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|Medications commonly prescribed to treat other conditions that occur frequently in patients with the condition under study should be allowed to be used during clinical trials,5 either in the pivotal phase 3 trials or вЂ” if better recruitment results would be expected вЂ” in a separate trial. Excessive вЂњconfounder cleansingвЂќ may result in the study of nonrepresentative populations. |
The acquisition of relevant data to elucidate the benefitвЂ“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.
One must, of course, weigh any observed drug-associated risk against clinical benefits, so it's appropriate to consider the possibility that certain offsetting benefits of azithromycin may not have been reflected in the risk data analyzed by Ray et al. For example, other studies have suggested that macrolides have an advantage over other antibacterial agents in terms of overall survival from community-acquired pneumonia. In a recent Canadian observational study, researchers followed 2973 outpatients with community-acquired pneumonia and found significantly lower 30-day mortality among patients receiving macrolides than among those receiving fluoroquinolones (adjusted odds ratio, 0.28; 95% CI, 0.09 to 0.86).2 A recent meta-analysis of observational studies showed a statistically significant 25% difference in mortality among hospitalized patients with community-acquired pneumonia favoring macrolides over nonmacrolide antibacterials.3 Such findings, which must be considered with due regard for the limits of observational studies, do not necessarily contradict the results of Ray et al. Past the 5-day period of risk of azithromycin-associated cardiovascular death, the drug might reduce the longer-term (e.g., more-than-30-day) rate of death due to pneumonia. Pneumonia was an uncommon indication among the Tennessee Medicaid patients treated with azithromycin.
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 вЂњthe 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.вЂќ3 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 вЂњarbitrary discriminationвЂќ against the pharmaceutical industry) and the comparative effectiveness provisions (considering вЂњproof of superiorityвЂќ necessary only if superiority was actually being вЂњclaimed by the manufacturerвЂќ).4 The pharmaceutical industry amplified such concerns about comparative effectiveness, arguing that any a priori determination of which medicines were вЂњme-tooвЂќ and which were true innovations would be arbitrary. Efficacy was hard enough to prove, they suggested; proving comparative efficacy would be вЂњcompletely impracticable.вЂќ3
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 ConformitГ© EuropГ©enne (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 вЂњnotified bodiesвЂќ 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.
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 risks and benefits of antibacterial therapy should be considered in prescribing decisions. Pharmacologic and epidemiologic data point to lethal arrhythmias as a potential consequence of QT-interval prolongation with use of azithromycin, other macrolides, and fluoroquinolones. This possibility should give clinicians pause when they're considering prescribing antibacterial drugs, especially for patients with preexisting cardiovascular risk factors or clinical conditions in which antibacterial drug therapy has limited benefits.
The use of data extrapolation for the approval of Budeprion XL 300 mg should be considered in historical context. When applications for generic versions of Wellbutrin XL 300 mg began to come under FDA review in 2005, more than 11 million prescriptions for the brand-name product were being written each year. Programs to develop generic bupropion products, and the requisite bioequivalence studies, were important for addressing the widespread need for the treatment of major depressive disorder. At the same time, the FDA and sponsors recognized that bupropion conferred a dose-related risk of seizures, which the agency believed warranted a conservative approach to bioequivalence testing of bupropion in healthy volunteers. Bioequivalence studies that used only the lower strength (150 mg) reflected this conservative approach.
Kefauver initially stuck to his guns on issues of compulsory licensing and patents, but his persistence ultimately cost him control of his own bill. In June of 1962, officials from the Kennedy administration and the pharmaceutical industry presented the subcommittee with an alternate bill вЂ” with no regulatory language about patents included. Kefauver cried foul, the Kennedy administration eased off its support, and S.1552 seemed to all observers to be a dead letter. It was only by chance timing that the summer of 1962 also produced a highly visible tragedy (thalidomide), a hero (Frances Kelsey), and enough ensuing public outcry to persuade Kefauver and Kennedy to embrace the gutted bill.
Another unintended consequence of the amendments was that the new structures of proof changed not only the behavior of the pharmaceutical industry but also the conceptual categories used by biomedical researchers around the world.5 Pharmaceutical research came to be overwhelmingly organized around the placebo-controlled, randomized, controlled trial. Although this system has greatly helped researchers gauge the efficacy of an individual drug, it has also rendered data on comparative efficacy much more difficult вЂ” and much more expensive вЂ” to find or produce.
If the corporate fines are too small, the False Claims Act will need to be amended so that a higher percentage of the revenues derived from fraudulent activities is recouped. At the same time, federal law must insist on greater transparency for clinical trial results, so that negative safety data are not hidden from clinicians and regulators.
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.
According to current guidance from the FDA Center for Drug Evaluation and Research, conclusions that two drug products are bioequivalent should reflect significant agreement in pharmacokinetic parameters such that the entire 90% confidence interval associated with the generic-to-reference ratio of geometric means should fall within the bioequivalence limits of 80 to 125%.1 Budeprion XL 300 mg did not meet these criteria in our bioequivalence study, which involved 24 healthy fasting volunteers and used a single-dose crossover design (see graphMean Plasma Concentration of Bupropion (Budeprion XL and Wellbutrin XL) as a Function of Time in 24 Fasting Healthy Volunteers.). The extent of bupropion absorption after the administration of the generic product, as reflected in the area under the curve of the plasma concentrations plotted over time, was 86% of the absorption with the brand-name product (see graph), but the corresponding 90% confidence interval was 77 to 96%. In addition, the mean peak plasma concentration (Cmax) observed after the administration of Budeprion XL 300 mg was only 75% of that observed after the administration of Wellbutrin XL 300 mg (90% confidence interval, 65 to 87). In certain study participants, the Cmax and the area under the plasma-concentration curve for Budeprion XL were less than 40% of the values with Wellbutrin XL. The Cmax values for hydroxybupropion, the major active metabolite of bupropion hydrochloride, also failed to meet the FDA bioequivalence criteria.
After the approval of Budeprion XL, the Tmax disparity between Budeprion XL 150 mg and Wellbutrin XL 150 mg remained a source of concern. This concern, along with the reports that began surfacing after initial marketing of Budeprion XL 300 mg, prompted the FDA to recommend, in November 2007, that the sponsor conduct a clinical comparison with the 300-mg product. The FDA believed that the most appropriate population for this study would be patients who had reported a lack of efficacy or unwanted side effects after switching from Wellbutrin XL 300 mg to Budeprion XL 300 mg; the protocol therefore stipulated the enrollment of such patients. By early 2008, the sponsor had begun preparing to conduct the recommended study. Unfortunately, the study was terminated because of an inability to enroll a sufficient number of patients who met the entry criteria.
However, a well-circulated grievance pointed to one unanticipated consequence of the amendments: the new burden of proof appeared to make the process of drug development both more expensive and much longer, leading to increasing drug prices and a вЂњdrug lagвЂќ in which innovative compounds reached markets in Europe long before they reached the U.S. market. Industry agitation surrounding the вЂњdrug lagвЂќ finally led to modification of the drug patenting system in the Drug Price Competition and Patent Term Restoration Act of 1984 вЂ” through further extension of drug patents. Indirectly, then, Kefauver's amendments ultimately affected both pharmaceutical pricing and patenting вЂ” in a manner diametrically opposed to the one he intended.
These numbers may not fully capture the reasons why a device reaches the market more quickly in one country than in another and do not reflect experiences with all innovative, high-risk devices. However, unless one uses equivalent standards in terms of the level of risk, the start and end points of the process, and the key end point of market access, accurate comparisons cannot be made.
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.
The circumstances surrounding the SUPPORT study have unquestionably created controversy in the research community, but the situation has created an opportunity for a better understanding of the scientific and ethical issues that must be addressed when designing such studies in the future. We look forward to working with the OHRP, the research community, and patient advocates to improve the effectiveness and ethical standards of research involving human participants.
Renewed attention to comparative effectiveness research in the 21st century illustrates the consequences of sidelining Kefauver's initial demand for comparative data for evaluating the promotion of novel therapeutics. By 2000, pharmaceutical expenditures had become one of the fastest-growing parts of the budget of many U.S. states and third-party insurers. But the kind of knowledge required for entry into the U.S. drug market offers consumers and payers little information relevant to choosing between subtly different вЂњme-tooвЂќ drugs within the same therapeutic class вЂ” whose therapeutic effect may or may not be the same. Only in the past decade, through the action of the Reforming States Group, the Drug Effectiveness Review Project, and most recently funding of comparative effectiveness research through the American Recovery and Reinvestment Act, the Affordable Care Act, and now the Patient-Centered Outcomes Research Institute, have we begun to catch up on the vital project of comparing therapeutics so that American consumers and their physicians can make meaningful treatment decisions вЂ” the project that motivated Kefauver's original investigations a half century ago.
The amendments granted the FDA the power to demand proof of efficacy вЂ” in the form of вЂњadequate and well-controlled investigationsвЂќ вЂ” before approving a new drug for the U.S. market. They also led to a retrospective review of all drugs approved between 1938 and 1962 (the Drug Efficacy Study Implementation program), which by the early 1970s had categorized approximately 600 medicines as вЂњineffectiveвЂќ and forced their removal from the market. These market-making and unmaking powers were also tied to a new structure of knowledge generation: the orderly sequence of phase 1, phase 2, and phase 3 trials now seen as a natural part of any pharmaceutical life cycle.
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