Strict clinical trial eligibility criteria exclude patients most likely to benefit from cancer treatment

Clinical trials routinely use strict enrollment criteria that exclude patients who are most likely to benefit from the treatment under investigation, according to study results published in Leukemia.

Trials are not being designed to include participants who are representative of society, Mikkael A. Sekeres, MD, MS, director of the leukemia program in the department of hematologic oncology and blood disorders at Cleveland Clinic Taussig Cancer Institute, and colleagues concluded.

Mikkael A. Sekeres

Consequently, trial results may not reflect what will occur outside of a clinical trial.

“For patients, access to advanced therapies — especially for life-threatening diseases with undefined first-line treatment — is vital,” Sekeres said in a press release. “However, fewer than 5% of adult [patients with cancer] enroll in clinical trials, due in part to eligibility and screening failures.”

HemOnc Today spoke with Sekeres about the study results, their potential implications, and how members of the clinical community can help drive change in this area.

Question: Can you describe the study and the key findings?

Answer: Abby Statler, MPH, MA, research regulatory quality assurance coordinator at Taussig Cancer Institute, served as lead author and initiated this study. In reviewing studies, she observed many similarities in the eligibility criteria of cancer trials. We decided to formally study this and see whether eligibility criteria were actually sensitive to known drug toxicities, or if they represented a ‘cut-and-paste’ job. We decided to focus on hematologic malignancies as a starting point. We searched journals with a high impact factor. We identified 97 studies, of which one-third were conducted in leukemia, 28% in lymphoma, 34% in multiple myeloma and 5% in myelodysplastic syndrome. We first assessed known toxicities of the drugs studied in each trial to see whether they aligned with eligibility criteria. For example, a study may say a patient is not eligible to participate if their creatinine is 1.5 times the upper limit of normal, or if their liver function is 2.5 times the upper limit of normal. We found that the known toxicities of these drugs did not correlate with the cardio-hepatic or renal eligibility criteria of the trials. Eligibility criteria were not sensitive to what was known about those drugs in terms of their toxicities. We then looked to see whether patients actually had the toxicities for which they may have been excluded. Once again, we found that for hepatic and renal eligibility criteria, they did not correlate with observed adverse events on those studies.

Q: What are the implications of these results?

A: We concluded the analyzed randomized controlled trials excluded patients with organ dysfunction that did not reflect either expected toxicities based upon the prescription and drug labels, or the reported adverse events seen on the trials. The eligibility criteria were overly restrictive, and the implications for this are huge.

Thinking about this from the patient perspective, I can name patients who have come to me and asked to go on a clinical trial because they had no other treatment options available. Yet, they were excluded from the trial because of an isolated liver function that was only slightly worse than it should have been to get on to the trial. This limits the options our patients have to undergo potentially life-saving treatments. From the societal perspective, the length of time it takes a drug to be approved by the FDA is, in part, dependent upon how quickly patients are enrolled onto clinical trials. The more restrictive eligibility criteria are, the longer it takes patients to enroll on clinical trials. In turn, it takes even longer to get answers about whether drugs work, and possibly even longer until these agents get approved by the FDA. Of note, one of the aspects of the national cancer moonshot initiative involves clinical trial enrollment. If we are going to meet former Vice President Joe Biden’s guidance to accelerate the rate of cancer discovery over the next 5 years, the only way we can do this is by loosening the enrollment criteria onto cancer clinical trials.

Q: Were you surprised by any of your findings?

A: I was not surprised by the findings, because those of us who have conducted cancer research long enough realize that eligibility criteria from one trial to the next are eerily similar. I would say I was disappointed by the results, and that our suspicion was confirmed. It does, however, open up opportunities for liberalizing enrollment onto clinical trials. The FDA is now exploring having additional arms on clinical trials that would be more reflective of real-world populations.

Q: How might changes in eligibility criteria come about?

A: Based on what we have found, we instituted modifications of our templates at Cleveland Clinic for investigator-initiated protocols. We now have specific language about eligibility criteria to make sure they do not exclude patients without justification based upon a drug’s known toxicity and metabolism. We have also asked the chairs of our scientific review committee to evaluate whether the eligibility criteria for trials they review are unnecessarily overly restrictive. We are trying to make changes within our own institution and react to the study findings to make eligibility criteria for our trials more reflective of the patients we actually see.

Q: How might members of the clinical community help drive the change?

A: Members of the clinical community can help by taking a long, hard look at cancer clinical trial eligibility criteria and ask whether it is really necessary that a study exclude a patient because of whatever given reason.

Q: Do you and your colleagues plan to conduct additional research on this topic?

A: We presented an abstract in December at the ASH Annual Meeting and Exposition that essentially took our study to the next step. We examined leukemia studies conducted through the Southwest Oncology Group over a 10-year period and identified patients deemed ineligible. Patients had been enrolled and treated on the trial, but during an audit after the study was complete, we found certain patients should not have been on the study to start with because they were deemed ineligible. Out of almost 2,400 patients treated on 13 trials, we identified 257 ineligible patients. Of these, 81 were excluded from analyses and 176 were included in analyses. It turns out that ineligible patients were just as likely as eligible patients to go into remission and had similar rates of adverse events. – by Jennifer Southall

References:

Statler A, et al. Leukemia. 2016;doi:10.1038/leu.2016.374.

Statler A, et al. Abstract 4002. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.

For more information:

Mikkael A. Sekeres, MD, MS, can be reached at Cleveland Clinic Taussig Cancer Institute, 2010 E. 90th St., Cleveland, OH 44195; email: sekerem@ccf.org.

Disclosure: Sekeres reports no relevant financial disclosures.

Clinical trials routinely use strict enrollment criteria that exclude patients who are most likely to benefit from the treatment under investigation, according to study results published in Leukemia.

Trials are not being designed to include participants who are representative of society, Mikkael A. Sekeres, MD, MS, director of the leukemia program in the department of hematologic oncology and blood disorders at Cleveland Clinic Taussig Cancer Institute, and colleagues concluded.

Mikkael A. Sekeres

Consequently, trial results may not reflect what will occur outside of a clinical trial.

“For patients, access to advanced therapies — especially for life-threatening diseases with undefined first-line treatment — is vital,” Sekeres said in a press release. “However, fewer than 5% of adult [patients with cancer] enroll in clinical trials, due in part to eligibility and screening failures.”

HemOnc Today spoke with Sekeres about the study results, their potential implications, and how members of the clinical community can help drive change in this area.

Question: Can you describe the study and the key findings?

Answer: Abby Statler, MPH, MA, research regulatory quality assurance coordinator at Taussig Cancer Institute, served as lead author and initiated this study. In reviewing studies, she observed many similarities in the eligibility criteria of cancer trials. We decided to formally study this and see whether eligibility criteria were actually sensitive to known drug toxicities, or if they represented a ‘cut-and-paste’ job. We decided to focus on hematologic malignancies as a starting point. We searched journals with a high impact factor. We identified 97 studies, of which one-third were conducted in leukemia, 28% in lymphoma, 34% in multiple myeloma and 5% in myelodysplastic syndrome. We first assessed known toxicities of the drugs studied in each trial to see whether they aligned with eligibility criteria. For example, a study may say a patient is not eligible to participate if their creatinine is 1.5 times the upper limit of normal, or if their liver function is 2.5 times the upper limit of normal. We found that the known toxicities of these drugs did not correlate with the cardio-hepatic or renal eligibility criteria of the trials. Eligibility criteria were not sensitive to what was known about those drugs in terms of their toxicities. We then looked to see whether patients actually had the toxicities for which they may have been excluded. Once again, we found that for hepatic and renal eligibility criteria, they did not correlate with observed adverse events on those studies.

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Q: What are the implications of these results?

A: We concluded the analyzed randomized controlled trials excluded patients with organ dysfunction that did not reflect either expected toxicities based upon the prescription and drug labels, or the reported adverse events seen on the trials. The eligibility criteria were overly restrictive, and the implications for this are huge.

Thinking about this from the patient perspective, I can name patients who have come to me and asked to go on a clinical trial because they had no other treatment options available. Yet, they were excluded from the trial because of an isolated liver function that was only slightly worse than it should have been to get on to the trial. This limits the options our patients have to undergo potentially life-saving treatments. From the societal perspective, the length of time it takes a drug to be approved by the FDA is, in part, dependent upon how quickly patients are enrolled onto clinical trials. The more restrictive eligibility criteria are, the longer it takes patients to enroll on clinical trials. In turn, it takes even longer to get answers about whether drugs work, and possibly even longer until these agents get approved by the FDA. Of note, one of the aspects of the national cancer moonshot initiative involves clinical trial enrollment. If we are going to meet former Vice President Joe Biden’s guidance to accelerate the rate of cancer discovery over the next 5 years, the only way we can do this is by loosening the enrollment criteria onto cancer clinical trials.

Q: Were you surprised by any of your findings?

A: I was not surprised by the findings, because those of us who have conducted cancer research long enough realize that eligibility criteria from one trial to the next are eerily similar. I would say I was disappointed by the results, and that our suspicion was confirmed. It does, however, open up opportunities for liberalizing enrollment onto clinical trials. The FDA is now exploring having additional arms on clinical trials that would be more reflective of real-world populations.

Q: How might changes in eligibility criteria come about?

A: Based on what we have found, we instituted modifications of our templates at Cleveland Clinic for investigator-initiated protocols. We now have specific language about eligibility criteria to make sure they do not exclude patients without justification based upon a drug’s known toxicity and metabolism. We have also asked the chairs of our scientific review committee to evaluate whether the eligibility criteria for trials they review are unnecessarily overly restrictive. We are trying to make changes within our own institution and react to the study findings to make eligibility criteria for our trials more reflective of the patients we actually see.

Q: How might members of the clinical community help drive the change?

A: Members of the clinical community can help by taking a long, hard look at cancer clinical trial eligibility criteria and ask whether it is really necessary that a study exclude a patient because of whatever given reason.

Q: Do you and your colleagues plan to conduct additional research on this topic?

A: We presented an abstract in December at the ASH Annual Meeting and Exposition that essentially took our study to the next step. We examined leukemia studies conducted through the Southwest Oncology Group over a 10-year period and identified patients deemed ineligible. Patients had been enrolled and treated on the trial, but during an audit after the study was complete, we found certain patients should not have been on the study to start with because they were deemed ineligible. Out of almost 2,400 patients treated on 13 trials, we identified 257 ineligible patients. Of these, 81 were excluded from analyses and 176 were included in analyses. It turns out that ineligible patients were just as likely as eligible patients to go into remission and had similar rates of adverse events. – by Jennifer Southall

References:

Statler A, et al. Leukemia. 2016;doi:10.1038/leu.2016.374.

Statler A, et al. Abstract 4002. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.

For more information:

Mikkael A. Sekeres, MD, MS, can be reached at Cleveland Clinic Taussig Cancer Institute, 2010 E. 90th St., Cleveland, OH 44195; email: sekerem@ccf.org.

Disclosure: Sekeres reports no relevant financial disclosures.