Open Letter by U.S. Doctors: JAMA Ivermectin Study Is Fatally Flawed
We the undersigned physicians present this letter to call attention to multiple, integral flaws in the Journal of the American Medical Association’s recently published paper “Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19”[1]. Above all, the data reported do not support the authors’ conclusion that ivermectin is ineffective as a treatment for mild COVID-19.
The study’s flaws span subject population, design, execution and controls. The small sample size (n = 400) had a median age of 37 and a BMI of 26, making them extremely low risk for COVID-19 hard endpoints. Faced with this low-relevance study group, the study authors improperly changed primary endpoint midway, moving the main endpoint to full symptom resolution by day 21. This self-reported subjective endpoint, obtained through telephone survey, is not credible for avoiding nondifferential nullward bias of the results.
We note other major errors in study conduct. The authors incorrectly administered ivermectin on an empty stomach, reducing drug bioavailability in lung tissue, the critical drug target, by a factor of roughly 2.5. Additionally, ivermectin is readily available over-the-counter in Colombia, where sales have been ubiquitous (1.6 doses per COVID-19 case) in Cali during the study period.[2] Lack of serum testing in the study prevented identification of subjects who may have used the drug at intervals longer than the study lookback.
Contrary to the authors’ stated conclusion, the findings suggest lower rates of disease progression, hospitalization, ICU admission, and mortality with ivermectin, which might have been confirmed to be statistically significant with a larger sample and more rigorous study design.
Indeed, notwithstanding these limitations, the available data indicate a 9% faster daily symptom resolution, which when generalized to large populations would have a meaningful impact.[3]
The severe weaknesses of this study make it uninformative about whether ivermectin is beneficial in early COVID-19 treatment. Yet, the authors misleadingly conclude that their findings “do not support the use of ivermectin for treatment of mild COVID-19”, as if they had enough quality data to make that case, which they do not.
Physicians have a solemn duty to care for patients, and randomized controlled trials can provide valuable information. But, as is the case here, they can also be flawed and must therefore always be weighed within the totality of evidence in order to provide the most appropriate patient care.
Over the past year, many government agencies, academic journals, the broader media, and medical associations have departed from historic norms and elevated the status of randomized controlled trials. Such trials are seemingly presented as the only valid basis for making clinical recommendations about COVID-19 treatment, no matter how flawed. This trend has severely hindered the ability of physicians to use clinical experience and observational trials to offer their patients guidance on early treatment for this still not well-understood infection.
We oppose this fixation on randomized controlled trials at the expense of other clinical and scientific evidence and urge medical policymakers to restore balance to the practice of medicine.
Physicians must be free to use all appropriate methodologies in determining the best approach to COVID-19, and to other conditions underlying health disparities throughout our country.
Respectfully,
Reem Abu-Sbaih DO, Greenvale, NY
Charles C. Adams MD, Ringgold, GA
Susan Allen MD, Appleton, WI
Miguel Antonatos MD, Chicago, IL
Robert J. Aquino MD, Huntington, NY
Margaret Aranda MD PhD, West Hills, CA
Alan Bain DO, Chicago, IL
Robert J. Beckman DO, Sault Ste. Marie, MI
Keith Berkowitz MD, New York, NY
Karam Bhalla MD, Corrales, NM
Marsha Y. Blakeslee DO, Severna Park, MD
Bruce L. Boros MD, Key West, FL
Ginge Brien MD, Deerfield Beach, FL
Martha Bouchard MD, Brewster, NY
Kathleen A. Boyls MD, Broken Arrow, OK
Robert C. Bransfield MD, Red Bank, NJ
Peter R. Breggin MD, Ithaca, NY
Kelly Busby DO, Cortez, CO
Andrew L. Buscemi DO, Parkton, MD
Carrie Cannon MD, Orlando, FL
Wesley Allen Carr Jr. MD, Anderson, SC
Ralph Carter MD, Laurinburg, NC
Lillian Checchio MD, Warren, NJ
R. L. Chilton III MD, Austin, TX
David B. Clark MD, Jackson, MO
Teryn B. Clarke MD, Newport Beach, CA
Ryan N. Cole MD, Boise, ID
Stan Crown MD, St. Louis, MO
Anthony M. D’Agostino MD, Naples, FL
Parvez Dara MD, New York, NY
Mary L. Davenport MD, El Sobrante, CA
Stephen M. Davidson DO, Phoenix, AZ
John W. Day MD, Austin, TX
Franklin O. De La Cruz MD, Bardstown, KY
James DelloRusso MD, Huntington Beach, CA
Linda D’Eramo DO, Moon Township, PA
John R. Diggs Jr. MD, Monson, MA
Jeffrey Hall Dobken MD MPH, Valhalla, NY
Larry Doss MD, Lancaster, OH
Alieta Eck MD, Piscataway, NJ
John Eck MD, Piscataway, NJ
W. Benjamin Edwards MD, Lubbock, TX
Susan Tillman Elliott MD, Washington, DC
Edward Elmer MD, Pleasanton, TX
Jack D. England DO, Montrose, CO
Matthew George Erickson MD PhD, Gainsville, FL
George Fareed MD, Brawley, CA
Angelina Farella MD, Webster, TX
Arezo Maria Fathie MD, Las Vegas, NV
Umbrine Fatima MD, Clarence, NY
Harold G. Felter Jr. MD, Corpus Christi, TX
Celia M Fernandez MD, Cullman, AL
Laura Fisher MD, Providence, UT
Patricia L. Foster MD, Boulder, CO
Joseph N. Freund MD, Edmond, OK
Laszlo Galffy MD, Los Angeles, CA
Ariel H. Garcia MD, Moreno Valley, CA
Allison Garza MD, Edinburg, TX
Jacqueline Genova MD, Darby, PA
Shane Gilliam MD, Stephenville, TX
Scott Glickman DO PhD MPH, Las Vegas, NV
Russell S. Gonnering MD, Milwaukee, WI
Beverly Goode-Kanawati DO, Raleigh, NC
Irene Goranitis MD, Dedham, MA
Karladine Graves DO, Kansas City, MO
Jeffrey W. Grolig MD, Redding, CA
Miriam Grossman MD, Airmont, NY
Joseph Guarino MD MPH, Reidsville, NC
Noah E. Gudel DO, Birmingham AL
Laura Hammons MD, Gallup, NM
David L. Hartsuch MD, Bettendorf, IA
Sabine Hazan MD, Ventura, CA
Vernon J. Hershberger MD, Akron, OH
James R. Hessler MD PhD, Wooster, OH
Joseph N. Holmes MD, Salisbury, NC
Brian D. Hopkins MD, Walnut Creek, CA
Jane Lindell Hughes MD, San Antonio, TX
Corey Hunt MD, Newberry, SC
Jose Iglesias DO, West Orange, NJ
George Isajiw MD, Darby, PA
Jan Iwata DO, Chicago , IL
Sara Kaltreider MD, Charlottesville, VA
Robert Karas MD, Fayetteville, AR
Jeffrey A. Keenan MD, Farragut, TN
Samuel N. Key III MD, Austin, TX
Michael E. Klein MD MPH, Jarrettsville, MD
Howard Kornfeld MD, Mill Valley, CA
Pierre Kory MD, Madison, WI
Barry Krakow MD, Savannah, GA
Joseph A. Ladapo MD PhD, Los Angeles, CA
Vance Lassey MD, Holton, KS
Daniel T. Layish MD, Orlando, FL
Peter Lazzopina MD, Harlingen, TX
Lionel Lee DO, Phoenix, AZ
Nancy Lefever MD, Tate, GA
Andrew Levine MD, Weslaco, TX
Katrina Lewis MD, Great Falls, MT
Barry Liberoni MD, Sugar Land, TX
John T. Littell MD, Ocala, FL
Victor Lopez-Cuenca MD, Beverly Hills, CA
Anne Marie Manning MD, Mechanicsburg, PA
Ben Marble MD, Gulf Breeze, FL
Paul E. Marik MD, Norfolk, VA
Jane Marke MD, Brooklyn, NY
Robert L. Mauss DO, Gettysburg, PA
Peter A. McCullough MD MPH, Dallas, TX
Mark McDonald MD, Los Angeles, CA
John McFadden, MD, Clinton, MS
Hope McIntyre MD, Mount Airy, MD
Gregory McNamara MD, Jacksonville Beach, FL
Clyde Meckel MD, Lincoln, NE
Kenneth S. Merriman MD, Hastings MI
Cynthia Miley MD, Tucson, AZ
Kimberly D. Milhoan MD, Kihei, HI
Geoff Mitchell MD, Toledo, OH
Whitney Bethel Morgan MD, Seguin, TX
Jeffrey Mueller MD, Winter Park, FL
Meryl Nass MD, Ellsworth, ME
Gerald D. Natzke DO, Grand Blanc, MI
Douglas F. Nederostek MD, Laurinburg, NC
Thanhmy Nguyen MD, Tampa, FL
Bogna M. Nowak MD, Phoenix, AZ
John M. Nowins MD, Las Vegas, NV
Amy Offutt MD, Marble Falls, TX
Kyong Christopher Oh MD, Niles, IL
Jane M. Orient MD, Tucson, AZ
Eric Osgood MD, Trenton, NJ
Ramin Oskoui MD, Washington, DC
Sheila Page DO, Aledo, TX
Ephraim Palmero MD, Berrien Springs, MI
James A. Panter MD, Gainesville, GA
Donald C. Pompan MD, Salinas, CA
Margaret O. Powell MD, Madison, MS
Jean-Jacques Rajter MD, Fort Lauderdale, FL
Bose Ravenel MD (Retired), Colfax, NC
Gina Reghetti DO, Warren, OH
Kristin Clague Reihman MD, Allentown, PA
Stephen Replogle DO, Yuma, AZ
Robin Ridinger MD, Leesburg , VA
Harvey A. Risch MD PhD, New Haven, CT
Michael J. A. Robb MD, Phoenix, AZ
Scott Robinson MD, Mill Valley, CA
Michael A. Ross MD, McLean, VA
Steve Rovenstine DO, Overland Park, KS
Molly Rutherford MD MPH, Crestwood, KY
Elie N. Saber MD, Houston TX
Alessandro D. Santin MD, New Haven, CT
Keith E. Schulze MD, Sugar Land, TX
Larry C. Sears MD, Gainesville, TX
Jackie R. See MD, Fullerton, CA
Denise Sibley MD, Johnson City, TN
Frank Sievert MD, Albany, OR
Corydon Siffring MD, Springfield, IL
Marilyn M. Singleton MD, Los Angeles, CA
Scott L. Sledge MD, San Antonio, TX
Douglas A. Smith MD, Minnetonka, MN
Daniel Sneed DO, Fort Wort, TX
Donald G. Spaeth DO PhD, Alpena, MI
Stuart Spitzer MD, Kaufman, TX
Timothy Stonesifer MD, Chambersburg, PA
Carol K. Tharp MD, Winnetka, IL
Shereen Underwood DO, Eugene, OR
Richard G. Urso MD, Houston, TX
Kenneth G. Varley MD, Birmingham, AL
Kelly Victory MD, Steamboat Springs, CO
Lee L. Vliet MD, Tucson, AZ
Khanh Vu DO, Lubbock, TX
Mark D. Vuolo MD, Casper, WY
Fred Wagshul, MD, Centerville, OH
Craig M. Wax DO, Mullica Hill, NJ
Nancy H. Weres MD, Barstow, CA
Clayton Young MD, Conroe, TX
Jospeh Young MD, Jefferson, NJ
Andrew Zak MD, Dallas, TX
Note: An earlier version of this letter was submitted to the Journal of the American Medical Association but was not accepted for publication. If you are a doctor and would like to add your name to this letter, email sign@jamaletter.com with your full name, credentials, and location exactly as they appear above.
References
[1] López-Medina, Eduardo, et al. “Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19.” JAMA, March 4, 2021. Doi:10.1001/jama.2021.3071.
[2] Scheim, David, et al. “Protocol violations in López-Medina et al.: 38 switched ivermectin (IVM) and placebo doses, failure of blinding, widespread IVM sales OTC in Cali, and nearly identical AEs for the IVM and control groups.” Preprint, March 8, 2021. Doi:10.31219/osf.io/u7ewz.
[3] McCullough PA, et al. “Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19).” Rev Cardiovasc Med. 2020 Dec 30;21(4):517-530. Doi:10.31083/j.rcm.2020.04.264. PMID: 33387997.