The Food and Drug Administration (FDA) reviews and approves all drugs. But what criteria does the FDA use to evaluate new drugs? Namely that they are effective (i.e., improve health outcomes) and safe (i.e., have limited adverse health events). In a 2007 guidance document from the FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) branches, the institution states:
The requirement that new drugs show effectiveness is based on a 1962 amendment to the Federal Food, Drug, and Cosmetic Act. This law requires substantial evidence of effectiveness and specifies that this evidence must be derived from adequate and well-controlled clinical investigations. Similarly, the Public Health Service Act requires biological products to be safe, pure, and potent. Clinical benefits that have supported drug approval have included important clinical outcomes (e.g., increased survival, symptomatic improvement) but have also included effects on established surrogate endpoints (e.g., blood pressure, serum cholesterol).
However, what does efficacy mean? What is the burden of proof for drugs that treat life-threatening illnesses. The guidance document states that these drugs can receive accelerated approval using surrogate endpoints to measure efficacy:
…additional endpoints for approval of drugs or biological products that are intended to treat serious or life-threatening diseases and that either demonstrate an improvement over available therapy or provide therapy where none exists. In this setting, the FDA may grant approval based on an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit… A drug is approved under the accelerated approval regulations on condition that the manufacturer conducts clinical studies to verify and describe the actual clinical benefit.
What endpoints does the FDA use to approve cancer drugs?
In the 1970s, the FDA usually approved cancer drugs based on objective response rate (ORR), determined by tumor assessments from radiological tests or physical examinations. In the early 1980s…the FDA determined that cancer drug approval should be based on more direct evidence of clinical benefit, such as improvement in survival, improvement in a patient’s quality of life (QOL), improved physical functioning, or improved tumor-related symptoms. These benefits may not always be predicted by, or correlate with, ORR.
Since then, the FDA now considers endpoints such as:
- Overall survival (OS): The time from randomization until death from any cause and is measured in the intent-to-treat population
- Disease free survival (DFS): DFS is defined as the time from randomization until recurrence of tumor or death from any cause. The most frequent use of this endpoint is in the adjuvant setting after definitive surgery or radiotherapy. DFS has been the primary basis of approval for adjuvant breast cancer hormonal therapy, adjuvant colon cancer, and adjuvant cytotoxic breast cancer therapy.
- Objective response rate (ORR): The proportion of patients with tumor size reduction of a predefined amount and for a minimum time period. Response duration usually is measured from the time of initial response until documented tumor progression. Generally, the FDA has defined ORR as the sum of partial responses plus complete responses.
- Time to progression (TTP): The time from randomization until objective tumor progression; TTP does not include deaths.
- Progression-free survival (PFS): The time from randomization until objective tumor progression or death.
- Time to treatment Failure (TTF): A composite endpoint measuring time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death. TTF is not recommended as a regulatory endpoint for drug approval.
Both TTP and PFS seem similar. Which one is better to use? The FDA guidance doc states:
Compared with TTP, PFS is the preferred regulatory endpoint. PFS includes deaths and thus can be a better correlate to overall survival. In TTP analysis, deaths are censored, either at the time of death or at an earlier visit representing informative censoring (nonrandom pattern of loss from the study). PFS assumes patient deaths are randomly related to tumor progression. However, in situations where the majority of deaths are unrelated to cancer, TTP can be an acceptable endpoint.
So, if you are a scientist working from for a pharmaceutical company, which endpoint should you use? The process is likely to be a negotiation between the research firm and the FDA. In fact, the FDA recommends that “applicants meet with the FDA before submitting protocols intended to support NDA [new drug applications] or BLA [biologics license applications] marketing applications.”