Why “Efficacy” Is Greater Than “Effectiveness”

Some literature in medicine distinguishes between the “efficacy” of a medicine and the “effectiveness” of a medicine. The efficacy is measured by the medicine’s success in a randomized clinical trial; the “effectiveness” is measured by the medicine’s success in actual clinical practice. Since medicines are usually administered under better conditions, and often to cherry-picked patients, in randomized clinical trails, the “efficacy” of a medicine is almost always higher than the “effectiveness” of the same medicine.

In recent months a study has shown that airline air ventilation technology has very high efficacy in preventing the spread of Covid-19. Yet other studies have shown that in actual practice the “effectiveness” of airline technology has allowed cases of substantial transmission of Covid-19. The article quoted below, plausibly explains that ventilation systems are often turned off, or operate at low levels, when planes are on the ground. Puzzle solved.

(p. A9) The Federal Aviation Administration has few ventilation requirements in cabins, generally deferring to requirements from manufacturers. This has been an issue in the past, when cabins were left without ventilation for long periods with passengers on board. The FAA has issued guidance to airlines recommending passengers be taken off planes if cabin ventilation is shut down for more than 30 minutes, an FAA spokeswoman says.

Leonard Marcus, the director of Harvard’s Aviation Public Health Initiative, says that researchers have found that it’s important to have ventilation running full force on the ground.

“The risk of transmission is increased when people are walking up and down the aisle, when they are putting their luggage in the overhead, when they are breathing on top of one another,” Dr. Marcus says. “So to compensate for that, you have to keep the airflow moving, which is true for all communicable diseases of this nature.”

American says its procedures call for the use of ground air while at the gate and during boarding. Spokeswoman Sarah Jantz says captains have discretion to turn on the APU “if the flow of preconditioned air is not sufficient” or not cooling the aircraft enough. American didn’t change procedures during the pandemic, but did provide additional education to crews “to ensure optimal ventilation,” she says.

. . .

Airline claims about the safety of travel are predicated on functioning ventilation systems. An October [2020] study from Harvard University’s School of Public Health, funded by the airline industry, used mathematical models and found a low risk of coronavirus transmission on airplanes because of a layered approach, including aircraft ventilation and masks.

The study, directed by Dr. Marcus, did recommend extending “in-flight level of ventilation while on the ground.” It didn’t estimate the risk of being in an airplane with even brief periods of little or no ventilation.

For the full commentary, see:

Scott McCartney. “THE MIDDLE SEAT; The Importance of Airflow Before Takeoff.” The Wall Street Journal (Thursday, April 8, 2021): A9.

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

(Note: the online version of the commentary has the date April 7, 2021, and has the title “THE MIDDLE SEAT; The Key to Safe Airflow for Planes Before Takeoff.”)

Where Hospitals Charge Higher Prices for C-Sections, More C-Sections Are Performed

(p. B6) The more a hospital profits from a cesarean delivery, the more likely a woman is to get one, a new analysis suggests.

For the study, published in JAMA Network Open, researchers analyzed records of 13.2 million deliveries nationwide from 2010 to 2014, using a large database of generally healthy women.

. . .

During that period, profit from C-sections varied, from an average of $4,969 for the one-quarter of hospitals with the lowest charges to $26,129 for the quarter that charge the most.

The researchers found that compared with the one-quarter of hospitals that averaged the lowest profit per cesarean, those that made the most per formed 8 per cent more C-sections.

For the full story, see:

Nicholas Bakalar. “In Brief; Making Profits From C-Sections.” The New York Times (Tuesday, April 13, 2021): D6.

(Note: ellipsis added.)

(Note: after considerable search, I could not find this article in the online version of the NYT as of 4/24/21.)

The JAMA Network Open article discussed in the passages quoted above is:

Sakai-Bizmark, Rie, Michael G. Ross, Dennys Estevez, Lauren E. M. Bedel, Emily H. Marr, and Yusuke Tsugawa. “Evaluation of Hospital Cesarean Delivery–Related Profits and Rates in the United States.” JAMA Network Open 4, no. 3 (2021): e212235-e35.

Differences in Study Results Are Seldom Due to Whether Study Design Is Observational or a Randomized Clinical Trial

(p. A17) The health system would be less burdened if more patients were treated before they require hospitalization, and there are promising therapeutic options that patients can administer themselves at home. This was the subject of a Nov. 19 [2020] hearing before the Senate Homeland Security and Governmental Affairs Committee.

Testimony from the hearing underscored an important issue: Too many doctors have interpreted the term “evidence-based medicine” to mean that the evidence for a treatment must be certain and definitive before it can be given to patients. Because accusing a physician of not being “evidence based” can be a career-damaging allegation, fear of straying from the pack has prevailed, favoring inertia and inaction amid uncertainty about Covid-19 treatments.

For diseases with established treatment options, holding out for certainty may be prudent. But when options are limited and there are safe treatments with evidence for effectiveness, holding out for certainty can be catastrophic. Requiring a high degree of certainty during a crisis may elevate the augustness of medical organizations and appease the sensibilities of medical professionals, but it does nothing for patients who need help.

The penchant for certainty is visible in the frequently updated treatment guidelines for Covid-19 from the National Institutes of Health. These guidelines were developed by scientists around the country, but because of a mentality that is biased toward virtually irrefutable evidence, no distinction is made for treatments with evidence for effectiveness that falls below the mark of certainty. This framework almost certainly has contributed to many avoidable deaths during this pandemic.

. . .

While some health officials dismiss nonrandomized studies, the Cochrane organization, an international leader in evidence-based medicine, published a review of several hundred studies showing that randomized clinical trials and nonrandomized studies of treatments generally yield similar findings. Modern epidemiologic and statistical methods can usually overcome biases inherent in nonrandomized study designs.

For the full commentary, see:

Joseph A. Ladapo. “Too Much Caution Is Killing Covid Patients.” The Wall Street Journal (Wednesday, Nov. 25, 2020): A17.

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

(Note: the online version of the commentary has the date November 24, 2020, and has the same title as the print version.)

The Cochrane organization review mentioned above is:

Anglemyer, Andrew, Hacsi T. Horvath, and Lisa Bero. “Healthcare Outcomes Assessed with Observational Study Designs Compared with Those Assessed in Randomized Trials.” In Cochrane Database of Systematic Reviews, 2014.

“A Public Choice Analysis of Mandated Randomized Double-Blind Clinical Trials”

My “A Public Choice Analysis of Mandated Randomized Double-Blind Clinical Trials” was presented on April 13, 2021 in the Law & Economics session of the Association of Private Enterprise Education meetings. I am grateful to Ray DeGennaro and Matthew McClanahan for including me in McClanahan’s session and to Lauren Nicole Hughes for recording the session on her smartphone.

To some extent, the presentation was an outgrowth of my book:

Diamond, Arthur M., Jr. Openness to Creative Destruction: Sustaining Innovative Dynamism. New York: Oxford University Press, 2019.

Unintended Consequences of Centralized Lockdown in India Spread Covid-19

(p. A1) SURAT, India — The crowds surged through the gates, fought their way up the stairs of the 160-year-old station, poured across the platforms and engulfed the trains.

It was May 5 [2020], around 10 a.m. Surat was beastly hot, 106 degrees. Thousands of migrant laborers were frantic to leave — loom operators, diamond polishers, mechanics, truck drivers, cooks, cleaners, the backbone of Surat’s economy. Two of them were Rabindra and Prafulla Behera, brothers and textile workers, who had arrived in Surat a decade ago in search of opportunity and were now fleeing disease and death.

. . .

They were among tens of millions of migrant workers stranded without work or food after Prime Minister Narendra Modi imposed a national coronavirus lockdown in March. By spring and summer, these workers were so desperate that the government provided emergency trains to carry them back to their home villages. The trains were called Shramik Specials, because shramik means “laborer” in Hindi.

But they became the virus trains.

India has now reported more coronavirus cases than any country besides the United States. And it has become clear that the special trains operated by the government to ease suffering — and to counteract a disastrous lack of lockdown planning — instead played a significant role in spreading the coronavirus into almost every corner of the country.

The trains became contagion zones: Every passenger was supposed to be screened for Covid-19 before boarding but few if any were tested. Social distancing, if promised, was nonexistent, as men pressed into passenger cars for journeys that could last days. Then the trains disgorged passengers into distant villages, in regions that before had few if any coronavirus cases.

. . .

(p. A12) On March 24 [2020], at 8 p.m., Mr. Modi hit the lockdown switch. In a televised address, he ordered the entire nation to stay inside their homes for three weeks — starting in four hours.

The decision was pure Modi: sudden, dramatic and firm, like when he abruptly wiped out nearly 90 percent of India’s currency bills in 2016, a bolt-from-the-blue measure that he said was necessary to fight corruption but proved economically devastating.

Prafulla and Rabindra Behera had just finished a dinner of rice, lentils and potatoes, their usual fare. They lived in squalid, bare rooms in Surat’s industrial zone, sleeping wall to wall on the floor with a half dozen other laborers. Within minutes of Mr. Modi’s address, they started getting calls.

“Everyone was thinking the same: This will be over soon and somehow we’ll pass the days,” Rabindra said.

At the time, India had fewer than 600 known virus cases.

Many experts have criticized Mr. Modi’s government for overlooking the plight of migrant laborers, who suddenly had no work, no income and no support network in the cities. The government’s Covid-19 task force lacked migrant specialists and was hardly representative of India. Of its 21 members, only two were women and the rest were largely upper-caste men. Many of the migrant laborers came from lower castes and economically underprivileged backgrounds.

. . .

In Surat, the Behera brothers were down to their last bag of rice. They could not work — the factories were closed. But they weren’t allowed to leave the city, where virus cases were beginning to surge.

“We were trapped,” Rabindra said.

On May 1, India’s Labor Day, the railways ministry made a grand announcement: Shramik Specials. Routes were drawn up from Surat, Mumbai, Chennai, New Delhi, Ahmedabad and other cities deep into rural areas.

. . .

The Beheras were told they would quarantine for 21 days at a center and each was given a toothbrush, a slice of soap, a bucket to wash with and a thin sheet to sleep on.

But the next morning, Prafulla awoke with a splitting headache. A doctor didn’t think he had coronavirus but suggested, as a precaution, that he be moved into the courtyard, away from the other men.

The following morning, Prafulla could barely breathe and called his wife on his cellphone.

“Come and bring the girls,” he whispered. “I need to see you.”

An hour later, he was dead. A subsequent test revealed that Prafulla Behera was Ganjam’s first coronavirus death.

For the full story, see:

Jeffrey Gettleman, Suhasini Raj, Sameer Yasir, Karan Deep Singh and Atul Loke. “Rails Spread Virus as Workers Fled India’s Cities.” The New York Times (Wednesday, December 16, 2020): A1 & A12-A13.

(Note: ellipses added.)

(Note: the online version of the story was updated Feb. [sic] 2, 2021, and has the title “The Virus Trains: How Lockdown Chaos Spread Covid-19 Across India.”)

On Vaccines and Economics, Europe Suffers “the Same Bureaucratic and Intellectual Rigidity”

(p. A25) Europe’s vaccination debacle will almost surely end up causing thousands of unnecessary deaths. And the thing is, the continent’s policy bungles don’t look like isolated instances, a few bad decisions made by a few bad leaders. Instead, the failures seem to reflect fundamental flaws in the continent’s institutions and attitudes — including the same bureaucratic and intellectual rigidity that made the euro crisis a decade ago far worse than it should have been.

The details of the European failure are complex. But the common thread seems to be that European officials were not just risk averse, but averse to the wrong risks. They seemed deeply worried about the possibility that they might end up paying drug companies too much, or discover that they had laid out money for vaccines that either proved ineffective or turned out to have dangerous side effects.

So they minimized these risks by delaying the procurement process, haggling over prices and refusing to grant liability waivers. They seemed far less worried about the risk that many Europeans might get sick or die because the vaccine rollout was too slow.

For the full commentary, see:

Paul Krugman. “A Fiasco That’s Very European: Vaccines.” The New York Times (Friday, March 19, 2021): A25.

(Note: the online version of the commentary has the date March 18, 2021, and has the title “Vaccines: A Very European Disaster.”)

Are We Right to Experiment on Animals to Save Humans?

I believe that higher animals feel emotions and maybe even have souls, so we should try to treat them humanely. I am deeply conflicted on how far animal experiments are justified in the pursuit of curing human diseases. Whenever possible, animal experiments should have the potential to benefit the animals in the experiments, as well as the human experimenters.

(p. A15) The “title characters” of Brandy Schillace’s admirable biography “Mr. Humble and Dr. Butcher: A Monkey’s Head, the Pope’s Neuroscientist, and the Quest to Transplant the Soul” were one and the same person: Robert J. White, a distinguished neurosurgeon, an accomplished neuroscientist and a man dedicated to searching for the means to transplant souls by transplanting the human brain. If this makes White sound macabre, Ms. Schillace’s account of his life, work and temperament is anything but. She deftly persuades the reader to take White seriously (he wasn’t even eccentric) and to ponder profound medical-scientific-philosophical issues. Best of all, the book is fascinating.

. . .

White felt it was his religious and medical duty to devise techniques for rescuing healthy brains from otherwise diseased and dying bodies. His solution was to transplant heads (containing their brains) onto cadavers that were brain dead but otherwise physiologically viable.

Before he could attempt such surgery on people, White experimented, mostly on monkeys, dozens of times, to ascertain and refine the necessary procedures. In March 1970 he succeeded in transplanting a monkey’s head onto another monkey’s body.

. . .

During the era in which White conducted his experiments, politicians, doctors, journalists and celebrities were becoming deeply and increasingly dismayed by scientific experiments on animals. White ran afoul of the animal-rights advocacy organization People for the Ethical Treatment of Animals (PETA) and was threatened by animal-rights extremists (he remained imperturbable). White prided himself on scrupulously avoiding harm to his animal subjects. But he didn’t believe that animals had souls: For him, Ms. Schillace writes, “the human was more than animal, and equating the two was not only wrong, it was dangerous.” One of White’s rejoinders to those who would halt animal experimentation was, to paraphrase: If you were a surgeon, how would you like to tell parents that their young child is going to die because the operation that might save him or her was impossible to perform, mainly because the necessary animal-dissection research that would have permitted it was forbidden by law or the medical canon of ethics? His foes never had a good answer.

For the full review, see:

Howard Schneider. “A Heart in the Right Place.” The Wall Street Journal (Monday, February 22, 2021): A15.

(Note: ellipses added; italics in original.)

(Note: the online version of the review has the date February 21, 2021, and has the title “Mr. Humble and Dr. Butcher’ Review: A Heart in the Right Place.”)

The book under review is:

Schillace, Brandy. Mr. Humble and Dr. Butcher: A Monkey’s Head, the Pope’s Neuroscientist, and the Quest to Transplant the Soul. New York: Simon & Schuster, 2021.

Vaccine Immunity, Plus Natural Immunity from Getting Covid-19, Equals Herd Immunity Soon

The author of the passages I quote below is a surgeon and professor at the Johns Hopkins School of Medicine and has authored The Price We Pay, which I recently read. It is a disturbing, eye-opening, excellent account of why the costs of drugs are high and rising.

(p. A17) Anthony Fauci has been saying that the country needs to vaccinate 70% to 85% of the population to reach herd immunity from Covid-19. But he inexplicably ignores natural immunity. If you account for previous infections, herd immunity is likely close at hand.

. . .

Dr. Fauci’s vaccination-only path to herd immunity has significantly influenced the national conversation. KNBC-TV in Los Angeles has a county-by-county vaccine tracker showing a bar graph of the percentage of Californians vaccinated, with the zone 70% to 85% labeled “herd immunity.” Currently, it’s at 26%. The false construct does create a greater urgency for everyone to get vaccinated. But it also creates false justification for continued excessive restrictions on freedom. And it raises the possibility that authorities are misallocating the limited vaccine supply by failing to direct it toward people without natural antibodies.

. . .

Some experts claim they don’t talk about natural immunity because we shouldn’t trust it. But a recent Public Health England study found that less than 1% of 6,614 healthcare workers who had Covid-19 developed a reinfection within five months—even though many of them work with Covid patients. Other experts believe natural immunity is powerful. “Natural immunity after Covid-19 infection is likely lifelong, extrapolating from data on other coronaviruses that cause severe illness, SARS and MERS,” says Monica Gandhi, an infectious-disease physician and professor at the University of California.

For the full commentary, see:

Marty Makary. “Herd Immunity Is Near, Despite Fauci’s Denial.” The Wall Street Journal (Thursday, March 25, 2021): A17.

(Note: ellipses added.)

(Note: the online version of the commentary has the date March 24, 2021, and has the same title as the print version.)

The Makary book praised above is:

Makary, Marty. The Price We Pay: What Broke American Health Care–and How to Fix It. New York: Bloomsbury Publishing, 2019.

Rebates to Formulary Middlemen Are a Growing Part of Drug Costs

(p. B14) To actually sell medication, a drugmaker needs to persuade public and private health plans to place their product on the plan’s formulary, which is a list of drugs the plan is willing to purchase. That means paying middlemen rebates and discounts to choose their drug over any other rival treatments. Failure to secure favorable formulary access could mean low sales even for a highly-effective and safe medication..

. . .

“To secure that formulary position costs us more and more every year,” said Adam Gluck, Sanofi’s head of U.S. corporate affairs, in an interview. The company says that the average list price for its insulin products is up 141% since 2012 but that the net price is down 53% over that same period.

It isn’t just Sanofi facing this dynamic. Merck & Co. said last month that its average U.S. sticker price rose 3.1% in 2020 even as its average net price fell slightly. That is a sea change from recent years: In both 2015 and 2016 Merck’s average list price rose by about 10% while the net price realized by the drug giant rose by 5.5%. Nearly half of Merck’s gross sales went out the door to third parties as discounts last year. A decade ago, that tally was around 27%. Other drugmakers like Bristol-Myers Squibb report similarly high spreads between gross and net sales.

For the full commentary, see:

Charley Grant. “Pharma Giants Are Getting Their Pennies Pinched.” The Wall Street Journal (Saturday, March 13, 2021): B14.

(Note: ellipsis added.)

(Note: the online version of the commentary was updated March 12, 2021, and has the title “Pharma Giants Get Their Pennies Pinched on Drug Pricing.”)

Freireich on Chemo-Cocktail Cure for Childhood Leukemia: “I Thought About It and I Knew It Would Work”

(p. A20) Dr. Emil Freireich, a renowned cancer doctor and relentless researcher who helped devise treatments for childhood leukemia that transformed the lives of patients thought to have little hope of survival, died on Feb. 1 [2021] at the University of Texas MD Anderson Cancer Center in Houston, where he had worked since 1965.

. . .

When Dr. Freireich (pronounced FRY-rike) started work at the N.C.I., in Bethesda, Md., in 1955, acute childhood leukemia was considered a death sentence. Entering the ward where the children were being treated, he recalled their hemorrhaging because their blood had virtually no platelets, the disc-shaped cells that clot blood.

. . .

Dr. Freireich, a hematologist and oncologist, tested his hypothesis that the lack of platelets was causing the hemorrhaging by mixing some of his own blood with some of the children’s.

“Would it behave normally?” he said in interview for an N.C.I. oral history project in 1997. “Sure enough, it did.”

Further testing, done to persuade his skeptics at the cancer institute, proved him right.

. . .

. . . Dr. Freireich’s most important and most enduring achievement was in using a combination of drugs to send leukemia into remission. He explored options in chemotherapy with several N.C.I. colleagues, including Dr. Emil Frei III, who was known as Tom.

They made an aggressive assault on childhood leukemia by devising a cocktail of four drugs that would be administered simultaneously — a technique similar to the three-drug regimen used to treat tuberculosis — so that each one would attack a different aspect of the physiology of the cancer cells.

“It was crazy,” Dr. Freireich told Mr. Gladwell. “But smart and correct. I thought about it and I knew it would work. It was like the platelets. It had to work!”

But not without peril and concern. Some of the children nearly died from the drugs. Critics called Dr. Freireich inhumane for experimenting with his young patients.

“Instead, 90 percent went into remission immediately,” he told USA Today in 2015. “It was magical.” But temporary. One round of the cocktail was not enough to eliminate all the cancer, so Dr. Freireich and his team treated them with the drugs monthly for more than a year.

. . .

Dr. Freireich compared his early fight to cure childhood leukemia to being in a battle in which he and the N.C.I. team had an alliance that was “forged under fire.”

To cure cancer, he added: “Motivate people and give them the opportunity. People are innately motivated. Nobody likes to be lazy and do nothing. Everybody wants to be significant.”

For the full obituary, see:

Richard Sandomir. “Emil Freireich, 93, Pioneering Researcher and Cancer Doctor, Is Dead.” The New York Times (Saturday, February 13, 2021): A20.

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

(Note: the online version of the obituary was updated Feb. 8, 2021, and has the title “Emil Freireich, Groundbreaking Cancer Researcher, Dies at 93.”)

Malcolm Gladwell devoted a chapter to Freireich in Gladwell’s book:

Gladwell, Malcolm. David and Goliath: Underdogs, Misfits, and the Art of Battling Giants. New York, NY: Little, Brown and Company, 2013.

FDA Should Approve Faster Clinical Trials for Boosters to Block New Covid-19 Variants

(p. A17) . . . , it is essential to design clinical trials that can be completed within several months, to avert potential outbreaks of new variants. It’s fast, but given today’s scientific capabilities that could be enough time to do the required trials.

Take the South African variant known as B1351. The existing trials will be used to establish that the current vaccines provide clinical protection against Covid disease. But to prove the new versions targeting B1351 work as well as the current vaccines, the FDA can measure the antibody levels in the plasma from patients who have recovered from B1351 and establish a benchmark for the number of antibodies needed to neutralize that virus. Then the FDA can use those antibody levels as a proxy to evaluate whether updated vaccines are able to generate sufficient levels of protection.

This could allow vaccine makers to test new boosters in clinical trials that enroll 300 or 400 patients rather than 40,000, an enormous savings in cost and time. Larger and longer studies can be started at the same time, including ones that follow vaccinated patients.

For the full commentary, see:

Scott Gottlieb. “Another Promising Vaccine, This One From Johnson & Johnson.” The Wall Street Journal (Monday, February 1, 2021): A17.

(Note: ellipsis added.)

(Note: the online version of the commentary has the date January 31, 2021, and has the same title as the online version.)