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Clinical Trial Design Fails Too Many Patients

August 18, 2022

September 2022

Matthew Matasar, MDMatthew Matasar, MD
Medical Oncologist, Memorial Sloan Kettering (MSK) Cancer Center
Regional Care Network Medical Site Director, MSK Bergen

 

 

A colleague recently reached out on behalf of a patient in need. He had relapsed lymphoma, for which all standard options had been exhausted. The patient was up and about (still working part-time even!) and very motivated to find another treatment. We all know this story, in one way or another, and isn’t this why we do clinical trials?

In theory, this patient was a great candidate for a novel therapy. He had no other illnesses of note, and all of his systems were working just fine, other than the bone marrow that had been replaced by lymphoma. In fact, his bone marrow was the only site of disease, which was a real problem. Despite this, we just couldn’t find a trial he would qualify for because he lacked “measurable disease,” which in this case meant some mass that could be measured by a CT or PET scan. His and our collective disappointment was matched only by our frustration.

Why can’t we do better?

The history of clinical trials in general, in hematology specifically, and in lymphoma very specifically – OK, I’m a lymphoma guy, what did you expect? – is one that both inspires and disappoints. Yes, the breadth and pace of innovation is breathtaking and gives hope to doctors and patients alike, but how well does the clinical research enterprise serve the patients for whom we intend it? Yeah, not so well.

When we look at who’s eligible for trials as compared to who our patients actually are, it turns out it’s not uncommon that patients are left out. One study found that randomized clinical trials for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) exclude more than half of “real-world” patients.1 Another found that among patients who were receiving standard treatment for DLBCL at the time – good old R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) – a quarter would have been ineligible for trials in which their treatment was the comparator arm.2

This problem isn’t restricted to DLBCL or lymphoma, of course. Similar disparities between eligibility criteria and real patients have been reported in AML,3 multiple myeloma,4 and many others. Yes, even solid tumors!

The problem is further compounded by our history as a profession of underserving marginalized populations in our research efforts, including people of color, those with non-cis or non-binary gender identities, or those who are older, are underinsured, or live in rural settings. The list goes on. It’s something that, as a clinical researcher, I honestly find uncomfortable to ruminate about.

Efforts to improve outreach and incorporate patients’ perspectives have made a visible impact. Patients’ voices are heard in every institutional review board meeting, and more hospitals are establishing patient and family advisory councils to help guide research missions as well as clinical care programs. It’s a start, but only that, and meanwhile, deep disparities persist. At my institution, we’re also working on the practical side of things. Protocol inclusion and exclusion criteria are being pushed to better represent real-world patients. For example, HIV that is well-controlled should absolutely not preclude participation in most clinical trials. And prior history of treatment for a different cancer really doesn’t complicate the interpretation of a trial for a patient who is at risk of imminent death from their current cancer. Overly stringent laboratory requirements benefit neither the patient nor the trial. Our research process, from principal investigator review through research council and institutional review board, increasingly focuses on the scientific and ethical merit of these inclusion and exclusion criteria, and I would encourage all to approach clinical research with similar scrutiny.

It’s clear to me that systematic work is required to widen the tent of who is able to participate in clinical trials. Equity and inclusiveness have to be thought through trial-by-trial and center-by-center, but this isn’t enough. The truth persists that even while most patients at academic centers will not participate in clinical trials, the majority receive care from trusted and capable physicians in their communities who may not have access to clinical trial resources, resulting in even lower rates of participation. All told, fewer than one in 10 patients will participate in a clinical trial.5

Thankfully, we are beginning to see real innovation in how to better match clinical trial resources with the patients who need access. Fueled in part by innovation in response to the COVID-19 pandemic, the expanded ability to deliver telemedicine and provide at-home care means that decentralized trials could be the future of a more inclusive clinical research infrastructure. The abilities to hold an “e-consent” conversation and document informed consent over a digital platform, use remote lab and drug shipping resources, and offer high-quality telemedicine visits allow for experimental therapy at a distance that was not previously possible. In the midst of the pandemic, we had a patient on a clinical trial who was stuck in Brazil but was able to have their visits, lab draws, and drug shipments without deviating from protocol requirements, thus enabling ongoing therapy with a medicine that was working well in the treatment of relapsed small lymphocytic lymphoma. This model truly holds the potential to revolutionize access to, and perhaps even equity in, clinical research.

Whatever answers we arrive at as a professional community, be it decentralized trials that allow care at local oncologists’ offices or patients’ homes, realignment of inclusion and exclusion criteria to better mirror the characteristics of patients with the disease in question, or discarding traditional and outdated criteria, we need to commit ourselves to making sure our clinical research programs better serve the patients who trust us and science when they generously consent to participate in this shared enterprise of advancing clinical care.

Matthew Matasar, MD
Associate Editor

References

  1. Loh Z, Salvaris R, Chong G, et al. Evolution of eligibility criteria for diffuse large B-cell lymphoma randomised controlled trials over 30 years. Br Jour Haem. 2021;193(4):741-749.
  2. Khurana A, Mwangi R, Nowakowski GS, et al. Impact of organ function–based clinical trial eligibility criteria in patients with diffuse large B-cell lymphoma: who gets left behind? J Clin Oncol. 2021;39(15):1641-1649.
  3. Orvain C, Othus M, Johal G, Hunault-Berger M, Appelbaum FR, Walter RB. Evolution of eligibility criteria for non-transplant randomized controlled trials in adults with acute myeloid leukemia [published online 2022 June 3]. Leukemia. doi: 10.1038/s41375-022-01624-y.
  4. Hungria V, Lee HC, Abonour R, et al. Real-world (RW) multiple myeloma (MM) patients (Pts) remain under-represented in clinical trials based on standard laboratory parameters and baseline characteristics: analysis of over 3,000 pts from the insight MM global, prospective, observational study. Blood. 2019;134(Suppl_1):1887.
  5. Unger JM, Vaidya R, Hershman DL, et al. Systematic review and meta-analysis of the magnitude of structural, clinical, and physician and patient barriers to cancer clinical trial participation. J Natl Can Instit. 2019;111(3):245-255.

The content of the Editor's Corner is the opinion of the author and does not represent the official position of the American Society of Hematology unless so stated. Have a comment about this editorial?

Let us know what you think; we welcome your feedback. Email the editor at ACNEditor@hematology.org.

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