When a Therapy Fails in a Clinical Trial, Is That the Fault of the Therapy or of the Trial?

When a proposed therapy fails in a clinical trial is that because the therapy can’t work, or is it because the trial itself was flawed? It is far from written in stone how a clinical trial should be set up. Should the therapy be given by pill or intravenously? In what doses? How often, for how long? At what stage of the disease? Because Stage 3 clinical trials are so expensive and difficult to implement, some therapies may have only one shot to succeed. How many therapies that could have helped some people, will never do so, because the researchers had bad luck, or less skill, in implementing the trial? This problem could be reduced the regulatory mandate to requiring only the Stage 1 and Stage 2 clinical trials, that mainly establish safety (as opposed to the much-more-expensive Stage 3 that mainly establishes efficacy). That way researchers who lacked the deep pockets of the researchers discussed in the article quoted below, could still more often afford multiple shots at designing a trial that would succeed at identifying what therapy, applied to which patients, in what modalities, might cure them, or at least lengthen their lives, or reduce their symptoms. Some of the greatest advances in medicine occurred in an environment of quick trial and error, as when medicine has to be precticed on the battlefield of war, or when Emil Freireich improvised new ingredients for his chemo cocktail to cure some children of childhood leukemia or when Freireich’s protégé Vincent DaVita did the same to cure some adults of Hodgkin’s lymphoma. Ideally I would eliminate all mandates, both to enhance liberty, and to speed trial-and-error therapies. But here I suggest eliminating only Stage 3 clinical trials, not because I think that is ideal, but (following Milton Freidman) because I suspect that policy reform may be the best that is politically feasible. We would maximize trial and error adjustments by eliminating all mandated clinical trials. In the vast majority of decisions in life we make judgements without the benefit of a clinical trial. And such judgements usually are effective and improve with experience. [Gary Klein persuasively makes this point through a multitude of examples, in his tour de force Sources of Power.] What is done in life generally, can also be done in medicine in particular, bringing us more cures, faster.

(p. D4) “There is no reason why cancer vaccines would not work if given at the earliest stage,” said Sachet A. Shukla, who directs a cancer vaccine program at MD Anderson Cancer Center. “Cancer vaccines,” he added, “are an idea whose time has come.” (Dr. Shukla owns stock in companies developing cancer vaccines.)

That view is a far cry from where the field was a decade ago, when researchers had all but given up. Studies that would have seemed like a pipe dream are now underway.

“People would have said this is insane,” said Dr. Susan Domchek, the principal investigator of a breast cancer vaccine study at the University of Pennsylvania.

. . .

“We had this trial, 63 patients, Stage 4 cancer. They had failed all therapies,” Dr. Finn said.

. . .

In their initial studies, it became clear to Dr. Finn and her colleagues that the cancers were too far advanced for immunizations to work. After all, she notes, with the exception of rabies, no one vaccinates against an infectious disease in people who are already infected.

“I said, ‘I don’t want to do that again,’” Dr. Finn said. “It is not the vaccines. We have to look at different patients.”

Now, she and her colleague at Pittsburgh, Dr. Robert Schoen, a gastroenterologist, are trying to prevent precancerous colon polyps with a vaccine. But intercepting cancer can be tricky.

They focused on people whose colonoscopies had detected advanced polyps — lumps that can grow in the colon, but only a minority of which turn into cancer. The goal, Dr. Schoen said, was for the vaccine to stimulate the immune system to prevent new polyps.

It worked in mice.

“I said, ‘OK, this is great,’” Dr. Schoen recalled.

But a recently completed study of 102 people at six medical centers randomly assigned to receive the preventive vaccine or a placebo had a different result. All had advanced colon polyps, giving them three times the risk of developing cancer in the next 15 years compared to people with no polyps.

Only a quarter of those who got the vaccine developed an immune response, and there was no significant reduction in the rate of polyp recurrences in the vaccinated group.

“We need to work on getting a better vaccine,” Dr. Schoen said.

. . .

Dr. Domchek said she can envision a future in which people will have blood tests to find cancer cells so early that they do not show up in scans or standard tests.

“To paint a grand future,” she said, “if we knew the tests predicted cancer we could say, ‘Here’s your vaccine.’”

For the full story see:

Gina Kolata. “New Hopes for a Cancer Vaccine.” The New York Times (Tuesday, Oct. 11, 2022 [sic]): D4.

(Note: ellipses added.)

(Note: the online version of the story has the date Oct. 10, 2022 [sic], and has the title “After Giving Up on Cancer Vaccines, Doctors Start to Find Hope.” Where the wording of the versions differs, the passages quoted above follow the online version.)

Gary Klein’s main book that I praise in my initial comments is:

Klein, Gary A. Sources of Power: How People Make Decisions. 20th Anniversary ed. Cambridge, MA: The MIT Press, 2017.

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