Category: Methodology

Randomized Controlled Trials Can Obscure “Nuances and Complexities”

(p. A17) You’ve probably heard of the “gold standard”—randomized controlled trials—for evaluating new pharmaceutical therapies, including for Covid-19. Many treatments that showed promise in other studies have turned up muddy results in randomized controlled trials. But that doesn’t mean they’re necessarily ineffective. Doctors and regulators need to consider the totality of medical evidence when treating patients.

. . .

“Randomized trials for some purposes is the gold standard, but only for some purposes,” Harvard’s Donald Berwick, a former health adviser to President Barack Obama, said in an interview with GNS Health Care CEO Colin Hill in 2013. “Context does matter. We’re learning in a very messy world, and the context that neatens up that world may make it hard to know how to manage in the real world.”

. . .

As Thomas Frieden, who directed the Centers for Disease Control and Prevention under Mr. Obama, wrote in a 2017 New England Journal of Medicine article: “Elevating RCTs at the expense of other potentially highly valuable sources of data is counterproductive.” Such limitations affect their use for “urgent health issues, such as infectious disease outbreaks.” He added: “No study design is flawless, and conflicting findings can emerge from all types of studies.”

. . .

Some experts have dismissed the antimalarial hydroxychloroquine, or HCQ, even though more than a dozen observational studies have found it beneficial. A retrospective observational study of Covid-infected nursing-home residents in France, for instance, found those treated with HCQ and azithromycin were 40% less likely to die.

But a few randomized controlled trials found no benefit. A Spanish randomized trial of HCQ for prophylaxis found it didn’t reduce risk of illness among a large group of people exposed in nursing homes, households and health-care settings. Yet two-thirds of the subjects “reported routine use of masks at the time of exposure,” so they were probably less likely to be infected. Nursing-home residents, who may be less likely to wear masks, were 50% less likely to become sick if they took HCQ. But this finding was statistically insignificant, because the trial included only 293 residents.

. . .

Another problem with Covid-19 randomized trials: Patients at different stages of an illness are often assigned the same dosage. Trials don’t reveal differences in how patients respond to a drug at different dosages or illness severity.

Observational studies can do so. Consider a large study by the Mayo Clinic, which found no overall benefit among patients who received a higher-antibody convalescent plasma versus a lower one. Yet the researchers reported a 37% reduction in mortality among patients under 80 who weren’t on a ventilator and received a high-antibody plasma within three days of hospitalizations.

A randomized trial might have obscured these nuances and complexities, denying doctors important information about treatment options. Randomized controlled trials can yield important insights, but it is a medical mistake and a disservice to patients to dismiss other types of evidence.

For the full commentary, see:

Allysia Finley. “Medical Research’s Cross of ‘Gold’ Imperils Covid Treatments.” The Wall Street Journal (Wednesday, September 9, 2020): A17.

(Note: ellipses added.)

(Note: the online version of the commentary has the date Sep. 8, 2020, and has the same title as the print version.)

The review article by Frieden mentioned above is:

Frieden, Thomas R. “Evidence for Health Decision Making — Beyond Randomized, Controlled Trials.” New England Journal of Medicine 377, no. 5 (Aug. 3, 2017): 465-75.

“All You Need Is a Pair of Eyes”

(p. 1) MUNICH — Dr. Camilla Rothe was about to leave for dinner when the government laboratory called with the surprising test result. Positive. It was Jan. 27 [2020]. She had just discovered Germany’s first case of the new coronavirus.

But the diagnosis made no sense. Her patient, a businessman from a nearby auto parts company, could have been infected by only one person: a colleague visiting from China. And that colleague should not have been contagious.

The visitor had seemed perfectly healthy during her stay in Germany. No coughing or sneezing, no signs of fatigue or fever during two days of long meetings. She told colleagues that she had started feeling ill after the flight back to China. Days later, she tested positive for the coronavirus.

. . .

Dr. Rothe and her colleagues were among the first to warn the world. But even as evidence accumulated from other scientists, leading health officials expressed unwavering confidence that symptomless spreading was not important.

In the days and weeks to come, politicians, public health officials and rival academics disparaged or ignored the Munich team. Some actively worked to undermine the warnings at a crucial moment, as the disease was spreading unnoticed in French churches, Italian soccer stadiums and Austrian ski bars. A cruise ship, the Diamond Princess, would become a deadly harbinger of symptomless spreading. Continue reading ““All You Need Is a Pair of Eyes””

Volunteer “Challenge Trials” Could Speed Covid-19 Vaccine

(p. A10) It’s a controversial idea: Intentionally infect people with the virus that causes Covid-19 to test the effectiveness of a potential vaccine.

The approach is called a human challenge trial, and it’s not the usual way a vaccine is tested. More commonly, researchers track thousands of people, some of whom receive a vaccine, and others a placebo, and then see who becomes infected in the natural course of their lives. It’s a slower process, but poses fewer risks than deliberately infecting people after they’ve received a vaccine.

But some scientists now argue the risks of such a challenge trial are worth taking if it could potentially speed the development of a vaccine. Three groups of health experts have recently published articles advocating for the idea.

. . .

A company in London called hVIVO that specializes in human challenge trials is “very actively looking into how we could build a Covid-19 challenge study to help speed up the world wide development of an effective vaccine,” said Cathal Friel, executive chairman of Open Orphan, a clinical trials company that acquired hVIVO earlier this year. He says at least 10 pharmaceutical companies have already expressed interest in their potentially conducting a challenge trial of their vaccine candidates.

Ssome people say they would be willing to volunteer. Josh Morrison, a 34 year old in New York City, has started a group called 1Day Sooner where people can express interest in participating in a future challenge trial for Covid-19. So far around 16,000 people from more than 100 countries have signed up, including him, despite the fact that he donated a kidney in 2011.

“Obviously I would prefer not to get Covid-19,” he says. “But I also felt like this was a chance to be part of saving thousands or even hundreds of thousands of lives. And I felt so powerless at the time that being able to take action and do something meaningful was a strong motivator to me.”

For the full commentary, see:

Sumathi Reddy. “YOUR HEALTH; One Idea to Speed a Vaccine: Deliberately Infect People.” The Wall Street Journal (Tuesday, May 12, 2020): A10.

(Note: ellipsis added.)

(Note: the online version of the commentary was the date May 11, 2020 and has the title “YOUR HEALTH; One Idea for Speeding a Coronavirus Vaccine: Deliberately Infecting People.” Where the print and online versions differ, the passages quoted above follow the print version. For instance, the online version says that about “15,000” people have signed up.)

Mainstream Science, and Governments, Rejected Early Evidence of Symptomless Transmission

(p. 1) MUNICH — Dr. Camilla Rothe was about to leave for dinner when the government laboratory called with the surprising test result. Positive. It was Jan. 27 [2020]. She had just discovered Germany’s first case of the new coronavirus.

But the diagnosis made no sense. Her patient, a businessman from a nearby auto parts company, could have been infected by only one person: a colleague visiting from China. And that colleague should not have been contagious.

The visitor had seemed perfectly healthy during her stay in Germany. No coughing or sneezing, no signs of fatigue or fever during two days of long meetings. She told colleagues that she had started feeling ill after the flight back to China. Days later, she tested positive for the coronavirus.

. . .

Dr. Rothe and her colleagues were among the first to warn the world. But even as evidence accumulated from other scientists, leading health officials expressed unwavering confidence that symptomless spreading was not important.

In the days and weeks to come, politicians, public health officials and rival academics disparaged or ignored the Munich team. Some actively worked to undermine the warnings at a crucial moment, as the disease was spreading unnoticed in French churches, Italian soccer stadiums and Austrian ski bars. A cruise ship, the Diamond Princess, would become a deadly harbinger of symptomless spreading.

. . .

(p. 10) Though estimates vary, models using data from Hong Kong, Singapore and China suggest that 30 to 60 percent of spreading occurs when people have no symptoms.

. . .

After two lengthy phone calls with the woman, doctors at the Robert Koch Institute were convinced that she had simply failed to recognize her symptoms. They wrote to the editor of The New England Journal of Medicine, casting doubt on Dr. Rothe’s findings.

Editors there decided that the dispute amounted to hairsplitting. If it took a lengthy interview to identify symptoms, how could anyone be expected to do it in the real world?

“The question was whether she had something consistent with Covid-19 or that anyone would have recognized at the time was Covid-19,” said Dr. Eric Rubin, the journal’s editor.

“The answer seemed to be no.”

The journal did not publish the letter. But that would not be the end of it.

. . .

On Monday, Feb. 3, the journal Science published an article calling Dr. Rothe’s report “flawed.” Science reported that the Robert Koch Institute had written to the New England Journal to dispute her findings and correct an error.

. . .

Dr. Rothe’s report quickly became a symbol of rushed research. Scientists said she should have talked to the Chinese patient herself before publishing, and that the omission had undermined her team’s work. On Twitter, she and her colleagues were disparaged by scientists and armchair experts alike.

“It broke over us like a complete tsunami,” Dr. Hoelscher said.

. . .

If Dr. Rothe’s paper had implied that governments might need to do more against Covid-19, the pushback from the Robert Koch Institute was an implicit defense of the conventional thinking.

Sweden’s public health agency declared that Dr. Rothe’s report had contained major errors. The agency’s website said, unequivocally, that “there is no evidence that people are infectious during the incubation period” — an assertion that would remain online in some form for months.

French health officials, too, left no room for debate: “A person is contagious only when symptoms appear,” a government flyer read. “No symptoms = no risk of being contagious.”

. . .

(p. 11) Dr. Rothe, . . ., was shaken. She could not understand why much of the scientific establishment seemed eager to play down the risk.

“All you need is a pair of eyes,” she said. “You don’t need rocket-science virology.”

. . .

While public health officials hesitated, some doctors acted. At a conference in Seattle in mid-February, Jeffrey Shaman, a Columbia University professor, said his research suggested that Covid-19’s rapid spread could only be explained if there were infectious patients with unremarkable symptoms or no symptoms at all.

In the audience that day was Steven Chu, the Nobel-winning physicist and former U.S. energy secretary. “If left to its own devices, this disease will spread through the whole population,” he remembers Professor Shaman warning.

Afterward, Dr. Chu began insisting that healthy colleagues at his Stanford University laboratory wear masks. Doctors in Cambridge, England, concluded that asymptomatic transmission was a big source of infection and advised local health workers and patients to wear masks, well before the British government acknowledged the risk of silent spreaders.

The American authorities, faced with a shortage, actively discouraged the public from buying masks. “Seriously people — STOP BUYING MASKS!” Surgeon General Jerome M. Adams tweeted on Feb. 29.

. . .

By the end of the month [March 2020], the U.S. Centers for Disease Control announced it was rethinking its policy on masks. It concluded that up to 25 percent of patients might have no symptoms.

Since then, the C.D.C., governments around the world and, finally, the World Health Organization have recommended that people wear masks in public.

Still, the W.H.O. is sending confusing signals. Earlier this month, Dr. Van Kerkhove, the technical lead, repeated that transmission from asymptomatic patients was “very rare.” After an outcry from doctors, the agency said there had been a misunderstanding.

“In all honesty, we don’t have a clear picture on this yet,” Dr. Van Kerkhove said. She said she had been referring to a few studies showing limited transmission from asymptomatic patients.

Recent internet ads confused the matter even more. A Google search in mid-June for studies on asymptomatic transmission returned a W.H.O. advertisement titled: “People With No Symptoms — Rarely Spread Coronavirus.”

For the full story, see:

Matt Apuzzo, Selam Gebrekidan and David D. Kirkpatrick. “How the World Missed Covid’s Symptom-Free Carriers.” The New York Times, First Section (Sunday, June 28, 2020): 1 & 10-11.

(Note: ellipses, and bracketed dates, added.)

(Note: the online version of the story was updated June 27, 2020 and has the title “How the World Missed Covid-19’s Silent Spread.”)

Modern Physics Puts Elegance and Beauty Over Practical Value

(p. C9) Fundamental physics, says David Lindley, has lost its way. “I am ready to declare that research in this area, no matter its intellectual pedigree and exacting demands, is better thought of not as science but as philosophy.” His book aims to show how physics emerged out of airy speculation in the 17th century and, in recent years, has sunk back into it. “The Dream Universe” is not a book that will please philosophers, nor indeed historians, though physicists will find the argument a familiar one.

The problem, says its author, has been an excessive reliance on “mathematical elegance and beauty and whatnot” in fields such as “particle physics, the unification of gravity with quantum mechanics, and cosmology.” . . .

“The Higgs mechanism is no one’s idea of beautiful mathematics,” Mr. Lindley writes. “There’s nothing natural or inevitable about it, certainly nothing elegant. But it does its job.” The same applies, it appears, to one of the biggest breakthroughs in astronomy of recent decades, the confirmed reality of a previously theorized quantity driving universal expansion at an accelerating rate. “The beauty or otherwise of the cosmological constant is a non-issue,” the author writes. “It has practical value, and that’s what matters.”

. . .

The modern rot set in, he maintains, with theoreticians such as Hermann Weyl and Paul Dirac, who spoke of beauty as well as truth in physics. “Galileo would have been aghast,” Mr. Lindley writes. “He had no patience with mystical blather.”

. . .

Mr. Lindley complains that “the more physics pushes into the subatomic world, the more arcane the mathematical tools it draws upon.”

For the full review, see:

Andrew Crumey. “Pulling on a String.” The Wall Street Journal (Saturday, June 13, 2020): C9.

(Note: ellipses added.)

(Note: the online version of the review has the date June 12, 2020, and has the title “‘The Dream Universe’ Review: Pulling on a String.”)

The book under review, is:

Lindley, David. The Dream Universe: How Fundamental Physics Lost Its Way. New York: Doubleday, 2020.

Oliver Williamson’s Subtle Attempt to Get Pablo Spiller to Turn Down the Music

Several years ago, I presented a paper in an economic methodology session at the AEA in which Williamson also presented a paper. He was a fellow pluralist in method. I think his work deserves more attention than I have given it. The profession will be worse for his absence.

(p. A9) Building on the work of Ronald Coase, Dr. Williamson developed transaction-cost economics, examining costs that go beyond the price of a good or service.

. . .

Some of Dr. Williamson’s thinking took shape when he worked for the Justice Department’s antitrust division in 1966 and 1967.

The department had accused Schwinn & Co. of restraining trade by limiting the retailing of its bicycles to authorized merchants. The conventional wisdom among antitrust enforcers was that such arrangements could be explained only as an effort to reduce competition.

Dr. Williamson found the question more complicated and argued that Schwinn’s motive might be to reduce costs. For instance, a restricted number of retailers would make it less costly to control quality and agree on how to share advertising expenses. The resulting increase in efficiency could benefit consumers.

. . .

Pablo Spiller, a friend and Berkeley colleague who lived across the street from Dr. Williamson, recalled that he spoke precisely but not always directly. One night Dr. Spiller was playing music a bit too loudly. Dr. Williamson called. Rather than mentioning the volume, he said: “You know, I actually like the current song more than all the previous ones.”

For the full obituary, see:

James R. Hagerty. “Economist Explored Inner Life of Firms.” The Wall Street Journal (Tuesday, June 6, 2020): A9.

(Note: ellipses added.)

(Note: the online version of the obituary has the date June 4, 2020, and the title “Oliver Williamson, Nobel Economics Winner, Studied Inner Life of Firms.”)

Hydroxychloroquine Clinical Trials Suspended on Basis of Lancet Article Containing “Major Inconsistencies”

(p. A11) A group of scientists who raised questions last week about a study in The Lancet about the use of antimalarial drugs in coronavirus patients have now objected to another paper about blood pressure medicines in the New England Journal of Medicine, which was published by some of the same authors and relied on the same data registry.

Moments after their open letter was posted online Tuesday morning [June 2, 2020], the editors of the N.E.J.M. posted an “expression of concern” about the paper, and said they had asked the paper’s authors to provide evidence that the data are reliable.

The Lancet followed later in the day with a statement about its own concerns regarding the malarial drugs paper, saying that the editors have commissioned an independent audit of the data.

. . .

In their letter to the N.E.J.M., critics of the work wrote: “Serious, and as yet unanswered, concerns have been raised about the integrity and provenance of these data.”

The letter points out “major inconsistencies” between the number of coronavirus cases recorded in some countries during the study period and the number of patient outcomes reported by the researchers over the same period.

. . .

Many of the scientists who first raised concerns about the database are involved in clinical trials of chloroquine and hydroxychloroquine, and they were forced to pause the studies for safety reviews after The Lancet study was published.

James Watson, a senior scientist with MORU Tropical Health Network, said his unit had to immediately suspend work on a large randomized clinical trial to see if chloroquine or hydroxychloroquine can protect health care workers exposed on the job to the coronavirus from infection.

“I saw very quickly this paper didn’t hold up to much scrutiny at all,” he said. “We started wondering, ‘Who’s been collecting this data, and where did it come from?’ We were quite surprised to see a global study with only four authors listed and no acknowledgment of anyone else.”

. . .

David Glidden, a professor of biostatistics at University of California, San Francisco, who reads all new publications about Covid-19 antiviral therapies as a member of a National Institutes of Health clinical guidelines panel, said he was immediately struck by the vagueness of the descriptions in both papers.

For the full story, see:

Roni Caryn Rabin. “Scientists Question Medical Data From Single Company Used in Two Studies.” The New York Times (Wednesday, June 3, 2020): A11.

(Note: ellipses, and bracketed date, added.)

(Note: the online version of the article was updated June 2, 2020, and had the title “Scientists Question Medical Data Used in Second Coronavirus Study.”)

Trump Walks the Walk on Hydroxychloroquine

(p. A6) WASHINGTON—President Trump said he is taking hydroxychloroquine, an antimalarial drug that he has cited as a possible defense against the novel coronavirus but that some scientists have cautioned needs further study and could be dangerous.

“I happen to be taking it, hydroxychloroquine,” he told reporters at the White House on Monday. He said he had consulted with the White House doctor and suggested he is taking the drug as a preventive measure. Mr. Trump said he has been checked regularly for Covid-19, has tested negative and has no symptoms. He said he has been taking hydroxychloroquine for about a week and a half.

. . .

On Monday [May 18, 2020], Mr. Trump continued to stress anecdotal evidence in favor of the drug and told reporters, “I was just waiting to see your eyes light up when I said this.” He also expressed confidence in the drug’s safety. “I’m not going to get hurt by it. It’s been around for 40 years for malaria, for lupus, for other things.”

For the full story, see:

Catherine Lucey, Jared S. Hopkins. “President Trump Says He Is Taking Hydroxychloroquine as Preventive.” The Wall Street Journal (Tuesday, May 19, 2020): A6.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the story has the date May 18, 2020, and has the title “Trump Says He Takes Contested Drug for Prevention.”)

The key reference on advocates of a drug who take it first themselves, without confirmation from randomized double-blind clinical trials, is:

Altman, Lawrence K. Who Goes First?: The Story of Self-Experimentation in Medicine. Berkeley, CA: University of California Press, 1998.

Physicians Fighting Covid-19 Use Social Media “to Share Improvised Solutions”

(p. A9) In mid-March [2020], as U.S. hospitals scrambled for ventilators to treat a surge of coronavirus cases, a Vermont pulmonologist proposed a different treatment on a blog popular with emergency-medicine doctors.

Joshua Farkas observed in the post on the EMCrit blog that many Covid-19 patients seemed to benefit from less-invasive alternatives to help their breathing, including pressure therapy used to treat sleep apnea—sometimes referred to as CPAP, for continuous positive airway pressure.

. . .

The post helped galvanize an emerging theory about the treatment of Covid-19 patients, which in recent weeks has taken hold in U.S. hospitals. In New York City, where ventilators are in perilously short supply, doctors say they have since embraced CPAP and other treatments to improve breathing in Covid-19 patients.

The shift is one example of how health-care workers are writing the playbook for treating coronavirus patients on the fly, knowing they can’t wait for peer-reviewed articles or studies in established medical journals. Instead they are tapping into social media, podcasts, inside-baseball medical blogs and text-message groups to share improvised solutions to supply shortages and patient care, forcing hospitals to quickly re-evaluate their practices.

“This has been a rapidly evolving process,” said Dr. Farkas, who has treated Covid-19 patients in the intensive-care unit at the University of Vermont in Burlington. “As we struggle with how to treat a disease that so recently was totally unknown, this rapid exchange and updating of information is crucial.”

. . .

Last week, Michelle Romeo, a chief emergency-medicine resident at NYU Langone and Bellevue hospital in Manhattan, tweeted photos of a jury-rigged breathing device involving a mask used for BiPAP—an airway pressure therapy similar to CPAP.

At Mount Sinai Hospital in Manhattan, pulmonologists worked with the hospital’s sleep lab to figure out a way to use BiPAP machines like a ventilator. The result was posted on Reddit, and got “all kinds of different responses,” said Valerie Burgos-Kneeland, a registered nurse in the hospital’s Medical Intensive Care Unit. “It’s kind of been an opportunity for people to get creative.”

For the full story, see:

Rebecca Davis O’Brien. “Doctors Improvise, Share Treatments.” The Wall Street Journal (Friday, April 10, 2020): A9.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the story has the date April 9, 2020, and has the title “Doctors Are Improvising Coronavirus Treatments, Then Quickly Sharing Them.”)

“Real World Evidence” on Effectiveness of Experimental Drugs Can Be Extracted From Electronic Health Records

(p. A7) . . . analysis of compassionate-use data, about the experimental drug remdesivir from Gilead Sciences Inc. published in the New England Journal of Medicine, came under criticism. Scientists pointed out that the Covid-19 patients received the drug in centers around the world where care may have differed, data on some patients was incomplete and there was no comparison group.

That study’s first author, Jonathan Grein, of Cedars-Sinai Medical Center in Los Angeles, said given how little is known about the coronavirus and how to treat it, “I think at this point any information is potentially helpful.” He said the study, funded by Gilead Sciences, noted the findings were limited and preliminary. “It is a starting point, an opportunity to aggregate our initial experiences,” he said.

. . .

The FDA . . . has worked closely with companies trying to extract “real world evidence” about patients’ experiences with new or experimental drugs from sources such as electronic health records.

For the full story, see:

Amy Dockser Marcus. “Hundreds Get Plasma in National Study.” The Wall Street Journal (Wednesday, April 22, 2020): A7.

(Note: ellipses added.)

(Note: the online version of the story has the date April 21, 2020, and has the title “Hundreds Receive Plasma From Recovered Coronavirus Patients in National Study.”)

Early Promising Results from Gilead-Sponsored Study on Remdesivir

(p. B3) A doctor in Chicago told colleagues that Gilead’s drug remdesivir appeared to help many patients enrolled in a clinical trial site at the University of Chicago Medicine hospital, according to a news report in online health publication STAT, which cited a video of the remarks. The doctor said that the hospital had enrolled 125 patients in two remdesivir studies sponsored by Gilead, and that most had been discharged from the hospital, and two had died.

. . .

“Partial data from an ongoing clinical trial is by definition incomplete and should never be used to draw conclusions about the safety or efficacy of a potential treatment that is under investigation,” a University of Chicago spokeswoman said in an email. “Drawing any conclusions at this point is premature and scientifically unsound.”

. . .

Last week, Gilead reported in the New England Journal of Medicine that remdesivir showed encouraging results in treating 53 patients with severe Covid-19 symptoms. The patients were given the drug under so-called compassionate use, which allows for doctors to request unapproved drugs for patients in emergency situations.

Of the 53 compassionate use patients who received remdesivir, nearly half were discharged from the hospital and seven patients died, or 13% of the total, according to the New England Journal paper. Of 30 patients using breathing tubes connected to ventilators, 17 had their tubes disconnected after remdesivir treatment.

For the full story, see:

Joseph Walker. “Gilead Shares Up 9.7% On Encouraging Signs In Covid-19 Drug Trial.” The Wall Street Journal (Saturday, April 18, 2020): B3.

(Note: ellipses added.)

(Note: the online version of the story has the date April 17, 2020, and has the title “Coronavirus Drug Report, Though Inconclusive, Sends Gilead Higher.” Where the versions differ, the passages quoted above follow the somewhat longer online version.)