Chicago/London: In 2006 when doctors started testing a melanoma treatment made by Roche Holding AG on patients, they were used to facing slim odds - about one in eight - that the tumors would shrink on chemotherapy. This time, they couldn't believe their eyes.
With Zelboraf, a drug that targets specific mutations in cancer cells, eight out of 10 patients in an early-stage trial experienced significant tumor shrinkage. Roche clearly had a remarkable drug, though it only worked for people with a specific genetic makeup.
Research like the Zelboraf tests, that fine-tune treatments to the genetic profile of patients, is fuelling a rethink over how new cancer drugs are tested. The promise: medicines that, in theory at least, can win approval more easily and cheaply.
That also raises ethical questions. If you know a certain treatment is genetically bound to work much better on some people than on others, is it right to conduct randomized trials to see which works best? Zelboraf led some doctors to question whether to go ahead with the trials they had planned, trials that would pit Zelboraf against the standard treatment, a chemotherapy developed in 1975 called dacarbazine.
Some doctors believed that would risk patients' lives unnecessarily. US Food and Drug Administration cancer drug czar Dr. Richard Pazdur pushed for changes to shorten the trial. Others, such as Dr. Patrick Hwu of MD Anderson Cancer Center in Texas, refused to participate in a study that seemed bound to disadvantage some patients.
Ultimately, the trial proceeded and the drug won US approval in 2011. But experts say the controversy over Zelboraf broke the mould, potentially pointing the way to lower-cost drug development.
At least one company has already indicated it will cut prices. Earlier this year, GlaxoSmithKline Plc won approval from the US Food and Drug Administration for Tafinlar, a drug targeting the same mutant genes as Zelboraf, based on a single clinical trial of just 250 patients. It said the drug would cost $7,600 a month, 30 percent less than Zelboraf.
Whether others follow suit in cutting prices will depend on a host of issues, perhaps the biggest of which is the vast difference in the way the United States and Europe regulate drugs.
Pressure is mounting. A new and highly promising class of immunotherapy drugs - which some analysts see as a potential $35 billion a year market - may force companies' hands.
These therapies will come to market just as more people are asking if health insurers and governments will keep paying sky-high prices.
Dr. Alexander Eggermont, chief executive of Institut Gustave-Roussy, France's largest cancer center, was one of those who held a hard line on Zelboraf testing, insisting on a randomized trial.
But Eggermont now says the standard of proof has changed and he believes immunotherapy - which he calls the "biggest game changer we have ever seen" - will cement the new approach to testing.
"We won't have to do those dinosaur trials," he said.
"It will change the whole attitude in drug development."
Randomized controlled trials - where some patients are given the treatment that is being tested and others get a "control" substance for comparison - became known as the gold standard of drug testing because they were the most effective way of seeing if a drug worked.
But for patients whose cancers are driven by specific genetic mutations, some argue that randomized approach could become obsolete.
"The types of drugs that we're seeing now are different. They are just simply better in terms of efficacy," says Pazdur, the FDA expert who wanted to shorten the Zelboraf trial.
The new drugs are born out of a better understanding of the molecular changes that fuel cancer growth.
For example, an estimated 50 to 60 percent of melanoma patients have a specific genetic mutation.
Zelboraf and Tafinlar target these people. By testing such treatments only on people with a specific mutation, researchers can work out more quickly, and with fewer patients, if a treatment is effective.
Zelboraf represented a watershed in treating melanoma, a notoriously deadly cancer, although it is not a cure: Most patients eventually develop resistance to the drug.
The Zelboraf trial fuelled support for a new "breakthrough therapy" regulatory pathway that was signed into US law last year.
It could shave years off the traditional drug approval process.
To qualify, a drug must show remarkable clinical activity in early stages of testing. The FDA's Pazdur, who has spent the past 14 years overseeing cancer drug approvals, calls them "knock-your-socks-off" treatments.
He says the FDA has already become more flexible in the kinds of evidence it will accept to speed new cancer drugs to patients.
For example, Stivarga is a pill from Bayer AG for some advanced gastrointestinal tumors. It was approved in February; just three years after the first patient with the condition received it in clinical tests.
That's nearly twice as fast as Zelboraf. "That was like a land-speed record," says Dr. George Demetri of the Dana Farber Cancer Institute in Boston, who worked to develop the medicine.
The drug was reviewed under another FDA scheme called the priority review program, which provides an expedited six-month process.
The step-change in the pace of cancer drug development has helped drive a recent improvement in overall pharmaceutical industry productivity.
New cancer medicines are the main driver of a pick-up in the number of products coming to market.
Since the start of 2012, one third of the 54 drugs approved by the FDA across all diseases areas have been for cancer.
But despite the faster approval times, the impact on drug prices so far has been limited. Clinical trials are the biggest single cost in drug company R&D, accounting for 36 percent of total research expenditure in 2012, according to Thomson Reuters CMR International.
Drug makers traditionally argue that it is only by ploughing an average of a $1 billion-plus into each new medicine that treatments can be improved.
"The costs should be coming down tremendously," said Paul Workman, head of drug discovery at Britain's Institute of Cancer Research. "What's disappointing is that we haven't seen it happen yet.
We are in a fascinating but frustrating period of transition." Don Light, a Harvard professor who is a long-time critic of the drugs industry, is blunt. He says companies are deliberately clinging to the notion of huge research costs despite the advantages of smaller trials in cancer.
"Claimed high costs are like bragging rights - the higher companies say they are, the more they create the impression of heroism and financial suffering," Light says.
Still, not everyone in the industry is toeing the line. GSK Chief Executive Andrew Witty startled a number of his peers earlier this year by telling a British National Health Service conference that the $1 billion price tag was "one of the great myths of the industry."
Since the figure includes the cost of failures, any drug company that can improve its success rate should be able to charge less for new medicines.
"For the first time in my career, pricing is becoming a really interesting piece of the dynamic," Witty said in an interview.