Patients Vulnerable When Cash-Strapped Scientists Cut Corners

Sep 15, 2014
Originally published on September 16, 2014 9:09 am

There's a funding crunch for biomedical research in the United States — and it's not just causing pain for scientists and universities. It's also creating incentives for researchers to cut corners — and that's affecting people who are seriously ill.

Take, for example, the futile search for drugs to treat ALS, better known as Lou Gehrig's disease. The progressive, degenerative disease of the brain and nerve cells has been the focus of recent publicity, thanks to the Ice Bucket Challenge.

Four years ago, Tom Murphy went to see his doctor when he started noticing some slight muscle weakness.

"I actually thought I was just getting old," says the 56-year-old resident of Gainesville, Va. "I went to my general practitioner. He asked a few questions and told me to take my shirt off."

The doctor noticed some unusual muscle twitches — and sent Murphy directly to a neurologist. It turns out the news was bad. Murphy had ALS.

Tough News: 'You Won't Be Able To Use Your Hands And Arms'

"They told me I had two to four years," Murphy recalls. " 'Going to be pretty tough living, probably be in a wheelchair soon, won't be able to use your hands and arms.' So that was kind of tough — kind of tough news."

It's been 75 years since baseball great Lou Gehrig was diagnosed with this disease. Surely, Murphy thought, a good treatment has been developed since then. But, no.

"I said, 'Are you guys telling me that there's really nothing you can do about this, after so many years?' " Murphy says. "And they said, 'Yeah, unfortunately we don't have anything.' "

The last hope was that Murphy could enroll in a clinical trial — the test of an experimental drug. A few U.S. trials were going on in the East, he learned.

Most patients fade so quickly, they only get one shot at an experimental treatment.

Murphy chose one. It was a long shot, and it turns out the odds were worse than he knew.

Evidence Flimsy For Most Experimental Treatments OF ALS

Most of the experimental ALS drugs, it turns out, undergo very perfunctory testing in animals before moving into human tests — based on flimsy evidence.

Story Landis, director of the National Institute of Neurological Disorders and Stroke, says her institute plunked down $20 million to test one of these drugs in more than 400 ALS patients, "and what we discovered in the trial was the particular compound was of no benefit to the patients."

In hopes of figuring out why, scientists went back to take a second look at the mouse experiments that were the basis for the human study, and found them to be meager. Additional, more careful tests found no compelling reason to think the experimental drug would have ever worked.

Landis has thought a lot about how those last-chance patients ended up in this untenable situation. There is no single answer, she says, but part of the explanation relates to a growing issue in biomedical science: the mad scramble for scarce research dollars.

"The field has become hypercompetitive," she says.

Many excellent grant proposals get turned down, simply because there's not enough money to go around. So Landis says scientists are tempted to oversell weak results.

"Getting a grant requires that you have an exciting story to tell, that you have preliminary data and you have published," she says. "In the rush, to be perfectly honest, to get a wonderful story out on the street in a journal, and preferably with some publicity to match, scientists can cut corners."

According to a research paper published earlier this year, corner-cutting turned out to be the rule, rather than the exception, in animal studies of ALS.

Stefano Bertuzzi, the executive director of the American Society for Cell Biology, says that's partly because there is little incentive for scientists to take the time to go back and verify results from other labs.

"You want to be the first one to show something," he says — not the one to verify or dispute a finding, "because you won't get a big prize for that."

It's even hard to get funding to run those sorts of confirmatory experiments in this hypercompetitive environment. (You can check here to learn how any and every U.S. university has fared in garnering research money from NIH.)

'Wishful Science' Plagues Testing Of Drug Candidates

Landis says ALS is not the only example of this type of wishful science. Similar problems emerged in the study of a drug being tested to see if it could protect the brain from the damage of a stroke. She says that test, too, showed the drug to be a dismal failure.

"A number of people have gone back and looked at the evidence and discovered that, in fact, there are a number of very straightforward things about the conduct of those studies that made it likely that the drug would fail when it went into people," she says.

Landis has since added new guidelines that scientists must follow before the neurology institute will fund large drug tests on people.

"There are now clinical trials that would have been funded five to seven years ago which won't be funded until the preclinical studies are done in a way that is actually believable," she says.

In principle, this should help scientists focus on more promising therapies. But it is also potentially discouraging for ALS patients like Murphy. In the short run, at least, animal studies are not identifying drugs that are promising candidates for treating ALS.

"Basically everybody says animal studies don't work," Murphy says. "They aren't representative of humans, at least in this disease. It's a really big issue in the ALS world."

Progress in treating the illness will likely require scientists to take a step back to identify better ways of searching for promising drugs. This means more painstaking work, not simply quick, cross-your-fingers studies with animals.

NIH expects to spend about $40 million this year on ALS research; the ALS Association hasn't yet decided how much of the more than $100 million it has raised so far through its wildly successful Ice Bucket Challenge will go to funding research.

One strategy for further research might be to look at the few people — including Murphy — who have done a bit better than average in the drug trials that have otherwise failed. That could simply be luck — or it could be a clue about individual differences in the way the disease plays out.

Whatever the outcome for the particular experimental drug he's getting, Murphy says he's grateful he has at least had the chance to try it.

Copyright 2018 NPR. To see more, visit http://www.npr.org/.

STEVE INSKEEP, HOST:

Today in Your Health, we're going to look more deeply into the effort to find treatments for ALS. That disease has received plenty of attention because of the the Ice Bucket Challenge. Many people have been doused in hopes of raising money for a cure, but the very reason that better treatment is needed is because studies of the disease have largely been failures. And that is in part because a scramble for dwindling research dollars has led scientists to cut corners. NPR's Richard Harris continues the series on the squeeze in federal funding for biomedical research.

RICHARD HARRIS, BYLINE: Tom Murphy was clearly once a strong man. He played multiple sports while he was in high school. He settled down, raised a family in the Washington, D.C. suburbs and had a good job. Four years ago, at the age of 52, he went to see his doctor when he started noticing some slight muscle weakness.

TOM MURPHY: I actually thought I was just getting old. I went to my general practitioner. He asked a few questions, told me to take my shirt off.

HARRIS: The doctor noticed some unusual muscle twitches.

MURPHY: He said I think you need to go to a neurologist.

HARRIS: It turns out the news was bad. Murphy had ALS, a neurodegenerative disease better known as Lou Gehrig's disease.

MURPHY: And they told me I had two to four years and that it was going to be pretty tough living. You know, I'd probably be in a wheelchair soon. You wouldn't be able to use your hands and arms, and so that was kind of tough - kind of tough news.

HARRIS: Murphy soaked up what he could learn about the disease. He came across a video of Lou Gehrig being honored by an overflow crowd in Yankee Stadium 75 years ago, after his celebrated career came to an end because of the illness.

(SOUNDBITE OF ARCHIVED RECORDING)

LOU GEHRIG: Today, I consider myself the luckiest man on the face of the Earth.

(APPLAUSE)

GEHRIG: That I might've been given a bad break, but I've got an awful lot to live for. Thank you.

MURPHY: I listened to that speech by Lou Gehrig on that TV show at least a 100 times. I said, you guys are telling me that there's really nothing you can do about this, after so many years, they said, yeah, unfortunately we don't have anything.

HARRIS: The last hope was Murphy could enroll in a clinical trial, the test of an experimental drug. A few trials were going on in the eastern U.S.

MURPHY: You know, for most of us, it's the only chance we have. I mean, at least that's the way I looked at it.

HARRIS: So - and you figured that you would have one shot at a clinical trial presumably, right?

MURPHY: Yeah, maybe one. Most ALS patients maybe get one, especially if it lasts more than a year because pretty soon you don't qualify.

HARRIS: The disease is usually progressed too far by then. So Murphy signed up for a test of an experimental drug. It was a long shot, and it turns out the odds were worse than he knew. Most of the experimental ALS drugs had undergone very perfunctory testing in animals and federal health officials didn't realize that. Story Landis, director of the National Institute of Neurological Disorders and Strokes, says her institute plunked down $20 million to test one of these drugs in more than 400 ALS patients.

STORY LANDIS: We moved into a clinical trial based on a preclinical study using a small number of mice, and what we discovered in the trial was that the particular compound was of no benefit to the patients.

HARRIS: So afterward scientists went back to take a second look at the mouse experiments that were the basis for the human study.

LANDIS: The results couldn't be replicated when the study was actually done.

HARRIS: Landis has thought a lot about how these last chance patients ended up in this untenable situation. There's not one single answer, but she says part of the explanation relates to a growing issue in biomedical science, the mad scramble for scarce research dollars.

LANDIS: The field has become hypercompetitive.

HARRIS: Federal funding for health research has declined by about 20 percent over the past decade when you factor in inflation. Many excellent grant proposals get turned down, simply because there's not enough money to go around. So Landis says scientists are tempted to oversell weak results.

LANDIS: Getting a grant requires that you have an exciting story to tell, that you have preliminary data and that you have published. And in a rush, to be perfectly honest, to get a wonderful story out on the street in a journal, and preferably with some publicity to match, scientists can cut corners.

HARRIS: According to a research paper published earlier this year, corner-cutting turned out to be the rule, rather than the exception in animal studies of ALS. Stefano Bertuzzi, executive director of the American Society for Cell Biology, says it's partly because there's little reward for scientists to take the time to go back and verify results from other labs.

STEFANO BERTUZZI: You want to be the first one to show something and not the one to say, you know, what he or she said is actually doable because you won't get a big prize for that.

HARRIS: But Bertuzzi says that can be just as valuable as finding something splashy and new.

BERTUZZI: If I have done an experiment and I tried something, and I find out that it doesn't work or it's a negative result of some sort, for the scientific community to know that is very important.

HARRIS: But truth is - it's not valued in this hypercompetitive environment. Story Landis says ALS research is not the only example of this type of wishful science. Similar problems emerged in the study of a drug being tested to see if it would protect the brain from the effects of a stroke. She called that test a dismal failure.

LANDIS: A number of people have gone back and looked at the evidence and discovered that in fact there are a number of very straightforward things about the conduct of those studies that made it likely that the drug would fail when it went into people.

HARRIS: Landis has since added new guidelines that scientists must follow before the Neurology Institute will fund large drug tests on people.

LANDIS: There are now clinical trials that would've been funded five or seven years ago which won't be funded until the preclinical studies have been done in a way that actually is believable.

HARRIS: It's a step in the right direction, but not a cure for the problem. More money - say from the Ice Bucket Challenge - could help some. But Dr. Landis sees a problem that's infiltrating the culture of research, and it is also potentially discouraging for ALS patients like Tom Murphy. That's because, in the short-run at least, animal studies are not identifying drugs that are promising candidates for ALS.

MURPHY: Basically everybody says animal studies don't work. They're not representative of humans, at least in this disease. It's a really big issue in the ALS world.

HARRIS: Likely, progress in this disease will require scientists to take a step back, to identify better ways of searching for promising drugs. One strategy would be to look at the few people - including Murphy - who've done a bit better than average in the drug trials that overall have failed. That could be due to luck, or it could be a clue about the disease that could be ferreted out with more thorough follow-up studies. Murphy has been an activist patient, trying to push for studies like that. But it's hard to build a community of people who are all in rapidly failing health.

MURPHY: It's tough. It's tough, but I feel really lucky, though, because most of the people I've gotten to know over the last almost four years, most of them have died. You know, I feel like I'm the only one left.

HARRIS: Still, he's grateful that he had a chance to try an experimental drug, even if the science behind it wasn't strong.

MURPHY: Talk to somebody with a terminal disease, and the answer is, if that's the best they can do right now, well, that's probably the best we can expect.

HARRIS: But patients should expect more says Neurology Institute director Story Landis. She is about to retire, and her more rigorous research standards may be her legacy. Richard Harris, NPR News. Transcript provided by NPR, Copyright NPR.