Chicago Tribune (CT) - SUNDAY July 10, 1988 Edition: FINAL EDITION Section: PERSPECTIVE Page: 1 Word Count: 1,859
Peter Gorner, a Tribune science writer

The agency's mandate is to make sure a drug is safe, stable and effective before it is released to the public. But with AIDS, the agency's role seems to be changing.

As of July 4, according to the Centers for Disease Control in Atlanta, 66,464 cases of AIDS had been reported, and 37,535 people had died from the disease. AIDS patients, running out of time, are smuggling drugs in from other countries and dosing themselves. Doctors are going undercover and conducting ad hoc clinical trials, trying to come up with something-anything-that keeps their patients alive.

Should the FDA continue to try to protect the dying from themselves? Or should the government allow dying people to try any new drug that they think might help them?

The potentially inflammatory issue echoes the battles over the purported cancer drugs Krebiozen in the 1960s and laetrile in the 1970s. AIDS is challenging one of the very linchpins of federal drug regulation: efficacy. The FDA is, in effect, being urged to get new AIDS drugs out to doctors fast, before anyone knows for sure if they work.

A year ago, the agency overhauled its regulations and, with considerable fanfare, announced a new program called Treatment IND, for investigational new drugs. The program ostensibly is designed to rush experimental drugs to critically ill patients once they are deemed safe, even though their efficacy has not been fully proven.

Last week, the program was called a success by FDA Commissioner Frank Young. After reviewing 12 applications, the agency quickly approved 5 new experimental drugs that became available to people suffering from mental disorders, cancer and Parkinson's disease, and patients trying to retain transplanted kidneys.

As originally announced, the Treatment IND program was specifically aimed at AIDS. Four new applications over the past year involved AIDS-related drugs. But only one was approved for early release to AIDS patients.

That drug is trimetrexate, which may help combat pneumocystis pneumonia. About 75 percent of all AIDS patients suffer from this type of pneumonia, and people are often diagnosed as suffering from AIDS after a bout with pneumocystis pneumonia.

Yet even the clinical use of trimetrexate has been so tightly restricted by the FDA that only a relative handful of patients, 89, have received it.

"The incongruity is that the commissioner considers this an advance," said Martin Delaney of Project INFORM, a San Francisco group that monitors the epidemic.

"They set it up in such an illogical way that only patients who have a toxic reaction to other treatment for (pneumocystis pneumonia) are allowed to get this drug. Many others could use it. The FDA is dangerously literal- minded. They take their science far too literally for our own good."

The President's AIDS Commission, in its June 24 report, called the FDA fast-track drug program a failure. It has produced nothing that attacks the AIDS virus and, moreover, a climate of total confusion exists about new drugs, the commission said. In short, people don't know what to do.

"There was no centralized information network, and no one to help them through the FDA maze," the report said.

Last week, leaders of AIDS support organizations attacked Treatment IND as a sham.

"The complaint is nothing new," said Steve Beck, of the National Association of People with AIDS. "There are 600 AIDS organizations in this nation. They formed to meet the needs of patients not adequately handled by existing health care services."

The FDA blames the paucity of new AIDS drugs on the inability of basic science to make dramatic headway against the perplexing disease. State-of-the- art molecular biology was able to identify and characterize the AIDS retrovirus with remarkable speed. Conquering it is another story, however.

"People are desperate. But we can't clear (approve) what's not there," FDA Commissioner Young said last week.

"He's simply flat out wrong," Delaney countered. "There are plenty of promising new drugs. What's wrong is that Frank Young and the FDA says that isn't good enough. Despite their own regulations, they're insisting that a drug be proven effective according to the most stringent and traditional standards of medical science before dying people can use it."

AIDS patients argue that the agency must live up to its own promises, that it must release drugs without waiting for the absolute proof typically required for the licensing of a drug.

Since 1962, with passage of the Kefauver amendments to the Food and Drug Act, a drug's efficacy must be proven before it can be put on the market. The amendments followed in the wake of the thalidomide scandal in Europe. Before that, and as far back as 1938, a drug manufacturer merely had to prove that its product was safe.

Today, any new drug normally must undergo three phases of testing by its inventor before gaining FDA approval. Phase I is testing for toxicity. Phase II is effectiveness testing in small groups of humans. Phase III is extensive clinical testing in humans.

The price of efficacy, though, is time. Controlled double-blind studies at multiple centers take time, normally as long as nine years to progress through the FDA drug development, review and acceptance program.

However, the only federally approved anti-AIDS drug, azidothymidine (AZT), which has been shown to prolong the lives of many patients, made it through the bureaucracy in 18 months. The drug was given a Treatment IND that speeded it to about 4,000 patients even before it was granted final approval.

If the Kefauver amendments were suspended, as FDA critics are recommending, the mechanism would return to where it was from 1938 to 1962. Once a drug was deemed reasonably safe, it immediately would be released-to researchers, to doctors and to patients.

AIDS patients say the failure of the FDA has forced them, in effect, to create their own underground version of the agency.

"It's a nationally coordinated effort," said Beck, "with guerrilla clinics and buying clubs that purchase vast quantities of material and send it across the country. People are saying, 'The hell with FDA. We're going to find out what works ourselves.' "

Patients by the thousands, advocates say, have been forced to investigate new treatments and therapies, from controversial macrobiotics and magic crystals to the egg lecithin compound, AL-721, which may possess antiviral properties.

"I was diagnosed with AIDS more than two years ago," said one victim. "Why shouldn't I try these drugs? I'm not saying they're going to work. But I'm given no hope anyway. Why can't I try egg lecithin? It looks like butter. I put it on toast and eat it."

AIDS patients are importing the antiviral drug dextran sulfate from Japan, where for 20 years it has been available without prescription. That drug is under study by the FDA, although patients were using it for a year before the government got around to testing it.

Said another AIDS sufferer: "We make sure we're getting the true product in the proper packaging. We're not buying 10 pills in a Baggie."

The network led desperate victims early to what has become the treatment of choice for pneumocystis-the aerosol version of the drug pentamidine. Of necessity, the evidence for efficacy of a drug is mainly anecdotal, not statistical, advocates admit.

"But most of the drugs have shown real promise in early studies," Delaney said. "They merely have not gone the full nine yards as required by FDA regulations."

Said Beck: "Hope turns people on. They say they feel better. At least they're doing something, not going passively to their deaths."

FDA sources, however, say there is tremendous pressure within the agency to get promising drugs out as fast as possible.

"The critical question is: What do you do with drugs whose effects you don't know?" said an FDA insider. "Some drugs seem great in a test tube. But if you put them into people you'd kill them. I think it's fair to argue about our criteria. But it's not fair to say: 'We want drugs that are safe and effective, and we want them right now.' "

Sources admit privately, however, that the FDA traditionally has tended to move at a stately pace. As a result, new drugs are often available in foreign countries long before the FDA approves their use in the U.S.

The pharmaceutical industry has long chafed over the delays wrought by the federal bureaucracy. Many drugmakers feel that federal regulators make no points by clearing a drug. In fact, the safest thing a regulator can do is to make no decision.

If he clears a drug and there's an unanticipated disaster, he has a big problem. If he doesn't clear it and the product is meritorious, eventually outside pressures will build and the drug will be released.

So the best thing a regulator can do, industry sources assert, is to ask for more studies. Yet this position, critics concede, also is consistent with the role of an honorable FDA scientist trying to predict what a new substance will do.

The government has long provided a "compassionate use" provision to allow research-based pharmaceutical companies to make medicines available to desperately ill people as soon as there is sufficient evidence of safety and effectiveness.

The industry, in fact, wanted this provision used for new AIDS drugs, instead of the FDA's fast-track program. The industry worried about implementation of the Treatment IND rule. Few patients would be likely to enroll in classic clinical trials of a new drug if they could obtain it quickly under the federal program. The industry, thus, might be severely hampered in determining the efficacy of its products.

As the Pharmaceutical Manufacturer's Association stressed in a policy statement: "The Treatment IND provision . . . is to serve as an interim, emergency measure. A careful balance must be struck between the physician's concern about the life of a single patient and the government's concern for protecting the health of the entire public."

The drugmakers called for "cooperation and vigilance" to ensure that "the noble intentions of the Treatment IND rule do not open the door to the charlatans and quacks who prey on the misery of desperately ill people."

As the AIDS-drug debate escalates in the coming weeks, there would seem to be one small ray of optimism.

According to industry figures, the FDA has approved testing of 15 new antiviral drugs. Twenty-one new "immuno-modulators," drugs that enhance the immune system, also are in the works. Thirty-three new diagnostic tests are on the way. Nine vaccines and three infection-fighting drugs are in research.

"But the vast majority of stuff that goes through this process doen't make it out the other end," said Delaney.

"It's our position that HIV infection, if treated early enough, can be a manageable chronic illness using treatments that already are either available, or in testing.

"Unfortunately, access to many of those treatments is still blocked by the FDA."

CAPTION: Graphic: (Two "AIDS" test tubes.)

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