Assessment of Adverse Events in Protocols, Clinical Study Reports, and Published Papers of Trials of Orlistat: A Document Analysis.

BACKGROUND: Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials. METHODS AND FINDINGS: We received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report. None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were "bothersome," a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that "all adverse events were recorded." For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student's t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper. Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs. CONCLUSIONS: In the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.

Weight loss at a high cost: Orlistat-induced late-onset severe kidney disease.

AIM: This report describes a case of kidney failure secondary to orlistat, a lipase inhibitor commonly used in the treatment of obesity. CASE REPORT: An 80-year-old man with type 2 diabetes who was being treated with orlistat developed rapidly progressive kidney failure. Low-grade albuminuria argued against diabetic nephropathy. Renal biopsy showed tubulointerstitial nephritis associated with numerous calcium oxalate crystals. Enteric hyperoxaluria was attributed to the orlistat treatment. The latter was stopped and the patient received calcium supplements. Six months after orlistat withdrawal, oxaluria was normalized and kidney function stabilized. CONCLUSION: Oxalate nephropathy may result from hyperoxaluria secondary to orlistat treatment. This suggests that kidney function and oxaluria be closely monitored in patients taking orlistat.

Safety assessment of FDA-approved (orlistat and lorcaserin) anti-obesity medications.

INTRODUCTION: Options for treating obesity remain limited despite it being a chronic, recurrent and morbid condition. New drugs that are proposed for its treatment encounter strong reluctance by regulatory agencies and many doctors. AREAS COVERED: This review will focus on the safety of an older drug, orlistat (the only one still approved in the European Union) and a newer recently FDA-approved one, lorcaserin. Both are approved as long-term monotherapy for obesity in the United States of America and they have demonstrated median weight loss of nearly 3% over placebo. EXPERT OPINION: Research, development and approval of new anti-obesity drugs are necessary for improved management of this chronic condition. Orlistat and lorcaserin are two FDA-approved drugs with limited overall efficacy. Nevertheless they are useful weapons for at least some obese individuals. Orlistat has a long and solid safety profile, whereas the safety of lorcaserin is still a matter of debate, mainly due to a lack of long-term data. However, lorcaserin's selective agonism on 5HT2c serotonin receptors diminishes concerns about valvulopathy associated with other serotonin agonists, such as fenfluramine.

Benefit-risk assessment of orlistat in the treatment of obesity.

Orlistat, an inhibitor of intestinal lipase, has been available for the treatment of obesity for nearly two decades. In conjunction with a hypocaloric diet, orlistat treatment results in a placebo-subtracted reduction in body weight of around 3 kg at 1 year, and increases the likelihood of achieving clinically significant (≥5%) weight loss by around 20%. Orlistat-induced weight loss also confers modest improvements in systolic and diastolic blood pressure, low-density lipoprotein (LDL) cholesterol, glycemic parameters, and progression to diabetes in people with impaired glucose tolerance. Overall, it has a good safety profile, and serious adverse events (including reports of severe kidney and liver injury) are rare. However, a high rate of gastrointestinal side effects limits adherence to treatment.

The deception and fallacies of sponsored randomized prospective double-blinded clinical trials: the bisphosphonate research example.

The randomized prospective double-blinded clinical trial (RCT) is accepted as Level I evidence and is highly regarded. However, RCTs that gained FDA approval of drugs such as Vioxx, Fen-Phen, and oral and intravenous bisphosphonates have proven to generate misleading results and have not adequately identified serious adverse reactions. The development, research, and clinical marketing of the oral and intravenous bisphosphonates can serve as a representative example for the deteriorated value of many of today's RCTs. The expected high value of RCTs is jeopardized by: (1) sponsorship that incorporates bias; (2) randomization that can select out an expected improved result or eliminate higher-risk individuals; (3) experimental design that can avoid recognition of serious adverse reactions; (4) blinding that can easily become unblinded by the color, shape, odor, or administration requirements of a drug; (5) definitions that can define an observation as something other than what it actually represents, or fail to define it as an adverse reaction; (6) labeling of retrospective data as a prospective trial by using adjudicators prospectively to look at retrospective data; (7) change of the length of study to avoid the longer-term adverse reaction from accumulation of drug or treatment effects; (8) ghost writing, as when drug company physicians or a hired corporation either edit or write the entire protocol and/or manuscript for publication. Such corruption of the well-intended properly conducted RCT should be viewed with a sense of outrage by practitioners and requires a restructuring of the levels of evidence accepted today.

[Drug-related claims in the Norwegian system of compensation to patients]. / Legemiddelsaker i Norsk pasientskadeerstatning.

BACKGROUND: Patients subjected to drug-related injuries can, in accordance with Norwegian legislation, seek compensation from the Norwegian System of Patient Injury Compensation (NPE). The aim of this study was to examine what drugs and injuries instigate claims against NPE, and how these cases are resolved. MATERIAL AND METHODS: We have assessed anonymised summaries of 992 consecutive indemnity applications received and evaluated by NPE over the period 2003-2009. We recorded the age and gender of applicants, treatment diagnosis, drugs implicated, outcome, and NPE's decision in each case. RESULTS: A total of 964 claims were included. The most commonly implicated drugs were those affecting the nervous system (34.6%) and the musculoskeletal system (26.1%). Rofecoxib at 18.9% was the predominant single drug implicated. In two-thirds of the cases, adverse effects were given as the reason for the claim, whereas the last one-third consisted of claims for medication errors. The most common injuries were related to cardiovascular diseases (28.7%) or non-specific conditions (17.5%). 8.4% of the cases related to fatalities. In all, 26.3% of the claims resulted in compensations. INTERPRETATION: Few patients made use of the NPE. Most of the compensation claims in the years 2003-2009 involved rofecoxib and psychoactive drugs, and the majority of claims were rejected.

Concordance with guideline recommendations: previous and more recent nonsteroidal anti-inflammatory drug prescriptions in Quebec, Canada.

BACKGROUND: Clinical practice guidelines for appropriate nonsteroidal anti-inflammatory drug (NSAID) utilisation focus on preventing NSAID-related gastrointestinal (GI), cardiovascular (CV), congestive heart failure (CHF) and renal adverse events. We compared concordance of NSAID prescriptions with clinical practice guideline recommendations in Quebec, pre and post rofecoxib withdrawal from market. METHODS: Data were obtained from the Quebec Health Insurance Agency (RAMQ). All prescriptions for celecoxib and traditional NSAIDs (tNSAIDs) dispensed to patients ≥50 years of age were evaluated for concordance with clinical practice guidelines. Prescriptions were stratified by time period (pre and post rofecoxib withdrawal) and, GI, CV, CHF and renal risk factors at the dispensing date. Gastro-protective agent (GPA) co-prescriptions were also evaluated. RESULTS: We assessed 1,966,793 celecoxib and 1,743,481 tNSAIDs prescriptions. Of celecoxib prescriptions, 87.2% and 86.5% were appropriate in the post- and pre-periods, respectively, compared to 72.6% and 70.1% of tNSAIDs prescriptions, respectively. In logistic regression, 'appropriateness' of celecoxib prescriptions increased with age, rheumatoid arthritis and osteoarthritis (OA), and was higher in the post- versus pre-period (odds ratio 1.22, 95% confidence interval 1.18-1.26); it was lower in women and in patients with higher income. 'Appropriateness' of tNSAID prescriptions decreased in the post-period (0.92, 0.89-0.95), was lower in older persons and those with OA, and higher in women and in higher income patients. Of tNSAID prescriptions that should have received a GPA co-prescription, only 45.6% did. CONCLUSION: Concordance with guideline recommendations increased for celecoxib and decreased for tNSAIDs after rofecoxib withdrawal; GPA co-prescription with tNSAIDs remained suboptimal.

The Vioxx pharmaceutical scandal: Peterson v Merke Sharpe & Dohme (Aust) Pty Ltd (2010) 184 FCR 1.

In early March 2010, Federal Court Justice Jessup in Peterson v Merke Sharpe & Dohme (Aust) Pty Ltd (2010) 184 FCR 1 ruled that Merke Sharpe & Dohme Pty Ltd had produced a defective product contrary to the Trade Practices Act 1974 (Cth), the anti-arthritic drug Vioxx. Promoted as relieving arthritic pain without the side effect of gastric ulceration, the drug also doubled the risk of heart attack in those prescribed it. The court also heard that the manufacturing company had engaged in misleading practices to promote the prescription and usage of Vioxx, including "fake" journals and guidelines to "drug reps" that minimised the adverse cardiovascular risks. The manufacturer had already settled a class action in the United States for more than US$7 billion for those harmed by the drug but this was the first such case to be decided in Australia. The court awarded the applicant, Graeme Peterson, A$300,000 in damages. This column examines this judgment and analyses evidence there presented that Merck may have misled the scientific community, the medical profession and Australia's drug regulation system to get Vioxx on the market and keep it there. It considers whether the case reveals the need for more rigorous post-marketing surveillance and other changes to Australia's drug regulatory system, including a replacement of self-regulation in pharmaceutical promotion with a United States-style system of rewarded informant-led criminal penalties and civil damages claims.

[The relation between publication bias and clinical trials funding]. / Publikationsbias in Abhängigkeit von der Art der Finanzierung bei klinischen Studien.

Publication bias describes the distortion of data in scientific journals resulting from the fact that studies with significant and positive results are more likely to be published than studies with negative or insignificant results. In studies funded by pharmaceutical companies publication bias has a considerable impact. It has been shown that more than half of the studies that are conducted as part of the drug approval process will remain unpublished. In addition, multiple publications of the same results, the selective use of data and the withholding of data relating to adverse drug reactions were also demonstrated. It is unclear, however, whether the probability of publication of studies funded by pharmaceutical companies is different from those not funded by pharmaceutical companies. Also, data vary as to the correlation between the type of funding of clinical studies and the length of time to publication. For the benefit of patients, everyone involved in clinical studies ought to take responsibility and facilitate access to all data.

A quantitative evaluation of the regulatory assessment of the benefits and risks of rofecoxib relative to naproxen: an application of the incremental net-benefit framework.

PURPOSE: To undertake a quantitative benefit-risk analysis of rofecoxib relative to naproxen using an incremental net-benefit (INB) analysis from the societal perspective, using the same data evaluated by the Health Canada and US FDA expert advisory panels. METHODS: We developed a discrete event simulation model to calculate the INB of rofecoxib relative to naproxen in arthritis patients over a 1-year time horizon. All outcomes were weighted using societal utilities for each health state which facilitated the use of quality-adjusted life years (QALYs) as the outcome. Probability distributions were incorporated for each model parameter to facilitate a probabilistic analysis using second-order Monte Carlo simulation. RESULTS: In the base case analysis, the mean INB (SD) of rofecoxib relative to naproxen was 0.0002 (0.415) QALYs per patient over 12 months of treatment, or 0.2 QALYs per 1000 patients treated. The probabilistic sensitivity analysis resulted in a mean INB of 0.0022 QALYs (95%CI -0.0005, 0.0051). Overall, the INB associated with rofecoxib relative to naproxen was ≥0 in 94% of the iterations of the model. CONCLUSIONS: This analysis illustrates the application of the incremental net-benefit framework to quantitative benefit-risk evaluation, and suggests that the potential benefits of rofecoxib outweigh the potential harms relative to naproxen over 1 year from the societal perspective under the assumptions of this model.

Pooled analysis of rofecoxib placebo-controlled clinical trial data: lessons for postmarket pharmaceutical safety surveillance.

BACKGROUND: In September 2004, rofecoxib was voluntarily withdrawn from the worldwide market. Our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib before its withdrawal as an example to inform future postmarket pharmaceutical safety surveillance efforts. METHODS: We conducted a cumulative subject-level pooled analysis of data from all randomized, placebo-controlled trials of rofecoxib conducted by the manufacturer before September 2004. Our main outcome measurement was incidence of any investigator-reported death from any cause or cardiovascular thromboembolic (CVT) adverse event. RESULTS: We identified 30 randomized, placebo-controlled trials of rofecoxib that enrolled a combined 20 152 subjects. Trial duration ranged from 4 weeks to 4 years; enrollment ranged from 17 to 2586 subjects prescribed either rofecoxib or placebo; and rofecoxib dose ranged from 12.5 mg to 50 mg. As of December 2000, 21 of these trials had been completed (70%), and the risk of a CVT adverse event or death was greater among subjects assigned to the rofecoxib group (rate ratio [RR], 2.18; 95% confidence interval [CI], 0.93-5.81) (P = .07), raising concerns from a safety standpoint. Subsequently collected data through June 2001 showed that rofecoxib was associated with a 35% increased risk of a CVT adverse event or death (RR, 1.35; 95% CI, 1.00-1.96) (P = .05). Analyzing data available as of April 2002, we found a 39% increased risk (RR, 1.39; 95% CI, 1.07-1.80) (P = .02), and using data available as of September 2004, we found a 43% increased risk (RR,1.43; 95% CI, 1.16-1.76) (P < .001). CONCLUSION: Cumulative pooled analysis of all randomized, placebo-controlled trials demonstrates a trend toward increased cardiovascular risk associated with rofecoxib compared with placebo as early as December 2000, the comparison reaching a P value of .05 by June 2001, nearly 3(1/2) years before the manufacturer's voluntary market withdrawal.

Changes in physicians' practice of prescribing cyclooxygenase-2 inhibitor after market withdrawal of rofecoxib: a retrospective study of physician-patient pairs in Taiwan.

BACKGROUND: Safety concerns regarding severe cardiovascular events associated with the use of selective cyclooxygenase-2 (COX-2) inhibitors resulted in the market withdrawal of rofecoxib in September 2004. OBJECTIVE: Using Taiwan's National Health Insurance 2003-;2004 claims database, this population-based retrospective cohort study assessed changes in physicians' practice of prescribing a COX-2 inhibitor after market withdrawal of rofecoxib. METHODS: Patients with rheumatoid arthritis (RA) or osteoarthritis (OA) who were chronic users of COX-2 inhibitors before market withdrawal of rofecoxib were identified. Eligible chronic users of COX-2 inhibitors were patients who received >or=3 consecutive prescriptions for celecoxib or rofecoxib to treat RA or OA between April 1 and September 30, 2004. The main outcome evaluated in this study was the volume of celecoxib prescribing for each patient by his or her prescribing physician at the first postwithdrawal outpatient visit related to RA or OA. For each matched physician, we calculated the prescribing practice indexes before and after the withdrawal of rofecoxib to assess changes in prescribing practice. A higher value of the index represented less potential that patients with a history of cardiovascular events who were seen by a physician received a prescription for a COX-2 inhibitor. A 2-stage model analysis was used to assess changes, in physicians' prescribing practice after rofecoxib's withdrawal, in the volume of prescribing a COX-2 inhibitor for each matched patient by his or her prescribing physician. RESULTS: Of the chronic users of COX-2 inhibitors identified, 13,101 were taking celecoxib and 8763 were taking rofecoxib before rofecoxib was withdrawn from the market. Concerns about safety after the mar- ket withdrawal of rofecoxib reduced physicians' volume of prescribing a COX-2 inhibitor, particularly in patients who had previously received rofecoxib. After rofecoxib's withdrawal, 72.50% of previous rofecoxib users (n = 6353) and 49.50% of previous celecoxib users (n = 6485) stopped taking COX-2 inhibitors. Only 27.50% of the rofecoxib users (n = 2410) were switched to celecoxib after rofecoxib's withdrawal. Overall, physicians' prescribing practice for celecoxib increased, from baseline to 3 months after rofecoxib's withdrawal, from 0.66 to 0.79 for academic medical center physicians, 0.71 to 0.82 for metropolitan hospital physicians, 0.77 to 0.88 for local community hospital physicians, and 0.86 to 0.92 for primary care clinic physicians. After controlling for patients' demographics, the linear regression analysis revealed that changes in physicians' prescribing practice after the withdrawal of rofecoxib affected the volume of prescribing a COX-2 inhibitor (P < 0.001). CONCLUSIONS: The volume of celecoxib prescribing was greatly reduced after rofecoxib was withdrawn from the market. Physicians' prescribing practice for COX-2 inhibitors significantly changed after the withdrawal, and it had a significant impact on the postwithdrawal volume of celecoxib prescribing.