X-rays May Not Accurately Assess Cancer; Drug Approvals Way Down

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December 21, 2005

New Drug Points Up Problems in Developing Cancer Cures

By GARDINER HARRIS

WASHINGTON, Dec. 20 - Despite promising discoveries and multibillion-

dollar investments, cancer research is quietly undergoing a crisis.

Federal drug regulators will soon announce several initiatives that

they hope will help salvage the field.

Few drugs are being marketed, and most of those that have been

introduced are enormously expensive and provide few of the benefits

that patients expect. Officials of the Food and Drug Administration

suggest that the failures may result from an obsolete testing system.

There is growing evidence that X-rays, long the standard, may not

accurately assess a patient's disease. The drug agency is creating

collaborations to develop imaging, blood and other tests that better

signal the progression of cancer.

" We need to develop cancer drugs differently, " the chief operating

officer of the agency, Dr. Janet Woodcock, said in an interview. " The

tools we have to develop these treatments are not what we need in

cancer. "

On Tuesday, the agency approved Nexavar, a drug that officials

described as " a major advance " in treating kidney cancer.

That action demonstrates the global confusion surrounding cancer. The

manufacturer of Nexavar, Bayer, used X-rays to determine that the

drug doubled the time, to 167 days from 84, before tumors grew

substantially in number or size, a finding called " progression-free

survival. "

Officials of the drug agency found the findings so compelling that

they urged Bayer to stop the trial early and give Nexavar to subjects

who had been taking placebos.

European regulators, on the other hand, wanted the trial to continue

because they wanted Bayer to prove that Nexavar actually extended

lives, a finding that would have taken many more months to establish,

a deputy commissioner of the drug agency, Dr. Gottlieb, said

Tuesday in an interview.

" Nexavar is a good example of how we have developed better science

around the development process itself that not only enables these

drugs to come to market but to come to market more quickly, " Dr.

Gottlieb said.

Much work remains to be done, he said, adding: " The crux of the

crisis in oncology is that for years we have developed tremendous

scientific advances in looking at how cancer develops, and that's not

being translated into practical solutions that are benefiting

patients at the pace you would expect. Look at what the government

and all the drug companies are spending, and yet drugs are not

reaching the market. "

Groups of cancer patients say they, too, want better ways to measure

success against cancer.

" That doesn't mean we want drugs pushed through faster, " the

president of the National Breast Cancer Coalition, Frances M. Visco,

said. " It means we want better science, meaningful endpoints and

drugs that have less toxicity and actually prolong survival. "

There have been successes in oncology besides Nexavar, of course.

Platinum-based drugs have mostly ended deaths from testicular cancer.

Tamoxifen and Herceptin have saved thousands of women from breast

cancer. And early screening has helped push down death rates.

Researchers are not alone in their failures. Drug makers are in the

midst of a dry spell that threatens the foundations of the industry.

After peaking in 1996 at 53, the number of new drug approvals has

steadily declined. This year, it is unlikely to exceed 17.

Although every field has suffered, cancer has had the greatest chasm

between hope and reality. One in 20 prospective cancer cures used in

human tests reaches the market, the worst record of any medical

category. Among those that gained approval in the last 20 years,

fewer than one in five have been shown to extend lives, life

extensions usually measured in weeks or months, not years.

True cancer cures are still exceptionally rare. Medicines have been

approved for colorectal cancer. Patients who take every one of the

high-tech drugs has to spend, on average, $250,000, suffer serious

side effects and gain, on average, months of life, according to

studies.

Drug companies have been promising for years that gene-hunting

techniques would yield targeted nontoxic therapies that melt cancer,

but few cancer medicines fit that profile.

" There are all these myths having to do with cancer drugs, " Dr.

Hirschfeld, an F.D.A. medical officer with expertise in

cancer, said. " That they're very targeted, when in fact all these

drugs have multiple targets. That they're nontoxic, when in fact the

latest ones have their own set of side effects. And that they're

cures, when they are not. "

Nexavar, for instance, seems to affect a variety of crucial molecules

involved in powering cancer cells, but its real effects are

uncertain. It can cause rashes, diarrhea and increases in blood

pressure, although drug agency officials said it was far less toxic

than previous therapies.

The disappointing track record in cancer has mostly resulted, of

course, because it is not one disease, but hundreds, whose

progression is governed by a dizzying array of genetic and

environmental factors that are just beginning to be understood.

Drug agency officials are increasingly concerned that failures with

cancer may result because the science of human testing, called drug

development, has not advanced as rapidly as the understanding of the

biology of cancer. " My concern is that these novel drugs being

discovered will bump up against an aging development process that

can't adapt as quickly, " Dr. Gottlieb said.

The agency will soon release a report that lists more than 12

research areas that it will address to try to improve clinical

trials. Among the efforts is a search for new ways to measure cancer

progression.

For decades, X-rays have been the principal means for researchers to

judge whether a cancer drug works. If tumors appear to shrink or stop

growing after therapy, the drug is thought to be working.

There is growing evidence that tumor size may not matter much. Small

tumors can sometimes be as deadly as large tumors. That discovery has

unmoored drug development. Researchers could track which patients

live or die. But trials that measure life expectancy often take years

and tens of millions of dollars to complete. Researchers and

companies would dearly love an interim measure akin to cholesterol or

blood pressure readings.

The anxiety over measuring success in trials has led drug regulators

around the world to try to provide guidance to companies. By

coincidence, the Food and Drug Administration and drug regulators in

Europe and Japan all released papers over the summer on cancer drug

measurements.

" But I think it's more instructive what these documents didn't say, "

Dr. Hirschfeld said.

None endorsed any one measurement, he noted.

For Nexavar, the drug agency accepted X-ray measures because the

changes were so dramatic, said Dr. Pazdur, director of the

oncology office.

The agency also encourages tests of new imaging equipment. Officials

are hopeful about research into positron emission tomography, or PET

scans. The scans show not only a tumor's size, but also its vigor.

The drug agency is also setting up collaborations with the National

Cancer Institute, the Centers for Medicaid and Medicare Services, and

other groups to pursue other technologies, blood tests and genetic

screens.

In the end, though, the search for new ways to measure cancer may not

be successful, said Dr. S. Ellenberg, the associate dean for

clinical research at the University of Pennsylvania School of

Medicine, who spent much of her career at the drug agency and the

cancer institute.

Dr. Woodcock said success was vital.

" The science is at a point where we shouldn't let this opportunity

escape us, " she said. " There are ways to figure this out, and it's

not like I'm some wild-eyed idealist. I'm the F.D.A., for heaven's

sake. This is going to happen. "