Vishvas Garg

Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project.

BACKGROUND In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts. METHODS We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012). RESULTS The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [CI], 3.44 to 5.92) for bisphosphonate use and nonhealing femoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures. CONCLUSIONS Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing.

Anaphylaxis associated with gadolinium-based contrast agents: data from the Food and Drug Administration's Adverse Event Reporting System and review of case reports in the literature.

Objectives: To summarize reports of anaphylaxis associated with gadolinium-based contrast agents (GBCAs) reported to the Food and Drug Administrations Adverse Event Reporting System (FAERS), examine the safety signals of anaphylaxis from GBCAs, and perform a literature review of relevant case reports. Methods: FAERS (1/1988-8/2012) was searched using groups of preferred event terms for anaphylaxis combined with all drug names for GBCAs Signal detection involved determination of proportional reporting ratios (PRRs) and empirical Bayes geometric means (EBGM). Published case reports were identified through a Medline search (1/1988-7/2013). Results: There were 614 GBCA FAERS reports of anaphylaxis, resulting in a safety signal (PRR = 6.2, 95% confidence interval (CI) = 5.7 – 6.7; EBGM = 5.1 CI = 5.6 – 6.6). Among GBCAs, 43% were associated with gadopentetate dimeglumine (PRR = 4.9, CI = 4.3 – 5.5; EBGM = 4.8, CI = 4.3 – 5.4), 29% with gadobenate dimeglumine (PRR = 17.5, CI = 15.2 – 20.2; EBGM = 17.1, CI = 14.6 – 19.8) , and 17% with gadoteridol (PRR = 5.7, CI = 4.7 – 6.8; EBGM = 5.6, CI = 4.6 – 56.7). There were 14 anaphylaxis case reports in the literature. Conclusions: GBCAs used as medical imaging agents, can cause life-threatening or fatal anaphylaxis. There were differences in disproportionality of reporting between between agents. Although differences in numbers of reports of anaphylaxis reflect relative utilization rates of the various agents, disproportionality analyses (PRR, EBGM) disclose significant safety signals of anaphylaxis associated with most GBCAs.

Life-threatening dermatologic adverse events in oncology.

The incidences of life-threatening toxicities such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are inconsistently reported. The potential association of anticancer agents with SJS or TEN has not been systematically investigated. We searched the literature (Ovid: 1950 to June 2013 and PubMed: 1948 to June 2013) using terms for SJS/TEN and anticancer therapies. Primary case reports, case series, and clinical trials were included. In addition, MedWatch, the Food and Drug Administration Adverse Event Reporting System (FAERS), was searched (1968 to August 2012) for SJS/TEN reports associated with anticancer therapies. Proportional reporting ratios (PRR>2, N>3), empirical Bayes geometric mean (EBGM>2, N>3), and lower 95% confidence interval (EBGM0.05>2) were used as thresholds to constitute a signal of association between SJS/TEN and anticancer drugs. There were 46 SJS and 37 TEN cases associated with 18 and 22 anticancer drugs in the literature, respectively. Among cases in the FAERS, significant signals were associated with SJS for bendamustine and with TEN for bendamustine, busulfan, chlorambucil, fludarabine, lomustine, and procarbazine. Several drugs reported in the published literature to be associated with SJS/TEN were not found to have significant signals in FAERS. Proactive pharmacovigilance to detect and define safety signals serves to aid oncology practitioners in the recognition of possible, yet uncommon, serious, and/or life-threatening skin reactions.

Health disparities in clinical practice patterns for prostate cancer screening by geographic regions in the United States: a multilevel modeling analysis.

Background:To our knowledge, no previous study has examined state-level geographic variability and its predictors in clinical practice patterns to screen for prostate cancer in the United States.Methods:We used the Behavioral Risk Factor Surveillance System 2010 data set to analyze geographic variability (by state) and its associated predictors in receiving a PSA test and/or a digital rectal examination (DRE). The study population consisted of men aged ⩾50 years who responded as yes/no when asked about having a PSA test or DRE performed during the last year. We build two multilevel logistic regression models, differing in dependent variables, that is, (1) any prostate cancer screening (PCS) (either PSA and/or DRE), and (2) PCS based on PSA testing (PSAT). Individual characteristics (age, education, employment, marriage, income, race/ethnicity, self-reported health status, obesity, alcohol consumption, smoking status, personal physician presence, and health insurance coverage) were treated as level-1 variables and state characteristics (number of doctors per 100 000 persons per state, US regions and metropolitan statistical area (MSA) codes) were treated as level-2 variables.Results:We found significant geographic variability in receiving PCS and PSAT screening in the United States. For PCS, MSA code was an independent predictor, with men living in urban areas having lower odds of screening (odds ratio (OR)=0.8, 95% confidence interval (CI)=0.7–0.9). In PSAT, the number of doctors per 100 000 persons per state was an independent predictor, with lowest quartile states (0–25% quartile) having lower odds of PSA-based screening (OR=0.78, 95% CI=063–0.94). In both models, all level-1 variables were independent predictors (P<0.05) of PCS, except self-reported health status.Conclusions:Men living in urban areas and states with lower prevalence of doctors have lower odds of screening for prostate cancer and PSAT, respectively, after adjusting for individual variables. Future studies should examine the reasons for these health disparities.

A literature review of cost-effectiveness analyses of prostate-specific antigen test in prostate cancer screening.

Prostate cancer is the most common non-skin cancer in American men, and prostate-specific antigen (PSA) testing is its common screening procedure. In May 2012, the US Preventive Services Task Force recommended against PSA-based screening. These recommendations contradict the current recommendations of other organizations such as the American Urological Association. The authors conducted a systematic review of PubMed, EMBASE and Cochrane to examine the published literature reporting the cost–effectiveness of PSA-based screening. The authors found ten studies each for US and non-US jurisdiction population. All reviewed studies concluded PSA-based screening to be cost effective in younger men (≤60 years of age) and at higher PSA levels (≥3 ng/ml). Further cost–effectiveness analyses reflecting latest clinical practice and current perspectives regarding adverse outcomes of potentially unnecessary treatment are required, especially from the US government perspective.

Noninsulin pharmacological management of type 1 diabetes mellitus.

The injectable nature and other shortcomings of insulin have stimulated interest in studying the noninsulin pharmacological therapies to manage type 1 diabetes mellitus (T1DM). The purpose of this study is to conduct a systematic literature review of noninsulin pharmacological therapies for the management of T1DM. For this, the following PubMed search was conducted: Diabetes Mellitus, Type 1/therapy”[Mesh] Limits: Review Sort by: Publication Date. After applying various inclusion and exclusion criteria, a total of 63 studies were reviewed. Based on this review, noninsulin pharmacological therapies can be divided into following classes: (1) Insulin-sensitizing agents (biguanides and thiazolidinediones), (2) gastrointestinal nutrient absorption modulators (α-Glucosidase inhibitors and amylin), (3) immunotherapeutic agents, (4) incretin-based therapies, (5) recombinant human insulin-like growth factors, and (6) other promising therapeutics. Some of these are already used either as monotherapy or adjuvant to insulin, whereas, to manage T1DM, the benefits and risks of the others are still under evaluation. Nonetheless, insulin still remains the cornerstone to manage the T1DM.

Impact of united states food and drug administration's boxed warnings on adverse drug reactions reporting rates and risk mitigation for multiple myeloma drugs

Purpose: To determine the relationship between boxed warnings issuance by the US Food and Drug Administration (FDA) and the proportional reporting rates of the associated adverse drug reactions (ADRs) to the FDAs Adverse Event Reporting System (FAERS) for multiple myeloma (MM) drugs. Methods: We compiled a list of all FDA approved MM drugs and identified their associated ADR boxed warnings, through FDAs website and physician desk reference. Drugs that were issued boxed warnings after their market launch were included in the analysis, i.e., melphalan, thalidomide, vincristine, carmustine and doxorubicin. For each drug/ADR boxed warning combination, we retrieved all reported cases from the FAERS and calculated their Empiric Bayes Geometric Means (EBGMs), in pre- and post-boxed warning periods. Chi-square tests were performed to compare serious adverse drug events before and after boxed warnings for all drug/ADR combinations. Results: A total of 10 drug/ADR boxed warning combinations were identified, of which EBGM signals increased for six combinations after a boxed warning was issued. Reports of serious adverse drug events also increased significantly (p < 0.05). Conclusion: Boxed warnings were associated with increased FAERS reporting, indicating increased awareness of ADRs for MM drugs. Proactive pharmacovigilance programs, such as the FDAs Mini-Sentinel Project, may improve timeliness of detection of rare ADRs.

Use of Number Needed to Treat in Cost-Effectiveness Analyses

OBJECTIVE To review the use of number needed to treat (NNT) and/or number needed to harm (NNH) values to determine their relevance in helping clinicians evaluate cost-effectiveness analyses (CEAs). DATA SOURCES PubMed and EconLit were searched from 1966 to September 2012. STUDY SELECTION AND DATA EXTRACTION Reviews, editorials, non–English-language articles, and articles that did not report NNT/NNH or cost-effectiveness ratios were excluded. CEA studies reporting cost per life-year gained, per quality-adjusted life-year (QALY), or other cost per effectiveness measure were included. Full texts of all included articles were reviewed for study information, including type of journal, impact factor of the journal, focus of study, data source, publication year, how NNT/NNH values were reported, and outcome measures. DATA SYNTHESIS A total of 188 studies were initially identified, with 69 meeting our inclusion criteria. Most were published in clinician-practice–focused journals (78.3%) while 5.8% were in policy-focused journals, and 15.9% in health-economics–focused journals. The majority (72.4%) of the articles were published in high-impact journals (impact factor >3.0). Many articles focused on either disease treatment (40.5%) or disease prevention (40.5%). Forty-eight percent reported NNT as a part of the CEA ratio per event. Most (53.6%) articles used data from literature reviews, while 24.6% used data from randomized clinical trials, and 20.3% used data from observational studies. In addition, 10% of the studies implemented modeling to perform CEA. CONCLUSIONS CEA studies sometimes include NNT ratios. Although it has several limitations, clinicians often use NNT for decision-making, so including NNT information alongside CEA findings may help clinicians better understand and apply CEA results. Further research is needed to assess how NNT/NNH might meaningfully be incorporated into CEA publications.

Health economic evaluation of dipeptidyl peptidase-4 inhibitors

Sir, The predicted loss of national income from diabetes in India is 336.6 billion International Dollars.[1] Furthermore, studies have demonstrated that the prevalence of diabetes in India is rising with the progression of time.[2] Therefore, this financial burden is bound to increase. About 90-95% of all the diabetes patients are of the type-2 diabetes mellitus (T2DM). A range of classes of oral therapeutic agents exists for the treatment of T2DM. Among these classes, the newest US FDA-approved drug therapeutic class is of the DPP-4 inhibitors. DPP-4 inhibitors offer substantial glycemic control in T2DM patients. However, DPP-4 inhibitors come at increased costs. Thus a systematic review of the health economic evaluation of DPP-4 inhibitors is required. Separately, the PubMed was searched using the following search strategies: (1) (“saxagliptin” [Supplementary Concept]) AND “Economics”[Mesh] 2) (“sitagliptin” [Supplementary Concept]) AND “Economics”[Mesh] 3) (“vildagliptin” [Supplementary Concept]) AND “Economics”[Mesh] 4) (“BI 1356” [Supplementary Concept]) AND “Economics”[Mesh]. The references cited in all the above retrieved publications were also reviewed for relevance and were obtained and included in the search results when applicable. Currently, saxagliptin is approved at once a daily dosage of 2.5 mg and 5 mg in individuals with normal renal functioning and at 2.5 mg in individuals with moderate-to-severe renal insufficiency or end-stage renal disease (ESRD).[3,4] Furthermore, several clinical trials have shown the effectiveness, safety, and tolerability of saxagliptin in terms of HbA1C, FPG, and PPG reductions.[3,4] A total of three studies were obtained when the PubMed was searched for saxagliptin and economics, combined. These searches were examined as follows. The abstracts of these three studies were reviewed for the inclusion criterion of the cost-effectiveness analysis of saxagliptin. This lead to non-inclusion of all three studies, as none of them met the above described inclusion criterion. This indicates that, including India, no health economic evaluation of saxagliptin has been conducted till date in any part of the world. Currently, the recommended daily dosage of sitagliptin is 100 mg once daily which may be taken without regard to food.[4] The efficacy, safety, and tolerability of sitagliptin is well established in several well designed clinical trial studies.[4] A total of 11 studies were obtained when the PubMed was searched for sitagliptin and economics, combined. The articles obtained were examined for the inclusion criterion of the health economic evaluation of sitagliptin. Based on this criterion, only one study evaluating the cost and consequences associated with sitagliptin was found.[5] As per this study, in comparison to glyburide and exenatide, sitagliptin was found cost-effective. Nonetheless, this study was conducted in the United States settings, and, therefore, the results of cost-effectiveness analysis, if conducted in any other country, may differ. No other study evaluating the pharmacoeconomics of sitagliptin was found in the conducted literature search. Vildagliptin is currently not approved by the US FDA, but is in India, European countries, and Japan for the treatment of T2DM patients. Currently, vildagliptin is given 50 mg twice a day in combination with metformin or a thazolidinedione and 50 mg once a day in combination with sulfonylurea.[6] The efficacy, safety, and tolerability of vildagliptin have been established in various clinical trials of durations of 12 to 104 weeks.[6] Only one study was found when PubMed was searched for vildagliptin and economics, combined. The full-text article for this study was retrieved and was reviewed for the health economic evaluation of vildagliptin.[4] On reviewing the full-text article, no health economic evaluation of vildagliptin was found. This indicates that, including India, no health economic evaluation of vildagliptin has been conducted in any part of the world till date. Currently, the recommended dose of linagliptin (BI 1356) is 5 mg once a day, with or without food. No active-comparator clinical trial study of linagliptin monotherapy has been conducted till now. However, in two double-blinded, placebo-controlled clinical trials, the efficacy, safety, and tolerability of linagliptin was established.[7] No studies were found when PubMed was searched for linagliptin (BI 1356) and economics, combined. This indicates that no health economic evaluation of linagliptin has been conducted till date in any part of the world. Sitagliptin, saxagliptin, vildaglitpin, and linagliptin have been approved worldwide including in places such as India, USA, and Europe. However, this literature review demonstrates that, except for sitagliptin, no formal economic evaluation of DPP-4 inhibitors has been conducted till date in any part of the world. For sitagliptin also, only one cost-effectiveness analysis conducted in the US settings was found. Therefore, formal and systematic health economic evaluations for assessing the cost-effectiveness of DPP-4 inhibitors in the treatment of T2DM are required in India as well as in other parts of the world.