Lack of Volunteers May Hurt AIDS Drug Trials : Health: Eligible subjects often have access to new medications through other channels. They are thus unwilling to participate in lengthy lab research.
There are early signs that AIDS researchers conducting formal clinical trials of the newest antiviral drug DDI may be having a difficult time finding eligible volunteers, a circumstance that they attribute in part to the widespread availability of the drug through other newly approved channels, The Times has learned.
AIDS researchers who attended a three-day closed meeting at the National Institutes of Health that ended Wednesday expressed serious concerns that many patients who may be eligible for the formal studies instead have qualified for DDI, or dideoxyinosine, under a new plan that allows distribution of the drug before human studies have proved it effective against the disease, according to sources who were present at the meeting.
Their anxiety underscores the difficulty of achieving the balance between delivering potentially life-saving drugs to terminally ill patients as quickly as possible and the need to evaluate the long-term effectiveness and safety of these drugs, which can only be achieved through traditional highly structured clinical trials.
When the decision to make drugs available to AIDS patients outside the formal scientific process was announced several months ago, many researchers said they were worried that people would not participate in formal trials.
Fewer Than 100
Thus far, fewer than 100 patients have been enrolled in the formal studies, while about 1,000 have signed up for the drug under the new mechanism, sources said.
The researchers cautioned, however, that many of the centers conducting the formal studies have not yet begun to recruit patients and that a clearer picture should emerge within two weeks, once all the formal DDI studies are underway. “It may be too early to conclude that the trials are impaired,” said one researcher who attended the meeting.
Nevertheless, “people are concerned,” said another researcher who was there. “There are more people concerned now than there were several months ago. There is enough preliminary evidence to make people worried. I fear that the hype about DDI has been such that people are doing back-flips to get on it, one way or the other.”
Traditionally, new drugs are not released until rigorous human studies have shown them to be both safe and effective, a process that typically takes several years. Further, these drugs usually were only available to patients who qualified for such trials. In a formal trial, one group is given the new drug and another is given something else for comparison purposes.
In recent months, however, federal health officials, under increasing pressure by AIDS activists and others, have indicated their willingness to make promising but unproved drugs accessible earlier for life-threatening conditions, and have announced several routes for doing so.
These include a proposal to establish less formal “parallel track” trials and the increased use of a designation known as the “Treatment IND”, for “investigational new drug,” both of which would enable patients to receive drugs while the drugs are still being formally studied.
In September, the Food and Drug Administration announced that it would make DDI available to certain AIDS patients under the IND designation, which makes a drug available for “compassionate use.” In the parallel track trials, there would not be a comparison arm, and it would include those patients who could not qualify for entry into traditional trials.
“I don’t know what’s going to happen but everyone is watching it; we’re following it very closely,” said Dr. Daniel Hoth, director of the division of AIDS for the National Institute of Allergy and Infectious Diseases, which sponsors the formal AIDS clinical trials program.
“The (IND) started before the research track--it had a head start. We would have preferred that they had started together. There is a tremendous pent-up demand, and those patients--if they all go in one direction--once they’re gone, they’re gone. That’s not to say there’s nobody left. But it does mean we may be losing the opportunity to accrue patients into the research trials,” Hoth said.
Another scientist at the session, which was a regularly scheduled meeting of researchers who belong to the 46 units of the AIDS Clinical Trials Group, which are funded by NIAID to conduct trials of potential AIDS therapies, said: “you can have accrual problems with any trial.”
But, he added, “If we see a continuous increase in the numbers of patients in the Treatment IND for DDI” without a corresponding increase in the numbers participating in the trials, “then we would have to worry that the IND was a mistake. We have to achieve a scientific evaluation of DDI if the drug is to have a future.”
Allergic to AZT
Under the IND, all patients who cannot medically tolerate AZT, the only approved antiviral AIDS drug, will automatically receive DDI. There are three formal DDI trials scheduled, which require a total of more than 2,000 participants. Two of the three clinical trials are intended to compare DDI to AZT. A third trial would compare two different doses of DDI among individuals who cannot take AZT.
Federal health officials have insisted all along that individuals who were otherwise eligible for formal trials would not be allowed access to the drug through other channels. However, at the NIH meeting this week, some researchers suggested that the entry criteria for the formal studies may be too strict, enabling patients to use the easier alternative to get the drug, sources said.
“People are asking for more flexibility,” one researcher said. “It’s too easy to rule someone out and lose him to parallel track. We may have to loosen up the rules a little to attract the patients.”
For example, one of the formal studies is designed to determine whether individuals who develop anemia taking AZT do better with DDI. To be eligible for the formal study, an individual must demonstrate that AZT has reduced the oxygen-carrying capacity of his blood by more than 40%, as measured through his level of hemoglobin.
“Many physicians would stop AZT before a patient’s hemoglobin got that low, or give him a blood transfusion, so he would not qualify for the formal trial,” one researcher said. “Also, if the physician has the option of getting his patient on DDI in a Treatment IND--which is easier than getting him into a formal trial--that’s what he’s going to do.”
Thus, he said, in these circumstances, an individual might “never even know” that he qualified for a clinical trial and would not be motivated to find out since the drug was available elsewhere.
“What we are anxious to do is to make sure that if someone is eligible for a DDI trial, that the trial is the route he takes to get that drug,” the researcher said.
The NIAID’s Hoth said that NIAID would continue to monitor the situation closely.
“This is absolutely critical to allow us to tell whether the (IND and proposed parallel track) is adversely impacting the research,” he said.
He said he is hopeful that the competing tracks will benefit the formal research.
