ROCKVILLE, Maryland- Members of the Oncology Drugs Advisory Committee (ODAC) have recommended that the Food and Drug Administration (FDA) expand the clinical study endpoints it accepts in approving drugs for treatment of non-small-cell lung cancer (NSCLC). ODAC overwhelmingly urged the FDA to use improvement in diseasefree survival (DFS) resulting from adjuvant chemotherapy to support regular approval for NSCLC drugs and to consider progression-free survival (PFS) in granting accelerated approval to such agents. By a narrower vote, ODAC members also recommended 11 to 8 the use of PFS as an endpoint for granting regular approval of a drug for first-line treatment of metastatic NSCLC. The ODAC meeting on new NSCLC endpoints, was its first in a series of sessions to evaluate possible new endpoints for approving drugs for specific cancers. It followed a workshop to address the issue as it relates to NSCLC. FDA convened the day-long public session in consultation with the American Society of Clinical Oncology (ASCO) and the National Cancer Institute (NCI). FDA has focused primarily on survival and secondarily on improved quality of life as approval endpoints: In the classic assertion by FDA official Robert Temple, MD, "Survival trumps everything." To shorten the drug testing period and in response to the need for new ways to determine the efficacy of targeted cancer therapies, however, the FDA is investigating which additional approval endpoints might be scientifically valid. The ODAC members readily approved DFS improvement from adjuvant chemotherapy as a supportive endpoint to give regular approval for NSCLC drugs. David Johnson, MD, director, Division of Hematology and Oncology, Vanderbilt University, and a voting consultant to ODAC, cited evidence from two studies to support his vote-an international study presented at the 39th annual meeting of the American Society of Clinical Oncology and a Japanese trial. In both studies, DFS closely tracked the ultimate survival rate. PFS as an Endpoint During its discussion and voting, ODAC dropped the term "time to progression" and adopted "progression- free survival" instead. According to an FDA document, although PFS has been proposed generally as a surrogate endpoint for regular approval of cancer drugs, researchers have not rigorously validated it as such. In favor of PFS, the agency said:
- It measures tumor effect in all patients rather than just in a subset.
- Oncologists and patients widely view progression as an indicator of disease worsening that necessitates a change in therapy.
- Tumor progression is in the direct causal path of morbidity and death.
- PFS is an indirect measure of patient benefit.
- The clinical meaning of a small difference in PFS remains unclear.
- Researchers have questioned the reliability of PFS in an unblinded setting.
- PFS findings are difficult for independent reviewers and the FDA to verify.