Drug Research and Development for Adults Across the Older Age Span Proceedings of a Workshop (2021) / Chapter Skim
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3 Overcoming Key Barriers
3 Overcoming Key Barriers
Pages 19-34
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From page 19... ...
• Clinical trials that focus on diseases specific to older adults have demonstrated successful enrollment of large numbers of older adults, so "there is no inherent reason that older adults cannot or will not participate in clinical trials." (Sridhara) • An individual's decision to participate in research is a func tion of trust, altruism, and expectation of benefit; these attri butes may be modified to increase likelihood of participation.
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From page 20... ...
One concern of such underrepresentation, said Allore, is that financial coverage decisions are made based on these clinical trials. For example, in one cardiovascular trial study where trials that were used for Medicare coverage decisions were analyzed, it was found that the trial participants differed significantly from Medicare beneficiaries on various characteristics, including age, and that the trials rarely stratified outcomes by age, sex, or race (Dhruva and 1 Healthy Aging Facts.
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From page 21... ...
found that older adults are regularly excluded from cancer clinical trials, and that the exclusion is not due to age alone, but rather because of comorbidities, organ dysfunction, and prior malignancies. These types of exclusion criteria, said Allore, often make older adults ineligible for participation, regardless of whether the criteria have any bearing on the treatment being studied.
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From page 22... ...
In addition to these approaches, alternative trial designs could be considered to improve the relevance and generalizability of study results obtained from older adults. The traditional parallel group RCT has long been the gold standard for information, said Allore, but it may be time to consider alternatives such as adaptive platform designs.
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From page 23... ...
In summary, said Allore, "if we continue to conduct traditional clinical trials by excluding older adults … and these are our greatest users of medications, then we will continue to have unacceptably high levels of adverse drug reactions." She highlighted the need to better inform clinical decision making for older adults, and added that many trials still do not address outcomes that matter most to older adults. Allore suggested that inclusion of older adults in clinical trials should be monitored and this information shared to improve the relevance and generalizability of study findings, and that consideration should be given to alternative trial
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Lichtman, medical oncologist at Memorial Sloan Kettering Cancer Center, said that patients are being eliminated from clinical trials because of eligibility criteria that may not be clinically relevant. The American Society of Clinical Oncology and Friends for Cancer Research developed an initiative to examine the eligibility criteria for cancer trials in an effort to broaden the criteria to make trials more representative of the population.2 Although the initiative was not specifically designed to look at older adults, said Lichtman, the fact that comorbidities are common in older adults means that they may be underrepresented in clinical trials due to these same types of eligibility criteria.
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He explained that abnormal creatinine clearance is less common in the breast cancer population, which skews younger, and more common in the bladder cancer population, which skews older. To increase the number of patients eligible for clinical trials, the group recommended that eligibility should be based on creatinine clearance rather than serum creatinine, and that liberal creatinine clearance (e.g., >30 mL/min)
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From page 26... ...
To gather this needed evidence, said Lichtman, clinical trials should be designed to capture the "real-world" patient population; patients from underrepresented groups should be sought out; and eligibility criteria should be in line with the goals of the trial. For example, if the drug is hepatically metabolized and in vitro studies show that the drug is not a substrate for transporters that could be inhibited by the accumulation of uremic toxins, there is no reason to have a rigid creatinine clearance threshold to make patients eligible for trial participation.
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From page 27... ...
To increase participation of older adults in clinical trials, said Sridhara, investigators should consider factors including the prevalence of the disease in the older age population; access to a care facility; frequency of outcome assessment; whether outcome assessments are invasive or noninvasive; and thoughtful consideration of exclusion criteria, including toxicity and potential drug–drug interactions. During all phases of clinical trials, there are ways to include older adults without sacrificing safety or efficiency, she said.
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From page 28... ...
Sridhara provided some examples of trial design options, and described some of the benefits and drawbacks. In an RCT, a restricted homogeneous population is usually enrolled so that any treatment effect can be evaluated with a minimum number of patients.
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Respondent's answers are compiled into a composite score, and this score is considered to be a strong predictor of willingness to participate in clinical trials. Karlawish suggested that evidence gleaned from the use of the Research Attitudes Questionnaire further strengthens the theory that attitudes of trust, altruism, and expectation of benefit are what drive people to make the decision to enroll in a specific study.
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From page 30... ...
NOTE: A positive value indicates that the factor is associated with increased willingness to participate and a negative value indicates a factor is associated with a decreased willingness to participate. SOURCES: As presented by Jason Karlawish, August 5, 2020.
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From page 31... ...
Finally, the role of the caregiver deserves greater attention; whether the caregiver is a spouse, family member, or friend, caregivers take on a lot of the work of participating in a trial, and investigators should consider compensating them for this work, said Karlawish. DISCUSSION Watanabe led the presenters in a panel discussion, covering topics including the gap between the study population and user population; barriers for older adults; postmarket research; and target populations for trials.
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Target Populations for Trials Given that drugs are often approved based on studies in relatively narrow populations, Watanabe asked, how should researchers decide which additional trials to conduct? What are the considerations for determining which populations to target?
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From page 33... ...
Karlawish noted that while there are many stakeholders in the clinical trial space -- including pharmaceutical companies, FDA, NIH, payers, providers, and patients -- each of these stakeholders has their own perspective and priorities. There is not currently an entity or institution that can look at the considerations that have been discussed in this session and determine whether the populations enrolled in clinical trials are appropriate, he said.
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