Statement of Harvey A. Risch, MD, PhDProfessor of Epidemiology, Yale School of Public HealthSenators and colleagues: thank you for convening this hearing. We all understand the endemicdisease that we are facing, that we have to face it head-on and not hide from it hoping that itwill go away. I want to give you my perspective.In May of this year I observed that results of studies of a drug suggested to treat Covid,hydroxychloroquine, were being misrepresented by what I thought at the time was sloppyreporting. We have heard from Dr. McCullough how Covid disease progresses in phases, fromviral replication, to florid pneumonia to multi-organ attack. Viral replication is an outpatientcondition, but the pneumonia that fills the lungs with immune-system debris is hospitalizableand potentially life-threatening. We have also heard how each phase, each pathologic aspectof the disease, has to have its own specific treatments that apply to its own biologicmechanisms. Thus, I was frankly astounded that studies of hospital treatments were beingrepresented as applying to outpatients, in violation of what I learned in medical school abouthow to treat patients.We are now finally coming to address why over the last six months, our government researchinstitutions have invested billions of dollars in expensive patent medication and vaccinedevelopment but almost nothing in early outpatient treatment, the first line of response tomanaging the pandemic. It is not that we lacked candidate medications to study, we have hada number of promising agents. But I believe that the early-on conflation of hospital withoutpatient disease served to imply that treatment of outpatient disease had been studied andfound ineffective. This illogical premise motivated me to look at the evidence for outpatienttreatment.I reiterate: we are considering the evidence for early treatment of high-risk outpatients toprevent hospitalization and mortality. That is it. Treatment starting in the first five days or soafter the onset of symptoms. Treatment of older patients or patients with chronic conditionssuch as diabetes, obesity, heart diseases, lung diseases, kidney diseases, immune-systemdiseases, survivors of cancer etc. These are the people most likely to die from Covid, and theyare the people most needing protection. I have sought to obtain reports of every study ofevery medication pertaining to early treatment of high-risk outpatients. I monitor the literaturedaily. And what I have found is actually quite remarkable. What I have observed is that whilethere have been positive reports about a number of drugs, every study of outpatient use of onedrug, hydroxychloroquine, with or without accompanying agents, has shown substantial benefitin reducing risks of hospitalization and mortality.These studies break down into two major types. The first is double-blinded, randomizedcontrolled trials, and the second is non-randomized but still controlled trials. You have heardfrom various government and scientific personalities that randomized controlled trials providethe strongest form of evidence. Many of these people have also claimed that randomized trials provide the only trustworthy form of evidence. There is some truth in these assertions, butthere is also lots of falsehood. We know for example that the great majority of drugs used totreat heart diseases were established with non-randomized trials. Cholesterol-lowering drugswere in widespread use before randomized trials were ever done. Azithromycin, the mostcommonly used antibiotic in children, was not established by randomized trials. The idea thatonly randomized trials provide trustworthy evidence is a simplistic notion that may sound goodin theory, but the comparison between randomized and non-randomized trials is somethingthat has actually been extensively studied in the medical literature. I am an epidemiologistbecause even though I love biological theories, I develop them all the time to study how natureworks, but it is from the human empirical data that we learn how indeed nature works.And we have huge amounts of empirical data to show that randomized trials and theircorresponding non-randomized trials give the same answers. Dr. Tom Frieden, previouslyDirector of the CDC, in 2017 wrote an extensive essay in the New England Journal of Medicineshowing that non-randomized trials can provide fully compelling evidence, especially when theyare done carefully to account for reasons why patients received the drugs, and importantly,when circumstances are such that the cost of waiting for randomized trials involves majorsickness and mortality as we have been experiencing this year. But Dr. Frieden’s essay, asauthoritative as it is, provides only snapshots of the empirical evidence for his observations.The real evidence comes from a meta-analysis of meta-analyses done by the Cochrane LibraryConsortium, a British international organization formed to organize medical research findings tofacilitate evidence-based choices about health interventions. The Cochrane investigatorsexamined what involve tens of thousands of comparisons between randomized trials and theirnon-randomized counterparts and found that the two types of studies arrived at virtuallyidentical conclusions. This is the real evidence about why good non-randomized trials compriseevidence every bit as important as randomized trials. Large amounts of consistent empiricaldata are the evidence, not plausible but simplistic assumptions, no matter who says them.So what did I find about hydroxychloroquine in early use among high-risk outpatients? The firstthing is that hydroxychloroquine is exceedingly safe. Common sense tells us this, that amedication safely used for 65 years by hundreds of millions of people in tens of billions of dosesworldwide, prescribed without routine screening EKGs, given to adults, children, pregnantwomen and nursing mothers, must be safe when used in the initial viral-replication phase of anillness that is similar at that point to colds or flu. In fact, a study by researchers at theUniversity of Oxford showed that in 14 large international medical-records databases of olderrheumatoid arthritis patients, no significant differences were seen in all-cause mortality forpatients who did or did not use hydroxychloroquine. The Oxford investigators also looked atcardiac arrhythmias and found no increase for hydroxychloroquine users. This was in morethan 900,000 hydroxychloroquine users. This is examined at length in my paper in theAmerican Journal of Epidemiology in May. Now, the FDA posted a warning on July 1 on itswebsite about hydroxychloroquine used in outpatients, but we can discuss this later; the FDA has had no systematic evidence in outpatients and erroneously extrapolated from hospitalinpatients to outpatients, what I said earlier was invalid.About studies of hydroxychloroquine early use in high-risk outpatients, every one of them, andthere are now seven studies, has shown significant benefit: 636 outpatients in São Paulo, Brazil;199 clinic patients in Marseille, France; 717 patients across a large HMO network in Brazil; 226nursing-home patients in Marseille; 1,247 outpatients in New Jersey; 100 long-term careinstitution patients in Andorra (between France and Spain); and 7,892 patients across SaudiArabia. All these studies pertain to the early treatment of high-risk outpatients—and allshowed about 50 percent or greater reductions in hospitalization or death. The Saudi studywas a national study and showed 5-fold reduction in mortality for hydroxychloroquine plus zincvs zinc alone. Not a single fatal cardiac arrhythmia was reported among these thousands ofpatients attributable to the hydroxychloroquine. These are the non-randomized but controlledtrials that have been published.Now we also know that all of the outpatient randomized controlled trials this year also togethershow statistically significant benefit. These six studies comprised generally much youngerpatients, only a fraction of whom were at high risk, so they individually had too fewhospitalizations or deaths to be statistically significant. But they all suggested lower risks withhydroxychloroquine use, and when they were analyzed together in meta-analysis as mycolleagues and I found, this lower risk was statistically significant across the studies.We have spent the last six months with formal government policies and warnings against earlyoutpatient treatment, with large government investments in vaccines and expensive newtreatments yet to be proven and almost no support of inexpensive but useful medications, anda quarter of a million Americans have died from this mismanaged approach. Even with newlypromising vaccines, we have almost no information about how they will perform in older andhigh-risk patients, in whom respiratory virus vaccines are known to have weak efficacy; it willbe a number of months before they become widely available; and we don’t know how longvaccine immunity will last, or even if the vaccines will work for the newly increasing mutantstrains of the virus. As I have said on many occasions, the evidence for benefit ofhydroxychloroquine used early in high-risk outpatients is extremely strong, and the evidenceagainst harm is also equally strong. This body of evidence dramatically outweighs therisk/benefit evidence for remdesivir, monoclonal antibodies or the difficult to usebamlanivimab that the FDA has approved for emergency use authorizations while denying theemergency use authorization for hydroxychloroquine. This egregious double standard forhydroxychloroquine needs to be overturned immediately and its emergency use authorizationapplication approved. This is how we will get on the road to early outpatient treatment and themajor curtailment of mortality. Thank you.ReferencesBarbosa Esper R, Souza da Silva R, Teiichi Costa Oikawa F, et al. Empirical treatment withhydroxychloroquine and azithromycin for suspected cases of COVID-19 followed-up bytelemedicine. April 15, 2020. Accessed April 30, 2020.https://pgibertie.files.wordpress.com/2020/04/2020.04.15-journal-manuscript-final.pdfHeras E, Garibaldi P, Boix M, et al. COVID-19 mortality risk factors in older people in a longterm care center. Preprints September 9, 2020. https://doi.org/10.21203/rs.3.rs-70219/v2Ip A, Ahn J, Zhou Y, et al. Hydroxychloroquine in the treatment of outpatients with mildlysymptomatic COVID-19: A multi-center observational study. Preprints August 25, 2020.https://doi.org/10.1101/2020.08.20.20178772Ladapo JA, McKinnon JE, McCullough PA, Risch HA. Randomized Controlled Trials of EarlyAmbulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, andDeath: Meta-Analysis. Preprints September 30, 2020.https://doi.org/10.1101/2020.09.30.20204693Lagier JC, Million M, Gautret P, et al. Outcomes of 3,737 COVID-19 patients treated withhydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospectiveanalysis. Travel Med Infect Dis 2020 Jun 25:101791.https://www.sciencedirect.com/science/article/pii/S1477893920302817Ly TDA, Zanini D, Laforge V, Arlotto S, Gentile S, Mendizabal H, Finaud M, Morel D, Quenette O,Malfuson-Clot-Faybesse P, Midejean A, Le-Dinh P, Daher G, Labarriere B, Morel-Roux AM,Coquet A, Augier P, Parola P, Chabriere E, Raoult D, Gautret P. Pattern of SARS-CoV-2 infectionamong dependant elderly residents living in long-term care facilities in Marseille, France,March-June 2020. Int J Antimicrob Agents. 2020 Nov 6:106219.https://www.sciencedirect.com/science/article/pii/S0924857920304301Risch HA. Early Outpatient Treatment of Symptomatic, High-Risk COVID-19 Patients ThatShould Be Ramped Up Immediately as Key to the Pandemic Crisis. Am J Epidemiol. 2020 Nov2;189(11):1218-1226. https://academic.oup.com/aje/article/189/11/1218/5847586Sulaiman T, Mohana A, Alawdah L, et al. The effect of early hydroxychloroquine-based therapyin COVID-19 patients in ambulatory care settings: A nationwide prospective cohort study.Preprints September 13, 2020. https://doi.org/10.1101/2020.09.09.20184143Szente Fonseca SN, de Queiroz Sousa A, Wolkoff AG, Moreira MS, Pinto BC, Valente Takeda CF,Rebouças E, Vasconcellos Abdon AP, Nascimento ALA, Risch HA. Risk of hospitalization forCovid-19 outpatients treated with various drug regimens in Brazil: Comparative analysis. TravelMed Infect Dis. 2020 Oct 31;38:101906.https://www.sciencedirect.com/science/article/pii/S1477893920304026