Author: Art Diamond

Time Constraints for Tenure, Promotion, and Funding Decisions Lead Academic Biologists to Over-Study Already-Studied Genes

George Stigler argued that when most economists were self-funded business practitioners economics was more applied and empirical, while after most economists were academics funded by endowments or the government economics became less applied and more formal. [In a quick search I failed to identify the article where Stigler says this–sorry.] A similar point was made to science more broadly by Terence Kealey in his thought-provoking The Economic Laws of Scientific Research. The article quoted below argues persuasively that research on human genes is aligned with the career survival goals of academics, rather than with either the faster advance of science or the quicker cure of diseases like cancer. The alignment could be improved if more of research funding came from a variety of private sources.

(p. D3) In a study published Tuesday [Sept. 18, 2018] in PLOS Biology, researchers at Northwestern University reported that of our 20,000 protein-coding genes, about 5,400 have never been the subject of a single dedicated paper.

Most of our other genes have been almost as badly neglected, the subjects of minor investigation at best. A tiny fraction — 2,000 of them — have hogged most of the attention, the focus of 90 percent of the scientific studies published in recent years.

A number of factors are largely responsible for this wild imbalance, and they say a lot about how scientists approach science.

. . .

It was possible, . . ., that scientists were rationally focusing attention only on the genes that matter most. Perhaps they only studied the genes involved in cancer and other diseases.

That was not the case, it turned out. “There are lots of genes that are important for cancer, but only a small subset of them are being studied,” said Dr. Amaral.

. . .

A long history helps, . . . . The genes that are intensively studied now tend to be the ones that were discovered long ago.

Some 16 percent of all human genes were identified by 1991. Those genes were the subjects of about half of all genetic research published in 2015.

One reason is that the longer scientists study a gene, the easier it gets, noted Thomas Stoeger, a post-doctoral researcher at Northwestern and a co-author of the new report.

“People who study these genes have a head start over scientists who have to make tools to study other genes,” he said.

That head start may make all the difference in the scramble to publish research and land a job. Graduate students who investigated the least studied genes were much less likely to become a principal investigators later in their careers, the new study found.

“All the rewards are set up for you to study what has been well-studied,” Dr. Amaral said.

“With the Human Genome Project, we thought everything was going to change,” he added. “And what our analysis shows is pretty much nothing changed.”

If these trends continue as they have for decades, the human genome will remain a terra incognito for a long time. At this rate, it would take a century or longer for scientists to publish at least one paper on every one of our 20,000 genes.

That slow pace of discovery may well stymie advances in medicine, Dr. Amaral said. “We keep looking at the same genes as targets for our drugs. We are ignoring the vast majority of the genome,” he said.

Scientists won’t change their ways without a major shift in how science gets done, he added. “I can’t believe the system can move in that direction by itself,” he said.

Dr. Stoeger argued that the scientific community should recognize that a researcher who studies the least known genes may need extra time to get results.

“People who do something new need some protection,” he said.

For the full commentary see:

Carl Zimmer. “Matter; The Problem With DNA Research.” The New York Times (Tuesday, September 25, 2018 [sic]): D3.

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

(Note: the online version of the commentary has the date Sept. 18, 2018 [sic], and has the title “Matter; Why Your DNA Is Still Uncharted Territory.” Where there are differences in wording between the versions, the passages quoted above follow the online version.)

The paper in PLOS Biology co-authored by Thomas Stoeger and mentioned above is:

Stoeger, Thomas, Martin Gerlach, Richard I. Morimoto, and Luís A. Nunes Amaral. “Large-Scale Investigation of the Reasons Why Potentially Important Genes Are Ignored.” PLOS Biology 16, no. 9 (2018): e2006643.

Kealey’s book, praised above, is:

Kealey, Terence. The Economic Laws of Scientific Research. New York: St. Martin’s Press, 1996.

The Patterns in Unexpected Cancer Cures Can Yield Actionable Insight

The method for fighting cancer discussed by Gina Kolata in the passages quoted below, is similar to the method that led William Coley to first develop immunotherapy in the late 1800s. Coley searched the archives of his hospital, seeking any cases in which cancer seemed to have been spontaneously cured. When he had a few cases he looked for a common feature that might explain the cures. He found that in each case the patient had a severe viral or bacterial infection. When the patient’s immune system cured them of the infection, it also, as a desirable side-effect, cured them of the cancer. In the case of the rare ovarian discussed below, Dr. Levine hypothesizes that the common feature of the rare single-mutation cancers that can be cured by immunotherapy drugs, is that there is a mutated master gene that turns on and off other genes–creating an abnormal variation that somehow alerts the immune system of the presence of tumor cells that should be attacked. (The article quoted below is now over six years old–I wonder if in those six years Dr. Levine has found evidence to support, modify, or reject his hypothesis?) [My memory is foggy on this, but I think Steven Rosenberg may also have applied a similar method after he encountered a case of spontaneous cancer cure when he was working in a veteran’s hospital early in his career–see Rosenberg and Barry, 1992.]

Notice that the four patients only were cured because they had the courage and boldness to ask their oncologist to try a therapy that the standard protocol said would fail. And notice that the four patients only were cured because they had oncologists who had the courage and boldness to violate accepted protocols. Or maybe something besides courage and boldness explains the oncologists’ actions. Maybe the oncologists were practicing medicine in countries were hospitals, regulatory agencies, and health insurance companies did not exert as much pressure to follow the protocol as is exerted in the United States? (I wonder if there is enough information publicly available to check this possibility.)

Notice that instead of searching a dusty archive, Levine joined a patient ovarian cancer Yahoo discussion group. Patients were trying to be in control of their cancers, and unlike some doctors, Levine had the humility to think he could learn from what these activist patients reported. Citizen science is a resource to be used, not a distraction to be tamped down or ridiculed. [Amy Dockser Marcus defends citizen science, and gives an extended example, in her We the Scientists.]

Finally note that the method pursued by Coley and Levine can yield genuine actionable knowledge. Randomized double-blind clinical trials are not the only sources of knowledge.

Gina Kolata has written many thought-provoking articles. I hope to follow-up on this one sometime.

(p. D1) No one expected the four young women to live much longer. They had an extremely rare, aggressive, and fatal form of ovarian cancer. There was no standard treatment.

The women, strangers to one another living in different countries, asked their doctors to try new immunotherapy drugs that had revolutionized treatment of cancer. At first, they were told the drugs were out of the question — they would not work against ovarian cancer.

Now it looks as if the doctors were wrong. The women managed to get immunotherapy, and their cancers went into remission. They returned to work; their lives returned to normalcy.

. . .

“We need to study the people who have a biology that goes against the conventional generalizations.”

Four women hardly constitutes a clinical trial. Still, “it is the exceptions that give you the best insights,” said Dr. Drew Pardoll, who directs the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine in Baltimore.

The cancer that struck the young women was hypercalcemic small cell ovarian cancer, which typically occurs in a woman’s teens or 20s. It is so rare that most oncologists never see a single patient with it.

. . .

(p. D3) Women with this form of ovarian cancer were sharing news and tips online in a closed Yahoo group. Dr. Levine asked to become part of the group and began joining the discussions. There he discovered patients who had persuaded doctors to give them an immunotherapy drug, even though there was no reason to think it would work.

The women reported that their tumors shrank immediately.

. . .

Lung cancer, a genetic type of colorectal cancer and melanoma have huge numbers of mutations, and immunotherapy drugs often are successful in treating them. Cancers of the prostate, pancreas, breast, ovaries — and most other tumors — carry few mutations.

“These are the cancers that rarely respond,” Dr. Pardoll said.

The idea that the drugs might work against something like hypercalcemic ovarian cancer, which is fueled by just one genetic mutation, just made no sense.

“For the vast majority of cancers, there is an amazingly clean correlation between response to therapy and mean mutational load,” Dr. Pardoll said.

. . .

And then came a handful of women with a rare ovarian cancer. Oriana Sousa, 28, a psychologist in Marinha Grande, Portugal, was one of them.

She found out she had cancer in December 2011.

. . .

For the next four years, Ms. Sousa’s doctors tried to control the cancer, giving her rounds of chemotherapy, radiotherapy and surgery. But every time, new tumors emerged.

. . .

Things are different now. In 2015, she finally persuaded a doctor to give her an immunotherapy drug, nivolumab. Immediately, her tumors shrank and continued shrinking as she continued with the drug — so much that her doctors now say she has no evidence of disease. Life has returned to normal.

. . .

What saved her? Dr. Eliezer M. Van Allen, a cancer researcher at Dana-Farber Cancer Institute, has come across one clue.

He found that a gene mutated in kidney cancer was sort of a master regulator of other genes, controlling which were turned on and when. But the regulated genes were normal and did not produce proteins that the immune system might recognize as abnormal.

Nonetheless, patients responding to immunotherapy were the ones with the master gene mutation. “We saw this result and weren’t sure what to make of it,” he said.

Dr. Levine and his colleagues found the same phenomenon in patients with hypercalcemic ovarian cancers. One explanation, he and Dr. Van Allen said, is that the immune system may recognize that cells in which genes are erratically turning on and off are dangerous and should be destroyed.

“That is strictly hypothesis,” Dr. Levine cautioned.

For the full story see:

Gina Kolata. “Cured Unexpectedly.” The New York Times (Tuesday, February 20, 2018 [sic]): D1 & D3.

(Note: ellipses added.)

(Note: the online version of the story has the date Feb. 19, 2018 [sic], and has the title “Doctors Said Immunotherapy Would Not Cure Her Cancer. They Were Wrong.”)

The academic article co-authored by Dr. Levine that reports on the remission of a rare ovarian cancer in four women is:

Jelinic, Petar, Jacob Ricca, Elke Van Oudenhove, Narciso Olvera, Taha Merghoub, Douglas A. Levine, and Dmitriy Zamarin. “Immune-Active Microenvironment in Small Cell Carcinoma of the Ovary, Hypercalcemic Type: Rationale for Immune Checkpoint Blockade.” Journal of the National Cancer Institute 110, no. 7 (2018): 787-90.

The book by Marcus that I praise above is:

Marcus, Amy Dockser. We the Scientists: How a Daring Team of Parents and Doctors Forged a New Path for Medicine. New York: Riverhead Books, 2023.

Rosenberg’s encounter with a case of spontaneous cancer cure, that I mention above, can be found somewhere early in:

Rosenberg, Steven A., and John M. Barry. The Transformed Cell: Unlocking the Mysteries of Cancer. New York: G.P. Putnam’s Sons, 1992.

“Sunlight Can Degrade Polystyrene in Centuries or Even Decades”

Oregon, New York, Colorado, and Washington D.C. forbid restaurants from giving plastic straws to patrons. When I drink from a paper straw in those locales, the straw routinely collapses before I finish the drink, causing me to curse intrusive regulators. The anti-plastic-straw regulations are one example of the environmentalist fear of the effects of plastic. On Thurs., Oct. 10, 2019, Collin P. Ward, the lead author of a 2019 study, said: “Policymakers generally assume that polystyrene lasts forever. That’s part of the justification for writing policy that bans it” (as quoted in Broad 2019, p. D4). We often hear, for instance from the United Nations Environment Program, that the most common plastic in the environment, polystyrene (used for instance in Styrofoam), will likely take thousands of years to degrade. But is what we hear true?

Ward’s 2019 paper answered the question. It turns out that instead of lasting almost forever, “sunlight can degrade polystyrene in centuries or even decades” (Broad 2019, p. D4). Previous claims that polystyrene lasts almost forever were based on the finding that bacteria cannot consume polystyrene. But previous claimants did not let the sun shine in!

The article discussed and quoted above is:

William J. Broad. “Sun Breaks Down Common Ocean Pollutant, Study Says.” The New York Times (Tuesday, October 22, 2019 [sic]): D4.

(Note: the online version of the story was updated Oct. 11, 2019 [sic], and has the title “In the Sea, Not All Plastic Lasts Forever.”)

Ward’s co-authored 2019 academic article discussed above is:

Ward, Collin P., Cassia J. Armstrong, Anna N. Walsh, Julia H. Jackson, and Christopher M. Reddy. “Sunlight Converts Polystyrene to Carbon Dioxide and Dissolved Organic Carbon.” Environmental Science & Technology Letters 6, no. 11 (2019): 669-74.

Government Gave “40 Years of Seriously Incorrect Advice” on Trans Fats

The government’s advice often turns out to be wrong. That is an added argument for not giving the government the power to enforce its advice through mandatory regulations. (“Added” to the fundamental argument based the right to free choice.)

[In May 2021 Nicholas Wade, the author of the review quoted below, showed enormous courage in being one of the first few to risk cancelation by presenting a cogent case that Covid leaked from a Wuhan lab.]

(p. C9) Rachel Carson rightly complained in “Silent Spring” that farmers were sloshing far too many harmful pesticides into the environment. But she took aim at the wrong one. DDT, a mild and enormously effective pesticide, helped rid the United States of malaria and its benefits, if more discriminately pursued, could have outweighed its costs.

The overstrict verdict against DDT is an instance of the harms that can ensue when scientific evidence is ignored. This and other cases described by Paul A. Offit in “Pandora’s Lab: Seven Stories of Science Gone Wrong” raise provocative questions about the reasons that science is misused in modern society.

. . .

Another case of medical advice based on insufficient data is that of dietary fat. As Dr. Offit tells the story, in the 1970s the government advised cutting down on fat consumption. In the 1980s the message changed. Unsaturated fats were good; only saturated fats were bad: Eat margarine, not butter. But then it turned out that unsaturated fats came in two forms, known to chemists as “cis” and “trans,” and that “trans fats” were appallingly active promoters of heart disease. Margarine and hydrogenated vegetable cooking oils, whose use had been encouraged, were rich in trans fats. After 40 years of seriously incorrect advice, trans fats were mostly eliminated from the American diet only in 2012.

. . .

Besides his overconfidence in the checking mechanisms of science, Dr. Offit goes too easy on the motives of those who abuse science. Environmentalists, for instance, are interested in achieving political results, not in distracting scientific caveats and uncertainties, which they do their best to suppress. It is their propensity to take everything to excess that leads to obscurantist positions, such as irrational fear of genetically modified crops.

For the full review see:

Nicholas Wade. “A Little Knowledge.” The Wall Street Journal (Saturday, April 8, 2017 [sic]): C9.

(Note: ellipses added.)

(Note: the online version of the review was updated April 7, 2017 [sic], and has the same title as the print version.)

The book under review is:

Offit, Paul A. Pandora’s Lab: Seven Stories of Science Gone Wrong. Washington, D.C.: National Geographic, 2017.

Potential Malaria Breakthrough Drug Forgotten and Now Ignored Due to Its Chemical Relative and Its Venue of Invention

Progress in science, like progress everywhere, is not inevitable. Progress often requires champions or entrepreneurs to persist in overcoming obstacles. In the case of DFDT, the obstacles arise due to the drug’s association with the chemical DDT and with Nazi Germany, the first of which is unjustly reviled and the second of which is justly reviled. But DFDT should not be judged by either its relatives or its venue of origins It should be judged by its efficacy against malaria, and by its effects, if any, on the environment.

(p. D1) In postwar Allied intelligence reports examined by Dr. Ward and his colleagues, German scientists claimed their insecticide, now called DFDT, was more effective than DDT. Allied officials dismissed those assertions as fanciful, especially given the deplorable behavior of Hoechst, the German chemical manufacturer that developed the insecticide, during the war. The company had forced residents of countries occupied by Germany to work in its factories, and it tested drugs on concentration camp prisoners.

The insecticide was forgotten for decades.

Now, work by Dr. Ward and his colleagues, reported this month [Oct. 2019] in an article in the Journal of the American Chemical Society, appears to corroborate the German claims. The forgotten compound killed mosquitoes in as little as one-fourth the time as DDT.

. . .

(p. D4) Conceivably the more lethal DFDT could be used in even smaller, possibly safer doses. A new option could allow public health officials to rotate insecticides and thwart the resistance to DDT in many mosquitoes today.

“It’s exciting and desperately needed,” said Duane J. Gubler, an emeritus professor in the emerging infectious diseases program at Duke University and the National University of Singapore Graduate Medical School. He was not involved in the study.

But will anyone today risk the time and money needed to determine whether DFDT could be a safe and effective tool against malaria as well as other mosquito-borne diseases like Zika, dengue and yellow fever?

“Donors, governments, they just don’t want the backlash, even if it’s not wholly justified,” said Bart Kahr, Dr. Ward’s colleague at N.Y.U. and an author of the paper.

. . .

The N.Y.U. chemists started the research with no interest in insecticides whatsoever.

They were studying materials that crystallize in a twisted helical pattern. One of the ways to identify such molecules is to scan the internet for images of crystals made by hobbyists. DDT, they found, exhibited the characteristic pinwheel gradients of a helical crystal when illuminated with polarized light.

Jingxiang Yang, a postdoctoral researcher at N.Y.U., started growing DDT crystals and found not only the expected crystals but also more jumbled, chaotic patterns.

“There was some organized and some crazy,” Dr. Kahr said. “We didn’t expect the other stuff, and that other stuff turned out to be a different arrangement of molecules in the crystal. That form wasn’t known to science.”

That led to the next set of experiments. “Since we have two forms,” Dr. Kahr said, “it was natural to ask, which of these forms was the historical killer of insects?”

It turned out that the chaotic form of DDT is deadlier.

As they were going through early scientific data on DDT, the N.Y.U. chemists found mentions of DFDT.

The compound, difluoro-diphenyl-trichloro-ethane is the same molecule as DDT, except with fluorine atoms replacing two of the chlorines.

The Germans developed DFDT at least in part to avoid paying the licensing fees for DDT to the Swiss. It is also possible that the chemical ingredients for DFDT, although considerably more expensive at the time than those for DDT, may have been more readily available in wartime Germany.

. . .

Dr. Kahr wonders: If DFDT had displaced DDT, would the 1955 push have succeeded in bringing malaria under control before resistance set in? “What if this compound wasn’t forgotten,” he said. “What would the world be like? Science doesn’t go as linearly as the general public thinks it does.”

For the full story see:

Kenneth Chang. “Old Mix To Fight Malaria?” The New York Times (Tuesday, October 22, 2019 [sic]): D1 & D4.

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

(Note: the online version of the story was updated Oct. 22, 2019 [sic], and has the title “A Nazi Version of DDT Was Forgotten. Could It Help Fight Malaria?” Where the more detailed online version differs from the print version, the passages quoted above follow the print [sic] version.)

The academic article co-authored by Ward, Kahr, and others, and mentioned above, is:

Zhu, Xiaolong, Chunhua T. Hu, Jingxiang Yang, Leo A. Joyce, Mengdi Qiu, Michael D. Ward, and Bart Kahr. “Manipulating Solid Forms of Contact Insecticides for Infectious Disease Prevention.” Journal of the American Chemical Society 141, no. 42 (2019): 16858-64.

The Efficacy of Personalized Drugs Designed for Only One Patient Cannot Be Tested by Randomized Double-Blind Clinical Trials (RCTs)

We know that there are times when therapies work for some patients, but not for others. But clinical trials often do not account for such differences. If the effects of the new drug are not widespread enough among the general population, the trial will be deemed a failure, and the F.D.A. will not allow the drug to be taken even by the patients who would have benefitted from it. Maybe the solution is liberty. Allow physicians liberty on what therapies to suggest, and patients liberty on what therapies to try. This especially makes sense when the disease is dire and no effective therapy is yet widely known.

Many predict that we are moving toward personalized medicine. We need less regulation and more liberty so personalized medicine can progress, and more patients can be more quickly cured of more diseases. We need a sense of urgency in requesting liberty.

(p. D3) A new drug, created to treat just one patient, has pushed the bounds of personalized medicine and has raised unexplored regulatory and ethical questions, scientists reported on Wednesday [Oct. 9, 2019].

The drug, described in The New England Journal of Medicine, is believed to be the first “custom” treatment for a genetic disease. It is called milasen, named after the only patient who will ever take it: Mila (mee-lah) Makovec, who lives with her mother, Julia Vitarello, in Longmont, Colo.

. . .

Ms. Vitarello . . . set up Mila’s Miracle Foundation and was appealing for donations on GoFundMe. So, she began fund-raising in earnest, eventually raising $3 million for a variety of research efforts.

Dr. Yu’s team oversaw development of the drug, tested it in rodents, and consulted with the Food and Drug Administration. In January 2018, the agency granted permission to give the drug to Mila. She got her first dose on Jan. 31, 2018.

With continued treatments, the number of seizures has diminished so much that the girl has between none and six a day, and they last less than a minute.

Milasen is believed to be the first drug developed for a single patient (CAR-T cancer therapies, while individualized, are not drugs). But the path forward is not clear, Dr. Yu and his colleagues acknowledged.

. . .

. . . how might a custom drug’s efficacy might be evaluated, and how should regulators weigh the urgency of the patient’s situation and the number of patients who could ultimately be treated.

For the full story see:

Gina Kolata. “Drug Designed for One Raises Many Questions.” The New York Times (Tuesday, October 15, 2019 [sic]): D3.

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

(Note: the online version of the story has the date Oct. 9, 2019 [sic], and has the title “Scientists Designed a Drug for Just One Patient. Her Name Is Mila.” Where the more detailed online version differs from the print version, the passages quoted above follow the print [sic] version.)

The academic article co-authored by Dr. Yu that reports on the personalized drug milasen is:

Kim, Jinkuk, Chunguang Hu, Christelle Moufawad El Achkar, Lauren E. Black, Julie Douville, Austin Larson, Mary K. Pendergast, Sara F. Goldkind, Eunjung A. Lee, Ashley Kuniholm, Aubrie Soucy, Jai Vaze, Nandkishore R. Belur, Kristina Fredriksen, Iva Stojkovska, Alla Tsytsykova, Myriam Armant, Renata L. DiDonato, Jaejoon Choi, Laura Cornelissen, Luis M. Pereira, Erika F. Augustine, Casie A. Genetti, Kira Dies, Brenda Barton, Lucinda Williams, Benjamin D. Goodlett, Bobbie L. Riley, Amy Pasternak, Emily R. Berry, Kelly A. Pflock, Stephen Chu, Chantal Reed, Kimberly Tyndall, Pankaj B. Agrawal, Alan H. Beggs, P. Ellen Grant, David K. Urion, Richard O. Snyder, Susan E. Waisbren, Annapurna Poduri, Peter J. Park, Al Patterson, Alessandra Biffi, Joseph R. Mazzulli, Olaf Bodamer, Charles B. Berde, and Timothy W. Yu. “Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.” New England Journal of Medicine 381, no. 17 (Oct. 9, 2019): 1644-52.

An accompanying editorial commenting on the regulatory challenges raised by personalized drugs like milasen is:

Woodcock, Janet, and Peter Marks. “Drug Regulation in the Era of Individualized Therapies.” New England Journal of Medicine 381, no. 17 (Oct. 9, 2019): 1678-80.

A Cheap Nonrefrigerated Drug that Could Have Saved Tens of Thousands of Women’s Lives Languished for Half a Century Waiting for a Clinical Trial

They already knew tranexamic saved lives of bleeding soldiers and bleeding car crash victims. Why did regulators make the world wait 50 years, and finally do an expensive randomized double-blind clinical trial, to know that it also would save the lives of bleeding new mothers? You can’t blame drug companies. The drug’s patent had expired long ago, so no drug company would make profits from the sale of the drug sufficient to pay the expense of the clinical trial.

(p. D3) An inexpensive generic drug that saves the lives of wounded soldiers and civilian car crash victims has now been shown to rescue women suffering hemorrhages in childbirth.

. . .

In a major six-year trial involving over 20,000 women in 21 countries, researchers showed that tranexamic acid, a little-known blood-clotter invented in the 1950s, reduced maternal bleeding deaths by a third if it was given within three hours. It costs less than $2 a dose and does not require refrigeration.

The trial — known as Woman, short for World Maternal Antifibrinolytic — was led by doctors at the London School of Hygiene and Tropical Medicine and paid for by the Wellcome Trust, Pfizer, Britain’s health department and the Bill and Melinda Gates Foundation. Results were published in The Lancet on Wednesday [April 26, 2017].

. . .

The World Health Organization currently recommends treating birth hemorrhages by massaging the uterus and injecting uterus-shrinking drugs like oxytocin.

Tranexamic acid acts in a different way — it allows blood to clot more quickly — and so it should be given in addition to the usual measures and at the same time, said Dr. Ian Roberts, one of the study’s lead authors.

. . .

The drug was invented in Japan by a husband-wife research team, Shosuke and Utako Okamoto. They hoped it would be used to prevent birth hemorrhages, but local obstetricians declined to organize a clinical trial.

Ultimately, they turned the patent over to a Japanese pharmaceutical company, which sold it as treatment for heavy menstrual periods and as an ingredient in skin-whitening creams. Some oral surgeons used it when doing dental work on hemophiliacs, Dr. Roberts said.

For the full commentary see:

Donald G. McNeil Jr. “Global Health; A Cheap Drug Can Save Hemorrhaging Mothers.” The New York Times (Tuesday, May 2, 2017 [sic]): D3.

(Note: ellipses, and bracketed date, added. The Wednesday, April 26, 2017 date is the date The Lancet posted a co-author discussion of the results of the study.)

(Note: the online version of the commentary has the date April 26, 2017 [sic], and has the title “Global Health; Inexpensive Drug Prevents Deaths in New Mothers, Study Finds.” Where the more detailed online version differs from the print version, the passages quoted above follow the print [sic] version.)

The academic article in The Lancet and mentioned above is:

Shakur, Haleema, Ian Roberts, Bukola Fawole, Rizwana Chaudhri, Mohamed El-Sheikh, Adesina Akintan, Zahida Qureshi, Hussein Kidanto, Bellington Vwalika, Abdulfetah Abdulkadir, Saturday Etuk, Shehla Noor, Etienne Asonganyi, Zarko Alfirevic, Danielle Beaumont, Carine Ronsmans, Sabaratnam Arulkumaran, Adrian Grant, Kaosar Afsana, Metin Gülmezoglu, Beverley Hunt, Oladapo Olayemi, Ian Roberts, Iain Chalmers, Pisake Lumbiganon, Gilda Piaggio, Tony Brady, Haleema Shakur, Ian Roberts, Zarko Alfirevic, Diana Elbourne, Metin Gülmezoglu, Carine Ronsmans, Eni Balogun, Tracey Pepple, Danielle Prowse, Nigel Quashi, Lin Barneston, Collette Barrow, Danielle Beaumont, Lisa Cook, Lauren Frimley, Daniel Gilbert, Catherine Gilliam, Rob Jackson, Taemi Kawahara, Hakim Miah, Sergey Kostrov, Maria Ramos, Ian Roberts, Haleema Shakur, Phil Edwards, Tom Godec, Sumaya Huque, Bukola Fawole, Olujide Okunade, Olusade Adetayo, Rizwana Chaudhri, Aasia Kayani, Kiran Javaid, Bukola Fawole, Rizwana Chaudhri, Chrstine Biryabarema, Zahida Qureshi, Robert Tchounzou, Mohamed El-Sheikh, Hussein Kidanto, Mohan Regmi, Bellington Vwalika, Kastriot Dallaku, Mateus Sahani, Sayeba Akhter, Abdulfetah Abdulkadir, Nicolas Meda, Anthony Kwame Dah, Adesina Akintan, Olufemi Odekunle, Oluwabusola Monehin, Austin Ojo, Grace Akinbinu, Ifeoma Offiah, Saturday Etuk, Ubong Akpan, Uduak Udofia, Useneno Okon, Ezukwa Omoronyia, Okpe James, Oladapo Olayemi, Nike Bello, Blessed Adeyemi, Chris Aimakhu, Olufemi Akinsanya, Bamidele Adeleye, Oluwaseun Adeyemi, Kayode Oluwatosin, Abiodun Aboyeji, Abiodun Adeniran, Adebayo Adewale, Noah Olaomo, Lawrence Omo-Aghoja, Emmanuel Okpako, Lucky Oyeye, Francis Alu, John Ogudu, Ezekiel Ladan, Ibrahim Habib, Babasola Okusanya, Olatunde Onafowokan, David Isah, Abalaka Aye, Felix Okogbo, Egbaname Aigere, Mark Ogbiti, Temitope Onile, Olaide Salau, Yinka Amode, Kamil Shoretire, Adebola Owodunni, Kehinde Ologunde, Akintunde Ayinde, Moses Alao, Olalekan Awonuga, Babatunde Awolaja, Omololu Adegbola, Fatimah Habeebu-Adeyemi, Adeyemi Okunowo, Hadiza Idris, Ola Okike, Nneka Madueke, Josiah Mutihir, Nankat Joseph, Babatunde Adebudo, Adeniyi Fasanu, Olugbenga Akintunde, Olufemi Abidoye, Owigho Opreh, Sophia Udonwa, Gladys Dibia, Simeon Bazuaye, Arafat Ifemeje, Aniefiok Umoiyoho, Emmanuel Inyang-Etoh, Sununu Yusuf, Kayode Olayinka, Babalola Adeyemi, Olusegun Ajenifuja, Umar Ibrahim, Yusuf Baffah Adamu, Oluwarotimi Akinola, Grace Adekola-Oni, Paul Kua, Roseline Iheagwam, Audu Idrisa, Ado Geidam, Andrea Jogo, Joseph Agulebe, Joseph Ikechebelu, Onyebuchi Udegbunam, Jacob Awoleke, Oluseyi Adelekan, Hajaratu Sulayman, Nkeiruka Ameh, Nurudeen Onaolapo, Affiss Adelodun, William Golit, Dachollom Audu, Adetunji Adeniji, Folasade Oyelade, Lamaran Dattijo, Palmer Henry, Babalola Adeyemi, Olabisi Loto, Odidika Umeora, Abraham Onwe, Emily Nzeribe, Bartthy Okorochukwu, Augustine Adeniyi, Emmanuel Gbejegbe, Akpojaro Ikpen, Ikemefuna Nwosu, Abdulrasaq Sambo, Olubunmi Ladipo, Sola Abubakar, Ola Nene Okike, Enyinnaya Chikwendu Nduka, Eziamaka Pauline Ezenkwele, Daniel Onwusulu, Theresa Azonima Irinyenikan, Swati Singh, Amaitari Bariweni, Hadiza Galadanci, Peter Achara, Osagie Osayande, Mohammed Gana, Rizwana Chaudhri, Kiran Jabeen, Ayesha Mobeen, Sadaf Mufti, Maliha Zafar, Shehla Noor, Basharat Ahmad, Maimoona Munawar, Jeharat Gul, Naseema Usman, Fehmida Shaheen, Mariam Tariq, Nadia Sadiq, Rabia Batool, Habiba Sharaf Ali, Manahil Jaffer, Asma Baloch, Noonari Mukhtiar, Tasneem Ashraf, Raheela Asmat, Salma Khudaidad, Ghazala Taj, Roshan Qazi, Saira Dars, Faryal Sardar, Sanobar Ashfaq, Saeeda Majeed, Sadaqat Jabeen, Rukhsana Karim, Farzana Burki, Syeda Rabia Bukhari, Fouzia Gul, Musarrat Jabeen, Akhtar Sherin, Qurratul Ain, Shahid Rao, Uzma Shaheen, Samina Manzoor, Shabween Masood, Shabana Rizvi, Anita Ali, Abida Sajid, Aisha Iftikhar, Shazia Batool, Lubna Dar, Shahenzad Sohail, Shazia Rasul, Shamsa Humayun, Rashida Sultana, Sofia Manzoor, Syeda Mazhar, Afshan Batool, Asia Nazir, Nasira Tasnim, Hajira Masood, Razia Khero, Neelam Surhio, Samana Aleem, Naila Israr, Saba Javed, Lubna Bashir, Samina Iqbal, Faiza Aleem, Rubina Sohail, Saima Iqbal, Samina Dojki, Alia Bano, Naseem Saba, Maimoona Hafeez, Nishat Akram, Naila Israr, Riffat Shaheen, Haleema Hashmi, Sharmeen Arshad, Rubina Hussain, Sadia Khan, Nighat Shaheen, Safia Khalil, Pushpa Sachdev, Gulfareen Arain, Amtullah Zarreen, Sara Saeed, Shamayela Hanif, Nabia Tariq, Mahwish Jamil, Shama Chaudhry, Hina Rajani, Tayyiba Wasim, Summera Aslam, Nilofar Mustafa, Huma Quddusi, Sajila Karim, Shazia Sultana, Misbah Harim, Mohd Chohan, Nabila Salman, Fareesa Waqar, Shamsunnisa Sadia, Lubna Kahloon, Shehla Manzoor, Samar Amin, Umbreen Akram, Ambreen Ikram, Samina Kausar, Tahira Batool, Brigadier Naila, Tahir Kyani, Christine Biryabarema, Ruth Bulime, Regina Akello, Bernadette Nakawooya Lwasa, Joselyn Ayikoru, Christine Namulwasira, Patrick Komagum, Isabirye Rebecca, Nayiga Annet, Nakirigya Nuulu, Elizabeth Nionzima, Rose Bwotya, Margret Nankya, Sarah Babirye, Joseph Ngonzi, Cesar Sanchez, Nkonwa Innocent, Kusasira Anitah, Ayiko Jackson, Elizabeth Ndagire, Christine Nanyongo, Dominic Drametu, Grace Meregurwa, Francis Banya, Rita Atim, Emmanuel Byaruhanga, Lema Felix, Hussein Iman, Vincent Oyiengo, Peninah Waigi, Rose Wangui, Faiza Nassir, Musimbi Soita, Rophina Msengeti, Zeinab Zubier, Hillary Mabeya, Antony Wanjala, Henry Mwangi, Brian Liyayi, Evelyn Muthoka, Alfred Osoti, Amos Otara, Veronicah Ongwae, Zahida Qureshi, Victor Wanjohi, Bonface Musila, Kubasu Wekesa, Alex Nyakundi Bosire, Etienne Asonganyi, Alice Ntem, Angeline Njoache, Alice Ashu, André Simo, Robert Tchounzou, Dorothy Keka, Kenfack Bruno, Amadou Ndouoya, Martin Saadio, Mesack Tchana, Odel Gwan, Pauline Assomo, Venantius Mutsu, Nji Eric, Pascal Foumane, Philemon Nsem, Jeanne Fouedjio, Ymele Fouelifack, Pierre Marie Tebeu, Georges Nko’ayissi, Eta Ngole Mbong, Wisal Nabag, Riham Desougi, Hadia Mustafa, Huida Eltaib, Taha Umbeli, Khalid Elfadl, Murwan Ibrahim, Abdalla Mohammed, Awadia Ali, Somia Abdelrahiem, Mohammed Musa, Khidir Awadalla, Samirra Ahmed, Mahdi Bushra, Omer Babiker, Hala Abdullahi, Mohamed Ahmed, Elhassan Safa, Huida Almardi, Duria Rayis, Saeed Abdelrahman Abdelgabar, Zarko Alfirevic, Gillian Houghton, Andrew Sharpe, Jim Thornton, Nick Grace, Carys Smith, Kim Hinshaw, Dawn Edmundson, Paul Ayuk, Alison Bates, George Bugg, Joanne Wilkins, Clare Tower, Alysha Allibone, Eugene Oteng-Ntim, Hussein Kidanto, Ahmad Kazumari, Anna Danford, Matilda Ngarina, Muzdalifat Abeid, Khadija Mayumba, Magreth Zacharia, George Mtove, Leonard Madame, Anthony Massinde, Berno Mwambe, Rwakyendela Onesmo, Sebastian Kitengile Ganyaka, Mohan Regmi, Shyam Gupta, Rabindra Bhatt, Ajay Agrawal, Pramila Pradhan, Nikita Dhakal, Punita Yadav, Gyanendra Karki, Bhola Ram Shrestha, Bellington Vwalika, Mwansa Lubeya, Jane Mumba, Willies Silwimba, Isaiah Hansingo, Noojiri Bopili, Ziche Makukula, Alexander Kawimbe, Mwansa Ketty Lubeya, Willard Mtambo, Mathew Ng’ambi, Kastriot Dallaku, Saimir Cenameri, Ilir Tasha, Aferdita Kruja, Besnik Brahimaj, Armida Tola, Leon Kaza, Mateus Sahani, Desire Tshombe, Elizabeth Buligho, Roger Paluku-Hamuli, Charles Kacha, Kato Faida, Badibanga Musau, Herman Kalyana, Phanny Simisi, Serge Mulyumba, Nzanzu Kikuhe Jason, Jean Robert Lubamba, Willis Missumba, Ferdousi Islam, Nazneen Begum, Sayeba Akhter, Ferdousi Chowdhury, Rokeya Begum, Farjana Basher, Nazlima Nargis, Abu Kholdun, Shahela Jesmin, Shrodha Paul, Hailemariam Segni, Getachew Ayana, William Haleke, Abdulfetah Abdulkadir, Hassen Hussien, Fikre Geremew, Moussa Bambara, Adolphe Somé, Amadou Ly, Roamba Pabakba, Horace Fletcher, Leslie Samuels, Henry Opare-Addo, Roderick Larsen-Reindorf, Kwadwo Nyarko-Jectey, Glen Mola, Malts Wai, Magdy El Rahman, Wafaa Basta, Hussein Khamis, Maria Fernanda Escobar, Liliana Vallecilla, and Gabriel Essetchi Faye. “Effect of Early Tranexamic Acid Administration on Mortality, Hysterectomy, and Other Morbidities in Women with Post-Partum Haemorrhage (Woman): An International, Randomised, Double-Blind, Placebo-Controlled Trial.” The Lancet 389, no. 10084 (May 27, 2017): 2105-16.

In an interview shortly before her death, and before the clinical trial was completed, Utako Okamoto said that she already knew that the trial would show that tranexamic acid works to stop bleeding:

Tranexamic Acid (TXA) History

When the Highly Restrictive Enrollment Criteria for Clinical Trials Steal Hope from the Innocently Desperate, It “Just Feels Unjust”

Muscular dystrophy is sometimes called “Duchenne.” The full name of the disease is “Duchenne muscular dystrophy.” When I was a student at Monroe elementary school a classmate named Frank Goldsberry played on the basketball team. In high school he was in a wheel chair with muscular dystrophy. When the high school principle, Howard Crouch, proposed to do away with the academic honor of valedictorian on the ground that there was some arbitrariness in who received it, I argued that to do would be to diminish the honor given to academic achievement. Crouch relented. It turned out that our valedictorian was Frank Goldsberry. He died a few years later in his early 20s. Frank’s father told my mother that Frank was grateful to me for speaking up. Howard Crouch had a point, but I am glad that after working hard under dire circumstances, Frank received the award.

The F.D.A. should stop mandating randomized double-blind clinical trials (RCTs) so that those who have muscular dystrophy can seek any therapy that they, their parents, and their physicians believe has promise. Not everyone will be cured, but we will learn what works through a Bayesian process of trial and error. More parents and boys will be allowed to hold on to hope.

(p. D1) Lucas was 5 before his parents, Bill and Marci Barton of Grand Haven, Mich., finally got an explanation for his difficulties standing up or climbing stairs. The diagnosis: muscular dystrophy.

Mr. Barton turned to Google.

“The first thing I read was, ‘no cure, in a wheelchair in their teens, pass in their 20s,” Mr. Barton said. “I stopped. I couldn’t read any more. I couldn’t handle it.”

Then he found a reason to hope. For the first time ever, there are clinical trials — nearly two dozen — testing treatments that might actually stop the disease.

The problem, as Mr. Barton soon discovered, is that the enrollment criteria are so restrictive that very few children qualify. As a result, families like the Bartons often are turned away.

. . .

Ryan and Brooke Saalman know how hard it can be to know what to do. “We did a lot of praying,” said Ms. Saalman, mother of two boys with Duchenne in Columbus, Ga.

They decided to enroll their oldest son, Jacob, 6, in a trial of a highly experimental drug.

. . .

. . . they discovered that gene therapy may be irreversible. And if it didn’t work, Ja-(p. D3)cob would be ineligible for an even more promising approach in the future: gene editing, to snip out the deadly mutation that causes Duchenne, an effort now in preclinical development.

. . .

The Bartons found out about a gene-therapy trial at Nationwide Children’s Hospital in Columbus, Ohio, testing a treatment by Sarepta Therapeutics.

They watched a miraculous video of a little boy struggling to walk up a flight of stairs before treatment — and then doing it easily afterward.

“This was what we were hoping for,” Mr. Barton said.

Lucas was the right age, and he seemed to qualify. But testing showed that he carries antibodies to the virus used to deliver the treatment. It would not work for him.

The Bartons were drained, devastated. And for now, there is no other trial that Lucas qualifies for.

“I had my put my hopes into this,” Mr. Barton said. “It was the miracle.”

Dr. Jeffrey Bigelow, a neurologist, and his wife, Alexis Bigelow, of Millcreek, Utah, hoped against hope that their son Henri, 8, would qualify for the only gene therapy trial that will accept boys his age.

Then the Bigelows found out that enrollees of Henri’s age have to be able to lie down and then stand up with their hands at their sides in less than 10 seconds.

It took Henri 10 seconds to do that last spring, when he was evaluated for another trial. Now it would probably take him 20 seconds, his father said.

“It feels like Henri is being punished for losing the ability to stand up from the ground too soon,” Dr. Bigelow said.

He also worries about older boys with Duchenne who are lucky enough to still walk. They are shut out from the trial because they are not yet in wheelchairs. And other trials won’t accept boys that old.

“These are boys who, like Henri, desperately need the treatment, and if they don’t get it in the next one to two years, likely will be confined to a wheelchair, to never walk again,” Dr. Bigelow said.

“This just feels unjust.”

For the full story see:

Gina Kolata. “One Shot To Qualify For Hope.” The New York Times (Tuesday, March 26, 2019 [sic]): D1 & D3.

(Note: ellipses added.)

(Note: the online version of the story has the date March 25, 2019 [sic], and has the title “For Many Boys With Duchenne Muscular Dystrophy, Bright Hope Lies Just Beyond Reach.”)

Rigid Guidelines Don’t Allow for Individualizing Treatment and Discount the Doctor’s Clinical Judgment

The criticism of the Clovers sepsis clinical trial is that the the treatment and placebo arms of the trial each require rigid adherence to a protocol, and such adherence rules out personalizing individual treatment based on individual differences among patients and doctors’ clinical judgment based on past experiences. That criticism seems plausible and also seems to apply, not just to the Clovers sepsis clinical trial, but to all< randomized double-blind clinical trials.

(p. D1) A large government trial comparing treatments for a life-threatening condition called sepsis is putting participants at risk of organ failure and even death, critics charge, and should be immediately shut down.

A detailed analysis of the trial design prepared by senior investigators at the National Institutes of Health Clinical Center in Bethesda, Md., concluded that the study “places seriously ill patients at risk without the possibility of gaining information that can provide benefits either to the subjects or to future patients.”

In a letter to the federal Office for Human Research Protection, representatives of Public Citizen’s Health Research Group compared the study, called Clovers, to “an experiment that would be conducted on laboratory animals.”

“The human subjects of the Clovers trial, as designed and currently conducted, are unwitting guinea pigs in a physiology experiment,” Dr. Michael Carome and Dr. Sidney M. Wolfe wrote in their letter.

Begun in March, Clovers is funded by the N.I.H. — despite the criticism of its own investigators — and aims to enroll 2,320 pa-(p. D3)tients at 44 hospitals around the country.

. . .

At issue is whether patients participating in Clovers are being given treatment that deviates from usual care — so much so that lives may be endangered by the research.  . . .

When patients experience septic shock, current guidelines call for raising blood pressure by administering fluids within the first three hours of care, and then administering vasopressors within the first six hours if patients do not respond to fluids.

Vasopressors can be administered early on, during or after the infusion of fluids; a new treatment guideline for hospitals says the drugs should be started within the first hour if patients aren’t responding to intravenous fluids.

Many physicians have been critical of rigid guidelines like this one because they don’t allow for individualizing treatment and appear to discount the doctor’s clinical judgment.

Both fluids in large amounts and vasopressors can cause serious complications, but when a patient’s condition continues to deteriorate, doctors use both interventions, adjusting them depending on the severity of illness.

They generally start with fluids, which in small amounts are considered less toxic than vasopressors.

But participants in Clovers are randomly assigned to a “liberal fluids” group who receive large infusions of fluids in a very short time but limits the use of vasopressors, or to a “restrictive fluids” group in which fluids are minimized and drug treatment begun earlier.

For the full story see:

Roni Caryn Rabin. “Critics Demand Halt of a Sepsis Trial.” The New York Times (Tuesday, September 25, 2018 [sic]): D1 & D3.

(Note: ellipses added.)

(Note: the online version of the story has the date Sept. 24, 2018 [sic], and has the title “Trial by Fire: Critics Demand That a Huge Sepsis Study Be Stopped.”)

The Number of Alzheimer’s Patients Is Too Few to Populate the Many Promising Clinical Trials

When the F.D.A. mandates randomized double-blind clinical trials (RCTs) be successfully performed before allowing the use of a new drug, it also mandates that diverse promising drugs will never be tested. Some of those drugs might help or even cure Alzheimer’s. The reason that some diverse promising drugs will never be tested, as explained by Gina Kolata in the passage quoted below, is that there are too few diagnosed and willing Alzheimer’s patients to conduct the number and kind of RCTs that the government mandates, for all the promising drugs under development. What is the alternative to mandated RCTs? Allow physicians to prescribe drugs that have a promising rationale. If their patients benefit the physicians will continue to prescribe the drug and they will tell their colleagues.

(p. D1) The task facing Eli Lilly, the giant pharmaceutical company, sounds simple enough: Find 375 people with early Alzheimer’s disease for a bold new clinical trial aiming to slow or stop memory loss.

There are 5.4 million Alzheimer’s patients in the United States. You’d think it would be easy to find that many participants for a trial like this one.

But it’s not. And the problem has enormous implications for treatment of a disease that terrifies older Americans and has strained families in numbers too great to count.

The Global Alzheimer’s Platform Foundation, which is helping recruit participants for the Lilly trial, estimates that to begin finding participants, it will have to inform 15,000 to 18,000 people in the right age groups about the effort.

Of these, nearly 2,000 must pass the initial screening to be selected for further tests to see if they qualify.

Just 20 percent will meet the criteria to enroll in Lilly’s trial: They must be aged 60 to 89, have mild but progressive memory loss for at least six months, and have two types of brain scans showing Alzheimer’s is underway.

Yet an 80 percent screening failure rate is typical for Alzheimer’s trials, said John Dwyer, president of the foundation. There is just no good way to quickly diagnose the disease.

The onerous process of locating just 375 patients illustrates a grim truth: finding patients on whom to test new Alzheimer’s treatments is becoming an insurmountable obstacle — no matter how promising the trial.

With brain scans, lab tests and memory tests, the cost per diagnosis alone is daunting — as much as $100,000 for each person who ends up enrolled in a trial, Mr. Dwyer said — even before they begin the experimental treatment.

Complicating the problem, the number of trials has exploded in recent years. There (p. D4) are more than 100 Alzheimer’s studies looking for a whopping 25,000 participants, Mr. Dwyer said.

To begin filling them all, 37.5 million patients in the right age group would first have to be informed. Ten percent would be referred to a trial site for screening.

Just 4 percent will move forward with an evaluation, and of these, just over 17 percent will drop out, given the current rate, leaving roughly 125,000 to be screened. And with an 80 percent screening failure rate, that leaves 25,000 participants of the 37.5 million who were first informed.

The numbers make it clear: There’s no way scientists are going to find 25,000 participants for all of the Alzheimer’s trials that have been approved.

“The irony is that the science has never been more promising,” Mr. Dwyer said. “How many promising drugs will be abandoned or their evaluation seriously delayed? Some good science is going to be left on cutting-room floor.”

For the full story see:

Gina Kolata. “Alzheimer’s Trials Hit a Roadblock.” The New York Times (Tuesday, July 24, 2018 [sic]): D1 & D4.

(Note: the online version of the story has the date July 23, 2018 [sic], and has the title “For Scientists Racing to Cure Alzheimer’s, the Math Is Getting Ugly.”)

F.D.A. Chief Sets Low Bar for Cancer Progress–Three Months of Longer Life Is “A Major Therapeutic Advance”

F.D.A. regulations have slowed progress toward curing cancer. Rather than reduce regulations, the head of the F.D.A. redefines “progress” as occurring when a new drug increases average lifespan by a mere three months.

(p. D3) Was there a moment when you realized a new era had begun?

It was a gradual thing. I wish I could say I had an “a-ha” moment.

I remember though, one of our first approvals of a PD-1 drug (a drug that unleashes the immune system to fight cancer). A division director sent me an email with a survival curve for patients in a study. It was a Friday afternoon. I saw it and I nearly fell off my seat. It was such a positive study for these patients with squamous cell lung cancer. They lived an average of six months with standard chemotherapy. With the new drug they lived 9.2 months.

I called the division director and said, “What are we going to do to expedite this?”

We had to get a submission from the drug company and that can take several months. Sometimes it takes six months and sometimes up to a year because of the voluminous amount of material that must be provided.

We got the submission in a couple of months. Nivolumab was approved in March of 2015.

It was a major therapeutic advance. These were people who heretofore had few therapeutic options.

. . .

. . ., my regret? I won’t be here in 2049, my presumed 50th F.D.A. anniversary.

I would love to see what oncology looks like given the rapid changes in the past 25 years. Hang on tight. The velocity of innovation will only increase.

For the full interview see:

Gina Kolata, interviewer. “F.D.A.’s Cancer Chief Is Forward Focused.” The New York Times (Tuesday, November 19, 2024): D3.

(Note: ellipses added.)

(Note: the online version of the interview has the date Nov. 8, 2024, and has the title “He’s the F.D.A.’s Cancer Chief, Not a Fortune Teller.” The question is from the interviewer Gina Kolata. The rest of the words are quoted from the answers of Dr. Richard Pazdur.)