Since 2000, the FDA has issued more than 25 warnings and safety communications regarding biologic drugs.
By John Fauber and Kevin Crowe, Milwaukee Journal Sentinel.
With her kidneys and liver failing and a 106-degree temperature that had smoldered for days, Helen Tschannen was being kept alive on a ventilator.
Doctors were not certain what was happening, but the family knew this: Tschannen, 77, did not want to be kept alive by machines. After 21 days in an Illinois hospital, they gathered at her bedside and wrestled with whether they were doing the right thing.
A nurse unhooked the equipment. Tschannen took one breath on her own and died.
It was Oct. 19, 2004.
In the weeks after Tschannen’s death, her family learned she had been suffering from a common fungal infection known as histoplasmosis. For most people, it produces no symptoms or only mild ones.
But Tschannen, it turns out, was at special risk of a bad infection, not because of her age or because she lived in a region where the fungus lurks, but because of a drug she had started taking a few months earlier to tame her rheumatoid arthritis.
The drug, Remicade, had been approved for her condition in 1999. It was at the forefront of a class of drugs known as biological medicines, or biologics, that treat autoimmune diseases of the skin, joints and gastrointestinal system. Unlike drugs made chemically, biologics are cultured in the laboratory from animal cells and are given by injection or IV.
In the past 20 years, the drugs — which can cost some $40,000 a year — have flooded the market. Ads for several, including Humira and Cosentyx, are fixtures on television, promising improved gastrointestinal symptoms or clearer skin with “sexy elbows.”
Preliminary numbers for 2018 show that group of biologics was on pace to top 6 million prescriptions last year, a nearly 50% increase from 2013, according to data from IQVIA, a pharmaceutical market research firm.
The drugs are effective in treating rheumatoid arthritis, psoriasis and other autoimmune disorders. They often lead to significant improvement in symptoms, even remission.
But there is a darker aspect to the drugs that is less known to the public: They leave patients more susceptible to a growing number of infections and other serious side effects.
Tschannen’s case is one of at least 34,000 reports to the U.S. Food and Drug Administration of people who died while using biologic drugs since 2004, according to an extensive analysis by the Milwaukee Journal Sentinel of data from the agency.
More than 1 million “adverse events” were reported in people using the drugs during that time, including nearly 500,000 that were deemed serious, the investigation found.
The FDA defines an adverse event as any undesirable experience associated with a medical product. To be considered serious, the situation must involve death, disability, hospitalization, permanent damage or a life-threatening issue. The FDA’s database, though, does not verify any cause-and-effect relationship between the drug and what happened.
While the drugs make up only a small slice of the $450 billion-plus prescription drug industry — they were on pace for about $45 billion last year — they have an outsized effect.
Among all prescription drugs over the last 15 years, the biologics Humira and Enbrel are the most-cited in the FDA’s database, the Journal Sentinel review found.
Humira was linked to 169,000 reported serious adverse events and 13,000 reports of deaths, followed by Enbrel with 135,000 serious events and 8,000 deaths. Yet neither is among the top 20 prescribed medications in America, according to IQVIA data.
“Those numbers are important,” said Steven Woloshin, a professor of medicine at Dartmouth Geisel School of Medicine. “It certainly is a signal that can’t be ignored.”
Remicade, the drug Tschannen was taking, had 98,000 reports of serious adverse events, including 6,000 reports of deaths, the analysis found.
Tschannen’s daughter, Bev Webber of Mukwonago, Wisconsin, said she remains troubled that a drug people take to help them live better also can make them susceptible to a deadly infection.
“I still have the unanswered question of how many deaths related to a drug does it take before it is taken off the market?” said Webber, a retired nurse. “I realize there isn’t a clear answer.”
People using biologics run the risk of having a more severe infection because their immune systems are weaker, said Chadi Hage, an associate professor of clinical medicine at Indiana University who has done research on histoplasmosis in people who use biologics.
Patients should be fully informed about the risks, he said.
“They take these drugs so they can live a life, but at the same time, the more they are educated about what is risky and what is not, the better the story will be.”
A crowded market
There are 21 biologic drugs on the market, up from seven in 2004; two others were launched, but taken off the market. Many of the drugs are approved to treat multiple conditions.
Before going on the 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.
But a study published in January found that only 26% of 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, published in the Joint Commission Journal on Quality and Patient Safety, concluded.
The screening involves relatively inexpensive skin and blood tests that can have results in a matter of days, said study co-author Jinoos Yazdany, an associate professor of medicine at the University of California, San Francisco.
Safety could be improved with drug company or medical society funding of registries of patients who use biologics to monitor side effects, she said. Other measures could involve better tracking of safety procedures used by doctors and enhanced safety education for patients and health care providers.
“There has been very little investment in patient safety,” Yazdany said.
Indeed, part of the problem may be the FDA’s own drug-approval system.
That system allows drug trials that may last a year or even less, when real-world patients may be on the drugs for much longer periods. What’s more, the drugmakers designing the trials are allowed to exclude less healthy people as test subjects.
In short, that means people can come down with serious or even deadly side effects that might not have been foreseen at the time a drug is approved to be sold.
Though the conditions the drugs treat may not be life-threatening, many patients are willing to accept the serious risks of the drugs because their disease may be debilitating, said Alison Huffstetler, an assistant professor of family medicine at Georgetown University Hospital School of Medicine.
“For most of my patients, they are willing to take a risk that will enhance their quality of life,” she said. “It certainly is a balancing act.”
A 2018 paper in the journal JAMA Dermatology found that real-world psoriasis patients were two to three times more likely to get a serious adverse event than those who were allowed in the trials. The drugs also didn’t work as well in them.
Consider the drug Cosentyx, which the FDA approved in 2015 to treat psoriasis, a condition that causes red, scaly patches on the skin. It is not life-threatening in the vast majority of cases.
The clinical trial excluded people for 12 health reasons, including women who were pregnant or nursing and people with uncontrolled high blood pressure; congestive heart failure; a history of cancer; or with any underlying liver, kidney, blood, heart, brain or gastrointestinal condition that might significantly compromise the immune system.
Since 2015, there have been nearly 13,000 reports of serious adverse events with Cosentyx, including 581 deaths.
A spokesman for Novartis, manufacturer of the drug, noted there have been more than 200 studies of the drug — one of the largest such study programs.
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, said Novartis spokesman Eric Althoff.
Warning after warning
Since 2000, the FDA has issued more than 25 warnings and safety communications regarding biologic drugs or required the drugs’ labels be updated to list information about serious new risks — all after the drugs were approved for use in patients.
The Journal Sentinel review found warnings for various fungal and bacterial infections, as well as a rare viral brain infection. Other warnings included tuberculosis, a flesh-eating bacteria, various neurological conditions, liver failure and heart failure, as well as lymphoma and other cancers.
In 2001, the FDA issued a “black box” warning, its most stringent, alerting doctors to the potential of histoplasmosis infections in patients on biologic drugs.
But it was not until 2008 — four years after Tschannen’s death — that the FDA issued a new such warning for Remicade and three related drugs, Humira, Enbrel and Cimzia. The warning noted fungal infections “are not consistently recognized in patients” taking those drugs.
By then, there had been 45 deaths among 240 reports of serious infections, with more than 207 involving Remicade.
According to data from the U.S. Centers for Disease Control and Prevention, histoplasmosis infections leading to hospitalization increased by 15% a year between 2001 and 2012 with a reported mortality rate of 20%.
Biologics are “likely to be one of the factors behind the increase in hospitalizations,” said CDC spokeswoman Brittany Behm.
FDA spokesman Nathan Arnold said there is intense scrutiny of drugs by his agency before they are approved, but acknowledged “much work still remains to monitor approved drugs over time.”
“No drug is risk-free, and it is not uncommon for new information to be discovered after a drug is on the market and being used by larger numbers of patients,” he said. “Simply put, for a drug to be on the market, the FDA must determine that the drug is effective and that its expected benefits outweigh its potential risks to patients.”
The FDA says its adverse events reporting system can’t be used to determine the safety of a drug or its side-effect rate, and notes other drugs also may have been used. The database, though, is increasingly used by researchers and the agency itself to detect potential problems.
Drug companies are required to report to the FDA any issues that come to their attention. For others, such as doctors and patients, reporting is voluntary. None of the reports are considered verified. Nevertheless, there is widespread agreement the system undercounts what is actually happening among patients.
The most recent numbers, based on a 2005 Government Accountability Office report, estimate the system captures 10% or less of all adverse events.
Linda Davis, a spokeswoman for Johnson & Johnson, the maker of Remicade, said the FDA’s database is not a reliable measure of a drug’s risks and just because a report is made, it does not necessarily mean the drug caused the adverse event. Remicade’s safety has been established in nearly 3 million patients around the world, she said in a statement.
“We are proud of the impact Remicade has made on transforming the lives of patients.”
Meanwhile, the makers of Enbrel and Humira issued similar statements.
“While changes to a product’s safety information may occur over time as more real-world and clinical data are collected, analyzed and incorporated, Enbrel’s benefits outweigh its risks,” said Trish Hawkins, a spokeswoman for Amgen, the maker of Enbrel.
Jillian Griffin, a spokeswoman for Abbvie, said Humira is one of the most comprehensively tested biologics and “has a well-established safety profile and is a trusted treatment that is supported by more than 16 years of physician and patient experience.”
A new risk: suicide
In at least one case, the FDA approved a biologic drug — Siliq — against the recommendation of an agency expert who raised a new concern: The increased risk of suicide.
Six suicides were reported among the 6,200 people who participated in studies, all within three years of receiving their first dose, including four who had no history of depression, according to an FDA internal analysis. In all, 34 people in the studies reported experiencing suicidal thoughts or behavior.
The analysis found the suicide rate was three to four times higher than for other biologics used to treat psoriasis.
“This number of suicides in a psoriasis (drug) development program is unprecedented,” an FDA physician said in a 2016 internal review, obtained by the Journal Sentinel.
Nevertheless, the FDA approved the drug in 2017. At the time, there already were 10 other drugs approved to treat psoriasis.
The agency required the drug to carry a “black box” warning label for suicidal behavior, as well as other warnings for serious infections, tuberculosis and the development of Crohn’s disease.
Bill Humphries, president of Ortho Dermatologics, which markets Siliq, noted that, at $42,000 a year, Siliq is the lowest priced biologic for psoriasis on the market.
He stressed no “causal association” has been established between the drug and suicidal thinking and said that since Siliq was introduced in the U.S. in July 2017 there have been no reports of suicides or attempted suicides.
Data from the FDA’s adverse events reporting system indicate 108 serious adverse events, including two deaths, were reported for Siliq last year.
A deadly tradeoff
For some patients, biologic drugs can reduce the need for steroids and other drugs that also have bad side effects.
Life expectancy, which can be several years shorter for people with autoimmune diseases such as rheumatoid arthritis, has been increasing in recent decades. While the biologic drugs may play a role, that has not been proven and there are other factors as well, such as other medical advances.
In any case, research underlines the sometimes deadly tradeoff.
A 2013 U.S. Department of Veterans Affairs review of research papers focused on biologic drugs used to treat psoriasis and a related arthritis — drugs in the same class as Humira, Enbrel and Remicade.
The review found while the biologic drugs don’t have the predictable potential for organ damage found with some older, conventional drugs, they “are associated with relatively unpredictable major harms, including serious infections (e.g., sepsis, tuberculosis, and viral infections), autoimmune dysfunction (e.g., lupus, demyelinating disorders), and malignancies (e.g., lymphoma).”
Fungal infections are a particular concern.
The U.S. Centers for Disease Control and Prevention identified a total of more than 260,000 hospitalizations between 2000 and 2013 for four fungal infections: histoplasmosis, aspergillosis, mucormycosis and coccidioidomycosis.
All the infections increased substantially over that time frame; between 5% and 20% involved deaths.
“Providers should be vigilant for fungal infection among patients taking biologics,” CDC researchers warned in a 2016 paper.
Behm, the CDC spokeswoman noted that the number of biologics on the market only has grown since the paper was published. Indeed, eight new biologic drugs have been approved since 2016 alone.
The life-threatening condition known as sepsis has surfaced as a particular concern among people who use biologics, especially those with rheumatoid arthritis.
Sepsis, a body-wide inflammatory reaction to an infection, affects about 1.7 million people a year, including 270,000 who die, according to the CDC.
Beginning in the early 2000s there was a spike in sepsis cases among people with rheumatoid arthritis. A 2018 paper by researchers at Boston University School of Medicine found that hospitalizations for sepsis more than tripled between 1993 and 2013.
The big uptick seemed to occur beginning in about 2002 when the number jumped from 4,700 cases to 2013, when there were 32,000 cases.
A substantial portion of the increase may have been due to more accurate hospital coding for sepsis, said lead author Sadao Jinno.
However, the increases coincided with the rise of biologic drugs. In the period between 1999 and 2002, three popular biologics — Remicade (1999), Enbrel (2000) and Humira (2002) — were approved to treat rheumatoid arthritis.
Ali Wilson, who lives in the Tampa, Florida, area, is one of those who was affected by sepsis.
After years of using a non-biologic drug to control her rheumatoid arthritis, Wilson went on Humira in 2013. Wilson, a nurse, gave herself her first injection on Oct. 17 that year.
“On October 29,” she said, “I was in the ER dying.”
Wilson, 53, had rapidly developed a case of sepsis. She had severe joint pain, a temperature of 101 and was vomiting and shaking. Paramedics barely could feel her pulse. She spent nine days in the hospital, including four in the intensive care unit.
Wilson said she and her doctor believe Humira may have weakened her immune system and allowed an infection that she might have picked up during gallbladder surgery several months earlier to flare up.
The change was so dramatic, she said, “it was like somebody flicked a light switch.”
She recovered from the bout with sepsis, but has avoided Humira. She now is taking a generic drug and recently started on another biologic, Orencia, that she thinks may be safer.
Since 2004, there have been nearly 10,000 reports to the FDA of sepsis in people using biologics, according to a Journal Sentinel analysis.
Steven Simpson, who treats sepsis patients and is medical director of the Sepsis Alliance, a patient advocacy group, said people using the drugs need to be aware of potential warning signs such as fever or confusion.
If a person on a biologic drug gets a fever above 101?
“I’d get to the doctor immediately,” said Simpson, a professor of pulmonary and critical care medicine at the University of Kansas.
Autopsy finds histoplasmosis
In the case of Tschannen, the 77-year-old who died of a histoplasmosis infection, she went to the doctor as soon as symptoms emerged.
But no one recognized the cause of what was happening — or the relationship between the condition and the drug she had just started taking.
The diagnosis of histoplasmosis didn’t come until the autopsy.
Tschannen had suffered from rheumatoid arthritis for years. She had been taking three other drugs for the condition and only added Remicade a few months before she got ill. The drug was given by infusion every few weeks.
“She only had two doses,” said Webber, her daughter.
Tschannen had suffered a brain aneurysm several years earlier and had high blood pressure.
“Adding Remicade was a lot,” Webber said. “It was too much for somebody with all those conditions.”
Unlike many people who develop a histoplasmosis infection, a CDC paper found those using biologic drugs often have a type of the infection that is harder to diagnose.
Since 2004, nearly 1,800 cases of histoplasmosis and other fungal infections in people using biologics have been reported to the FDA, according to the Journal Sentinel analysis of FDA data.
A 2011 paper on the risk of hospitalized infections in rheumatoid arthritis patients showed Remicade with the highest rate among several biologic drugs. Yet, rather than doom the drug to diminished sales, prescriptions increased from 2013 through 2018.
In the months after her mother’s death, Webber sought answers from her mother’s doctor and Johnson & Johnson, the maker of the drug.
The doctor, Steven Baak, wrote back describing the tricky balance with treating rheumatoid arthritis — how if not controlled, it can lead to joint damage or an even the risk of heart disease.
“It is nerve-wracking,” he wrote, “to try to control severe symptoms knowing all the bad things that can happen.”
She sent multiple emails and letters to the drugmaker, hoping to make sure the company was aware of the case.
“I realize that this medication has helped many patients,” Webber wrote in one letter. “I also know my mother died a horrible death.
“I wish we had never heard of this medication.”
May 30, 2019