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By Julie Steenhuysen and Ben Hirschler
CHICAGO/LONDON, Sept 26 (Reuters) - In 2006 when doctorsstarted testing a melanoma treatment made by Roche Holding AG onpatients, they were used to facing slim odds - about one ineight - that the tumors would shrink on chemotherapy. This time,they couldn't believe their eyes.
With Zelboraf, a drug that targets specific mutations incancer cells, eight out of 10 patients in an early-stage trialexperienced significant tumor shrinkage. Roche clearly had aremarkable drug, though it only worked for people with aspecific genetic makeup.
Research like the Zelboraf tests, that fine-tune treatmentsto the genetic profile of patients, is fuelling a rethink overhow new cancer drugs are tested. The promise: medicines that, intheory at least, can win approval more easily and cheaply.
That also raises ethical questions. If you know a certaintreatment is genetically bound to work much better on somepeople than on others, is it right to conduct randomized trialsto see which works best? Zelboraf led some doctors to questionwhether to go ahead with the trials they had planned, trialsthat would pit Zelboraf against the standard treatment, achemotherapy developed in 1975 called dacarbazine.
Some doctors believed that would risk patients' livesunnecessarily. U.S. Food and Drug Administration cancer drugczar Dr. Richard Pazdur pushed for changes to shorten the trial.Others, such as Dr. Patrick Hwu of MD Anderson Cancer Center inTexas, refused to participate in a study that seemed bound todisadvantage some patients.
Ultimately, the trial proceeded and the drug won U.S.approval in 2011. But experts say the controversy overZelboraf broke the mould, potentially pointing the way tolower-cost drug development.
At least one company has already indicated it will cutprices. Earlier this year, GlaxoSmithKline Plc won approval fromthe U.S. Food and Drug Administration for Tafinlar, a drugtargeting the same mutant genes as Zelboraf, based on a singleclinical 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 ona host of issues, perhaps the biggest of which is the vastdifference in the way the United States and Europe regulatedrugs.
Pressure is mounting. A new and highly promising class ofimmunotherapy drugs - which some analysts see as a potential $35billion a year market - may force companies' hands. Thesetherapies will come to market just as more people are asking ifhealth insurers and governments will keep paying sky-highprices.
Dr. Alexander Eggermont, chief executive of InstitutGustave-Roussy, France's largest cancer center, was one of thosewho held a hard line on Zelboraf testing, insisting on arandomized trial. But Eggermont now says the standard of proofhas changed and he believes immunotherapies - which he calls the"biggest game changer we have ever seen" - will cement the newapproach to testing.
"We won't have to do those dinosaur trials," he said. "Itwill change the whole attitude in drug development."
BETTER SCIENCE
Randomized controlled trials - where some patients are giventhe treatment that is being tested and others get a "control"substance for comparison - became known as the gold standard ofdrug testing because they were the most effective way of seeingif a drug worked. But for patients whose cancers are driven byspecific genetic mutations, some argue that randomized approachcould 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 themolecular changes that fuel cancer growth. For example, anestimated 50 to 60 percent of melanoma patients have a specificgenetic mutation. Zelboraf and Tafinlar target these people. Bytesting 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, anotoriously deadly cancer, although it is not a cure: Mostpatients eventually develop resistance to the drug. The Zelboraftrial fuelled support for a new "breakthrough therapy"regulatory pathway that was signed into U.S. law last year. Itcould shave years off the traditional drug approval process.
To qualify, a drug must show remarkable clinical activity inearly stages of testing. The FDA's Pazdur, who has spent thepast 14 years overseeing cancer drug approvals, calls them"knock-your-socks-off" treatments.
He says the FDA has already become more flexible in thekinds of evidence it will accept to speed new cancer drugs topatients.
For example, Stivarga is a pill from Bayer AG for someadvanced gastrointestinal tumors. It was approved in February,just three years after the first patient with the conditionreceived it in clinical tests. That's nearly twice as fast asZelboraf. "That was like a land-speed record," says Dr. GeorgeDemetri of the Dana Farber Cancer Institute in Boston, whoworked to develop the medicine.
The drug was reviewed under another FDA scheme called thepriority review program, which provides an expedited six-monthprocess.
The step-change in the pace of cancer drug development hashelped drive a recent improvement in overall pharmaceuticalindustry productivity. New cancer medicines are the main driverof a pick-up in the number of products coming to market. Sincethe start of 2012, one third of the 54 drugs approved by the FDAacross all diseases areas have been for cancer.
PRICING BACKLASH
But despite the faster approval times, the impact on drugprices so far has been limited.
Clinical trials are the biggest single cost in drug companyR&D, accounting for 36 percent of total research expenditure in2012, according to Thomson Reuters CMR International. Drugmakerstraditionally argue that it is only by ploughing an average of a$1 billion-plus into each new medicine that treatments can beimproved.
"The costs should be coming down tremendously," said PaulWorkman, head of drug discovery at Britain's Institute of CancerResearch. "What's disappointing is that we haven't seen ithappen yet. We are in a fascinating but frustrating period oftransition."
Don Light, a Harvard professor who is a long-time critic ofthe drugs industry, is more blunt. He says companies aredeliberately clinging to the notion of huge research costsdespite the advantages of smaller trials in cancer.
"Claimed high costs are like bragging rights - the highercompanies say they are, the more they create the impression ofheroism and financial suffering," Light says.
Still, not everyone in the industry is toeing the line. GSKChief Executive Andrew Witty startled a number of his peersearlier this year by telling a British National Health Serviceconference that the $1 billion price tag was "one of the greatmyths of the industry." Since the figure includes the cost offailures, any drug company that can improve its success rateshould be able to charge less for new medicines.
"For the first time in my career, pricing is becoming areally interesting piece of the dynamic," Witty said in aninterview. "If you believe you have a sustainable model that canchurn out more product than anybody else, why wouldn't you dothis?"
That could be particularly important as drug companies beginto combine treatments in hopes of achieving longer-lastingbenefits. GSK, for instance, has a second melanoma drug calledMekinist that it plans to combine with Tafinlar. Both arecheaper than existing drugs, though combined, of course, theywill still cost many thousands of dollars a year.
Doctors are getting restive. In April, more than 100leukemia specialists from around the world took the unusual stepof complaining publicly in the American Society of Hematology'sjournal Blood that cancer drug prices were "too high,unsustainable, may compromise access of needy patients to highlyeffective therapy, and are harmful to the sustainability of ournational healthcare systems."
With 11 of the 12 cancer drugs launched in the United Stateslast year costing more than $100,000 a year per patient,according to the paper, the debate is not going away.
UNITED STATES VS. EUROPE
But faster trials in the United States won't alwaystranslate into cheaper drug development for companies that dobusiness globally, in part because European authorities may notbe willing to accept products based on the FDA's more flexibleclinical trial standards.
Dr. Eric Rubin, head of oncology clinical development atMerck & Co Inc., said the FDA's willingness to allow acceleratedapproval based upon single-arm studies - without the traditionalcontrol group - is "a big step forward, but it's not universallyagreed upon," especially in Europe.
Part of the issue is not with drug safety regulators butwith government funding agencies, such as the National Institutefor Health and Clinical Excellence, or NICE, Britain's healthcost watchdog. It decides whether the state-run health systemwill pay for a new treatment or drug. It often knocks backexpensive drugs as not cost-effective.
"In Europe, it's a different world because you can get adrug approved by the European regulatory agencies - but if thegovernments won't approve funding for it, people can't accessit," Demetri said.
As a result, companies may be forced to into longer, largertrials just to satisfy cost regulators.
"POSITIVE RESULTS"
It's a problem that Merck and other companies developing newimmunotherapy drugs will have to solve. The drugs, includingMerck's MK-3475 and Bristol-Myers' nivolumab, help the immunesystem fight cancer cells by disabling a protein called"programmed death 1" or PD-1 that acts as a brake on the body'sability to detect them.
Andrew Baum, an analyst at Citi, estimates treatments thatcoax the immune system to target cancer will become the backbonetherapy for up to 60 percent of cancers over the next decade,generating $35 billion in annual sales.
Dr. Antoni Ribas at the University of California, LosAngeles says the immunotherapies are showing so much promisethat they, like Zelboraf, raise doubts over whether randomizedtrials are needed. He believes they could be approved in theUnited States on the basis of a single-arm trial. Yet Merck hasstarted enrolling patients in a study where patients will berandomized to get the new treatment or existing chemotherapy.
One patient who has already put himself forward for MK-3475is Stew Scannell, 65, head of operations at global defensecompany Northrop Grumman in Oklahoma City. Scannell, who serveda couple of tours in Vietnam and spent several years in variousdeserts testing helicopters, figures his melanoma may be theresult of cumulative sun damage.
When his doctors were talking about buying him anothercouple of months, he decided to do his own research. He startedMK-3475 shortly after his first meeting with Ribas, in April2012.
Several of his tumors have disappeared. At his last scan inApril, there was no sign of any tumor in his brain. In Merck'strial, the most common side effects of the drug include fatigue,fevers, skin rash, loss of skin color and muscle weakness. Butso far, Scannell has had none. "I really haven't missed a step.I've continued working. The radiation was difficult. But themarvelous thing about the immunotherapy is no side effects. Nolethargy. No loss of appetite. No anything."
South African melanoma patient Christina Chrysostomou, 45,would be more than happy to see the end of randomized trialswhen a treatment has shown early promise.
After her cancer got worse on Bristol-Myers' immunotherapyYervoy, she and her husband and 8-year-old son headed for theUnited States in the hopes of trying one of the new anti-PD-1drugs.
But when she arrived in late June, Merck's Phase I trial hadclosed, and she was told she would have to take her chances in arandomized test. Luckily for her, a spot opened up in anon-randomized Phase I study and she is now getting MK-3475 -but she feels for others less fortunate.
"It's really hard knowing there is something out there thatcould possibly help and having to go through a gamble and maybenot even get that," she said.
