Clinical Trials: The Elephant in the Room

Andre Goy, MD

Editor-in-Chief of Oncology & Biotech News

Chairman and Director Chief of Lymphoma Director, Clinical and Translational Cancer Research Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates John Theurer Cancer Center at Hackensack University Medical Center

We are without a doubt in the midst of an ongoing revolution in cancer care, as I have often previously discussed in this column. It is estimated that over two-thirds of the entire pipeline of medicine is in oncology, and we have a greater understanding than ever before of cancer cell biology (and its incredible diversity), which hopefully will help guide patient management with the end goal of precise medicine.

However, despite these unprecedented and exciting changes, only 3% of patients in the United States are enrolled in clinical trials. Up to 60% of oncology trials, according to Covance, fail to enroll more than a single patient! As per the NCI, up to 40% of oncology trials fail to achieve the minimum patient enrollment and over 60% of phase III trials do not reach planned enrollment. This dismal participation rate has not budged in years, and complicating matters, cancer incidence is predicted to increase by 40% in the next 20 years, due to an aging population, among other factors.

The root causes involved in this complex issue are evidently multifactorial:

• There is a crucial lack of information from patients and caregivers, as well as physicians. Recent surveys suggest that 50% to 80% of patients do not have any information on potential clinical trials for their condition. This might be one of the causes for the well-documented disparities in minority access to clinical trials.
• Patients (and sometimes care providers, as well) often still believe the default “standard of care” is a priori better or at least less risky—though no one would argue that we do not have satisfactory regimens in the relapse/refractory setting in most situations in oncology, particularly in solid tumors. Meanwhile, several of the recently approved drugs or those in development are game changers, such as B-cell receptor inhibitors, checkpoint inhibitor, and CAR T-cell therapies, which have all shown dramatic results, even in chemorefractory patients.
• The complexity of clinical trials has significantly worsened. It is estimated that for an average phase III trial, the number of endpoints and/or eligibility criteria has increased by at least 50% in the last 10 to 15 years.
• Among these inclusion criteria, the number of prior therapies allowed (to find the clinical “unmet” need) is often a limit to enrollment. Meanwhile, most novel agents, such as ibrutinib and lenalidomide, work by mechanisms distinct from chemotherapy, and have been approved and showed efficacy regardless of prior regimens received. Evidently, this issue gets worse as additional drugs get approved, changing the paradigm in a given disease. This can make some trials impossible to enroll as the studies then either require patients to have all received the latest newly approved drug (next clinical benefit benchmark) or on the opposite end, to not have received the latest newly approved treatment (“me-too drug” concept).
• Finally, patients are often selected (ie, excluded) based on comorbidities. In a study from Duke comparing patients treated in the real world (after approval of the drug) with those in the corresponding phase III trial, up to 40% of patients would have failed to qualify to receive the drug on trial that they were receiving in the real world.
• Not surprisingly, issues related to coverage and cost of clinical trials are adding to the complexity and pace of enrollment.

Failed clinical trials come at a huge cost to pharmaceutical sponsors, patients’ lives, and society through impact on innovation. For example, it can cost a sponsor about $50,000 for a site start-up, which is estimated at an almost $2 billion loss between 2005 and 2010 from non-performing sites.

Unfortunately, there is a clear misalignment of all stakeholders involved in clinical research and discovery. Zillions of papers and reports have been written on the subject, with—sadly to say—no major improvement, so far.

There needs to be a real concerted effort to encourage research, while involving patients, communities and all players together. This will require true changes in design of future trials. When possible “molecularly relevant trials” (biomarkers are available) should be able to lead to approval in refined populations (“find trees in the forest”). Otherwise, trials should at least focus on a defined subset of patients who are as similar as possible (ie, based on clinical and molecular features) to reduce the variance that might dilute the benefit of a tested compound and hypothesis. For example, in the LymphoCare study in follicular lymphoma, the diversity of management (hence of prior therapies at the time of relapse) was at best surprising.

We also need to foster drug development away from the standard randomized trials paradigm as the only alternative that will enroll heterogeneous populations (or the best of the high-risk patients) at the risk of being negative though the phase II data were robust.

Finally, one needs to be able to develop initiatives/ support for investigators as well as simplify the incredibly complex current regulatory environment. The use of technology (ie, mheath [mobile health]) might help bring all the stakeholders together and help solve some of the challenges detailed above and truly embrace—and not hinder—our fight against cancer.