Preapproval Studies Research Articles

56 ANALYSIS OF A 23,270-PATIENT STUDY: UNSUPERVISED MACHINE LEARNING WITH CLUSTER ANALYSIS IN PATIENTS DISCHARGED AFTER AN ACUTE CORONARY SYNDROME

Abstract Background Characterization and management of patients with acute coronary syndromes (ACS) remain challenging, and it is unclear whether currently available clinical and procedural features can suffice to inform adequate decision making. Methods Details on patients discharged after an ACS were obtained by querying an extensive multicenter registry, detailing patient features as well as management details. Clinical outcomes included fatal and non-fatal cardiovascular events at 1-year follow-up. After missing data imputation, two unsupervised machine learning approaches (k-means and Clustering Large Applications [CLARA]) were used to generate separate clusters with different features. Bivariate and multivariable-adjusted analyses were performed to compare different clusters for clinical outcomes. Findings: 23,270 patients discharged after ACS were included. Two clusters were identified by k-mean algorithm (k1 and k2), and two clusters by CLARA algorithm (C1 and C2). Differences in 2-years outcomes between k1 and k2 and between C1 and C2 were substantial. K2 cluster (N=21,988) in comparison with k1 cluster (N=1,282) had significantly higher occurrence of death (9.5% vs 3.8%, p<0.001), reinfarction (7.2% vs 3.7%, p<0.001), and major bleeding (6.0% vs 3.0%, p<0.001). Similarly, C1 cluster (N=11,268) showed a worse prognosis than C2 cluster (N=12,002): death (4.8% vs 3.5%, p<0.001), reinfarction (4.5% vs 3.4%, p<0.001), and major bleeding (3.6% vs 2.8%, p=0.001). Most associations did not hold at multivariable analysis based on supervised learning techniques, with the exception of major bleeding (odds ratio=1.37 [95% confidence interval 1.02-1.83] for the k1/C1 subcluster vs k1/C2 subcluster, p=0.039. Conclusions A machine-learning based clustering approach is effective at face value to inform on the prognosis of patients with ACS managed invasively. These findings can be leveraged to inform decision-making in this setting, but also highlight the potential role of cluster analysis in first-in-man, and preapproval studies of medical devices.

Co‐Culture of Human Primary Hepatocytes and Nonparenchymal Liver Cells in the Emulate® Liver‐Chip for the Study of Drug‐Induced Liver Injury

Drug-induced liver injury (DILI) is a significant public health issue, but standard animal tests and clinical trials sometimes fail to predict DILI due to species differences and the relatively low number of human subjects involved in preapproval studies of a new drug, respectively. In vitro models have long been used to aid DILI prediction, with primary human hepatocytes (PHHs) being generally considered the gold standard. However, despite many efforts and decades of work, traditional culture methods have been unsuccessful in either fully preserving essential liver functions after isolation of PHHs or in emulating interactions between PHHs and hepatic nonparenchymal cells (NPCs), both of which are essential for the development of DILI under in vivo conditions. Recently, various liver-on-a-chip (Liver-Chip) systems have been developed to co-culture hepatocytes and NPCs in a three-dimensional environment on microfluidic channels, enabling better maintenance of primary liver cells and thus improved DILI prediction. The Emulate® Liver-Chip is a commercially available system that can recapitulate some in vivo DILI responses associated with certain compounds whose liver safety profile cannot be accurately evaluated using conventional approaches involving PHHs or animal models due to a lack of innate immune responses or species-dependent toxicity, respectively. Here, we describe detailed procedures for the use of Emulate® Liver-Chips for co-culturing PHHs and NPCs for the purpose of DILI evaluation. First, we describe the procedures for preparing the Liver-Chip. We then outline the steps needed for sequential seeding of PHHs and NPCs in the prepared Liver-Chips. Lastly, we provide a protocol for utilizing cells maintained in perfusion culture in the Liver-Chips to evaluate DILI, using acetaminophen as an example. In all, use of this system and the procedures described here allow better preservation of the functions of human primary liver cells, resulting in an improved in vitro model for DILI assessment. © 2022 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA. Basic Protocol 1: Liver-Chip preparation Basic Protocol 2: Seeding primary human hepatocytes and nonparenchymal cells on Liver-Chips Basic Protocol 3: Perfusion culture for the study of acetaminophen-induced liver injury.

Testing the Fit of Regression Models Estimated with Extremely Small Samples: Application in Pharmaceutical Stability Studies

Pharmaceutical stability studies are conducted to estimate the shelf life, i.e. the period during which the drug product maintains its identity and stability. In the evaluation of process, regression curve is fitted on the data obtained during the study and the shelf life is determined using the fitted curve. The evaluation process suggested by ICH considers only the case of the true relationship between the measured attribute and time being linear. However, no method is suggested for the practitioner to decide if the linear model is appropriate for their dataset. This is a major problem, as a falsely selected model may distort the estimated shelf life to a great extent, resulting in unreliable quality control. The difficulty of model misspecification detection in stability studies is that very few observations are available. The conventional methods applied for model verification might not be appropriate or efficient due to the small sample size. In this paper, this problem is addressed and some developed methods are proposed to detect model misspecification. The methods can be applied for any process where the regression estimation is performed on independent small samples. Besides stability studies, frequently performed construction of single calibration curves for an analytical measurement is another case where the methods may be applied. It is shown that our methods are statistically appropriate and some of them have high efficiency in the detection of model misspecification when applied in simulated situations which resemble pre-approval and post-approval stability studies.

Teriparatide in individuals with a prior history of radiation therapy-a case series.

Teriparatide is a highly effective anabolic therapy for use in patients with osteoporosis at elevated fracture risk but carries a warning about an increased risk of osteosarcoma based on findings from pre-approval animal studies. Since approval, follow-up of individuals treated with teriparatide has not shown an increased risk of osteosarcoma, but it is still recommended to avoid teriparatide in patients with risk factors for osteosarcoma. One such risk factor is radiotherapy; deciding whether to use teriparatide therapy in patients at high risk of fracture but with a history of radiotherapy is therefore a frequent clinical problem. We sought to identify whether clinicians are using teriparatide in patients with a history of radiotherapy despite the warning and to explore the rationale for this choice. Herein, we describe six cases where the likelihood of fracture, osteosarcoma, and the benefits of teriparatide treatment are assessed to determine the appropriateness of prescribing teriparatide in the setting of prior or concurrent radiotherapy. All six patients had severe osteoporosis with limited treatment options. For those who completed 2 years of teriparatide, no further fractures during the follow-up period have occurred, and improvements in bone density (as measured by dual-energy X-ray absorptiometry) were observed. Despite radiotherapy being a relative contraindication to teriparatide use, there may be a role for teriparatide in select cases where osteoporosis is complex and severe and where other treatment options are not suitable or have been exhausted. The risks vs. benefits of prescribing teriparatide in this population should always be carefully considered, and both the patient and treating oncologist should be educated on the potential risk of osteosarcoma development when teriparatide is continued during radiotherapy.

Characteristics of Preapproval and Postapproval Studies of Vaccines Granted Accelerated Approval by the US Food and Drug Administration.

Characteristics of Preapproval and Postapproval Studies of Vaccines Granted Accelerated Approval by the US Food and Drug Administration.

Preclinical Pharmacokinetic/Pharmacodynamic Studies and Clinical Trials in the Drug Development Process of EMA-Approved Antibacterial Agents: A Review.

Development of new antibacterial agents is necessary as drug-resistant bacteria are a threat to global health. In Europe, the European Medicines Agency has been guiding this development process for more than two decades. We investigated preclinical and clinical pre-approval studies to illuminate the current authorization process with emphasis on pharmacokinetic/pharmacodynamic approaches and clinical phases. All centrally authorized systemic antibacterial and antimycobacterial drugs within the European Union were included without any time restriction. Additionally, US Food and Drug Administration-approved antibiotics of the previous 3 years, which were not yet approved by the European Medicines Agency, were included. We focused on preclinical pharmacokinetic/pharmacodynamic studies and phase II and phase III clinical trials. Furthermore, we looked at the recommended dosing regimens and approved indications. In this review, we designed tree diagrams as a new means of illustrating the development process of antibiotics to relate pharmacokinetic/pharmacodynamic phase II and III studies to approved indications. We included 23 (European Medicines Agency, 18; US Food and Drug Administration, 5) antimicrobial agents. Tetracyclines, carbapenems, and cephalosporins were the leading classes. The recommended dosing intervals were significantly shorter in time- vs exposure-dependent drugs (median 8 vs 12, p = 0.006). The majority of approved indications (i.e., acute bacterial skin and soft-tissue infection, community-acquired pneumonia, complicated intra-abdominal infection, complicated urinary tract infection, and complicated skin and soft-tissue infection) used non-inferiority trials. Phase II and III clinical trials investigating community-acquired pneumonia involved the fewest patients. Some promising drugs were marketed in recent years; the individual steps to their authorizations are illuminated. We confirmed the relevance of preclinical pharmacokinetic/pharmacodynamic studies in dosing optimization and decision making in antimicrobial drug development. Non-inferiority clinical trials predominated.

Aztreonam Lysine Inhalation Solution in Cystic Fibrosis.

Patients with cystic fibrosis (CF) develop pulmonary disease secondary to airway infection and dysregulated inflammation. Therapeutic innovations such as nebulized antimicrobial therapy targeting specific pathogens have resulted in improvements in quality of life and life expectancy. Aztreonam lysine for inhalation (AZLI) solution was initially approved to improve respiratory symptoms in CF patients with Pseudomonas aeruginosa (PA) in 2010 by the Food and Drug Administration. Since then, research broadening labeling and clinical application has been developed. In this review, we analyze published and ongoing research regarding AZLI therapy in CF. A search of the Cochrane Database of Systematic Reviews and the PubMed and ClinicalTrials.gov databases was conducted to identify publications about AZLI. Three pre-approval studies were identified and assessed. Two are Phase 3, placebo-controlled trials, assessing a variety of safety and efficacy endpoints, leading to FDA approval. The third is an open-label extension of the two previous trials. An additional seven post-approval, completed trials were identified and are included in this review. They represent a variety of study designs including safety and efficacy in patients with mild lung disease and young patients, an active comparator trial vs inhaled tobramycin, an eradication study, a study among patients with Burkholderia cepacia, and a study assessing continuous alternating antibiotic therapy. Finally, five ongoing clinical trials are discussed. Overall, studies demonstrated that inhaled aztreonam is a safe and effective antimicrobial treatment for the eradication of newly acquired P. aeruginosa and long-term suppressive therapy of chronic endobronchial infection among people with cystic fibrosis.

Tu1914 PRACTICE PATTERNS IN BARIATRIC ENDOSCOPY: A SURVEY OF THE MEMBERS OF THE ASSOCIATION FOR BARIATRIC ENDOSCOPY

A wide range of endoscopic bariatric technologies (EBT) have been introduced in the United States in the past two years with many others in various phases of development. Endoscopic bariatric procedures have demonstrated safety and efficacy in achieving weight loss in conjunction with diet and lifestyle interventions in a clinical trial setting. Limited data exists on the adoption of EBT in clinical practice. To report current practice patterns and perceived barriers to wider adoption of EBT among members of the Association for Bariatric Endoscopy (ABE). All members of the ABE were invited to complete an anonymous electronic survey of domains relevant to knowledge, practice patterns and barriers to wider adoption of EBT. Participants were queried on the following: a) personal and practice demographics b) familiarity with current availability of EBT, c) practice patterns in EBT, d) barriers to wider adoption of EBT. Content validity was established by survey review by 4 experts in EBT. The survey response rate was 5.8% (28/480). The majority of responders had been in practice for >10 years (57.1%), were gastroenterologists (92.8%) and were in private practice (78.5%). Eighty two percent of responders performed >50 endoscopic procedures per month and a majority (60.7%) performed ERCP; 32.1% had been involved in pre-approval studies of EBT. Sixty percent of responders offered medical weight management in their practice and 39.3% prescribed weight loss medications. A majority of responders received education and training in EBT from the ABE (75%) as well as industry (71.4%) and rated there familiarity with EBT as 8.6±18.3 on a 10 cm VAS scale. Table 1 describes EBT practices among responders. The EBT most frequently offered was Orbera® intragastric balloon (IGB) (57.1%), while Aspire Assist® was the least utilized EBT (10.7%). Endoscopic sleeve gastroplasty and transoral outlet reduction were offered by 35.7%. In the 12 months prior to the survey, 35.7% of responders had performed NO endoscopic bariatric procedures, while 25% had performed >20. The most frequently cited barrier to wider adoption of EBT was lack of insurance reimbursement/cost (85.7%), followed by lack of physician awareness (50%). Members of the ABE are familiar with the available EBT, and most obtain education and training in EBT from professional societies and industry. Intragastric balloons are currently the most widely utilized EBT. Despite enthusiasm from physicians and professional societies, EBT volumes among responders are low, with 36% having performed NO endoscopic bariatric procedures in the past 12 months. Lack of insurance reimbursement/cost is felt to be the most significant barrier to wider adoption of EBT.Tabled 1Table 1: Baseline demographics and EBT practice patternsYears in practice<59 (32.1%)5-103 (10.7%)>1016 (57.2%)How do you obtain education about EBTASGE/ABE21 (75%)Industry20 (71.4%)Other professional society7 (25%)Perform ERCP17 (60.7%)Offer medical weight management17 (60.7%)Prescribe weight loss medications11 (39.3%)EBT Offered in PracticeOrbera IGB16 (57.1%)ReShape Duo IGB5 (20.8%)Obalon IGB4 (16.7%)Aspire Assist3 (12.5%)Endoscopic sleeve gastroplasty10 (41.7%)Volume Endoscopic Bariatric Procedures in the past 12 monthsNone10 (35.7%)10-2011 (39.3%)>207 (25%)Barriers to wider adoption of EBT in your practicePatient awareness11 (39.3%)Physician awareness14 (50%)Poor weight loss efficacy7 (25%)Concern for complications8 (28.6%)Lack of insurance coverage/cost24 (85.7%)Lack of infrastructure for weight loss program12 (42.9%) Open table in a new tab

Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration

Drugs treating serious or life-threatening conditions can receive US Food and Drug Administration (FDA) accelerated approval based on showing an effect in surrogate measures that are only reasonably likely to predict clinical benefit. Confirmatory trials are then required to determine whether these effects translate to clinical improvements. To characterize preapproval and confirmatory clinical trials of drugs granted accelerated approval. Publicly available FDA documents were reviewed to identify the preapproval trials leading to accelerated approval between 2009 and 2013. Information on the status and findings of required confirmatory studies was extracted from the FDA's database of postmarketing requirements and commitments, ClinicalTrials.gov, and matched peer-reviewed publications. Follow-up ended on April 7, 2017. Granting of accelerated approval. Characteristics of preapproval and confirmatory studies were compared in terms of study design features (randomization, blinding, comparator, primary end point). Subsequent regulatory decisions and estimated time between accelerated approval and fulfillment of regulatory requirements were summarized. The FDA granted accelerated approval to 22 drugs for 24 indications (19 for indications involving cancer treatment) between 2009 and 2013. A total of 30 preapproval studies supported the 24 indications. The median number of participants enrolled in the preapproval studies was 132 (interquartile range, 89-224). Eight studies (27%) included fewer than 100 participants and 20 (67%) included fewer than 200. At a minimum 3 years of follow-up, 19 of 38 (50%) required confirmatory studies were completed, including 18 published reports. Twenty-five of the 38 (66%) examined clinical efficacy, 7 (18%) evaluated longer follow-up, and 6 (16%) focused on safety The proportion of studies with randomized designs did not differ before and after accelerated approval (12/30 [40%] vs 10/18 [56%]; difference, 16%; 95% CI, -15% to 46%; P = .31). Postapproval requirements were completed and demonstrated efficacy in 10 of 24 indications (42%) on the basis of trials that evaluated surrogate measures. Among the 14 of 24 indications (58%) that had not yet completed all requirements, at least 1 of the confirmatory studies failed to demonstrate clinical benefit in 2 (8%), were terminated in 2 (8%), and were delayed by more than 1 year in 3 (13%). Studies were progressing according to target timelines for the remaining 7 indications (29%). Clinical benefit had not yet been confirmed for 8 indications that had been initially approved 5 or more years prior. Among 22 drugs with 24 indications granted accelerated approval by the FDA in 2009-2013, efficacy was often confirmed in postapproval trials a minimum of 3 years after approval, although confirmatory trials and preapproval trials had similar design elements, including reliance on surrogate measures as outcomes.

Real-world utilization of once-daily extended-release abuse deterrent formulation of hydrocodone: a comparison with the pre-approval randomized clinical trials.

Background and objectiveHydrocodone bitartrate extended release (Hysingla® ER, HYD) was previously studied in a 12-week randomized, double-blind, placebo-controlled trial and a 52-week open-label safety study. Both of these preapproval studies allowed dose titration to efficacy. The purpose of the present analysis was to compare dosing and utilization patterns in these previous clinical trials with real-world data (RWD) usage in a retrospective claim analysis performed 12–14 months post approval in the US.MethodsIn the claim analysis (Truven Health Analytics MarketScan® Research Database), patients prescribed HYD between January 1, 2015, and April 30, 2016, were followed for up to 6 months of continuous HYD use. Daily average consumption (DACON), initial dose, rescue opioid use and total milligram dose over time were also evaluated.ResultsHYD daily dose stabilized at ~60 mg dose once daily across all three studies. There was also a reduced need for rescue medication with HYD, resulting in a lower total opioid milligram dose over time. In the claim analysis, the mean monthly HYD dose increased from 49 to 55 mg in month 2 and then remained stable through month 6. The mean (standard deviation [SD]) time on drug was 79.5 days (61.42 days), and DACON was 1.04 pills/day, corresponding to the approved full prescribing information (FPI) and once-daily dosing.ConclusionIn 12–14 months post approval, real-world dosing and utilization of HYD mirrored registration and open-label study findings, with stable once-daily dosing of ~60 mg and no increase in rescue medicine utilization.

Biosimilar Oncology Drugs in Europe: Regulatory and Pharmacovigilance Considerations.

The introduction in clinical practice of pharmaceutical products known as biosimilars, as part of a more complex series of progress in the field of biological drugs, represents an excellent therapeutic resource. A biosimilar drug is a biological/biotechnological drug that is highly similar to an approved reference biologic product. Given their complexity, biosimilars require attention and a continued vigilance to ensure appropriate use, especially in cancer therapy. There is the urgent need, both at Italian and European levels, of clear and more comprehensive guidelines to elucidate the open questions. Probably, the acquisition of new data, obtained from larger samples of patients than those used in the pre-approval studies and with extremely variable clinical conditions, will allow clarifying the extent to which biosimilar drugs are similar in safety and efficacy to their biologic reference drug. The aims of this article are to provide health professionals with basic, but essential information about biosimilars, and to identify current critical points and future perspectives for clinical practice, cancer care, regulatory aspects, and pharmacovigilance.

Vortioxetine: a New Treatment for Major Depressive Disorder

ABSTRACTIntroduction: Vortioxetine is a structurally novel medication that has recently been approved for treatment of major depressive disorder (MDD). This medication is a serotonin reuptake inhibitor that also has a number of other potentially relevant effects on serotoninergic receptors, which may differentiate the drug’s effects from those of current first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).Areas Covered: This article will review the basic clinical pharmacology of vortioxetine, summarize the major clinical trials that were performed prior to approval by the US Food and Drug Administration (FDA), discuss relevant post-marketing studies of this drug, and offer expert commentary on the significance of this new agent in clinical practice. Pre-approval studies were identified as all randomized, placebo-controlled studies of vortioxetine listed on clinicaltrials.gov. Other referenced studies were identified via a MEDLINE database literature search in August 2015 using the key search terms, vortioxetine and Lu AA21004, combined with additional terms that included pharmacological profile, pharmacokinetics, drug interactions, adverse effects, side effects, safety, major depression, and major depressive disorder. We identified relevant systematic reviews, meta-analyses, randomized trials and preclinical studies of importance.Expert Opinion: Results of placebo-controlled trials suggest efficacy and an overall safety profile comparable to existing first-line antidepressants. The most common side effects are nausea, vomiting and constipation. Results of several studies indicate that vortioxetine may have therapeutic effects on cognition (e.g., memory and executive functioning) that exceed that of standard antidepressants. Disadvantages include cost and the current paucity of long-term efficacy data from large clinical trials. The authors suggest that vortioxetine is currently a good second-line antidepressant option and shows promise, pending additional long-term data, to become a first-line antidepressant option.

The First-in-Class Potassium-Competitive Acid Blocker, Vonoprazan Fumarate: Pharmacokinetic and Pharmacodynamic Considerations.

Vonoprazan fumarate (Takecab) is a first-in-class potassium-competitive acid blocker that has been available in the market in Japan since February 2015. Vonoprazan is administered orally at 20 mg once daily for the treatment of gastroduodenal ulcer, at 20 and 10 mg once daily for the treatment and secondary prevention of reflux esophagitis, respectively, at 10 mg once daily for the secondary prevention of low-dose aspirin- or non-steroidal anti-inflammatory drug-induced peptic ulcer, and at 20 mg twice daily in combination with clarithromycin and amoxicillin for the eradication of Helicobacter pylori. It inhibits H(+),K(+)-ATPase activities in a reversible and potassium-competitive manner with a potency of inhibition approximately 350 times higher than the proton pump inhibitor, lansoprazole. Vonoprazan is absorbed rapidly and reaches maximum plasma concentration at 1.5-2.0 h after oral administration. Food has minimal effect on its intestinal absorption. Oral bioavailability in humans remains unknown. The plasma protein binding of vonoprazan is 80% in healthy subjects. It distributes extensively into tissues with a mean apparent volume of distribution of 1050 L. Being a base with pKa of 9.6 and with acid-resistant properties, vonoprazan is highly concentrated in the acidic canaliculi of the gastric parietal cells and elicited an acid suppression effect for longer than 24 h after the administration of 20 mg. The mean apparent terminal half-life of the drug is approximately 7.7 h in healthy adults. Vonoprazan is metabolized to inactive metabolites mainly by cytochrome P450 (CYP)3A4 and to some extent by CYP2B6, CYP2C19, CYP2D6, and SULT2A1. A mass balance study showed that 59 and 8% of the orally administered radioactivity was recovered in urine as metabolites and in an unchanged form, respectively, indicating extensive metabolism. Genetic polymorphism of CYP2C19 may influence drug exposure but only to a clinically insignificant extent (15-29%), according to the population pharmacokinetic study performed in Japanese patients. When vonoprazan was co-administered with clarithromycin, the mean AUC from time 0 to time of the next dose (dosing interval) of vonoprazan and clarithromycin were increased by 1.8 and 1.5 times, respectively, compared with the corresponding control values, indicating mutual metabolic inhibition. The mean area under the curve from time zero to infinity obtained from patients with severe liver and renal dysfunction were elevated by 2.6 and 2.4 times, respectively, compared with healthy subjects, with no significant changes in plasma protein binding. Vonoprazan increases intragastric pH above 4.0 as early as 4 h after an oral dose of 20 mg, and the extensive anti-secretory effect is maintained up to 24 h post-dose. During repeated dosing of 20 mg once daily, the 24-h intragastric pH >4 holding time ratios were 63 and 83 % on days 1 and 7, respectively. Because vonoprazan elicited a more extensive gastric acid suppression than the proton pump inhibitor, lansoprazole, it also gave rise to two to three times greater serum gastrin concentrations as compared with lansoprazole. In pre-approval clinical studies for the treatment of acid-related disorders, mild to moderate adverse drug reactions (mostly constipation or diarrhea) occurred at frequencies of 8-17%. Neither severe liver toxicity nor neuroendocrine tumor has been reported in patients receiving vonoprazan.

Ig-001 in the Treatment of Lung Cancer: Results of a Post-Marketing Surveillance Study

ABSTRACT Aim: Abraxane® is a Cremophor-free (CF), albumin-encapsulated nanoparticle formulation of paclitaxel approved globally for metastatic breast cancer (MBC), non-small cell lung cancer (NSCLC), and pancreatic cancer. IG-001 (Genexol®-PM) is a CF, non-biologic, micellar formulation of paclitaxel composed of a biodegradable di-block copolymer of methoxy poly (ethylene glycol)-poly (lactide). IG-001 is approved in Korea for MBC, ovarian cancer, and NSCLC. IG-001 is being developed as bioequivalent to Abraxane. The availability of two similar clinical stage, CF nanoparticle formulations of paclitaxel allows us to compare and confirm clinical activities of CF paclitaxel formulations in NSCLC. Methods: Bioequivalence of IG-001 was demonstrated by comparing preclinical tumor efficacy data, in vitro dissolution data, and animal pharmacokinetic data. Clinical comparison to Abraxane was examined by comparing the preapproval and PMS studies of IG-001 + cisplatin in NSCLC. This PMS was a single-arm study of IG-001, 230 mg/m2 plus cisplatin 60 mg/m2 once every 3 weeks in patients (pts) with lung cancer. Results: 316 pts were treated for up to 9 cycles. Of the 316, 64% had NSCLC, 77.2% were male. Mean age = 59.44 ± 9.43 years. 76%, 23%, and 1% had stages IV, III, and I/II disease, respectively. Best overall response: 0.66% of pts had complete response (CR), 43.85% had partial response (PR), 26.91% had stable disease, 21.93% had progressive disease, and 6.64% were not assessable for a total 44% efficacy (CR + PR). AEs were reported in 83.23% of pts. Serious AEs were reported in 11.1% of pts, with the most frequent being dyspnea (2.5%), pneumonia (1.9%), leukopenia (1.9%), febrile neutropenia (1.6%), neutropenia (1.6%), and lung neoplasm malignant (1.3%). None of the factors assessed were deemed to selectively affect outcomes. Conclusions: IG-001 in combination with cisplatin for the treatment of lung cancer is effective with an acceptable safety profile. The response rate for IG-001 (44%) compares favorably to historical data for Abraxane (33%) and Taxol® (25%). The IG-001 safety profile is similar to historical safety data for Abraxane. The data suggest that IG-001 may be an alternative to Abraxane for NSCLC. Disclosure: R.H. Murdock: Both authors are clinical research professionals and employees of Sorrento Therapeutics, a pharmaceutical company developing IG-001 for marketing approval; V. Trieu: The authors are clinical research professionals and employees of Sorrento Therapeutics, a pharmaceutical company developing IG-001 for marketing approval.

Evaluating the Safety of COPD Medications: An Evidence-Based Review

The goals of management of COPD include reducing exposure to risk factors; improving lung function, exercise tolerance, and quality of life; and decreasing exacerbations and mortality. Pharmacologic treatments, such as inhaled β₂-agonists, anticholinergics, and inhaled corticosteroids, are widely used to help achieve these goals. In addition to efficacy, medication safety is an important consideration in selecting COPD treatments. Clinical trials conducted in support of the regulatory review and approval process establish the general efficacy and tolerability of pharmacologic treatments for COPD, and these data are reflected in product labeling. Following approval, further research continues to provide more data with longer follow-up and in broader settings than feasible in clinical trials. These data add to our knowledge of the efficacy of medications. Understanding medication safety requires assessment of the quality and appropriateness of study design, as well as knowledge of study findings, and is of paramount importance in making sound clinical judgments in the treatment of patients with COPD. In recent years, a wealth of data on COPD medications has been published from different sources, including randomized clinical trials, meta-analyses, systematic reviews, and observational studies. This review discusses important considerations in interpreting data from different types of studies, summarizes the tolerability profile of COPD medications established in preapproval studies, and discusses new findings from more recent postapproval data.

A postlicensure evaluation of the safety of Ann Arbor strain live attenuated influenza vaccine in children 24–59 months of age

BackgroundIn the United States, live attenuated influenza vaccine (LAIV) was initially approved for use in individuals aged 5–49 years in 2003, which was extended to individuals aged 2–49 years in 2007. At that time, a postlicensure commitment was made to describe the safety of LAIV within a cohort of eligible children aged 2–5 years. MethodsA prospective observational postmarketing study was conducted to evaluate the safety of LAIV. Rates of medically attended events (MAEs) and serious adverse events (SAEs) in eligible children aged 24–59 months receiving LAIV as part of routine care from October 2007 to March 2010 were compared with rates in a within-cohort self-control, as well as matched unvaccinated and matched trivalent inactivated influenza vaccine (TIV)-vaccinated controls. Children with asthma and other high-risk medical conditions before vaccination were excluded. All MAEs and SAEs through 42 days postvaccination and all hospitalizations and deaths through 6 months postvaccination were analyzed. Statistical significance was declared without multiplicity adjustment. ResultsA total of 28,226 unique LAIV recipients were matched with similar numbers of TIV-vaccinated and unvaccinated children. Of 4696 MAE incidence rate comparisons, 83 (1.8%) were statistically significantly higher and 221 (4.7%) were statistically significantly lower in LAIV recipients versus controls. No pattern of MAE rate differences suggested a safety signal with LAIV. Asthma/wheezing MAEs were not statistically increased in LAIV recipients. No anaphylaxis events occurred within 3 days postvaccination. Rates of SAEs were similar between LAIV and control groups. ConclusionsResults of this postlicensure evaluation of LAIV safety in US children are consistent with preapproval clinical studies and Vaccine Adverse Event Reporting System reports, both of which demonstrated no significant increase in asthma/wheezing events or other adverse outcomes among eligible children aged 24–59 months who received LAIV.

A postmarketing evaluation of the safety of Ann Arbor strain live attenuated influenza vaccine in children 5 through 17 years of age

BackgroundLive attenuated influenza vaccine (LAIV) was licensed in 2003 in the United States for use in individuals aged 5–49 years. MethodsA prospective observational postmarketing study was conducted to evaluate the safety of LAIV. Rates of medically attended events (MAEs) and serious adverse events (SAEs) in eligible children aged 5–17 years receiving LAIV as part of routine care from October 2003 to March 2008 were compared with rates in nonrandomized self, matched unvaccinated, and matched trivalent inactivated influenza vaccine (TIV)-vaccinated controls. All MAEs and SAEs through 42 days postvaccination and all hospitalizations and deaths through 6 months postvaccination were analyzed. Statistical significance was assigned without multiplicity adjustment. Results43,702 LAIV recipients were matched with similar numbers of TIV-vaccinated and unvaccinated children. Of approximately 9500 MAE incidence rate comparisons, 204 were statistically significantly higher and 168 were statistically significantly lower in LAIV recipients versus controls. No pattern of MAE rate differences suggested a safety signal with LAIV. Asthma/wheezing MAEs were not statistically increased in LAIV recipients. No anaphylaxis events occurred within 3 days postvaccination. Rates of SAEs were similar between LAIV and control groups. Two SAEs were considered possibly related to LAIV: Bell's palsy and nonspecific paroxysmal spell. ConclusionsResults of this postlicensure evaluation of LAIV safety in US children aged 5–17 years are consistent with preapproval clinical studies and Vaccine Adverse Event Reporting System reports, both of which demonstrated no significant increase in asthma/wheezing events or other adverse outcomes among eligible children who received LAIV.

New LTC Approvals And a P.R.N. Caution

New LTC Approvals And a P.R.N. Caution

Allopurinol Still Called First Therapy for Gout

Allopurinol Still Called First Therapy for Gout

131I-Labeled Lipiodol-Induced Interstitial Pneumonia: A Series of 15 Cases

Background The drug 131I-labeled lipiodol is used as internal radiotherapy for unresectable hepatocellular carcinoma. Although the drug was considered safe during preapproval studies, we observed several cases of interstitial pneumonia following its administration. Methods Cases were retrospectively identified through the drug safety unit database of Rennes University Hospital. Results From 1994 to 2009, interstitial pneumonia developed in 15 patients following 131I-labeled lipiodol administration, with an estimated prevalence of 15.5 cases (95% CI, 7.7-23.2) per 1,000 treated patients. Mean age of the patients was 60 ± 8 years, and the male to female ratio was 6.5:1. All patients had cirrhosis, mainly related to long-term alcohol intoxication (n = 12). Most (n = 10) cases occurred after the second 131I-labeled lipiodol injection. The median delay between last 131I-labeled lipiodol administration and first respiratory symptoms was 30 days (interquartile range, 16.5-45 days). All patients presented with shortness of breath. Physical examination mostly revealed fever (n = 11) and bilateral crackles (n = 12). Chest CT scan showed bilateral ground-glass opacities (n = 8) with septal thickening, retraction, or both (n = 8). BAL (n = 7) was remarkable for increased neutrophils (n = 4) or CD8+ T cell count (n = 3). Despite corticosteroids, 12 (80%) patients died, mostly of untractable respiratory failure (n = 9). Median delay between last 131I-labeled lipiodol injection and death was 63 days (interquartile range, 34-129 days). Conclusions Interstitial pneumonia may be a serious and not uncommon complication of 131I-labeled lipiodol administration. The drug 131I-labeled lipiodol is used as internal radiotherapy for unresectable hepatocellular carcinoma. Although the drug was considered safe during preapproval studies, we observed several cases of interstitial pneumonia following its administration. Cases were retrospectively identified through the drug safety unit database of Rennes University Hospital. From 1994 to 2009, interstitial pneumonia developed in 15 patients following 131I-labeled lipiodol administration, with an estimated prevalence of 15.5 cases (95% CI, 7.7-23.2) per 1,000 treated patients. Mean age of the patients was 60 ± 8 years, and the male to female ratio was 6.5:1. All patients had cirrhosis, mainly related to long-term alcohol intoxication (n = 12). Most (n = 10) cases occurred after the second 131I-labeled lipiodol injection. The median delay between last 131I-labeled lipiodol administration and first respiratory symptoms was 30 days (interquartile range, 16.5-45 days). All patients presented with shortness of breath. Physical examination mostly revealed fever (n = 11) and bilateral crackles (n = 12). Chest CT scan showed bilateral ground-glass opacities (n = 8) with septal thickening, retraction, or both (n = 8). BAL (n = 7) was remarkable for increased neutrophils (n = 4) or CD8+ T cell count (n = 3). Despite corticosteroids, 12 (80%) patients died, mostly of untractable respiratory failure (n = 9). Median delay between last 131I-labeled lipiodol injection and death was 63 days (interquartile range, 34-129 days). Interstitial pneumonia may be a serious and not uncommon complication of 131I-labeled lipiodol administration.