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But controversies such as this are also an opportunity to advance shared understanding, provide clarification, and encourage progress. The public debate surrounding the SUPPORT study has set the stage for a substantive national dialogue with the research, advocacy, and ethics communities on how best to respect and protect participants in research studies conducted within the standard of care and how to define “reasonably foreseeable risks” in this setting. The timing is critical — the clinical research community, bioethicists, regulators, IRBs, and prospective research participants are paying close attention now. The NIH is happy to work with all stakeholders to advance this important dialogue and its translation into clear guidance, in accordance with the plan just announced by the DHHS (www.hhs.gov/ohrp/). In addition, a new letter to the University of Alabama at Birmingham from the OHRP, stating its intention to put all compliance actions on hold until the process of producing appropriate guidance is completed, is available now on the OHRP website (www.hhs.gov/ohrp/detrm_letrs/YR13/jun13a.pdf).
Within a year after gaining approval at the end of 2006, Budeprion XL 300 mg became the subject of intense media coverage describing adverse events in patients being treated for major depressive disorder who had switched to the generic drug from Wellbutrin XL. Approval of Budeprion XL 300 mg was based on the results of a bioequivalence study of Budeprion XL 150 mg and Wellbutrin XL 150 mg, which were extrapolated to the 300-mg product. Our new data provide direct comparative pharmacokinetic analyses of the 300-mg products.
Most European patients do not have access to innovative, high-risk devices as soon as the devices receive a CE marking. Each country must first make a decision about reimbursement, a process that varies substantially among countries.5 Though a CE marking can be granted on the basis of fewer clinical data than are required for FDA approval, European standards for reimbursement are often similar to or higher than those that the FDA imposes for device approval. European countries may require additional data on the device's safety and effectiveness, as well as on cost-effectiveness.
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 long delay between the approval of Budeprion XL 300 mg in late 2006 and the appearance of the bioequivalence results reported here, during which the product remained listed by the FDA as a generic substitute for Wellbutrin XL 300 mg, is problematic. Because of the risk of seizure associated with high doses of bupropion, the agency initially took a conservative approach to trial design. Today, the FDA has greater understanding of the risk of seizure with bupropion. At the time of the sponsor's 2007 study, some critics considered its design to be flawed. The results of the recent study by the FDA show that a design entailing the enrollment of a more accessible trial population might well have brought the bioequivalence data to light sooner. In retrospect, the conservative approach did not provide the right conclusions regarding therapeutic equivalence in a timely manner.
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.
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.
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.
These measures can certainly be improved. For one thing, though all these provisions seem advisable, they are imposed only under a corporate integrity agreement, as opposed to official regulations, and expire in 5 years. Legislative reformers should consider whether the entire industry should be regulated on a level playing field, as opposed to through piecemeal agreements. In addition, individuals must be held responsible in appropriate circumstances. Models might include federal tax law, under which directors and officers of nonprofit corporations cannot be indemnified against fines imposed on them as individuals for particularly egregious violations.3 Key leaders can also be excluded from participation in federal health programs. The academic researchers involved in the controversy regarding the safety data for Avandia has thus far escaped sanctions as well.4
One partial solution would be to impose penalties on corporate executives rather than just the company as a whole. Boston whistleblower attorney Robert M. Thomas, Jr., embraces this approach: “GSK is a recidivist. How can a company commit a $1 billion crime and no individual is held responsible?”
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.
Finally, these types of fraud are hard to detect from the outside. Internal documents are often critical to these cases. Most of the time, these documents are provided by internal whistleblowers. In a recent survey, researchers identified several ways in which the whistleblower provisions of the False Claims Act could be strengthened to encourage whistleblowers to come forward and to protect them from retaliation.5 Whistleblowers should be encouraged, not punished for their testimony.
First, the strategy recognizes that older people are the main users of medications — not a minority or special population (a fundamental difference between the geriatric and pediatric populations). Therefore, legislative and regulatory frameworks must be designed to ensure that the use of newly approved medicines in the intended population is supported by relevant data on the benefit–risk balance. The strategy's second aim is to improve the availability of information to patients and prescribers, to support safer use of medications.
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.
The process started in 2006, when the EMA provided an opinion on the adequacy of guidance on the elderly regarding medicinal products. In 2011, the agency's Committee for Human Medicinal Products adopted the EMA geriatric medicines strategy,1 marking its commitment to improving our understanding of how best to evaluate the benefit–risk ratio for a medication in older patients.
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.
Chronologic age alone is inadequate for characterizing the population enrolled in a clinical trial. Frailty is a predictor of clinical outcomes,4 and the reduction of frailty has benefits for individuals and society. The EMA is exploring the possibility of reaching a consensus on an operational definition of frailty and tools for evaluating it that could be used for clinical research and to guide therapeutic decisions.
In a letter dated March 7, 2013, the OHRP asserted that the study's consent form failed to convey that “the level of oxygen being provided to some infants, compared to the level they would have received had they not participated, could increase the risk of brain injury or death.”3 That finding was influenced by research conducted in the 1950s, but in our view, it failed to assign proper weight to studies conducted in premature infants in the 2000s, which used more sophisticated oxygen-monitoring and oxygen-measurement devices, similar to those used in SUPPORT.4 The more recent studies showed no increased risk of death or neurodevelopmental impairment at saturation levels as low as 70%.5
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 amendments granted the FDA the power to demand proof of efficacy — in the form of “adequate and well-controlled investigations” — 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 “ineffective” 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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