Too Much Too Fast? : Drug Rules: AIDS Spurs New Climate

“Silence Equals Death,” read the buttons worn by the busload of protesters who descended on the National Institutes of Health last February to demand access to an experimental AIDS drug that showed promise but had not yet been thoroughly tested.

After a two-hour meeting, Dr. Anthony S. Fauci, the NIH official responsible for all federal AIDS research and a scientist that the protesters had once labeled a “murderer” and a “Nazi,” surprised the protesters by promising to intervene on their behalf. Within months, the drug was released.

“It was a breakthrough moment,” recalls AIDS activist Jim Eigo. After three years of effort, Eigo and others like him were on their way to winning an across-the-board acceleration of the approval process for experimental AIDS drugs.

It was a breakthrough for more than AIDS drugs.

Profound Change

The AIDS activists’ desperate assault on the scientific and governmental agencies that develop, test and approve new prescription drugs is producing a profound change in the way those agencies handle all kinds of experimental drugs involving critical, life-threatening diseases--not just those dealing with AIDS. It is not only accelerating the process but creating a new atmosphere--a presumption favoring action over delay.

And to most scientists and government officials, the change is a welcome one. The pendulum had swung too far in the direction of caution at the Food and Drug Administration, the government agency responsible for approving new drugs, they say.

At the same time, some also raise a yellow caution flag, warning that the present trend could also cause serious problems if it should go too far, permitting ineffective or even dangerous drugs to reach patients with a wide range of life-threatening diseases.

Could Compound Problems

Confrontational tactics of the kind pioneered by AIDS activists could, if applied inappropriately, damage the basic research and testing processes of science, for instance. Or the commendable streamlining of government procedures, if carried too far, could erode necessary safeguards.

Even critically ill patients who have few or no therapeutic alternatives need protection from inadequately tested drugs that could compound their problems, scientists caution.

“I don’t think anybody wants to do any harm to patients for the greater good of science, but the greater good of science is to learn as much as we can as fast as we can--and as safely as we can,” says Dr. Robert T. Schooley, an AIDS specialist at Massachusetts General Hospital and Harvard Medical School.

In the case of AIDS, which was killing all who contracted it with brutal swiftness, activists argued that patients could not wait for the traditional testing procedures to run their course. They considered it largely irrelevant that new drugs might have dangerous side effects or prove ineffective.

“The arithmetic is terrifyingly simple,” said Larry Kramer, a New York writer and founder of the AIDS Coalition to Unleash Power (ACT UP). “An average study takes seven to 10 years. The average life after diagnosis with AIDS is two years. Of course, activists are screaming for faster access to treatments. Otherwise, most of us won’t be here when the answers come.”

Before AIDS, the burden of proof was on the developers of a new drug to prove its safety and effectiveness. The FDA released new drugs only after the most rigorous testing in clinical trials--a process that commonly took several years to complete.

Rights of Victims

“AIDS forced everybody to change how they thought about life-threatening diseases and the rights of people who are suffering from them,” said Dr. Sam Broder, director of the National Cancer Institute. “AIDS raised everybody’s consciousness.”

Now, where potentially fatal diseases are concerned, the regulators are far more inclined to move quickly and to seek ways for critically ill patients to obtain drugs that are promising but not yet thoroughly tested.

“This will go to cancer and to Alzheimer’s and to Parkinson’s--there’s no question about it,” said David Rothman, professor of social medicine at Columbia College of Physicians and Surgeons. “The AIDS community has been the shock troops of change. As the notion of consumers’ rights advances in AIDS, it will inevitably be picked up by those with other diseases.”

Lost Sight of Needs

Many members of the medical community believe the regulatory system has been so focused about producing scientifically valid information about new drugs that it has lost sight of patients’ needs for quick help.

Patients with critical diseases, they say, should have the right to decide whether to gamble on a drug that shows early promise.

“Many drugs will be released with less knowledge,” Rothman said. “But if you were a patient facing a terminal illness, wouldn’t you want the ultimate right to make choices of risk and benefits? My answer would be: absolutely.”

Rothman acknowledged that the consequence might be some delay in gathering scientific data about the impact of some drugs.

“But in all human experimentation, there is always conflict between the interests of the particular patients and the research community and outside society,” he said. “Delays may ultimately benefit all future patients--but not this particular patient at this particular moment. But should this particular patient be required to sacrifice his interest for the larger social good?”

Frustration, Suffering

Dr. Jerome Groopman, an AIDS researcher at New England Deaconess Hospital, still sees patients one day a week, and he said that he understands their frustration and suffering.

“It makes you step back and say: ‘If this were my son, I’d go to the ends of the Earth to make sure he got something that could help him,’ ” Groopman said. “But if we totally demolish the scientific system, we’ll never learn what we need to learn about drugs and how to use them. There’s got to be a balance. Before AIDS, the balance was too far in the other direction. It was so restrictive that people couldn’t get any access.”

Drug manufacturers, impatient with the pace of the old system, support the new philosophy, although they acknowledge that the changes may bring some new problems.

“Liability is one of our concerns,” said Dr. John C. Petricciani, vice president for medical and regulatory affairs of the Pharmaceutical Manufacturers Assn. Risks are greater, he said, when drugs are made available earlier in the development process.

“In principle,” he quickly added, “I think most people agree that we’d all like to get life-saving drugs through the process as quickly as possible.”

Accelerated the Trend

If AIDS activists have speeded up the process, they have merely accelerated a trend that had been under way before. When Dr. Frank Young became FDA commissioner in 1984, he said: “I’ve been through the experience of literally having patients dying before my eyes while they’re waiting for medicine to be approved that could save them.”

Under Young, the FDA has trimmed the average overall time it needs to approve a new drug from 7.8 years to 4.2 years. It also has injected new life into a previously little-used mechanism for the widespread distribution of a drug for “compassionate use” after it has demonstrated its safety and effectiveness, but before it is approved for marketing.

“I would say that AIDS gave a national understanding for these reforms,” Young said. “It provided an imperative that enabled us to focus on these issues. And it helped me convince the nation that it was necessary.”

‘Compassionate Use’

Within weeks, the FDA is expected to use its “compassionate use” mechanism to approve the widespread use of DDI, a new anti-viral AIDS drug, at the same time formal clinical trials to measure its effectiveness are scheduled to start. The FDA is considering making the new drug available to AIDS patients who cannot tolerate AZT, the only anti-viral AIDS drug thus far approved for marketing.

In a separate departure, a panel appointed by President Bush has been discussing these very same issues, all with the same end in mind: how to speed access of promising drugs to people who would otherwise face death.

“AIDS put a magnifying glass to everything, in terms of all life-threatening issues,” says Broder of the National Cancer Institute. “AIDS reminded everybody that the things we are trying to do touch on people’s lives.”

Cancer Drug Battles

Broder remembers having frequent battles with the FDA in the 1970s over making experimental drugs available to cancer patients. The drug cis-platinum, for example, which Broder called “one of the most important anti-cancer agents ever discovered,” was the object of numerous “delays and unnecessary bureaucratic roadblocks” at the FDA, he said.

“It was clear to everyone in the oncology community that this drug was going to be a major advance,” Broder said. “But there was an unwarranted and unrealistic preoccupation (at the FDA) with its side effects, without equal consideration of the good it could do. And that was being used to hold back a drug that had enormous value.”

Today, by contrast, Broder said, the FDA is much more willing to release cancer drugs earlier. About two months ago, he said, the cancer institute asked the FDA for the “compassionate use” release of levamisole, a drug that showed promise in treating early colon cancer. “It was approved with the speed of light, in about one day,” Broder said.

This new attitude marks an important shift among regulators from the posture that had prevailed since the thalidomide scare in the 1960s.

Thalidomide, a sedative that caused serious limb abnormalities and other defects in babies born to women who had taken it while pregnant, was widely used in Europe in the 1960s. But in the United States, cautious regulators at the FDA held up approval of the drug for public sale when they found the scientific studies of its safety to be suspect.

They were proved right, and, as Rothman said, “the FDA that emerged . . . was an FDA that was charged to put safety first, to minimize risk and to enhance the protection of the consumer.” The specter of a thalidomide disaster in this country has guided federal regulators ever since--until AIDS came along.

“Now the nightmare case is no longer thalidomide,” Rothman said. “It is that of a young man dying of a fatal disease in a painful, wasting and ultimately tragic fashion. Once that becomes the nightmare image, you make a very different calculus of risk and benefit.”

Extraordinary Meeting

This image clearly moved top FDA and NIH officials, particularly during that extraordinary encounter last February between Fauci and the activists.

Fauci vividly remembers that meeting. The activists were demanding access to ganciclovir, a drug that had shown promise of preventing AIDS patients from going blind. Fauci found the protesters to be extremely responsible.

“I had always stated that I understood and appreciated their frustration, but I’d never seen any constructive criticisms, only lashing out in anger,” Fauci said. “Then I began reading some of the documents written by the ACT UP people. They were surprisingly articulate and well-informed.”

After meeting with the protesters, Fauci talked with the FDA’s Young. His intervention helped speed the FDA’s decision to release ganciclovir.

Network of Activists

Rothman doubts that such a radical shift in regulatory approach could have been achieved by cancer patients or any group suffering from any other terminal illness. Most AIDS activists, he said, are already part of a large political base through the gay rights movement.

“There was no network of cancer patients,” Rothman said. “They are united only by their disease. With AIDS, you have a community already united. This is the first time you’ve got an organization in medicine lobbying this way on a disease in which the organization preceded the disease.”

Before AIDS, experimental drugs--even for invariably fatal diseases--were available to the public only through limited and highly structured clinical trials that compared their effects to those of medically inactive placebos or other drugs.

These studies often took years to complete and many patients could not participate because they did not qualify or have access to them. Only after these painstaking studies established a drug as both safe and effective could other people take it.

Many regulators and researchers had long argued that such lengthy scrutiny was necessary to achieve scientific certainty and to ensure that dangerous or worthless drugs did not proliferate.

Now federal regulators have begun to relax the process. A new, federally sponsored program of community-based research efforts will allow local physicians and facilities to participate at the grass-roots level in various aspects of AIDS research.

Parallel Track Research

Beyond that, in the most controversial of the innovations now under way, Fauci has proposed a parallel research track that would allow new and unproved drugs to be used by AIDS patients even while traditional clinical trials were going ahead. The only persons allowed to take such drugs on the “parallel track” would be those ineligible for the formal, highly structured clinical trials.

AIDS activists and others believe that parallel track drug trials ultimately will prove effective in the fight against such diseases as cancer, advanced heart disease, Parkinson’s disease, Alzheimer’s disease and other major illnesses.

“This is not an issue about AIDS, but in the testing of all drugs for life-threatening illnesses,” said Tom Stoddard, executive director of the Lambda Legal Defense and Education Fund, a national gay rights organization. “Ultimately, all Americans will benefit from this new approach to drug testing.”

Dr. Sidney Wolfe, director of the Public Citizen Health Research Group, said that a different standard should apply to the treatment of fatal diseases. The parallel track, he said, should provide “a good opportunity for a major rethinking of the purpose of the drug approval process in this country--which should be, first and foremost, to approve drugs for diseases where someone is otherwise going to die or suffer severe impairment of health.”

Wolfe, for years a vocal critic of the FDA, predicted that the parallel track, if it works for AIDS, “will be useful in other equally life-threatening circumstances--the only circumstances where you should be willing to take such risks, when you’re really up against the wall.”

But some researchers fear that the parallel track, the most radical departure from past practice, goes too far.

Early access to experimental drugs, they warn, could subject individuals to additional suffering and even divert them from potentially more beneficial treatment--chemotherapy and radiation for cancer, for example. And with the drug AZT showing promise, even AIDS patients might be taking a bad risk by trying unproven alternatives.

The skeptics cite the example of Laetrile, a drug that lured many cancer patients to Mexico and elsewhere when the FDA refused to make it available in the United States. The drug, a derivative of apricot pits, ultimately proved worthless.

“If they give away the store, we can all worry,” said an academic physician and longtime adviser to the FDA, who asked not to be identified. “If we loosen this up too much, then we’ll be like some parts of the rest of the world, where drug regulation varies between less rigorous than desirable and abysmal.”

Safety, Efficacy Judgments

The FDA’s Young and others insist that, even under parallel track, drugs will not be released uncontrollably. They must be shown to be relatively safe and indicate at least some early evidence of efficacy.

“We’re not going to just cavalierly experiment on people just because they’re desperately ill,” Young said.

“I don’t think you have to worry about quack remedies,” added Petricciani of the Pharmaceutical Manufacturers Assn. “You will still have FDA in the loop making judgments about safety and efficacy. I don’t think there will be room for mischief.”

Not everyone is so sanguine. A former FDA adviser and longtime observer of the drug-approval process said that many drugs have been approved for sale to the public in recent years, only to be shown later to cause serious problems.

Oraflex, which was widely hailed at the outset as an arthritis medication that was better than aspirin with fewer side effects, was approved by the FDA in 1982. It was later removed from the market after its use was associated with at least 49 deaths in this country and several hundred deaths abroad.

“And that’s with the most careful regulation,” the former FDA adviser said. “Once you move away from that, the likelihood of more moves way up.”

Serious Reservations

Some researchers who are conducting controlled clinical AIDS trials favor the parallel track in theory but have serious reservations about whether it will work in practice. They fear that if the parallel track experiments are not carefully monitored, the results could be disastrous.

They point to several recent instances in which promising AIDS drugs have appeared safe in early human testing but proved more toxic after being given to larger numbers of people. They are also concerned about potential problems caused by drug interactions.

“We can argue very strongly that if a drug looks safe and can be given in a safe setting, the drug should be offered to patients with AIDS as early as possible,” said Harvard’s Schooley. “But if these drugs are administered by people who aren’t experienced in looking for unexpected side effects, we’re likely to cause more harm to people who could otherwise be taking drugs we know a lot more about, like AZT.”

Many researchers also worry that parallel track may jeopardize traditional clinical trials for AIDS drugs because individuals will simply refuse to participate. Or potential participants may find some way of becoming ineligible for the formal trial because they want the certainty of receiving the experimental drug.

‘Instrument of Compassion’

The cancer institute’s Broder called the parallel track “an instrument of compassion” that is “designed to meet human needs.” What it is not, he warned, is “a scientific instrument (or) a way of doing a clinical trial.”

Its purpose, he said, is “to not leave people totally out on a limb without anything, and to make sure patients do not feel disenfranchised and isolated. Those are legitimate goals, and I support them. But parallel track cannot be used as a substitute for clinical trials or as a vehicle for advancing the more rapid development of drugs.”

Fauci acknowledged that there may be problems but declared that “many important and good ideas have met resistance early on. We have to have flexibility in allowing people who have no alternative. This is an important new approach. Let’s worry about the problems as they arise. You can’t abort the whole process because of potential problems.”

Despite their worries about the immediate impact of the parallel track on current or planned AIDS clinical trials, most researchers are confident that, in general, the future of controlled clinical trials is safe.

May Aid Clinical Trials

“If parallel track works in AIDS, there will be pressure from people with other severe chronic illness to have similar access to drugs,” said Schooley. “But I don’t think this will deliver a blow to clinical trials. . . . In a clinical trial, you’re talking about more than just access to drugs. You’re also talking about free access to the best specialists in the area and everything that goes with it. I don’t think clinical trials will ever dry up. This might even make them better.”

Groopman of New England Deaconess Hospital said that he believes “a middle position ultimately will prevail” in drug regulation that “will benefit both patients and the research establishment.”

“This is how change occurs,” Groopman said. “The more radical elements trigger it, and then the more liberal and central elements put it into real practice.”