To glean further insights on the topic, Hematology Advisor interviewed Dr Kanapuru as well as Mikkael Sekeres, MD, MS, director of the Leukemia Program at Cleveland Clinic in Ohio.
Hematology Advisor: What are some of the issues resulting from underrepresentation of older patients in hematologic malignancy trials?
Dr Kanapuru: The number of adults aged 65 and older who are diagnosed with blood cancers is only expected to rise as the population ages. Differences may exist between older and younger adults in how they respond to the drug in terms of efficacy and safety. Adequate representation of older adults in hematologic malignancy trials is important to facilitate better understanding of the safety and effectiveness of new therapies in the patient population likely to receive the drug once the drug is approved.
Dr Sekeres: As clinical trials are designed to show safety and efficacy of a drug or drug combination in patients with specified diseases, ideally the patients enrolled in trials would be representative of the patients who eventually would receive the new drug. Trials are designed, however, with an eye towards regulatory approval. Consequently, the healthiest of patients with the fewest comorbidities, are preferentially enrolled, as specified by overly restrictive trial eligibility criteria.
Older adults are underrepresented in trials either because of comorbidities that cause them to be excluded, or through unconscious bias on the part of study teams that they may not be able to tolerate the study drug. Thus, patients enrolled in trials don’t represent the “real world” population of patients who would ultimately be treated with the new drug.
Hematology Advisor: What are some potential solutions to this problem?
Dr Kanapuru: There are multiple barriers to enrolling older patients – particularly patients aged 75 and older – in clinical trials. One important reason often noted is narrow or restrictive clinical trial eligibility criteria. For example, patients with certain characteristics are regularly excluded from clinical trials for cancer treatments, including a history of previous cancers; less-than-optimal functioning of the heart, liver, kidneys, or other organs; or other co-existing illnesses. Many of these criteria serve to exclude older adults, who may be more likely than younger people to have co-existing illnesses or changes in organ function associated with aging.
The FDA has engaged directly with sponsors and other stakeholders to examine ways to broaden eligibility criteria in clinical trials. The Agency also has published guidance documents to facilitate inclusion of specific populations of patients including older adults who are commonly excluded in cancer trials.3 [Editor’s note: In March 2020, the FDA also released a brief encouraging inclusion of older adults in cancer trials.4]
Dr Sekeres: Trials can include an arm to enroll patients with comorbidities or at extremes of age to demonstrate that the drug is safe and effective in broader populations of patients.
Hematology Advisor: What are the relevant implications for clinicians – for example, how might they advocate for greater representation of this population in trials?
Dr Kanapuru: It is important for clinicians not to consider age alone as a sole criterion to evaluate patients’ suitability for enrollment in a clinical trial, but to consider other tools that can help identify how older patients will fare in a clinical trial. Additionally, considering broadening eligibility criteria in clinical trial protocols when it is safe and ethical to do so can facilitate increased enrollment of older adults in hematologic malignancy trials.
Dr Sekeres: One method we’ve adopted at Cleveland Clinic is to include in our investigator-initiated trial templates specific language that an investigator defining eligibility criteria cannot exclude patients with comorbidities without justification based on drug toxicity or metabolism. This sort of approach can be adopted at any institution.
Hematology Advisor: What are examples of the most pressing research needs in this area?
Dr Kanapuru: [Remaining needs include] raising awareness of the importance of enrolling older adults in cancer clinical trials and understanding barriers to enrollment of older adults in hematologic malignancy trials.
Dr Sekeres: We need more clinical trials to include septuagenarians and octogenarians to demonstrate that drugs are safe and effective in these populations, particularly as the population as a whole is aging.
- Kanapuru B, Singh H, Kwitkowski V, Blumenthal G, Ferrell AT, Pazdur R. Older adults in hematologic malignancy trials: Representation, barriers to participation and strategies for addressing underrepresentation. [Published online February 7, 2020] Blood Rev. doi: 10.1016/j.blre.2020.100670
- Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999;341(27):2061-2067.
- US Food and Drug Administration. Inclusion of older adults in cancer clinical trials. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/inclusion-older-adults-cancer-clinical-trials Accessed online March 11, 2020.
- US Food and Drug Administration. FDA In Brief: FDA encourages inclusion of older adult patients in cancer clinical trials. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-encourages-inclusion-older-adult-patients-cancer-clinical-trials Accessed online March 11, 2020.