Development of New Cancer Therapies

Abstract

Systemic therapies for cancer are required for advanced disease and regional disease that is at high risk of systemic dissemination. This is the most difficult therapeutic challenge because of the extreme clonal heterogeneity in advanced cancers and the high probability of therapeutic resistance, either preexistent or evolving as a “fitness” trait in response to the evolutionary selection pressure of the drug. Despite this fact, new drugs for cancer are developed with the goal of prolonging survival even if cure is unobtainable. Even modest improvements in outcomes measured in weeks to weeks are difficult to achieve. New drug development is a highly regulated, labor-intensive, inordinately expensive, and protracted process and has a failure rate estimated to be about 95%. The US Food and Drug Administration oversees the process, requiring proof of the new drug’s safety for human use and efficacy in its intended context of use before a new drug is approved for commercialization and use in patients. The development process moves slowly from discovery in the laboratory of an agent’s activity against a biological target in cancer through preclinical testing of the agent in a biological system. Animals serve as patient surrogates in this required phase of testing, despite the fact that animal models do not accurately predict the safety or the efficacy of new drugs in patients. Human testing in clinical trials is required for the ultimate determination of safety and efficacy of the new agent. Human experimentation is governed by international rules of ethics that are further codified and enforced through the US Office of Human Research Protection in the federal government. The requirements for a clinical trial, among many other things, include the freely informed consent of research participants, a scientifically sound research protocol that also minimizes potential harms to participants, the approval of institutional review boards that are populated by members who are free of conflicts of interest related to the new drug or the proposed study, and the approval of the National Cancer Institute, if federal funding supports the trial. Executing a trial to acquire statistical proof of efficacy can take many years. This chapter reviews the many challenges and requirements of cancer drug development, the high rate of failure in bringing a new cancer therapy to market, and the need for process improvement without compromise of scientific rigor or ethical requirements.