Adverse Events Associated With Radium-223 in Metastatic Prostate Cancer: Disproportionality Analysis of FDA Data Reflecting Worldwide Utilization

Journal Pre-proof Adverse Events Associated with Radium-223 in Metastatic Prostate Cancer: Disproportionality Analysis of FDA Data Reflecting Worldwide Utilization Minh-Phuong Huynh-Le, MD, MAS, Randall C. Shults, BS, Michael J. Connor, MD, Jona A. Hattangadi-Gluth, MD PII:

S1558-7673(19)30368-4

DOI:

https://doi.org/10.1016/j.clgc.2019.11.017

Reference:

CLGC 1409

To appear in:

Clinical Genitourinary Cancer

Received Date: 26 September 2019 Revised Date:

6 November 2019

Accepted Date: 27 November 2019

Please cite this article as: Huynh-Le M-P, Shults RC, Connor MJ, Hattangadi-Gluth JA, Adverse Events Associated with Radium-223 in Metastatic Prostate Cancer: Disproportionality Analysis of FDA Data Reflecting Worldwide Utilization, Clinical Genitourinary Cancer (2020), doi: https://doi.org/10.1016/ j.clgc.2019.11.017. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.

MicroAbstract

Radium-223 improves overall survival in metastatic castrate-resistant prostate cancer (mCRPC), but realtime international utilization is unknown. We used US FDA data to identify adverse events associated with radium-223, including health deterioration, bone pain, and hematologic toxicities. mCRPC patients experiencing toxicity are only receiving half the radium-223 prescription dose. These real-world data are critical for risk-benefit assessments of radium-223 use.

Adverse Events Associated with Radium-223 in Metastatic Prostate Cancer: Disproportionality Analysis of FDA Data Reflecting Worldwide Utilization Minh-Phuong Huynh-Le, MD, MAS Randall C. Shults, BS Michael J. Connor, MD Jona A. Hattangadi-Gluth, MD Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, United States Corresponding Author: Jona A. Hattangadi-Gluth, MD Associate Professor Department of Radiation Medicine and Applied Sciences University of California San Diego 9500 Gilman Dr. Mail Code 0861 La Jolla, CA 92093-0861 [email protected] Short Running Title: FDA reported adverse events for radium-223 Key Words: radium-223, FDA, FAERS, disproportionality analysis, unsealed source radiotherapy, pharmacovigilance Word Count: 3,130 Tables and Figures: 5 Tables, 1 Figure Supplemental Tables and Figures: 1 eTable, 1 eFigure Funding: This work was supported in part by National Institutes of Health (NIH) grant #1KL2TR001444 (JAH-G) and R01CA238783-01 (JAH-G). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

1

Conflicts of Interest: Dr. Hattangadi-Gluth reports research funding from Varian Medical Systems, unrelated to the present study.

2

MicroAbstract

Radium-223 improves overall survival in metastatic castrate-resistant prostate cancer (mCRPC), but realtime international utilization is unknown. We used US FDA data to identify adverse events associated with radium-223, including health deterioration, bone pain, and hematologic toxicities. mCRPC patients experiencing toxicity are only receiving half the radium-223 prescription dose. These real-world data are critical for risk-benefit assessments of radium-223 use.

3

Abstract Objectives: Radionuclide radium-223 improves survival in men with metastatic castrate-resistant prostate cancer (mCRPC). The FDA Adverse Events Reporting System (FAERS) is a post-market pharmacovigilance database valuable for adverse event (AE) assessments. We analyzed FAERS to identify disproportionate AE signals related to radium-223, and to explore radium-223’s international utilization.

Methods: We identified 2,182 radium-223 cases associated with AE(s) from 2013-2018. The duration of radium-223 therapy was calculated. Reporting odds ratio (ROR) and proportional reporting ratio (PRR), with 95% confidence intervals, were calculated for AEs of interest. ROR shows disproportionate signals if the lower limit of the 95% CI>1. PRR shows disproportionate signals if PRR≥2, Chi-square statistic≥4, and ≥3 AEs were reported. We identified any FDA enforcement actions for radium-223.

Results: A majority (60.8%) of events occurred outside the US. Among patients with radium-223associated AEs, median therapy duration was only 56 days (corresponding to 2-3 treatment cycles). Disproportionate signals were detected for general health deterioration (ROR 5.03, 95% CI:4.23-5.98; PRR 4.94, 95% CI:4.16-5.87), bone pain (ROR 4.53, 95% CI:3.67-5.59; PRR 4.48, 95% CI:3.63-5.53), and hematologic AEs including anemia (ROR 2.89, 95% CI:2.55-3.27; PRR 2.80, 95% CI:2.48-3.17), thrombocytopenia (ROR 3.22, 95% CI:2.77-3.74; PRR: 3.16, 95% CI:2.72-3.67), and pancytopenia/bone marrow failure (ROR 4.83, 95% CI:4.11-5.67; PRR 4.73, 95% CI:4.03-5.55). There were no enforcement actions for radium-223.

Conclusions: mCRPC patients experiencing AEs are only receiving half the prescription dose of radium223 required for survival benefit. Radium-223 is associated with health deterioration, bone pain, and hematologic AEs. Real-world analyses are important for ongoing radium-223 risk-benefit assessments.

4

Introduction In 2013, the ALpharadin in SYMptomatic Prostate CAncer (ALSYMPCA) trial revealed improved overall survival in men with metastatic castrate-resistant prostate cancer (mCRPC) and bone metastases treated with alpha-emitter radium-2231. These results led to radium-223 being recommended (with a flash update July 9, 2013) as a category one treatment option per the National Comprehensive Cancer Network guidelines for men with mCPRC and symptomatic bone metastases2,3. Radium-223 has a 11.4-day half-life, is given to patients intravenously monthly for six total injections4, and is selectively taken up by bone with high osteoblastic activity by acting as a calcium analog5. Radium-223 is mainly excreted from the body via the gastrointestinal tract5. As of 2017, an estimated >27,000 men have received radium-223 worldwide5. The US Food and Drug Administration (FDA) has a publicly available Adverse Events Reporting System (FAERS) which is critical for post-market surveillance of drugs approved for use in the USA6–8. Toxicity and safety data from drug randomized clinical trials (RCTs)—which are meticulously run with strict patient enrollment criteria—can be underreported9,10, and may conflict with real-world adverse events (AEs). FAERS studies can identify AEs not previously recognized in RCTs6–8, suggesting there is considerable value in analyzing these data. Rather than just reporting the incidence rates of AEs11, disproportionality analyses are valuable for detecting AEs by searching for signals relative to other AEs reported to the FDA. Disproportionate AEs signals for multiple cancer drugs, including immunotherapies, chemotherapies, and targeted therapies, have been identified via FAERS12–18. Prior work evaluating radiotherapy AEs reported to the FDA has focused primarily on medical devices (CT simulators, external beam devices, brachytherapy systems, etc.) and software systems19, and the associated FDA-mandated recalls of these devices20. Little is known about reported AEs regarding radionuclides. Given FAERS’ uniqueness as a real-world risk assessment tool, we performed a comprehensive disproportionality analysis to determine AE signals related to radium-223 use. Furthermore, we explored radium-223’s real-world utilization: who is receiving this radionuclide, and for what indication? Are

5

patients receiving the entire 6-injection course, and what is the relationship of AE onset with therapy duration? Finally, what are the trends of radium-223 use and reported AEs over time?

Methods Data Source FAERS is a live, spontaneous reporting system containing AE or medication error reports submitted to the FDA from sources including pharmaceutical companies, physicians, lawyers, consumers, and the general public6. Direct reports are voluntarily sent by consumers and medical professionals. Mandatory reports are submitted by drug manufacturers and are “expedited” 15-day reports (containing at least one AE not currently in the product labeling and for which the outcome is serious) or “periodic” reports (these reports do not meet criteria for an expedited report and must be submitted quarterly for the first three years after approval, and annually after)21. One report may contain multiple drugs, indications, or AEs. FAERS is a relational database. Data is aggregated into quarterly extract files. There are seven files in each release: “DEMO” containing demographics about the patient who experienced the event (age, sex, country) and the reporter occupation, “DRUG” with drug information and its suspected role in the reported AE, “INDI” with the drug use indication, “RPSR” detailing the report source, “THER” containing the start and end dates of the therapy, “REAC” containing the AE(s), and “OUTC” revealing the outcome and severity. All files are linked by a unique primary ID consisting of the case ID and the revision number. Each case represents one patient and is linked to all drugs administered to that individual. Because patient outcomes are listed on a per-patient basis (not a per-drug basis), we limited the cases to those where radium-223 was the primary or secondary suspect drug. Because the FDA approved radium-223 use on May 15, 20134, we queried FAERS from 2013 quarter 2 (2013Q2) through 2018 quarter 2 (2018Q2). Quarterly data files were downloaded on September 6, 2018. Duplicate reports were removed as per FDA guidelines of adopting the most recent case number for disproportionality analyses22. Analyses were performed in Python 3.6.

6

Radium-223 Adverse Events and Outcomes We searched for all reports in the “DRUG” files where the drug name contained one of the following terms: “radium” or the brand name “Xofigo.” Case IDs were subsequently used to search for AEs of interest related to radium-223 as composite groups. These AEs were chosen a priori from radium223’s mechanisms of action5 and clinical trials1,23,24, and are classified using the Medical Dictionary for Regulatory Activities Preferred Term nomenclature. AEs of interest were: general health deterioration, fatigue, decreased appetite, dehydration, vomiting, diarrhea, nausea, bone pain, anemia, thrombocytopenia, leukopenia, neutropenia, pancytopenia/bone marrow failure, peripheral edema, pulmonary toxicity, and renal toxicity. Full search terms are detailed in eTable 1. A patient could be binned into multiple AE composite groups but could only be placed into each group once. We categorized the following FAERS pre-specified patient outcomes in mutually exclusive outcome groups in order of seriousness: death, life-threatening, hospitalization, disability, required intervention, and “other serious/important medical event”18. The median and interquartile range (IQR) for radium-223 therapy duration, AE onset after radium-223 therapy initiation, AE persistence after radium223 was stopped, and AE reporting time lag (time between AE occurrence and report submission) were calculated.

Disproportionality Analysis A disproportionality analysis was then performed using established FAERS data mining methods25–27. A proportional reporting ratio (PRR) and reporting odds ratio (ROR), and their respective 95% confidence intervals, were calculated for each AE. The PRR represents the rate of reporting one event among all events for a given drug (e.g, radium-223), compared to the reporting rate for all drugs in the database26. The ROR is the ratio of the odds of reporting one event vs. all other events for a given drug, compared to the odds for all other drugs in FAERS26. The PRR, ROR, and their 95% confidence

7

intervals (CI) are calculated based on a two-by-two contingency table (Table 1) and are defined in Equations (1) and (2). A/(A+B) ; C/(C+D)

PRR=

A/C

ROR=

B/D

95% CI=e

; 95% CI=e

1 1 1 1 A B C D

lnሺPRRሻ±1.96ට + + +

1 1 1 1 A B C D

lnሺRORሻ±1.96ට + + +

(1)

(2)

A PRR shows a disproportionate, or strong, signal for an AE if PRR≥2, the Chi-square statistic χ2≥4, and ≥3 events were reported28. A ROR shows a disproportionate signal if the lower limit of the 95% CI>1, and ≥2 events were reported29.

Report Characteristics and Events over Time To evaluate whether there was a statistically significant increase in cases reported over time, we performed linear regressions of the number of cases reported against time (in quarters). We additionally performed linear regressions of the number of outcomes (death, hospitalization, life-threatening, disability) and all AEs reported against time. Analyses were corrected for multiple comparisons to control the false discovery rate30. Statistical significance was set at α=0.05.

Drug Enforcement and Recalls As a secondary analysis of radium-223 events, we searched the FDA Drug Recall Enforcement Reports31 to identify any recalls or enforcement actions from 2013Q2-2018Q2.

Results There were 6,356,962 patient cases involving AEs reported to FAERS from 2013Q2-2018Q2; of these, 5,898,241 were unique cases. There were 2,182 unique patient cases involving radium-223 (eFigure 1).

8

Patients and Report Characteristics Patient and report characteristics of all unique cases are shown in Table 2. Of the 1,270 (58.2%) cases where age was reported, the mean age of patients receiving radium-223 was 71.6 years (SD=9.6). Over 90% of reported cases were of male patients (n=1981). Radium-223 indications included prostate cancer (n=1429, 59.6%), metastases (n=814, 35.1%), pain (n=17, 0.7%), disease progression (n=4, 0.1%), and palliative care (n=2, 0.0%); 105 (4.4%) cases did not have a reported indication. Reported cases occurred in 43 countries with the majority (60.8%) occurring outside the US. The five most common countries of occurrence were: USA (n=856, 39.2%), Japan (n=303, 13.9%), Switzerland (n=133, 6.1%), Israel (n=122, 5.6%), and Germany (n=102, 4.7%). Most cases occurred in North America (41.3%), Europe (38.7%), or Asia (16.2%). Regarding the reports, most were submitted by physicians (n=1167, 53.5%), followed by consumers (n=597, 27.4%), and other health professionals (n=364, 17.6%). Most reports were expedited (n=1850, 84.8%), 301 (13.8%) were periodic, and 31 (1.4%) were direct.

Outcomes, AEs, and Disproportionality Characteristics of the events and outcomes are delineated in Table 3. The event outcomes were death in 425 (19.5%) cases, life-threatening in 42 (1.9%), hospitalization in 484 (22.2%), disability in 9 (0.4%), other serious outcome in 942 (43.2%); 280 (12.8%) had no reported outcome. Radium-223 was the primary suspect in the AE in 39.1% of cases. The median duration of radium-223 therapy was 56 days (IQR: 1-98). The median AE onset after radium-223 initiation was 48 days (IQR: 14-97), while the median AEs persistence after radium-223 was stopped was 16 days (IQR: 3-31). The median AE reporting time lag was 67 days (IQR: 25-157). Table 4 shows the disproportionality results for radium-223 AEs. Disproportionate signals were detected for general health deterioration (ROR 5.03, 95% CI: 4.23-5.98; PRR 4.94, 95% CI: 4.16-5.87) and bone pain (ROR 4.53, 95% CI: 3.67-5.59; PRR 4.48, 95% CI: 3.63-5.53). Strong signals were detected for hematologic toxicities, including anemia (ROR 2.89, 95% CI: 2.55-3.27; PRR 2.80, 95% CI:

9

2.48-3.17), thrombocytopenia (ROR 3.22, 95% CI: 2.77-3.74; PRR: 3.16, 95% CI: 2.72-3.67), and pancytopenia/bone marrow failure (ROR 4.83, 95% CI 4.11-5.67; PRR 4.73, 95% CI: 4.03-5.55). There was a strong leukopenia signal with the ROR (1.47; 95% CI: 1.16-1.86) but not the PRR (1.47; 95% CI: 1.16-1.86). No disproportionate ROR or PRR signals were detected for the other AEs.

Time Trends Linear regression of total reported radium-223 cases by quarter showed a significant increase in the raw number of cases reported to FAERS over time (R2=0.86, p<0.001, Figure 1A). After correction for multiple comparisons, similar significant increases were seen for the raw number of outcomes of disability (R2=0.25, p=0.02), hospitalization (R2=0.83, p<0.001), and death (R2=0.82, p<0.001), but not life-threatening (R2=0.13, p=0.11). The proportions of outcomes reported per quarter remained relatively constant throughout the study period (Figure 1B). Linear regressions of AEs against report quarter revealed that all AEs increased significant over time, after correction for multiple comparisons (Table 5).

Drug Enforcement and Recalls There have been no FDA enforcement actions or recalls for radium-223 to date.

Discussion Radium-223 is a key drug which improves survival in the treatment of patients with mCRPC. We present the first pharmacovigilance study of alpha-emitter radium-223. FAERS offers an important tool in the post-market surveillance of drugs approved by the FDA, by allowing for early identification of AEs— which may have been previously unrecognized—in a real-world setting. We found AEs associated with radium-223 reported from six continents, with nearly 80% of reported cases occurring in North America and Europe. International radium-223 use was associated with disproportionate signals for general health deterioration, bone pain, and hematologic AEs. Furthermore, the median duration of radium-223 use was

10

less than half the number of cycles expected for maximum survival benefit. While RCTs remain the gold standard for answering drug safety and efficacy questions, they may underreport AEs9,10, and are run under controlled environments with highly-selected patients. FAERS offers powerful population-level, international insight into spontaneous reporting of radium-223 toxicity, including duration of use and temporal changes over time, and into the actual patients who are receiving this radionuclide. Patients receiving radium-223 identified through FAERS were treated mainly for metastatic prostate cancer and were older (mean age 71.6 years), reflecting the patient population eligible for radium-2231,23,24. The median duration of radium-223 use was only 56 days, corresponding to 2-3 monthly injections. This suggests some patients did not complete an entire radium-223 course; plausible reasons include toxicities, the development of visceral metastases, disease progression, or health deterioriation23. All six cycles of radium-223 should be given for maximum survival benefit32 (the treatment arm in the ALSYMPCA trial received a median of 6 injections)1, so if therapy was halted due to dose-limiting toxicities, these AEs need thorough evaluation. Additionally, the median AE onset after radium-223 initiation was 46 days, but once an AE occurred and radium-223 was stopped, the AE persistence was relatively short (median 16 days). Radium-223 toxicities, therefore, appear to dissipate rapidly after treatment is stopped, suggesting that therapy could be reinitiated in certain patients who experienced serious AEs. Our disproportionality analysis, conducted in a heterogenous and large group of patients, revealed strong PRR and ROR signals detected for multiple hematologic AEs (anemia, thrombocytopenia, pancytopenia/bone marrow failure, and leukopenia): these are concordant with known radium-223 AEs. Common toxicities in the ALSYMPCA trial were nausea, bone pain, and anemia1. Similar toxicities were seen in a separate study evaluating radium-223 with concomitant abiraterone and enzalutamide, where AEs included anemia, thrombocytopenia, fatigue, and bone pain24. As FAERS represent real-world usage of radium-223, disproportionate AE signals are even more meaningful (as these are the AEs being observed by real-world radium-223 users) and can help clinicians in their counseling of patients receiving this radionuclide.

11

Interestingly, leukopenia had disproportionate ROR, but not PRR, signals for radium-223. This is likely because the ROR and PRR infer disproportionality differently26. The PRR determines disproportionate AE reporting for a specific drug compared to the same AE for all other drugs reported to FAERS; it cannot estimate relative risk28,29,33. Conversely, the ROR interprets FAERS as a case-control study (where the cases are reports of an AE and controls are reports of all other AEs), thus providing a measure of relative risk18,33. This comparison of odds ratios can be unduly influenced by AE underreporting; the PRR is not similarly affected. Both PRRs and RORs, however, demonstrate stronger disproportionality with higher values26,28,33. Our most disproportionate signals were detected for general health deterioration, bone pain, and pancytopenia/bone marrow failure. Confidence intervals are also needed to identify ROR signals and reduce false positives. When the observed and expected counts are both low, the CIs are wider, leading to decreased reliability27. Notably, we did not find signals for diarrhea or nausea, a slightly discordant finding given radium-223’s gastrointestinal excretion and previously reported toxicity profile1,23,24. This may be because gastrointestinal AEs are fairly common. If a toxicity is frequently reported for all drugs in FAERS, the observed/expected values used in the PRR and ROR calculations are too similarly proportional. Disproportionality requires that an AE is reported more (or less) frequently for a specific drug. Lack of disproportionality from FAERS does not imply no gastrointestinal toxicity with radium-223 use. Rather, the only conclusion is that there was no disproportion seen for these gastrointestinal AEs. The most common named outcomes associated with radium-223 use were death (19.5%) and hospitalization (22.2%). While this death rate appears high, 35% of patients receiving radium-223 on the ALSYMPCA trial died, and the median survival was only 14.9 months1. FAERS does not provide cause of death information, but these older patients may be dying of their mCRPC or from unrelated causes. Potentially some patients were hospitalized or died due to other comorbidities/medications: radium-223 was the primary suspect drug in less than half of reported cases. The delineation of a drug as the primary/secondary suspect in an AE is designated by the reporter, but is subject to user interpretation of the AE in the context of the patient’s other medications at the time of the event. This may lead to under-

12

reporting of radium-223 as the primary suspect. Most radium-223 reports were physician- (53.5%) or manufacturer-reported (>98%); this is consistent with other FAERS reports evaluating cancer-directed therapies12,14,18, and with AEs for radiation oncology devices reported to the FDA19. The high percentage of manufacturer reports may be because manufacturers are required to notify the FDA when a physician informs a drug manufacturer of AE(s). Perhaps these data altogether reflect the real-world usage of radium-223 where patients are not receiving radium-223 as monotherapy for their mCRPC, but are receiving it concomitantly with other therapies (i.e. enzalutamide or abiraterone)24, or as in ongoing RCTs evaluating the efficacy of radium-223 combined with hormonal therapies, chemotherapy, or external beam radiotherapy5. Our time-series data revealed an increase in the total cases of radium-223 reported to FAERS, and for each AE. These findings are consistent with expanded radium-223 research24 and increased use34,35. Additionally, reporting patterns to the FDA can change over time, influenced by external factors including media marketing after approval27. The Weber effect describes rapid increases in AE reporting, usually in the first two years after a drug’s FDA approval; these reporting rates eventually level out and decrease36–39. This effect has been partially attributed to advertisement efforts and increased attention by physicians to novel therapies26, and can be further affected if a drug has recalls or regulatory actions placed against it40. While there was no Weber effect in radium-223 reports to FAERS over the five years spanned by this study, a future plateau may be forthcoming. Therapies newly approved by the FDA generally have lag-time before widespread adoption41,42. Barriers unique to radionuclide use include reimbursement issues5, prescribing licensing requirements, and specialized clinic infrastructure35. These requirements may have contributed to slower radium-223 uptake, causing persistently increasing radium223 AEs reports to the FDA over time. Limitations to our work include the inability to infer direct causality which is inherent to the FAERS dataset. However, FAERS is well validated for toxicity evaluations across many cancer and noncancer drugs11–14,17,18,43–45. Also, reporting is mandatory for manufacturers, but voluntary for physicians and patients, thus the extent of AEs in our study may be underreported46. Despite this, we found signals

13

for general health deterioration, bone pain, and hematologic AEs. Reporting bias may also exist, such that more serious AEs are reported. Also, the FAERS dataset may be subject to variability in data completeness26. Additionally, we cannot infer the true incidence/prevalence of radium-223 AEs. Despite this, we performed disproportionality analyses, which are pharmacovigilance techniques designed for this very reason21,25,33. FAERS is the only dataset with which questions regarding worldwide drug utilization and toxicities can be examined. Despite these limitations, this is the first robust analysis of AEs associated with radium-223 use in the real-world and provides important insight into how patients actually receive radium-223.

Conclusions International patients experiencing AEs reported to FAERS are only receiving half the prescription dose of radium-223—a finding highly relevant to clinical practice. Post-market, populationbased radium-223 signal detection suggests associations with general health deterioration, bone pain, and hematologic AEs, highlighting the possible toxicity issues associated with radium-223. As there were increases in radium-223 cases reported to FAERS and in each AE over time, and radium-223 use does not appear to have reason to abate in the future, clinicians must continue careful counseling, observation, and monitoring of patients receiving radium-223. Overall, the benefit-to-risk ratio for radium-223 appears favorable given the known survival advantage it affords men with mCRPC and bone metastases and the reasonable safety profile shown in this real-world analysis. Clinicians should reconsider early termination of radium-223 treatment as the 6-injection course is needed to maximize survival. Further investigation into how to mitigate and/or prevent radium-223 AEs is needed to increase the number of men able to complete therapy, but in the meantime, physicians should maximally optimize patients to receive a full radium-223 prescription.

14

Clinical Practice Points

Radium-223 is an alpha-emitting radionuclide shown to improve overall survival in men with metastatic castrate-resistant prostate cancers (mCRPC) and painful osseous metastases. It is given to patients intravenously for 6 total injections for maximal survival advantage. The US Food and Drug Administration (FDA) has a publicly available Adverse Events Reporting System (FAERS) which is critical for post-market surveillance of drugs approved for use in the USA. We performed a comprehensive disproportionality analysis to determine adverse event (AE) signals related to radium-223 use and we explored the real-world use of radium-223 to determine who is receiving this medication (and why), and to identify trends of radium-223 use over time. We found that that mCRPC patients experiencing AEs are only receiving half the prescription dose of radium-223 required for survival benefit. Radium-223 is associated with general health deterioration, bone pain, and hematologic AEs. Linear regression of total reported radium-223 cases by quarter showed a significant increase in cases reported to FAERS over time. There have been no FDA enforcement actions or recalls for radium-223 to date. Real-world analyses using FAERS are important for ongoing risk-benefit assessment of radium-223 use in a population-based, longitudinal setting, with implications for clinical practice and patient counseling.

15

References 1.

Parker C, Nilsson S, Heinrich D, et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. N Engl J Med. 2013;369(3):213-236. doi:10.1056/NEJMoa1213755

2.

NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer version 2.2018.

3.

NCCN Guidelines® Updated: NCCN Flash Update sent July 9, 2013. https://www.nccn.org/about/news/ebulletin/ebulletindetail.aspx?ebulletinid=16. Accessed December 12, 2018.

4.

FDA. Xofigo® (Radium Ra 223 Dichloride) Injection, 1000 KBq/ML (0.027 Microcurie/ML).; 2013. http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Accessed December 10, 2018.

5.

Deshayes E, Roumiguie M, Thibault C, et al. Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017;11:2643-2651. doi:10.2147/DDDT.S122417

6.

US Food and Drug Administration. Questions and Answers on FDA’s Adverse Event Reporting System (FAERS). https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDru gEffects/default.htm. Accessed December 10, 2018.

7.

Wysowski DK, Swartz L. Adverse drug event surveillance and drug withdrawals in the United States, 1969-2002: The importance of reporting suspected reactions. Arch Intern Med. 2005;165(12):1363-1369. doi:10.1001/archinte.165.12.1363

8.

Rodriguez EM, Staffa JA, Graham DJ. The role of databases in drug postmarketing surveillance. Pharmacoepidemiol Drug Saf. 2001;10(5):407-410. doi:10.1002/pds.615

9.

Seruga B, Sterling L, Wang L, Tannock IF. Reporting of serious adverse drug reactions of targeted anticancer agents in pivotal phase III clinical trials. J Clin Oncol. 2011;29(2):174-185. doi:10.1200/JCO.2010.31.9624

10.

Sivendran S, Latif A, McBride RB, et al. Adverse event reporting in cancer clinical trial publications. J Clin Oncol. 2014;32(2):83-89. doi:10.1200/JCO.2013.52.2219

16

11.

Brinker A, Cheng C, Chan V. Association of Noninfectious Pneumonia With Ustekinumab Use. JAMA Dermatology. December 2018. doi:10.1001/jamadermatol.2018.4118

12.

Shamloo BK, Chhabra P, Freedman AN, Potosky A, Malin J, Smith SW. Novel adverse events of bevacizumab in the US FDA adverse event reporting system database: A disproportionality analysis. Drug Saf. 2012;35(6):507-518. doi:10.2165/11597600-000000000-00000

13.

Sanagawa A, Hotta Y, Kataoka T, et al. Hepatitis B infection reported with cancer chemotherapy: analyzing the US FDA Adverse Event Reporting System. Cancer Med. 2018;7(6):2269-2279. doi:10.1002/cam4.1429

14.

Ali AK, Watson DE. Pharmacovigilance Assessment of Immune-Mediated Reactions Reported for Checkpoint Inhibitor Cancer Immunotherapies. Pharmacotherapy. 2017;37(11):1383-1390. doi:10.1002/phar.2035

15.

Soldatos TG, Dimitrakopoulou-Strauss A, Larribere L, et al. Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Diagnostics. 2018;8(4):76. doi:10.3390/diagnostics8040076

16.

Jhaveri KD, Sakhiya V, Fishbane S. Nephrotoxicity of the BRAF Inhibitors Vemurafenib and Dabrafenib. JAMA Oncol. 2015;1(8):1133. doi:10.1001/jamaoncol.2015.1713

17.

Oshima Y, Tanimoto T, Yuji K, Tojo A. EGFR–TKI-Associated Interstitial Pneumonitis in Nivolumab-Treated Patients With Non–Small Cell Lung Cancer. JAMA Oncol. 2018;4(8):1112. doi:10.1001/jamaoncol.2017.4526

18.

Wittayanukorn S, Qian J, Johnson BS, Hansen RA. Cardiotoxicity in targeted therapy for breast cancer: A study of the FDA adverse event reporting system (FAERS). J Oncol Pharm Pract. 2017;23(2):93-102. doi:10.1177/1078155215621150

19.

Connor MJ, Marshall DC, Moiseenko V, et al. Adverse Events Involving Radiation Oncology Medical Devices: Comprehensive Analysis of US Food and Drug Administration Data, 1991 to 2015. Int J Radiat Oncol Biol Phys. 2017;97(1):18-26. doi:10.1016/j.ijrobp.2016.08.050

20.

Connor MJ, Tringale K, Moiseenko V, et al. Medical Device Recalls in Radiation Oncology:

17

Analysis of US Food and Drug Administration Data, 2002-2015. Int J Radiat Oncol Biol Phys. 2017;98(2):438-446. doi:10.1016/j.ijrobp.2017.02.006 21.

U.S. Food and Drug Administration. FDA Adverse Events Reporting System (FAERS) - Reports Received and Reports Entered into FAERS by Year. https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/surveillance/adversedrugeff ects/ucm070434.htm. Published 2014. Accessed March 29, 2019.

22.

Sakaeda T, Tamon A, Kadoyama K, Okuno Y. Data mining of the public version of the FDA adverse event reporting system. Int J Med Sci. 2013;10(7):796-803. doi:10.7150/ijms.6048

23.

Parker C, Heidenreich A, Nilsson S, Shore N. Current approaches to incorporation of radium-223 in clinical practice. Prostate Cancer Prostatic Dis. 2018;21(1):37-47. doi:10.1038/s41391-0170020-y

24.

Saad F, Carles J, Gillessen S, et al. Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, singlearm phase 3b trial. Lancet Oncol. 2016;17(9):1306-1316. doi:10.1016/S1470-2045(16)30173-5

25.

Hesha J, Duggirala CJ, Joseph M, et al. Data Mining at FDA. https://www.fda.gov/downloads/ScienceResearch/DataMiningatFDA/UCM443675.pdf. Accessed August 27, 2018.

26.

Poluzzi E, Raschi E, Piccinni C, De F. Data Mining Techniques in Pharmacovigilance: Analysis of the Publicly Accessible FDA Adverse Event Reporting System (AERS). In: Data Mining Applications in Engineering and Medicine. Vol 37. InTech; 2012:421-431. doi:10.5772/50095

27.

Bate A, Evans SJW. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf. 2009;18(6):427-436. doi:10.1002/pds.1742

28.

Evans SJW, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001;10(6):483486. doi:10.1002/pds.677

29.

Finney DJ. Systemic signalling of adverse reactions to drugs. Methods Inf Med. 1974;13(1):1-10.

18

http://www.ncbi.nlm.nih.gov/pubmed/4826353. Accessed December 12, 2018. 30.

Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc. 1995;57(1):289-300. doi:10.2307/2346101

31.

US Food and Drug Administration. Enforcement Reports. https://www.fda.gov/Safety/Recalls/EnforcementReports/default.htm. Accessed December 12, 2018.

32.

Saad F, Gillessen S, Heinrich D, et al. Disease Characteristics and Completion of Treatment in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With Radium-223 in an International Early Access Program. Clin Genitourin Cancer. October 2019. doi:10.1016/j.clgc.2019.05.012

33.

Rothman KJ, Lanes S, Sacks ST. The reporting odds ratio and its advantages over the proportional reporting ratio. Pharmacoepidemiol Drug Saf. 2004;13(8):519-523. doi:10.1002/pds.1001

34.

Gregory CM, Gordon AB. Successfully Integrating Radium Ra 223 Dichloride Injection Into a Urology Practice. Rev Urol. 2017;19(4):248-251. doi:10.3909/riu0782

35.

Seeber JC, Oncology AMPR. Radium Ra 223 Dichloride Therapy in the Private Practice Environment. Rev Urol. 2016;18(2):106-109. doi:10.3909/riu0720

36.

Weber JCP. Epidemiology of adverse reactions to nonsteroidal anti-inflammatory drugs. In: Rainsford, K.D. and Velo GD, ed. Side-Effects of Anti-Inflammatory Drugs, Advances in Inflammation Research. New York: Raven Press; 1984:1-7.

37.

McAdams MA, Governale LA, Swartz L, Hammad TA, Pan GJD. Identifying patterns of adverse event reporting for four members of the angiotensin II receptor blockers class of drugs: Revisiting the Weber effect. Pharmacoepidemiol Drug Saf. 2008;17(9):882-889. doi:10.1002/pds.1633

38.

Hartnell NR, Wilson JP. Replication of the Weber effect using postmarketing adverse event reports voluntarily submitted to the United States Food and Drug Administration. Pharmacotherapy. 2004;24(6):743-749. doi:10.1592/phco.24.8.743.36068

39.

Wallenstein EJ, Fife D. Temporal patterns of NSAID spontaneous adverse event reports: The

19

weber effect revisited. Drug Saf. 2001;24(3):233-237. doi:10.2165/00002018-200124030-00006 40.

Motola D, Vargiu A, Leone R, et al. Influence of regulatory measures on the rate of spontaneous adverse drug reaction reporting in Italy. Drug Saf. 2008;31(7):609-616. doi:10.2165/00002018200831070-00006

41.

Felgner S, Ex P, Henschke C. Physicians’ Decision Making on Adoption of New Technologies and Role of Coverage with Evidence Development: A Qualitative Study. Value Heal. 2018;21(9):1069-1076. doi:10.1016/J.JVAL.2018.03.006

42.

Alexander GC, O’Connor AB, Stafford RS. Enhancing prescription drug innovation and adoption. Ann Intern Med. 2011;154(12):833-837, W-301. doi:10.7326/0003-4819-154-12-20110621000012

43.

Araujo AGS, Borba HHL, Tonin FS, et al. Safety of Biologics Approved for the Treatment of Rheumatoid Arthritis and Other Autoimmune Diseases: A Disproportionality Analysis from the FDA Adverse Event Reporting System (FAERS). BioDrugs. 2018;32(4):377-390. doi:10.1007/s40259-018-0285-2

44.

Yoshimura K, Sakaeda T, Kadoyama K, Sugino Y, Ogawa O, Okuno Y. A survey of the FAERS database concerning the adverse event profiles of α1-adrenoreceptor blockers for lower urinary tract symptoms. Int J Med Sci. 2013;10(7):864-869. doi:10.7150/ijms.5892

45.

Min J, Osborne V, Kowalski A, Prosperi M. Reported Adverse Events with Painkillers: Data Mining of the US Food and Drug Administration Adverse Events Reporting System. Drug Saf. 2018;41(3):313-320. doi:10.1007/s40264-017-0611-5

46.

Alvarez-Requejo A, Carvajal A, Bégaud B, Moride Y, Vega T, Martín Arias LH. Under-reporting of adverse drug reactions. Estimate based on a spontaneous reporting scheme and a sentinel system. Eur J Clin Pharmacol. 1998;54(6):483-488. doi:10.1007/s002280050498

20

Figure Captions Figure 1. Radium-223 outcomes reported to FAERS, 2013Q2-2018Q2. There was a significant increase in raw number of cases reported to FAERS over time (Panel A); similar significant increases were seen in the raw number of the disability, hospitalization, and death outcomes. The slopes (β) indicate reports per quarter. Panel B shows the proportion of each outcome, by quarter.

21

Table 1. Two-by-two contingency table used for calculation of the reporting odds ratio (ROR) and A/C

proportional reporting ratio (PRR). The ROR is defined as B/D; 95% CI = e A/(A+B)

PRR is defined C/(C+D); 95% CI = e

1 1 1 1 A B C D

lnሺPRRሻ±1.96ට + + +

1 1 1 1 A B C D

lnሺRORሻ±1.96ට + + +

.

Adverse drug event of interest

All other drug adverse events

Total

Radium-223 (drug of interest)

A

B

A+B

All other drugs in FAERS database

C

D

C+D

Total

A+C

B+D

A+B+C+D

, while the

Table 2. Patient and report characteristics of the 2,182 unique cases of radium-223 reported to FAERS, 2013Q2-2018Q2. Characteristic Patient's age, years (n, %) Mean (SD) <50 50-59 60-69 70-79 80-89 >90 Unknown/other

Radium-223 reports, n of cases=2,182 71.6 (9.6) 22 (1.0%) 84 (3.8%) 417 (19.1%) 467 (21.4%) 261 (12.0%) 19 (0.9%) 912 (41.8%)

Sex (n, %) Male Unknown/other

1981 (90.8%) 201 (9.2%)

Continent of occurrence (n, %) * North America (a) Europe (b) Asia (c) South America (d) Australia (e) Africa (f) Unknown

901 (41.3%) 844 (38.7%) 354 (16.2%) 56 (2.6%) 11 (0.5%) 4 (0.2%) 12 (0.5%)

Indication for radium-223 use (n, %) ** Prostate cancer (g) Metastases (h) Pain (i) Disease progression (j) Palliative care (k) Unknown/other

n=2,398 1429 (59.6%) 841 (35.1%) 17 (0.7%) 4 (0.1%) 2 (0.0%) 105 (4.4%)

Reporter occupation (n, %) Physician Consumer Other health professional Pharmacist Unknown/other

1167 (53.5%) 597 (27.4%) 385 (17.6%) 28 (1.3%) 5 (0.2%)

Report type (n, %) Expedited (15-day report from manufacturer)

1850 (84.8%)

Periodic (non-expedited report from manufacturer)

301 (13.8%)

Direct (voluntary reports submitted by nonmanufacturers)

31 (1.4%)

Report year (n, %) 2013 2014 2015 2016 2017 2018

69 (3.2%) 277 (12.7%) 362 (16.6%) 391 (17.9%) 657 (30.1%) 426 (19.5%)

* Countries were placed into geographic continents: (a) North America: USA (n=856), Canada (n=37), Mexico (n=7), Puerto Rico (n=1) (b) Europe: Switzerland (n=133), Germany (n=102), United Kingdom (n=91), Netherlands (n=67), Belgium (n=63), Spain (n=46), Ireland (n=33), Finland (n=25), France (n=25), Austria (n=21), Hungary (n=15), Italy (n=14), Sweden (n=14), Slovakia (n=12), Norway (n=12), Portugal (n=10), Bulgaria (n=9), Denmark (n=8), Slovenia (n=8), Croatia (n=4), Luxembourg (n=4), Russia (n=3), Lithuania (n=2), Greece (n=1), Poland (n=1) (c) Asia: Japan (n=303), Israel (n=122), Singapore (n=23), China (n=9), Hong Kong (n=9), Taiwan (n=5), South Korea (n=2), Thailand (n=2), India (n=1) (d) South America: Brazil (n=35), Colombia (n=13), Argentina (n=8) (e) Australia: n=11 (f) Africa: South Africa (n=4) ** Numbers add up to more than the number of cases as there may be more than one indication per case (g) "hormone-dependent prostate cancer," "hormone-refractory prostate cancer," "neoplasm prostate," "prostate cancer," "prostate cancer metastatic," "prostate cancer stage IV," "prostatic specific antigen increased" (h) "metastases," "metastatic pain," "metastases to bone," "metastases to bone marrow," "metastases to spine" (i) "pain," "bone pain," "cancer pain," "pain in extremity," "pain management," "back pain" (j) "disease progression" (k) "palliative care"

Table 3. Outcome of events and temporality information for the 2,182 cases of radium-223 reported to FAERS.

Characteristic Outcome of serious event (n, %) Death Life-threatening Hospitalization Disability Required intervention Other serious / important medical event Unknown Radium-223 role in event Primary suspect Secondary suspect Temporality in days (median and IQR*), number of valid cases Duration of radium-223 therapy (a) Onset of AE after radium-223 started (b) Persistence of AE after radium-223 stopped (c) AE reporting time lag (d) * IQR=Interquartile range

Radium-223 reports, n of cases=2,182 425 (19.5%) 42 (1.9%) 484 (22.2%) 9 (0.4%) 0 (0.0%) 942 (43.2%) 280 (12.8%)

855 (39.1%) 1327 (60.8%)

56 (IQR: 1, 98), n=790 48 (IQR: 14, 97), n=647 16 (IQR: 3, 31), n=333 67 (IQR: 25, 157), n=760

(a) Time between date of radium-223 start and stop (b) Time between date of radium-223 start and AE occurrence (c) Time between date of radium-223 stop and AE occurrence (d) Time between date of AE occurrence and report submission

Table 4. Disproportionality analysis of adverse events for radium-223, with the reporting odds ratio (ROR) and proportional reporting ratio (PRR), their respective 95% confidence intervals, and the Chisquare value.

Adverse event General health deterioration Fatigue Decreased Appetite Dehydration Vomiting Diarrhea Nausea Bone Pain Anemia Thrombocytopenia Leukopenia Neutropenia Pancytopenia or bone marrow failure Peripheral edema Pulmonary toxicity

Number of events reported for radium-223

ROR (95% CI)

PRR (95% CI)

Chi-square

133 193 76 35 72 122

5.03 (4.23, 5.98) * 0.50 (0.43, 0.58) 1.10 (0.88, 1.38) 0.86 (0.62, 1.20) 0.53 (0.42, 0.67) 0.65 (0.54, 0.78)

4.94 (4.16, 5.87) * 0.52 (0.45, 0.60) 1.09 (0.87, 1.37) 0.86 (0.62, 1.20) 0.53 (0.42, 0.67) 0.65 (0.54, 0.78)

413.45 92.19 0.53 0.69 29.49 22.62

131 88 265 177 71 60

0.55 (0.46, 0.65) 4.53 (3.67, 5.59) * 2.89 (2.55, 3.27) * 3.22 (2.77, 3.74) * 1.47 (1.16, 1.86) * 1.11 (0.86, 1.43)

0.56 (0.47, 0.67) 4.48 (3.63, 5.53) * 2.80 (2.48, 3.17) * 3.16 (2.72, 3.67) * 1.47 (1.16, 1.86) 1.11 (0.86, 1.43)

47.99 234.01 309.96 260.23 10.18 0.58

154 39 80

4.83 (4.11, 5.67) * 0.46 (0.34, 0.63) 0.30 (0.24, 0.37)

4.73 (4.03, 5.55) * 0.46 (0.34, 0.63) 0.31 (0.25, 0.39)

449.09 24.16 124.69

Renal toxicity 60 0.42 (0.33, 0.54) 0.43 (0.33, 0.55) * Indicates a statistically significant disproportionate signal based on the PRR or ROR.

46.50

Table 5. Linear regressions of adverse events of interest by quarter. The slopes (β) indicate reports per quarter. Adverse event General health deterioration Fatigue Decreased Appetite

β 0.76 0.89 0.78

R-squared 0.57 0.79 0.61

p-value <0.001* <0.001* <0.001*

Dehydration Vomiting Diarrhea Nausea Bone Pain Anemia

0.76 0.47 0.85 0.63 0.78 0.84

0.57 0.22 0.72 0.40 0.61 0.71

<0.001* 0.03* <0.001* 0.002* <0.001* <0.001*

Thrombocytopenia Leukopenia Neutropenia Pancytopenia or bone marrow failure Peripheral edema Pulmonary toxicity

0.81 0.58 0.63 0.79 0.56 0.72

0.65 0.34 0.39 0.63 0.32 0.51

<0.001* 0.006* 0.002* <0.001* 0.008* <0.001*

Renal toxicity 0.68 0.47 0.001* * Indicates a statistically significant p-value after corrections for the false-discovery rate.

A

Outcomes of Radium-223, by report quarter

300

250

Number of Outcomes

Unknown

200

Other

150

Disability: ß=0.50, R-squared=0.25, p=0.02*

NCCN flash update: July 9, 2013

Hospitalization: ß=0.91, R-squared=0.83, p<0.001*

100

Life-threatening: ß=0.36, R-squared=0.13, p=0.11 Death: ß=0.90, R-squared=0.82, p<0.001*

50 Total: ß=0.93, R-squared=0.86, p<0.001*

0

Report Quarter

* Indicates a statistically significant p-value, after corrections for the false-discovery rate.

B

Proportion of Outcomes of Radium-223, by report quarter

Proportion of Outcomes Reported per Quarter

1 0.9 0.8 0.7

Death

0.6

Life-threatening

0.5

Hospitalization Disability

0.4

Other

0.3

Unknown 0.2 0.1 0

Report Quarter

Supplemental eFigure 1. Flow diagram of FAERS case selection.

All cases reported to FAERS, 2013Q2-2018Q2: 6,356,962 Duplicates cases removed: 458,721 All unique cases: 5,898,241 All other cases: 5,896,059 Unique radium-223 cases where drug name contained “radium” or “Xofigo”: 2,182

Supplemental eTable 1. Adverse event queries. Adverse event of interest General health deterioration Fatigue Decreased appetite Dehydration Vomiting Diarrhea Nausea Bone pain Anemia

Thrombocytopenia Leukopenia

Neutropenia

Pancytopenia or bone marrow failure

Peripheral edema

Pulmonary toxicity

MedDRA PT a General physical health deterioration Malaise Fatigue Decreased appetite Dehydration Vomiting Diarrhoea Nausea Bone pain Anaemia Haemoglobin decreased Haematocrit decreased Red blood cell count decreased Red blood cell count Erythropenia Haemoglobin abnormal Thrombocytopenia Platelet count decreased White blood cell count decreased Leukopenia White blood cell count White blood cell disorder Lymphocyte count abnormal Lymphocyte count decreased Lymphopenia Neutrophil count decreased Febrile neutropenia Neutropenia Neutrophil count abnormal Pancytopenia Bone marrow failure Blood count abnormal Full blood count decreased Lymphoedema Generalised oedema Oedema peripheral Peripheral swelling Dyspnoea Pneumonia

Renal toxicity

Acute kidney injury Renal failure acute Renal disorder Renal impairment Renal failure Haematuria Blood creatinine increased a MedDRA = Medical Dictionary for Regulatory Activities; PT = Preferred Term.

Clinical Practice Points

Radium-223 is an alpha-emitting radionuclide shown to improve overall survival in men with metastatic castrate-resistant prostate cancers (mCRPC) and painful osseous metastases. It is given to patients intravenously for 6 total injections for maximal survival advantage. The US Food and Drug Administration (FDA) has a publicly available Adverse Events Reporting System (FAERS) which is critical for post-market surveillance of drugs approved for use in the USA. We performed a comprehensive disproportionality analysis to determine adverse event (AE) signals related to radium-223 use and we explored the real-world use of radium-223 to determine who is receiving this medication (and why), and to identify trends of radium-223 use over time. We found that that mCRPC patients experiencing AEs are only receiving half the prescription dose of radium-223 required for survival benefit. Radium-223 is associated with general health deterioration, bone pain, and hematologic AEs. Linear regression of total reported radium-223 cases by quarter showed a significant increase in cases reported to FAERS over time. There have been no FDA enforcement actions or recalls for radium-223 to date. Real-world analyses using FAERS are important for ongoing risk-benefit assessment of radium-223 use in a population-based, longitudinal setting, with implications for clinical practice and patient counseling.