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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.
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.
Each year in the United States, nearly 500,000 infants — 1 in every 8 — 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 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.
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.
Analysis of the data submitted in support of recent applications for marketing authorization shows that the current regulatory environment has ensured reasonable representation of “younger old” patients, but drug-usage patterns reveal a high prevalence of use in “older old” 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
Fifty years ago this month, President John F. Kennedy signed into law the Kefauver–Harris Amendments to the Federal Food, Drug, and Cosmetic Act (see photoPresident John F. Kennedy Signing the 1962 Kefauver–Harris 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 — 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 Kefauver–Harris 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 — and left out of our memories since — have not disappeared but continue to confront those who would ensure access to innovative, safe, efficacious, and affordable therapeutics.
An important finding of the study was a reduced incidence of ROP in the lower oxygen-saturation range. However, contrary to what was known at the time, the study also showed a slightly but significantly increased incidence of death — 19.9% versus 16.2% (P=0.04) — among infants assigned to the lower as compared with the upper range. As a result, last year the AAP amended its guidelines, citing SUPPORT, and physicians treating very premature infants are starting to use higher saturation rates to reduce the risk of death, even with the potentially higher risk of ROP at these levels. Studies such as SUPPORT that compare two alternatives, both within current standard clinical practice, often lead to critical improvements in medical care.
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.
Given continuing questions about the efficacy of the 300-mg product, the FDA decided to conduct, under its own auspices, the bioequivalence study described here. Because the results indicated that Budeprion XL 300 mg cannot be considered therapeutically equivalent to Wellbutrin XL 300 mg, the FDA requested that the sponsors of Budeprion XL (Impax Laboratories and Teva Pharmaceuticals) voluntarily withdraw the 300-mg version from the market, which they agreed to do.
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.
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.
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.
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 “older old” 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.
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.
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
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 “drug lag” in which innovative compounds reached markets in Europe long before they reached the U.S. market. Industry agitation surrounding the “drug lag” finally led to modification of the drug patenting system in the Drug Price Competition and Patent Term Restoration Act of 1984 — through further extension of drug patents. Indirectly, then, Kefauver's amendments ultimately affected both pharmaceutical pricing and patenting — in a manner diametrically opposed to the one he intended.
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.
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 — and much more expensive — to find or produce.
Inappropriate formulations and packaging may contribute to low adherence, medication errors, and safety and efficacy problems. Additional considerations for a largely elderly population will include the need for easy administration, possible dose reduction, the effects of visual and motor impairment, and the likelihood of polypharmacy. If appropriate, protocols should be designed for evaluating patients' ability to manage their own medications. Regulators should also look favorably on nondrug technologies such as information and communication technology systems for monitoring adherence or clinical signs.
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