Inadequate statistical power to detect clinically significant differences in adverse event rates in randomized controlled trials

ObjectiveTo determine the statistical power to detect potentially clinically significant differences in serious adverse events between drug therapies reported in a sample of randomized controlled trials (RCTs).Study Design and SettingSystematic review of RCTs with positive efficacy endpoint and at least a twofold difference in the proportion of patients with serious adverse events between treatment groups from six major journals. The power of each study to detect statistically significant differences in serious adverse events was calculated.ResultsOf the six included trials, all performed statistical analysis on adverse events without disclosure of the statistical power for detecting the reported differences between groups. The power of each study to detect the reported differences in adverse events was calculated and yielded values ranging from 0.07 to 0.37 among trials with non–statistically significant differences.ConclusionStatistical testing for differences in the proportion of patients experiencing an adverse event is common in RCTs; non–statistically significant differences are associated with low statistical power. A high probability of type II error may lead to erroneous clinical inference resulting in harm. The statistical power for nonsignificant tests should be considered in the interpretation of results.     

The “Temporary Recommendations for Use”: A dual-purpose regulatory framework for off-label drug use in France

In 2012, following the Mediator^® (benfluorex) scandal, France displayed the ambitious goal to implement a regulatory framework for controlling off-label drug use: the “Temporary Recommendations for Use” (RTUs). It aims to regulate the use of pharmaceuticals outside the scope of a marketing authorization (MA) by establishing a framework for patient monitoring and data collection. This is intended to ensure that the benefit/risk ratio is favorable for the indication approved by the RTU. The granting of an RTU enables the reimbursement of off-label drug use and encourages pharmaceutical companies to expand their MA. Between 2012 and 2014, the regulator framework for RTUs was amended twice in order to allow the bypassing of an MA for economic reasons, when a licensed alternative drug exists (so far, this is only illustrated by the bevacizumab (Avastin^®)/ranibizumab (Lucentis^®) case). The primary purpose of the RTU framework is interesting by implementing an original national control for off-label uses that respond to a public health need. The secondary purpose is more controversial as it promotes off-label use. This has raised legal issues and has created a ground for litigation between pharmaceutical firms and health authorities. RTUs provide an interesting example for other countries that are exploring the possibility of regulating off-label drug use. At the same time, the processes surrounding the implementation of RTUs illustrate the difficulties of public policies to balance public health needs, safety and economic goals.     

Pharmacological trials: primary and secondary prevention of coronary heart disease

This brief overview of outcome in studies on the primary and secondary prevention of CHD with drugs influencing cholesterol-lipid-lipoprotein metabolism or with platelet-influencing drugs indicates the following conclusions: (1) The central finding of the European trial on primary prevention with clofibrate—significant adverse effects on long-term mortality from all causes—compels the conclusion that this drug has no place in the broad effort to reduce CHD risk by lowering plasma lipids-lipoproteins. (2) No other disease endpoint data are as yet available on lipid reduction by other drugs for primary prevention; data from a U.S. cholestyramine trial are due in 1983 or 1984. (3) Results of the Coronary Drug Project with lipid-influencing drugs for secondary prevention in middle-aged post-MI men were negative for 5.0 and 2.5 mg/day mixed conjugated equine estrogens, and for dextrothyroxine, with early termination of all three of these regimens because of possible adverse effects. At the scheduled end of the trial, clofibrate showed no evidence of benefit and some signs of adverse effects. Nicotinic acid showed no evidence of benefit in regard to the primary CDP endpoint, all causes mortality, but it yielded a significant reduction in rates of nonfatal MI, nonfatal MI + CHD death, and stroke events. (4) Combined therapy with resin + nicotinic acid has a much greater capacity—over and above diet—than any single lipid-lowering drug to reduce markedly all atherogenic lipids-lipoproteins, while simultaneously raising HDL, but no disease endpoint data are available on benefit/risk ratio with this regimen. (5) Eight secondary prevention trials with platelet—influencing drugs indicate encouraging but not statistically significant results in five of six aspirin trials, in a trial with aspirin + dipyridamole, and in a trial with sulfinpyrazone. (6) Viewed in perspective, these discouraging data on lipid—influencing drugs for the primary and secondary prevention of CHD, and these equivocal data with platelet-influencing drugs for secondary prevention reinforce the fundamental conclusion that the main strategic thrust for the control of epidemic premature CHD must be primary prevention by nutritional-hygienic means, i.e., avoidance and correction of the lifestyles—especially “rich” diet and cigarette smoking, also sedentary living and incongruent behavior—that are the cause of the mass problem.     

Biotechnology and Medicare's new technology policy: lessons from three case studies

Biotechnology has figured prominently in recent Medicare coverage and payment policies. Biotech treatments push policy boundaries for several reasons: They attract strong patient demand; they often treat rare or life-threatening diseases; they may have uncertain evidence of health benefits; and they are often costly. This paper considers case studies of Medicare coverage for off-label uses of biotech cancer drugs and payments for anemia biopharmaceuticals. The cases suggest Medicare's ongoing challenge to balance access considerations, the role and strength of evidence, and cost consequences of new treatments.     

Off-Label-Verordnungen in der Onkologie

Off-label use is common practice in oncology for two reasons: either there is no licensed drug for a given tumor or the therapeutic standard becomes obsolete if a new drug licensed for another tumor promises better efficacy or fewer unwanted side effects. In such cases, only off-label use can guarantee the legally required treatment according to the newest scientific findings.Current jurisdiction specifies the conditions for off-label use. Its significance for the achievement of therapeutic progress is being discussed.The Federal Minister of Health and Social Security has established an expert commission to evaluate scientifically off-label use and provide advice on such practice.The necessity of off-label use and its importance for therapeutic progress in oncology are discussed. The danger of insufficient drug safety in off-label use is considered minimal if the drug has passed the legally required safety tests. The treatment of early and advanced prostate cancer offers examples for the usefulness of off-label use.     

What Is Wrong with Orphan Drug Policies?

The effects of orphan drug policies raise serious concerns among payer organizations and lead to often-tragic disappointment for patients who are denied much anticipated drug reimbursements. We evaluate the effects of orphan drug policies on the basis of this concern for real accessibility to drugs. We highlight two unforeseen effects of orphan drug policies: 1) they provide unique business opportunities for manufacturers and 2) drugs approved through these policies are often inaccessible because of their high price. We identify six causes of this emergence of effects. The first four are the direct result of incentives included in orphan drug policies. The fifth cause is the “off-label” use of orphan drugs. These emergent effects have several implications: 1) they raise doubts about the equity of access to drugs, 2) they highlight the limitations of the cohort paradigm in medicine, and c) they force third-party payers to make drugs accessible even when the prices of drugs are believed to be disproportionate to the clinical effects obtained.     

PAYMENTS,PROMOTION, AND THE PURPLE PILL

Understanding competition in the US drug market requires knowing how sensitive demand is to prices. The relevant prices for insured consumers are copayments. There are many studies of copayment elasticity in the health literature, but they are of limited applicability for studies of competition. Because of a paucity of data, such studies typically control for neither competitor copayment nor advertising. Whereas previous studies examined copayment sensitivity when copayments for branded drugs move in unison, this study examines copayment sensitivity when copayments diverge. This study uses unique panel data of insurance copayments and utilization for 77 insurance groups, as well as data on advertising. The results indicate that demand can be much more sensitive to copayment than previously recognized. Manufacturers selling drugs with higher copayments than branded competitors can lose substantial market share. Manufacturers can offset the loss of demand by increasing advertising to physicians, but it is costly. Copyright © 2013 John Wiley & Sons, Ltd.     

A framework for evaluating activities to reduce the demand for drugs in Europe

This paper describes a provisional framework that could be used to help compare and evaluate activities concerned with reducing the demand for illicit drugs in the European Community. It provides a background to European concern in this field, and comments on some methodological problems that arise regarding evaluation. The overall goal of demand reduction may be attempted through a diverse range of activities--treatment and rehabilitation, reduction of secondary harm arising from drug use, primary prevention, and suppression of drug availability and use--each of which may involve different interventions at different levels of generality and with different subsidiary objectives. Thus it is essential that data for evaluation are collected in terms of a framework where demand reduction activities and their objectives are clearly specified, together with criteria for success or failure, appropriate measures for those criteria and suitable methods to obtain those measures. The paper provides some examples of how this framework could be applied to evaluating attempts to reduce demand for drug through treating addicts, and comments on the use of global measures (indicators) of trends in the demand for drugs. A possible administrative structure for comparing drug demand activities in different countries through a European network on health data is suggested.     

Use Pattern and Off-Label Use of Atypical Antipsychotics in Bipolar Disorder, 1998–2002

Background

Postmarketing surveillance that identifies patients at high risk for receiving off-label medications will help ensure that the benefits of such treatment outweigh the risks. Because many off-label uses have little scientific support, tracking the extent to which they occur as well as the particular circumstances under which they occur is important.

Objective

To describe the drug-use pattern for patients with bipolar disorder, and to identify demographic and clinical factors associated with off-label use of atypical antipsychotics before US Food and Drug Administration approval for this indication.

Methods

Using the PHARMetrics medical claims database, a total of 105,771 adult patients with a diagnosis of bipolar disorder were evaluated during the 5-year (1998–2002) study period. Study drugs included mood stabilizers, antipsychotics, and antidepressants. Off-label use of an atypical antipsychotic was defined as a patient taking olanzapine before March 2000 (when it received an indication for bipolar disorder) or any other atypical antipsychotic during the entire study period. Logistic regression analysis was used to determine the odds ratio of receiving a drug off-label.

Results

Utilization of and reimbursement for atypical antipsychotics increased during the 5-year period. Of the 10.5% of patients who took atypical antipsychotics, 7.1% took these drugs off-label. In addition, 11% of patients received lithium, 25% received other anticonvulsants, and 34% received antidepressants. Off-label use of atypical antipsychotics was associated with psychiatry specialist prescribers (odds ratio = 1.52; 95% CI, 1.44–1.59) and certain comorbidities, such as substance abuse (odds ratio = 1.51; 95% CI, 1.38–1.66), anxiety disorder (odds ratio = 1.20; 95% CI, 1.14–1.26), diabetes mellitus (odds ratio = 1.26; 95% CI, 1.16–1.37), cerebral vascular disease (odds ratio = 1.26; 95% CI, 1.10–1.45), and hypertension (odds ratio = 1.12; 95% CI, 1.05–1.20). Over time, there has been an increase in the number of drug therapies, including atypical antipsychotics, used to treat bipolar disorder.

Conclusion

Because of the significant association found between atypical antipsychotic use and several key comorbidities, it is important for physicians to recognize these associations and weigh the risks and benefits of atypical antipsychotics in their treatment strategies.Bipolar disorder (BPD) is a chronic, recurrent psychiatric illness characterized by episodes of both mania and depression. It is estimated that up to 2.6% of the US adult population is affected by this disorder,1 and that the lifetime prevalence rate for bipolar spectrum disorders ranges from 3.0% to 6.5%.2 Direct treatment costs are sizable, at $11,600 per patient-year.3 Medication is an essential part of successful treatment for BPD. Although mood stabilizers (eg, lithium, divalproex sodium, carbamazepine, lamotrigine) have traditionally been used for primary treatment of BPD, atypical antipsychotics (ie, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have also been found helpful for stabilizing mood and have been used with increasing frequency since the mid-1990s.4,5Atypical antipsychotics have been used for BPD even before they received a US Food and Drug Administration (FDA) indication (very recently) for this condition. Patients with BPD may need antidepressant medication during periods of depression. Because of the risk of triggering mania, physicians often prescribe antidepressants (ie, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors) with a mood stabilizer.In March 2000, olanzapine was the first atypical antipsychotic to receive FDA indication for the treatment of mania. The off-label use of some atypical antipsychotics for BPD occurred before that. Subsequently, all the other atypical antipsychotics, with the exception of clozapine, received FDA approval for the treatment of BPD6:

• Risperidone—in December 2003
• Quetiapine—in January 2004
• Aripiprazole—in September 2004
• Ziprasidone—in March 2006.

The use of medications for conditions other than those approved by the FDA is known as off-label use. Although medications are often used off-label in the pediatric patient population,7–9 off-label use has also been common in adult clinical practice for diseases such as cancer, cardiovascular disorders, psychiatric disorders, and dementia.10–13 Indeed, more than 60% of patients taking antipsychotics received these medications for at least 1 off-label use.14Off-label use of antipsychotics plays an important role in psychiatry because of the number of different indications for which there is no single, clearly preferred treatment.5,13,15 Currently, atypical antipsychotics have limited efficacy in, but are being used off-label for, dementia, non–BPD-related depression, obsessive compulsive disorder, and posttraumatic stress disorder.Given drug safety considerations, postmarketing surveillance that can identify patients who are at high risk for receiving medications off-label will help ensure that the benefits of off-label treatment outweigh its risks. Because most off-label uses have little to no scientific support,12 it is important to keep track of the extent to which such uses occur, as well as the particular circumstances under which they occur.We therefore proposed this study to determine the degree to which atypical antipsychotics were used off-label in patients with BPD and to identify patient characteristics most associated with off-label use. Although other drugs were prescribed off-label for patients with BPD, we focused specifically on atypical antipsychotics. This relatively new class of drugs has seen a tremendous rise in utilization and in spending,15 and has become a focus of attention for both private and public healthcare payers.

KEY POINTS

• ▸ Many off-label uses have little to no scientific support, so tracking the extent and circumstances under which they occur can enhance safety.
• ▸ This study focused on off-label use of atypical antipsychotics for patients with bipolar disorder, because this relatively new class has seen a tremendous rise in utilization and spending, thus becoming a focus for private and public payers.
• ▸ Results show a 5-year growing trend in the use of and spending on atypical antipsychotics and antidepressants for bipolar disorder. Reimbursement for atypical antipsychotics increased from $1050 per 100 patients to $4800, a more than 4-fold increase.
• ▸ During the study period, psychiatrists were more likely to prescribe off-label atypical antipsychotics than general physicians, which could be the result of earlier evidence showing benefits for these agents in bipolar disorder. The majority of these medications have since received an indication for this condition.
• ▸ Metabolic complications should be carefully considered when prescribing atypical antipsychotics for patients with bipolar disorder.

     

剖宫产围手术期预防使用抗菌药物分析

目的：探讨剖宫产围手术期用药情况,观察分析抗菌药物整治活动前后应用抗菌药物的变化。方法：对2010-2012年1569例妇产科剖宫产手术患者进行调查,用SPSS 13．0统计软件对剖宫产围手术期用药、用药种类、联合用药、药品费用等资料进行统计分析。结果：1569例剖宫产患者抗菌药物应用率100%;其中抗菌药物整治活动前使用率排名前三位的是阿奇霉素、头孢硫脒和奥硝唑,抗菌药物整治活动后排名前三位的是头孢硫脒、头孢呋辛、克林霉素,选择药物趋于合理化,两组切口感染率无显著性差异。联合用药比例降低。药品费用分析提示抗菌药物整治活动对药费影响具有统计学意义。结论：医院剖宫产围手术期抗菌药物整治活动有助于合理用药,并降低抗菌药物使用费用。     

Predictive probability of success using surrogate endpoints

The predictive probability of success of a future clinical trial is a key quantitative tool for decision-making in drug development. It is derived from prior knowledge and available evidence, and the latter typically comes from the accumulated data on the clinical endpoint of interest in previous clinical trials. However, a surrogate endpoint could be used as primary endpoint in early development and, usually, no or limited data are collected on the clinical endpoint of interest. We propose a general, reliable, and broadly applicable methodology to predict the success of a future trial from surrogate endpoints, in a way that makes the best use of all the available evidence. The predictions are based on an informative prior, called surrogate prior, derived from the results of past trials on one or several surrogate endpoints. If available, in a Bayesian framework, this prior could be combined with data from past trials on the clinical endpoint of interest. Two methods are proposed to address a potential discordance between the surrogate prior and the data on the clinical endpoint. We investigate the patterns of behavior of the predictions in a comprehensive simulation study, and we present an application to the development of a drug in Multiple Sclerosis. The proposed methodology is expected to support decision-making in many different situations, since the use of predictive markers is important to accelerate drug developments and to select promising drug candidates, better and earlier.     

Statistical validation of intermediate endpoints for chronic diseases.

We discuss the implementation of a criterion due to Prentice for the statistical validation of intermediate endpoints for chronic disease. The criterion involves examining in a cohort or intervention study whether an exposure or intervention effect, adjusted for the intermediate endpoint, is reduced to zero. For example, to examine whether serum cholesterol level is an intermediate endpoint for coronary heart disease (CHD), we may investigate the effect of the cholesterol lowering drug cholestyramine on CHD incidence adjusted for serum cholesterol levels. We show that use of this criterion will usually demand some form of model selection. When the unadjusted exposure or treatment effect is less than four times its standard error, the analysis can usually lead only to a weak form of validation, a conclusion that the data are not inconsistent with the validation criterion. More significant unadjusted exposure effects offer the potential for stronger types of validation statement such as 'the intermediate endpoint explains at least 50 per cent (or 75 per cent) of the exposure effect'.     

药物使用的调查研究

由于药物不合理使用造成了临床上的严重后果和大量经济损失，人口增长及一些疾病发病率的升高所引起的对药品资源需求的日益增长，如何安全、有效、经济地合理用药，已引起了世界各国的高度重视。近几十年来，许多国家开展了大量有关药物使用的调查研究，获得了许多有关药物使用的信息，为制定药物管理政策和指导医生、病人合理用药提供了科学依据。此文对国内外开展的此类研究的方法、内容、取得的结果以及存在的问题进行了评述