinemia occurring in critically ill COVID-19 patients from a

single institution.

Additional Information Reviewed

Outcome Data Reported to BARDA

The Health Care Provider Fact Sheets for EUA 39 state that the prescribing health care provider

and/or the provider’s designee are/is responsible for submitting patient outcomes via an on-line

reporting form.

However, few reports have been submitted to date. As of May 22, 2020, the

Strategic National Stockpile reports dispensing approximately 2.4 million HCQ 7-day treatment

courses to State and local health authorities. The approximate number of treatment courses

dispensed to hospitals by State and local health authorities is not available at this time. As of

May 26, 2020, outcome data for 1763 patients receiving HCQ (1762) or CQ (1) through the EUA

have been reported to BARDA (see TABLE 2).

TABLE 2: Outcome Data Reported to BARDA for 1762 Patients as of May 26, 2020

Baseline Characteristics

• The mean (SD) age was 62.6 (15.50) years

• Sex: 35% male, 23.3% female, 41.7% missing

• Baseline severity of illness: 5% mild, 33% moderate, 45% severe, 17% critical

• Comorbidities: 6% had cardiovascular disease, 23% had HTN, and 20% had DM

Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-

hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or

Naymagon L, Berwick S, Kessler A, Lancman G, Gidwani U, Troy K. The emergence of methemoglobinemia

amidst the COVID-19 pandemic. American Journal of Hematology epub ahead of print 15 May 2020.

https://doi.org/10.1002/ajh.25868

See: Mandatory Patient Outcome Reporting Survey - EUA for Chloroquine Phosphate and Hydroxychloroquine

Sulfate. Available at: https://euachloroquine-hydroxychloroquine-outcome.ppdi.com/.

pg. 10

Clinical Characteristics

• The mean (SD) number of days patients received a dose was 4.1 (2.24), maximum number of days was 23

• The mean (SD) number of days hospitalized was 9.7 (12.12)

• 68.3% of patients were discharged and 31.7% of patients were deceased

• Ventricular arrhythmias were reported in 6 (0.34%) subjects

• Other cardiac AEs were reported in 30 (1.70%) subjects

Treatment Outcomes and Characteristics

• The mean number of days of dosing was the same in the discharged and deceased groups

• The rate of ventricular arrhythmia was similar in the discharged and deceased groups

• Other cardiac AEs were reported in 17 (1.41%) of discharged patients and 12 (2.33%) of deceased patients

Data interpretation is limited due to the low number of patients with a reported outcome and the

absence of a comparison group.

Office of Surveillance and Epidemiology Memorandum – Literature Review on CQ and

HCQ Use in the COVID-19 Population

The CDC Stephen B. Thacker Library of COVID-19 research articles was searched for articles

that contain “hydroxychloroquine” or “chloroquine” in the title or abstract and at a minimum had

the following design features: conducted in a population with confirmed COVID-19 infection,

reported quantitative estimates of treatment effectiveness or safety associated with HCQ or CQ

use, and included a reference group that was not treated with HCQ or CQ. The search identified

317 articles. After excluding non-observational studies (e.g., RCTs) and studies not designed to

evaluate HCQ or CQ treatment outcomes in the COVID-19 population, there were 10

observational studies eligible for review and one additional study that had been shared with FDA

in manuscript proof format. All 11 studies were cohort studies conducted in hospitalized

COVID-19 populations. All 11 studies reported findings on HCQ or CQ treatment effectiveness.

FDA reviewers concluded that the findings on the effectiveness endpoints were inconsistent

across all reviewed studies. Most of the point estimates reported were imprecise, with confidence

intervals that crossed the null.

Only one study evaluated cardiac safety associated with HCQ treatment (Rosenberg et al

). This

study was a retrospective multicenter cohort study of patients with laboratory-confirmed

COVID-19 admitted to one of 25 participating New York metropolitan region hospitals. The

primary effectiveness outcome was in-hospital mortality. After adjustment for demographic

characteristics, hospital, preexisting conditions and illness severity, no significant differences in

mortality were found between patients receiving HCQ + azithromycin, HCQ alone or

azithromycin alone compared with neither drug. The secondary cardiac safety outcomes were

cardiac arrest and abnormal ECG findings (based on chart review). Compared to patients who

received neither HCQ nor azithromycin, risks of cardiac arrest were higher among patients

Office of Surveillance and Epidemiology Memorandum - Literature review on hydroxychloroquine or

chloroquine use in COVID-19 population, EUA 039, Submitted May 28, 2020.

Rosenberg ES, Dufort EM, Udo T, et al. Association of Treatment with Hydroxychloroquine or Azithromycin

With In-Hospital Mortality in Patients With COVID-19 in New York State [published online ahead of print, 2020

May 11]. JAMA. 2020;e208630. doi:10.1001/jama.2020.8630

pg. 11

receiving HCQ + azithromycin, and those receiving HCQ alone, although the risk estimates were

not statistically significant for the monotherapy group. FDA reviewers concluded that this study

is limited by potential for residual confounding and bias due to outcome misclassification, and

overall, the available observational data are of insufficient quality to inform the effectiveness or

safety of HCQ or CQ use in the COVID-19 population.

In an Addendum included in the Memorandum, reviewers additionally evaluated a large

observational study of HCQ and CQ with or without a macrolide for the treatment of patients

hospitalized with COVID-19, based on data from a multinational registry (Mehra et al

). This

publication was subsequently withdrawn by the authors

and will not be included in this

Memorandum.

Conclusion

Since FDA initially authorized CQ and HCQ for emergency use on March 28, 2020, new

scientific and clinical data, as well as published literature, have raised questions regarding

whether CQ and HCQ may be effective in treating COVID-19 and whether CQ and HCQ’s

known and potential benefits outweigh the known and potential risks associated with their

authorized use. FDA has reviewed this information and data as part of its ongoing assessment of

whether an EUA remains appropriate.

Based on its review, the Agency has determined the following:

• The suggested dosing regimens for CQ and HCQ as detailed in the Fact Sheets are

unlikely to produce an antiviral effect.

• Earlier reports of decreased viral shedding with HCQ or CQ treatment have not been

consistently replicated and recent data from a randomized controlled trial assessing

probability of negative conversion showed no difference between HCQ and standard of

care alone.

• Current U.S. treatment guidelines do not recommend the use of HCQ or CQ in

hospitalized patients with COVID-19 outside of a clinical trial, and the NIH guidelines

now recommend against such use outside of a clinical trial.

• Recent data from a large randomized controlled trial showed no evidence of benefit for

mortality or other outcomes such as hospital length of stay or need for mechanical

ventilation of HCQ treatment in hospitalized patients with COVID-19.

Therefore, based on the totality of scientific evidence available, it is no longer reasonable to

believe that CQ and HCQ may be effective in treating COVID-19 for the authorized uses

detailed in EUA 039. Further, in considering the known safety profile for both CQ and HCQ and

Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide

for treatment of COVID-19: a multinational registry analysis [published online ahead of print, 2020 May 22] 6

Mandeep R Mehra, Frank Ruschitzka, Amit N Patel. Retraction—Hydroxychloroquine or chloroquine with or

without a macrolide for treatment of COVID-19: a multinational registry analysis

The Lancet Published: June 5, 2020 Available at:

https://www.thelancet.com/journals/lancet/article/PIIS0140-

6736(20)31324-6/fulltext

pg. 12

the ongoing reports of serious cardiac adverse events, in addition to several new reports of

methemoglobinemia in COVID-19 patients, it is no longer reasonable to believe that the known

and potential benefits of CQ and HCQ outweigh the known and potential risks associated with

the authorized use.

BARDA has received few reports from healthcare providers and/or provider designees detailing

outcome data as requested in the EUA. Interpretation of these data is limited due to the low

number of patients with a reported outcome and the absence of a comparison group. A review of

recent published literature describing observational studies does not provide informative findings

given residual confounding and other methodological issues.

Based on the above, FDA concludes that the criteria for Emergency Use Authorization as

outlined in Section 564(c)(2) of the FD&C Act are no longer met and is revoking EUA 039 for

CQ and HCQ for the treatment of COVID-19.