The First Human

Should the first human be healthy? Why? Won't you learn more from patients? If the target disease makes the patient so fragile that he is at special risk for an unexpected serious adverse reaction, begin with a healthy volunteer but move quickly to patients. Phase I trials can include both volunteers and patients braided together.

There are not many such diseases. Life-threatening hepatitis B severely compromises patients. Fialuridine, a nucleoside that seemed very promising in a National Institutes of Health (NIH) trial in hepatitis B, killed five patients despite liver transplants through very delayed unexpected toxicity. This toxicity was not observed in extensive animal and prior clinical studies in several patient populations. Perhaps the toxicity is only manifest in humans with fatally progres sive chronic hepatitis B. Healthy volunteers might have contributed nothing or even false encouragement to these trials. If the deaths had been in healthy volunteers instead of patients, would that be more ethical?

Patients may respond favorably to a new treatment. They may manifest improvement in at least surrogate endpoints and thereby contribute more information for their risk of participation. As a reward, they can be promised that they will be allowed to participate in later pivotal efficacy trials and they may be promised compassionate use of the drug until a regulatory decision is made about its marketing, pricing, and reimbursement.

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