Real-World Evidence for Regulatory Decisions: Concomitant Administration of Zoster Vaccine Live and Pneumococcal Polysaccharide Vaccine

Real-World Evidence for Regulatory Decisions: Concomitant Administration of Zoster Vaccine Live... Abstract The US Food and Drug Administration is charged with expanding the use of real-world evidence for regulatory decisions. As a test case for real-world evidence to support regulatory decisions, we present the scenario of concomitant vaccination with zoster vaccine live (ZVL) and 23-valent pneumococcal polysaccharide vaccine (PPSV23). The prescribing information states that these vaccines should not be given concurrently, based on a small trial using varicella zoster virus antibody levels as a correlate of ZVL efficacy, even though ZVL protects against herpes zoster via cell-mediated immunity. We conducted an observational cohort study involving more than 35,000 members of Kaiser Permanente Southern California receiving concomitant ZVL and PPSV23 versus PPSV23 prior to ZVL. Occurrence of herpes zoster was assessed through electronic health records from January 1, 2007, to June 30, 2016. The adjusted hazard ratio comparing incidence rates of herpes zoster in the concomitant vaccination cohort and the prior vaccination cohort was 1.04 (95% confidence interval: 0.92, 1.16). This real-world evidence study provides direct evidence for a lack of vaccine interference, relying on herpes zoster occurrence rather than an intermediate marker of immunity. Real-world evidence is essential for regulators and policy makers in addressing evidentiary gaps regarding safety, effectiveness, compliance, and vaccine interactions for the new recombinant zoster vaccine. herpes zoster, herpes zoster vaccine, pneumococcal polysaccharide vaccine, real-world evidence, vaccination The role of real-world evidence in regulatory health-care decision making is a growing area of interest and recent discourse. Real-world evidence is evidence derived from real-world data on patient health status or routine health-care delivery (1, 2). Real-world data are typically generated outside of conventional clinical trials and include data from electronic health records, product or disease registries, and mobile health-tracking devices. For regulatory applications, real-world evidence is the clinical evidence regarding the use and potential benefits or risks derived from analysis of real-world data through the application of research methods. Real-world evidence has the potential to efficiently fill evidentiary gaps in safety and effectiveness that are difficult to address through randomized controlled trials, such as long-term outcomes or generalizability to broader populations with multiple comorbidities (3). The US Food and Drug Administration (FDA) uses real-world evidence for regulatory decisions related to safety, but rarely has real-world evidence been used to inform label changes such as indication expansions or dosing modifications (4). Current evidence-grading systems give higher weight to randomized controlled trials and may inadequately consider data from other study designs (5). However, recent legislation in the 21st Century Cures Act and Sixth Prescription Drug User Fee Act (PDUFA VI) requires that the FDA develop guidance for expanding the use of real-world evidence in regulatory decision making (6, 7). The FDA has published commentaries expressing commitment to the use of real-world evidence (2, 4, 8) and has convened stakeholder meetings to develop a framework for the application of real-world evidence (3). The framework emphasizes the need to match high-quality data sources and rigorous methods to answer specific clinical and regulatory questions. As an example of a context in which real-world evidence is ideal for supporting regulatory decisions, we present the scenario of concomitant vaccination with zoster vaccine live (ZVL) (Zostavax; Merck and Co., Inc., Whitehouse Station, New Jersey) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) (Pneumovax23; Merck and Co., Inc., Whitehouse Station, New Jersey). In 2009, the FDA approved a revision to the Drug Interaction section of the prescribing information for ZVL and PPSV23 to state that these vaccines “should not be given concurrently” (9–11). This revision was based on a randomized, blinded, placebo-controlled trial conducted by the manufacturer, which found that concomitant administration of ZVL and PPSV23 resulted in lower varicella zoster virus (VZV) antibody levels compared with administration of the vaccines 4 weeks apart (12). This decision based on VZV antibody levels as a measure of ZVL efficacy was disputed (13, 14). Zoster vaccine is thought to protect against herpes zoster by boosting VZV-specific T-cell mediated immunity, not through a humoral response (15–17). Subsequently, a 3.5-year cohort study was conducted, finding no difference in the incidence of herpes zoster in subjects concomitantly vaccinated with ZVL and PPSV23 compared with subjects receiving PPSV23 at least 4 weeks prior to ZVL (18). The FDA approved a second revision to the prescribing information in March 2011 to soften the language: “Consider administration of the 2 vaccines separated by at least 4 weeks” (11). Despite the FDA revisions to the prescribing information, the Advisory Committee on Immunization Practices continued to recommend concomitant administration of ZVL and PPSV23 for eligible persons (19). The present work describes a 9.5-year cohort study evaluating the incidence of herpes zoster after concomitant administration of ZVL and PPSV23. The study provides a test case for using real-world evidence to inform future regulatory decisions for vaccines and emphasizes the importance of clinically meaningful endpoints. METHODS Study setting Kaiser Permanente Southern California (KPSC) is an integrated health-care organization that serves approximately 4.4 million residents of Southern California. Members of KPSC have diverse sociodemographic backgrounds largely representative of the underlying population (20). Because KPSC provides recommended vaccines free of charge, members have a strong incentive to receive vaccinations within the system; nevertheless, vaccinations received outside the system are captured with appropriate documentation from the member. At the time of this study, recommended vaccines included ZVL for members aged 60 years or older and PPSV23 for all members age 65 years or older (and members less than 65 years of age in high-risk groups). Electronic health records store information on vaccinations as well as sociodemographic factors, utilization (outpatient, emergency department, and inpatient), and diagnoses. Because the prepaid system motivates members to use services internally, and claims for reimbursement of outside care must be submitted to the health plan with documentation, data captured in the electronic health records are comprehensive. Study design A retrospective cohort study was conducted from January 1, 2007, to June 30, 2016. The exposed cohort (concomitant vaccination group) consisted of KPSC members 60 years of age or older who were vaccinated with ZVL and PPSV23 on the same day between January 1, 2007, and December 31, 2014. The comparator cohort (prior vaccination group) consisted of KPSC members 60 years of age or older who were vaccinated with ZVL during the same period as the exposed cohort but were previously vaccinated with a dose of PPSV23 from 365 days to 30 days prior to receiving ZVL. Both groups had been continuous KPSC members in the year prior to date of ZVL vaccination, allowing for a 31-day gap in membership. Subjects from both groups were followed from the date of ZVL vaccination until the date of herpes zoster occurrence, termination of KPSC membership (allowing for a 31-day gap), death, or June 30, 2016, whichever was earliest. Outcomes Incident cases of herpes zoster between January 1, 2007, and June 30, 2016, were identified from electronic health records. Through September 30, 2015, cases were identified from the first diagnosis of International Classification of Diseases, Ninth Revision (ICD-9), code 053.xx in any diagnostic position from inpatient, outpatient, and emergency department records. Cases starting from October 1, 2015, were identified from corresponding International Classification of Diseases, Tenth Revision, codes (B02.xx). Incident cases were defined as herpes zoster cases without a herpes zoster diagnosis in the previous 6 months, to avoid carryover of prevalent cases into the follow-up period. Herpes zoster diagnoses within 30 days after ZVL vaccination were excluded, because these patients could have been experiencing reactivation of VZV at the time of vaccination. Covariates were examined to assess the characteristics of the concomitant vaccination and prior vaccination cohorts. These included age, sex, race/ethnicity, health-care utilization, vaccination year, and comorbid chronic diseases. Health-care utilization was defined as the number of outpatient, emergency department, or inpatient visits within 1 year before the date of ZVL vaccination. Chronic diseases were defined as a diagnosis within 1 year before the date of ZVL vaccination, and included cancer (ICD-9 codes 140–239), diabetes (ICD-9 codes 250), kidney disease (ICD-9 codes 403, 581–583, 585–588), heart disease (ICD-9 codes 410–414, 428), liver disease (ICD-9 codes 571–573), or lung disease (ICD-9 codes 491–492). Subjects could be assigned multiple conditions. Statistical analysis Incidence rates of herpes zoster were calculated by dividing the number of incident cases by the number of person-years. The 95% confidence intervals were estimated assuming that the occurrence of herpes zoster followed a Poisson distribution. The cumulative risk of herpes zoster was computed by the Kaplan-Meier method, with the log-rank test performed to assess the difference in cumulative risks between the concomitant vaccination and prior vaccination cohorts. The adjusted hazard ratio for herpes zoster associated with concomitant vaccination versus prior vaccination was estimated with a Cox proportional hazards regression model, controlling for age, sex, race/ethnicity, health-care utilization, vaccination year, and chronic disease comorbidities. SAS, version 9.3 (SAS Institute, Inc., Cary, North Carolina), was used for all analyses. This study was approved by the KPSC Institutional Review Board. RESULTS Characteristics of subjects in the concomitant vaccination and prior vaccination cohorts There were 16,532 subjects concomitantly vaccinated with ZVL and PPSV23 and 18,493 subjects who received PPSV23 from 365 days to 30 days prior to ZVL vaccination. Compared with the prior vaccination cohort, the concomitant vaccination cohort was slightly younger, was more likely to be male, had a slightly different distribution of race/ethnicity and vaccination year, had fewer health-care encounters (outpatient, emergency department, and inpatient visits), and had a lower prevalence of chronic diseases (Table 1). Table 1. Baseline Characteristics of the Concomitant Vaccination Cohort and the Prior Vaccination Cohorta, Kaiser Permanente Southern California, 2007–2016 Characteristic Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) P Value No. % No. % Age group, years <0.0001  60–64 4,663 28.2 4,262 23.0  65–69 8,901 53.8 9,761 52.8  70–74 1,608 9.7 2,301 12.4  75–79 838 5.1 1,273 6.9  ≥80 522 3.2 896 4.8 Mean age, yearsb 66.9 (5.04) 67.9 (5.67) Sex <0.0001  Female 8,897 53.8 10,404 56.3  Male 7,635 46.2 8,089 43.7 Race/ethnicity <0.0001  White 10,093 61.1 11,170 60.4  Black 1,363 8.2 1,397 7.6  Hispanic 2,554 15.4 3,132 16.9  Asian/Pacific Islander 1,835 11.1 2,219 12.0  Multiple/other/unknown 687 4.2 575 3.1 Vaccination year <0.0001  2007 1,826 11.0 2,403 13.0  2008 2,500 15.1 1,976 10.7  2009 2,858 17.3 2,992 16.2  2010 1,240 7.5 1,413 7.6  2011 1,631 9.9 2,002 10.8  2012 2,584 15.6 2,718 14.7  2013 2,091 12.6 2,668 14.4  2014 1,802 10.9 2,321 12.6 No. of outpatient visits during year prior to zoster vaccination date <0.0001  0 3,076 18.6 538 2.9  1–4 8,271 50.0 7,949 43.0  5–10 3,911 23.7 6,825 36.9  ≥11 1,274 7.7 3,181 17.2  Meanb 3.9 (4.28) 6.4 (5.33)  Medianc 3 (1.0, 5.0) 5 (3.0, 9.0) No. of emergency department visits during year prior to zoster vaccination date <0.0001  0 13,993 84.6 14,240 77.0  1 1,912 11.6 2,796 15.1  ≥2 627 3.8 1,457 7.9  Meanb 0.2 (0.66) 0.4 (0.98)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) No. of inpatient visits during year prior to zoster vaccination date <0.0001  0 15,294 92.5 15,832 85.6  1 962 5.8 1,858 10.0  ≥2 276 1.7 803 4.3  Meanb 0.1 (0.42) 0.2 (0.70)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) Chronic conditions during year prior to zoster vaccination date  Cancer 2,606 15.8 4,142 22.4 <0.0001  Diabetes 2,570 15.5 4,685 25.3 <0.0001  Kidney disease 1,232 7.5 2,385 12.9 <0.0001  Heart disease 1,170 7.1 2,224 12.0 <0.0001  Liver disease 238 1.4 534 2.9 <0.0001  Lung disease 176 1.1 401 2.2 <0.0001 Characteristic Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) P Value No. % No. % Age group, years <0.0001  60–64 4,663 28.2 4,262 23.0  65–69 8,901 53.8 9,761 52.8  70–74 1,608 9.7 2,301 12.4  75–79 838 5.1 1,273 6.9  ≥80 522 3.2 896 4.8 Mean age, yearsb 66.9 (5.04) 67.9 (5.67) Sex <0.0001  Female 8,897 53.8 10,404 56.3  Male 7,635 46.2 8,089 43.7 Race/ethnicity <0.0001  White 10,093 61.1 11,170 60.4  Black 1,363 8.2 1,397 7.6  Hispanic 2,554 15.4 3,132 16.9  Asian/Pacific Islander 1,835 11.1 2,219 12.0  Multiple/other/unknown 687 4.2 575 3.1 Vaccination year <0.0001  2007 1,826 11.0 2,403 13.0  2008 2,500 15.1 1,976 10.7  2009 2,858 17.3 2,992 16.2  2010 1,240 7.5 1,413 7.6  2011 1,631 9.9 2,002 10.8  2012 2,584 15.6 2,718 14.7  2013 2,091 12.6 2,668 14.4  2014 1,802 10.9 2,321 12.6 No. of outpatient visits during year prior to zoster vaccination date <0.0001  0 3,076 18.6 538 2.9  1–4 8,271 50.0 7,949 43.0  5–10 3,911 23.7 6,825 36.9  ≥11 1,274 7.7 3,181 17.2  Meanb 3.9 (4.28) 6.4 (5.33)  Medianc 3 (1.0, 5.0) 5 (3.0, 9.0) No. of emergency department visits during year prior to zoster vaccination date <0.0001  0 13,993 84.6 14,240 77.0  1 1,912 11.6 2,796 15.1  ≥2 627 3.8 1,457 7.9  Meanb 0.2 (0.66) 0.4 (0.98)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) No. of inpatient visits during year prior to zoster vaccination date <0.0001  0 15,294 92.5 15,832 85.6  1 962 5.8 1,858 10.0  ≥2 276 1.7 803 4.3  Meanb 0.1 (0.42) 0.2 (0.70)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) Chronic conditions during year prior to zoster vaccination date  Cancer 2,606 15.8 4,142 22.4 <0.0001  Diabetes 2,570 15.5 4,685 25.3 <0.0001  Kidney disease 1,232 7.5 2,385 12.9 <0.0001  Heart disease 1,170 7.1 2,224 12.0 <0.0001  Liver disease 238 1.4 534 2.9 <0.0001  Lung disease 176 1.1 401 2.2 <0.0001 a The concomitant vaccination cohort received zoster vaccine live and pneumococcal polysaccharide vaccine on the same day. The prior vaccination cohort received pneumococcal polysaccharide vaccine 365 to 30 days prior to zoster vaccine live. b Values are expressed as mean (standard deviation). c Values are expressed as median (25th, 75th percentile). Table 1. Baseline Characteristics of the Concomitant Vaccination Cohort and the Prior Vaccination Cohorta, Kaiser Permanente Southern California, 2007–2016 Characteristic Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) P Value No. % No. % Age group, years <0.0001  60–64 4,663 28.2 4,262 23.0  65–69 8,901 53.8 9,761 52.8  70–74 1,608 9.7 2,301 12.4  75–79 838 5.1 1,273 6.9  ≥80 522 3.2 896 4.8 Mean age, yearsb 66.9 (5.04) 67.9 (5.67) Sex <0.0001  Female 8,897 53.8 10,404 56.3  Male 7,635 46.2 8,089 43.7 Race/ethnicity <0.0001  White 10,093 61.1 11,170 60.4  Black 1,363 8.2 1,397 7.6  Hispanic 2,554 15.4 3,132 16.9  Asian/Pacific Islander 1,835 11.1 2,219 12.0  Multiple/other/unknown 687 4.2 575 3.1 Vaccination year <0.0001  2007 1,826 11.0 2,403 13.0  2008 2,500 15.1 1,976 10.7  2009 2,858 17.3 2,992 16.2  2010 1,240 7.5 1,413 7.6  2011 1,631 9.9 2,002 10.8  2012 2,584 15.6 2,718 14.7  2013 2,091 12.6 2,668 14.4  2014 1,802 10.9 2,321 12.6 No. of outpatient visits during year prior to zoster vaccination date <0.0001  0 3,076 18.6 538 2.9  1–4 8,271 50.0 7,949 43.0  5–10 3,911 23.7 6,825 36.9  ≥11 1,274 7.7 3,181 17.2  Meanb 3.9 (4.28) 6.4 (5.33)  Medianc 3 (1.0, 5.0) 5 (3.0, 9.0) No. of emergency department visits during year prior to zoster vaccination date <0.0001  0 13,993 84.6 14,240 77.0  1 1,912 11.6 2,796 15.1  ≥2 627 3.8 1,457 7.9  Meanb 0.2 (0.66) 0.4 (0.98)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) No. of inpatient visits during year prior to zoster vaccination date <0.0001  0 15,294 92.5 15,832 85.6  1 962 5.8 1,858 10.0  ≥2 276 1.7 803 4.3  Meanb 0.1 (0.42) 0.2 (0.70)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) Chronic conditions during year prior to zoster vaccination date  Cancer 2,606 15.8 4,142 22.4 <0.0001  Diabetes 2,570 15.5 4,685 25.3 <0.0001  Kidney disease 1,232 7.5 2,385 12.9 <0.0001  Heart disease 1,170 7.1 2,224 12.0 <0.0001  Liver disease 238 1.4 534 2.9 <0.0001  Lung disease 176 1.1 401 2.2 <0.0001 Characteristic Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) P Value No. % No. % Age group, years <0.0001  60–64 4,663 28.2 4,262 23.0  65–69 8,901 53.8 9,761 52.8  70–74 1,608 9.7 2,301 12.4  75–79 838 5.1 1,273 6.9  ≥80 522 3.2 896 4.8 Mean age, yearsb 66.9 (5.04) 67.9 (5.67) Sex <0.0001  Female 8,897 53.8 10,404 56.3  Male 7,635 46.2 8,089 43.7 Race/ethnicity <0.0001  White 10,093 61.1 11,170 60.4  Black 1,363 8.2 1,397 7.6  Hispanic 2,554 15.4 3,132 16.9  Asian/Pacific Islander 1,835 11.1 2,219 12.0  Multiple/other/unknown 687 4.2 575 3.1 Vaccination year <0.0001  2007 1,826 11.0 2,403 13.0  2008 2,500 15.1 1,976 10.7  2009 2,858 17.3 2,992 16.2  2010 1,240 7.5 1,413 7.6  2011 1,631 9.9 2,002 10.8  2012 2,584 15.6 2,718 14.7  2013 2,091 12.6 2,668 14.4  2014 1,802 10.9 2,321 12.6 No. of outpatient visits during year prior to zoster vaccination date <0.0001  0 3,076 18.6 538 2.9  1–4 8,271 50.0 7,949 43.0  5–10 3,911 23.7 6,825 36.9  ≥11 1,274 7.7 3,181 17.2  Meanb 3.9 (4.28) 6.4 (5.33)  Medianc 3 (1.0, 5.0) 5 (3.0, 9.0) No. of emergency department visits during year prior to zoster vaccination date <0.0001  0 13,993 84.6 14,240 77.0  1 1,912 11.6 2,796 15.1  ≥2 627 3.8 1,457 7.9  Meanb 0.2 (0.66) 0.4 (0.98)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) No. of inpatient visits during year prior to zoster vaccination date <0.0001  0 15,294 92.5 15,832 85.6  1 962 5.8 1,858 10.0  ≥2 276 1.7 803 4.3  Meanb 0.1 (0.42) 0.2 (0.70)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) Chronic conditions during year prior to zoster vaccination date  Cancer 2,606 15.8 4,142 22.4 <0.0001  Diabetes 2,570 15.5 4,685 25.3 <0.0001  Kidney disease 1,232 7.5 2,385 12.9 <0.0001  Heart disease 1,170 7.1 2,224 12.0 <0.0001  Liver disease 238 1.4 534 2.9 <0.0001  Lung disease 176 1.1 401 2.2 <0.0001 a The concomitant vaccination cohort received zoster vaccine live and pneumococcal polysaccharide vaccine on the same day. The prior vaccination cohort received pneumococcal polysaccharide vaccine 365 to 30 days prior to zoster vaccine live. b Values are expressed as mean (standard deviation). c Values are expressed as median (25th, 75th percentile). Herpes zoster cases in the concomitant vaccination and prior vaccination cohorts There were 599 incident herpes zoster cases in the concomitant vaccination cohort and 741 incident herpes zoster cases in the prior vaccination cohort. The average follow-up time was 4.72 years for the concomitant vaccination cohort and 4.67 years for the prior vaccination cohort, with herpes zoster incidence rates of 7.7 and 8.6 per 1,000 person-years, respectively (Table 2). Incidence rates were highest in the oldest age groups and in women. Table 2. Comparison of Herpes Zoster Incidence in the Concomitant Vaccination Cohort and the Prior Vaccination Cohort, Kaiser Permanente Southern California, 2007–2016 Subgroups Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI All 16,532 599 78,023 7.7 7.1, 8.3 18,493 741 86,322 8.6 8.0, 9.2 Age group, years  60–64 4,663 154 20,790 7.4 6.3, 8.7 4,262 137 18,229 7.5 6.4, 8.9  65–69 8,901 318 41,887 7.6 6.8, 8.5 9,761 378 45,318 8.3 7.5, 9.2  70–74 1,608 61 8,542 7.1 5.6, 9.2 2,301 117 11,953 9.8 8.2, 11.7  75–79 838 36 4,364 8.2 6.0, 11.4 1,273 57 6,779 8.4 6.5, 10.9  ≥80 522 30 2,439 12.3 8.6, 17.6 896 52 4,043 12.9 9.8, 16.9 Sex  Female 8,897 385 42,359 9.1 8.2, 10.0 10,404 475 49,115 9.7 8.8, 10.6  Male 7,635 214 35,664 6.0 5.2, 6.9 8,089 266 37,207 7.1 6.3, 8.1 Race/ethnicity  White 10,093 381 48,777 7.8 7.1, 8.6 11,170 485 53,333 9.1 8.3, 9.9  Black 1,363 39 6,678 5.8 4.3, 8.0 1,397 38 6,530 5.8 4.2, 8.0  Hispanic 2,554 99 11,495 8.6 7.1, 10.5 3,132 118 13,720 8.6 7.2, 10.3  Asian/Pacific Islander 1,835 67 8,870 7.6 5.9, 9.6 2,219 84 10,627 7.9 6.4, 9.8  Multiple/other/unknown 687 13 2,203 5.9 3.4, 10.2 575 16 2,114 7.6 4.6, 12.4 Subgroups Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI All 16,532 599 78,023 7.7 7.1, 8.3 18,493 741 86,322 8.6 8.0, 9.2 Age group, years  60–64 4,663 154 20,790 7.4 6.3, 8.7 4,262 137 18,229 7.5 6.4, 8.9  65–69 8,901 318 41,887 7.6 6.8, 8.5 9,761 378 45,318 8.3 7.5, 9.2  70–74 1,608 61 8,542 7.1 5.6, 9.2 2,301 117 11,953 9.8 8.2, 11.7  75–79 838 36 4,364 8.2 6.0, 11.4 1,273 57 6,779 8.4 6.5, 10.9  ≥80 522 30 2,439 12.3 8.6, 17.6 896 52 4,043 12.9 9.8, 16.9 Sex  Female 8,897 385 42,359 9.1 8.2, 10.0 10,404 475 49,115 9.7 8.8, 10.6  Male 7,635 214 35,664 6.0 5.2, 6.9 8,089 266 37,207 7.1 6.3, 8.1 Race/ethnicity  White 10,093 381 48,777 7.8 7.1, 8.6 11,170 485 53,333 9.1 8.3, 9.9  Black 1,363 39 6,678 5.8 4.3, 8.0 1,397 38 6,530 5.8 4.2, 8.0  Hispanic 2,554 99 11,495 8.6 7.1, 10.5 3,132 118 13,720 8.6 7.2, 10.3  Asian/Pacific Islander 1,835 67 8,870 7.6 5.9, 9.6 2,219 84 10,627 7.9 6.4, 9.8  Multiple/other/unknown 687 13 2,203 5.9 3.4, 10.2 575 16 2,114 7.6 4.6, 12.4 Abbreviations: CI: confidence interval; HZ, herpes zoster. Table 2. Comparison of Herpes Zoster Incidence in the Concomitant Vaccination Cohort and the Prior Vaccination Cohort, Kaiser Permanente Southern California, 2007–2016 Subgroups Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI All 16,532 599 78,023 7.7 7.1, 8.3 18,493 741 86,322 8.6 8.0, 9.2 Age group, years  60–64 4,663 154 20,790 7.4 6.3, 8.7 4,262 137 18,229 7.5 6.4, 8.9  65–69 8,901 318 41,887 7.6 6.8, 8.5 9,761 378 45,318 8.3 7.5, 9.2  70–74 1,608 61 8,542 7.1 5.6, 9.2 2,301 117 11,953 9.8 8.2, 11.7  75–79 838 36 4,364 8.2 6.0, 11.4 1,273 57 6,779 8.4 6.5, 10.9  ≥80 522 30 2,439 12.3 8.6, 17.6 896 52 4,043 12.9 9.8, 16.9 Sex  Female 8,897 385 42,359 9.1 8.2, 10.0 10,404 475 49,115 9.7 8.8, 10.6  Male 7,635 214 35,664 6.0 5.2, 6.9 8,089 266 37,207 7.1 6.3, 8.1 Race/ethnicity  White 10,093 381 48,777 7.8 7.1, 8.6 11,170 485 53,333 9.1 8.3, 9.9  Black 1,363 39 6,678 5.8 4.3, 8.0 1,397 38 6,530 5.8 4.2, 8.0  Hispanic 2,554 99 11,495 8.6 7.1, 10.5 3,132 118 13,720 8.6 7.2, 10.3  Asian/Pacific Islander 1,835 67 8,870 7.6 5.9, 9.6 2,219 84 10,627 7.9 6.4, 9.8  Multiple/other/unknown 687 13 2,203 5.9 3.4, 10.2 575 16 2,114 7.6 4.6, 12.4 Subgroups Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI All 16,532 599 78,023 7.7 7.1, 8.3 18,493 741 86,322 8.6 8.0, 9.2 Age group, years  60–64 4,663 154 20,790 7.4 6.3, 8.7 4,262 137 18,229 7.5 6.4, 8.9  65–69 8,901 318 41,887 7.6 6.8, 8.5 9,761 378 45,318 8.3 7.5, 9.2  70–74 1,608 61 8,542 7.1 5.6, 9.2 2,301 117 11,953 9.8 8.2, 11.7  75–79 838 36 4,364 8.2 6.0, 11.4 1,273 57 6,779 8.4 6.5, 10.9  ≥80 522 30 2,439 12.3 8.6, 17.6 896 52 4,043 12.9 9.8, 16.9 Sex  Female 8,897 385 42,359 9.1 8.2, 10.0 10,404 475 49,115 9.7 8.8, 10.6  Male 7,635 214 35,664 6.0 5.2, 6.9 8,089 266 37,207 7.1 6.3, 8.1 Race/ethnicity  White 10,093 381 48,777 7.8 7.1, 8.6 11,170 485 53,333 9.1 8.3, 9.9  Black 1,363 39 6,678 5.8 4.3, 8.0 1,397 38 6,530 5.8 4.2, 8.0  Hispanic 2,554 99 11,495 8.6 7.1, 10.5 3,132 118 13,720 8.6 7.2, 10.3  Asian/Pacific Islander 1,835 67 8,870 7.6 5.9, 9.6 2,219 84 10,627 7.9 6.4, 9.8  Multiple/other/unknown 687 13 2,203 5.9 3.4, 10.2 575 16 2,114 7.6 4.6, 12.4 Abbreviations: CI: confidence interval; HZ, herpes zoster. The cumulative risk of herpes zoster estimated by the Kaplan-Meier method was lower in the concomitant vaccination cohort than the prior vaccination cohort (log-rank test, P = 0.04) (Figure 1). In the fully adjusted analysis, the hazard ratio comparing herpes zoster in the concomitant vaccination cohort and the prior vaccination cohort was 1.04 (95% confidence interval: 0.92, 1.16). There were no significant differences in adjusted hazard ratios for herpes zoster between the cohorts by age, sex, or race/ethnicity (Table 3). Figure 1. View largeDownload slide Kaplan-Meier estimates of the cumulative risk of herpes zoster in the concomitant vaccination cohort and the prior vaccination cohort, Kaiser Permanente Southern California, 2007–2016. Figure 1. View largeDownload slide Kaplan-Meier estimates of the cumulative risk of herpes zoster in the concomitant vaccination cohort and the prior vaccination cohort, Kaiser Permanente Southern California, 2007–2016. Table 3. Hazard Ratio of Herpes Zoster in the Concomitant Vaccination Cohort and the Prior Vaccination Cohort, Kaiser Permanente Southern California, 2007–2016 Subgroups Unadjusted Adjusteda HR 95% CI HR 95% CI All 0.89 0.80, 1.00 1.04 0.92, 1.16 Age group, years  60–64 0.99 0.78, 1.24 1.06 0.83, 1.36  65–69 0.91 0.78, 1.06 1.01 0.87, 1.18  70–74 0.73 0.54, 0.99 0.92 0.66, 1.26  75–79 0.98 0.65, 1.49 1.18 0.76, 1.82  ≥80 0.96 0.61, 1.50 1.29 0.81, 2.08 Sex  Female 0.94 0.82, 1.08 1.07 0.93, 1.23  Male 0.84 0.70, 1.00 0.97 0.80, 1.17 Race/ethnicity  White 0.86 0.75, 0.98 0.98 0.85, 1.12  Black 1.00 0.64, 1.57 1.23 0.77, 1.95  Hispanic 1.00 0.77, 1.31 1.16 0.88, 1.54  Asian/Pacific Islander 0.96 0.69, 1.32 1.13 0.81, 1.59  Multiple/other/unknown 0.78 0.37, 1.62 1.28 0.57, 2.83 Subgroups Unadjusted Adjusteda HR 95% CI HR 95% CI All 0.89 0.80, 1.00 1.04 0.92, 1.16 Age group, years  60–64 0.99 0.78, 1.24 1.06 0.83, 1.36  65–69 0.91 0.78, 1.06 1.01 0.87, 1.18  70–74 0.73 0.54, 0.99 0.92 0.66, 1.26  75–79 0.98 0.65, 1.49 1.18 0.76, 1.82  ≥80 0.96 0.61, 1.50 1.29 0.81, 2.08 Sex  Female 0.94 0.82, 1.08 1.07 0.93, 1.23  Male 0.84 0.70, 1.00 0.97 0.80, 1.17 Race/ethnicity  White 0.86 0.75, 0.98 0.98 0.85, 1.12  Black 1.00 0.64, 1.57 1.23 0.77, 1.95  Hispanic 1.00 0.77, 1.31 1.16 0.88, 1.54  Asian/Pacific Islander 0.96 0.69, 1.32 1.13 0.81, 1.59  Multiple/other/unknown 0.78 0.37, 1.62 1.28 0.57, 2.83 Abbreviations: CI, confidence interval; HR, hazard ratio. a Adjusted for age, sex, race/ethnicity, health-care utilization, vaccination year, and chronic disease in the model. Table 3. Hazard Ratio of Herpes Zoster in the Concomitant Vaccination Cohort and the Prior Vaccination Cohort, Kaiser Permanente Southern California, 2007–2016 Subgroups Unadjusted Adjusteda HR 95% CI HR 95% CI All 0.89 0.80, 1.00 1.04 0.92, 1.16 Age group, years  60–64 0.99 0.78, 1.24 1.06 0.83, 1.36  65–69 0.91 0.78, 1.06 1.01 0.87, 1.18  70–74 0.73 0.54, 0.99 0.92 0.66, 1.26  75–79 0.98 0.65, 1.49 1.18 0.76, 1.82  ≥80 0.96 0.61, 1.50 1.29 0.81, 2.08 Sex  Female 0.94 0.82, 1.08 1.07 0.93, 1.23  Male 0.84 0.70, 1.00 0.97 0.80, 1.17 Race/ethnicity  White 0.86 0.75, 0.98 0.98 0.85, 1.12  Black 1.00 0.64, 1.57 1.23 0.77, 1.95  Hispanic 1.00 0.77, 1.31 1.16 0.88, 1.54  Asian/Pacific Islander 0.96 0.69, 1.32 1.13 0.81, 1.59  Multiple/other/unknown 0.78 0.37, 1.62 1.28 0.57, 2.83 Subgroups Unadjusted Adjusteda HR 95% CI HR 95% CI All 0.89 0.80, 1.00 1.04 0.92, 1.16 Age group, years  60–64 0.99 0.78, 1.24 1.06 0.83, 1.36  65–69 0.91 0.78, 1.06 1.01 0.87, 1.18  70–74 0.73 0.54, 0.99 0.92 0.66, 1.26  75–79 0.98 0.65, 1.49 1.18 0.76, 1.82  ≥80 0.96 0.61, 1.50 1.29 0.81, 2.08 Sex  Female 0.94 0.82, 1.08 1.07 0.93, 1.23  Male 0.84 0.70, 1.00 0.97 0.80, 1.17 Race/ethnicity  White 0.86 0.75, 0.98 0.98 0.85, 1.12  Black 1.00 0.64, 1.57 1.23 0.77, 1.95  Hispanic 1.00 0.77, 1.31 1.16 0.88, 1.54  Asian/Pacific Islander 0.96 0.69, 1.32 1.13 0.81, 1.59  Multiple/other/unknown 0.78 0.37, 1.62 1.28 0.57, 2.83 Abbreviations: CI, confidence interval; HR, hazard ratio. a Adjusted for age, sex, race/ethnicity, health-care utilization, vaccination year, and chronic disease in the model. DISCUSSION This study describes a context where real-world data based on a clinically valid correlate of vaccine protection provides reliable and rigorous evidence for regulatory decisions. As in the previous 3.5-year study at KPSC (18), this 9.5-year study with over 35,000 subjects found no evidence of increased risk of herpes zoster in KPSC members vaccinated concomitantly with ZVL and PPSV23 compared with members vaccinated with PPSV23 from 365 to 30 days prior to receiving ZVL (adjusted hazard ratio = 1.04, 95% confidence interval: 0.92, 1.16). These results suggest no evidence of a diminished VZV immune response following concomitant administration of ZVL with PPSV23. The single randomized clinical trial that served as the basis for the 2009 and 2011 revisions to the ZVL and PPSV23 prescribing information involved a total of 473 enrolled subjects and used an endpoint that was less meaningful clinically (12). The results of the trial were based on observation of lower VZV antibody levels 4 weeks after ZVL vaccination in the group receiving PPSV23 concomitantly compared with the group receiving PPSV23 4 weeks before ZVL. However, VZV antibody levels are not likely to be an appropriate measure of ZVL efficacy, given that increased VZV antibody levels do not appear to protect against herpes zoster; rather, elevated VZV antibody levels are the result of more severe herpes zoster disease (14, 21). Protection against reactivation of VZV causing herpes zoster is largely maintained by VZV-specific T-cell mediated immunity, which declines with age and correlates with incidence and severity of herpes zoster (16, 21). In contrast, our study provides compelling evidence for a lack of vaccine interference, because it relies on the measurement of the occurrence of herpes zoster rather than an intermediate marker of immunity (14). While randomized controlled trials are often considered the gold standard of evaluation, this real-world, observational study design offered distinct advantages. First, the study population consisted of a large number of highly diverse subjects followed over 9.5 years through comprehensive electronic health records. It would be cost prohibitive to conduct such a large study over such a long period as a prospectively recruited clinical trial (4, 22). Second, clinical trials are designed to control variability through strict eligibility criteria. In this observational study using real-world data, we included a broad range of subjects with multiple comorbidities who are more generalizable to the general population, resulting in high external validity. Third, randomization is an important tool for minimizing bias by balancing the underlying risk between treatment groups (2), but balance is not guaranteed. In the sole clinical trial (12) that was the basis for the statement in the ZVL and PPSV23 prescribing information that these vaccines should not be given concurrently, the concomitant group had a substantially higher mean VZV antibody titer at baseline than the nonconcomitant group despite randomization, casting doubt on the validity of the study (14). On the other hand, in observational studies using real-world data, potential bias can be mitigated through careful study design and analysis (1, 5). In our study, both groups received both ZVL and PPSV23, minimizing concerns regarding confounding by indication between treatment groups. Furthermore, important covariates were measured and controlled for in the Cox proportional hazards analysis. Our results, therefore, are likely to be robust, indicating no evidence for increased risk of herpes zoster associated with concomitant administration of ZVL and PPSV23. One potential limitation in our study is that the concomitant vaccination cohort and prior PPSV23 cohort could differ by unrecognized factors related to the outcome of interest (i.e., receipt of care for herpes zoster) due to differences in underlying risk of herpes zoster or health-care seeking behavior. This was addressed in our previous study by comparing the incidence of 13 unrelated medical conditions between the cohorts, as described elsewhere (18, 23). Given that incidence rate ratios for these conditions all clustered around the null, similar to the estimate for herpes zoster, confounding due to underlying risks or health-care seeking behaviors is likely minimal. In addition, it is possible that vaccines delivered outside the system might have been missed, although this factor is expected to be minimal given the incentive to receive care within the system. Furthermore, misclassification of herpes zoster either by clinician diagnosis or professional coders is also possible but would most likely be nondifferential with respect to the vaccination exposure. Concomitant vaccination is recommended to minimize barriers to patients and providers and improve vaccination coverage, provided there are no concerns regarding safety and interference with the immune response (24). ZVL vaccination coverage has been low (30.6% of adults aged 60 years or older) (25, 26). The statements discouraging concomitant administration of ZVL and PPSV23 in the prescribing information may have resulted in missed opportunities for vaccination. Revision of the prescribing information based on this real-world evidence should be carefully considered to avoid missing critical opportunities for improving vaccination coverage and reducing the disease burden in older adults. Real-world evidence will be even more critical in the evaluation of the safety and effectiveness of the newly licensed zoster vaccine, recombinant zoster vaccine (RZV) (Shingrix; GlaxoSmithKline, Research Triangle Park, North Carolina). RZV is indicated for the prevention of herpes zoster in adults aged 50 years or older (27) and was recently preferentially recommended over ZVL by the Advisory Committee on Immunization Practices (28). While clinical trials have shown RZV to be safe and effective (29, 30), limited data are available for long-term outcomes, high-risk populations, and interactions with other vaccines. Lingering concerns remain regarding safety, including the use of an adjuvanted vaccine in the elderly and increased reactogenicity compared with ZVL. Also, RZV requires 2 doses for optimal efficacy, but compliance with a 2-dose schedule in the elderly is unknown. Concomitant administration with other vaccines may be vital for achieving higher coverage. Real-world data from rigorous studies, together with carefully designed and expeditiously executed and published phase IV studies (31), will be essential to appropriately address evidentiary gaps in vaccine safety and effectiveness and to inform regulatory and policy decisions. ACKNOWLEDGMENTS Author affiliations: Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California (Katia Bruxvoort, Lina S. Sy, Yi Luo, Hung Fu Tseng). K.B. and L.S.S. contributed equally to this manuscript. This study was supported by Kaiser Permanente Southern California internal research funds. Conflicts of interest: H.F.T. served as a paid consultant to GlaxoSmithKline for their recombinant zoster vaccine. Abbreviations FDA US Food and Drug Administration ICD-9 International Classification of Diseases, Ninth Revision KPSC Kaiser Permanente Southern California PPSV23 23-valent pneumococcal polysaccharide vaccine RZV recombinant zoster vaccine VZV varicella zoster virus ZVL zoster vaccine live. REFERENCES 1 US Food and Drug Administration . Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff. Rockville, MD : US Food and Drug Administration ; 2017 . https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM513027.pdf. Accessed November 3, 2017. 2 Sherman RE , Anderson SA , Dal Pan GJ , et al. . Real-world evidence—what is it and what can it tell us? N Engl J Med . 2016 ; 375 ( 23 ): 2293 – 2297 . Google Scholar CrossRef Search ADS PubMed 3 Berger M , Daniel G , Frank K , et al. . A Framework for Regulatory Use of Real-World Evidence. Washington, DC : Duke University Margolis Center for Health Policy ; 2017 . https://healthpolicy.duke.edu/sites/default/files/atoms/files/rwe_white_paper_2017.09.06.pdf. Accessed November 3, 2017. 4 Jarow JP , LaVange L , Woodcock J . Multidimensional evidence generation and FDA regulatory decision making: defining and using “real-world” data . JAMA . 2017 ; 318 ( 8 ): 703 – 704 . Google Scholar CrossRef Search ADS PubMed 5 Frieden TR . Evidence for health decision making—beyond randomized, controlled trials . N Engl J Med . 2017 ; 377 ( 5 ): 465 – 475 . Google Scholar CrossRef Search ADS PubMed 6 US Food and Drug Administration . PDUFA Reauthorization Performance Goals And Procedures Fiscal Years 2018 Through 2022. 2016 . https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM511438.pdf. Accessed May 31, 2018. 7 21st Century Cures Act, H.R. 34, 114th Cong, 2nd Sess (2016). https://www.congress.gov/bill/114th-congress/house-bill/34/. Accessed November 3, 2017. 8 Califf RM , Robb MA , Bindman AB , et al. . Transforming evidence generation to support health and health care decisions . N Engl J Med . 2016 ; 375 ( 24 ): 2395 – 2400 . Google Scholar CrossRef Search ADS PubMed 9 Pneumovax . Prescribing information [package insert]. 2015 . https://www.merck.com/product/usa/pi_circulars/p/pneumovax_23/pneumovax_pi.pdf. Accessed October 4, 2017. 10 Zostavax . Prescribing information [package insert]. 2017 . https://www.merck.com/product/usa/pi_circulars/z/zostavax/zostavax_pi2.pdf. Accessed October 4, 2017. 11 US Food and Drug Administration . Summary Basis for Regulatory Action [for Zostavax (zoster vaccine live)] . 2016 . http://wayback.archive-it.org/7993/20170723093318/https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM249230.pdf. Accessed May 31, 2018. 12 MacIntyre CR , Egerton T , McCaughey M , et al. . 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National and state-specific shingles vaccination among adults aged ≥60 years . Am J Prev Med . 2017 ; 52 ( 3 ): 362 – 372 . Google Scholar CrossRef Search ADS PubMed 26 Williams WW , Lu PJ , O’Halloran A , et al. . Surveillance of vaccination coverage among adult populations—United States, 2015 . MMWR Surveill Summ . 2017 ; 66 ( 11 ): 1 – 28 . Google Scholar CrossRef Search ADS PubMed 27 Shingrix . Prescribing information [package insert]. 2017 . https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Shingrix/pdf/SHINGRIX.PDF. Accessed December 7, 2017. 28 Dooling KL , Guo A , Patel M , et al. . Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines . MMWR Morb Mortal Wkly Rep . 2018 ; 67 ( 3 ): 103 – 108 . Google Scholar CrossRef Search ADS PubMed 29 Cunningham AL , Lal H , Kovac M , et al. . Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older . N Engl J Med . 2016 ; 375 ( 11 ): 1019 – 1032 . Google Scholar CrossRef Search ADS PubMed 30 Lal H , Cunningham AL , Godeaux O , et al. . Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults . N Engl J Med . 2015 ; 372 ( 22 ): 2087 – 2096 . Google Scholar CrossRef Search ADS PubMed 31 Woloshin S , Schwartz LM , White B , et al. . The fate of FDA postapproval studies . N Engl J Med . 2017 ; 377 ( 12 ): 1114 – 1117 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Epidemiology Oxford University Press

Real-World Evidence for Regulatory Decisions: Concomitant Administration of Zoster Vaccine Live and Pneumococcal Polysaccharide Vaccine

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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10.1093/aje/kwy076
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Abstract

Abstract The US Food and Drug Administration is charged with expanding the use of real-world evidence for regulatory decisions. As a test case for real-world evidence to support regulatory decisions, we present the scenario of concomitant vaccination with zoster vaccine live (ZVL) and 23-valent pneumococcal polysaccharide vaccine (PPSV23). The prescribing information states that these vaccines should not be given concurrently, based on a small trial using varicella zoster virus antibody levels as a correlate of ZVL efficacy, even though ZVL protects against herpes zoster via cell-mediated immunity. We conducted an observational cohort study involving more than 35,000 members of Kaiser Permanente Southern California receiving concomitant ZVL and PPSV23 versus PPSV23 prior to ZVL. Occurrence of herpes zoster was assessed through electronic health records from January 1, 2007, to June 30, 2016. The adjusted hazard ratio comparing incidence rates of herpes zoster in the concomitant vaccination cohort and the prior vaccination cohort was 1.04 (95% confidence interval: 0.92, 1.16). This real-world evidence study provides direct evidence for a lack of vaccine interference, relying on herpes zoster occurrence rather than an intermediate marker of immunity. Real-world evidence is essential for regulators and policy makers in addressing evidentiary gaps regarding safety, effectiveness, compliance, and vaccine interactions for the new recombinant zoster vaccine. herpes zoster, herpes zoster vaccine, pneumococcal polysaccharide vaccine, real-world evidence, vaccination The role of real-world evidence in regulatory health-care decision making is a growing area of interest and recent discourse. Real-world evidence is evidence derived from real-world data on patient health status or routine health-care delivery (1, 2). Real-world data are typically generated outside of conventional clinical trials and include data from electronic health records, product or disease registries, and mobile health-tracking devices. For regulatory applications, real-world evidence is the clinical evidence regarding the use and potential benefits or risks derived from analysis of real-world data through the application of research methods. Real-world evidence has the potential to efficiently fill evidentiary gaps in safety and effectiveness that are difficult to address through randomized controlled trials, such as long-term outcomes or generalizability to broader populations with multiple comorbidities (3). The US Food and Drug Administration (FDA) uses real-world evidence for regulatory decisions related to safety, but rarely has real-world evidence been used to inform label changes such as indication expansions or dosing modifications (4). Current evidence-grading systems give higher weight to randomized controlled trials and may inadequately consider data from other study designs (5). However, recent legislation in the 21st Century Cures Act and Sixth Prescription Drug User Fee Act (PDUFA VI) requires that the FDA develop guidance for expanding the use of real-world evidence in regulatory decision making (6, 7). The FDA has published commentaries expressing commitment to the use of real-world evidence (2, 4, 8) and has convened stakeholder meetings to develop a framework for the application of real-world evidence (3). The framework emphasizes the need to match high-quality data sources and rigorous methods to answer specific clinical and regulatory questions. As an example of a context in which real-world evidence is ideal for supporting regulatory decisions, we present the scenario of concomitant vaccination with zoster vaccine live (ZVL) (Zostavax; Merck and Co., Inc., Whitehouse Station, New Jersey) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) (Pneumovax23; Merck and Co., Inc., Whitehouse Station, New Jersey). In 2009, the FDA approved a revision to the Drug Interaction section of the prescribing information for ZVL and PPSV23 to state that these vaccines “should not be given concurrently” (9–11). This revision was based on a randomized, blinded, placebo-controlled trial conducted by the manufacturer, which found that concomitant administration of ZVL and PPSV23 resulted in lower varicella zoster virus (VZV) antibody levels compared with administration of the vaccines 4 weeks apart (12). This decision based on VZV antibody levels as a measure of ZVL efficacy was disputed (13, 14). Zoster vaccine is thought to protect against herpes zoster by boosting VZV-specific T-cell mediated immunity, not through a humoral response (15–17). Subsequently, a 3.5-year cohort study was conducted, finding no difference in the incidence of herpes zoster in subjects concomitantly vaccinated with ZVL and PPSV23 compared with subjects receiving PPSV23 at least 4 weeks prior to ZVL (18). The FDA approved a second revision to the prescribing information in March 2011 to soften the language: “Consider administration of the 2 vaccines separated by at least 4 weeks” (11). Despite the FDA revisions to the prescribing information, the Advisory Committee on Immunization Practices continued to recommend concomitant administration of ZVL and PPSV23 for eligible persons (19). The present work describes a 9.5-year cohort study evaluating the incidence of herpes zoster after concomitant administration of ZVL and PPSV23. The study provides a test case for using real-world evidence to inform future regulatory decisions for vaccines and emphasizes the importance of clinically meaningful endpoints. METHODS Study setting Kaiser Permanente Southern California (KPSC) is an integrated health-care organization that serves approximately 4.4 million residents of Southern California. Members of KPSC have diverse sociodemographic backgrounds largely representative of the underlying population (20). Because KPSC provides recommended vaccines free of charge, members have a strong incentive to receive vaccinations within the system; nevertheless, vaccinations received outside the system are captured with appropriate documentation from the member. At the time of this study, recommended vaccines included ZVL for members aged 60 years or older and PPSV23 for all members age 65 years or older (and members less than 65 years of age in high-risk groups). Electronic health records store information on vaccinations as well as sociodemographic factors, utilization (outpatient, emergency department, and inpatient), and diagnoses. Because the prepaid system motivates members to use services internally, and claims for reimbursement of outside care must be submitted to the health plan with documentation, data captured in the electronic health records are comprehensive. Study design A retrospective cohort study was conducted from January 1, 2007, to June 30, 2016. The exposed cohort (concomitant vaccination group) consisted of KPSC members 60 years of age or older who were vaccinated with ZVL and PPSV23 on the same day between January 1, 2007, and December 31, 2014. The comparator cohort (prior vaccination group) consisted of KPSC members 60 years of age or older who were vaccinated with ZVL during the same period as the exposed cohort but were previously vaccinated with a dose of PPSV23 from 365 days to 30 days prior to receiving ZVL. Both groups had been continuous KPSC members in the year prior to date of ZVL vaccination, allowing for a 31-day gap in membership. Subjects from both groups were followed from the date of ZVL vaccination until the date of herpes zoster occurrence, termination of KPSC membership (allowing for a 31-day gap), death, or June 30, 2016, whichever was earliest. Outcomes Incident cases of herpes zoster between January 1, 2007, and June 30, 2016, were identified from electronic health records. Through September 30, 2015, cases were identified from the first diagnosis of International Classification of Diseases, Ninth Revision (ICD-9), code 053.xx in any diagnostic position from inpatient, outpatient, and emergency department records. Cases starting from October 1, 2015, were identified from corresponding International Classification of Diseases, Tenth Revision, codes (B02.xx). Incident cases were defined as herpes zoster cases without a herpes zoster diagnosis in the previous 6 months, to avoid carryover of prevalent cases into the follow-up period. Herpes zoster diagnoses within 30 days after ZVL vaccination were excluded, because these patients could have been experiencing reactivation of VZV at the time of vaccination. Covariates were examined to assess the characteristics of the concomitant vaccination and prior vaccination cohorts. These included age, sex, race/ethnicity, health-care utilization, vaccination year, and comorbid chronic diseases. Health-care utilization was defined as the number of outpatient, emergency department, or inpatient visits within 1 year before the date of ZVL vaccination. Chronic diseases were defined as a diagnosis within 1 year before the date of ZVL vaccination, and included cancer (ICD-9 codes 140–239), diabetes (ICD-9 codes 250), kidney disease (ICD-9 codes 403, 581–583, 585–588), heart disease (ICD-9 codes 410–414, 428), liver disease (ICD-9 codes 571–573), or lung disease (ICD-9 codes 491–492). Subjects could be assigned multiple conditions. Statistical analysis Incidence rates of herpes zoster were calculated by dividing the number of incident cases by the number of person-years. The 95% confidence intervals were estimated assuming that the occurrence of herpes zoster followed a Poisson distribution. The cumulative risk of herpes zoster was computed by the Kaplan-Meier method, with the log-rank test performed to assess the difference in cumulative risks between the concomitant vaccination and prior vaccination cohorts. The adjusted hazard ratio for herpes zoster associated with concomitant vaccination versus prior vaccination was estimated with a Cox proportional hazards regression model, controlling for age, sex, race/ethnicity, health-care utilization, vaccination year, and chronic disease comorbidities. SAS, version 9.3 (SAS Institute, Inc., Cary, North Carolina), was used for all analyses. This study was approved by the KPSC Institutional Review Board. RESULTS Characteristics of subjects in the concomitant vaccination and prior vaccination cohorts There were 16,532 subjects concomitantly vaccinated with ZVL and PPSV23 and 18,493 subjects who received PPSV23 from 365 days to 30 days prior to ZVL vaccination. Compared with the prior vaccination cohort, the concomitant vaccination cohort was slightly younger, was more likely to be male, had a slightly different distribution of race/ethnicity and vaccination year, had fewer health-care encounters (outpatient, emergency department, and inpatient visits), and had a lower prevalence of chronic diseases (Table 1). Table 1. Baseline Characteristics of the Concomitant Vaccination Cohort and the Prior Vaccination Cohorta, Kaiser Permanente Southern California, 2007–2016 Characteristic Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) P Value No. % No. % Age group, years <0.0001  60–64 4,663 28.2 4,262 23.0  65–69 8,901 53.8 9,761 52.8  70–74 1,608 9.7 2,301 12.4  75–79 838 5.1 1,273 6.9  ≥80 522 3.2 896 4.8 Mean age, yearsb 66.9 (5.04) 67.9 (5.67) Sex <0.0001  Female 8,897 53.8 10,404 56.3  Male 7,635 46.2 8,089 43.7 Race/ethnicity <0.0001  White 10,093 61.1 11,170 60.4  Black 1,363 8.2 1,397 7.6  Hispanic 2,554 15.4 3,132 16.9  Asian/Pacific Islander 1,835 11.1 2,219 12.0  Multiple/other/unknown 687 4.2 575 3.1 Vaccination year <0.0001  2007 1,826 11.0 2,403 13.0  2008 2,500 15.1 1,976 10.7  2009 2,858 17.3 2,992 16.2  2010 1,240 7.5 1,413 7.6  2011 1,631 9.9 2,002 10.8  2012 2,584 15.6 2,718 14.7  2013 2,091 12.6 2,668 14.4  2014 1,802 10.9 2,321 12.6 No. of outpatient visits during year prior to zoster vaccination date <0.0001  0 3,076 18.6 538 2.9  1–4 8,271 50.0 7,949 43.0  5–10 3,911 23.7 6,825 36.9  ≥11 1,274 7.7 3,181 17.2  Meanb 3.9 (4.28) 6.4 (5.33)  Medianc 3 (1.0, 5.0) 5 (3.0, 9.0) No. of emergency department visits during year prior to zoster vaccination date <0.0001  0 13,993 84.6 14,240 77.0  1 1,912 11.6 2,796 15.1  ≥2 627 3.8 1,457 7.9  Meanb 0.2 (0.66) 0.4 (0.98)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) No. of inpatient visits during year prior to zoster vaccination date <0.0001  0 15,294 92.5 15,832 85.6  1 962 5.8 1,858 10.0  ≥2 276 1.7 803 4.3  Meanb 0.1 (0.42) 0.2 (0.70)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) Chronic conditions during year prior to zoster vaccination date  Cancer 2,606 15.8 4,142 22.4 <0.0001  Diabetes 2,570 15.5 4,685 25.3 <0.0001  Kidney disease 1,232 7.5 2,385 12.9 <0.0001  Heart disease 1,170 7.1 2,224 12.0 <0.0001  Liver disease 238 1.4 534 2.9 <0.0001  Lung disease 176 1.1 401 2.2 <0.0001 Characteristic Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) P Value No. % No. % Age group, years <0.0001  60–64 4,663 28.2 4,262 23.0  65–69 8,901 53.8 9,761 52.8  70–74 1,608 9.7 2,301 12.4  75–79 838 5.1 1,273 6.9  ≥80 522 3.2 896 4.8 Mean age, yearsb 66.9 (5.04) 67.9 (5.67) Sex <0.0001  Female 8,897 53.8 10,404 56.3  Male 7,635 46.2 8,089 43.7 Race/ethnicity <0.0001  White 10,093 61.1 11,170 60.4  Black 1,363 8.2 1,397 7.6  Hispanic 2,554 15.4 3,132 16.9  Asian/Pacific Islander 1,835 11.1 2,219 12.0  Multiple/other/unknown 687 4.2 575 3.1 Vaccination year <0.0001  2007 1,826 11.0 2,403 13.0  2008 2,500 15.1 1,976 10.7  2009 2,858 17.3 2,992 16.2  2010 1,240 7.5 1,413 7.6  2011 1,631 9.9 2,002 10.8  2012 2,584 15.6 2,718 14.7  2013 2,091 12.6 2,668 14.4  2014 1,802 10.9 2,321 12.6 No. of outpatient visits during year prior to zoster vaccination date <0.0001  0 3,076 18.6 538 2.9  1–4 8,271 50.0 7,949 43.0  5–10 3,911 23.7 6,825 36.9  ≥11 1,274 7.7 3,181 17.2  Meanb 3.9 (4.28) 6.4 (5.33)  Medianc 3 (1.0, 5.0) 5 (3.0, 9.0) No. of emergency department visits during year prior to zoster vaccination date <0.0001  0 13,993 84.6 14,240 77.0  1 1,912 11.6 2,796 15.1  ≥2 627 3.8 1,457 7.9  Meanb 0.2 (0.66) 0.4 (0.98)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) No. of inpatient visits during year prior to zoster vaccination date <0.0001  0 15,294 92.5 15,832 85.6  1 962 5.8 1,858 10.0  ≥2 276 1.7 803 4.3  Meanb 0.1 (0.42) 0.2 (0.70)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) Chronic conditions during year prior to zoster vaccination date  Cancer 2,606 15.8 4,142 22.4 <0.0001  Diabetes 2,570 15.5 4,685 25.3 <0.0001  Kidney disease 1,232 7.5 2,385 12.9 <0.0001  Heart disease 1,170 7.1 2,224 12.0 <0.0001  Liver disease 238 1.4 534 2.9 <0.0001  Lung disease 176 1.1 401 2.2 <0.0001 a The concomitant vaccination cohort received zoster vaccine live and pneumococcal polysaccharide vaccine on the same day. The prior vaccination cohort received pneumococcal polysaccharide vaccine 365 to 30 days prior to zoster vaccine live. b Values are expressed as mean (standard deviation). c Values are expressed as median (25th, 75th percentile). Table 1. Baseline Characteristics of the Concomitant Vaccination Cohort and the Prior Vaccination Cohorta, Kaiser Permanente Southern California, 2007–2016 Characteristic Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) P Value No. % No. % Age group, years <0.0001  60–64 4,663 28.2 4,262 23.0  65–69 8,901 53.8 9,761 52.8  70–74 1,608 9.7 2,301 12.4  75–79 838 5.1 1,273 6.9  ≥80 522 3.2 896 4.8 Mean age, yearsb 66.9 (5.04) 67.9 (5.67) Sex <0.0001  Female 8,897 53.8 10,404 56.3  Male 7,635 46.2 8,089 43.7 Race/ethnicity <0.0001  White 10,093 61.1 11,170 60.4  Black 1,363 8.2 1,397 7.6  Hispanic 2,554 15.4 3,132 16.9  Asian/Pacific Islander 1,835 11.1 2,219 12.0  Multiple/other/unknown 687 4.2 575 3.1 Vaccination year <0.0001  2007 1,826 11.0 2,403 13.0  2008 2,500 15.1 1,976 10.7  2009 2,858 17.3 2,992 16.2  2010 1,240 7.5 1,413 7.6  2011 1,631 9.9 2,002 10.8  2012 2,584 15.6 2,718 14.7  2013 2,091 12.6 2,668 14.4  2014 1,802 10.9 2,321 12.6 No. of outpatient visits during year prior to zoster vaccination date <0.0001  0 3,076 18.6 538 2.9  1–4 8,271 50.0 7,949 43.0  5–10 3,911 23.7 6,825 36.9  ≥11 1,274 7.7 3,181 17.2  Meanb 3.9 (4.28) 6.4 (5.33)  Medianc 3 (1.0, 5.0) 5 (3.0, 9.0) No. of emergency department visits during year prior to zoster vaccination date <0.0001  0 13,993 84.6 14,240 77.0  1 1,912 11.6 2,796 15.1  ≥2 627 3.8 1,457 7.9  Meanb 0.2 (0.66) 0.4 (0.98)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) No. of inpatient visits during year prior to zoster vaccination date <0.0001  0 15,294 92.5 15,832 85.6  1 962 5.8 1,858 10.0  ≥2 276 1.7 803 4.3  Meanb 0.1 (0.42) 0.2 (0.70)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) Chronic conditions during year prior to zoster vaccination date  Cancer 2,606 15.8 4,142 22.4 <0.0001  Diabetes 2,570 15.5 4,685 25.3 <0.0001  Kidney disease 1,232 7.5 2,385 12.9 <0.0001  Heart disease 1,170 7.1 2,224 12.0 <0.0001  Liver disease 238 1.4 534 2.9 <0.0001  Lung disease 176 1.1 401 2.2 <0.0001 Characteristic Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) P Value No. % No. % Age group, years <0.0001  60–64 4,663 28.2 4,262 23.0  65–69 8,901 53.8 9,761 52.8  70–74 1,608 9.7 2,301 12.4  75–79 838 5.1 1,273 6.9  ≥80 522 3.2 896 4.8 Mean age, yearsb 66.9 (5.04) 67.9 (5.67) Sex <0.0001  Female 8,897 53.8 10,404 56.3  Male 7,635 46.2 8,089 43.7 Race/ethnicity <0.0001  White 10,093 61.1 11,170 60.4  Black 1,363 8.2 1,397 7.6  Hispanic 2,554 15.4 3,132 16.9  Asian/Pacific Islander 1,835 11.1 2,219 12.0  Multiple/other/unknown 687 4.2 575 3.1 Vaccination year <0.0001  2007 1,826 11.0 2,403 13.0  2008 2,500 15.1 1,976 10.7  2009 2,858 17.3 2,992 16.2  2010 1,240 7.5 1,413 7.6  2011 1,631 9.9 2,002 10.8  2012 2,584 15.6 2,718 14.7  2013 2,091 12.6 2,668 14.4  2014 1,802 10.9 2,321 12.6 No. of outpatient visits during year prior to zoster vaccination date <0.0001  0 3,076 18.6 538 2.9  1–4 8,271 50.0 7,949 43.0  5–10 3,911 23.7 6,825 36.9  ≥11 1,274 7.7 3,181 17.2  Meanb 3.9 (4.28) 6.4 (5.33)  Medianc 3 (1.0, 5.0) 5 (3.0, 9.0) No. of emergency department visits during year prior to zoster vaccination date <0.0001  0 13,993 84.6 14,240 77.0  1 1,912 11.6 2,796 15.1  ≥2 627 3.8 1,457 7.9  Meanb 0.2 (0.66) 0.4 (0.98)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) No. of inpatient visits during year prior to zoster vaccination date <0.0001  0 15,294 92.5 15,832 85.6  1 962 5.8 1,858 10.0  ≥2 276 1.7 803 4.3  Meanb 0.1 (0.42) 0.2 (0.70)  Medianc 0 (0.0, 0.0) 0 (0.0, 0.0) Chronic conditions during year prior to zoster vaccination date  Cancer 2,606 15.8 4,142 22.4 <0.0001  Diabetes 2,570 15.5 4,685 25.3 <0.0001  Kidney disease 1,232 7.5 2,385 12.9 <0.0001  Heart disease 1,170 7.1 2,224 12.0 <0.0001  Liver disease 238 1.4 534 2.9 <0.0001  Lung disease 176 1.1 401 2.2 <0.0001 a The concomitant vaccination cohort received zoster vaccine live and pneumococcal polysaccharide vaccine on the same day. The prior vaccination cohort received pneumococcal polysaccharide vaccine 365 to 30 days prior to zoster vaccine live. b Values are expressed as mean (standard deviation). c Values are expressed as median (25th, 75th percentile). Herpes zoster cases in the concomitant vaccination and prior vaccination cohorts There were 599 incident herpes zoster cases in the concomitant vaccination cohort and 741 incident herpes zoster cases in the prior vaccination cohort. The average follow-up time was 4.72 years for the concomitant vaccination cohort and 4.67 years for the prior vaccination cohort, with herpes zoster incidence rates of 7.7 and 8.6 per 1,000 person-years, respectively (Table 2). Incidence rates were highest in the oldest age groups and in women. Table 2. Comparison of Herpes Zoster Incidence in the Concomitant Vaccination Cohort and the Prior Vaccination Cohort, Kaiser Permanente Southern California, 2007–2016 Subgroups Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI All 16,532 599 78,023 7.7 7.1, 8.3 18,493 741 86,322 8.6 8.0, 9.2 Age group, years  60–64 4,663 154 20,790 7.4 6.3, 8.7 4,262 137 18,229 7.5 6.4, 8.9  65–69 8,901 318 41,887 7.6 6.8, 8.5 9,761 378 45,318 8.3 7.5, 9.2  70–74 1,608 61 8,542 7.1 5.6, 9.2 2,301 117 11,953 9.8 8.2, 11.7  75–79 838 36 4,364 8.2 6.0, 11.4 1,273 57 6,779 8.4 6.5, 10.9  ≥80 522 30 2,439 12.3 8.6, 17.6 896 52 4,043 12.9 9.8, 16.9 Sex  Female 8,897 385 42,359 9.1 8.2, 10.0 10,404 475 49,115 9.7 8.8, 10.6  Male 7,635 214 35,664 6.0 5.2, 6.9 8,089 266 37,207 7.1 6.3, 8.1 Race/ethnicity  White 10,093 381 48,777 7.8 7.1, 8.6 11,170 485 53,333 9.1 8.3, 9.9  Black 1,363 39 6,678 5.8 4.3, 8.0 1,397 38 6,530 5.8 4.2, 8.0  Hispanic 2,554 99 11,495 8.6 7.1, 10.5 3,132 118 13,720 8.6 7.2, 10.3  Asian/Pacific Islander 1,835 67 8,870 7.6 5.9, 9.6 2,219 84 10,627 7.9 6.4, 9.8  Multiple/other/unknown 687 13 2,203 5.9 3.4, 10.2 575 16 2,114 7.6 4.6, 12.4 Subgroups Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI All 16,532 599 78,023 7.7 7.1, 8.3 18,493 741 86,322 8.6 8.0, 9.2 Age group, years  60–64 4,663 154 20,790 7.4 6.3, 8.7 4,262 137 18,229 7.5 6.4, 8.9  65–69 8,901 318 41,887 7.6 6.8, 8.5 9,761 378 45,318 8.3 7.5, 9.2  70–74 1,608 61 8,542 7.1 5.6, 9.2 2,301 117 11,953 9.8 8.2, 11.7  75–79 838 36 4,364 8.2 6.0, 11.4 1,273 57 6,779 8.4 6.5, 10.9  ≥80 522 30 2,439 12.3 8.6, 17.6 896 52 4,043 12.9 9.8, 16.9 Sex  Female 8,897 385 42,359 9.1 8.2, 10.0 10,404 475 49,115 9.7 8.8, 10.6  Male 7,635 214 35,664 6.0 5.2, 6.9 8,089 266 37,207 7.1 6.3, 8.1 Race/ethnicity  White 10,093 381 48,777 7.8 7.1, 8.6 11,170 485 53,333 9.1 8.3, 9.9  Black 1,363 39 6,678 5.8 4.3, 8.0 1,397 38 6,530 5.8 4.2, 8.0  Hispanic 2,554 99 11,495 8.6 7.1, 10.5 3,132 118 13,720 8.6 7.2, 10.3  Asian/Pacific Islander 1,835 67 8,870 7.6 5.9, 9.6 2,219 84 10,627 7.9 6.4, 9.8  Multiple/other/unknown 687 13 2,203 5.9 3.4, 10.2 575 16 2,114 7.6 4.6, 12.4 Abbreviations: CI: confidence interval; HZ, herpes zoster. Table 2. Comparison of Herpes Zoster Incidence in the Concomitant Vaccination Cohort and the Prior Vaccination Cohort, Kaiser Permanente Southern California, 2007–2016 Subgroups Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI All 16,532 599 78,023 7.7 7.1, 8.3 18,493 741 86,322 8.6 8.0, 9.2 Age group, years  60–64 4,663 154 20,790 7.4 6.3, 8.7 4,262 137 18,229 7.5 6.4, 8.9  65–69 8,901 318 41,887 7.6 6.8, 8.5 9,761 378 45,318 8.3 7.5, 9.2  70–74 1,608 61 8,542 7.1 5.6, 9.2 2,301 117 11,953 9.8 8.2, 11.7  75–79 838 36 4,364 8.2 6.0, 11.4 1,273 57 6,779 8.4 6.5, 10.9  ≥80 522 30 2,439 12.3 8.6, 17.6 896 52 4,043 12.9 9.8, 16.9 Sex  Female 8,897 385 42,359 9.1 8.2, 10.0 10,404 475 49,115 9.7 8.8, 10.6  Male 7,635 214 35,664 6.0 5.2, 6.9 8,089 266 37,207 7.1 6.3, 8.1 Race/ethnicity  White 10,093 381 48,777 7.8 7.1, 8.6 11,170 485 53,333 9.1 8.3, 9.9  Black 1,363 39 6,678 5.8 4.3, 8.0 1,397 38 6,530 5.8 4.2, 8.0  Hispanic 2,554 99 11,495 8.6 7.1, 10.5 3,132 118 13,720 8.6 7.2, 10.3  Asian/Pacific Islander 1,835 67 8,870 7.6 5.9, 9.6 2,219 84 10,627 7.9 6.4, 9.8  Multiple/other/unknown 687 13 2,203 5.9 3.4, 10.2 575 16 2,114 7.6 4.6, 12.4 Subgroups Concomitant Vaccination Cohort (n = 16,532) Prior Vaccination Cohort (n = 18,493) No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI No. of Plan Members No. of HZ Cases No. of Person-Years Incidence per 1,000 Person-Years 95% CI All 16,532 599 78,023 7.7 7.1, 8.3 18,493 741 86,322 8.6 8.0, 9.2 Age group, years  60–64 4,663 154 20,790 7.4 6.3, 8.7 4,262 137 18,229 7.5 6.4, 8.9  65–69 8,901 318 41,887 7.6 6.8, 8.5 9,761 378 45,318 8.3 7.5, 9.2  70–74 1,608 61 8,542 7.1 5.6, 9.2 2,301 117 11,953 9.8 8.2, 11.7  75–79 838 36 4,364 8.2 6.0, 11.4 1,273 57 6,779 8.4 6.5, 10.9  ≥80 522 30 2,439 12.3 8.6, 17.6 896 52 4,043 12.9 9.8, 16.9 Sex  Female 8,897 385 42,359 9.1 8.2, 10.0 10,404 475 49,115 9.7 8.8, 10.6  Male 7,635 214 35,664 6.0 5.2, 6.9 8,089 266 37,207 7.1 6.3, 8.1 Race/ethnicity  White 10,093 381 48,777 7.8 7.1, 8.6 11,170 485 53,333 9.1 8.3, 9.9  Black 1,363 39 6,678 5.8 4.3, 8.0 1,397 38 6,530 5.8 4.2, 8.0  Hispanic 2,554 99 11,495 8.6 7.1, 10.5 3,132 118 13,720 8.6 7.2, 10.3  Asian/Pacific Islander 1,835 67 8,870 7.6 5.9, 9.6 2,219 84 10,627 7.9 6.4, 9.8  Multiple/other/unknown 687 13 2,203 5.9 3.4, 10.2 575 16 2,114 7.6 4.6, 12.4 Abbreviations: CI: confidence interval; HZ, herpes zoster. The cumulative risk of herpes zoster estimated by the Kaplan-Meier method was lower in the concomitant vaccination cohort than the prior vaccination cohort (log-rank test, P = 0.04) (Figure 1). In the fully adjusted analysis, the hazard ratio comparing herpes zoster in the concomitant vaccination cohort and the prior vaccination cohort was 1.04 (95% confidence interval: 0.92, 1.16). There were no significant differences in adjusted hazard ratios for herpes zoster between the cohorts by age, sex, or race/ethnicity (Table 3). Figure 1. View largeDownload slide Kaplan-Meier estimates of the cumulative risk of herpes zoster in the concomitant vaccination cohort and the prior vaccination cohort, Kaiser Permanente Southern California, 2007–2016. Figure 1. View largeDownload slide Kaplan-Meier estimates of the cumulative risk of herpes zoster in the concomitant vaccination cohort and the prior vaccination cohort, Kaiser Permanente Southern California, 2007–2016. Table 3. Hazard Ratio of Herpes Zoster in the Concomitant Vaccination Cohort and the Prior Vaccination Cohort, Kaiser Permanente Southern California, 2007–2016 Subgroups Unadjusted Adjusteda HR 95% CI HR 95% CI All 0.89 0.80, 1.00 1.04 0.92, 1.16 Age group, years  60–64 0.99 0.78, 1.24 1.06 0.83, 1.36  65–69 0.91 0.78, 1.06 1.01 0.87, 1.18  70–74 0.73 0.54, 0.99 0.92 0.66, 1.26  75–79 0.98 0.65, 1.49 1.18 0.76, 1.82  ≥80 0.96 0.61, 1.50 1.29 0.81, 2.08 Sex  Female 0.94 0.82, 1.08 1.07 0.93, 1.23  Male 0.84 0.70, 1.00 0.97 0.80, 1.17 Race/ethnicity  White 0.86 0.75, 0.98 0.98 0.85, 1.12  Black 1.00 0.64, 1.57 1.23 0.77, 1.95  Hispanic 1.00 0.77, 1.31 1.16 0.88, 1.54  Asian/Pacific Islander 0.96 0.69, 1.32 1.13 0.81, 1.59  Multiple/other/unknown 0.78 0.37, 1.62 1.28 0.57, 2.83 Subgroups Unadjusted Adjusteda HR 95% CI HR 95% CI All 0.89 0.80, 1.00 1.04 0.92, 1.16 Age group, years  60–64 0.99 0.78, 1.24 1.06 0.83, 1.36  65–69 0.91 0.78, 1.06 1.01 0.87, 1.18  70–74 0.73 0.54, 0.99 0.92 0.66, 1.26  75–79 0.98 0.65, 1.49 1.18 0.76, 1.82  ≥80 0.96 0.61, 1.50 1.29 0.81, 2.08 Sex  Female 0.94 0.82, 1.08 1.07 0.93, 1.23  Male 0.84 0.70, 1.00 0.97 0.80, 1.17 Race/ethnicity  White 0.86 0.75, 0.98 0.98 0.85, 1.12  Black 1.00 0.64, 1.57 1.23 0.77, 1.95  Hispanic 1.00 0.77, 1.31 1.16 0.88, 1.54  Asian/Pacific Islander 0.96 0.69, 1.32 1.13 0.81, 1.59  Multiple/other/unknown 0.78 0.37, 1.62 1.28 0.57, 2.83 Abbreviations: CI, confidence interval; HR, hazard ratio. a Adjusted for age, sex, race/ethnicity, health-care utilization, vaccination year, and chronic disease in the model. Table 3. Hazard Ratio of Herpes Zoster in the Concomitant Vaccination Cohort and the Prior Vaccination Cohort, Kaiser Permanente Southern California, 2007–2016 Subgroups Unadjusted Adjusteda HR 95% CI HR 95% CI All 0.89 0.80, 1.00 1.04 0.92, 1.16 Age group, years  60–64 0.99 0.78, 1.24 1.06 0.83, 1.36  65–69 0.91 0.78, 1.06 1.01 0.87, 1.18  70–74 0.73 0.54, 0.99 0.92 0.66, 1.26  75–79 0.98 0.65, 1.49 1.18 0.76, 1.82  ≥80 0.96 0.61, 1.50 1.29 0.81, 2.08 Sex  Female 0.94 0.82, 1.08 1.07 0.93, 1.23  Male 0.84 0.70, 1.00 0.97 0.80, 1.17 Race/ethnicity  White 0.86 0.75, 0.98 0.98 0.85, 1.12  Black 1.00 0.64, 1.57 1.23 0.77, 1.95  Hispanic 1.00 0.77, 1.31 1.16 0.88, 1.54  Asian/Pacific Islander 0.96 0.69, 1.32 1.13 0.81, 1.59  Multiple/other/unknown 0.78 0.37, 1.62 1.28 0.57, 2.83 Subgroups Unadjusted Adjusteda HR 95% CI HR 95% CI All 0.89 0.80, 1.00 1.04 0.92, 1.16 Age group, years  60–64 0.99 0.78, 1.24 1.06 0.83, 1.36  65–69 0.91 0.78, 1.06 1.01 0.87, 1.18  70–74 0.73 0.54, 0.99 0.92 0.66, 1.26  75–79 0.98 0.65, 1.49 1.18 0.76, 1.82  ≥80 0.96 0.61, 1.50 1.29 0.81, 2.08 Sex  Female 0.94 0.82, 1.08 1.07 0.93, 1.23  Male 0.84 0.70, 1.00 0.97 0.80, 1.17 Race/ethnicity  White 0.86 0.75, 0.98 0.98 0.85, 1.12  Black 1.00 0.64, 1.57 1.23 0.77, 1.95  Hispanic 1.00 0.77, 1.31 1.16 0.88, 1.54  Asian/Pacific Islander 0.96 0.69, 1.32 1.13 0.81, 1.59  Multiple/other/unknown 0.78 0.37, 1.62 1.28 0.57, 2.83 Abbreviations: CI, confidence interval; HR, hazard ratio. a Adjusted for age, sex, race/ethnicity, health-care utilization, vaccination year, and chronic disease in the model. DISCUSSION This study describes a context where real-world data based on a clinically valid correlate of vaccine protection provides reliable and rigorous evidence for regulatory decisions. As in the previous 3.5-year study at KPSC (18), this 9.5-year study with over 35,000 subjects found no evidence of increased risk of herpes zoster in KPSC members vaccinated concomitantly with ZVL and PPSV23 compared with members vaccinated with PPSV23 from 365 to 30 days prior to receiving ZVL (adjusted hazard ratio = 1.04, 95% confidence interval: 0.92, 1.16). These results suggest no evidence of a diminished VZV immune response following concomitant administration of ZVL with PPSV23. The single randomized clinical trial that served as the basis for the 2009 and 2011 revisions to the ZVL and PPSV23 prescribing information involved a total of 473 enrolled subjects and used an endpoint that was less meaningful clinically (12). The results of the trial were based on observation of lower VZV antibody levels 4 weeks after ZVL vaccination in the group receiving PPSV23 concomitantly compared with the group receiving PPSV23 4 weeks before ZVL. However, VZV antibody levels are not likely to be an appropriate measure of ZVL efficacy, given that increased VZV antibody levels do not appear to protect against herpes zoster; rather, elevated VZV antibody levels are the result of more severe herpes zoster disease (14, 21). Protection against reactivation of VZV causing herpes zoster is largely maintained by VZV-specific T-cell mediated immunity, which declines with age and correlates with incidence and severity of herpes zoster (16, 21). In contrast, our study provides compelling evidence for a lack of vaccine interference, because it relies on the measurement of the occurrence of herpes zoster rather than an intermediate marker of immunity (14). While randomized controlled trials are often considered the gold standard of evaluation, this real-world, observational study design offered distinct advantages. First, the study population consisted of a large number of highly diverse subjects followed over 9.5 years through comprehensive electronic health records. It would be cost prohibitive to conduct such a large study over such a long period as a prospectively recruited clinical trial (4, 22). Second, clinical trials are designed to control variability through strict eligibility criteria. In this observational study using real-world data, we included a broad range of subjects with multiple comorbidities who are more generalizable to the general population, resulting in high external validity. Third, randomization is an important tool for minimizing bias by balancing the underlying risk between treatment groups (2), but balance is not guaranteed. In the sole clinical trial (12) that was the basis for the statement in the ZVL and PPSV23 prescribing information that these vaccines should not be given concurrently, the concomitant group had a substantially higher mean VZV antibody titer at baseline than the nonconcomitant group despite randomization, casting doubt on the validity of the study (14). On the other hand, in observational studies using real-world data, potential bias can be mitigated through careful study design and analysis (1, 5). In our study, both groups received both ZVL and PPSV23, minimizing concerns regarding confounding by indication between treatment groups. Furthermore, important covariates were measured and controlled for in the Cox proportional hazards analysis. Our results, therefore, are likely to be robust, indicating no evidence for increased risk of herpes zoster associated with concomitant administration of ZVL and PPSV23. One potential limitation in our study is that the concomitant vaccination cohort and prior PPSV23 cohort could differ by unrecognized factors related to the outcome of interest (i.e., receipt of care for herpes zoster) due to differences in underlying risk of herpes zoster or health-care seeking behavior. This was addressed in our previous study by comparing the incidence of 13 unrelated medical conditions between the cohorts, as described elsewhere (18, 23). Given that incidence rate ratios for these conditions all clustered around the null, similar to the estimate for herpes zoster, confounding due to underlying risks or health-care seeking behaviors is likely minimal. In addition, it is possible that vaccines delivered outside the system might have been missed, although this factor is expected to be minimal given the incentive to receive care within the system. Furthermore, misclassification of herpes zoster either by clinician diagnosis or professional coders is also possible but would most likely be nondifferential with respect to the vaccination exposure. Concomitant vaccination is recommended to minimize barriers to patients and providers and improve vaccination coverage, provided there are no concerns regarding safety and interference with the immune response (24). ZVL vaccination coverage has been low (30.6% of adults aged 60 years or older) (25, 26). The statements discouraging concomitant administration of ZVL and PPSV23 in the prescribing information may have resulted in missed opportunities for vaccination. Revision of the prescribing information based on this real-world evidence should be carefully considered to avoid missing critical opportunities for improving vaccination coverage and reducing the disease burden in older adults. Real-world evidence will be even more critical in the evaluation of the safety and effectiveness of the newly licensed zoster vaccine, recombinant zoster vaccine (RZV) (Shingrix; GlaxoSmithKline, Research Triangle Park, North Carolina). RZV is indicated for the prevention of herpes zoster in adults aged 50 years or older (27) and was recently preferentially recommended over ZVL by the Advisory Committee on Immunization Practices (28). While clinical trials have shown RZV to be safe and effective (29, 30), limited data are available for long-term outcomes, high-risk populations, and interactions with other vaccines. Lingering concerns remain regarding safety, including the use of an adjuvanted vaccine in the elderly and increased reactogenicity compared with ZVL. Also, RZV requires 2 doses for optimal efficacy, but compliance with a 2-dose schedule in the elderly is unknown. Concomitant administration with other vaccines may be vital for achieving higher coverage. Real-world data from rigorous studies, together with carefully designed and expeditiously executed and published phase IV studies (31), will be essential to appropriately address evidentiary gaps in vaccine safety and effectiveness and to inform regulatory and policy decisions. ACKNOWLEDGMENTS Author affiliations: Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California (Katia Bruxvoort, Lina S. Sy, Yi Luo, Hung Fu Tseng). K.B. and L.S.S. contributed equally to this manuscript. This study was supported by Kaiser Permanente Southern California internal research funds. Conflicts of interest: H.F.T. served as a paid consultant to GlaxoSmithKline for their recombinant zoster vaccine. Abbreviations FDA US Food and Drug Administration ICD-9 International Classification of Diseases, Ninth Revision KPSC Kaiser Permanente Southern California PPSV23 23-valent pneumococcal polysaccharide vaccine RZV recombinant zoster vaccine VZV varicella zoster virus ZVL zoster vaccine live. REFERENCES 1 US Food and Drug Administration . Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff. Rockville, MD : US Food and Drug Administration ; 2017 . https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM513027.pdf. Accessed November 3, 2017. 2 Sherman RE , Anderson SA , Dal Pan GJ , et al. . Real-world evidence—what is it and what can it tell us? N Engl J Med . 2016 ; 375 ( 23 ): 2293 – 2297 . Google Scholar CrossRef Search ADS PubMed 3 Berger M , Daniel G , Frank K , et al. . A Framework for Regulatory Use of Real-World Evidence. Washington, DC : Duke University Margolis Center for Health Policy ; 2017 . https://healthpolicy.duke.edu/sites/default/files/atoms/files/rwe_white_paper_2017.09.06.pdf. Accessed November 3, 2017. 4 Jarow JP , LaVange L , Woodcock J . Multidimensional evidence generation and FDA regulatory decision making: defining and using “real-world” data . JAMA . 2017 ; 318 ( 8 ): 703 – 704 . Google Scholar CrossRef Search ADS PubMed 5 Frieden TR . Evidence for health decision making—beyond randomized, controlled trials . N Engl J Med . 2017 ; 377 ( 5 ): 465 – 475 . Google Scholar CrossRef Search ADS PubMed 6 US Food and Drug Administration . PDUFA Reauthorization Performance Goals And Procedures Fiscal Years 2018 Through 2022. 2016 . https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM511438.pdf. Accessed May 31, 2018. 7 21st Century Cures Act, H.R. 34, 114th Cong, 2nd Sess (2016). https://www.congress.gov/bill/114th-congress/house-bill/34/. 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N Engl J Med . 2016 ; 375 ( 11 ): 1019 – 1032 . Google Scholar CrossRef Search ADS PubMed 30 Lal H , Cunningham AL , Godeaux O , et al. . Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults . N Engl J Med . 2015 ; 372 ( 22 ): 2087 – 2096 . Google Scholar CrossRef Search ADS PubMed 31 Woloshin S , Schwartz LM , White B , et al. . The fate of FDA postapproval studies . N Engl J Med . 2017 ; 377 ( 12 ): 1114 – 1117 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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American Journal of EpidemiologyOxford University Press

Published: Apr 11, 2018

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