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Enrollment of older adults on oncology trials: An FDA perspective
JGO-00393; No. of pages: 2; 4C: Journal of Geriatric Oncology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Journal of Geriatric Oncology
Perspectives
Enrollment of older adults on oncology trials: An FDA perspective☆ Harpreet Singh ⁎, Julia A. Beaver, Geoffrey Kim, Richard Pazdur Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States
Older adults are a growing segment of our oncology population, with an expected increase in cancer incidence of 67% from 2010 to 2030 in people age 65 and older [1]. However, older adults are proportionally underrepresented in oncology clinical trials [2]. Because most of what we know about cancer therapeutics is based on clinical trials conducted in younger patients, oncology lacks robust knowledge of the risks and benefits of cancer treatments in older adults, especially those over age 75. Elderly patients can respond differently from younger patients to drug therapy in several ways, and these differences can be most pronounced in those over age 75. Age-related physiologic changes in older adults can affect the pharmacokinetics of the drug and the pharmacodynamic response to the drug, both of which can impact the drug response. In addition, elderly patients often have comorbidities and are taking concomitant medications that may interact with the investigational agent, making them more vulnerable to adverse events. To truly assess the risk-benefit profile of a drug that will be used in an elderly population, it is imperative that cancer clinical trials include a greater representation of these patients. The FDA has made a concerted effort to encourage enrollment of older adults in registration clinical trials. In 1989, the Agency published a Guidance for Industry to encourage sponsors to study new drugs in the full range of patients who will receive them, including older adults. This guidance also recommended that information on pharmacokinetics related to age, conditions associated with age, and clinical data should be collected and analyzed to learn whether the drug has different effects in older adults [3]. In a 1994 Guidance for Industry, the FDA formally defined geriatric patients as those ages 65 and older, with the intent of harmonizing clinical testing of drugs in Europe, Japan, and the US [4]. While the geriatric population is arbitrarily defined in this guideline, it is increasingly important to seek patients in the older range, such as 75 and above, given our country's shifting demographics. Due to possible differences in pharmacokinetic (PK) response as a result of age or age-associated conditions, formal PK studies comparing older adults with young healthy volunteers should be conducted early in the drug development process. More recently, in 2012, the FDA published an updated Guidance for Industry, E7 Studies in Support of Special Populations: Geriatrics, to answer specific questions regarding previous guidance, including a ☆ Note: This is a U.S. Government work. There are no restrictions on its use. ⁎ Corresponding author at: OHOP, OND, CDER, Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 2137, Silver Spring, MD 20993, United States. E-mail address: [email protected] (H. Singh).
discussion of eligibility criteria [5]. The Guidance suggested that geriatric patients with comorbidities or taking concomitant therapies should not be automatically excluded, because including such patients in trials provides data that may help to detect drug-disease interactions. Eligibility criteria must be closely examined so as not to exclude patients who would be considered vulnerable or “frail.” Randomized trials would allow appropriate attribution of findings either to the investigational drug or other factors. In addition, protocols should not arbitrarily include an upper age cutoff. Older adults should be enrolled in clinical trials if they are stable, can be safely and ethically enrolled, and are willing to participate. Efforts are underway to encourage sponsors to take a more rational approach to eligibility criteria for clinical trials, and include the potential to relax certain laboratory requirements that encompass multiple organ functions if safety is not compromised [6]. The FDA also has required that the package inserts of approved products include a “Geriatric Use” subsection that provides pertinent information about the drug's experience in older adults [7]. Any limitations, need for specific monitoring, specific toxicities associated with use, and other information related to the safe and effective use of the product in older adults must be included in this section. However, for many newly approved hematology and oncology products, there is inadequate prescribing information about efficacy and safety data for patients older than 65 or 75 and no data or conclusions can be presented in labeling [8]. Healthcare providers who treat older adults with cancer are left to extrapolate safety and efficacy data from trials conducted in younger, healthier populations when developing treatment plans. Updating current thinking about standardized age categories—for example, grouping older adults in more discrete categories for analysis such as 65 to 74 years old, or 75 to 84 years old, rather than “older than 65 years old” or simply using birth year—has been a recurring recommendation in FDA guidelines and at public meetings. Reporting clinical trial data for oncology drugs in a more standardized and granular way may be clinically informative and can enhance our understanding of clinical outcomes and trends in specific populations. Although the demographic composition and subgroup analyses are already included in medical product reviews located on FDA's Web site, they can be difficult to find. In response to public feedback and in an effort to be more transparent, FDA is considering how to make demographic information for newly-approved drugs and biologics more accessible and user-friendly. This includes the introduction of Drug Trials Snapshots, which outlines the participation of people in clinical trials by sex, race, and age. This information is publically available and gathered in a central location on the FDA's website [9].
http://dx.doi.org/10.1016/j.jgo.2016.11.001 1879-4068/Published by Elsevier Ltd.
Please cite this article as: Singh H, et al, Enrollment of older adults on oncology trials: An FDA perspective, J Geriatr Oncol (2016), http:// dx.doi.org/10.1016/j.jgo.2016.11.001
2
H. Singh et al. / Journal of Geriatric Oncology xxx (2016) xxx–xxx
The FDA encourages drug sponsors as well as clinical trial cooperative groups to devise strategies to recruit patients that are reflective of their intended population. While we recognize that the health of older adults is heterogeneous, little information is routinely captured about older adults who enroll in clinical trials besides chronological age and performance status. Thus, incorporating elements from geriatric assessment tools, such as functional status, cognitive function, and a thorough assessment of comorbid medical conditions, may help identify older adults most likely to benefit from treatment. The FDA encourages discussion of incorporating these elements into clinical trial design and collecting data prospectively, which may better inform patient selection for registration trials. The FDA's frequent communications with sponsors during the product development process provide opportunities to remind sponsors to consider the age demographics of their target population early in the development of clinical trials. In breast cancer, for example, up to 19.7% of patients are over age 75. Thus, a development program in a drug for breast cancer should aim to enroll a representative population of older adults. As further encouragement to include a representative cohort of patients on clinical trials, more detailed labeling information that reflects the clinical experience with older adults could be considered. In some cases, enrollment of adequate representation of elderly patients may be challenging, and it could be appropriate to collect data in a post-marketing setting. However, the adequacy of, and the need for, data in these populations should be considered during drug development and discussed in the marketing application submission. Post-marketing commitments or requirements may be unnecessary if these populations are included up front. Collection of data from all possible sources should be optimized, because adverse reactions in elderly populations are generally underreported. Sponsors and cooperative groups may also work to harness “big data” and explore real-world outcomes to answer questions about practice patterns and safety in older adults after drug approval. By 2030, the fastest growing segment of the U.S. population will be individuals aged 80 years and older. We encourage those conducting trials to include adequate numbers of older adults in oncology trials. Multiple stakeholders, including investigators, advocates, government, industry, and the American Society of Clinical Oncology, are discussing
ways to provide direction and garner support for the generation of evidence on older adults with cancer. To better serve the American public, provide access to novel drugs, and allow for representative populations to be studied during drug development, a more rational and thoughtful approach to enrollment of older adults in oncology clinical trials should be pursued, and we encourage early dialogue with FDA on these matters. Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed by the authors. Author Contributions Primary author - Harpreet Singh remaining authors are supportive. References [1] Smith BD, Smith GL, Hurria A, et al. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol 2009;27:2758–65. [2] Talarico Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. Clin Oncol 2004;22:4626–31. [3] Guideline for the Study of Drugs Likely to Be Used in the Elderly. http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072048. pdf; November 1989. [4] Guidance for industry — studies in support of special populations: geriatrics (ICH E7). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM073131.pdf; August 1994. [5] Guidance for industry — E7 studies in support of special populations: geriatrics questions and answers. http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM189544.pdf; February 2012. [6] http://www.ascopost.com/issues/august-10-2016/asco-and-friends-of-cancerresearch-launch-initiative-to-modernize-eligibility-criteria-for-clinical-trials/. [7] Guidance for industry: content and format for geriatric labeling. http://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM075062.pdf; October 2001. [8] Hinshaw T, Kapusnik-Uner J, Zarowitz B, Matuszewski K. Identifying knowledge gaps in the labeling of medications for geriatric patients. Pharm Ther 2013;38(9): 535–40. [9] Drug trials snapshots. http://www.fda.gov/Drugs/InformationOnDrugs/ucm412998. htm.
Please cite this article as: Singh H, et al, Enrollment of older adults on oncology trials: An FDA perspective, J Geriatr Oncol (2016), http:// dx.doi.org/10.1016/j.jgo.2016.11.001
Contents lists available at ScienceDirect
Journal of Geriatric Oncology
Perspectives
Enrollment of older adults on oncology trials: An FDA perspective☆ Harpreet Singh ⁎, Julia A. Beaver, Geoffrey Kim, Richard Pazdur Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States
Older adults are a growing segment of our oncology population, with an expected increase in cancer incidence of 67% from 2010 to 2030 in people age 65 and older [1]. However, older adults are proportionally underrepresented in oncology clinical trials [2]. Because most of what we know about cancer therapeutics is based on clinical trials conducted in younger patients, oncology lacks robust knowledge of the risks and benefits of cancer treatments in older adults, especially those over age 75. Elderly patients can respond differently from younger patients to drug therapy in several ways, and these differences can be most pronounced in those over age 75. Age-related physiologic changes in older adults can affect the pharmacokinetics of the drug and the pharmacodynamic response to the drug, both of which can impact the drug response. In addition, elderly patients often have comorbidities and are taking concomitant medications that may interact with the investigational agent, making them more vulnerable to adverse events. To truly assess the risk-benefit profile of a drug that will be used in an elderly population, it is imperative that cancer clinical trials include a greater representation of these patients. The FDA has made a concerted effort to encourage enrollment of older adults in registration clinical trials. In 1989, the Agency published a Guidance for Industry to encourage sponsors to study new drugs in the full range of patients who will receive them, including older adults. This guidance also recommended that information on pharmacokinetics related to age, conditions associated with age, and clinical data should be collected and analyzed to learn whether the drug has different effects in older adults [3]. In a 1994 Guidance for Industry, the FDA formally defined geriatric patients as those ages 65 and older, with the intent of harmonizing clinical testing of drugs in Europe, Japan, and the US [4]. While the geriatric population is arbitrarily defined in this guideline, it is increasingly important to seek patients in the older range, such as 75 and above, given our country's shifting demographics. Due to possible differences in pharmacokinetic (PK) response as a result of age or age-associated conditions, formal PK studies comparing older adults with young healthy volunteers should be conducted early in the drug development process. More recently, in 2012, the FDA published an updated Guidance for Industry, E7 Studies in Support of Special Populations: Geriatrics, to answer specific questions regarding previous guidance, including a ☆ Note: This is a U.S. Government work. There are no restrictions on its use. ⁎ Corresponding author at: OHOP, OND, CDER, Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 2137, Silver Spring, MD 20993, United States. E-mail address: [email protected] (H. Singh).
discussion of eligibility criteria [5]. The Guidance suggested that geriatric patients with comorbidities or taking concomitant therapies should not be automatically excluded, because including such patients in trials provides data that may help to detect drug-disease interactions. Eligibility criteria must be closely examined so as not to exclude patients who would be considered vulnerable or “frail.” Randomized trials would allow appropriate attribution of findings either to the investigational drug or other factors. In addition, protocols should not arbitrarily include an upper age cutoff. Older adults should be enrolled in clinical trials if they are stable, can be safely and ethically enrolled, and are willing to participate. Efforts are underway to encourage sponsors to take a more rational approach to eligibility criteria for clinical trials, and include the potential to relax certain laboratory requirements that encompass multiple organ functions if safety is not compromised [6]. The FDA also has required that the package inserts of approved products include a “Geriatric Use” subsection that provides pertinent information about the drug's experience in older adults [7]. Any limitations, need for specific monitoring, specific toxicities associated with use, and other information related to the safe and effective use of the product in older adults must be included in this section. However, for many newly approved hematology and oncology products, there is inadequate prescribing information about efficacy and safety data for patients older than 65 or 75 and no data or conclusions can be presented in labeling [8]. Healthcare providers who treat older adults with cancer are left to extrapolate safety and efficacy data from trials conducted in younger, healthier populations when developing treatment plans. Updating current thinking about standardized age categories—for example, grouping older adults in more discrete categories for analysis such as 65 to 74 years old, or 75 to 84 years old, rather than “older than 65 years old” or simply using birth year—has been a recurring recommendation in FDA guidelines and at public meetings. Reporting clinical trial data for oncology drugs in a more standardized and granular way may be clinically informative and can enhance our understanding of clinical outcomes and trends in specific populations. Although the demographic composition and subgroup analyses are already included in medical product reviews located on FDA's Web site, they can be difficult to find. In response to public feedback and in an effort to be more transparent, FDA is considering how to make demographic information for newly-approved drugs and biologics more accessible and user-friendly. This includes the introduction of Drug Trials Snapshots, which outlines the participation of people in clinical trials by sex, race, and age. This information is publically available and gathered in a central location on the FDA's website [9].
http://dx.doi.org/10.1016/j.jgo.2016.11.001 1879-4068/Published by Elsevier Ltd.
Please cite this article as: Singh H, et al, Enrollment of older adults on oncology trials: An FDA perspective, J Geriatr Oncol (2016), http:// dx.doi.org/10.1016/j.jgo.2016.11.001
2
H. Singh et al. / Journal of Geriatric Oncology xxx (2016) xxx–xxx
The FDA encourages drug sponsors as well as clinical trial cooperative groups to devise strategies to recruit patients that are reflective of their intended population. While we recognize that the health of older adults is heterogeneous, little information is routinely captured about older adults who enroll in clinical trials besides chronological age and performance status. Thus, incorporating elements from geriatric assessment tools, such as functional status, cognitive function, and a thorough assessment of comorbid medical conditions, may help identify older adults most likely to benefit from treatment. The FDA encourages discussion of incorporating these elements into clinical trial design and collecting data prospectively, which may better inform patient selection for registration trials. The FDA's frequent communications with sponsors during the product development process provide opportunities to remind sponsors to consider the age demographics of their target population early in the development of clinical trials. In breast cancer, for example, up to 19.7% of patients are over age 75. Thus, a development program in a drug for breast cancer should aim to enroll a representative population of older adults. As further encouragement to include a representative cohort of patients on clinical trials, more detailed labeling information that reflects the clinical experience with older adults could be considered. In some cases, enrollment of adequate representation of elderly patients may be challenging, and it could be appropriate to collect data in a post-marketing setting. However, the adequacy of, and the need for, data in these populations should be considered during drug development and discussed in the marketing application submission. Post-marketing commitments or requirements may be unnecessary if these populations are included up front. Collection of data from all possible sources should be optimized, because adverse reactions in elderly populations are generally underreported. Sponsors and cooperative groups may also work to harness “big data” and explore real-world outcomes to answer questions about practice patterns and safety in older adults after drug approval. By 2030, the fastest growing segment of the U.S. population will be individuals aged 80 years and older. We encourage those conducting trials to include adequate numbers of older adults in oncology trials. Multiple stakeholders, including investigators, advocates, government, industry, and the American Society of Clinical Oncology, are discussing
ways to provide direction and garner support for the generation of evidence on older adults with cancer. To better serve the American public, provide access to novel drugs, and allow for representative populations to be studied during drug development, a more rational and thoughtful approach to enrollment of older adults in oncology clinical trials should be pursued, and we encourage early dialogue with FDA on these matters. Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed by the authors. Author Contributions Primary author - Harpreet Singh remaining authors are supportive. References [1] Smith BD, Smith GL, Hurria A, et al. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol 2009;27:2758–65. [2] Talarico Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. Clin Oncol 2004;22:4626–31. [3] Guideline for the Study of Drugs Likely to Be Used in the Elderly. http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072048. pdf; November 1989. [4] Guidance for industry — studies in support of special populations: geriatrics (ICH E7). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM073131.pdf; August 1994. [5] Guidance for industry — E7 studies in support of special populations: geriatrics questions and answers. http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM189544.pdf; February 2012. [6] http://www.ascopost.com/issues/august-10-2016/asco-and-friends-of-cancerresearch-launch-initiative-to-modernize-eligibility-criteria-for-clinical-trials/. [7] Guidance for industry: content and format for geriatric labeling. http://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM075062.pdf; October 2001. [8] Hinshaw T, Kapusnik-Uner J, Zarowitz B, Matuszewski K. Identifying knowledge gaps in the labeling of medications for geriatric patients. Pharm Ther 2013;38(9): 535–40. [9] Drug trials snapshots. http://www.fda.gov/Drugs/InformationOnDrugs/ucm412998. htm.
Please cite this article as: Singh H, et al, Enrollment of older adults on oncology trials: An FDA perspective, J Geriatr Oncol (2016), http:// dx.doi.org/10.1016/j.jgo.2016.11.001