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Chloroquine and hydroxychloroquine in covid-19

BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1432 (Published 08 April 2020) Cite this as: BMJ 2020;369:m1432

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Re: Chloroquine and hydroxychloroquine in covid-19

Dear Editor

Ferner and Aronson provide a thorough review of clinical and laboratory evidence related to chloroquine and hydroxychloroquine. But the implications of the premature embrace of these products extend also into the realm of regulatory decision-making and indeed to scientific decision-making more generally.

In the United States, the Food and Drug Administration has struggled against the proponents of unproven experimental treatments since its inception more than 100 years ago. As far back as there has been an FDA, there have been FDA Commissioners complaining about the power of “testimonials” -- reports from single patients that led to a wave of premature excitement about a new therapy. The 1950s had Krebiozen and the 1970s had laetrile, both purported cures for cancer that ultimately proved ineffective. In the 2000s, a group called the Abigail Alliance sued FDA seeking access to drugs for terminal illnesses as long as Phase I testing had been completed. That effort foundered at the appellate court level, but there are still clinics offering treatments such as stem cell therapy with bold promises but unclear value.

Recently, the U.S. Congress passed the Right to Try Law of 2018, which established a pathway for certain patients with life-threatening conditions to obtain access to investigational drugs. FDA already operated a similar decades-old program called expanded access, under which the agency approves patient requests more than 99 percent of the time. The Right to Try law differed in that it allowed patients to obtain the drug without oversight from FDA or review by an Institutional Review Board. Signing the bill into law, President Trump declared, "We're going to be saving tremendous numbers of lives."

To date, however, only approximately 10 patients have obtained access through Right to Try, with none for COVID-19 (Allison Bateman-House, NYU Langone Health, personal communication, April 7, 2020), even as FDA permits well over 1,000 single patient expanded access applications to proceed each year. [1]

The suspicion of federal oversight of experimental treatment has continued to guide the administration’s approach to the COVID-19 pandemic. Relying in part on information provided by a private physician in New Jersey, his personal attorney Rudolph Giuliani and Fox News host Laura Ingraham, the President, began touting chloroquine and hydroxychloroquine as potential cures. “I’m not a doctor,” he said, “But I have common sense.” Separately he asked, “What do you have to lose? I’ll say it again: What do you have to lose? Take it. I really think they should take it.”

Existing knowledge about the drugs provides considerable basis for caution. Hydroxychloroquine is a well-known cause of QT prolongation and the sometimes fatal torsades de pointes. The risk of arrhythmia is enhanced in patients with myocarditis, a known complication of COVID-19. FDA also warns of other adverse effects, including nephropathy, hepatotoxicity, and retinopathy.

Ferner and Aronson have reviewed the evidence supporting the efficacy of hydroxychloroquine and so we won’t review that here. Despite that, on March 28, 2020, under apparent pressure from the President, FDA granted an Emergency Use Authorization (EUA) to deliver hydroxychloroquine and chloroquine to the Strategic National Stockpile, and the President stated that 29 million doses would be distributed around the country. An EUA permits the use of unapproved medical products or unapproved uses of approved medical products in certain emergency situations when there are no adequate, approved, and available alternatives and the potential benefits exceed the potential risks. In its letter granting the EUA for the drugs, FDA mentioned “limited in-vitro and anecdotal clinical data in case series,” [3] but provided no citations.

Sixteen clinical trials of chloroquine/hydroxychloroquine are currently planned or in progress according to ClinicalTrials.gov. These trials will inform the question of whether the treatment is of meaningful value to patients, and, if it is, at what point in the illness and at what dosage. In the meantime, the push for broad treatment in the absence of these data is ill-advised for the following reasons.

First, many patients and doctors may believe the treatment to be safe and effective, when neither has been established.

Second, the demand for hydroxychloroquine for COVID-19 is depriving patients currently dependent on the drug for rheumatoid arthritis and systemic lupus erythematosus.

Third, FDA may find it increasingly difficult to apply scientific standards to other products in the context of the pandemic. Already, FDA has allowed more than 70 manufacturers of antibody tests to market their products with the statement “This test has not been reviewed by the FDA,” forcing federal officials to concede it isn’t clear whether the tests actually work as intended. Questions about the effectiveness of the available tests have already been raised.

Fourth, the excessive promotion of these products may result in the public not accepting negative results from high quality trials. In our current environment, it is not hard to imagine clinical trial data dismissed as “fake news.”

To defeat the novel coronavirus, there are many questions that need answers quickly, and objective scientific data should guide how they are prioritized. These include which other therapeutic agents might work at different stages of illness, which diagnostic tests are rapid and reliable, and, ultimately, which vaccines are effective in preventing infection.

The requirement for high quality clinical data has guided drug development since 1962, when Congress passed amendments to the Food, Drug, and Cosmetic Act in the wake of the thalidomide disaster requiring the demonstration of effectiveness (not just safety) prior to marketing. This requirement for data is not red tape; it is the difference between hoping that something works and knowing that it does.

Amid the urgency of a crisis, it is tempting to cast aside the scientific method and adopt interventions offering even a glimmer of hope. But history instructs us otherwise. Effective treatments are not identified by anecdote, wishful thinking, or lobbying; they are instead the product of the systematic application of the very scientific principles that for decades have delivered so many safe and effective treatments.

1 Food and Drug Administration. Expanded Access (compassionate use) submission data. Available at:
https://www.fda.gov/news-events/expanded-access/expanded-access-compassi... (accessed April 11, 2020).
2 Rucker P, Costa R, McGinley L, Dawsey J. ‘What do you have to lose?’: Inside Trump’s embrace of a risky drug against coronavirus. Washington Post, April 6, 2020. Available at: https://www.washingtonpost.com/politics/what-do-you-have-to-lose-inside-... (accessed April 11, 2020).
3 Hinton DM, Food and Drug Administration. Letter to Bright R, Biomedical Advanced Research and Development Authority. Available at: https://www.fda.gov/media/136534/download (accessed April 11, 2020).
4 Perrone M. Fears of 'Wild West' as COVID-19 blood tests hit the market. Associated Press, April 12, 2020. Available at: https://hosted.ap.org/journalrecord/article/6f918ac77eefa34beaa381003a76... (accessed April 13, 2020).

Competing interests: No competing interests

16 April 2020
Peter G Lurie
President
Joshua M. Sharfstein
Center for Science in the Public Interest
1220 L Street, NW #300, Washington, DC 20005