Assessment of Outcomes Associated With the Use of Newly Approved Oncology Drugs in Medicare Beneficiaries

Key Points Question What are the real-world outcomes for Medicare patients with metastatic cancer receiving recently approved oncology drugs and how do they compare with pivotal clinical trial outcomes? Findings In this retrospective cohort study, outcomes were compared between clinical trial participants and treated Medicare patients across 22 cancer drugs approved by the US Food and Drug Administration for 29 indications. Median duration of therapy and overall survival among treated Medicare patients were generally shorter than among trial participants, and dose reductions were common among Medicare patients. Meaning Pivotal clinical trials may provide inadequate data for the purpose of clinical decision-making among Medicare beneficiaries with advanced cancer.


Introduction
Differences between clinical trial participants and the broader patient population they are intended to represent can impair the generalizability of study results. [1][2][3][4][5][6] Elderly, minority, poor, and chronically ill patients, for instance, are often underrepresented in cancer clinical trials. [7][8][9][10][11][12] Lack of generalizability of clinical trials for cancer drugs used to treat patients with metastatic cancers may be of particular concern. Such therapies tend to have modest efficacy and produce substantial toxic effects even in young, fit clinical trial participants. Thus, additional scrutiny is warranted when applying these trial data to patients at a higher risk of harm from therapy. 13,14 Adults 65 years and older are projected to account for 70% of cancer diagnoses by 2030.
Medicare, the US federal health insurance program for elderly and disabled people, provides coverage for more than 50 million older adults, including nearly 7.5 million with cancer. In 2018, more than 40% of prescription dispensations for oral cancer drugs used to treat metastatic cancers were to Medicare beneficiaries. 15 However, trial representation of patients in this age group is routinely lower, and age disparities between trial participants and the incident disease population is widening. [16][17][18] Adequate power for subgroup analyses is needed for clinical trial results to be generalizable.
Although this is not the same as representativeness-the extent to which a clinical trial cohort reflects the underlying disease population-improving the representation of older patients could increase the sample size sufficiently to perform these subgroup analyses needed for scientific inference.
Given that older patients may experience more toxic effects when receiving cancer treatments, inadequate generalizability may be of clinical consequence. 19 Prior research 20 23 however, found that patients receiving pazopanib for advanced renal cell carcinoma in everyday practice lived longer than individuals in the pivotal clinical trial (median, 29.9 vs 22.9 months).
Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we conducted a study aimed to examine the generalizability of pivotal cancer clinical trial data. First, we compared the survival of Medicare patients treated with new drugs with that among pivotal clinical trial participants. Second, we examined whether the duration of treatment differed between Medicare patients and pivotal clinical trial participants. Third, we assessed the frequency of early discontinuation of drug use and dose reductions among Medicare patients treated with new drugs.
We did not assess the incremental survival benefit of newly approved cancer drugs among Medicare patients.
contains deidentified data, informed consent was not possible, and the study was approved as exempt research by the institutional review board at Memorial Sloan Kettering Cancer Center.

Approved Cancer Drug Indications
We abstracted sequential cancer drug approvals for metastatic and locally advanced indications without curative intent approved between January 1, 2008, and December 31, 2013, from the US Food and Drug Administration (FDA) Hematology/Oncology (Cancer) Approvals and Safety Notifications website 24 (eFigure 1 in the Supplement). We only included drugs for which median overall survival in the intervention arm of the pivotal trial, defined as the trial cited on the package insert (the label) and the FDA approval announcement, was published in a peer-reviewed journal.
Median duration of therapy, dose reductions, and age-specific survival results were recorded from the trial publication or FDA package insert when available.

Medicare Patient Outcomes
We identified patients in the SEER-Medicare database diagnosed with cancer between January 1, 2006, and December 31, 2015, whose disease type and stage matched the FDA indication and who received at least 1 dose of the relevant cancer drug via intravenous infusion or filled 1 prescription for oral therapy (eTable 1 in the Supplement). We did not further limit the patient population to those who met trial eligibility criteria because our goal was to study those treated in general. We assumed the presence of biomarkers when relevant because SEER does not routinely capture such information. SEER is a population-based cancer registry that covers 28% of the US population.
Medicare claims capture health care use and date of death. 25 Patients had stage IV disease at diagnosis unless the indication included patients with locally advanced disease not amenable to curative surgery or radiotherapy. In such cases, patients with stage III disease at diagnosis were included if they had no cancer-directed surgery and/or radiotherapy documented in the SEER-Medicare database. Treatment was determined from J codes in Medicare Part B for intravenous drugs and generic and brand names in Medicare Part D for oral drugs. Median duration of therapy was measured from the date of first fill to the end of the days supplied of the last fill for oral drugs and from the first to last date of drug administration, unless the trial duration of therapy was reported in cycles, for the intravenous drugs. If so, we approximated number of cycles in the SEER-Medicare database and converted to months of therapy for more accurate comparison (eTable 2 in the Supplement). We restricted the sample to patients with continuous enrollment in Medicare Parts A and B for 6 months before and after diagnosis or until death or end of follow-up. More than 99% of patients receiving oral therapy in our analysis had continuous Medicare Part D enrollment.

Statistical Analysis
We included drug indications for which 30 or more SEER-Medicare patients met eligibility criteria. We compared age by regressing the mean age of patients in the SEER-Medicare database (weighted by sample size) against the mean age in the intervention arm of the pivotal trial because variance was not available for the trial population. A test of proportions was used to examine significant differences in race/ethnicity and sex composition. Statistical significance was defined as a 2-sided estimates were also calculated among the subgroup of Medicare patients with 1 or no comorbidities (Charlson comorbidity index, 0-1).
If a prescription for an oral drug was filled for less than any of the approved doses for that indication and there was no later claim for a recommended dose, this was counted as a dose reduction. It is not possible to determine whether intravenous doses match those approved by the FDA. 28 When a patient received only 1 prescription claim (for 30-90 days) or a single cycle of an intravenous drug, we labeled this a single treatment.

JAMA Network Open | Oncology
Outcomes Several associated factors are likely to explain these differences. In the analysis, the mean age of Medicare patients receiving treatment exceeded the mean age of clinical trial participants by 11 years (73 vs 62 years). Advanced age is on average associated with frailty and a higher prevalence of

JAMA Network Open | Oncology
Outcomes comorbidities, which may heighten drug toxicity and reduce patients' ability to tolerate cancer drugs. 29 These factors may lead to earlier discontinuation of therapy, treatment interruptions, or suboptimal dosages, negatively impacting survival. Although this study found that Medicare beneficiaries received shorter durations of therapy than study participants, including a sizeable percentage receiving only a single prescription or cycle as well as dose reductions, this was likely not solely attributable to their age but also to other factors, including comorbidities, performance status,

JAMA Network Open | Oncology
Outcomes tumor prognostic factors, access to care, racial disparities, systemic discrimination, and other socioeconomic factors that could lead to differential treatment and outcomes in the Medicare population compared with clinical trial participants.
In the few trials in which age-specific survival was reported in the publication or FDA package insert, survival was generally similar between older and younger study participants, suggesting that age alone does not explain our findings. However, this result was only available in 6 (20.7%) of the pivotal trials included. Another reason why advanced age might be associated with poorer outcomes is that older patients die at higher rates from other causes. However, this study found that nearly 90% of deaths among SEER-Medicare patients were associated with cancer.
Beyond older age, comorbidities or illness from more advanced or aggressive cancer that impairs drug tolerability could explain why, among Medicare patients, therapies were routinely discontinued early, doses were reduced, or medication was given for a single prescription or cycle of Real-world data can be used to generate additional information to help guide treatment decisions in understudied patients and could also be required by the FDA as part of postmarketing commitments. However, postapproval trials and mandatory surveillance studies are often underresourced and inconsistently performed. 33-35 Regardless, evidence of poorer outcomes or increased toxic effects in specific subgroups could lead to a requirement for more formal phase 4 studies.

Limitations
This study has limitations. An important limitation is the lack of a comparator group of Medicare patients who did not receive the treatment being evaluated; therefore, any estimate of the relative survival benefit from these drugs among Medicare patients could not be determined. The generalizability of clinical trial outcomes to younger, non-Medicare patients could also not be assessed, and similar differences may be evident among these patients. Because of limitations of claims-based data, the role of such factors as age, comorbidities, and socioeconomic and demographic variables in the observed differences in clinical trial efficacy in Medicare patients cannot be quantified. This analysis was limited to patients with stage IV or noncurative stage III cancer at diagnosis because these patients can be reliably identified in the SEER database. Many of the pivotal trials also include participants with newly metastatic disease; however, this was unlikely to influence the study findings because the difference in prognosis among patients with recurrence vs stage IV disease at diagnosis is mixed, 36,37 and stage IV diagnosis at presentation is common for cancers included in this analysis. 38-41

Conclusions
Among Medicare patients with advanced solid cancers treated with FDA-approved drugs, median survival was shorter than that reported among clinical trial participants treated with the same drugs for all but 1 drug used for 1 indication. Many Medicare patients were also treated for only brief duration, had dose reductions, or received a single prescription or treatment cycle. These findings raise concerns regarding the generalizability of clinical trial data for treatment decision-making in Medicare patients. Furthermore, prescribing patterns in Medicare patients require additional scrutiny to ensure optimal dosing to avoid overtreatment or undertreatment in this population. Pivotal trials can be improved, and regulatory requirements could emphasize the importance of generating data relevant to the older patients who constitute an increasing number of all patients with cancer in the US. 11