| ledzereflug | Date: Vineri, 2013-07-05, 10:02 PM | Message # 22 |
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Group: Vizitator
| Clinicians must consider the arrhythmogenic potential not only of azithromycin but also of potential alternative antibacterial drugs. An earlier study showed an association between the use of erythromycin and sudden cardiac death, augmented by concomitant use of inhibitors of the cytochrome P-450 3A isozymes that metabolize erythromycin.4 Labels for erythromycin and clarithromycin include warnings regarding QT-interval prolongation and arrhythmias. All labels for fluoroquinolone products similarly have warnings regarding QT-interval prolongation, and grepafloxacin was withdrawn from the market because of that risk. A recent observational study of elderly residents of Quebec, Canada, showed an association between outpatient fluoroquinolone use and serious arrhythmias (as defined by hospital discharge diagnoses of ventricular arrhythmia or sudden or unattended death).5 And although Ray et al. found the risk of cardiovascular death to be greater with azithromycin than with ciprofloxacin, they found the risk with levofloxacin similar to that with azithromycin. The authors interpreted this similarity as evidence that levofloxacin may be proarrhythmic; however, levofloxacin was not implicated as proarrhythmic in the Canadian study.
In France, a centralized body makes reimbursement decisions after assessing the safety and effectiveness of individual devices. Reimbursement decisions in Italy are devolved to the various regions, and Britain and Germany conduct broader assessments of device types or procedures, rather than of individual devices. Typically, innovative devices not covered under an existing diagnosis-related group (DRG) require review under the lengthier Health Technology Assessment process, which assesses safety, clinical benefit, and cost-effectiveness. Government-provided information on time to reimbursement varies by country. Estimated time frames are an average of 71.3 months in Germany, a range of 36.0 to 48.0 months in France, a range of 16.4 to 26.3 months in Italy, and an estimated 18 months in Britain.
The NIH is committed to ensuring that prospective research participants — and the people who speak for and love them — are given clear, complete, and accurate information about the risks and benefits of participating in research. We are strongly committed to supporting critical research studies like SUPPORT, which inform clinical care by providing rigorous evidence for use in daily practice. This controversy has alarmed some of the parents of infants who were in the study, confused the biomedical research community, and befuddled IRBs. Several other studies seeking new insights to improve care for these vulnerable infants have been put on hold as the field tries to understand the OHRP findings.
In Europe, by contrast, most of the 27 member countries of the European Union (EU) have publicly financed health care systems; such systems cover approximately four fifths of the populations of the four largest device markets. All EU countries require devices to first obtain a Conformité Européenne (CE) marking, which refers to a symbol shown on products that indicates market approval throughout the EU. The CE marking process is conducted by for-profit, third-party “notified bodies” that have been accredited by a member country to assess device safety and performance but do not evaluate effectiveness (which requires more clinical data). Although publicly available data are limited, anecdotal information from notified bodies suggests that the process takes 1 to 3 months, excluding sponsor time.
We investigated the most common ambulatory indications for azithromycin by analyzing data from a survey conducted by Encuity Research of approximately 3200 office-based physicians for the decade from 2002 through 2011. Across all age groups of patients, the two most common indications for azithromycin were chronic sinusitis and bronchitis. The tableAgents Associated with Drug-Use Mentions for Chronic Sinusitis and Bronchitis, According to U.S. Office-Based Physician Practices (January 2002–December 2011). shows the antibacterial drugs that were used most commonly in the United States for these indications. Azithromycin was the leading antibacterial drug for outpatient treatment of bronchitis during this period (even if amoxicillin is combined with amoxicillin–clavulanate). For chronic sinusitis, azithromycin ranked second after amoxicillin. Because the indications are reported by the prescribing physicians, these data don't allow us to assess the diagnostic certainty regarding the infections being treated.
The other major difference observed between Budeprion XL 300 mg and Wellbutrin XL 300 mg was in the time to peak drug concentration in the blood (Tmax) (see graph). Although FDA guidance does not include Tmax as a criterion for bioequivalence of bupropion hydrochloride products, the Tmax for Budeprion XL (4 hours) is shorter than that for Wellbutrin XL (5 hours). A similar difference in Tmax values was also observed in the bioequivalence study of the 150-mg products that was originally used for extrapolation of data for Budeprion XL 300 mg. But because the comparative area-under-the-curve and Cmax values for the 150-mg products fell within FDA parameters and were supported by data on the performance of the product in vitro, Budeprion XL 300 mg was approved.
The acquisition of relevant data to elucidate the benefit–risk ratio in the target population requires more than merely balancing the absolute numbers of patients. Depending on the drug's profile and the target population, investigators will face a learning curve with regard to acquiring data and modulating risk for patients who might be more susceptible to adverse outcomes, such as frail patients or those taking multiple medications. In designing a strategic plan for drug development, it will be important to engage in a dialogue with regulators to ensure that the needs and requirements of older patients are considered. Investigation of population pharmacokinetics or a specific pharmacokinetic study including the very elderly should be performed and will help inform prescribing. Modeling and simulation can offer powerful tools for quantitatively evaluating differences in pharmacokinetics and pharmacodynamics, recommending dosing regimens, and identifying patients at risk. Some of the lessons learned from the experience in pediatric clinical trials can be applied to the older population; heterogeneity can, in some measure, be allowed and analyzed in clinical-trial design both before and after market authorization.
Despite such caveats, the results presented by Ray et al. warrant serious attention. A chief strength of the results is the time-limited pattern of the risk: the azithromycin-associated increase in the rates of death from any cause and from cardiovascular causes spanned days 1 through 5, reflecting the typical 5-day duration of azithromycin administration (e.g., Zithromax Z-Pak). On days 6 through 10, an elevated risk of death from cardiovascular causes was no longer detected. This pattern is consistent with the timing of peak plasma azithromycin concentrations and the concomitant risk of QT-interval prolongation. The elevated risk was statistically significant, regardless of whether azithromycin treatment was compared with amoxicillin or with nonuse of an antibacterial drug. Furthermore, the observed excess mortality was attributable solely to cardiovascular deaths and, in particular, to sudden cardiac death; although sudden cardiac death can result from causes other than arrhythmias, an increase in deaths in this category would be the pattern expected from an arrhythmogenic, QT-interval–prolonging drug. Also, the azithromycin-associated risk was higher among patients with cardiovascular disorders, which is consistent with a drug-related arrhythmia.
The results of the FDA-sponsored study have led the agency to review its approach to other 300-mg extended-release generic bupropion products. The agency has determined that direct bioequivalence studies using the 300-mg strength of the brand-name and generic products are appropriate and feasible. Accordingly, the FDA has requested that other makers of generic extended-release bupropion hydrochloride (Anchen, Actavis, Watson, and Mylan) perform bioequivalence studies of their 300-mg products. The agency is also updating its bioequivalence guidance for these products. As new information regarding these products becomes available, the agency will take any appropriate regulatory actions and will inform the public. Patients who are taking the 300-mg strength of generic extended-release bupropion products and have questions about their medication should be encouraged to speak with their health care provider.
On July 2, 2012, the Department of Justice announced the largest settlement ever in a case of health care fraud in the United States. GlaxoSmithKline (GSK) agreed to plead guilty to three criminal counts and settle civil charges brought under various federal statutes; the company will pay a total of $3 billion to the federal government and participating states. Since 2009, the federal government has collected more than $11 billion in such settlements under the False Claims Act.
Kefauver's bill met strong resistance as it made its way through the Subcommittee on Antitrust and Monopoly.2 The American Medical Association firmly opposed the regulation of efficacy by a government agency, arguing that “the only possible final determination as to the efficacy and ultimate use of a drug is the extensive clinical use of that drug by large numbers of the medical profession over a long period of time.”3 The editors of the Journal, on the other hand, supported the efficacy provision and the expansion of generic drug names but opposed the patent provisions (considering them an “arbitrary discrimination” against the pharmaceutical industry) and the comparative effectiveness provisions (considering “proof of superiority” necessary only if superiority was actually being “claimed by the manufacturer”).4 The pharmaceutical industry amplified such concerns about comparative effectiveness, arguing that any a priori determination of which medicines were “me-too” and which were true innovations would be arbitrary. Efficacy was hard enough to prove, they suggested; proving comparative efficacy would be “completely impracticable.”3
The study by Ray et al. has limitations that are intrinsic to observational, nonrandomized clinical studies. In particular, nonrandomized studies cannot exclude the possibility that patients receiving a drug under evaluation differ from control patients in some important but undetected way, causing bias in the results. Such confounding may bias comparisons not only between patients receiving antibacterial drugs and those receiving no antibacterials but also between patients receiving different antibacterials. Although Ray et al. used appropriate analytic methods to address potential confounding, we cannot know for certain whether these methods were fully successful. Replication of the authors' results, through analysis of a distinct data set, would provide more confidence in the finding of increased cardiovascular mortality among patients receiving azithromycin.
Going forward, the NIH strongly and unequivocally supports the importance of the role of the OHRP in the oversight of human subjects research. But the community will benefit from an explicit description of the process the OHRP follows for investigating complaints. For example, when questions are raised about reasonably foreseeable risks and the state of the science relevant to a particular clinical trial, appropriate independent experts might need to be consulted. Finally, we are pleased to see the DHHS plans to ensure that investigators and IRBs will have a fair and transparent process for appealing OHRP findings and compliance actions, in those situations in which reasonable people disagree about the actions taken.
Although population aging is a mark of the success of public health policies, it also challenges the established way of implementing such policies. In the case of the European Medicines Agency (EMA), it has prompted an analysis of whether the regulatory system is adapted to taking the needs of older people into account in the development, approval, and use of medications.
The Food and Drug Administration (FDA) has completed a head-to-head bioequivalence study of single doses of the generic drug Budeprion XL 300 mg (extended-release bupropion hydrochloride, manufactured by Impax Laboratories and distributed by Teva Pharmaceuticals) and the brand-name drug Wellbutrin XL 300 mg (Biovail). The agency has concluded that Budeprion XL 300 mg cannot be considered therapeutically equivalent to the brand-name product. We at the FDA are therefore changing our bioequivalence recommendations for extended-release bupropion products and have asked other manufacturers of 300-mg extended-release bupropion products to conduct additional bioequivalence studies.
Second, an accurate comparison of time to market access requires measurement of the total time that elapses between application submission and market access. Previous studies have compared the chronologic dates of application submission and market access, but the date an application is submitted varies from country to country.
The GSK corporate integrity agreement does include some provisions that attempt to change corporate culture. First, GSK must revise its compensation systems to “ensure that financial incentives do not inappropriately motivate” sales representatives; these changes include new restrictions on compensation for off-label promotion. GSK has now implemented a program to eliminate incentive-based compensation for sales representatives based on “territory/individual level sales goals,” which will alter the financial incentives for sales representatives who meet with physicians. Second, GSK senior executives and other employees who are paid bonuses and other compensation may in the future be asked to repay those amounts if certain types of fraudulent behavior occur that violate the corporate integrity agreement. As has been noted in the financial press, this requirement does nothing to recoup several substantial recent bonuses given to senior management at such firms,2 but it does make it more difficult to repeat the practice, at least at GSK. Third, in view of the serious questions about failure to report negative data related to Avandia's safety, GSK must commit itself to “research and publication practices” designed to make more clinical trial information available to clinicians and regulators. These commitments have several disturbing exceptions: GSK will “generally” seek publication for research results, and summaries of clinical trial data will be posted on a clinical study register “with rare exception.” These are but partial steps toward transparency.
To further illustrate this point, we compared the time to approval for five innovative, high-risk medical devices available in France, Italy, and the United States (see tableComparison of Time to Market Access for Five Innovative Devices in France, Italy, and the United States.). These case studies indicate that the average time to market access for these devices was 26.3 months in France, 30.8 months in Italy, and 15.3 months in the United States.
Using this information, we determined that the time it takes to bring innovative, high-risk devices to patients in the United States is similar to or shorter than that in the top four European markets (see figureComparison of Time to Market in Premarket Approval and Reimbursement Processes.). The public (CMS) process in the United States takes approximately as long as those in Italy and Britain, approximately half as long as that in France, and less than a third as long as that in Germany. The difference in time to market access is even greater when it comes to private insurers (covering the majority of the U.S. population), which often make reimbursement decisions within a few months after FDA approval.
The federal Office for Human Research Protections (OHRP), which is charged with providing leadership in the protection of the rights, welfare, and well-being of persons involved in research conducted or supported by the U.S. Department of Health and Human Services (DHHS), asserted in March 2013, on the basis of its own examination of the evidence, that the SUPPORT researchers failed to provide prospective parents sufficient information about the risks posed by the study. After a detailed review of the protocol, the relevant consent documents, and the research literature, we respectfully disagree with the conclusions of the OHRP, which we believe resulted from a fundamental difference in interpretations of how the regulations should apply to the state of scientific understanding when the SUPPORT study commenced. Moreover, there is a larger issue here: how risks should be conveyed in the informed-consent process when research is comparing interventions that are all considered to be the standard of care.
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