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Refocusing Cancer Drug Approval on Patients

What the 21st Century Cures Act ignores is the prevailing, patient agnostic approach to drug development. We need to move toward a patient-centric approach to drug development and approval, and we should start with cancer treatments.
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On July 10th, the House approved health legislation, known as the 21st Century Cures Act, to streamline how the government approves drugs and medical devices. The bill includes proposals for the Food and Drug Administration to consider nontraditional sources of data to support drug approval, and it urges FDA to accept surrogate measures of drug efficacy -- such as tumor shrinkage -- rather than what has traditionally been the standard of a clinically meaningful endpoint, an improvement in overall survival. The legislation was popular, garnering overwhelming bipartisan support, reflecting the widespread belief that medications need to be made available to patients sooner. Nowhere is this more relevant than for patients with cancer.

But what the 21st Century Cures Act ignores is the prevailing, patient agnostic approach to drug development. We need to move toward a patient-centric approach to drug development and approval, and we should start with cancer treatments.

Medications in the United States are approved by the FDA only after rigorously demonstrating that they are both safe and effective. More than a century ago, the first laws in the U.S. that regulated drugs were developed to protect consumers from both physical and financial harm. In subsequent decades a variety of tragedies and near-misses have pushed the U.S. toward a fundamentally protective drug regulatory approach. Appropriate balance between rapid access to new therapies while avoiding undue harm has always been the goal, but early phase research studies have evolved to be more concerned with risk than benefit.

This approach emphasizes safety, then efficacy. Sequence matters, and clinical trials on the road to FDA approval overly prioritize safety over efficacy for these historic reasons.

How does this play out in cancer drug development? The first investigations in people, Phase I trials, involve gradually increasing the dose of a drug to determine the maximum tolerated dose. The initial dosing level is deliberately set low -- at a drug dose most would agree is not likely to be effective -- with an eye toward safety first, and is gradually increased until dose-limiting toxicities occur.

Inherent in this design is a focus not on the patient suffering from a given disease, but on the needs of the investigator and the pharmaceutical company who seek regulatory approval to bring the drug to market. This paradigm was developed in an era in which the dose, toxicity and efficacy of a drug against cancer were all tightly linked: while a higher dose of chemotherapy had an increased likelihood of killing more cancer cells, it also affected more healthy cells, which led to side effects. As therapies are increasingly designed to more precisely target cancer, though, the old paradigm has become obsolete.

There are also ethical reasons to rethink the 20th century framework for cancer drug development. Patients with terminal cancer and no other treatment options have traditionally been enrolled in Phase I trials. The consent process for such studies is fraught with difficulty because the scientific goals of the research (dose finding and safety) are at odds with the usual goal of the research participant (reducing cancer and hopefully cure). With the current low-dose approach to Phase I trial design, patients are used as a means to an end in what some might consider to be an ethically problematic way.

Later phase studies use the maximum tolerated dose identified in Phase I studies to treat patients with a given disease, continuing to assess the safety of the drug, along with efficacy. These tend to be conducted serially, over years. Pharmaceutical companies frequently limit access to these potential life-prolonging medications only to patients who qualify for a study, preventing patients not enrolled on a clinical trial from receiving the drug to avoid potential toxicities that would have to be reported to the FDA. Currently, market forces encourage conducting studies in common cancers that will result in broader drug use, and thus profitability, rather than responding to patient needs.

How can we do better?

By changing the prioritization of clinical trials so that there is a concomitant focus on safety and efficacy from the outset, cancer drug research can be transformed to be both ethically and scientifically better, giving patients a better shot at success as they would define it -- shrinking or eliminating the tumor -- from the very first in-human study. Efficacy data generated by them can be included in later phase studies, improving overall drug development efficiency. Trials should be conducted in multiple cancers simultaneously, and can be designed to seamlessly transition to comparative studies that could be used for regulatory approval. Finally, drug sponsors should not be penalized for making novel therapies available to desperate patients who aren't eligible for clinical trials.

While the risk of such participation may be higher, we expect most patients would embrace this change, accepting higher risk in exchange for a better, and faster, chance of benefit.

Dr. Sekeres is Director of the Leukemia Program, Professor of Medicine, and Vice-chair for Clinical research at the Cleveland Clinic Taussig Cancer Institute in Cleveland, Ohio. He is the former Chair of the Oncologic Drugs Advisory Committee of the U.S. Food and Drug Administration.

Dr. Kodish is the Director of the Center for Ethics, Humanities and Spiritual Care at Cleveland Clinic and Professor of Pediatrics, Oncology and Bioethics at the Cleveland Clinic Lerner College of Medicine