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Expanded Access to Investigational New Drugs - Case H3

Note: For purposes of discussion, assume that this case is taking place in the late 1980s, before development of "parallel track" and "expanded access" review mechanisms at the Food and Drug Administration (FDA).

Agnes Jones is a professor of pharmacology and a member of the FDA Antiviral Advisory Committee that reviews scientific data from studies on new AIDS therapies. She has just completed reviewing an investigational new drug (IND) application submitted by RETRORIX, a company wishing to conduct a clinical trial of their new agent, ANTIVIR, in clinically advanced cases of AIDS. The IND application described a double-blinded placebo- controlled treatment protocol in which ANTIVIR would be given in addition to the standard therapy.

When her advisory committee met, Dr. Jones, as primary reviewer, reported her critique of the ANTIVIR protocol. In Dr. Jones's opinion the study was well designed, and she recommended that it go forward with only minimal additions to the monitoring criteria. The end points were to be T -helper cell numbers, treatable infections, and survival. After Dr. Jones's report, RETRORIX's representatives were invited to sit at the table to discuss and to agree upon the final protocol. One of the members of the FDA advisory committee, Harold Hale, was an AIDS activist who argued forcefully that the protocol would get much more support from the HIV -infected community and could be completed much faster if all participants in the study received ANTIVIR. He stated that large amounts of historical data were already available and could provide a sufficient basis for comparison as a surrogate control population, especially for T -helper cell numbers and mortality. He and other victims of HIV infection should be afforded any treatment that holds even a modicum of hope for improvement, Mr. Hale asserted.

Dr. James Wolf, president of RETRORIX, was opposed to an "open" therapeutic trial. He was concerned that the study would be invalid because of the inadequacy of the historical controls. Dr. Wolf noted that these had been many small improvements in the ancillary care of AIDS patients and more were on the horizon, making the results for historical controls a dubious comparison. He also pointed out that in animal and Phase I studies, ANTIVIR had shown a very narrow therapeutic dosing range. Beneath this range, the drug was ineffective, and above it, the drug created severe side effects, Dr. Wolf explained. Making the drug so widely available at this point would complicate careful management of the drug's administration, exposing people to undue risk.

In response, Mr. Hale argued that clinically advanced HIV infection is invariably and rapidly fatal. Given the grim prognosis for patients in his situation, any improvement in survival outweighed concerns for the drug's side effects, he asserted, insisting on accelerated evaluation and an open clinical trial.

Questions:

  1. Identify and discuss the ethical dilemma at the core of this case.
  2. Dr. Wolf argued against the open trial. What do you believe are his concerns? Are they well founded?
  3. Mr. Hale was representative of a large number of AIDS sufferers. Should he have participated in the deliberations? Were his arguments relevant and/or convincing?
  4. Given the concerns and responsibilities of the parties involved, how should this clinical trial be conducted?------------------------------------------
    (Case H3 continued)

    Dr. Jones proposed that RETRORIX conduct two studies, a relatively small double-blinded placebo-controlled study and a larger open trial. The FDA Antiviral Advisory Committee agreed and, reluctantly, Dr. Wolf with numerous objections went along. He insisted, however, that the historical controls be a predetermined population for which complete data were available. Consequently, a specific cohort was selected.

    When the two-year trial was completed it was found, as shown in Table I, that the ANTIVIR group had a substantially better survival rate than the historical controls and fewer severe infections. The T - helper cell levels of the treatment group were also better on average.

    However, in the placebo-controlled study, the placebo group did nearly as well as the treatment group and there was not enough statistical power to determine unequivocally whether ANTIVIR was extending life. In any case, the side effects of the drug seemed acceptable under carefully supervised conditions. Pressure was mounting from AIDS activist groups for accelerated approval. Dr. Wolf asked for approval since the ANTIVIR trial fulfilled the standards of the FDA. He also noted that his company had exhausted the financial resources available for testing this drug. Dr. Jones was asked to give an opinion regarding approval at the next meeting of her FDA committee.

    TABLE 1

    T-Helper Cell Number, % Change from Baseline

    Significant Infections, %pts

    Mortality %Patients

    Placebo Control

    -15

    40

    23

    ANTIVIR Treated

    -10

    35

    17

    Historical Controls

    -40*

    90*

    40*

    Open ANTIVIR

    -10*

    35*

    20*

    * = Significant difference, p < .01

    Questions:

  5. Characterize the dilemma presented by the conflicting results of the two studies. How would you go about resolving it?
  6. Was there a better way to handle this situation? If so, how?
  7. "One of the most unethical forms of research on human subjects is that which is incapable of resolving the scientific question because of inadequacy in the experimental design." Discuss the validity and dimensions of this statement.
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