Like the others in the clinical trial, Patient No. 11561004 already had tried one treatment for his advanced kidney cancer, but it didn't work.
So the 69-year-old man volunteered to try an unprovendrug that offered some hope he might live longer.
Less than four months after going on the drug known as Inlyta, the man — identified only by age and a number in an FDA review of the clinical trial— developed severe abdominal pain, was admitted to the hospital and died that day from gastrointestinal bleeding.
The drug designed to keep him alive may have hastened his death.
For decades, researchers have focused ondeveloping new cancer drugs that save lives or improve the quality of life. But when the U.S. Food and Drug Administration allowed Inlyta, a $10,000 a month drug, on the market in 2012, there was no proof that it did either.
Inlyta is not an exception to the rule.
A Milwaukee Journal Sentinel/MedPage Today analysis of 54 new cancer drugs found that over the last decade the FDA allowed 74% of them on the market without proof that they extended life. Seldom was there proof of improved quality of life, either.
Nor has the FDA demanded companies provide such evidence.
Instead, the agency approved the drugs based on surrogate measures, such as a tumor shrinking, rather than the gold standard and most reliable measure of cancer research, patients actually surviving longer. The problem is cancer is complicated — a tumor might stop growing or shrink in one spot, then reappear somewhere else, or even in multiple places.
Inlyta, manufactured by Pfizer, was allowed on the market based on a commonly used surrogate known as progression-free survival, which means patients survived longer before doctors detected a tumor worsening.
Patients given Inlyta saw no noticeable progression of their disease for an average of 6.7 months, two months longer than those who got a control drug. But patients who got Inlyta did not live any longer.
Before Inlyta was approved, an FDA reviewer noted it would be the seventh drug for advanced kidney cancer approved by the FDA since 2005. Only one of them, a drug known as Torisel, had actually proven to help people live longer.
Prompted by politicians, pharmaceutical companies and advocacy groups seeking to speed up drug approvals, the FDA has allowed shortcuts to make it easier for companies to get products on the market.
A big part of that has been the use of surrogate measures.
For instance, diabetes drugs usually are approved based on lowering blood-sugar levels, rather than clinical benefits such as fewer amputations and heart attacks.
Heart drugs may be approved based on tests measuring various fats in the blood rather than fewer heart attacks, strokes or cardiovascular deaths.
Surrogate measures, which allow for shorter, smaller and cheaper clinical trials, have opened the gates to a steady stream of costly drugs of dubious value.
“The whole paradigm is broken, and it is an unmitigated disaster,” said Peter F. Thall, a biostatistician at MD Anderson Cancer Center in Houston who designs clinical trials for cancer research.
The system creates a veneer of innovation that hides a deeper problem, say Thall and other critics of this change in emphasis.
By encouraging drug companies to focus on surrogate measures, the critics say, the FDA is undermining the development of drugs that actually will improve and prolong people's lives.
“We've spent billions of dollars on trials that should have never been done in the first place,” Thall said.
Pharmaceutical companies now control the drug development agenda and, as a result, are able to price drugs at whatever they think the market will bear, said Leonard Saltz, chief of gastrointestinal oncology at Memorial Sloan Kettering Cancer Center in New York.
“We're paying top dollar for drugs that do very little,” Saltz said. “If we continue to pay for drugs the way we have been, we're actually stifling innovation.”
It is as though the FDA is teaching to the test — allowing pharmaceutical companies to focus on technical numbers instead of more powerful evidence. Saltz said statistical analyses, which were meant only to validate better health outcomes from positive drug trials, have replaced meaningful health improvements as goals.
“What we've been doing is pushing more and more drugs into the market to make more and more of a market,” Saltz said. “And we're doing so with the fantasy that we're doing better. But the evidence doesn't always support that.”
The system has swung from one extreme to the other.
In the 1970s, in the early days of treating cancer with chemotherapy, the FDA required a measure known as objective response rate, which determined tumor changes by scans or physical exams. Like progression-free survival, it was a surrogate measure.
In the 1980s, the agency demanded more direct measures, such as improvements in survival, quality of life and physical functioning.
Since 1992, the FDA has allowed for accelerated approval of new cancer drugs based on surrogates if it believes those measures are “reasonably likely” to predict a clinical benefit such as increased survival or improved quality of life.
But in many cases, proof of a survival benefit has not been provided even years after the drugs got on the market, the Journal Sentinel/MedPage Today examination found.
To check on how much follow-up researchwas being done, the analysis focused on cancer drugs approved based on surrogates between the years 2004 and 2011. That would allow at least two years for follow up.
Today, only three of those 26 drugs have been proven to increase survival. One increased survival 10 months; one by eight weeks and another increased the three-year survival rate to 70% from 61% compared with those who got a placebo.
Another drug subsequently was linked to slightly shorter survival. It remains on the market.
For the other 22, there still is no proof of improved survival.
“While it is acknowledged that shrinking a tumor or preventing it from progressing may not be a direct measure of improvement in survival, symptoms or function, as the magnitude of that shrinkage or delay in growth increases, our confidence that the result is likely to predict clinical benefit increases,” Stephanie Yao, an FDA spokeswoman, said in an email.
Even when studies show a cancer drug extended life, the Journal Sentinel/MedPage Today analysis showed that extra time often is short-lived — sometimes a matter of months or weeks and, in one case, days.
In 2007, Congress gave the FDA teeth to require follow-up safety trials and the ability to levy fines of up to $10 millionon pharmaceutical companies that were delinquent. The FDA has sent letters to drug companies, but according to Yao has never imposed any fines.
Rather, Yao said, some companies voluntarily withdrew certain uses rather than conduct trials.
In the case of Inlyta, the FDA did not require Pfizer to prove the drug offered a survival or quality-of-life benefit.
For its part, the company cites a paper published more than a year later in the British Journal of Cancer that found patient-reported symptoms in the clinical trial were comparable between Inlyta and those in a control group, who were being treated with another drug.
The paper, funded by Pfizer, concluded that because the Inlyta patients had two months more before their cancer progressed, they were able to stay on treatment longer. As a result, the time it takes for worsening of symptoms can be delayed, the study said.
However, the design of the clinical trial allowed patients to know what drug they were getting, an approach the FDA considers open to bias.
Pfizer spokeswoman Sally Beatty said Inlyta was approved on the same basis as other drugs approved to treat the disease — the length of time their cancer did not naturally progress.
“Inlyta is an important option for patients who face this devastating and rare cancer,” she said.
Drugs in other areas, such as heart care, show the difference between demanding proof of results and accepting surrogate measures as enough.
Statin drugs that lower cholesterol became widely used only after traditional long-term clinical trials, involving thousands of patients, proved real clinical benefits, including reductions in heart attacks and strokes.
But other drugs — such as Zetia and Vytorin, niacin-statin combination pills, and prescription fish oil — have been approved on the basis of improving surrogate measures such as cholesterol and triglyceride levels.
In those cases, clinical benefits were presumed by the FDA.
But they were not found after those drugs got on the market and researchers looked deeper.
“Fish oil has been handed out like candy for the last 15 years in the United States,” said James Stein, a professor of cardiovascular research at the University of Wisconsin School of Medicine and Public Health. “There is no evidence that in people who are healthy it does any good.”
Cancer doctors understandably may be more willing to try drugs that have shown only a surrogate benefit because the short-term risk of death is more pressing than with heart disease, Stein said. And patients may reach for the drugs out of hope or desperation.
In 2011, for example, the FDA approved Xalkori to treat certain lung cancers in patients with a genetic alteration known as ALK. Between 1% and 7% of these cancer patients have the ALK gene abnormality.
FDA records show Xalkori was approved based on the surrogate of objective response rate, the measure of how tumors respond to the drug.
In a later study, the drug also was shown to improve the surrogate progression-free survival, which was 7.7 months for Xalkori, compared with three months for conventional chemotherapy.
But an interim analysis showed there were more deaths among patients taking Xalkori than with chemotherapy. Xalkori patients lived a median of 20.3 months, compared with 22.8 months for those on chemotherapy.
The analysis was 40% complete at that time. And it was complicated by the design of the study, which allowed chemo patients to switch to Xalkori if their tumors worsened.
Three years after approval,Pfizer, which makes the $12,000-a-month drug, is continuing to look at overall survival data as required by the FDA. It is not known when final numbers might be ready that show whether Xalkori extends lives.
Kathy Stigler, a Stage 4 lung cancer patient from Hartford who started taking Xalkori in January 2013, said she realizes the drug may not extend her life.
“I feel like I am helping them further the data,” said Stigler, 56.
After three months on the drug, a scan showed her tumor had shrunk by about one-third.
Because the tumor was on her bronchial tube, the shrinkage made it easier for her to speak. In addition, the two pills she takes each day are not as grueling as the chemotherapy she had been undergoing.
Still, in June 2013, six months after going on the drug, another scan showed the tumor shrinkage had stopped.
“That's where I am today,” she said. “I will get scanned every three months.”
Stigler's doctor, Bruce Gershenhorn of the Cancer Treatment Centers of America in Zion, Ill., said Xalkori is an example of cancer treatments that are targeted to specific genes.
Gershenhorn said, in his experience, the effect the drug had on Stigler's tumor is fairly common for patients who have the ALK alteration.
“Unfortunately, these drugs stop working at some point,” he said.
Drugs cost thousands
The FDA's approval of new cancer drugs has improved the financial health of drug companies. Once the drugs are on the market, companies have charged an average of $10,000 a month for the 54 drugs examined, with four costing more than $20,000 a month and one priced at $40,000 a month.
Of those five most expensive drugs, the $40,000 drug has a proven survival benefit — extending life by four months — and the other four were approved based on surrogates, the Journal Sentinel/MedPage Today analysis found.
Spending on all oncology drugs hit $28 billion in 2013, an increase of 9.2% over the previous year, according to data from the drug market research firm IMS Health.
The average cancer prescription now costs 22 times more than it did a little over a decade ago, according to Express Scripts, a company that manages pharmacy benefits.
“If you are a drug company, what is your goal?” said Silvana Martino, director of the breast cancer program at the Angeles Clinic and Research Institute in Santa Monica, Calif. “It is to provide sufficient data to get your drug approved. You will aim for whatever that least amount is.
“I think the bar is too low.”
Martino, who has served on FDA cancer drug advisory committees, said the agency has been under public pressure for years to get drugs on the market quickly. The idea is to make potentially beneficial therapies available as soon as reasonably possible.
But that approach means shortcuts are taken, she said: “You don't have deep, solid studies that prove a point.”
When cancer drugs are approved based on proof that they extend life, it can mean a windfall for companies as doctors flock toward use of those agents.
The drug Zytiga, made by Johnson & Johnson, was approved in 2011 to treat metastatic prostate cancer by showing increased survival of four months.
The drug has become popular among urologists and grabbed a bigger share — 23% — of the market, according to a Wells Fargo report issued in August.
Zytiga, which costs $5,400 a month, has projected 2014 sales of $964 million in the United States and $2.3 billion worldwide.
FDA backs down
The FDA does not routinely push companies to do studies that prove a drug can extend or improve life as a condition of approval. When the agency does, drug companies sometimes ignore it.
Last year, the FDA approved the drug Mekinist to treat metastatic melanoma in patients who had certain genetic mutations.
The drug was approved because it showed an increase of progression-free survival of 3.3 months over standard chemotherapy.
But records show the agency initially wanted the maker of the drug, GlaxoSmithKline, to show an actual overall survival benefit as the primary measure of the drug's effectiveness. The FDA backed off that request and allowed the company to use the surrogate measure of progression-free survival.
A spokeswoman for GlaxoSmithKline said the company used the surrogate because that measure would not be affected if patients in the control group worsened and wanted to switch to Mekinist.
Often cancer clinical trials allow “crossover” of patients, which can make it more difficult to find out whether there is an actual survival benefit. In part, crossover is allowed for ethical reasons; it also creates an incentive for patients to enroll in clinical trials.
In the case of Tasigna, the FDA asked Novartis to follow a group of chronic leukemia patients on their experimental drug for 12 months. Novartis followed patients for only six.
Larger trials give greater credibility to research, and the FDA cautioned Novartis against reducing another study group's already small size of 132 patients. Novartis cut the study to 64 patients.
Patient No. 106-1 was a 46-year-old woman in Canada with no history of heart problems. A month after starting on the drug, she suffered a heart attack and died. It was termed a sudden death and a suspected consequence of taking the drug, according to an FDA medical review.
Novartis spokesman Eric Althoff said the company reported three such sudden deaths to the FDA, which resulted in black box warnings for Tasigna. A black box is the FDA's strongest warning on a product's label, alerting doctors to potential life-threatening risks and side effects.
Althoff added that after the company submitted the initial application, researchers enrolled additional patients, bringing the total to 105.
On the drug's most recent label there was no data that Tasigna provided a survival benefit.
Yao, the FDA spokeswoman, said the agency provides advice to companies on how to conduct their clinical trials before approval.
She added: “Sponsors must decide whether to accept the FDA's advice or move ahead with their original plans and take the regulatory risk when submitting the data in their application to market the drug.”
Conflict of interest
The system for approving new drugs dates to the 1992 Prescription Drug User Fee Act.
The law created a built-in conflict of interest for the FDA. A large portion of its budget is derived from fees that drug companies pay the agency to get products approved.
In 2013, the FDA collected $490 million from drug companies to review their drug applications under the law. That amounts to almost half of the budget of the agency's Center for Drug Evaluation and Research, according to a recent FDA report. Fees collected under the law are projected by the FDA to reach $800 million by 2015.
Yao said reviewing drug company applications requires a large team of doctors, chemists and statisticians. In exchange for the fees, she said, the FDA agrees to make a decision within a certain time period, but does not guarantee approval.
For fiscal year 2014, the fee for a new drug application that involves clinical data, such as that used in new cancer drugs, is $2.2 million.
The drugs involved, she said, must still meet basicsafety and effectiveness standards.
In 1996, at the behest of patient advocacy groups, President Bill Clinton and Vice President Al Gore issued their “Reinventing the Regulation of Cancer Drugs” initiative, further prodding the FDA to approve drugs based on surrogates.
Indeed, the FDA now judges its own performance based on a surrogate measure — speed of application decisions. Annual FDA performance evaluations reviewed by the Journal Sentinel/MedPage Today found them focused on how quickly the agency responded to drug approvals.
Yao said the agency's use of surrogates is not new. In oncology, she said, there are strong, objective surrogates such as CT scans or MRI images that can show the effect of a drug on a tumor.
“We have consistently heard from individual patients, patient groups and their elected representatives in Congress that FDA should use surrogate endpoints more frequently and broadly,” she said. “We believe we are striking the right balance between the extent of data necessary to make a careful risk-benefit assessment and the most efficient path to providing safe and effective cancer drugs to patients who need them.”
Patients are desperate, so demanding a survival benefit, which can delay approval, in some cases is unreasonable, said Mikkael Sekeres, director of the leukemia program at the Cleveland Clinic.
However, Sekeres who has served on FDA cancer advisory committees, acknowledged problems with the approval system.
“A lot of cancer therapeutics have, frankly, been a disappointment,” he said. “We need to show that people are either living longer or living better and, ideally, both.”