Person: Wang, Bo
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Publication Availability and utilization of cardiovascular fixed-dose combination drugs in the United States(Elsevier BV, 2015) Wang, Bo; Choudhry, Niteesh; Gagne, Joshua; Landon, Joan; Kesselheim, AaronBACKGROUND: Solid clinical evidence supports the effectiveness and safety of multiple drugs in treating diabetes, dyslipidemia, and hypertension, and numerous fixed-dose combination products (FDCs) containing such drugs have been developed for patients with more severe forms of these diseases. We sought to evaluate the extent to which utilization of treatment combinations for these conditions corresponded to the availability of FDCs. METHODS: Using claims data from a large national commercial insurer, we identified 2 cohorts of patients: those who filled multiple single-agent drugs to treat diabetes, dyslipidemia, and hypertension in 2012, and those who used FDCs containing these products during the same period. We determined the fill rate of single-agent pairs and FDCs, availability of FDCs for the most frequently filled single-agent and drug class pairs, and the number of conditions treated by frequently filled single-agent pairs and FDCs. RESULTS: During our study period, 848,082 patients filled prescriptions for 3,248 unique single-agent pairs (mean 4.7 per patient, standard deviation [SD] 5.0); and 568,923 patients received prescriptions for 43 unique FDCs (mean 1.1 per patient, SD 0.3). Three (15%) of the 20 most frequently filled single-agent pairs were available as FDCs, whereas 9 (45%) of the 20 most frequently filled drug class pairs were available as FDCs. Nearly all of the frequently filled FDCs had lower fill rates than the most frequently filled single-agent pairs. CONCLUSIONS: Utilization of drug combinations to treat cardiovascular conditions does not correspond well with availability of FDCs containing these agents. A concerted set of strategies should be implemented to streamline the development of useful combination products, including expedited approval pathways and increased investment in formulation studies.Publication Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome–associated PTPN11 mutation(American Society for Clinical Investigation, 2011) Marin, Talita M.; Keith, Kimberly; Davies, Benjamin; Conner, David; Guha, Prajna; Kalaitzidis, Demetrios; Wu, Xue; Lauriol, J; Wang, Bo; Bauer, Michael; Bronson, Roderick; Franchini, Kleber G.; Neel, Benjamin G.; Kontaridis, MariaLEOPARD syndrome (LS) is an autosomal dominant “RASopathy” that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11Y279C/+ (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.Publication Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study(BMJ Publishing Group Ltd., 2015) Kesselheim, Aaron; Wang, Bo; Franklin, Jessica; Darrow, Jonathan JObjective: To evaluate the use of special expedited development and review pathways at the US Food and Drug Administration over the past two decades. Design: Cohort study. Setting: FDA approved novel therapeutics between 1987 and 2014. Population Publicly available sources provided each drug’s year of approval, their innovativeness (first in class versus not first in class), World Health Organization Anatomic Therapeutic Classification, and which (if any) of the FDA’s four primary expedited development and review programs or designations were associated with each drug: orphan drug, fast track, accelerated approval, and priority review. Main outcome measures Logistic regression models evaluated trends in the proportion of drugs associated with each of the four expedited development and review programs. To evaluate the number of programs associated with each approved drug over time, Poisson models were employed, with the number of programs as the dependent variable and a linear term for year of approval. The difference in trends was compared between drugs that were first in class and those that were not. Results: The FDA approved 774 drugs during the study period, with one third representing first in class agents. Priority review (43%) was the most prevalent of the four programs, with accelerated approval (9%) the least common. There was a significant increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved agent (incidence rate ratio 1.026, 95% confidence interval 1.017 to 1.035, P<0.001), and a 2.4% increase in the proportion of drugs associated with at least one such program (odds ratio 1.024, 95% confidence interval 1.006 to 1.043, P=0.009). Driving this trend was an increase in the proportion of approved, non-first in class drugs associated with at least one program for drugs (P=0.03 for interaction). Conclusions: In the past two decades, drugs newly approved by the FDA have been associated with an increasing number of expedited development or review programs. Though expedited programs should be strictly limited to drugs providing noticeable clinical advances, this trend is being driven by drugs that are not first in class and thus potentially less innovative.Publication Clinical Evidence Supporting Pharmacogenomic Biomarker Testing Provided in US Food and Drug Administration Drug Labels(2016-05-17) Wang, BoBackground: Genetic biomarkers that predict a drug’s efficacy or likelihood of toxicity are assuming increasingly important roles in the personalization of pharmacotherapy, but there is concern that there may be insufficient evidence linking use of some biomarkers to clinical benefit. Nevertheless, information about the use of biomarkers appears in the drug label for many prescription medications. This may add confusion to the clinical decision-making process. Objective: To evaluate the evidence supporting pharmacogenomic biomarker testing in drug labels, how frequently testing is recommended, and completeness of citation of the supporting studies. Methods: We used publicly-available databases from the US Food and Drug Administration (FDA) to identify drug labels that described the use of a biomarker and evaluated whether the label contained or referenced convincing evidence of its clinical validity (i.e., the ability to predict phenotype) and clinical utility (i.e., the ability to improve clinical outcomes) using guidelines published by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) group. We graded the completeness of the citation of supporting studies and determined whether the label recommended incorporation of biomarker test results in therapeutic decision-making. Results: Of the 119 drug-biomarker combinations, only 36% (n=43) had labels that provided convincing clinical validity evidence while 15% (n=18) provided convincing evidence for clinical utility. Fifty-one percent of the labels (51%, n=61) made recommendations based on the results of a biomarker test; 30% of these contained convincing clinical utility data. A full description of supporting studies was included in 11% (n=13) of the labels. Discussion: Fewer than one-sixth of drug labels contained or referenced convincing evidence for clinical utility of biomarker testing while over half made recommendations based on biomarker test results. It may be premature to include biomarker testing recommendations in drug labels when convincing data linking testing to patient outcomes does not exist.Publication A structure-based mechanism for tRNA and retroviral RNA remodelling during primer annealing(Nature Publishing Group, 2014) Miller, Sarah; Yildiz, Fatma; Lo, Jennifer; Wang, Bo; D'Souza, VictoriaTo prime reverse transcription, retroviruses require annealing of a transfer RNA molecule to the U5 primer binding site (U5-PBS) region of the viral genome [1,2]. The residues essential for primer annealing are initially locked in intramolecular interactions [3,4,5]; hence, annealing requires the chaperone activity of the retroviral nucleocapsid (NC) protein to facilitate structural rearrangements [6]. Here we show that, unlike classical chaperones, the Moloney murine leukaemia virus NC uses a unique mechanism for remodelling: it specifically targets multiple structured regions in both the U5-PBS and \(tRNA^{Pro}\) primer that otherwise sequester residues necessary for annealing. This high-specificity and high-affinity binding by NC consequently liberates these sequestered residues—which are exactly complementary—for intermolecular interactions. Furthermore, NC utilizes a step-wise, entropy-driven mechanism to trigger both residue-specific destabilization and residue-specific release. Our structures of NC bound to U5-PBS and tRNA^{Pro} reveal the structure-based mechanism for retroviral primer annealing and provide insights as to how ATP-independent chaperones can target specific RNAs amidst the cellular milieu of non-target RNAs.Publication Did FDA Decisionmaking Affect Anti-Psychotic Drug Prescribing in Children?: A Time-Trend Analysis(Public Library of Science (PLoS), 2016) Wang, Bo; Franklin, Jessica; Eddings, Wesley; Landon, Joan; Kesselheim, AaronBackground: Following Food and Drug Administration (FDA) approval, many drugs are prescribed for non-FDA-approved (“off-label”) uses. If substantial evidence supports the efficacy and safety of off-label indications, manufacturers can pursue formal FDA approval through supplemental new drug applications (sNDAs). We evaluated the effect of FDA determinations on pediatric sNDAs for antipsychotic drugs on prescribing of these products in children. Methods: Retrospective, segmented time-series analysis using new prescription claims during 2003-2012 for three atypical antipsychotics (olanzapine, quetiapine, ziprasidone). FDA approved the sNDAs for pediatric use of olanzapine and quetiapine in December 2009, but did not approve the sNDA for pediatric use of ziprasidone. Results: During the months before FDA approval of its pediatric sNDA, new prescriptions of olanzapine decreased for both children and adults. After FDA approval, the increase in prescribing trends was similar for both age groups (P=0.47 for schizophrenia and bipolar disorder; P=0.37 for other indications). Comparable decreases in use of quetiapine were observed between pediatrics and adults following FDA approval of its pediatric sNDA (P=0.88; P=0.63). Prescribing of ziprasidone decreased similarly for pediatric and adult patients after FDA nonapproval of its pediatric sNDA (P=0.61; P=0.79). Conclusions: The FDA’s sNDA determinations relating to use of antipsychotics in children did not result in changes in use that favored the approved sNDAs and disfavored the unapproved 3 sNDA. Improved communication may help translate the agency’s expert judgments to clinical practice.Publication Conflict of Interest Reporting by Authors Involved in Promotion of Off-Label Drug Use: An Analysis of Journal Disclosures(Public Library of Science, 2012) Kesselheim, Aaron; Wang, Bo; Studdert, David Michael; Avorn, JeromeBackground: Litigation documents reveal that pharmaceutical companies have paid physicians to promote off-label uses of their products through a number of different avenues. It is unknown whether physicians and scientists who have such conflicts of interest adequately disclose such relationships in the scientific publications they author. Methods and Findings: We collected whistleblower complaints alleging illegal off-label marketing from the US Department of Justice and other publicly available sources (date range: 1996–2010). We identified physicians and scientists described in the complaints as having financial relationships with defendant manufacturers, then searched Medline for articles they authored in the subsequent three years. We assessed disclosures made in articles related to the off-label use in question, determined the frequency of adequate disclosure statements, and analyzed characteristics of the authors (specialty, author position) and articles (type, connection to off-label use, journal impact factor, citation count/year). We identified 39 conflicted individuals in whistleblower complaints. They published 404 articles related to the drugs at issue in the whistleblower complaints, only 62 (15%) of which contained an adequate disclosure statement. Most articles had no disclosure (43%) or did not mention the pharmaceutical company (40%). Adequate disclosure rates varied significantly by article type, with commentaries less likely to have adequate disclosure compared to articles reporting original studies or trials (adjusted odds ratio [OR] = 0.10, 95%CI = 0.02–0.67, p = 0.02). Over half of the authors (22/39, 56%) made no adequate disclosures in their articles. However, four of six authors with ≥25 articles disclosed in about one-third of articles (range: 10/36–8/25 [28%–32%]). Conclusions: One in seven authors identified in whistleblower complaints as involved in off-label marketing activities adequately disclosed their conflict of interest in subsequent journal publications. This is a much lower rate of adequate disclosure than has been identified in previous studies. The non-disclosure patterns suggest shortcomings with authors and the rigor of journal practices.