Drug trials may exclude those with most need
Unhealthy patients have more adverse reactions
When it comes to the risks and benefits of biologic drugs that treat autoimmune diseases such as rheumatoid arthritis and psoriasis, there are two kinds of patients:
Healthier people who are picked to test the drugs in medical trials.
And real-world patients who use them after they get on the market.
So the clinical trial results the U.S. Food and Drug Administration uses to declare drugs safe and effective may show fewer risks. But once the drugs start being used by a wider mix of people, dangerous side effects can emerge.
Of the 21 biologic drugs that have won FDA approval, 13 — 62% — have received the agency’s most stringent warning, known as a “black box,” a Milwaukee Journal Sentinel investigation found. In most of those cases, the warnings were added after the drugs were on the market.
The problem of using only more healthy patients for drug trials has long existed.
But doctors say it is especially concerning when the trials involve powerful, immune-suppressing biologic drugs that can leave patients susceptible to infections and other side effects.
In those cases, trial results can be magnified — for good or ill — in realworld patients.
“It is something that has been allowed to grow,” said John Kirwan, an emeritus professor of rheumatic diseases at the University of Bristol in the U.K. “We used to exclude only people who were really ill.”
There are reasons researchers focus on healthier patients: They may be less likely to drop out of a trial or, due to other medical conditions, use drugs that might confound the study results. Who can be excluded?
In 2017, the FDA approved the rheumatoid arthritis drug Kevzara based on clinical trials that excluded people for more than 35 categories of health reasons.
Among those excluded: Patients who weighed more than 242 pounds; had various cancers in the previous five years; had alcohol or drug abuse problems in the previous five years; had uncontrolled diabetes; or had a history of not responding to any other biologic drug.
Patients could also be barred if they had a history of any heart, kidney, brain, gastrointestinal, lung or hormonal illness that — in the opinion of the researchers — would adversely affect their participation in the trials.
Caleb Alexander, a drug safety expert with Johns Hopkins Bloomberg School of Public Health, said some ex
clusions are understandable, such as not allowing someone who has active cancer, HIV or who has received an organ transplant and is on an anti-rejection drug that already suppresses the immune system.
“Excluding someone who weighs over 250 pounds?” he said. “Come on. That’s one-fifth of America.”
Since 2017, there have been 2,100 reports to the FDA of what are termed “adverse events” in people using Kevzara, a Journal Sentinel analysis found. Among the reports: 600 deemed serious and 28 deaths.
While the FDA database has limitations, including a lack of verification of the reports, the potential for duplicates and the possibility that other drugs could have been used, it is the largest publicly available data set of reactions associated with prescription drugs.
If anything, experts say, it undercounts the potentially dangerous incidents.
Ashleigh Koss, a spokeswoman for Sanofi, which markets the drug with Regeneron Pharmaceuticals, said the FDA reports should not be considered as a lone indicator of the safety of any medicine.
She said Kevzara was developed in a controlled population “generally reflective” of patients with rheumatoid arthritis.
“The exclusion criteria includes certain conditions that may confound the results of the study or adversely affect the patient’s participation in the study,” she said. “Without such criteria it may be difficult to differentiate the risks attributable to the excluded conditions/life-style choices versus the investigational product.”
Problems more likely in real-world patients
A 2018 paper in the journal JAMA Dermatology found that real-world psoriasis patients who would not have been eligible for clinical trials were two to three times more likely to suffer a serious side effect in the year after going on a biologic than those who were eligible for the trials.
The drugs also didn’t work as well in them.
At the same time, patients in clinical trials may get more optimal medical attention than real-world patients, which can also impact study outcomes.
Before going on biologic drugs, people are supposed to be screened for infections, such as tuberculosis, hepatitis B and hepatitis C, all of which can lead to devastating effects if they flare up. In clinical trials, such screening is standard practice.
But a study published in January in the Joint Commission Journal on Quality and Patient Safety found that only 26% of real-world patients were fully screened by their doctors for those infections.
“More robust safety protocols are urgently needed to prevent serious patient safety events in this high-risk population,” the study concluded.
In 2015, the FDA approved Cosentyx to treat psoriasis based on a clinical trial that excluded people for 12 health reasons.
Those reasons included uncontrolled high blood pressure; congestive heart failure; a history of cancer; or any metabolic, blood, kidney, liver, lung, brain, hormonal, cardiac, infectious or gastrointestinal issues that, in the opinion of the researchers, significantly compromised their immune system or puts them at “unacceptable risk” for taking an immune-suppressing drug.
Since 2015, there have been 15,000 reports of serious adverse events with Cosentyx, including 600 deaths, according to the FDA’s database.
Novartis spokesman Eric Althoff said more than 200,000 patients worldwide have been prescribed Cosentyx and its safety is supported by five years of data, including in real-world patients.
Althoff said while some patients are excluded from initial trials, follow-up studies “aim to expand the eligible populations. Cosentyx has been studied in one of the largest clinical programs ever conducted, with over 100 studies ongoing or concluded.”
Several real-world studies of Cosentyx, he said, show it has maintained its safety profile.
The goal of designing clinical trials that better represent the kinds of patients who ultimately will get a drug has gotten increased attention in recent years.
Last year, the FDA held a workshop on the topic and noted that while excluding patients with health problems may reduce the number of adverse events in a trial, it also makes it difficult to determine if the drug will benefit or harm those kinds of patients.
Alexander, of Johns Hopkins, said drug companies will do what the FDA requires of them: “At the end of the day, the FDA is calling the shots.”