Newsday - May 5, 1992
Laurie Garrett

FOUR YEARS AGO New Yorker Mark Harrington was one of hundreds of AIDS activists who made themselves into human barricades, blocking entrances to Wall Street offices, the Food and Drug Aministration and the National Institutes of Health, denouncing federal officials and corporate representatives as "agents of genocide."

Last month the slight-framed Harrington, who still sports a flat-topped haircut and the jeans and sloganed T-shirt look of Manhattan's Lower East Side, spoke in the vernacular of federal regulators, and had a roomful of men and women in the palms of his hands.

Over 1,000 dressed-for-success drug company representatives were on the edges of their seats when Harrington addressed the AIDS Advisory Panel of the FDA in a filled-beyond-capacity Bethesda hotel ballroom. Harrington, who is a member of New York City's chapter of ACT UP, is officially designated a consultant to the FDA panel, and his recomendations for new drug approvals carry enormous weight. Among those on hand for all 20 hours of the panel meeting was FDA Commissioner David Kessler.

And though the ostensible purpose of the gathering was approval of Hoffmann-La Roche's anti-AIDS drug, ddC (dideoxycytidine), most of those in attendance saw it as a test of Kessler's commitment to a new Accelerated Approval program to get minimally tested drugs for life-threatening ailments to the marketplace rapidly, and at less expense to manufacturers.

Last week ddC became the first drug to gain official recommendation for Accelerated Approval under a program that was just formally introduced by Kessler on April 15. The program was accepted by the agency as a result of pressure from AIDS activists, scientists and drug companies.

"The industry has been very eager to see something like this to cut costs," regulatory analyst Tom Copmann of the Pharmaceutical Manufacturers Association said in an interview. "We've been after the agency on this thing for years."

Pharmaceutical companies have long complained about the mountains of pre-marketing animal and clinical tests required to gain FDA approval, and PMA representatives say it takes an average of $250 million and 12-20 years of research and development to get FDA license for sale of new drugs.

That change has finally come - change that Kessler says will affect approval of drugs for a broad range of life-threatening diseases, including cancer, diabetes, and Alzheimer's.

IT IS THE DIRECT result of the AIDS epidemic. Specifically, of the confluence of otherwise highly disparate interests that include scientists, the drug industry, people with AIDS and activists.

On April 21, the advisory panel of outside medical experts voted to recommend agency approval of ddC use in combination with the standard AIDS drug, AZT (azidothymidine). The recommendation came despite any evidence the drug provides patients clear clinical benefits, relieves AIDS symptoms, or extends life expectancy. And there was clear evidence the drug causes problems in patients: upwards of a third of the ddC users in Hoffmann-La Roche sponsored clinical trials suffered peripheral neuropathy, a nerve problem that can range in severity from tingling in the toes or fingers all the way to paralysis of arms and legs.

Six months earlier the FDA issued a landmark decision, giving the O.K. to another AIDS drug, ddI or dideoxyinosine, on the basis of so-called surrogate markers. As with ddC, Bristol-Myers' ddI failed to show clear clinical benefits at that time, but did produce severe side-effects. Still, AIDS patients were clammoring for an alternative to the only other available drug, AZT, which eventually causes anemia or loses its effectiveness.

So the FDA agreed to approve ddI on the basis of changes in blood levels of immune system components called CD4 cells. Activists and scientists from the National Institute of Allergy and Infectious Diseases argued that declines in CD4 levels were clearly associated with patient deterioration, so CD4 cells could be used as surrogate markers of drug efficacy, much the way changes in blood pressure serve as a marker of drugs' effects on heart disease.

"The FDA took the risk," as Kessler put it, approved licensing of ddI for use by people infected the human immunodeficiency virus who couldn't tolerate AZT, and ordered Bristol-Myers to return within six months with further clinical data for review.

Last month, to the relief of advisory committee members, the company presented evidence that ddI slowed the progression from infection to full AIDS more than did AZT.

Harrington told the doctors and scientists they should feel "the relief that should come from knowing that if they made a mistake [in approving ddI on the basis of surrogate markers], it was the right mistake. You took a risk last summer and today we saw genuine impact of the drug."

No voices equivalent to ACT UP in strength and volume have stepped forward to wield such power and demand rapid drug approval for such things as cancer, diabetes, heart disease, multiple sclerosis, Alzheimers or schizophrenia treatments. The PMA's Copmann predicts the next outcry will come from likely recipients of so-called orphan drugs, agents whose utility is limited to very small numbers of people, many suffering otherwise hopeless genetic disorders.

"Why do you need such stringent regulations for drugs for such small numbers of people?" Copmann said. "There are 286 orphan drugs in trial now, and we could get a lot more into the pipeline if they cut costs by reducing the burden of proof." The list of backlogged orphan drugs includes 27 for AIDS, 35 for genetic disorders, 58 for rare cancers, and 50 for childhood diseases.

Kessler won't comment on which other drugs are likely candidates for Accelerated Approval, and says the the program could rise or fall on ddC.

"We have to be willing to say we may be wrong here," Kessler said in an interview, adding, "but it's okay if we're wrong. Follow through and post marketing testing assures that, in the end, we make the right decision."

But even as Kessler - backed strongly by the White House - grows increasingly enthusiastic about rapid drug approval based on small studies and surrogate markers, some members of the AIDS community are having second thoughts. They worry, for example, that surrogate markers may not serve as ideal basises for drug approval.

"Wishing won't make it so," warned AIDS advisory panel member, Paul Meier. A University of Chicago statistician, Meier has repeatedly expressed skepticism about the utility of CD4 markers in AIDS drug approval.

"If the surrogate markers do not match up with clinical benefit, well, what good are they?" Meier asked. "If industry is sitting out there thinking, `all we need to do is show CD4 effects - any CD4 effects - and we'll get approval,' well, that's a dreadful message and a dreadful lesson."

Dr. Donald Abrams, who has treated AIDS patients through San Francisco General Hospital's prestigious program since the first days of the epidemic, was upset that even ddI, which seems to make patients feel better, hasn't improved long term AIDS survival.

"I am concerned about the lack of translation of CD4 into a clear clinical outcome and survival," he said, adding, "if we continue to improve things that elevate CD4 ten points for twelve weeks, that's the wrong message." A difference of 10 points often occurs in patients simply based on the time of day blood samples are drawn, he said.

The issue of what message, exactly, the pharmaceutical industry would take away from the Accelerated Approval of ddC was a key concern for activists, too. A few days before the panel meeting, Harrington, fellow AIDS activists and leading federal scientist Dr. Dan Hoth of the National Institute of Allergy and Infectious Diseases had a meeting in Bethesda. Just three years ago, ACT UP was denouncing Hoth, saying his drug research department was slowing down patient access to experimental drugs by insisting on conducting carefully controlled trials that would yield clear scientific results.

"We were having drinks and Mark [Harrington] said he was concerned by the quality of the ddC data," Hoth recalled. "And he said, `we shouldn't approve the drug because it will send the wrong signal to industry,' and I said, `you can't hold patients hostage to the problems of clinical trial design'."

The conversation came to a hush, Hoth said.

"It was an instant reaction. Everybody at the table looked at each other and said, `My God, what did they say?' It blew me away." Such a sharp role reversal, with some ACT UP members now demanding carefully controlled clinical trials and their former government foes arguing for patient access to experimental drugs, has startled everyone involved.

Within the activist community a rift has developed, with those from New York arguing for stronger clinical studies, and San Francisco-based advocates saying any drug, regardless of it's toxicity or efficacy, should be approved for life-threatening diseases.

"The issue is choice," Martin Delaney of San Francisco's Project Inform said. "And what is happening now that is so very important is the FDA recognizing that patients have the right and the intelligence to make their own treatment choices."

Attorney David Barr, of New York's Gay Mens Health Crisis, says choice is fine, "but simple approval of a drug doesn't make that a choice. It's approval coupled with a primary care doctor. If all there is, is approval, it just means the same people who are getting the drug now [through the AIDS underground] will continue to get it, but from their pharmacy."

Harvard University's Dr. Deborah Cotton, who was a member of the AIDS advisory panel, voted against approval of both ddI and ddC because the clinical data was very poor.

Cotton directly confronted Kessler on the issue, saying, "we really are moving here at lightning speed. And I'm very concerned that we've just made a decision that's going to weaken drug company clinical trials, if not end them."

Kessler insists the burden of proof on pharmaceutical companies is not lessening, it's simply moving for life threatening diseases to largely post-marketing testing. Drugs will be pulled off the market, Kessler insisted, if they prove dangerous.

But Cotton isn't convinced. "It would be extremely unlikely we could ever pull these drugs off the market. Patients and doctors will legitimately say that as long as the drug is benefitting even one patient, it can't be pulled off the market."

But Kessler, Delaney and Hoth think consumer choice will drive the post-marketing process. Bad drugs, they argue, simply won't get used and drug companies will voluntarily withdraw the products because of low profits.

Which left Dr. Neil Schram, an FDA panel consultant and long time Los Angeles-based AIDS physician distressed. Schram supports rapid drug approval and patient access to experimental treatments. But, he said, drug companies shouldn't be allowed to get away with sloppy studies.

"We don't have the data, as physicians, to tell us what to do," Schram said. "How do you set a standard of care now for AIDS? How do you decide who can benefit from ddI, AZT, from ddC? When? At what dose? What we have is treatment chaos."

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