Food And Drug Administration Recommendations Research Articles

Development and Validation of a New Clinically-Meaningful Rating Scale for Measuring Lateral Canthal Line Severity

Several scales have been employed for evaluating the effects of cosmetic treatments in the periorbital area. The Food and Drug Administration (FDA) has recently issued new recommendations specifying a rigorous process to validate new aesthetic scales. The authors describe and validate a new clinical rating scale: the Investigator's Global Assessment of Lateral Canthal Line (IGA-LCL) severity scale. The new FDA recommendations were utilized to validate the new scale. The first step was concept elicitation (based on direct input from clinicians, patients, and literature) and evaluation of content validity (appropriateness of concepts). The resulting five-point scale provided detailed descriptions of the lateral canthal lines (LCL), including quantitative assessment of LCL length and depth. Performance parameters, including intra- and interrater reproducibility and construct validity, were then evaluated in clinical studies. Finally, the scale's threshold for clinically-meaningful benefit and the ability of the scale to detect change were confirmed in two Phase 2b clinical studies involving a total of 270 subjects. Content validity was established and the IGA-LCL scale showed excellent interrater reliability (weighted Kappa = 0.89) and interrater reliability (weighted Kappa = 0.77; Kendall's coefficient of concordance = 0.89). In clinical trials, the scale was sensitive enough to detect clinically-meaningful one- and two-point changes in LCL severity following treatment with topical botulinum toxin type A (BoNT-A). The authors observed statistically-significant correlations between the physician-rated IGA-LCL results and patient-reported outcomes. The IGA-LCL scale was shown to be reliable, appropriate, and clinically meaningful for measuring LCL severity.

Regulatory Perspectives on Designing Pharmacokinetic Studies and Optimizing Labeling Recommendations for Patients With Chronic Kidney Disease

To optimize drug dosing, it is critical to understand how various intrinsic and extrinsic factors affect systemic exposure of the drug and the response. Chronic kidney disease (or renal impairment) can affect pharmacokinetic characteristics of a therapeutic drug and its metabolites and therefore is one of the most important intrinsic factors that can affect a patient's response to drugs. During drug development, it is critical to understand how renal impairment can affect a drug's pharmacokinetics so that appropriate dosing recommendations can be included in the label. The US Food and Drug Administration (FDA) has published various guidance documents and opinion papers to address scientific and regulatory issues in the study design, data analysis, and labeling recommendations related to dosing in patients with impaired renal function. The 2010 FDA draft guidance on renal impairment provides several updated recommendations that include criteria or principles for evaluating the pharmacokinetics of drugs that are either principally renally cleared or nonrenally cleared in subjects with renal impairment and for categorizing renal function by equations estimating glomerular filtration rate using the Modification of Diet in Renal Disease equations or creatinine clearance using the Cockcroft-Gault equation. The objective of this article is to discuss the FDA's current recommendations and provide examples that illustrate the importance of and challenges in studying effect of renal impairment during drug development.

Propoxyphene-induced torsades de pointes

t The U.S. Food and Drug Administration (FDA) recently recommended that propoxyphene (an opioid analgesic drug used for the relief of moderate pain) be withdrawn from the U.S. market. This FDA recommendation followed concerns of possible propoxyphene-induced cardiac side effects, including prolongation of the QT interval. The decision was based on experimental studies showing that propoxyphene blocks HERG channels as well as on a single “thorough QT study” showing an averaged 30-ms increment of QTc in healthy volunteers taking propoxyphene. Howver, propoxyphene has never been shown to trigger torsades e pointes and is not listed as a potentially torsadogenic drug in the most frequently quoted website on drug-induced QT prolongation. We present a case of propoxyphene-induced orsade in a patient with several risk factors for drug-induced ong QT syndrome.

A Randomized Crossover Study to Determine Relative Bioequivalence of Tenofovir, Emtricitabine, and Efavirenz (Atripla) Fixed-Dose Combination Tablet Compared With a Compounded Oral Liquid Formulation Derived From the Tablet

A Randomized Crossover Study to Determine Relative Bioequivalence of Tenofovir, Emtricitabine, and Efavirenz (Atripla) Fixed-Dose Combination Tablet Compared With a Compounded Oral Liquid Formulation Derived From the Tablet

Stability indicating reverse phase high performance liquid chromatography method for the estimation of capsaicin

Background: Stability Indicating Method (SIM) is a quantitative analytical procedure used to detect a decrease in the amount of the active pharmaceutical ingredient (API) present due to degradation. According to Food and Drug Administration (FDA) guidelines, an SIM is defined as a validated analytical procedure that accurately and precisely measures active ingredients (drug substance or drug product) free from potential interferences, such as degradation products, process impurities, excipients, or other potential impurities, and the FDA recommends that ail assay procedures for stability studies be stability indicating. Here in this study we developed simple precise and accurate stability indicating reverse-phase high-performance liquid chromatographic (RP-HPLC) assay to analyze capsaicin (CAP) at concentrations from 70 to 130 μg/mL. Materials and Methods: HPLC equipped with Photo diode Array (PDA) detector, Pump model 600E of Waters and Empower software. Column used for the separation is ODS (250 × 4.6 mm) with particle size 5 μm and ail the reagents and water were of HPLC grade. Results: The chromatographic separation was carried out using mobile phase Acetonitrile (ACN):water:bufter::75:10:15 with a flow rate of 1 mL/min on a C18 column. The concentration of the eluting compounds was monitored by a UV detector at 280 nm. No interferences were observed when stress conditions were applied and analyzed. Linearity was established using visual method, residuals plot, Dixon, and lack of fitness test. Limit of detection and limit of quantification was found to be 52.9 and 160 ng/mL, respectively. Recovery studies prove this method as useful in recovering the analytes. Relative Standard Deviation (RSD) of inter- and intraday precision within the acceptable limit of 2% proves that this method is precise. No degradation was found with alkaline conditions, thermal and photodegradation. Conclusions: This study can be used for successful separation of CAP and its potential degradants in bulk and formulations. UV spectra of one of the degradants are also presented here and can be the basis to generate chemistry of potential degradants when CAP is kept under environmental conditions.

Vapor Rub Better Than Petrolatum & No Treatment for Cold Symptoms

Vapor Rub Better Than Petrolatum & No Treatment for Cold Symptoms

The addition of long-acting beta-agonists to inhaled corticosteroids in asthma

although long-acting beta-agonists (LABAs) have been used for two decades, with many studies showing benefit versus increasing inhaled corticosteroid (ICS), controversy regarding safety has resulted in the United States Food and Drug Administration (FDA) recently mandating label changes restricting LABA use. This review addresses these safety concerns together with clinical studies and meta-analyses assessing the appropriate use of LABAs. effective use of LABAs requires sufficient ICS to control inflammation. Underuse of ICS, which is often manifest by exacerbations, may reflect undue emphasis on alleged steroid-sparing effects of LABAs. The FDA meta-analysis found that LABA with mandatory ICS was not associated with increased risks of serious adverse events. The role of LABA with ICS as initial therapy in steroid-naïve patients is debated, as is LABA use in children, with data indicating less benefit than in adults. The FDA recommendation that LABA be withdrawn once control is achieved remains problematic, as greater ICS reduction can be achieved when LABA is continued. the safe use of LABAs, which are clearly effective in many patients with moderate to severe asthma, requires high compliance with ICS therapy, which is best assured if ICS and LABA are provided in a single inhaler.

FDA's Recommendations on the Use of Long-Acting β2 Agonists in the Management of Asthma

The revised labeling for long-acting β(2) agonists (LABAs) by the Food and Drug Administration (FDA) is controversial and in part is inconsistent with the 2007 National Asthma Education and Prevention Program asthma guidelines. Two large randomized controlled studies, the Serevent Nationwide Surveillance (SNS) study and the Salmeterol Multicenter Asthma Research Trial (SMART), and a 2008 meta-analysis conducted by the FDA were the main sources of information used to determine the label changes. A paucity of large, well-designed, controlled, prospective studies evaluating the asthma-related risks associated with LABAs makes it difficult to reach a consensus regarding how best to use LABAs in patients with asthma.

Parents' decision following the Food and Drug Administration recommendation: the case of over‐the‐counter cough and cold medication

In 2007, the Food and Drug Administration (FDA) recommended against parents administering over-the-counter cough and cold medications (OTC-CCM) to children under 2 years of age because serious and potentially life-threatening side effects can occur. This study examined the impact of FDA's recommendations against giving children under 2 years old OTC-CCM. We asked parents (n= 377) whether they knew of and trusted the FDA recommendations, as well as whether they intended to follow them. We also examined parents' knowledge, perceptions and behaviours with respect to OTC-CCM. About 33% of our sample had never heard of the FDA recommendations. Of those who were aware, 32.9% intended to continue administering OTC-CCM, and another 36.7% were not sure what to do. Our results indicate that parents who trust the FDA recommendations are significantly more likely to stop giving OTC-CCM to their children. However, almost half did not trust the FDA recommendations or were not sure whether to trust them. Our results indicate that parents who trust the FDA recommendation are significantly more likely to discontinue using OTC-CCM. Our data also reveal that many parents give more than one drug simultaneously (32.9%), cannot identify the active ingredient(s) (28.9%) or fail to store the medications in a safe place (86.1%). Parents' confidence in the FDA recommendations predicted whether they would continue or stop administering OTC-CCM to their children. Our findings illustrate the urgent need for widespread public education about OTC-CCM products to ensure children's safety.

The FDA extended warning for intravenous haloperidol and torsades de pointes: How should institutions respond?

In September 2007, the Food and Drug Administration (FDA) strengthened label warnings for intravenous (IV) haloperidol regarding QT prolongation (QTP) and torsades de pointes (TdP) in response to adverse event reports. Considering the widespread use of IV haloperidol in the management of acute delirium, the specific FDA recommendation of continuous electrocardiogram (ECG) monitoring in this setting has been associated with some controversy. We reviewed the evidence for the FDA warning and provide a potential medical center response to this warning. Cases of intravenous haloperidol-related QTP/TdP were identified by searching PubMed, EMBASE, and Scopus databases (January 1823 to April 2009) and all FDA MedWatch reports of haloperidol-associated adverse events (November 1997 to April 2008). A total of 70 of IV haloperidol-associated QTP and/or TdP were identified. There were 54 reports of TdP; 42 of these events were reportedly preceded by QTP. When post-event QTc data were reported, QTc was prolonged >450 msec in 96% of cases. Three patients experienced sudden cardiac arrest. Sixty-eight patients (97%) had additional risk factors for TdP/prolonged QT, most commonly receipt of concomitant proarrhythmic agents. Patients experiencing TdP received a cumulative dose of 5 mg to 645 mg, patients with QTP alone received a cumulative dose of 2 mg to 1540 mg. While administration of IV haloperidol can be associated with QTP/TdP, this complication most often took place in the setting of concomitant risk factors. Importantly, the available data suggest that a total cumulative dose of IV haloperidol of <2 mg can safely be administered without ongoing electrocardiographic monitoring in patients without concomitant risk factors.

Therapeutic Protein–Drug Interactions and Implications for Drug Development

Many intrinsic and extrinsic factors can affect an individual patient's drug exposure and response. The US Food and Drug Administration (FDA) has published a number of guidances that recommend how and when to evaluate these factors during drug development. The most recent FDA draft guidance on drug interactions provides advice for in vitro and in vivo drug interaction studies, including suggestions for study design, dosing strategies and analysis, and interpretation of data for medical product labels. The draft guidance updated the FDA's recommendations on the evaluation of important cytochrome P450 (CYP) enzyme- and transporter-based drug interactions during drug development.

Antidepressants and suicide risk: how did specific information in FDA safety warnings affect treatment patterns?

From June 2003 through October 2004, the U.S. Food and Drug Administration (FDA) released five safety warnings related to antidepressant use and the increased risk of suicidality for children. Although researchers have documented a decline in antidepressant use among children over this period, less is known about whether specific safety information conveyed in individual warnings was reflected in treatment patterns. Thomson Reuters MarketScan claims data (2001-2005) for a national sample of privately insured children were used to construct treatment episodes (N=22,689). For each new episode of major depressive disorder, it was determined whether treatment followed specific recommendations included in warnings released by the FDA. Treatment recommendations pertained to the use of the antidepressants paroxetine and fluoxetine and to patient monitoring. Treatment patterns were expected to change as the risk information conveyed by the FDA changed over time. The timing of FDA recommendations was associated with trends in the use of paroxetine and fluoxetine by children with major depressive disorder who were initiating antidepressant treatment. However, no evidence of increases in outpatient visits (indicative of monitoring) among depressed children initiating antidepressant use was found. Release of specific risk and benefit information by the FDA was associated with changes in prescribing but not in outpatient follow-up. These results suggest that the FDA plays an important role in communicating information to the public and providers. Yet, although public health safety warnings were associated with changes in some practice patterns, not all recommendations conveyed in warnings were followed.

Erythropoietin Stimulating Agents (ESAs): Reassessment of Use in Cancer and Chronic Kidney Disease (CKD) Settings in the United States, Canada, and Europe.

Abstract 4538 IntroductionInternational reassessments of erythropoiesis stimulating agents (ESAs) for anemia have recently occurred. While ESAs prevent blood transfusions and, improve select quality of life domains among chronic kidney disease (CKD) patients, 8 trials individually identified increased mortality and/or tumor progression among cancer patients treated with ESAs. For CKD, one study of non-dialysis CKD patients targeted to higher versus lower hemoglobin (Hb) levels identified 34% increased relative risk (17.5% vs. 13.5%) for death, acute myocardial infarction, congestive heart failure hospitalization, or stroke with a higher Hb target. MethodsGuidelines, notifications from regulatory agencies and manufacturers, reimbursement policies, and utilization for ESAs in the cancer and CKD settings within the U.S., Europe, and Canada were reviewed. Results: Cancer SettingIn 2008, the Food and Drug Administration (FDA) restricted ESAs from cancer patients seeking cure. Reimbursement is limited to Hb levels < 10 g/dL. In the U.S., ESA usage increased 340% between 2001 and 2006, and decreased 60% since 2007. The European Medicines Agency (EMEA) reports that ESA benefits do not outweigh risks. In Europe, ESA reimbursement is included in global provider payments. Between 2001 and 2006, ESA use increased 51%; since 2006, use has decreased 10%. Canadian manufacturers recommend ESA usage based on patient preference. In Canada, reimbursement for myelosuppressive chemotherapy with ESAs is restricted to Hb levels of 10-11 g/dL in Alberta and 11-12.5 g/dL in British Columbia. Usage increased 20% between 2004 and 2007. CKD SettingThe FDA recommends Hb levels < 12 g/dL and Medicare reimbursement is restricted to Hb levels ≥ 13 g/dL. Between 2001 and 2006, usage increased 480% (non-dialysis) and 40% (dialysis) in the U.S. Since 2007, ESA use has decreased 30% (non-dialysis) and 17% (dialysis). The EMEA recommends target Hb levels of 10-12 g/dL. In Europe, ESA usage has increased 10% since 2001. The 2009 Canadian label recommends Hb levels < 12 g/dL. Within Canada, ESA usage increased 30% since 2004. ConclusionsWhile reassessments of ESA safety have occurred internationally, safety concerns in the U.S. have resulted in marked decrements in ESA use among cancer and CKD patients, whereas in Europe and Canada ESA use has increased over time.SettingUnited StatesEuropeCanadaCancerCKDCancerCKDCancerCKDGuideline2009:-ESAs indicated to prevent transfusions-ESAs may reduce fatigue-ESAs should not be administered to cancer patients seeking cure2007:-Patients should consider potential benefits and harms of ESAs-Target Hb levels: 11-12 g/dL, not >13 g/dL2007:-Consider ESA use in asymptomatic chemotherapy patients with Hb levels 11-11.9g/dL-Initiate ESA use in symptomatic anemic chemotherapy patients with Hb levels 9-11g/dL2009:-Hb levels should be maintained at 11-12g/dL, not >13g/dL2008:-Achieved Hb levels should be <12g/dL-Target Hb levels >12g/dL associated with higher risks of serious cardiovascular events and death2009:-Target Hb levels: 10-12 g/dLPackage Insert2008:-ESAs should not be administered to cancer patients seeking cure-Risk Evaluation and Management Systems for ESAs should include patient guide warning of increased tumor progression and death risks in chemotherapy patients-Removed text indicating ESA treatment is safe at Hb levels ≥ 12g/dL2008:-ESAs indicated for treatment of symptomatic anemic patients with chronic renal failure-Target Hblevels: 10-12g/dL, not >12g/dL2008:-ESAs indicated for treatment of symptomatic anemic patients receiving chemotherapy-ESAs may affect erythropoietin receptors on tumor cells, promoting tumors and accelerating mortality2008:-ESAs indicated for treatment of symptomatic anemic CKD patients with target Hb levels 10-12g/dL2009:-ESAs indicated for treatment of chemotherapy-associated anemia-Increased mortality risks with ESA administration to cancer patients with Hb levels >12 g/dL.- Patients with chemotherapy-associated anemia and reasonably long life expectancies should consider ESA risks and benefits and personal preferences.–Transfusions preferred in patients with long life expectancies receiving myelosuppressive chemotherapy2009:-ESAs indicated in treatment of anemia associated with chronic renal failure for dialysis and non-dialysis patients-Target Hb levels: 10-12g/dL Disclosures:No relevant conflicts of interest to declare.

Rx Report

Rx Report

VA Struggles to Meet Follow-Up Care Recommendation

VA Struggles to Meet Follow-Up Care Recommendation

Influence of prestorage leukoreduction and subsequent irradiation on in vitro red blood cell (RBC) storage variables of RBCs in additive solution saline‐adenine‐glucose‐mannitol

There exists only very few data on in vitro and in vivo effects of gamma irradiation of red blood cells (RBCs) that have been leukoreduced by filtration before a subsequent irradiation. Reported studies reflect neither the current Food and Drug Administration (FDA) nor the European recommendations on timing of irradiation and subsequent storage. We studied 40 RBC units that were prepared from inline filtered whole blood and 40 RBC units that were filtered after component separation. All RBCs were stored in the additive solution saline-adenine-glucose-mannitol and leukoreduced on the collection day. In both groups, 20 components were irradiated on Day +14 with 30 Gy, and 20 served as nonirradiated controls. In vitro evaluation of both irradiated and nonirradiated RBC units was performed before and after irradiation on Days +1, +7, +14, +21, +28, +35, and +42 from the collection day. Gamma irradiation induced enhanced leakage of potassium ions and lactate dehydrogenase and an enhanced in vitro hemolysis rate in the irradiated components. However, in vitro hemolysis rate of both nonirradiated and irradiated components was remarkably lower than 0.8 percent, and the preservation of adenosine triphosphate over 42 days was satisfying. This study reflects the current FDA and European recommendations on timing of irradiation and subsequent storage. Our findings together with recent results of other investigations on the effect of gamma irradiation on leukoreduced RBCs allow the proposal that a storage time up to 28 days after irradiation is allowable.

Nephrogenic systemic fibrosis and the role of gadolinium contrast media

Nephrogenic system fibrosis is a rare disease affecting patients with severe renal insufficiency or dialysis. Its aetiology is incompletely understood. Evidence is growing that gadolinium contrast media is a major risk factor, whereby risk increases with larger cumulative doses. The role of other risk factors, such as inflammation or electrolyte disturbances, is less clear. All published cases to date received gadodiamide, gadopentetate or gadoversetamide, which are considered to be less stable due to a linear molecular structure. The aetiological significance of stability differences between the non-ionic linear, ionic linear and macrocyclic agents remains to be shown. For prevention, strict indications for MRI in risk patients can be combined with Food and Drug Administration (FDA) or European Medicines Agency (EMEA) guidelines. These recommend checking for renal impairment by history or laboratory tests. The FDA recommends avoidance of all gadolinium contrast media in patients with renal insufficiency grades 4 and 5 (glomerular filtration rate <30 mL/min per 1.73 m(2)) or any grade of acute renal failure in liver transplantation patients or candidates. The EMEA differentiates between agents and advises avoidance of only gadodiamide and gadopentetate in the same patient categories. Other gadolinium contrast media should only be used after careful consideration of risks versus benefits. Post-procedural haemodialysis is only indicated in patients on regular dialysis.

Cost-effectiveness of Implementation Methods for ELISA Serology Testing of Trypanosoma cruzi in California Blood Banks

The first U.S. ELISA test for T. cruzi antibodies was licensed by the Food and Drug Administration (FDA) on December 13, 2006. Blood banks have begun screening in absence of FDA recommendations for best implementation methods. We surveyed 2,029 blood donors at five California sites with three risk-based Chagas risk-screening questions. Semi-Markov models compared the cost-effectiveness of three testing strategies. 30% of donors screened positively. Screening all dominated doing nothing, being less costly, and saving more lives. The choice to "screen and test" compared with "testing all" varied by Chagas prevalence, "screening and testing" being cost-effective for high (0.004) and low (0.00004) prevalences, and "testing all" cost-effective for moderate risk (0.0004). It is cost-effective to screen by ELISA rather than do nothing. The best strategy depends on site-specific risk. Census estimates of Hispanics do not predict donor risk well. We suggest using our screening questions to determine risk level and most cost-effective testing strategy.

Contact lenses purchased over the Internet place individuals potentially at risk for harmful eye care practices

Background Individuals are increasingly purchasing contact lenses over the Internet. No studies exist regarding Internet purchase of contact lenses and eye care health practices. Methods One hundred fifty-one college students were surveyed regarding contact lenses purchase category (doctor’s office, store, Internet). Pearson chi-square analyses compared purchase category with responses regarding U.S. Food and Drug Administration (FDA) recommendations for purchasing contact lenses online. Analysis of variance compared contact lenses purchase category with the Time Pressure Scale (TPS). Also, correlation analyses compared the TPS with Internet eye-health statements. Results Contact lens purchase categories included doctor’s office (43.0%), store (55.0%), and Internet (22.5%), with individuals purchasing at multiple venues. With regard to the FDA recommendations, those who purchased contact lenses at a doctor’s office more often adhered to the recommendations, whereas those who purchased contact lenses at a store or the Internet did so less often. Those who purchased contact lenses over the Internet had significantly higher TPS scores. In addition, higher TPS scores were significantly correlated with various statements regarding the Internet. Conclusions Those who purchase contact lenses via the Internet or store do not follow a number of FDA contact lenses recommendations. Also, those with higher TPS scores trust possible non-evidence–based contact lenses Internet information. Implications with regard to the Fairness to Contact Lens Consumers Act are discussed.

Many Physicians Fail to Heed Call to Monitor Youth on Antidepressants

Many Physicians Fail to Heed Call to Monitor Youth on Antidepressants