| CHICAGO/LONDON, Sept 26
CHICAGO/LONDON, Sept 26 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. U.S. 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 U.S.
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 U.S. 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
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
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 immunotherapies - 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 U.S. 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
He says the FDA has already become more flexible in the
kinds of evidence it will accept to speed new cancer drugs to
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
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. Drugmakers
traditionally argue that it is only by ploughing an average of a
$1 billion-plus into each new medicine that treatments can be
"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
Don Light, a Harvard professor who is a long-time critic of
the drugs industry, is more 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. "If you believe you have a sustainable model that can
churn out more product than anybody else, why wouldn't you do
That could be particularly important as drug companies begin
to combine treatments in hopes of achieving longer-lasting
benefits. GSK, for instance, has a second melanoma drug called
Mekinist that it plans to combine with Tafinlar. Both are
cheaper than existing drugs, though combined, of course, they
will still cost many thousands of dollars a year.
Doctors are getting restive. In April, more than 100
leukemia specialists from around the world took the unusual step
of complaining publicly in the American Society of Hematology's
journal Blood that cancer drug prices were "too high,
unsustainable, may compromise access of needy patients to highly
effective therapy, and are harmful to the sustainability of our
national healthcare systems."
With 11 of the 12 cancer drugs launched in the United States
last 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 always
translate into cheaper drug development for companies that do
business globally, in part because European authorities may not
be willing to accept products based on the FDA's more flexible
clinical trial standards.
Dr. Eric Rubin, head of oncology clinical development at
Merck & Co Inc., said the FDA's willingness to allow accelerated
approval based upon single-arm studies - without the traditional
control group - is "a big step forward, but it's not universally
agreed upon," especially in Europe.
Part of the issue is not with drug safety regulators but
with government funding agencies, such as the National Institute
for Health and Clinical Excellence, or NICE, Britain's health
cost watchdog. It decides whether the state-run health system
will pay for a new treatment or drug. It often knocks back
expensive drugs as not cost-effective.
"In Europe, it's a different world because you can get a
drug approved by the European regulatory agencies - but if the
governments won't approve funding for it, people can't access
it," Demetri said.
As a result, companies may be forced to into longer, larger
trials just to satisfy cost regulators.
It's a problem that Merck and other companies developing new
immunotherapy drugs will have to solve. The drugs, including
Merck's lambrolizumab and Bristol-Myers' nivolumab, help the
immune system fight cancer cells by disabling a protein called
"programmed death 1" or PD-1 that acts as a brake on the body's
ability to detect them.
Andrew Baum, an analyst at Citi, estimates treatments that
coax the immune system to target cancer will become the backbone
therapy 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, Los
Angeles says the immunotherapies are showing so much promise
that they, like Zelboraf, raise doubts over whether randomized
trials are needed. He believes they could be approved in the
United States on the basis of a single-arm trial. Yet Merck has
started enrolling patients in a study where patients will be
randomized to get the new treatment or existing chemotherapy.
One patient who has already put himself forward for
lambrolizumab is Stew Scannell, 65, head of operations at global
defense company Northrop Grumman in Oklahoma City. Scannell, who
served a couple of tours in Vietnam and spent several years in
various deserts testing helicopters, figures his melanoma may be
the result of cumulative sun damage.
When his doctors were talking about buying him another
couple of months, he decided to do his own research. He started
lambrolizumab shortly after his first meeting with Ribas, in
Several of his tumors have disappeared. At his last scan in
April, there was no sign of any tumor in his brain. In Merck's
trial, the most common side effects of the drug include fatigue,
fevers, skin rash, loss of skin color and muscle weakness. But
so far, Scannell has had none. "I really haven't missed a step.
I've continued working. The radiation was difficult. But the
marvelous thing about the immunotherapy is no side effects. No
lethargy. No loss of appetite. No anything."
South African melanoma patient Christina Chrysostomou, 45,
would be more than happy to see the end of randomized trials
when a treatment has shown early promise.
After her cancer got worse on Bristol-Myers' immunotherapy
Yervoy, she and her husband and 8-year-old son headed for the
United States in the hopes of trying one of the new anti-PD-1
But when she arrived in late June, Merck's Phase I trial had
closed, and she was told she would have to take her chances in a
randomized test. Luckily for her, a spot opened up in a
non-randomized Phase I study and she is now getting
lambrolizumab - but she feels for others less fortunate.
"It's really hard knowing there is something out there that
could possibly help and having to go through a gamble and maybe
not even get that," she said.