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The IOM Committee provides no comment in this section on compliance with the ethical norms calling for good research design and competence of investigators because these matters are discussed at length in other parts of this report.

Favorable Balance of Harms and Benefits

As discussed earlier, the ethical justification of research requires a determination that the balance of risks and anticipated benefits is—in the words of federal regulations—"favorable" or "reasonable." This determination, which must first be made by the investigators and then ratified by the IRB, must be accomplished at the outset, before the research is begun. These estimates of risk and anticipated benefits may turn out to be badly mistaken when the results are in, and all involved may regret doing the research, but the work should not be deemed unethical solely on that basis.

In this case there were reasonable grounds for great optimism about FIAU. It often inhibited hepatitis B virus DNA replication very promptly and virtually completely; no other therapeutic agent that could accomplish this salutary objective so efficiently was (or is) known. Moreover, it was an easily administered oral medication, and there was no advance indication of any serious adverse events.

In all research activities designed to evaluate a new drug, the initial estimation of risks must take into account the possibility of occurrence of novel injuries—harms that cannot be predicted on the basis of prior clinical or preclinical testing. Fortunately, injuries that are both serious and unanticipated are very unusual. In this case there occurred an injury that was both serious and unanticipated. This occurrence does not indicate that the research was ethically deficient. The IOM committee cannot—even in retrospect—suggest any tests that might have been done to anticipate this serious toxicity.

Responsiveness to this norm also requires that there be careful monitoring of all events that have a bearing on the assessment of both risks and benefits. In this case there have been allegations that the monitoring of safety data may have been faulty and that findings of adverse events did not result in indicated changes either in the protocol or in the risk information divulged to subjects. On review of this matter, the IOM committee finds that the monitoring of such data was not merely adequate; when considered in the light of prevailing practices in the field, the monitoring activities of these research groups and the sponsors were exemplary. Interpretation of such data, particularly data indicating either damage to the liver or diminishing liver function, was not recognized promptly as indicating drug toxicity for at least three reasons. (1) Since the patients had chronic hepatitis some fluctuation in the results of liver function test results is expected as the activity of the disease waxes and wanes. (2) Some of the patients in whom changes in liver function tests were detected had other factors that could have contributed to such changes. (3) Some, although not all, experts believe that improvement in patients with chronic hepatitis is often heralded by flare responses during which laboratory test results that most commonly indicate damage to the liver (elevated serum aminotransferase) may be observed.

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