FDA curbs the development of some experimental cancer drugs

From The New York Times:

Politicians and researchers have predicted for nearly four decades that a cure for cancer is near, but cancer death rates have hardly budged and most new cancer drugs cost a fortune while giving patients few, if any, added weeks of life. For this collective failure, the man atop the nation’s regulatory agency for new cancer drugs increasingly — and supporters say unfairly — gets the blame: Dr. Richard Pazdur (pictured).

Patient advocates have called Dr. Pazdur, director of the Food and Drug Administration’s cancer drug office, a murderer, conservative pundits have vilified him as an obstructionist bureaucrat, and guards are now posted at the agency’s public cancer advisory meetings to protect him and other committee members.

“The industry is not producing that many good drugs, so now they’re looking for scapegoats in Rick Pazdur and the F.D.A.,” said Ira S. Loss, who follows the drug industry for Washington Analysis, a service for investors.

In 10 years at the Food and Drug Administration, Dr. Pazdur, 57, has helped to loosen approval standards for cancer medicines and made it easier for dying patients to get experimental drugs. But he demands that drug makers prove with near certainty that their products are beneficial, a requirement that he repeated at a public advisory hearing on Sept. 1 in the slow, loud tones of someone disciplining a dog. After he spoke, the committee of experts voted to reject both drugs.

Critics say that Dr. Pazdur’s resolve has cost thousands of lives and set back the pace of discoveries.

“Patients are right to be angry and frustrated with Richard Pazdur,” said Steven Walker, co-founder of the Abigail Alliance, a patient advocacy group. “He is a dinosaur.”

But neither the controversies swirling about him nor his years as an oncologist treating terminal patients have dented Dr. Pazdur’s naturally sunny disposition. He laughs like Charles Nelson Reilly, eats like Gandhi and likens his tenure at the drug administration to that of a Roman Catholic priest from the 1960s who had to translate the Latin liturgy into plain language.

“You can’t win in this job,” Dr. Pazdur said in an interview in his office. “If you approve a drug, they accuse you of lowering standards. And if you don’t approve it, you’re the worst thing since the Nazi death camps and should be killed.”

Whether Dr. Pazdur has struck the right balance between hope and certainty has enormous consequences for patients and industry. Cancer is the second-leading cause of death in the United States; more than 562,000 people are expected to die of it this year.

Pharmaceutical and biotechnology companies are testing more than 860 new cancer medicines — more than in any other disease category, according to manufacturers. Because patients are desperate and insurers are often forced by law to pay, prices are soaring, making cancer medicines among the best ways for drug makers to make money. But cancer has proven difficult to crack, leading to frustration among executives and advocates who wonder why the Food and Drug Administration is not approving more drugs.

No cancer medicines can be sold to or even tested on people without the imprimatur of Dr. Pazdur and his staff of about 150 oncologists, toxicologists and other specialists. But pressure from advocacy groups and cancer researchers frustrated with failure have led the agency to abandon many of the usual approval requirements.

Federal law requires that the agency demand two “well controlled” trials before approving a drug; in cancer, the Food and Drug Administration is often satisfied with just one. With many experimental drugs, the agency demands trials with thousands of patients, while for cancer, it has accepted studies with a few dozen.

Before Dr. Pazdur’s arrival, the agency largely insisted that drug makers prove that their products extended life. Companies did this by giving the drug to one group of patients, providing a placebo or an older drug to another group and then seeing which group lived longer. But some cancers take a long time to kill, making survival trials lengthy and expensive.

So the drug administration under Dr. Pazdur’s leadership increasingly allowed some studies to track a drug’s effect with X-rays. If scans showed that tumors grew less rapidly, the drug could be approved.

Dr. Pazdur pressed for the changes because, he said, the growing number of approved cancer medicines made determining whether any one delayed death increasingly difficult. Many patients now cycle through several medicines before dying. And some drugs that have not been proven to extend life may delay more serious symptoms and medical interventions, he said.

For instance, the drug administration initially rejected oxaliplatin because no trial at the time proved that it delayed death. But the agency finally relented in 2002 — years after the drug’s approval in Europe — because scans showed that it postponed tumor growth. Oxaliplatin is now commonly used to combat colorectal cancer.

Criticizing Changes

Some patient advocates — mostly from older, more established organizations — bemoan these changes because even if a drug shrinks tumors, it may do nothing to delay death or improve patients’ last days. And because so many cancer medicines have toxic side effects and high prices, drugs that have no proven benefit may actually be harmful to patients’ health and economic well-being.

These advocates point to mistakes like toxic chemotherapy with bone marrow transplants in breast cancer, which in the 1980s and 1990s increased the suffering of nearly 30,000 women before studies finally showed that it was ineffective. When in doubt, the drug administration should not approve, they say.

“We want drugs that prolong survival, not drugs that just improve a test result,” said Frances M. Visco, president of the National Breast Cancer Coalition.

To others — mostly newer, more aggressive patient organizations — the F.D.A.’s cancer group under Dr. Pazdur’s leadership has not lowered standards or sped approvals nearly enough. If there is any hint that a drug works, dying patients — many of whom have run out of other options — should be allowed to buy them, they said.

And some cancer specialists say that Dr. Pazdur, after pushing for years to lower approval standards, has toughened them recently after being criticized for approving drugs that were later shown to have few benefits.

“I’m worried there’s been a change in his thinking that could be adverse for the field,” said Dr. Bruce A. Chabner, clinical director of the Massachusetts General Hospital Cancer Center and a member of the board of directors of PharmaMar, a Spanish biotech company whose drug Yondelis is approved in Europe but was rejected in July by the F.D.A.’s cancer advisory board after a critical introduction by Dr. Pazdur.

Little of this controversy surrounding Dr. Pazdur affects the development of truly powerful medicines. In 2001, his agency took just 11 weeks to approve Gleevec, which has miraculous effects on a form of leukemia. But when drugs have marginal benefits, figuring out whether they work is controversial and time consuming.

Taking a Drug to the F.D.A.

Many of the recent rejects have come from small biotechnology companies for which a single F.D.A. approval can be the difference between fiscal calamity and vast profits. On Sept. 1, tiny Vion Pharmaceuticals took its leukemia drug Onrigin to a Food and Drug Administration advisory committee for consideration.

One clinical trial found that Onrigin increased deaths threefold compared with a placebo. The drug administration told the company in meetings in 2004 and 2006 that another trial was so poorly designed that it was unlikely to pass muster. Vion persisted.

During the company’s presentation to the advisory committee, Dr. Pazdur seemed at times visibly pained — grimacing or shaking his head. When patients taken to the meeting by Vion spoke about Onrigin’s benefits, he turned away. (“Only patients who benefit from the drugs are brought to the meetings, not those who are harmed or get nothing,” he explained later.) He reminded the committee, “We only have one randomized trial here which shows an increase in death.”

The committee voted 13 to 0 to require a new study. Vion executives would not comment.

Some small companies seeking approval of a drug have waged public campaigns with the help of investors and advocacy groups that sometimes lead to vicious attacks on Dr. Pazdur. Take the case of Xcytrin, a brain cancer medicine made by Pharmacyclics of Sunnyvale, Calif. After a critical study failed to show that the drug worked, the company’s chief executive at the time, Dr. Richard Miller, blamed doctors at a hospital in France.

“They got a very negative result there, and it really skewed the data,” Dr. Miller said in an interview.

He lobbied top F.D.A. officials to approve the drug anyway. They refused. He became a prominent agency critic, writing four opinion columns in The Wall Street Journal in 2007 arguing that the agency was keeping vital treatments from dying patients.

Dr. Miller did not make public the drug agency’s reasons for rejecting Xcytrin and, because the law prevents the agency from discussing drug rejections, Dr. Pazdur remained mum.

A year ago, Dr. Miller was replaced as chief executive at Pharmacyclics by Robert W. Duggan. In an interview, Mr. Duggan said that the Xcytrin study was flawed and that the drug administration was right to reject the drug.

“It’s not just one hospital mishandling the data — that’s false,” said Mr. Duggan, who described the trial’s results as a “dog’s breakfast” of confusing signals. Biotech executives often blame the drug administration for their own failures so they can continue to raise money from investors, Mr. Duggan said.

Dr. Miller, who is raising money for a new company, responded, “I think Mr. Duggan is making nice to the F.D.A.”

Tony Fiorino, president and chief executive of EnzymeRx, in Paramus, N.J., said that biotech executives were often former scientists who believed so deeply in their products that “it’s an ecstatic experience.” When the drug administration rejects their application, these executives have every incentive, he said, to “go ballistic on the agency.”

“You’re going to pull out all the stops,” Mr. Fiorino said. “This is your one lottery ticket.”

And it is not just executives behind the attacks. Melvin Flores, an oxygen technician from Lowell, Ark., sent several e-mail messages last year to Dr. Pazdur, one of which said, “You’ve murdered enough innocent people already — enough is enough.”

Mr. Flores invested in a company whose cancer medicine did not get approved, pummeling its shares and depriving patients of a lifesaver, he said in an interview. “It’s a Holocaust that has happened,” he said.

Besides singling out Dr. Pazdur’s e-mail box, advocates have put his name on advertisements on city buses in the Washington area, sued him and shouted his name at protests. But Dr. Pazdur said he and his family had endured far worse.

In Perspective

His grandfather, a Polish immigrant, was crushed to death under a railroad car in the Great Depression while sweeping up loose corn kernels to feed his family. With six children, his grandmother remarried, had three more kids and was widowed again several years later when her second husband died in a construction accident.

His mother married her first husband two weeks before he shipped out for World War II; he was killed in the war. Dr. Pazdur’s father, a factory worker for Standard Oil of Indiana, went blind from glaucoma when Dr. Pazdur was a young teenager, impoverishing his family anew.

An avid gym cyclist who is greyhound thin, Dr. Pazdur does not eat meat because he believes that a vegetarian diet will help protect him from cancer, although the supporting evidence is as thin as vegetable broth. His wife, Mary, said that when he travels, she buys herself a nice steak.

Dr. Pazdur became intrigued with the Food and Drug Administration while overseeing drug trials at the University of Texas M. D. Anderson Cancer Center. When the cancer job became available, he applied. On his first day, he was struck by how much the agency resembled the Catholic Church of his childhood.

“We had a door in our old office that was controlled electronically, so someone had to buzz you in,” Dr. Pazdur said. “We had that same door in my grade school separating the convent from the school. It was such a secretive world here.”

He set about changing that by reaching out to cancer advocacy and medical groups. He has held cancer advisory meetings at the annual meeting of the American Society of Clinical Oncology, the world’s largest body of cancer scientists. And he began, in conjunction with others, an annual training program for cancer researchers.

The result is that Dr. Pazdur “has a lot of support within the mainstream cancer community,” said Dr. Otis W. Brawley, chief medical officer of the American Cancer Society. In May, the oncologists’ society gave him a special recognition award for “his outstanding service to the oncology community.”

Dr. Pazdur said that blaming the Food and Drug Administration for the dearth of new cancer medicines was “like blaming the failures of American education on the SAT test.”

“We just do the assessments,” he said.