How Some Patients In New-Drug Trials Can Get Cut Off

By Geeta Anand, the Wall Street Journal

December 8, 2003

PLANO, Texas - Twelve-year-old Thomas Tomeny has an aggressive brain tumor. It grew back after surgery last year and didn't respond to either chemotherapy or radiation. Then, in the spring, Thomas was able to join a tiny test of an experimental radioactive drug -- and his tumor shrank by 33% after the first dose.

But despite the improvement, he was told that he wouldn't be given any more of the drug after his third dose in August. He was approved for only three doses -- a condition made clear on the consent form the Tomenys signed in the spring when they agreed to participate.

"I just want to keep feeling this good," says the lanky, blond boy, who is known as "T.J.," and who hopes to become a professional basketball player when he grows up. T.J.'s father, Trey, adds: "This is the only medical treatment in the world that has helped. We don't understand why he can't get any more."

What happens to patients when a drug trial ends is one of the most ambiguous aspects of medical research. There are no government rules mandating that someone who is doing well on an experimental medicine must keep getting it. Clinical trials -- the tests required by the government before a drug is approved by the Food and Drug Administration for sale -- offer desperately ill patients a chance at potentially lifesaving treatments. Companies need patients willing to try unproven drugs. Yet because of the way these trials are structured, there is no guarantee that a person will continue receiving a new medicine, even if it's helping them.

"It's very much on a case-by-case basis," says Diane Young, vice president of clinical research in oncology at Novartis SA, the developer of OctreoTher, the drug T.J. tested.mber of drugs being tested, and patients participating in clinical trials, has soared in recent decades, powered by stock-market investments in drug companies and revolutionary advances in biology. Last year, the FDA reported receiving 2,374 applications to test drugs in clinical trials, up from 1,596 in 1986. Since each drug usually goes through at least three separate trials, there are tens of thousands of patients in such tests every year.

There are several reasons drug companies may not continue giving patients treatment after a clinical trial ends. One is the cost: even small trials can cost millions and larger ones may run up to $100 million. The majority of drugs tested in clinical trials fail. Many companies make only limited supplies of a new drug, just enough for testing.

From an analytical standpoint, "it's cleaner and easier to write protocols that say 'this is the beginning' and 'this is the end,' " of a trial, says an FDA spokeswoman. Once the trial ends, the government has special programs, she says, that allow patients to go back on the medicine, if the drug maker and doctor agree.

After the trial ends, researchers sometimes have another reason for not allowing patients to continue on the drug. If a person who does well in a trial continues on a medicine and later has a bad side effect, the company is required to report it to the FDA. Companies and researchers worry the FDA could ask questions or even suspend a drug development program if serious concerns about safety arise.

Waiting to get into special programs after clinical trials end can be difficult. In a small trial early this year, Jennifer McNeillie, a 47-year-old geologist with colorectal cancer, was given an experimental cancer drug called Erbitux, being developed by ImClone Systems Inc. and Bristol-Myers Squibb Co. During her first six months on the drug, the tumors, which had spread to her lungs and liver, shrank by more than 60%. After being so sick that she was bedridden, her condition improved enough that she was able to work and ski again.

But in March, a new tumor appeared in her liver, and she was dropped from the study, as required by the rules of the trial. Ms. McNeillie's cancer came back with such furor that fluid filled her stomach and chest and her right lung collapsed. The doctor and Ms. McNeillie's husband, Steve Walker, lobbied the drug companies and the FDA to get back on Erbitux.

They were successful, but it took six weeks. When she started taking the drug again, she felt much better. For a few weeks she was able to get out of bed and even do some gardening. Eventually, the drug stopped working. She died in June.

"If a person is in a clinical trial, contributing a great value to society, there's no reason she shouldn't be allowed to stay on it if she could still receive some benefit," says Mr. Walker, who is an advocate for the Abigail Alliance for Better Access to Developmental Drugs, a two-year-old, nonprofit organization based in Washington. "She might have had more time."

An ImClone official says the design of the trial is typical in the industry; patients who get new tumors are dropped because it is assumed the drug isn't working any more. If doctors want their patients to stay on Erbitux, ImClone tries to accommodate that, he says, adding that the company can get patients back on the drug in a matter of hours. He declined to say why it took weeks in Ms. McNeillie's case, saying the company doesn't discuss specific patients.

The World Medical Association, an international physicians' group that sets ethical standards, says patients in clinical trials should get continued access to drugs that benefit them. But some contend that could hurt drug development. "If we routinely required anybody who improves on a medicine in a trial to be given it for free, you may deter research," because of the cost involved, says New York lawyer Mark Barnes, an adviser to hospital boards and drug companies.

Patients can't always count on hospitals or doctors to go to bat for them. Hospitals compete for clinical trials that bring prestige and money. So hospital boards charged with regulating trials are sometimes reluctant to push too far on patients' behalf for fear companies will take their business elsewhere, says Mr. Barnes.

It is often up to patients to fight for post-trial access to a drug. Chuck Bowdish, 63, of Lake Tahoe, Calif., has metastatic prostate cancer that spread to his right hip. After enrolling in a clinical trial of an experimental Bristol-Myers drug in May 2002, the cancer in his hip improved. Where he had felt exhausted before, he felt so well on the drug he could snowboard and hike again.

After 10 months, a certain protein in his blood rose 25%, a possible sign his cancer was worsening -- and the clinical trial rules said he could no longer receive the drug. In February, he found himself out of the study and off the drug. A Bristol-Myers spokeswoman says the rules of the trial required that Mr. Bowdish be taken out.

Mr. Bowdish says he felt so sick he could barely walk up his stairs. He began calling and writing to legislators, advocacy groups, newspapers, the FDA and executives at Bristol-Myers. Six months later, Mr. Bowdish was allowed to go back on the drug under a special-use program and he's feeling better again. He found the process frustrating and confusing, he says. "As a patient, I had no idea what to do."

Bristol-Myers says it took six months because Mr. Bowdish's doctor didn't push. His doctor doesn't dispute this, saying he thought Mr. Bowdish was improving with a different drug. Bristol-Myers says it tries to allow patients testing cancer and AIDS drugs to continue getting medicine when it seems beneficial to them.

When T.J. Tomeny's first brain-tumor symptoms surfaced, he was an A student, a soloist in the Legacy Christian Academy program and the leading scorer on his youth basketball team. On a Saturday night in January 2002, as his family was driving to the Evangelical church where they worship, "I was trying to talk and nothing would come out," T.J. recalls. But it lasted only a few moments, so his family didn't worry about it. Mr. Tomeny says he thought T.J. was joking.

But that night, T.J. again couldn't talk, this time for about 20 minutes. His parents raced him to the emergency room. After an MRI scan, a neurologist concluded he had epilepsy and prescribed antiseizure medicine.

That summer, a follow-up MRI showed that the boy appeared to have a tumor in the area of the brain that controls speech. In September 2002, a neurosurgeon operated. But because the tumor was on such an important part of T.J.'s brain, he couldn't remove all of the growth.

Radiation and chemotherapy followed. At times, T.J. grew so sick he struggled to walk or eat. His mother, Kari, quit her job as a girls sports coach at a private school to take care of him. Mr. Tomeny later found himself unable to keep up with his responsibilities at work and lost his job as a school administrator.

T.J. grew a bit introverted, embarrassed by the hair loss. But buoyed by his religious faith, he remained convinced he would beat the brain tumor. He cried when the treatments made it hurt to swallow, but when the pain disappeared, he laughed as hard as ever at the same "Austin Powers" jokes. He played with his younger brother, Patrick, and his dogs, Angel and Aggie. "Most of all, he just seemed to want to be like every other kid in school," says Sheryl Beck, his sixth-grade teacher, and tried to finish every assignment.

In March, barely six months after the first surgery, a new MRI showed T.J.'s tumor had grown. The neurosurgeon removed a racquetball-sized piece of tumor and brain, and doctors told the Tomenys their son had as little as six months to live.

There was one long-shot chance: T.J.'s oncologist had been a medical-school professor of a doctor now running a clinical trial at the University of Iowa Hospitals and Clinic in Iowa City. The doctor, Sue O' Dorisio, was in the earliest stage of testing different doses of a new medicine in children, to measure how much could safely be administered. The drug had been tested in more than 300 adults, but she was running the only pediatric trial in the world. Although very few patients are saved by medicines in these early trials, the Tomenys decided it was better than doing nothing.

Dr. O'Dorisio and her husband, Tom, an endocrinologist at the same hospital, have spent 20 years studying how hormones that regulate cell growth can be used to contain cancer. Tom O'Dorisio was an early enthusiast of a synthetic hormone treatment developed by Sandoz AG, the company that became Novartis. Today, that treatment has become the standard for treating certain tumors. He has been a paid speaker for the product.

Three years ago, Novartis combined the product with radiation, called it OctreoTher and began to test its effectiveness in adults with various types of hard-to-treat tumors. Tom O'Dorisio enrolled 40 patients in one trial. Novartis confirms about 10% of patients saw their tumors shrink by at least 50%. The company won't comment on the status of its application for the drug with the FDA.

Sue O'Dorisio was also eager to test the therapy, and in 2000, she secured a $500,000 grant from the National Cancer Institute to fund a small study in children. Novartis agreed to donate drugs for the study and the University of Iowa said it would help cover hospital costs. The study has cost $112,000 so far. In very high doses, some adults experienced kidney failure on OctreoTher, so Dr. O' Dorisio agreed to start with just one-third of the adult dose.

On May 28, T.J. became Dr. O'Dorisio's third patient to receive the treatment -- a four-hour infusion of amino acids to protect his kidneys, followed by 15 minutes of the radioactive medicine.

T.J. felt restless and nauseous, then fell asleep and didn't wake up for about 10 hours. But when he did, he said he felt fine. He stayed in the hospital for 24 hours, as required, and then flew home with his family to Texas. He spent June biking and playing basketball with his brother.

The Tomenys returned to Iowa six weeks later for the second round and scans to see how well the first treatment had worked. To Dr. O'Dorisio's surprise, T.J.'s tumor had shrunk by about a third.

The dose was so low, she said, "I almost felt apologetic asking children to be on the first dose. It is remarkable that he had a response at all," she said. Mr. Tomeny says he was "over the moon." For the first time in a year-and-a-half, a medical treatment seemed to be helping T.J.

It was then that Mr. Tomeny first asked whether the boy could continue on the medicine after the trial ended. He knew he was broaching a sensitive topic. The consent form he and T.J. signed to enroll in the trial said the boy could get as many as three doses. Dr. O'Dorisio told him it was unlikely she could give T.J. more medicine in the near future.

On Aug. 14, as T.J. lay in his hospital bed recovering from his final clinical trial dose, Mr. Tomeny again pressed Dr. O'Dorisio about the possibility of more therapy. T.J.'s brain had been scanned again, and although the tumor hadn't shrunk, the drug appeared to have kept it from growing.

This time, the doctor was firm in her refusal. In a blue spiral notebook, Mr. Tomeny noted her response. "Issue is one of money," he wrote. Dr. O'Dorisio told him Novartis would no longer supply the drug because it was so difficult to make and cost $17,000 for each dose. It was the first time Mr. Tomeny had heard the cost figure. He had paid virtually nothing for his son's treatment so far.

Novartis's Dr. Young says the company has never indicated it would stop supplying the drug to Dr. O'Dorisio's trial. She said the drug is expensive to make but wouldn't be specific.

Instead, Dr. O'Dorisio suggested that Mr. Tomeny take T.J. to Europe to get a similar, experimental treatment being made by a hospital in Rotterdam. It would cost $10,000 for the treatment, plus travel expenses, and they would need to go every six weeks. In the U.S., companies usually don't charge patients for experimental drugs.

Dr. O'Dorisio says that at the time, she didn't tell the Tomenys she was reluctant to ask for another dose for the boy for another reason: If T.J. had a bad reaction later, she feared it might set off alarm bells at the FDA, and cause the trial to be halted. "Sending him to Europe was a way of not risking my trial shutting down," she says. She now says that was her main reason for not trying to get additional medicine for T.J.

John Bertolatus, co-chairman of the board regulating clinical trials at Dr. O' Dorisio's hospital, says the board left open the possibility of giving patients additional doses when approving the trial. But such decisions are at Dr. O'Dorisio's discretion, he says, and didn't need to be run by the board. In T.J.'s case, "it's unlikely this decision would have been criticized or any attempt made to change it."

Desperate to keep T.J. on the medicine, Mr. Tomeny called the FDA, Novartis, congressmen and the media. Following inquiries from The Wall Street Journal, Dr. O'Dorisio got permission from the FDA and the company to give T.J. a fourth dose in October. After saying that dose would be the last, Dr. O'Dorisio has in subsequent interviews said she would consider asking for permission to give T.J. more of the drug.

The FDA says it doesn't comment on specific cases. But the agency closely monitors clinical trials, particularly in children, to watch for unintended side effects, and asks doctors to suspend or stop studies if too many participants have bad side effects.

Dr. O'Dorisio defends the trade-offs she made in T.J.'s case. "We've given him at least six months of good quality of life and lots of hope."

The Tomenys say they are grateful for the six months, but they don't want to give up now. They are trying to look forward. Mr. Tomeny has started a new business, a dry-cleaning-delivery service. Mrs. Tomeny has gone back to school to finish her bachelor's degree and is working part-time as girls' coach at T.J.'s school. Depending on how T.J.'s health is, the family is hoping to go skiing at Christmas.

T.J., who wears a white baseball cap to cover a bald spot, went out this fall for his school basketball team. Thinner and weaker than he was before he began his battle with cancer, he didn't make it as a starter this time around. But he did squeeze into one of the two spots on the team reserved for player/managers. The team's next game is tonight.