Preventing Age Disparities in Cancer Trials
A clinician researcher at the University of Texas MD Anderson Cancer Center, Ethan Ludmir, MD, who has studied age disparities in cancer trials extensively, recently spoke with Medical Ethics Advisor about efforts to address this persistent issue. (Editor’s Note: This transcript has been lightly edited for length and clarity.)
MEA: Why should age disparities in clinical cancer trials concern the research community?
Ludmir: The top priority from the medical side is generalizability. When you get a trial result that says Therapy A is better than Therapy B, the question is: Are these results applicable to the general population? What if you run a clinical trial where the average age is 15 years younger than the general population in the real world that would be exposed to the therapy? If participants in a lung cancer trial had a median age of 55, and [the results show] that Drug A is better than Drug B, is that result generalizable for the 80-year-old patient sitting in your clinic?
The other dimension to this is one of equity. Patients should have equity with regard to their ability to access clinical trials, to the greatest extent reasonably possible.
MEA: Is the problem becoming better or worse?
Ludmir: Our data suggest that age disparities are worsening over time. Other data suggest that at the very least, age disparities are not getting better over time. Either way, it is still a persistent problem.
However, I remain optimistic. The geriatric oncology community has been advocating quite effectively to have this issue be investigated and addressed. The FDA recently issued a guidance encouraging older patient enrollment in cancer clinical trials — specifically, those sponsored by the biopharmaceutical industry.1 We know that in cancer at least, the vast majority of late-phase clinical trials — about 85% or so — are sponsored by the pharmaceutical industry. In many ways, effective engagement with the pharmaceutical industry is a critical path toward ameliorating these disparities.
Not only have we seen this regulatory push by the FDA, but there are also several investigators and research groups, including our own, trying to identify actionable and meaningful changes that could help push the needle in the right direction.
MEA: What are the most promising developments?
Ludmir: The rates of studies explicitly excluding patients based on age alone is very uncommon. Only about 10% of cancer trials exclude patients based on age alone.2 That is a rare phenomenon, and it is getting rarer.
MEA: Why do researchers tend to include stringent exclusion criteria in study protocols? Wouldn’t they want to include more people in the study?
Ludmir: If you’re running a clinical trial, in an ideal world, you’d fill all the spots as quickly as possible. The caveat is, if you’re the sponsor of that trial, if you’re taking everyone who could possibly be on that trial, and there’s a lot of heterogeneity of who you’re enrolling, then your signal may get lost in the noise. It’s not by definition an ethical problem. Some may feel otherwise, but I don’t necessarily think it’s an issue if you say upfront, "There are certain patients who have this disease who are not going to be eligible for this trial."
Maybe it’s increased risk of side effects, or maybe the biology of the disease is different, so they don’t really fit the parameters of the trial. There are legitimate reasons to try and look for some homogeneity in the clinical trial population without having it cross an ethical line.
On the other hand, that’s not the real world. In the real world, people are older and sicker, and have had previous cancers. If healthy 50-year-olds in the study do better on three drugs than two, does that conclusion apply to frail 80-year-olds? Or would it do more harm than good? With a more homogenous population, we get the clearest possible signal. However, maybe patients over 80 do better with one drug instead of two.
Randomized, controlled trials, ideally, would be able to inform differential treatment options for healthy 50-year-olds and frailer 85-year-olds who have the same condition. A lot of times, that’s something we have as an ideal. The issue is that a randomized, controlled trial is an incredibly ambitious undertaking. Forgetting the finances for a moment, the sheer effort and coordination required to make one happen is impossible to understate, and very often trials may not [be] complete[d] due to incomplete accrual. They take years to run. Often, in the time between when you start and end them, the whole landscape of the disease has changed.
Many people have run trials specifically for geriatric patients, or for older and sicker patients.3-5 That is also a very impressive thing we have seen more of in the last several years, running trials specifically targeted at those populations.
MEA: What can IRBs do?
Ludmir: IRBs, which tend to be judicious by nature, have the ability to critically examine inclusion and exclusion criteria in clinical trials. In general, it’s become harder to reasonably and scientifically justify an explicit cutoff based on age alone. But there are still exclusion criteria based on renal function, hepatic function, blood counts — which we know change naturally and physiologically with age. Those criteria can disproportionately skew enrollment away from older patients unnecessarily.
We recently found there is an independent association with prior malignancy exclusion criteria and age disparities.6 Very often, investigators will exclude patients who have had a previous cancer from participating in a current cancer trial. Participants with a previous cancer could certainly complicate the trial results.
If a patient is being treated for cancer A in a clinical trial, and had another known cancer B — and dies of cancer B — it may limit your information from the trial about optimal treatment for cancer A. As older patients are more likely to have had previous malignancies, these exclusion criteria may disproportionately impact older patients.
Our data show trials with prior malignancy exclusion criteria tend to suffer from wider age disparities. This allows for reasonable consideration by trialists, investigators, and sponsors to potentially omit or tighten prior malignancy exclusion criteria in order to reduce age disparities. These potentially actionable changes in trial design, including eligibility criteria, are only one piece of the puzzle in addressing age disparities. Ultimately, the onus is on the investigators to be more thoughtful, and perhaps more relaxed, about who participates in clinical trials.
- 87 FR 11718. Inclusion of older adults in cancer clinical trials; Guidance for industry; Availability. Federal Register. March 2, 2022.
- Ludmir EB, Subbiah IM, Mainwaring W, et al. Decreasing incidence of upper age restriction enrollment criteria among cancer clinical trials. J Geriatr Oncol 2020;11:451-454.
- Muss HB, Berry DA, Cirrincione CT, et al. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 2009;360:2055-2065.
- Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: A randomised controlled trial (RICOVER-60). Lancet Oncol 2008;9:105-116.
- Perry JR, Laperriere N, O’Callaghan CJ, et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med 2017;376:1027-1037.
- Patel RR, Parisi R, Verma V, et al. Association between prior malignancy exclusion criteria and age disparities in cancer clinical trials. Cancers (Basel) 2022;14:1048.
A leading researcher explains why patients should have equity regarding their ability to access clinical trials, to the greatest extent reasonably possible, in this Q&A.
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