FDA Cuts Time It Takes to Test Unproven Drugs

The powerful but poorly understood process by which the federal government protects the public from dangerous or unproven drugs is slowly being reshaped for the first time in a quarter-century, under the pressure of the AIDS epidemic.

The Food and Drug Administration moved last month to streamline the scientific trials required before pharmaceuticals can be marketed in the United States. Officials say they hope to cut the process, now averaging nearly nine years, by as much as one-half for certain drugs.

The agency is also attempting to broaden the access of dying people to some promising but unapproved experimental drugs, stressing in a new rule the willingness of patients and physicians to accept certain risks from drugs for deadly diseases.

Response to Pressure

The shifts at the FDA are occuring in part in response to pressure from people with AIDS, an invariably fatal disease for which there is currently only one approved treatment. Frustrated AIDS activists have formed a persistent and powerful patients’ lobby.

But top government cancer researchers also have been attacking the FDA, accusing it of narrow-mindedness in its scrutiny of experimental cancer treatments. Meanwhile, Reagan Administration officials favoring “regulatory relief” have turned their attention to the FDA bureaucracy.

“It’s clear that for certain kinds of diseases, the normal processes set up aren’t going to be working any more,” said Dr. Arthur J. Ammann, director of collaborative medical research at Genentech, a pioneering biotechnology firm in South San Francisco.

“A general review of the whole drug approval process needs to be done,” said Ammann, who also teaches at UC San Francisco. “I think basically the policies that have been instituted have been in place a long time. But we’re in a new era of both disease and types of drugs.”

FDA Responsibility

The FDA--the principal consumer protection agency in the federal government--is responsible, among other things, for ensuring that all drugs are proven “safe and effective” before they reach the market, and that their benefits outweigh their risks.

The massive agency regulates one of the nation’s top 10 industries. About 18,000 drug firms fall under its scrutiny. Its small army of reviewers carries a collective caseload of about 15,000 applications for permission to market drugs pending at any one time.

Drug manufacturers have complained for 15 years that the FDA process is excessively strict and cumbersome, putting U.S. firms at a competitive disadvantage against foreign manufacturers. Consumers, many manufacturers say, end up paying the high price of getting drugs approved.

“My sense is there is virtually a unanimous consensus that the FDA has to do a faster job in approving safe and effective new drugs,” said Gerald J. Mossinghoff, president of the Pharmaceutical Manufacturers’ Assn., in a recent interview.

Not All Agree

There are, however, exceptions to Mossinghoff’s rule. They include some academic researchers and consumer advocates who argue that the United States may take longer than other countries, but that it has been more successful in keeping dangerous drugs off the market. Dr. Sidney Wolfe, director of the Public Citizen Health Research Group, contends that the agency’s time is frittered away reviewing insignificant new drugs. Far from breakthroughs, most new drugs are simply another company’s version of what already exists, he said.

“In the world that we think would be much safer and better for patients, the FDA would not be able to approve a drug unless it were an important advance,” Wolfe said. “Most of their time and energy is wasted on drugs that do not even arguably offer an important advance.”

The drug approval process currently under fire goes something like this:

A drug’s sponsor--a firm or a research institute, for example--first tries out its new product on a few dozen volunteers. That study, called a phase-one trial, is designed to determine whether the product can be tolerated and metabolized in humans.

If it can, the product goes into longer and more extensive trials--on 50 to 200 people in phase two and on 200 to more than 1,000 people in phase three. Those trials, which usually take years, examine the drug’s safety and whether it is effective and at what doses.

Some Get Placebos

In those studies, the volunteers are placed randomly in different groups. Some receive the drug, others receive a placebo. The aim is to enable the researchers to recognize real effects of the drug by comparing the reactions of the two groups.

What finally emerges is a so-called New Drug Application--as much as 100,000 pages of data to be reviewed by the FDA. According to the FDA, the entire process, from a drug’s discovery to its final approval, takes an average of almost nine years.

AIDS, however, has posed a potent challenge to that system.

People with acquired immune deficiency syndrome, with perhaps only a few years to live, say they cannot wait for the drug-approval process to run its meticulous course. They say the FDA should make promising experimental drugs available more quickly, perhaps to anyone willing to take the risk.

AIDS activists have challenged the foundations of the FDA’s system. Is it ethical to give dying patients a placebo that, by definition, will do no good? Couldn’t drug trials be opened up, some have wondered, to anyone who wants to participate?

Last month, those challenges boiled over outside FDA headquarters in Rockville, Md., where about 1,000 demonstrators blocked an entrance to the building for nine hours. Police barriers were smashed; President Reagan was burned in effigy. Police arrested 176 protesters.

Others Challenge System

AIDS activists are not the only people challenging the system.

Dr. Bruce Chabner, director of the division of cancer treatment at the National Cancer Institute, which finances or conducts much of the nation’s cancer research, has been waging what he understatedly calls a “longstanding dialogue” with the FDA over approval of cancer drugs.

Chabner has challenged what he says is the FDA’s insistence that cancer drugs must improve a patient’s survival potential. He argues that it should be enough to prove that a drug has “activity”--for example, that it restores some biological function.

“Unless there is some essential change in approval criteria, it’s not going to make much of a difference,” Chabner said of the FDA’s new attempts to make drugs available more quickly--attempts that he, like others, supports while wondering whether they will work.

The new rule proposed last month--aimed at speeding availability of drugs for life-threatening diseases where no alternatives exist--offers sponsors of new drugs the opportunity to shortcut the usual approval process by working closely with the agency.

Dr. Frank Young, the FDA commissioner, said recently that it might be possible to cut the time required for trials by one-third to one-half by carefully designing and expanding phase-two trials to make them definitive, skipping the entire third phase.

Could Get Added Data

It might also be possible to open up the second phase of trials to include many more than the usual numbers of volunteers, Young said. That way, the drug’s sponsor and the agency could get additional data on safety, and more people would have early access to the drug.

In the new rule, the agency stated repeatedly that it was recognizing the willingness of patients and physicians “to accept greater risks or side-effects” from treatments for fatal diseases than from products for less-serious conditions.

“These procedures also reflect the recognition that the benefits of the drug need to be evaluated in light of the severity of the disease being treated,” the rule states.

That emphasis prompted some observers to wonder whether the FDA is recalculating the risk-benefit equation at the heart of the review process--a subtle computation by which it judges a drug’s “safety” by weighing its side-effects against its benefits.

“That’s a very important emphasis,” Nancy Buc, a former FDA chief counsel who is now a food and drug lawyer in Washington, said of the emphasis in the rule. “That’s an area where it will be real interesting to see how the FDA deals with this.”

Degree of Safety

Authorities say there has long been a tacit recognition that the degree of safety required of a drug depends to some extent on the drug’s purpose. For example, greater toxicity is acceptable in a cancer drug than in a drug to treat headaches.

In its calculations, the FDA has leaned on the side of safety. But safety is not an absolute standard. In making decisions about drugs, FDA officials say safety is defined as whether a drug’s benefits outweigh the risks.

“There will always be two questions,” Buc said. “One is what you know and don’t know. . . . The other is, given what you know, how do you strike the balance? There is plenty of room for debate.”

Agency officials deny that there has been any philosophical shift. They say the changes are procedural; there will be no lowering of standards. They say it is now possible to speed up the approval process because of a series of managerial changes.

Those changes include the issuing of guidelines to clarify FDA requirements for drug approval; attempts to improve communication between the agency and drug sponsors, and a new high-priority designation for AIDS drugs under review.

Now Using Computers

In addition, the FDA and the pharmaceutical industry have begun putting some new drug applications onto computers. The agency also has improved its application tracking system and has recently increased its number of clinical reviewers.

“The fundamental change is trying extra hard to get information (about a drug’s effectiveness) earlier,” said Dr. Robert Temple, a director of the FDA’s office of drug evaluation. “That involves effort on our part and the industry’s part.”

Nevertheless, the FDA’s latest moves have been met with some skepticism.

Many observers called the timing of the new rule blatantly political: The FDA announced it one month before the presidential election, taking pains to credit Vice President George Bush, the Republican candidate, for part of the impetus behind the change.

Adding to those suspicions is the agency’s acknowledgment that it already had the power to implement the new system and had done so well before announcing the new rule. Others counter that there is value in making it widely known that the new options exist.

Call for Greater Change

AIDS activists also say the changes do not go far enough.

For example, it is not mandatory that drug sponsors meet with the FDA to discuss the design of phase-two trials in the hope of eliminating the need for a third phase. Nor has the agency committed itself to apply the accelerated process to particular drugs.

Activists pointed out that the FDA’s earlier effort, in 1987, to broaden availability of experimental drugs had so far had little effect on people with AIDS. The half-dozen drugs that FDA officials say have been placed in that program include only one experimental AIDS drug.

“Time will tell if this is an important, small philosophical step or just political opportunism by the Bush campaign,” said Dr. Barry Gingell, director of medical information at Gay Men’s Health Crisis in New York City.