|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 benefitโrisk ratio for a medication in older patients.
Even when inclusion and exclusion criteria are set adequately, clinicians and ethics review boards often act as gatekeepers in the recruitment process, creating a selection bias by allowing enrollment of only some of the eligible patients. They are particularly likely to exclude the โolder oldโ and patients with coexisting conditions. Again, every effort should be made to gather evidence in these patients during the premarketing period of drug development. Regulatory guidance for these patients is often lacking, and more work is needed to strengthen the guidance on expectations concerning such patients when guidelines are drafted or revised.
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 โ and much more expensive โ to find or produce.
Fifty years ago this month, President John F. Kennedy signed into law the KefauverโHarris Amendments to the Federal Food, Drug, and Cosmetic Act (see photoPresident John F. Kennedy Signing the 1962 KefauverโHarris Amendments.). With the stroke of a pen, a threadbare Food and Drug Administration (FDA) was given the authority to require proof of efficacy (rather than just safety) before approving a new drug โ a move that laid the groundwork for the phased system of clinical trials that has since served as the infrastructure for the production of knowledge about therapeutics in this country. We often remember the KefauverโHarris Amendments for the thalidomide scandal that drove their passage in 1962. But there is much we have collectively forgotten about Senator Estes Kefauver (D-TN) and his hearings on administered prices in the drug industry. Many parts of the bill left on Congress's cutting-room floor in 1962 โ and left out of our memories since โ have not disappeared but continue to confront those who would ensure access to innovative, safe, efficacious, and affordable therapeutics.
It's important to provide adequate information to patients and prescribers. That's impossible if there are no good data, but sometimes data included in a drug-development dossier are not adequately reflected in the approval documents. There must be greater focus on the package insert, the regulatory document most widely referred to by the public, which must do a better job of explaining how to take the medication, whether dosage adjustments are advised for older patients, and what is known about use with concomitant medications.
In a 2012 observational study involving Tennessee Medicaid patients, Ray et al.1 quantified the risk of death from cardiovascular causes associated with azithromycin as compared with other antibacterial drugs or nonuse. The study showed that the risks of death, both from any cause and from cardiovascular causes, associated with azithromycin were greater than those associated with amoxicillin. For every 21,000 outpatient prescriptions written for azithromycin, one cardiovascular death occurred in excess of those observed with the same number of amoxicillin prescriptions. The excess risk over amoxicillin varied considerably according to cardiovascular risk factors; the researchers estimated that there was one excess cardiovascular death per 4100 prescriptions among patients at high cardiovascular risk but less than one per 100,000 among patients with lower cardiovascular risk.
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.
Analysis of the data submitted in support of recent applications for marketing authorization shows that the current regulatory environment has ensured reasonable representation of โyounger oldโ patients, but drug-usage patterns reveal a high prevalence of use in โolder oldโ patients (see graphThe Example of Cardiovascular Drugs: Percentages of All Patients in a Given Age Group Treated with Cardiovascular Drugs (Italy) versus Percentages in Each Age Group Included in Cardiovascular Drug Trials (Globally).). Patients who are 75 years old or older often present a complex picture involving coexisting conditions and frailty: they are the fastest-growing demographic group but are largely underrepresented in clinical trials given their disproportionately high actual use of drugs. This imbalance will make it increasingly difficult and potentially inappropriate to extrapolate data to these patients.2 Though trials are less likely to set unjustified age limits than they were a few decades ago, this improvement must be considered in the context of a rapidly aging population and the continued widespread use of exclusion criteria based on coexisting conditions. Corrective efforts must be maintained to ensure that a representative population of patients covering the entire age range is studied in the preauthorization phase, in accordance with international guidelines.3
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 Conformitรฉ Europรฉenne (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 โnotified bodiesโ 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.
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
Each year in the United States, nearly 500,000 infants โ 1 in every 8 โ are born prematurely, before 37 weeks of gestation. Despite substantial advances in their care, premature infants face a daunting array of challenges; they are at high risk for death in infancy and face severe and lifelong health problems if they survive.1 The National Institutes of Health (NIH) has a legal and moral responsibility to do research in partnership with scientists and families to optimize the care of these highly vulnerable infants. In recent weeks, a major public debate has arisen regarding a study designed to do just that. And the ramifications go well beyond this one study: the outcome of this debate could affect how we conduct and communicate about critical research on interventions that are within the standard of care for all diseases and conditions.
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.
Depending on patients' frailty and disability status, the desirable outcome and treatment choices might vary: different patients place different values on benefits and risks. Certain adverse events, such as dizziness leading to falls, may be of greater importance in the geriatric population. The design of a clinical trial should consider age-appropriate end points; for older people, functional outcomes may be most important, and an emphasis on such outcomes could lead to reduced costs for health care systems.
We do not believe that the results of the FDA study should cause concern regarding the overall reliability of the agency's approval process for generic drugs, including the use of extrapolation, when scientifically appropriate. Technical aspects of the Budeprion formulation may have led to the failure of extrapolation in this case. More information on this issue will be generated by the other sponsors' bioequivalence studies. The other 300-mg generic bupropion products do not use the same technology as Budeprion. The use of extrapolation for the approval of multiple strengths of generic drugs, which incorporates science-based reasoning, has been generally successful, and the FDA will continue to refine its approach to this method. The agency will also move more aggressively to perform its own studies when data are urgently needed. We wish to assure the public that drug products that are approved for generic use will continue to be held to high standards of quality, safety, and efficacy.
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.
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.
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-intervalโprolonging drug. Also, the azithromycin-associated risk was higher among patients with cardiovascular disorders, which is consistent with a drug-related arrhythmia.
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 2011, approximately 40.3 million people in the United States (roughly one eighth of the population) received an outpatient prescription for the macrolide azithromycin, according to IMS Health. During that year, we at the Food and Drug Administration (FDA) reviewed the labels of azithromycin and other approved macrolide antibacterials in view of cardiovascular risks that had become evident from published studies and reports emerging through postmarketing surveillance. On the basis of its review, the FDA approved revisions to azithromycin product labels regarding risks of QT-interval prolongation and the associated ventricular arrhythmia torsades de pointes. The revised labels advise against using azithromycin in patients with known risk factors such as QT-interval prolongation, hypokalemia, hypomagnesemia, bradycardia, or use of certain antiarrhythmic agents, including class IA (e.g., quinidine and procainamide) and class III (e.g., dofetilide, amiodarone, and sotalol) โ drugs that can prolong the QT interval. In March 2013, the FDA announced that azithromycin labels had been further revised to reflect the results of a clinical study showing that azithromycin can prolong the corrected QT interval.
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