Widespread Use of Experimental AIDS Drug Approved

WASHINGTON —  Federal health officials Thursday announced the approval of widespread use of the experimental AIDS drug DDI, but they expressed new concerns over its “potentially serious side effects.”

Although early data indicated that the drug could be tolerated by most AIDS patients, more recent studies have shown that some patients taking DDI, particularly at higher doses, have experienced alarming side effects, the Department of Health and Human Services said. The side effects include painful nerve damage to the feet and injury to the pancreas.

The decision to release DDI, or dideoxyinosine, was made amid a new regulatory climate of increased willingness to make unproved drugs available quickly for life-threatening conditions. Federal officials have been under increasing pressure from AIDS activists and others in recent years to move more rapidly to release such drugs.

In the case of DDI, the decision is considered highly unusual in several respects. First, formal human studies have not been conducted to determine if the drug is effective against AIDS. Further, the questions being raised about its safety probably would have been sufficient in the past to limit use of the drug at this stage of its development to carefully controlled clinical trials.

Worry over the new safety information delayed for several weeks the decision to allow widespread distribution of the drug, and the government is releasing it with serious reservations, department sources said.

Federal health officials said DDI’s continued distribution will depend on “satisfactory results” regarding safety and other factors, such as the ability to enroll enough participants in formal efficacy trials, which are also scheduled to start shortly. The program “will be closely monitored,” the department said.

But even if problems arise, one department source said, “the pressure is going to be on not to pull” the drug from circulation, adding, “How the hell do you stop it once it’s out there?”

The department said the side effects “appear to be reversible if detected early and if the drug is discontinued.”

The drug will be made available as a “treatment IND,” or investigational new drug. The designation allows the drug to be used for treatment before it has been approved for marketing and while research continues.

It will be available only to patients with AIDS or advanced AIDS-related complex who cannot medically tolerate AZT, or zidovudine, the only approved antiviral AIDS drug. AIDS patients who have experienced severe anemia or other “dose-limiting” adverse reactions to AZT will be eligible to receive DDI, the department said.

In addition, Bristol-Myers Co., the drug’s manufacturer, will distribute DDI in the United States and Canada under a special “compassionate use” program to those AIDS patients “whose disease has substantially progressed,” despite AZT therapy, and “who have no other treatment options,” the department said.

Patients who qualify for formal clinical trials of the drug may be ruled ineligible to receive the drug under the treatment IND or compassionate use programs, the company said.

“This plan offers some additional options for people with AIDS,” Health and Human Services Secretary Louis W. Sullivan said in a statement. “This plan . . . reaffirms our commitment to speeding both the development and availability of promising new drugs for patients with AIDS whenever possible.”

Like AZT, DDI works by inhibiting replication of the AIDS virus.

“I think the drug is very good and is clearly effective,” said Dr. Jerome Groopman, an AIDS researcher at New England Deaconess Hospital in Boston who has been involved in early studies of the drug. “It’s also clear that at several dose levels, particularly above 1 1/2 grams a day, there is significant neurological toxicity and pancreatitis. Lower doses appear to be well tolerated.”

Groopman said that DDI appears to be effective against the disease at lower doses, although he cautioned that his conclusions were based on preliminary knowledge.

He said patients have been receiving 750 milligrams of DDI daily, half of the dose known to cause problems. But he said researchers still do not know if lower doses of the drug could be cumulative, simply taking a longer period of time to cause the same side effects.

“DDI is a promising drug,” Groopman said. “But the bottom line is, our experience is still very limited.”

Bristol-Myers will provide DDI at no cost. Patients will be responsible for any physician and laboratory costs associated with receiving the drug.

A company official said that it is “simply too early to speculate” what the drug would cost if it receives final approval.

If approved, the drug, which would be marketed under the trade name Videx, would be the second antiviral AIDS drug on the market. Burroughs Wellcome Co., the manufacturer of AZT, has been criticized for the high price of AZT, which costs the average AIDS patient about $8,000 a year. Recently Burroughs announced that it will cut the price by 20%.

Formal clinical trials to determine if DDI is effective are scheduled to begin soon. About 2,600 participants will be enrolled in three different trials, sponsored by the National Institute of Allergy and Infectious Diseases.

Compare Drugs

The first trial will compare DDI to AZT in patients who have had little or no treatment with AZT. A second will compare DDI to AZT in patients who have been taking AZT for at least a year. A third will compare three different doses of DDI among patients who cannot tolerate AZT.

Bristol-Myers said that applications for the treatment IND and compassionate use programs will be considered by medical reviewers. Physicians who want information about enrolling patients in any of the programs, including the clinical trials, should telephone a toll-free number, 1 (800) 662-7999, between 5 a.m. and 5 p.m. PST.