A push for wider use of experimental drugs

Two-and-a-half years ago, several months before she died, Abigail Burroughs, a 21-year-old senior at the University of Virginia, sat with her father as chemotherapy drugs dripped, once again, into her body. Together, they mapped out a plan they hoped would save her life, and the lives of other desperately ill people.

Burroughs, who was diagnosed with head and neck cancer at 19, had taken every medication her doctors could think of, to no avail. Her last chance, she believed, might be two experimental drugs, Erbitux (still not approved by the Food and Drug Administration), and Iressa, approved in May.

The Burroughses begged the manufacturers, ImClone Systems Inc. and AstraZeneca, respectively, to give her the drugs on a “compassionate use” basis, but ImClone said it did not have such a program at that time (it does now). And AstraZeneca, which was giving Iressa free to 22,000 people with lung cancer, said no because Abigail had the wrong kind of cancer.

These drugs might not have helped Abigail. But she and her father, Frank, became convinced that seriously ill people should be allowed to get -- and even pay manufacturers for -- experimental drugs once they have passed preliminary (Phase I) safety trials in humans, even if the drugs might turn out to be dangerous or useless. In their view, the currently available ways to get experimental drugs are tragically inadequate.

So this summer, Frank Burroughs, who now heads the Abigail Alliance for Better Access to Developmental Drugs, teamed up with the Washington Legal Foundation and sued the FDA to loosen its rules.

They want the FDA to create a level of review called Tier 1 Initial Approval. Under this plan, patients would be able to get an experimental drug if it has passed Phase I trials, if the patient has been rejected from clinical trials of the drug and if nothing else has worked. Perhaps most controversially, they want to allow patients to pay manufacturers for these minimally tested medications.

Despite its powerful emotional appeal, the Tier 1 plan is creating a firestorm of opposition, even from other patient advocacy groups.

“We have a system in place to prove the safety and efficacy of therapies. We can’t afford to undermine that system,” said Fran Visco, president of the National Breast Cancer Coalition based in Washington, D.C. “The system is premised on [the idea that] drugs should not be available until they are proven safe and effective.”

Visco cited two instances in which medical interventions became widely used without adequate testing and later proved to be harmful or ineffective: bone marrow transplantation for breast cancer and hormone replacement therapy for menopause. Asked whether an individual should be free to choose his or her own risks, she replied, “When you start talking public policy, decisions have to be made. It’s not on the individual autonomy level.”

Nancy Roach, a director of the Marti Nelson Cancer Foundation in Vacaville, Calif., also is opposed to the Tier 1 idea. “It would rip the heart out of clinical research.” At the end of a Phase I (safety trial), a drug may have been tested in only a few dozen people, she said. (It is not until larger Phase II and Phase III trials that a drug is tested in more people and researchers study dosages and efficacy.) “You don’t give drugs to people unless there’s a good reason to, you know how to give them and the person has some chance of benefiting,” said Roach.

Medical ethicist Dr. Marcia Angell, a former editor of the New England Journal of Medicine and senior lecturer on social medicine at Harvard Medical School, also opposes the Tier 1 idea. “New drugs are far more likely to fail than to succeed, so the chances are that a patient will be hurt by a drug rather than helped,” she said.

She also rejected the idea that manufacturers need financial incentives to release them. Drug companies already “are profitable beyond any industry,” she said. Also opposed to Tier 1 is the pharmaceutical industry. Alan Goldhammer, associate vice president for regulatory affairs for the Pharmaceutical Research and Manufacturers of America, said it would be “potentially reckless” to release drugs after only Phase I trials because at that point there is “no proof of efficacy at all.” There also could “be potential product liability issues,” he added.

At the FDA, Terry Toigo, director of the office of special health issues, said the agency had no comment on the lawsuit but added, “We’re always looking to hear from people about ideas on where our system doesn’t work.”

For seriously ill patients like Burroughs, there are many parts of the system that one could argue don’t work. It takes at least 10 years (and $800 million) for the average drug to pass through Phase I, II and III clinical trials en route to full market approval. Many patients can’t wait that long, and four of five drugs fail along the way.

In addition to joining a clinical trial (which can be hard to get into for medical or geographic reasons), there are a few ways to cut the waiting time, but they involve navigating a complex, bureaucratic maze.

Under “compassionate use,” a doctor can write the manufacturer asking for a specific drug for a specific patient. The FDA reviews this request and usually approves it. The company then may -- but does not have to -- give the drug to the patient.

Another route is the “expanded access” program, in which a drug maker develops a protocol for giving the drug to an entire group of patients who meet the medical criteria.

If the FDA approves, the company enrolls the patients, but often there are more patients than supplies of the drug, in which case the company may set up a lottery. For their part, companies can try to rush drugs through the FDA process under the “accelerated approval” program, as occurred with AstraZeneca’s Iressa. In this case, the company gets approval on the basis of “surrogate markers,” such as regression of a tumor, rather than demonstrated clinical benefit, such as increased survival.

Companies also can ask for a “priority review” if a new drug would be a significant improvement over drugs already on the market. And they can “fast track” a drug by submitting data as the research marches along, not just at the end of the process.

For many patients, this works well enough. But for others, like Ruth-Ann Santino of Arlington, Mass., it doesn’t.

Two years ago, Santino “wrote the world” to put pressure on ImClone to give her Erbitux, said her husband, Fred. But she never got the drug.

She died in May 2001 of colon cancer.