William G. Nelson, MD, PhD Photo by Joe Rubino

THE DEVELOPMENT OF NEW CANCER TREATMENTS has changed radically over the past few decades, fueling an explosion in new drug approvals by the Food and Drug Administration (FDA) and substantially improving cancer survival rates. Maintaining this momentum will require timely conduct and completion of cancer clinical trials. A recent analysis suggests that more than 12,000 clinical trial participants are needed to support FDA registration of a single new cancer treatment. With only 8% of adults with cancer in the U.S. currently enrolled in therapeutic clinical trials, future progress is threatened.

Historically, cytotoxic (cell-killing) anti-cancer drugs were evaluated empirically for clinical use. The clinical trial challenge was to reach drug doses high enough to kill cancer cells in the body without harming too many vital normal cells. Patients with advanced cancers who participated in clinical trials of new cytotoxic drugs first received low doses. If they experienced no worrisome side effects, the drug doses were escalated for the next groups of trial participants until the maximum tolerated dose was determined. The courage of these selfless patients is remarkable: Less than 5% saw any significant clinical improvement attributable to drug treatment. Once a high but tolerable dose was established, the drugs would undergo efficacy testing in later-stage clinical studies that targeted many different types of cancers. Ultimately, the drugs would be tested in randomized clinical trials comparing the efficacy of the experimental treatment with the standard of care. Though this clinical trial pathway delivered some early cancer cures, the process took many years, required large financial investments and yielded too few successes.

Today, new classes of anti-cancer drugs target specific properties of cancer cells that arise from acquired gene defects driving cancer cell growth and progression. Many clinical trials now test optimal drug dosing, safety and efficacy selectively by enrolling patients with cancers harboring specific gene defects that are most likely to respond to the drug. This approach greatly increases the chance that participants will experience meaningful treatment responses, leading to more predictable and efficient approaches to anti-cancer drug evaluation.

Despite these advances, therapeutic clinical trials still require large numbers of cancer patients. What limits patient participation? Race, ethnicity, socioeconomic status and geographic region of residence have long been recognized as factors that can affect whether patients participate in trials. Cancer clinical trials typically require bureaucracies that oversee regulatory compliance, consume considerable financial resources and take up care providers’ time. For these reasons, many clinical studies are restricted to academic cancer centers often located far from where potential study participants live and work. All too often, these real-world barriers drive physicians to avoid discussions with their patients about clinical research opportunities.

Nonetheless, there may be some good news. New evidence hints that, despite all of the barriers, more than half of cancer patients actually offered clinical trial participation agreed to enroll. When invited, Black, Hispanic and Asian cancer patients participate at the same rates as white cancer patients. The major reasons for not participating are concern over side effects from experimental treatments and low enthusiasm for randomization. Worries about insurance coverage, out-of-pocket expenses and the need for travel are also factors.

These new insights indicate pragmatic policies that might encourage clinical trial participation, particularly those ensuring that clinical trial options are available and discussed with more cancer patients. Strengthening mandates for insurance coverage of routine care costs incurred during clinical trial participation will help. Telemedicine technologies that allow collaborative physician oversight of clinical trials between academic clinical researchers and community practitioners may reduce the number of on-site visits needed and reduce travel burdens. Improved logistical and supply chain tactics may allow shipment of investigational drugs to all geographic regions.

Cancer clinical research has long been impeded by low levels of clinical trial participation by patients. New technologies and straightforward tweaks to the process may allow the cancer clinical trials enterprise to finally keep pace with the rapid growth in new anti-cancer drugs.

William G. Nelson, MD, PhD, is the director of the Johns Hopkins Kimmel Cancer Center in Baltimore.