Balancing Access and Evaluation in the Approval of New Cancer Drugs

Abstract

PATIENTS WITH CANCER WHO LACK EFFECTIVE TREATment desperately seek novel interventions that might extend their lives. They do not have time to wait for the US Food and Drug Administration’s (FDA’s) regular approval process, which requires that sponsors demonstrate “substantial evidence of clinical benefit (or efficacy) from adequate and well-controlled investigations.” Clinicians, for their part, are eager to offer “rational” treatments targeted at the molecular signatures of disease to their sickest patients. Concern about the plight of desperate patients, along with the promise of targeted treatments, makes it easy to lose sight of the public interest in rigorous evaluation of experimental drugs before they are marketed to patients. Understandable focus on patients with serious illness diverts attention from the value to present and future patients and to society of ensuring the efficacy and safety of new treatments. Moreover, the case for rigorous evaluation rests on technical issues of study end points and statistical proof that are not widely understood or appreciated. How should the interests of individual patients and clinicians in access to novel cancer treatments be weighed against the public interest in rigorous evaluation? There is no easy solution to this dilemma. Any sound public policy must balance 2 types of error: speeding access to treatments that are not beneficial or have an unfavorable benefitharm ratio and unreasonably delaying access to beneficial treatments. The second error receives the most public attention. The first, however, is also critically important for current and future patients. In addition, society has a stake in the rigorous evaluation of new cancer drugs, especially in view of escalating costs. A major regulatory initiative introduced in 1992 in response to perceptions that the time required for regular approval was excessive allows “accelerated approval” of new drugs that are judged likely to provide benefits, compared with available treatments, for life-threatening conditions. Approval may be granted following positive results of trials assessing surrogate end points such as tumor response or progression-free survival. Sponsors seeking accelerated approval must conduct follow-up randomized controlled trials (RCTs) evaluating clinical benefit (eg, survival) or validated surrogate outcomes for clinical benefit to obtain regular approval and continue marketing. How well does this mechanism resolve the access/evaluation dilemma? A recent FDA review found that between late 1992 and mid-2010, 35 oncology drugs were granted accelerated approval for 47 new indications. Evaluating the success of the accelerated approval program is challenging. Although the advantages of speeding access to drugs for which the clinical benefits are later confirmed are clear, the drawbacks are less visible. Accelerated approval is usually based on results from small, often single-group trials. Of the 47 accelerated approvals, 28 were based on single-group trials and 35 on response rate end points. Although regular approval occasionally is warranted on the basis of high response rates compared with historical controls, RCTs assessing survival or validated surrogates for survival remain the default standard for rigorous evaluation. In addition, early access in clinical practice inevitably makes it difficult to complete confirmatory trials in a timely fashion, as once an agent is clinically available to treat a lifethreatening disease, the conduct of an RCT comparing the agent to a control becomes both ethically and practically challenging. Historical examples from both within and outside oncology provide compelling evidence that restricting access to experimental treatments to well-designed trials is the most efficient way to develop the rigorous data needed to evaluate efficacy and safety. The success of the accelerated approval depends on both the extent to which follow-up RCTs reliably confirm benefit and the timely completion of these trials. The FDA review indicated that only 3 of 29 oncology drugs for which confirmatory trials were completed failed to demonstrate benefit. Subsequently, the FDA determined that the benefits of a fourth drug, which received accelerated approval in 2008 for a subset of patients with metastatic breast cancer, could not be confirmed. Furthermore, the FDA faces important disincentives to withdrawing approval based on either unfavorable evidence from confirmatory trials or failure to com-