Like the others in the clinical trial, Patient No. 11561004 already had tried other treatments for his advanced kidney cancer, but those didn't work.

So the 69-year-old man volunteered to try an unproven drug that offered some hope he might live longer.

Less than 4 months after starting the novel drug, axitinib (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 on developing new cancer drugs that save lives or improve the quality of life. But in 2012 when the U.S. Food and Drug Administration approved axitinib, a $10,000 a month drug, there was no proof that it did either.

Action Points Note that this analysis from MedPage Today and the Milwaukee Journal Sentinel reveals that many cancer drugs approved on the basis of progression-free surivival have failed to show improvements in overall survival in postmarketing surveillance.

Be aware that requiring studies to address overall survival will increase study size, cost, and time to drug availability.

At the same time, such outcomes will ensure that the public is paying for efficacious therapies.

Read Part 2 of The Slippery Slope project: Risks and Confusion -- An examination of toxicity versus durable benefit.

Axitinib is not an exception to the rule.

A MedPage Today/Milwaukee Journal Sentinel analysis of 54 novel molecular entities for treating cancer found that over the last decade the FDA approved 40 (74%) to 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.

Axitinib, 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 axitinib saw no noticeable progression of their disease for an average of 6.7 months, 2 months longer than the 4.7 months for those who got a control drug (P<0.0001, 95% CI). But patients who got axitinib did not live any longer.

Before axitinib was approved, an FDA reviewer noted it would be the seventh drug for renal cell carcinoma approved by FDA since 2005. Only one of them, a drug known as temsirolimus (Torisel), had actually proven to help people live longer.

The FDA does not make decisions in a vacuum -- it is under constant pressure from politicians, pharmaceutical companies, and advocacy groups to speed up the drug approval process.

A key element in that speedier process is 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 lipids rather than major adverse cardiovascular events (MACE), which includes events such as heart attacks and strokes.

Broken Paradigm

"The whole paradigm is broken, and it is an unmitigated disaster," said Peter F. Thall, PhD, a biostatistician at MD Anderson Cancer Center in Houston, who designs clinical trials for cancer research.

Thall said companies rush through critical steps such as dose-finding and treatment scheduling refinement that could hone how drugs might be used most effectively before leaving clinical trials. That means researchers could have truly effective treatments that seem overly toxic or on the other hand lack efficacy.

The system creates a veneer of innovation that hides a deeper problem, Thall and other critics of this change in emphasis say.

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 peoples' lives.

"We've spent billions of dollars on trials that should have never been done in the first place," Thall said.

While that is true, the way forward is still unclear.

"In the future every cancer will be a rare cancer, and that means we need to be able to look for signals. But that does not mean we should forgo follow-up -- that can't just drop off," said Len Lichtenfeld, MD, deputy chief medical officer of the American Cancer Society, in a phone interview. "We have to keep drug companies honest so we know what happens to people. At the same time, we can't go back in time to the way we used to do clinical trials."

And yet, 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, MD, 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."

Saltz said statistical analyses that 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."

Moving Target

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, physical functioning, and other tumor-related symptoms.

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 MedPage Today/Journal Sentinel examination found.

To ascertain how much postmarketing research was being done, the MedPage Today/Journal Sentinel limited this analysis to 26 drugs approved using surrogate endpoints. The approvals occurred from 2004 though 2011, which would allow 2 years for follow-up. Fourteen drugs approved more recently were excluded from the analysis.

Only three of those 26 drugs approved in the period examined have been proven to increase survival for the use they were originally authorized. Azacitidine (Vidaza) increased survival 10 months; Sunitinib malate (Sutent) by 8 weeks and ruxolitinib (Jakafi) increased the 3-year survival rate to 70% from 61% compared with those who got a placebo.

Panitumumab (Vectibix) subsequently was linked to slightly shorter survival.

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 MedPage Today/Journal Sentinel analysis found that extra time often is short-lived -- sometimes a matter of months or weeks and, in one case, days.

In 2007, Congress authorized the FDA to require follow-up safety trials along with the authority to levy fines of up to $10 million on pharmaceutical companies that failed to conduct those studies.

Two years after the law passed, the FDA had sent 74 letters to pharmaceutical companies requiring follow-up studies for a variety of drugs, not just cancer. However, the FDA has never imposed any fines, Yao said.

Rather, she said, some companies voluntarily withdrew certain uses rather than conduct trials.

In the case of axitinib, 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 axitinib and those in a control group, who were being treated by another drug.

The paper, funded by Pfizer, concluded that because the axitinib patients had an additional 2 months of progression-free survival that was proof of both a quality-of-life and survival benefit.

However, the trial was open label, which is an approach the FDA considers open to bias.

Pfizer spokeswoman Sally Beatty said axitinib was approved on the same basis as other drugs approved to treat the disease -- the length of time their cancer did not progress.

"Inlyta is an important option for patients who face this devastating and rare cancer," she said.

Hope Is a Powerful Motive

The devastation that Beatty's describes often drives patients -- and their families -- to seek new drugs and to press the FDA to make those new drugs available even though their apparent benefits may be fleeting.

In 2011, for example, the FDA approved crizotinib (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 crizotinib was approved based on a surrogate known as objective response rate, a measure of how tumors respond to the drug.

In a later study, the drug was also show to improve progression-free survival by 4.7 months compared with 3 month PFS with standard chemotherapy.

But an interim analysis showed there were slightly more deaths among patients taking crizotinib -- median of 20.3 months overall survival versus 22.8 months for controls (HR 1.02; 0.68, 1.54, 95% CI P=0.54).

The analysis was 40% complete at that time. And it was complicated by the design of the study, which allowed chemo patients to cross over to crizotinib 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 a final analysis answering the overall survival issue will be completed.

The Patient

Kathy Stigler, a Stage 4 lung cancer patient from Hartford, who started taking crizotinib 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 3 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, 6 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 3 months."

Stigler's doctor, Bruce Gershenhorn, DO, of the Cancer Treatment Centers of America in Zion, Ill., said crizotinib 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.

The Payoff

Pharmaceutical companies point to research and development costs in the millions, but that investment can deliver a big payoff if that R & D results in a drug that wins FDA marketing approval. Once on the market, drug companies have charged an average of $10,000 a month for the 54 drugs examined in this report, with three costing more than $20,000 a month and one priced at $40,000 a month.

Of those four most expensive drugs, the $40,000 drug has a proven survival benefit -- extending life by 4 months -- and the other three were approved based on surrogates, the MedPage Today/Journal Sentinel analysis found.

Spending on all oncology drugs hit $28 billion in 2013, an increase of 9.2% over the previous year, according data from 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, DO, 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 abiraterone (Zytiga), made by Johnson and Johnson, was approved in 2011 to treat metastatic prostate cancer by showing increased survival of 4 months.

The drug has become popular among urologists and grabbed a bigger share -- 23% -- of the market, according to a Wells Fargo analyst reported issued in August.

Abiraterone, which costs $5,400 a month, has projected 2014 sales of $964 million in the U.S. and $2.3 billion worldwide.

When Push Comes to Shove

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 trametinib (Mekinist) to treat metastatic melanoma in patients who had certain genetic mutations.

The drug was approved because it increased progression-free survival by 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 into the group getting trametinib.

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 nilotinib (Tasigna), the FDA asked Novartis to follow a group of chronic leukemia patients on their experimental drug for 12 months. Novartis only followed patients for 6.

Larger trials generally 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 little over 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 that the company reported three such sudden deaths to the FDA, which resulted in black box warnings for nilotinib.

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 are no data that nilotinib provided a survival benefit.

In her email, Yao, the FDA spokesperson, said the FDA 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."

It Began in Congress

The current 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 close to $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 the decision 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 basic safety 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 -- the number and speed of application decisions. Annual FDA performance evaluations reviewed by the MedPage Today/Journal Sentinel 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.

But Is It Real?

"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, MD, MS, 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."

The Slippery Slope project is a 4 part series. Read about how we did it or search through 54 cancer drugs approved by the FDA in the last decade.