provides longer life, better function, or better quality of life, the FDA would approve it regardless of its cost.

In oncology presently, survival and improvement in patient-reported symptoms are considered unequivocally while weighing a drug’s clinical benefits. Other measures may be included as well, such as objective response rate and time to progression. While the FDA is very supportive of using health-related quality of life as an endpoint, generating the evidence has proved difficult, and few drugs have reached the market based only on this measure. Blinding is difficult in trials to determine health-related quality of life; very careful serial assessments are essential, and the clinical significance to patients of changes in quality of life may be unclear or of little utility compared to careful recording of toxicity data. In combination with objective antitumor effects, the quality-of-life outcomes are more credible. Nevertheless, it is hoped that advances will be made in methods for generating accurate health-related quality-of-life data, said Dr. Woodcock.

Many drugs reaching the market in recent decades have been approved after regulations were implemented allowing approval based on surrogate endpoints (accelerated approval). Put in place during the HIV epidemic, these regulations were set up for serious and life-threatening diseases in which a drug appears to provide benefit over existing therapies based on a surrogate endpoint thought to reasonably predict clinical benefit. Accelerated approval has been used extensively in cancer drug approvals in recent years. Accelerated approval is subject to legal requirements that the applicant complete longer-term postmarketing studies to verify and describe the clinical benefit of their drug. These postmarketing studies should usually be underway at the time of approval. Therefore the value of therapies approved this way is not fully clear at the time of launch and may remain unclear until confirmatory studies are complete.

Recently, time to tumor progression, or progression-free survival, has been suggested as a measure of clinical benefit. Often, time to progression involves measuring radiographic or other evidence of progression. Clearly, if tumor progression occurs, it will eventually lead to negative outcomes, but this must also be weighed against the harm a treatment may cause. This leads to more uncertainty than measuring objective survival (Table 4-1). Ultimately, the importance of time to progression depends on the size of the benefit. If the benefit is large and unequivocal, then our uncertainty is low. If the difference is only apparent statistically with equivocal impact on patient well-being, then the benefit of the drug remains quite uncertain, and the evidence is much less persuasive for approval.



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