Food And Drug Administration Advisory Research Articles

Disparities in Discontinuing Rosiglitazone Following the 2007 FDA Safety Alert.

Responsiveness to the Food and Drug Administration (FDA) rosiglitazone safety alert, issued on May 21, 2007, has not been examined among vulnerable subpopulations of the elderly. To compare time to discontinuation of rosiglitazone after the safety alert between black and white elderly persons, and across sociodemographic and economic subgroups. A cohort study. Medicare fee-for-service enrollees in 2007 who were established users of rosiglitazone identified from a 20% national sample of pharmacy claims. Outcome of interest was time to discontinuation of rosiglitazone after the May alert. We modeled the number of days following the warning to the end of the days' supply for the last rosiglitazone claim during the study period (May 21, 2007-December 31, 2007) using multivariable proportional hazards models. More than 67% of enrollees discontinued rosiglitazone within six months of the advisory. In adjusted analysis, white enrollees (hazard ratio=0.90; 95% confidence interval, 0.86-0.94) discontinued rosiglitazone later than the comparison group of black enrollees. Enrollees with a history of low personal income also discontinued later than their comparison group (hazard ratio=0.84; 95% confidence interval, 0.81-0.87). There were no observed differences across quintiles of area-level socioeconomic status. White race and a history of low personal income modestly predicted later discontinuation of rosiglitazone after the FDA's safety advisory in 2007. The impact of FDA advisories can vary among sociodemographic groups. Policymakers should continue to monitor whether risk management policies reach their intended populations.

Cardiovascular risk with DPP-4 inhibitors: latest evidence and clinical implications.

Cardiovascular risk with DPP-4 inhibitors: latest evidence and clinical implications.

Trends in the coprescription of proton pump inhibitors with clopidogrel: an ecological analysis.

In early 2009, 2 observational studies and a US Food and Drug Administration (FDA) advisory addressed the drug interaction between proton pump inhibitors (PPIs) and clopidogrel. One study suggested that pantoprazole could be used safely in this setting, whereas the other study and the FDA advisory did not distinguish among PPIs. We examined trends in PPI prescribing among clopidogrel recipients in the period following these events. We conducted a population-based time series analysis of Ontario residents aged 66 years or older for whom clopidogrel was prescribed between Apr. 1, 1999, and Sept. 30, 2013. We determined the proportion of clopidogrel recipients dispensed a PPI during each quarter and the proportions who received pantoprazole or other PPIs. The outcome of interest was change in the use of pantoprazole. In the final quarter of 2008, pantoprazole represented 23.7% of all PPI prescriptions dispensed to patients receiving clopidogrel. Following the publications and FDA advisory in early 2009, pantoprazole use increased substantially. By the end of 2009, this medication accounted for 52.5% of all PPI prescriptions issued to patients receiving clopidogrel; by the end of the study period, it accounted for 71.0% of all PPI prescriptions dispensed to such patients (p < 0. 001). We also observed a modest drop in overall PPI use among clopidogrel recipients beginning in early 2009. In 2009, the prescribing of PPIs with clopidogrel changed substantially in Ontario, with pantoprazole rapidly becoming the most commonly prescribed agent in its class. However, a modest decline in overall PPI use also occurred that may reflect suboptimal translation of emerging drug safety information to clinical practice.

Effects of Televised Direct-to-Consumer Advertising for Varenicline on Prescription Dispensing in the United States, 2006-2009.

Televised direct-to-consumer advertising (DTCA) for prescription drugs is controversial, especially for tobacco cessation products such as varenicline, given safety concerns that arose only after its market approval. We aim to quantify the extent to which DTCA influenced varenicline use. We linked monthly DTCA television ratings with monthly prescription data from IMS Health's National Prescription Audit across top 75 media markets in 2006-2009. We used Poisson models with Generalized Estimating Equations to analyze effects of exposures to DTCA for both varenicline and nicotine replacement therapies on rate of dispensed varenicline prescriptions among smokers, controlling for population characteristics and varenicline-related events. Varenicline prescriptions increased dramatically following DTCA launch and declined sharply after safety risks were publicized and US Food and Drug Administration (FDA) issued an advisory. DTCA had significant impact on new prescription dispensing in the subsequent month: before the FDA advisory, one additional exposure to varenicline DTCA was associated with a 1.8% (rate ratio [RR] = 1.018 [1.015-1.021]) higher rate of new prescriptions; no effect was observed after the advisory (RR = 1.000 [0.997-1.003]). Prior to the advisory, cross-product effects of nicotine replacement therapy advertising on varenicline prescribing were negligible (RR = 1.002 [0.999-1.004]); after the advisory, effects were positive (RR = 1.015 [1.012-1.019]). DTCA for varenicline had a significant impact on varenicline prescribing when the drug's safety profile was not well characterized, supporting arguments to limit DTCA for newly approved products whose real-world safety is unclear. We examined the fluctuations in varenicline use in association with DTCA for varenicline and other tobacco cessation aids. To our knowledge this is the first study to quantify the effects of televised DTCA for varenicline and other tobacco cessation aids on varenicline prescription dispensing. We believe that understanding these relationships is critical for formulating effective public health policy and interventions.

How Data Packages Lacking Phase III Pivotal Trial Data Can Support Regulatory Approval and Reimbursement for Oncologics in Australia

BackgroundOncology drugs lacking supportive phase III trial data have achieved Food and Drug Administration (FDA) and European Medicines Agency (EMA) regulatory approval and even European reimbursement approval where no therapeutic alternative exists and early-stage data indicate dramatic clinical benefits. ObjectiveThis research aimed to compare under what circumstances oncologics can obtain both regulatory and reimbursement approval in Australia on this basis. MethodsTherapeutic Goods Administration (TGA) Australian Public Assessment Reports, EMA, FDA, and Pharmaceutical Benefits Advisory Committee (PBAC) Public Summary Documents were extracted for any oncologic indication appraised in Australia on a pivotal trial package lacking phase III data, excluding pediatric indications and new formulations. ResultsAustralian Public Assessment Reports were available for six TGA-appraised oncologics across seven indications on such a data package: five of seven approved, one of seven restricted, and one of seven rejected. The EMA and the FDA issued recommendations on these indications an average of 1 and 2 years earlier, respectively. The PBAC appraised six oncologics across 10 indications on such a data package, with four (nilotinib, dasatinib, imatinib, and brentuximab vedotin) approved and two rejected (cetuximab and bevacizumab). Seven of the eight approved indications required multiple submissions, with inadequate clinical data frequently cited as key. Six of the eight PBAC-approved indications included economic modeling on a cost-benefit approach. ConclusionsThe TGA will approve oncologics that offer potentially substantial clinical benefits on the basis of an indirect comparison of single-arm trials but at a delay versus the EMA and the FDA. The PBAC reimbursement approval also requires more rigorous supportive clinical data and acceptable cost-effectiveness as demonstrated on a cost-benefit or cost-quality-adjusted life-year metric.

Non-steroidal anti-inflammatory drug administration after coronary artery bypass surgery: utilization persists despite the boxed warning

In 2005, the US Food and Drug Administration (FDA) issued a boxed warning against the administration of non-steroidal anti-inflammatory drugs (NSAIDs) after coronary artery bypass graft (CABG) surgery because of cardiovascular safety concerns. We assessed utilization rates before and after the advisory and evaluated predictors of NSAID administration following CABG. We assembled a cohort of 277,576 patients who underwent CABG from 2004 to 2010. Temporal trends in NSAID exposure were evaluated, and predictors of postoperative NSAID use were identified using generalized estimating equations. Over the study period, 92,938 CABG patients (33.5%) received NSAIDs following surgery. The frequency of NSAID administration declined steadily over time, from a peak of 38.9% in 2004 to a low of 29.0% in 2010 (p < 0.0007). Ketorolac was the most frequent NSAID prescribed, commonly on the first postoperative day. Surgery performed after the boxed warning was independently associated with a 20% lower odds of NSAID administration [odds ratio (OR): 0.80; p = 0.0003]. Other factors that predicted a lower odds of NSAID use following surgery included a history of renal disease (OR: 0.33; p < 0.0001) and liver disease (OR: 0.66; p < 0.0001), and the need for concurrent valve surgery (OR: 0.78; p < 0.0001). A mammary graft at the time of surgery increased the odds of NSAID administration (OR: 1.23; p < 0.0001). The frequency of NSAID administration after CABG has declined since the FDA advisory, yet many patients continue to receive them in recent years. Our data highlight the need for future research initiatives to further define the risks associated with NSAID use in this population.

FDA Advisory Meeting Clinical Pharmacology Review Utilizes a Quantitative Systems Pharmacology (QSP) Model: A Watershed Moment?

In the evolving discipline of quantitative systems pharmacology (QSP), QSP model (QSPM) applications are expanding. Recently, a QSPM was used by US Food and Drug Administration (FDA) clinical pharmacologists to evaluate the appropriateness of a proposed dosing regimen for a new biologic. This application expands the use-horizon for QSPMs into the regulatory domain. Here we retrace the evolution of the model and suggest a question-based approach to directing model scope, identifying applications, and understanding overall QSPM value.

Commentary: confidentiality of interim trial data-the emerging crisis.

Randomized controlled clinical trials (RCTs) represent the pinnacle of evidence used by clinicians and regulators to determine the effectiveness of therapeutic interventions. The importance of RCTs is so universally accepted that clinical practice guidelines for many fields of medicine assign the highest rating for quality of evidence (Class 1A) to recommendations supported by data derived from multiple RCTs. Similarly, regulators have generally required evidence derived from RCTs for approval of pharmacological interventions. These policies ensure that the therapies approved by regulatory agencies and endorsed by professional societies actually deliver the benefits promised to patients. Now, after decades of application, this paradigm is threatened by a looming crisis related to the ability to conduct cardiovascular safety trials of diabetes drugs using the highest standards of scientific integrity. As described by Fleming in this edition of Clinical Trials, maintaining the confidentiality of data for interim results from ongoing clinical trials is essential to maintaining the feasibility and reliability of these crucial studies. The current threat to clinical trial integrity arises from a regulatory crisis that emerged during the past decade. The US Food and Drug Administration (FDA) and global regulatory authorities traditionally approved diabetes drugs based primarily upon the ability of these agents to lower blood sugar in the absence of any apparent toxicity. Diabetes drugs were typically evaluated based upon short-term trials (6–12 months) showing a reduction in glycohemoglobin levels, a measure of average blood glucose values over the previous 3 months. In actual practice, most sponsors, to mitigate the risk of demonstrating toxicity, conducted relatively small trials (total sample size about 3000 patients) in populations with a predicted low likelihood of adverse clinical outcomes. However, like most surrogate outcomes, the use of average blood glucose values to approve diabetes drugs carried considerable theoretical risks. A therapeutic intervention could lower blood glucose, but worsen other important outcome measures, which would go undetected in the small, short-term trials conducted with glycemic endpoints. That’s exactly what happened. In 2005, the diabetes drug muraglitazar was presented to an FDA Advisory Panel, and a recommendation for approval received nearly unanimous support. A few weeks later, we published a meta-analysis of the clinical data presented to the FDA Panel, which showed an approximate doubling of the risk of major adverse cardiovascular events (MACE) in patients treated with muraglitazar compared with placebo or other glucoselowering therapies. Then, 2 years later, we published a meta-analysis of cardiovascular outcome data for an approved and widely prescribed drug, rosiglitazone, showing evidence for increased MACE. This latter publication resulted in considerable controversy with alarming newspaper headlines, Congressional inquiries, and public outcry. A consensus emerged that approval of diabetes drugs primarily on the basis of glucose lowering (without additional cardiovascular outcome data) was no longer tenable. Accordingly, the FDA assembled an advisory panel in 2008 to consider what changes in regulatory policy, if any, were needed. Two participants in that advisory committee meeting, Dr Fleming as a panel member and me as an invited speaker, proposed a new paradigm for diabetes drug approval. The approach we advocated was carefully designed to balance the need to approve new drugs for diabetes in a timely fashion with the compelling societal interest in making certain such drugs did not increase adverse cardiovascular outcomes. We weighed the risks and benefits of several approaches, including requiring a large-scale RCT prior to approval, but ultimately proposed a strategy that would require sponsors to rule out an upper 95% confidence interval (CI) for the hazard ratio (HR) for MACE of 1.8 prior to approval and an

Revisiting financial conflicts of interest in FDA advisory committees.

The Food and Drug Administration (FDA) Safety and Innovation Act has recently relaxed conflict-of-interest rules for FDA advisory committee members, but concerns remain about the influence of members' financial relationships on the FDA's drug approval process. Using a large newly available data set, this study carefully examined the relationship between the financial interests of FDA Center for Drug Evaluation and Research (CDER) advisory committee members and whether members voted in a way favorable to these interests. The study used a data set of voting behavior and reported financial interests of 1,379 FDA advisory committee members who voted in CDER committee meetings that were convened during the 15-year period of 1997-2011. Data on 1,168 questions and 15,739 question-votes from 379 meetings were used in the analyses. Multivariable logit models were used to estimate the relationship between committee members' financial interests and their voting behavior. Individuals with financial interests solely in the sponsoring firm were more likely to vote in favor of the sponsor than members with no financial ties (OR = 1.49, p = 0.03). Members with interests in both the sponsoring firm and its competitors were no more likely to vote in favor of the sponsor than those with no financial ties to any potentially affected firm (OR = 1.16, p = 0.48). Members who served on advisory boards solely for the sponsor were significantly more likely to vote in favor of the sponsor (OR = 4.97, p = 0.005). There appears to be a pro-sponsor voting bias among advisory committee members who have exclusive financial relationships with the sponsoring firm but not among members who have nonexclusive financial relationships (ie, those with ties to both the sponsor and its competitors). These findings point to important heterogeneities in financial ties and suggest that policymakers will need to be nuanced in their management of financial relationships of FDA advisory committee members.

Safety and Complications of Ocriplasmin

Our ability to examine the vitreoretinal interface has been greatly improved by the invention of spectral-domain optical coherence tomography (OCT). It has allowedearlier andmore accurate diagnosis of abnormalities of vitreomacular adhesion (VMA) that may contribute to vision loss and may benefit fromintervention.While subtle abnormalitiesofVMAmay be observed, symptomatic VMA or that associated with fullthicknessmacularhole (FTMH) requires surgical intervention.1 With improvements in vitreoretinal surgical techniques and better understanding of these conditions, outcomes of surgicalmanagementofVMA-relateddisorders areexcellent.1However, even in thehandsof themost experiencedsurgeon, there are associated surgical risks. There is also expected discomfort to the patient, delay in visual recovery, high cost, and, in cases of surgery for FTMH, postoperative positioning. Furthermore, advanced surgical skills are required for epiretinal membrane or internal limiting membrane peeling. Ocriplasmin (Jetrea) is a recombinant truncated form of human plasminwith amolecularweight of 27.2 kDa. It is a recombinantproteasewithactivity against fibronectinand laminin, which are components of the vitreoretinal interface.2 In 2 phase 3 clinical trials comparing a single intravitreal injection of ocriplasmin (0.125 mg/0.1mL)with aplacebo injection (drug vehicle diluted with saline) inpatientswith symptomaticVMA,where theprimaryendpointwas resolutionofVMAatday28, 26.5%ofocriplasmin-injected eyes had resolution comparedwith 10.1%of placebo-injectedeyes (P < .001).3Nonsurgical closureofmacular holeswas achieved in 40.6%of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (P < .001). Consequently, ocriplasminwas approved by the US Food and DrugAdministration (FDA) foruse in symptomaticVMA inOctober 2012. It is notable that ocriplasmin is a first-in-class pharmacologic agent that has been FDA approved to manage symptomatic VMA. Furthermore, the primary end point in the pivotal studieswasbasedonOCTchanges rather thanonvisual acuity improvement, the first time, to my knowledge, that OCT has beenusedas theprimaryoutcomeforaclinical trial inophthalmology. Finally, even when patients do not achieve release of abnormal VMA or closure of FTMH following intravitreal ocriplasmin injection, they can still undergo surgical management.Therefore,ocriplasminofferscliniciansanadditional tool tomanage the anatomical abnormalities of symptomatic VMA in a less invasivemanner thanwith surgery in select cases. However, since the real-worlduseof thedrugbegan, there have been unfavorable anecdotal reports of visual disturbancesafterocriplasmin injection, including transientbutprofound visual decline, raising concerns regarding its safety. While it is not possible to know the frequency of these events in postmarketing surveillance, it is worthwhile to pay attention to safety-related reports. In the report of phase 3 trials of ocriplasmin, ocular adverse events such as vitreous floaters, photopsia, conjunctival hemorrhage, blurred vision, and visual impairment were found to be significantly higher in the treatment group comparedwith theplacebogroup.3However, theauthors state that “most of the adverse events were transient and mild in severity.”3 TheWarnings and Precautions section of the package insert for ocriplasmin4 includesdecreaseof 3ormore lines of best-correctedvisual acuity in 5.6%ofpatients treatedwith ocriplasmin (comparedwith 3.2% in the control group), intravitreal injectionprocedure–associated effects (intraocular inflammation, intraocular hemorrhage, increased intraocular pressure), potential for lens subluxation, retinal breaks, and dyschromatopsia. It states that “dyschromatopsia (generally described as yellowish vision) was reported in 2% of all patients injectedwith Jetrea. In approximatelyhalf of thesedyschromatopsia cases therewerealsoelectroretinographic (ERG) changes reported (aand b-wave amplitude decrease).”4 According to the FDA Advisory Committee briefing document, 9 patients receiving ocriplasmin in various clinical trialswere reportedtohaveexperiencedanacutedecrease invisionwithin 24hours of injection, some to the handmotions level.5 In 8 of 9 patients, vision returned to baseline with a median recovery time of 2 weeks. Dyschromatopsia reportedly resolved within a median time of 3 months. Of the 141 ocriplasmintreatedpatientswhounderwentERGtesting, 11 (7.8%)hadERG changes and 9 of these patients also had dyschromatopsia. Among the 11 patientswithERGchanges, theERGchanges resolved in 6 patients (median time, 6 months), 3 did not have follow-up ERGs, 1 was still undergoing follow-up, and 1 case did not resolve and was thought to be due to concurrent vitelliform dystrophy. Recently, there was a report of a patient with symptomatic VMA, epiretinal membrane, and an impending FTMH who experienced transient vision loss after ocriplasmin injection.6 The patient was found to have disruption of the outer retina, in particular the ellipsoid zone (previously known as the inner segment/outer segment junction), on spectral-domain OCT that partially recovered by 3 weeks along with improvement in visual acuity.6 Two brief reports Related articles pages 484 and 487 Opinion

Safety of Computed Tomography in Patients With Cardiac Rhythm Management Devices: Assessment of the U.S. Food and Drug Administration Advisory in Clinical Practice

To assess the safety of computed tomography (CT) imaging in patients with cardiac rhythm management (CRM) devices, which was subject to an advisory from the U.S. Food and Drug Administration (FDA) in 2008. The FDA warned about potential interference of CT imaging with CRM devices and made recommendations for clinical practice despite only limited evidence. All 516 CT scans that involved direct radiation exposure of CRM devices (332 defibrillators, 184 pacemakers) at 2 large-volume centers between July 2000 and May 2010 were included. The primary outcome was a composite endpoint of death, bradycardia or tachycardia requiring termination of the scan or an immediate intervention, unplanned hospital admission, reprogramming of the device, inappropriate defibrillator shocks, or device replacement/revision thought to be due to CT imaging. Significant changes in device parameters were sought as a secondary outcome (control group 4:1 ratio). The main finding was that none of the CTs were associated with the primary outcome. With serial device interrogations, there were no differences in changes in battery voltage or lead parameters between devices exposed to radiation and their controls. Potentially significant changes in device parameters were observed in a small group of devices (both the CT group and control group), but no definitive link to CT was confirmed, and there were no associated clinical consequences. The findings suggest that the presence of CRM devices should not delay or result in cancellation of clinically indicated CT imaging procedures, and provide evidence that would be helpful when the FDA advisory is re-evaluated.

Trends in Bone Morphogenetic Protein Usage since the U.S. Food and Drug Administration Advisory in 2008: What Happens to Physician Practices When the Food and Drug Administration Issues an Advisory?

Study Design Retrospective cross-sectional study of spinal procedures from 2002 to 2010 using the Nationwide Inpatient Sample database. Objective To determine the patterns of bone morphogenetic protein (BMP) usage in fusion surgery before and after the U.S. Food and Drug Administration (FDA) 2008 advisory for the anterior cervical spine to understand how advisories affect U.S. physician practices. Methods Procedures were identified through International Classification of Diseases, Ninth Revision procedure codes and were plotted over time based on fusion procedure type, site, and area of fusion. U.S. national trends were approximated by polynomial regression analysis. Results The majority of the data trends of BMP usage reflect a second-order polynomial model. BMP usage in anterior cervical spine fusion procedures plateaued during the fourth quarter of 2007. The most apparent change in trend was noted in BMP usage pre- and postadvisory in the analysis of anterior cervical spine fusions. BMP percentage of use decreased in this area by 5% from the time of the FDA advisory to the fourth quarter of 2010. Conclusions The decrease in BMP usage in anterior cervical spinal fusion procedures coincided with the timing of the FDA advisory. The fact that BMP continued to be used in cervical spine fusion procedures, even at lower rates, despite the advisory, may reflect the availability of new clinical information that could lessen complications (i.e., lower BMP dose, perioperative steroids, BMP containment). Furthermore, factors like the natural ceiling effect of use or demand for new technology, complications, prohibitive institutional costs, access to information, and insurance compensation may have all contributed to the BMP usage trends observed.

FDA Advisory Panel Recommends Approval of Drug for Preoperative Treatment of Breast Cancer

In a nearly unanimous vote, an advisory panel for the US Food and Drug Administration (FDA) voiced its support on September 12 for the approval of the drug pertuzumab for use in the neoadjuvant (preoperative) treatment of breast cancer. Pertuzumab, a monoclonal antibody targeting the HER2/neu receptor, was approved by the FDA in 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who had not received prior anti-HER2 therapy or chemotherapy. If the FDA takes its advisory panel�s advice, pertuzumab would also be approved for use as neoadjuvant treatment in early HER2-positive breast cancers.

Effects of FDA Advisories on the Pharmacologic Treatment of ADHD, 2004–2008

This study assessed the effect of public health advisories issued between 2005 and 2007 by the U.S. Food and Drug Administration (FDA) on treatments of attention-deficit hyperactivity disorder (ADHD) and physician prescribing practices. Data obtained from the IMS Health National Disease and Therapeutic Index, a nationally representative audit of ambulatory physicians, were used to examine trends in office visits by children and adolescents (under age 18) during which ADHD was treated with Adderall, other psychostimulants, or atomoxetine. Segmented time series regressions were conducted to determine changes in use associated with three advisories issued between 2005 and 2007. In 2004, before the first FDA advisory, Adderall accounted for 36% of ADHD pharmacotherapy treatment visits. Other stimulants accounted for 46%, and atomoxetine accounted for 19%. Overall pharmacotherapy treatment rates were stable over the study period, but by 2008 the treatment visits accounted for by Adderall (that is, market share) declined to 24%, and the market share for atomoxetine declined to 8%. The market share for substitute therapies-clonidine, guanfacine, and bupropion-was stable over this period, ranging from 5% to 7%. Despite the declines in the use of Adderall and atomoxetine over the study period, results from the regression models suggest that the advisories did not have a statistically significant effect on ADHD medication prescribing. FDA advisories regarding potential cardiovascular and other risks of ADHD medications had little discernible incremental effect on the use of these medicines in this nationally representative ambulatory audit.

Electroconvulsive Therapy Device Classification: Response to FDA Advisory Panel Hearing and Recommendations

Electroconvulsive therapy (ECT) is a safe and highly effective treatment for management of acute episodes of a variety of serious mental disorders, particularly for major depressive episodes that are resistant to multiple interventions with treatment alternatives. As such, the National Network of Depression Centers (NNDC), a consortium of major academic centers with interest and expertise in this area, believes there is an important public health need for ECT to remain available for clinical use. As with all medical devices, ECT is regulated by the US Food and Drug Administration (FDA), which is presently involved in formulating a proposed rule as to how such devices should be classified. Since such classification may have substantial effects on the availability of ECT to patients for whom it is clinically indicated, the NNDC has reviewed the information provided by the FDA to its Advisory Panel, as well as the subsequent deliberations of the Panel itself at a January 2011 public hearing. This review indicates that the FDA may have substantially underestimated the efficacy of ECT as a means to produce large clinical improvements for individuals suffering from severe major depressive disorders and that such an underestimate likely affected the Panel's willingness to recommend reclassification of ECT devices to a less restrictive category. In addition, the NNDC's review generates support for a variety of methods by which the safety of ECT can be ensured, which is an essential requirement for such reclassification.

Implantable cardioverter-defibrillator FDA safety advisories: Impact on patient mortality and morbidity

A significant proportion of implantable cardioverter-defibrillators (ICDs) have been subject to Food and Drug Administration (FDA) advisories. The impact of device advisories on mortality or patient care is poorly understood. Although estimated risks of ICD generators under advisory are low, dependency on ICD therapies to prevent sudden death justifies the assessment of long-term mortality. To test the association of FDA advisory status with long-term mortality. The study was a retrospective, single-center review of clinical outcomes, including device malfunctions, in patients from implantation to either explant or death. Patients with ICDs first implanted at Cleveland Clinic between August 1996 and May 2004 who became subject to FDA advisories on ICD generators were identified. Mortality was determined by using the Social Security Death Index. In 1644 consecutive patients receiving first ICD implants, 704 (43%) became subject to an FDA advisory, of which 172 (10.5%) were class I and 532 (32.3%) were class II. ICDs were explanted before advisory notifications in 14.0% of class I and 10.1% of class II advisories. Among ICDs under advisory, 28 (4.0%) advisory-related and 15 non-advisory- related malfunctions were documented. Over a median follow-up of 70 months, 814 patients died. Kaplan-Meier 5-year survival rate was 65.6% overall, and 64.2, 61.1, and 69.3% in patients with no, class I, and class II advisories, respectively (P = .17). ICD advisories impacted 43% of the patients. Advisory-related malfunctions affected 4% within the combined advisory group. Based on a conservative management strategy, ICDs under advisory were not associated with increased mortality over a background of significant disease-related mortality.

FDA rejects novel diabetes drug over safety fears

Last month, US regulators informed AstraZeneca and Bristol-Myers Squibb that they are not yet able to approve dapaglifl ozin, an oral antidiabetic drug on which the two companies are partnered. In a joint press release, AstraZeneca and Bristol-Myers Squibb disclosed that the US Food and Drug Administration (FDA) had requested “additional clinical data to allow a better assessment of the benefi t-risk profi le”. The companies reaffi rmed their commitment to dapaglifozin, adding that it had already been the subject of 19 clinical trials in which over 5000 patients were treated with the drug. They promised to “work closely with the FDA to determine the appropriate next steps”. Dapaglifl ozin is the fi rst of a new class of drugs for tackling type 2 diabetes: sodium-glucose transporter-2 inhibitors. These drugs work by blocking the reabsorption of glucose in the kidneys. Patients simply excrete large quantities of glucose. “The drug has attracted a lot of interest because it has a new mode of action to treat hypo glycaemia and also assists weight-loss in an insulinindependent manner”, explains Cliff ord Bailey from Aston University, UK, principal investigator for a recent study of dapaglifl ozin published in The Lancet. A new class of agent with a new mechanism and a potentially sizeable market, small wonder that dapaglifl ozin is subject to particular scrutiny. But the FDA’s decision is not a huge surprise to many observers. In July, 2011, an FDA Advisory Committee voted against approving dapaglifl ozin. The committee cited higher rates of breast and bladder cancer in the treatment arms of trials included in their analysis (there was also one case of probable druginduced hepatic toxicity). Whether this is an ascertainment bias or something more worrying remains to be seen. “There is a lot of angst about all drugs related to diabetes in terms of cancer risk”, explains Rob Andrews from the University of Bristol, UK. “The main concern with dapaglifl ozin is bladder cancer.”

FDA Advisory Decision Highlights Some Problems Inherent in Pragmatic Trials

AMEETING OF AN ADVISORY COMmittee to the US Food and Drug Administration (FDA) regarding a drug to minimize stroke risk for patients with atrial fibrillation illuminated the difficulties of gleaning knowledge from pragmatic trials—studies designed to determine the effectiveness of therapies in everyday practice. In September, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9 to 2, with 1 abstention, to recommend that the agency approve rivaroxaban, an oral antithrombin, as an alternative treatment to warfarin, a vitamin K antagonist, for patients with atrial fibrillation. The FDA generally goes along with advisory committee recommendations. Rivaroxaban’s status as an alternative treatment is based on results from the Stroke Prevention Using the Oral Direct Factor Xa Inhibitor Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation (ROCKET AF) trial. This double-blind trial involved 14 264 patients with nonvalvular atrial fibrillation at increased risk for stroke who were randomized to a dose of 20 mg/d of the drug or to dose-adjusted warfarin. In that trial, researchers found rivaroxaban to be noninferior to warfarin for the prevention of stroke or systemic embolism (Patel MR et al. N Engl J Med. 2011;365[10]:883-891). But the FDA itself, in a briefing document submitted to the advisory committee, stated caveats that raised questions about the rigor of the ROCKET AF trial. The document’s authors said findings from ROCKET AF were not adequate to determine whether rivaroxaban was as effective for its proposed indication compared with warfarin when the existing treatment is used skillfully. The FDA’s concerns centered on how warfarin was used in ROCKET AF. To evaluate proper dosing of warfarin, physicians use a surrogate measure called time in therapeutic range (TTR). The FDA said the median TTR for warfarin in general use is about 65%,

ACCF/AHA 2011 Health Policy Statement on Therapeutic Interchange and Substitution

Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1291 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1291 1. Purpose of This Document . . . . . . . . . . . . . . .1291 2. Document Development Process . . . . . . . . . .1291 3. Definitions, Terminology, and Regulations . . .1292 1. Terminology . . . . . . . . . . . . . . . . . . . .1292 2. Generics . . . . . . . . . . . . . . . . . . . . . . . .1293 3. Bioequivalence . . . . . . . . . . . . . . . . . .1293 4. Biologics and Biosimilars. . . . . . . . . . .1294 2. Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . .1295 3. Federal Regulations and State Laws . . . . . . . . . . .1296 4. Therapeutic Approaches . . . . . . . . . . . . . . . . . . . . .1296 1. Therapeutic Interchange . . . . . . . . . . . . . . . . .1296 2. Therapeutic Substitution . . . . . . . . . . . . . . . . .1297 3. Generic Substitution . . . . . . . . . . . …

New Study Answers Questions About Cardiac Risk of ADHD Drugs

New Study Answers Questions About Cardiac Risk of ADHD Drugs