|
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.
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).
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.
A new study by Svanström and colleagues (pages 1704–1712), using Danish national health care data, found no difference between azithromycin and penicillin V in the 5-day risk of cardiovascular death (relative risk, 0.93; 95% confidence interval [CI], 0.56 to 1.55). However, the upper bound of the 95% confidence interval does not exclude an increased risk of as much as 55%. As Svanström et al. point out, the population they studied differed from that studied by Ray et al. with respect to the baseline risk of death and cardiovascular risk factors. Overall, the Danish patients had better cardiovascular health than the Tennessee Medicaid patients. In a subgroup analysis of patients with a history of cardiovascular disease, the risk ratio for azithromycin versus penicillin V was greater than 1, though the difference was not statistically significant (relative risk, 1.35; 95% CI, 0.69 to 2.64). Svanström et al. conclude that their results do not conflict with those of Ray et al. Rather, the effect on cardiovascular mortality may be limited to patients with cardiovascular disease.
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.
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 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.
But questions remain about the efficacy of fines and corporate integrity agreements in deterring corporate misbehavior. The 2012 fines against Abbott Laboratories and GSK represent a modest percentage of those companies' revenue.1 Companies might well view such fines as merely a cost of doing business — a quite small percentage of their global revenue and often a manageable percentage of the revenue received from the particular product under scrutiny. If so, little has been done to change the system; the government merely recoups a portion of the financial fruit of firms' past misdeeds.
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.
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
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.
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.
A 400-Gram Female Infant Delivered at 24 and 4/7 Weeks.
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.â€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
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.
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 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.
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.
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.
[url=http://www.marijuana.com/forums/growing-topics.184/members/orarmeceraics.233563/] finasteride adverse side effects [/url]
[url=http://aroundpassions.com/viewtopic.php?f=40&t=30097] what is finasteride made from [/url]
[url=http://forum.janiemarie.me/showthread.php?tid=276466] proscar after braki therapy [/url]
[url=http://www.mtvtrunk.com/malay/forum.php?mod=viewthread&tid=2193799&extra=] proscar winstrol [/url]
[url=http://www.biomedcofounder.com/wp-content/plugins/zingiri-forum/mybb/showthread.php?tid=13416] finasteride discount [/url]
[url=http://gisa.icmc.usp.br/forum/viewtopic.php?f=25&t=58067] side effects of the drug proscar [/url]
[url=http://portalliteracki.pl/modules.php?mop=modload&name=Splatt_Forums&file=newtopic&forum=1] proscar for prostate [/url]
[url=http://lspd.americanroleplay.com/showthread.php?51283-prostate-gland-growth-with-proscar&p=75422#post75422] finasteride overseas pharmacy 5 mg cheap [/url]
[url=http://vapaforum.org/forum/showthread.php?tid=146706] finasteride wieght gain [/url]
[url=http://sstsgiugt.forumup.net/viewtopic.php?p=8161&mforum=sstsgiugt#8161] finasteride massotherapy [/url]
[url=http://www.diskoteket.se/forum/viewthread.php?thread_id=236555] finasteride and photophobia [/url]
[url=http://forum.ksacam.com/1/showthread.php?p=368045#post368045] over the counter finasteride [/url]
[url=http://manyetik.byethost7.com/showthread.php?tid=3886] proscar and hebral supplements [/url]
[url=http://extralives.forumup.us/viewtopic.php?p=6604&mforum=extralives#6604] steroid discussion forum finasteride [/url]
[url=http://www.napatie.xtreemhost.com/forum/viewthread.php?thread_id=17396] proscar peg tube [/url]
[url=http://crosspointdota.com/forum/viewtopic.php?f=3&t=257883] how long for results with proscar [/url]
[url=http://novamarketplace.com/forum/viewtopic.php?p=22650#22650] proscar muscle strength [/url]
[url=http://infantmedia.com/viewtopic.php?f=24&t=73175] psa proscar flomax [/url]
[url=http://turkstud.com/showthread.php?4327-proscar-muscle-strength&p=4920#post4920] finasteride diabetes [/url]
[url=http://fefedev.fr/forum/showthread.php?tid=204118] canine prescribe proscar [/url]
|
