‘Freeze’ on Drug Testing Feared : Clinical Trials Under Attack on Many Fronts

One of the first signs that all was not well with Jon Usher showed up on the torque wrench in the truck repair shop where he worked. With chilling precision, the wrench’s gauge tracked his decline. His strength had plunged 50% in a single year.

Coffee would revive him, Usher kept hoping. An extra cup, with extra sugar, turned into three pots a day. Only when he was hospitalized with a heart attack, and his blood was tested for surgery, did he finally learn what was wrong.

Usher was diagnosed in 1984 with hairy cell leukemia, a rare cancer of the blood-forming tissues that affects mostly middle-aged men. The disease, which destroys blood cells that fight infection and bleeding, is incurable and its cause is unknown.

When standard treatment failed, Usher faced an unenviable choice. He could spend the remainder of his life hiding from the germs that one day would kill him. Or, he could entrust his fate to biomedical research--become a “human subject,” a guinea pig.

Usher enrolled in a study of an experimental drug, recombinant beta interferon. He learned to poke syringes at a 45-degree angle into his belly. He grew accustomed to the stinging eyes, aching bones and the vise-like headache that followed every injection.

To this day, Usher’s wife, Jo, still cannot sleep through the night. Every three hours, she wakes up in the darkness of their Palm Springs home and listens for the murmur of her husband’s breath--to be sure he is still alive.

“I wanted to have my life back, more than you’ll ever know,” Usher recalled recently. “The one thing I haven’t learned in life, I guess, is to give up. I hang on a bit longer than most.”

Usher is one of a relatively small number of Americans who volunteer to test experimental drugs--an essential step in advancing a promising new drug from the research laboratory to the pharmacist’s shelf.

Some do it in desperation because nothing else has worked. Some do it in rebellion against more conventional treatments. Some hope to make a contribution, searching for some sense of purpose in the bewildering experience of a fatal disease.

“They want to charge the machine-gun nest as they go out, to bring the army a little closer,” said Dr. John Glaspy, an assistant professor of medicine at UCLA. “Their sense being, ‘I can fight this disease for my species, even if I’m going to lose it for myself.’ ”

Drug trials explore a series of questions: Does the drug work? Do its benefits outweigh its risks? More often than not, the answers are no. Only a small fraction of trials culminate in an application for federal approval to market the drug.

But few recent advances in medical treatment could have happened without clinical trials. In cancer alone, they have contributed to the development of therapies for such diseases as childhood leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma and testicular cancer.

“Our ability to administer experimental therapy is fundamental to medical progress,” Dr. Robert E. Wittes, a prominent cancer specialist, wrote recently. He said that if no new treatments could be tested, the state of the art would “freeze.”

Challenge Posed

But clinical trials are now being challenged by the changing economics of health care and the growing assertiveness of patients with deadly diseases such as AIDS and cancer. Among the pressures:

* The increasingly competitive health-care market and efforts to rein in public and private health-care spending are sapping financial support for clinical trials--at a time, researchers say, when leads into possible new treatments are exploding.

* Insurance companies, health maintenance organizations and other third-party payers are less and less willing to assume the costs associated with clinical trials--not the cost of the experimental drugs, which cannot be charged for, but the costs of related services for patients on so-called research protocols.

“Two things will happen,” warned Dr. Karen Antman of the Dana-Farber Cancer Institute in Boston. “Only those who are relatively affluent will . . . have access to new treatments. Or we’ll have only one standard treatment available and won’t make progress in medicine.”

* Meanwhile, AIDS activists seeking faster access to experimental drugs have questioned the rules by which trials have traditionally been conducted--in particular the use, for purposes of comparison, of patients who are denied the drug and instead given a dummy drug or placebo.

* Some advocates have asked why the U.S. Food and Drug Administration should control which experimental drugs a person with AIDS or cancer might try. Some have wondered: Shouldn’t a person with little or nothing to lose have the right to risk taking an unapproved drug?

“You have the ultimate issue: Does it make any sense to exercise paternalism over a dying patient?” says David J. Rothman, a professor of social medicine at Columbia University. “Once you frame the question that way, paternalism takes on a quality of absurdity.”

Usher, now 49, is archetypally American: Born in Indiana, he married his childhood sweetheart, moved West and raised four children. A fleet mechanic for the Southern California Gas Co., he had been a man of massive size and strength, almost radically self-sufficient.

But on July 30, 1984, returning from a fishing trip, a heart attack landed Usher in a Palm Springs hospital. Tests done in preparation for bypass graft surgery showed Usher’s blood was dangerously low on platelets, tiny blood cells crucial in clotting.

Usher’s physicians postponed his surgery. Then they inserted a needle into his pelvis and withdrew a small sample of bone marrow. For two agonizing weeks, Usher lay in the hospital awaiting a diagnosis. It finally came back: chronic hairy cell leukemia.

Cell Production Disrupted

The disease, diagnosed annually in 800 to 1,200 Americans, occurs when unusual cells called hairy cells infiltrate the bone marrow, disrupting production of the red and white blood cells and platelets that protect people against infection and bleeding.

In Usher’s case, the disease destroyed his defenses. Spontaneous bruises pock-marked his wasted body. Small skin infections erupted into abscesses and golf-ball-sized boils. The pain was relentless. He says he grew so weak he could not lift his head.

In December, after recovering from cardiac bypass, Usher underwent surgery for the removal of his spleen--a treatment that helps about half of all hairy-cell patients. His condition improved briefly in the following months, then headed downhill.

Genetic Engineering Used

Fortunately for Usher, a team of researchers in Texas had recently discovered that patients with hairy cell leukemia responded to interferons, powerful proteins made in the body that can now be reproduced through the techniques of genetic engineering.

In response to the finding, drug companies had begun exploring the possibility of marketing alpha interferon as a treatment for hairy cell leukemia. By the mid-1980s, data suggested that the treatment worked against the disease--but caused significant side effects.

Meanwhile, a small California biotechnology company, Triton Biosciences in Alameda, had cloned and modified the gene that produces a related protein, beta interferon. The firm set up nationwide trials to test recombinant beta interferon in hairy-cell patients like Usher.

“There was information that alpha was working but it had not yet been licensed,” said Dr. Stephen Marcus of Triton. “We wanted to see if there was some way to separate the effect of beta rather than alpha, and see if it was in any way superior.”

In late spring of 1986, the Ushers traveled to Los Angeles to meet Dr. John Glaspy, a UCLA cancer researcher conducting part of the trial for Triton. Usher’s oncologist in Palm Springs knew Glaspy and his work and had suggested that Usher consider enrolling.

Confined to a wheelchair, Usher underwent a battery of tests at UCLA to determine whether he met the criteria for the trial: Were his blood counts low enough? Had he had a splenectomy and failed? Were his kidney, liver and heart function satisfactory?

‘Informed Consent’

Next, he received a three-page contract listing the conditions of participation. Required by law, the document was intended to show that he had given his “informed consent” to be a subject. It offered an unappealing preview of possible side effects.

“Frequently encountered: fever, fatigue, flu-like symptoms (headache, chills), gastrointestinal disturbances (anorexia, nausea, vomiting, diarrhea), transient lowering of white blood cells and platelets,” the form stated.

“Occasionally encountered: transient and reversible numbness, tingling of extremities, central nervous system side effects . . . including confusion, disorientation, comprehension difficulties, and disturbances in the level of consciousness. . . .

“Also there have been a few instances of kidney damage . . . and myocardial infarction (heart attack). Death is a possible risk of interferon therapy.”

The Ushers pondered their options, which were limited. Then Jon Usher signed up.

“All things considered, I’ve got to try it; I’ve got to fight,” he said recently, recalling why he agreed. “My only condition to the doctors was I want to be absolutely informed. Good, bad or indifferent.”

The beta interferon trial was one of an estimated 1,000 to 2,000 trials being conducted throughout the country at any given time in large university medical centers, some community hospitals and, occasionally, by individual physicians.

The system relies on about half a billion dollars annually from the National Institutes of Health, the federal biomedical research arm. In addition, the pharmaceutical industry spends as much as several billion dollars a year on clinical trials.

But in recent years, money has grown increasingly tight--while recent breakthroughs have spawned hundreds of proposals for new clinical research. Federal funding has risen steadily, but not sufficiently to meet the demand for research grants.

Patients Screened Out

Meanwhile, health insurers and other third-party payers are increasingly reluctant to cover patient costs related to experimental therapies. Computerization has given insurers new tools for screening out and rejecting claims filed by patients in clinical trials.

Researchers say patients have even been denied coverage for medical complications brought on by experimental therapies. Requirements for pre-admission approval have prevented patients from being admitted to hospitals to take part in clinical trials.

“Our ability to administer experimental therapy is fundamental to medical progress,” wrote Wittes of the National Cancer Institute. “If we cannot test new treatments, the state of the art will freeze at its present level.”

Most trials follow an elaborate, three-part process intended to explore whether the drug should be approved for sale. The testing process consumes most of the eight to 10 years it now takes to move a drug from discovery to the marketplace.

Maximum Safe Dose

A drug is first studied in healthy patients to identify the maximum safe dose. A phase II trial, such as the one Usher joined, examines the drug’s therapeutic effects in a relatively small number of patients with the disease to be treated.

The third phase involves hundreds, even thousands, of patients. It expands upon the information gathered in phase II, shedding further light on the relationship between risk and benefit and exploring less common side effects and adverse reactions.

Many phase II and III studies are so-called randomized and controlled trials. That is, one group of patients in the trial receives the drug under study, while a second group of patients similar to the first receives a standard treatment or an inactive placebo.

Objective Measure

Often such studies are also “blinded:” Neither the patients nor the researchers know which patients are receiving the drug. At the end, the code is broken and the drug group is compared to the placebo group for an objective measure of whether the drug really worked.

That aspect of the system--requiring some patients unwittingly to take a worthless placebo--is being challenged in light of the AIDS epidemic. Is it ethical to withhold treatment from patients who, untreated, will almost invariably experience a precipitous decline?

“There has been a kind of mystique about the placebo-controlled trial that probably was unjustified,” contended Carole Levine, an ethicist and executive director of the Citizens’ Commission on AIDS for New York City and northern New Jersey.

‘May Be Ethical’

“The question is: When is it valid, when is it not, and when can you get good data doing something else?”

Equally controversial is the issue of patients’ access to trials.

With some success, AIDS activists have challenged the centralized nature of trials, conducted mostly in university medical centers in big cities. They have also argued that trials should be opened to more patients, enabling more people to benefit from the drugs.

Under public pressure, the FDA agreed last summer to modify the rules in some instances for drugs for AIDS, cancer and other life-threatening illnesses, not only broadening participation in some cases but condensing the last two phases in order to reach a conclusion more quickly.

Philosophical Twist

Ethicists see in those and other changes a significant philosophical shift.

David J. Rothman, director of the Center for the Study of Society and Medicine at Columbia University, sees the end of a quarter-century of regulatory paternalism rooted in the thalidomide disaster of the early 1960s--in which use of the drug by European women led to thousands of babies being born with birth defects.

Ever since that time, Rothman argues, the “nightmare case” in drug regulation had involved an unsuspecting consumer and a dangerous drug. Now it is shifting to a case in which a dying patient is denied access to a drug because the FDA is too slow.

“That is one of the most remarkable reversals of the model case on which public policy is made,” Rothman said. “AIDS altered the nightmare case. That begins to alter the whole flow of consequences.

“The real question we’re going to face is how far this process is going to go,” said Rothman, referring to the pressure to relax oversight and regulatory standards. “How far should it go? That’s the $64,000 question.”

For a year, Jon Usher followed the prescribed routine.

Three days a week, he would take out a small bottle of freeze-dried powder and inject into it a measured amount of sterile water. When the bubbles subsided, he would draw the mixture into a syringe and inject it into the fat below his skin.

Every time, Usher says, the shot made him feel sick: “Everything hurts. It just aches. Neuralgia? Neuralgia’s the word.” Every time, the site of the shot swelled like a bee sting. Usher had to move the needle shots from his swollen thighs to his arms to his abdomen.

He struggled with fear and depression, he says. Having taken his health for granted, he suddenly felt there was nothing he could trust. His mood changed, he became short-tempered and imperious. He wondered to himself, “Am I going to get sicker and sicker?”

Other Cancer Patients

But on his weekly treks in the family motor home for check-ups at UCLA, Usher watched other cancer patients coming in for chemotherapy. He could hear them, he says, in a nearby treatment room retching: “It made it an awful lot easier to put that thing in my stomach.”

Gradually, Usher’s condition began to improve.

Within a month of starting, he says, he was out of the wheelchair. The sight and smell of food no longer made him nauseous. He went back to reading, mastered a home computer and learned to bake, becoming something of a specialist in breads and pecan tea rings.

In mid-1987, Usher had completed his course on the treatment. His blood counts had returned to normal. He left the study and attempted to return to his old life, knowing that sooner or later the disease would probably resurface.

Not a Cure

Precisely why the drug had worked remains unclear. Interferons are known to increase a type of white blood cell called natural killer cells. Those, in turn, may kill hairy cells; or the interferon may kill the hairy cells directly.

But interferons are not likely ever to cure the disease, Glaspy said. All they can do is fight a kind of holding action against the invading cells. Patients will experience long periods of remission, then their blood counts will drop again.

The beta interferon trial had been a partial success. It showed that beta interferon worked. But it did not prove that it worked any better than alpha interferon, which in the meantime had been approved by the FDA.

For that reason, Triton Biosciences turned its attention to other uses for the drug, testing it against AIDS, multiple sclerosis and certain brain tumors. The firm has dropped, at least temporarily, its quest to market the drug for hairy cell leukemia.

Good Prognosis

The prognosis for patients like Usher, nevertheless, appears good.

Glaspy, who has worked extensively with hairy cell leukemia, believes that the availability of alpha interferon, and the current testing of another experimental drug, mean that most hairy cell leukemia patients will not die of their disease any more.

“With hairy cell patients, the big problem now is they can’t get life insurance,” Glaspy said recently. “Whereas the problem before was they were going to die.”

As for Usher, his quest has continued.

When his blood counts dropped again last year, he joined a trial of another biotechnology product capable of increasing white blood cell counts. Again, the therapy worked; within months his cell counts had returned to an acceptable level.

When they dropped again, his doctor prescribed the newly approved alpha interferon. It, too, works, though not without side effects. It seems to increase the amount of water retained by Usher’s body--creating a new risk for an old problem, his heart.

So Usher’s physician is looking into yet another experimental drug.

“You must not give up,” Usher’s wife, Jo, said recently, drawing from her husband’s experience a lesson for others. “Because next week, next month, six months from now, there may be something available for you.”