A systematic review of real-world evidence (RWE) supportive of new drug and biologic license application approvals in rare diseases.

BACKGROUND: Real-world evidence (RWE) generated using real-world data (RWD) presents the potential to contextualize and/or supplement traditional clinical trials for regulatory approval of rare diseases (RDs). This systematic review evaluated the use of RWD for non-oncologic RD therapies with orphan drug designation (ODD) to support efficacy outcomes in regulatory application packages to the US Food and Drug Administration (FDA). New drug applications (NDAs) and biologic license applications (BLAs) submitted between January 2017 and October 2022 were obtained from publicly available FDA drug approval websites. NDAs and BLAs of non-oncologic RD therapies were screened, and manually reviewed using RWE-related keywords. Quantitative summary of number/proportion of study types was provided, whereas qualitative synthesis focused on key categories of output assessing the use of RWD in overall drug approval process, including agency's feedback on its strengths and key challenges. RESULTS: A total of 868 NDAs and BLAs were identified, of which 243 were screened for non-oncologic RDs with ODD, and 151 were subsequently reviewed for the RWD used to support efficacy outcomes. Twenty (12 NDAs, 8 BLAs) applications met the review inclusion criteria. Most (19; 95%) applications used only retrospective RWD, while one (5%) collected RWD both retrospectively and prospectively. RWD studies included natural history including registry-based/retrospective historical controls (14; 70%), retrospective medical chart-reviews (4; 20%), and external RWD controls from other studies (2; 10%). The FDA generally accepted RWD studies demonstrating a large effect size despite the noted concerns and criticisms. However, the agency expressed concerns about overall quality and comparability of RWD with trial data for some applications, including RWD study designs with respect to differences in patients' baseline characteristics, missing information, and potential bias and measurement errors. CONCLUSIONS: This systematic review highlights potential benefits of appropriately conducted RWE studies in RD, which can strengthen the clinical evidence for efficacy comparison and contextualization to support product approval efforts, particularly when a large magnitude of effect is observed for the new intervention. Nonetheless, quality and completeness of RWD and its comparability with trial data remain areas of concern that can serve as valuable learnings for advancing future science and regulatory approvals.

Factors associated with adherence to medications for lowering breast cancer risk between female Medicare beneficiaries in Alabama and nationwide.

PURPOSE: The U.S. Preventive Services Task Force recommends use of selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) for breast cancer (BC) prevention. We examined factors associated with adherence to SERMs/AI treatments among female Medicare beneficiaries in Alabama and those nationwide. METHODS: This retrospective new user cohort study analyzed the 2013-2016 Medicare administrative claims data files (100% Alabama and random 5% national samples). Female Medicare beneficiaries without invasive BC and osteoporosis, continuously enrolled in Medicare Parts A, B, and D for at least 18 months (with a 6-month washout and a 12-month follow-up period) in 2013-2016. Among beneficiaries who initiated (6-month washout) any of the SERMs/AIs (tamoxifen, raloxifene, anastrozole, and exemestane), we examined their 1-year treatment adherence using proportion of days covered (PDC) and operationalized as both continuous (0-1) and dichotomized (≥ 80% as adherent and < 80% as non-adherent) outcomes. Multivariable logistic models were used to identify factors associated with adherence (PDC ≥ 80%) among Alabama and national samples, respectively. RESULTS: A total of 885 women in Alabama and 1,213 women in national sample initiated these SERMs/AI treatments. Among those with ≥ 2 prescriptions (n = 479 in Alabama and n = 870 in national sample), Mean PDC was 0.74 [standard deviation (SD) = 0.30] among Alabamian women, similar to those in the national sample [0.71 (SD = 0.31), p = 0.09]. Use of mammography prior to treatment initiation was associated with higher likelihood of adherence to treatments in both samples. CONCLUSION: Our findings highlight the importance of access to preventive services such as mammography to better adherence to BC preventive treatments among female Medicare beneficiaries.

Comparative safety of generic versus brand calcineurin inhibitors in solid organ transplant patients: A systematic review and meta-analysis.

BACKGROUND: Although generic ciclosporin-A (CsA) and tacrolimus (TAC) have been used for the prophylaxis of organ rejection in transplant patients for decades, evidence in their safety profile compared to reference listed drugs (RLDs) in real-world transplant patients remains limited. OBJECTIVES: To compare safety outcomes of generic CsA and TAC with the reference-listed drugs in solid organ transplant patients. METHODS: We systematically searched MEDLINE, International Pharmaceutical Abstracts, PsycINFO, and Cumulative Index of Nursing and Allied Health Literature from inception until March 15, 2022, to select randomized and observational studies comparing safety profiles of generic versus brand CsA and TAC in de novo and/or stable solid organ transplant patients. Primary safety outcomes were changes in serum creatinine (Scr) and glomerular filtration rate (GFR). Secondary outcomes included incidences of infection, hypertension, diabetes, other serious adverse events (AEs), hospitalization, and death. Mean difference (MD) and relative risk (RR) with 95% confidence intervals (CIs) were calculated using random-effects meta-analyses. RESULTS: Of 2612 publications identified, 32 studies met inclusion criteria. Seventeen studies had a moderate risk of bias. Scr was statistically significantly lower in patients using generic CsA compared to brand at 1 month (MD = -0.07; 95% CI: -0.11, -0.04), while there were no statistically significant differences at 4 months, 6 months, and 12 months. No differences were detected in Scr (MD = -0.04; 95% CI: -0.13, 0.04) and estimated GFR (MD = -2.06; 95% CI: -8.89, 4.77) between patients using generic and brand TAC at 6 months. No statistically significant differences between generic CsA and TAC with their RLDs were observed for secondary outcomes. CONCLUSION: Findings support similarity in safety outcomes between generic and brand CsA and TAC in real-world solid organ transplant patients.

Methodological approaches for assessing certainty of the evidence in umbrella reviews: A scoping review.

INTRODUCTION: The number of umbrella reviews (URs) that compiled systematic reviews and meta-analysis (SR-MAs) has increased dramatically over recent years. No formal guidance for assessing the certainty of evidence in URs of meta-analyses exists nowadays. URs of non-interventional studies help establish evidence linking exposure to certain health outcomes in a population. This study aims to identify and describe the methodological approaches for assessing the certainty of the evidence in published URs of non-interventions. METHODS: We searched from 3 databases including PubMed, Embase, and The Cochrane Library from May 2010 to September 2021. We included URs that included SR-MAs of studies with non-interventions. Two independent reviewers screened and extracted data. We compared URs characteristics stratified by publication year, journal ranking, journal impact factor using Chi-square test. RESULTS: Ninety-nine URs have been included. Most were SR-MAs of observational studies evaluating association of non-modifiable risk factors with some outcomes. Only half (56.6%) of the included URs assessed the certainty of the evidence. The most frequently used criteria is credibility assessment (80.4%), followed by GRADE approach (14.3%). URs published in journals with higher journal impact factor assessed certainty of evidence than URs published in lower impact group (77.1 versus 37.2% respectively, p < 0.05). However, criteria for credibility assessment used in four of the seven URs that were published in top ranking journals were slightly varied. CONCLUSIONS: Half of URs of MAs of non-interventional studies have assessed the certainty of the evidence, in which criteria for credibility assessment was the commonly used method. Guidance and standards are required to ensure the methodological rigor and consistency of certainty of evidence assessment for URs.

Trends in gender and race/ethnicity of PharmD students and faculty in US pharmacy schools.

INTRODUCTION: This study described and compared trends in the distribution of gender and race/ethnicity for doctor of pharmacy (PharmD) students and faculty in schools and colleges of pharmacy in the United States. METHODS: Institution-level gender (male and female) and racial/ethnic (White, Black/African American, Hispanic/Latino) data for full-time faculty were obtained from the American Association of Colleges of Pharmacy institutional database for 2009-2019. PharmD students' demographic data during the same study period were collected separately for applications, enrollments, and degrees conferred. Generalized linear regression models were applied to examine trends in proportion of PharmD students and faculty distribution in subgroups of different gender and race/ethnicity at P < .05. All analyses were conducted using SAS, version 9.4 (SAS Institute). RESULTS: Significantly increasing trends in female full-time faculty, PharmD applications, and enrollments were observed; however, the trend in female PharmD degrees conferred remained stable from 2009 to 2019. While the trends in proportion of PharmD applications, enrollments, and degrees conferred for Black/African American and Hispanic/Latino students increased significantly, declines and stable trends in the proportion of Black/African American and Hispanic/Latino faculty, respectively, were identified during the same time. CONCLUSIONS: Upward trends in proportions of Black/African American and Hispanic/Latino PharmD applications, enrollments, and degrees conferred were not mirrored by trends in proportions of underrepresented faculty. Implementation of effective faculty diversity and inclusion strategies is warranted to better meet the educational needs of PharmD students.

Real world evidence in effectiveness, safety, and cost savings of generic levothyroxine: a systematic review.

PURPOSE: Generic levothyroxine, approved through Abbreviated New Drug Application (ANDA), is available for generic substitution. But ANDA does not require nonclinical or clinical data to establish safety and efficacy. Post-marketing evidence in generic equivalence for marketed levothyroxine products is limited. We conducted a systematic review to synthesize evidence in effectiveness, safety, and cost savings between patients using generic and branded levothyroxine. METHODS: We systematically searched published literature from Medline, International Pharmaceutical Abstracts, APA PsycInfo, and CINAHL from inception through 04/18/2021. Included studies were limited to post-marketing empirical studies including patients who used levothyroxine products, with direct comparison between generic and brand levothyroxine, and published in English. Risk of bias was assessed using the National Institute of Health Study Quality Assessment Tools. Two reviewers independently extracted data and conducted quality assessment for included studies. Given that the nine studies are so diverse, a meta-analysis was not possible. Therefore we provided a narrative review of the included studies. RESULTS: Of 349 studies identified, nine met the inclusion criteria. Six studies compared thyrotropin levels and adverse events between generic and brand users and provided mixed findings. In addition, generic users may generate prescription cost savings for payers but had suboptimal medication adherence than brand users. CONCLUSION: Findings from this systematic review highlighted the limited and mixed evidence in real-world clinical and economic outcomes for generic levothyroxine. Continuous post-marketing monitoring and assessment of generic drugs are warranted to ensure treatment effectiveness, patient safety, and achieve financial savings in prescription costs.

Comparative effectiveness and safety of eribulin in advanced or metastatic breast cancer: a systematic review and meta-analysis.

Eribulin is one of the few recommended chemotherapies for locally advanced breast cancer (LABC) or metastatic breast cancer (MBC). We systematically searched MEDLINE Ovid, Cochrane Library, IPA, CINAHL, Web of Science and ProQuest Dissertations for studies evaluating eribulin versus non-eribulin regimens in LABC/MBC till January 15, 2021. Primary effectiveness and safety outcomes were overall survival (OS) and adverse events (AE), respectively. Hazard ratios (HR) and relative risks (RR) with 95 % confidence intervals (CIs) were calculated using fixed or random-effects meta-analyses. Of 1183 publications identified, 13 studies were included in this review. Eribulin based therapy showed significantly increased OS [HR (95 % CI) = 0.77 (0.67-0.88)] compared to non-eribulin in both main and sensitivity analyses, as well as subgroup analyses according to receptor expression and line of therapy. Incidence of all-grade neutropenia was the only significant AE in eribulin than non-eribulin groups. Eribulin has a manageable toxicity profile and provides significant survival benefit in LABC/MBC patients.

Safety of Marketed Cancer Supportive Care Biosimilars in the US: A Disproportionality Analysis Using the Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

BACKGROUND: Since the approval and availability of the first biosimilar in 2015 in the United States (US), evidence regarding the post-marketing safety of cancer supportive care biosimilars remains limited. OBJECTIVE: The aim was to explore the adverse event (AE) reporting patterns and detect disproportionate reporting signals for cancer supportive care biosimilars in the US compared to their originator biologics. METHODS: The US Food and Drug Administration Adverse Event Reporting System database (January 1, 2004-March 31, 2020) was used to identify AE reports for filgrastim, pegfilgrastim, and epoetin alpha by type of product (originator biologics vs. biosimilars) and report characteristics. Plots of AE reports against years were used to reveal the reporting patterns. Disproportionality analyses using reporting odds ratios (RORs) were conducted to detect differences in serious and specific AEs between studied drugs and all other drugs. Breslow-Day tests were used to determine homogeneity between the originator biologic-biosimilar pair RORs for the same AE. RESULTS: Total numbers of AEs for all studied biosimilars increased after marketing. More AE reports were from female patients for all of the studied drugs. More AEs for originator biologics and filgrastim biosimilar were reported by health professionals, while the highest proportion of reports came from consumers for pegfilgrastim and epoetin alpha biosimilars (29% and 44.1%, respectively). Signals of disproportionate reporting in serious AEs were detected for a pegfilgrastim biosimilar (Fulphila®) compared to its originator biologic. CONCLUSION: Our findings support the similarity in the signals of disproportionate reporting between cancer supportive care originator biologics and biosimilars, except for Fulphila®.