Sunday, January 25, 2015

A Modern Clinical Trial

It was my ritual for seven years.

Every day, take two sets of pills—one labeled, the other a mystery. Every three months, take three sets of blood-pressure readings, twice a day for a week. Once a year, collect urine for 24 straight hours, lug it everywhere in an ice pack, then get it through airport security for a flight from Washington to Boston.

For me and about 1,000 other participants in our medical trial, the payoff for such tedious detail came back last month: The combination of the two common types of blood-pressure drugs being tested didn’t make any significant difference in the progression of our inherited kidney disease.

That was disappointing. But it didn’t necessarily mean that the trial was a failure, a waste of the time I spent on it, or a poor use of the $40-million in taxes that paid for it. The trial’s participants got top-notch medical attention for our polycystic kidney disease, and our records will almost certainly help others with PKD, now and in the future. (...)

Randomized clinical trials are widely recognized as the gold standard for proving whether a treatment or practice really works. In our trial, everyone took two sets of daily pills. For half of the participants, the second pill was just an inert placebo. Neither the patients nor the trial doctors knew who was really getting both medications, allowing for a rigorous test of the two-drug combination.

All of that logistical structure can mean a huge financial cost. Randomized trials now account for about 20 percent of the $30-billion annual budget of the National Institutes of Health. Private drug companies spend more than $30-billion on them.

Yet drug trials fail at a rate of about 90 percent. That level of failure has attracted serious attention now that U.S. medical research has entered a period of tighter budgets, accelerating technological advances, and extensive procedural reassessments. In that light, much about our trial’s design and execution illustrates a system of human experimentation that’s ripe for overhaul. (...)

One of the most important questions in any trial, of course, is what medical intervention to test.

My trial, like many, was heavily shaped by testing on animals. Jared J. Grantham, an emeritus professor of nephrology and hypertension at the University of Kansas who led the creation of the PKD Foundation 30 years ago, said there were many studies prior to the trial—typically involving mice—that gave scientists hope that PKD might be slowed by the combination of two drugs. Those drugs, Lisinopril and Telmisartan, use different chemical mechanisms to block angiotensin, a hormone that raises blood pressure by constricting blood vessels.

But for many diseases, mice and other animal models are proving notoriously unreliable in predicting drugs’ effect on human beings. "From the point of view of PKD specifically, we have a number of hypotheses that have come out of the basic-science laboratories, and to a large extent the animal models often don’t exactly mimic what’s going on in people," said Joseph V. Bonventre, a professor of medicine at Harvard University and chief of the renal unit at Brigham and Women’s Hospital.

More generally, many observers suspect researchers of becoming too enamored of their animal models.

"We’re extracting some cartoon version of the disease, and then treating it, so that the animal model becomes the focus of our research, not that actual human disease," said Susan M. Fitzpatrick, president of the James S. McDonnell Foundation and an adjunct associate professor of neurobiology at Washington University in St. Louis. "And we learn more and more about the model, but not the disease."

by Paul Baskin, Chronicle of Higher Education |  Read more:
Image: Julia Schmalz