FDA Labeling Research Articles

Simvastatin prescribing patterns before and after FDA dosing restrictions: a retrospective analysis of a large healthcare claims database.

Muscle-related events, or myopathies, are a commonly reported adverse event associated with statin use. In June 2011, the US FDA released a Drug Safety Communication that provided updated product labeling with dosing restrictions for simvastatin to minimize the risk of myopathies. Our objective was to describe prescribing patterns of simvastatin in combination with medications known to increase the risk of myopathies following updated product labeling dosing restrictions in June 2011. A retrospective observational analysis was carried out, in which administrative claims data were utilized to identify prescribing patterns of simvastatin in combination with calcium channel blockers (CCBs) and other pre-specified drug therapies. Prescribing patterns were analyzed on a monthly basis 24 months prior to and 9 months following product label changes. Incidence of muscle-related events was also analyzed. In June 2011, a total of 60% of patients with overlapping simvastatin-CCB claims and 94% of patients with overlapping simvastatin-non-CCB claims were prescribed an against-label combination. As of March 2012, a total of 41% and 93% of patients continued to be prescribed against-label simvastatin-CCB and simvastatin-non-CCB combinations, respectively. The most commonly prescribed dose of simvastatin was 20 mg (39%). Against-label combinations were most commonly prescribed at a simvastatin dose of 40 mg (56%). Amlodipine was the most commonly prescribed CCB in combination with simvastatin (70%) and the most common CCB prescribed against-label (67%). Despite improvements in prescribing practices, many patients are still exposed to potentially harmful simvastatin combinations. Aggressive changes in simvastatin prescribing systems and processes are needed to improve compliance with FDA labeling to improve medication and patient safety.

PIH75 - The Use of Patient Reported Outcomes (Pros) By the Pharmaceutical Industry in Japan – A Brief Review of Pmda Data in Comparison With Fda and Ema-Approved Label Claims

PIH75 - The Use of Patient Reported Outcomes (Pros) By the Pharmaceutical Industry in Japan – A Brief Review of Pmda Data in Comparison With Fda and Ema-Approved Label Claims

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AbstractInvestments Needed in Vocational Strategies for People with Mental IllnessWisconsin Program Using Rapid Employment Model for Consumers with Mental IllnessMental Health, Faith Community Partner to Reduce Stigma, Support RecoveryMHA Survey Finds Racial, Ethnic Groups Interested in ServicesEngaging Clinical MH Counselors in Integrated Care InitiativesSchizophrenia Trial Results Prompt FDA Label Update RequestBriefly NotedState NewsNames in the NewsComing up

Drug development for pediatric neurogenic bladder dysfunction: dosing, endpoints, and study design.

Pediatric drug development is challenging when a product is studied for a pediatric disease that has a different underlying etiology and pathophysiology compared to the adult disease. Neurogenic bladder dysfunction (NBD) is such a therapeutic area with multiple unsuccessful development programs. The objective of this study was to critically evaluate clinical trial design elements that may have contributed to unsuccessful drug development programs for pediatric NBD. Trial design elements of drugs tested for pediatric NBD were identified from trials submitted to the U.S. Food and Drug Administration. Data were extracted from publically available FDA reviews and labeling and included trial design, primary endpoints, enrollment eligibilities, and pharmacokinetic data. A total of four products were identified. Although all four programs potentially provided clinically useful information, only one drug (oxybutynin) demonstrated efficacy in children with NBD. The lack of demonstrable efficacy for the remainder of the products illustrates that future trials should give careful attention to testing a range of doses, using objectively measured, clinically meaningful endpoints, and selecting clinical trial designs that are both interpretable and feasible. Compiling the drug development experience with pediatric NBD will facilitate an improved approach for future drug development for this, and perhaps other, therapeutic areas.

Use of sapropterin dihydrochloride in maternal phenylketonuria. A European experience of eight cases.

Sapropterin dihydrochloride (SD) is the first drug treatment for phenylketonuria (PKU), but due to the lack of data, its use in maternal PKU must be undertaken with caution as noted in the FDA and EMEA labels. We collected data from eight pregnancies in PKU women treated with SD and we analysed the phenotypes of these patients, their tetrahydrobiopterin (BH4) responsiveness, the indications for SD treatment, the efficacy (metabolic control, phenylalanine (Phe) tolerance and offspring outcome) and the safety data. Results showed that in the seven patients known to be responsive to BH4, the use of SD during pregnancy was efficient in terms of metabolic control and Phe tolerance. The indications for giving SD included the failure of the low-Phe diet (n = 3), the fact that some of these women had never experienced the low Phe diet (n = 2), one unexpected pregnancy in a woman currently on SD and one pregnancy where the foetus was known to have PKU. The offspring of these seven pregnancies were all normal babies with normal birth measurements and outcomes. No side effect related to SD was observed in these seven cases. In the eighth case, SD was prescribed as a rescue treatment without previous knowledge of the BH4 responsiveness to a woman who was already 8weeks pregnant without diet. The birth occurred at 33weeks of gestational age with Potter syndrome (probably related to the absence of metabolic control during the first trimester) and the baby died in the first hours of life. In conclusion, the data presented here provides the first evidence that treatment with pharmacological doses of SD appears to be efficient and safe in women with PKU during pregnancy. Its use should, however, be restricted to those women previously identified to be clear responders to BH4.

Self-Declared Seafood Eco-Labels

The credibility and veracity of an environmental claim depends on a high degree of transparency, clarity and trust. Businesses that utilize eco-labels to market the environmental performance of their seafood products often turn to third party certifications to minimize the potential for greenwashing and provide a level of verification and independence. Others rely on a riskier approach by developing their own “self-declared” or “first-party” eco-labels. Seafood retailers and suppliers considering the creation and use of an eco-label, certification, or seal to be used in the marketing of seafood products should ensure compliance with applicable FDA and USDA labeling rules. Furthermore, entities pursuing “self-declared” or “first-party” seafood eco-labels should consult the FTC’s Green Guides, closely follow developments in greenwashing litigation under federal and state consumer protection and unfair competition laws, and heed the early advice of legal experts in the field.

Automated detection of off-label drug use.

Off-label drug use, defined as use of a drug in a manner that deviates from its approved use defined by the drug's FDA label, is problematic because such uses have not been evaluated for safety and efficacy. Studies estimate that 21% of prescriptions are off-label, and only 27% of those have evidence of safety and efficacy. We describe a data-mining approach for systematically identifying off-label usages using features derived from free text clinical notes and features extracted from two databases on known usage (Medi-Span and DrugBank). We trained a highly accurate predictive model that detects novel off-label uses among 1,602 unique drugs and 1,472 unique indications. We validated 403 predicted uses across independent data sources. Finally, we prioritize well-supported novel usages for further investigation on the basis of drug safety and cost.

Treatment with erythropoiesis-stimulating agents in chronic kidney disease patients with cancer

Treatment of anemia remains an important component in the care of patients with nondialysis chronic kidney disease (CKD) and end-stage renal disease (ESRD). Erythropoietin-stimulating agents (ESAs) remains a key anemia treatment strategy in this patient population. However, anemia management in this group can become more complicated by prior or current history of malignancy. There has been a great deal of work both scientifically and in clinical trials in oncology that have revealed certain concerns and risks of ESA use in patients with cancer. In this review, we will bring together knowledge from nephrology and oncology literature to help nephrologists understand the implications for ESA treatment when CKD/ESRD is complicated by cancer. We also suggest an approach to the management of anemia in this patient group with active or previous malignancy.

Characteristics Of Patients Included In The Myelofibrosis Real-World Practice-Based Network Research (ENRiCH) Data Platform

IntroductionThe prevalence of myelofibrosis (MF) is 3.6 to 5.6 cases per 100,000 in the United States. Overall median survival is 3 years and 1.3 years for patients with intermediate-2 and high-risk disease, respectively. The MF PracticE-Based Network ResearCH (ENRiCH) platform is an adaptive, dynamic, data hub designed to accumulate real-world data to identify MF patients, understand their treatment patterns and unmet needs, inform clinical trial design, and conduct research using clinically relevant outcomes. A descriptive analysis of the demographic and clinical characteristics of MF patients from the ENRiCH platform is reported in this study. MethodsThe ENRiCH platform was developed from patient-level data representing approximately 1 billion US private practitioner medical claims, >1.6 billion pharmacy claims, and electronic medical records from >500,000 cancer patients treated in community oncology practices at 344 locations in 37 states and encompassing approximately 550 treating providers. ENRiCH includes patients with a diagnosis of MF, polycythemia vera (PV), or essential thrombocytopenia (ET), and/or a ruxolitinib prescription between November 1, 2010 and October 31, 2012; patients who received ruxolitinib in a clinical trial were excluded. ResultsAs of March 2013, 6362 MF and 299 ruxolitinib patients were identified. Mean (SD) age was 67.0 (12.6) years for MF patients and 65.8 (15.0) years for the ruxolitinib subgroup, with 45% females. Hematologic comorbidities included myeloid disorders (80% MF; 70% ruxolitinib) and lymphoid disorders (10% MF; 5% ruxolitinib). The most common myeloid disorders were primary MF (47% MF; 29% ruxolitinib), myelodysplastic syndrome (35% MF; 26% ruxolitinib), ET (25% MF; 17% ruxolitinib), and PV (25% MF; 17% ruxolitinib). Common comorbidities of interest that were observed included infectious diseases (35% MF; 35% ruxolitinib), thrombocytopenia (33% MF; 23% ruxolitinib), pulmonary hypertension (7% MF; 7% ruxolitinib), and vitamin D deficiency (7% MF; 8% ruxolitinib). The mean (SD) Charlson comorbidity index (CCI) was 4.36 (2.4) for MF patients and 4.28 (2.4) for the ruxolitinib subgroup. Clinical characteristics and laboratory results among patients with diagnostic or clinical data from the index date forward are shown in the table.The 5 most common concomitant medication groups for ruxolitinib patients were loop diuretics (11%), gout agents (10%), hydrocodone combinations (9%), opioid agonists (9%), and proton pump inhibitors (9%). The top 5 most common medications taken within 180 days prior to new ruxolitinib starts were hydrocodone combinations (21%), antineoplastics (19%), gout agents (18%), glucocorticosteroids (15%), and fluoroquinolones (14%). The predominant [MF (ruxolitinib)] payer types observed were Medicare [48% (37%)], Medicaid [4% (1%)], and commercial insurance [37% (21%)]. ConclusionsThe observed demographic and clinical characteristics of MF patients are similar to prior MF epidemiological studies (Mehta J et al. Leuk Lymphoma. 2013;Early Online: 1-6), suggesting that the sample of MF ENRiCH patients is reflective of the broader US MF population and will allow for broad-based quantification of unmet needs and treatment outcomes. The addition of more MF patients and longer follow-up data will further enhance the value of this large US real-world MF patient data hub including those on current MF therapies.This study was sponsored by Sanofi. Disclosures:Fonseca:IMS Health - a company that received funds from Sanofi to conduct the study: Employment. Lee:Sanofi: Employment. Wang:Sanofi: Employment, Equity Ownership. Dhawan:Sanofi: Employment. Thompson:Sanofi: Employment. Iqbal:Sanofi: Employment, Equity Ownership. Redmond:IMS Health: Consultancy, Employment.Myelofibrosis PatientsRuxolitinib PatientsClinical CharacteristicsN6236181Splenomegaly22%15%Myeloid metaplasia45%14%Thrombocytopenia22%9%Laboratory Test ResultsN58390Hemoglobin <10 g/dL63%72%Platelet count <50,000/microlitera22%18%Platelet count <100,000/microliterb38%42%Platelet count 100,000-200,000/microliterb48%57%Platelet count >200,000/microliterb65%62%aPossible thrombocytopeniabAssociated with different dosing levels for ruxolitinib per FDA label.

The Drug Facts Box: Improving the communication of prescription drug information

Communication about prescription drugs ought to be a paragon of public science communication. Unfortunately, it is not. Consumers see $4 billion of direct-to-consumer advertising annually, which typically fails to present data about how well drugs work. The professional label--the Food and Drug Administration's (FDA) mechanism to get physicians information needed for appropriate prescribing--may also fail to present benefit data. FDA labeling guidance, in fact, suggests that industry omit benefit data for new drugs in an existing class and for drugs approved on the basis of unfamiliar outcomes (such as depression rating scales). The medical literature is also problematic: there is selective reporting of favorable trials, favorable outcomes within trials, and "spinning" unfavorable results to maximize benefit and minimize harm. In contrast, publicly available FDA reviews always include the phase 3 trial data on benefit and harm, which are the basis of drug approval. However, these reviews are practically inaccessible: lengthy, poorly organized, and weakly summarized. To improve accessibility, we developed the Drug Facts Box: a one-page summary of benefit and harm data for each indication of a drug. A series of studies--including national randomized trials--demonstrates that most consumers understand the Drug Facts Box and that it improves decision-making. Despite calls from their own Risk Communication Advisory Committee and Congress (in the Affordable Care Act) to consider implementing boxes, the FDA announced it needs at least 3-5 y more to make a decision. Given its potential public health impact, physicians and the public should not have to wait that long for better drug information.

Significant Cephalad Paddle-Lead Migration After Lumbar Spinal Cord Stimulation Implant

A 77-year-old female with peripheral arterial disease Stage II B (Leriche-Fontaine classification) and lower back pain underwent percutaneous paddle-lead implantation (Lamitrode S-8 Lead kit, 60 cm) under local anesthesia. By using a new device for percutaneous implantation (Epiducer, St. Jude Medical, Minneapolis, MN, USA) at L1-L2 level (based on the FDA labeling) with paramedian approach, the tip of the paddle-lead was placed on the vertebral body of T9 (Fig. 1a). A current standard anchoring technique and a standard strain relief loop were used to secure the lead in the paramedian pocket ( 1. Henderson JM Schade CM Sasaki J et al. Prevention of mechanical failures in implanted spinal cord stimulation systems. Neuromodulation. 2006; 9: 183-191 Crossref PubMed Scopus (55) Google Scholar ). Postoperative testing revealed 100% paresthesia coverage of the painful areas. For the first six days, the patient reported an excellent paresthesia coverage. On the seventh day, not being able to rule out an inappropriate movement of the spine, because of paresthesia reported above the nipple line, an X-ray of the spine confirmed the cephalad migration of the paddle lead, and the tip was found on the vertebral body of T1 (Fig. 1b). The patient underwent a successful lead revision in which a single paramedian incision technique was used to pick the electrode caudally under fluoroscopic guidance and to secure it with extra sutures.

Diabetes and Cancer—An AACE/ACE Consensus Statement

This document represents the official position of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Guidelines are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician. Executive Summary Epidemiologic data have demonstrated significant increases of various cancers in people with obesity and diabetes. Recently, concern has emerged that antihyperglyce-mic medications may also be associated with an increased prevalence of multiple cancers; however, available data are limited and conflicting. The American Association of Clinical Endocrinologists (AACE) convened a conference to review factors associated with cancer development in people with obesity and diabetes and to discuss the possible cancer risk of antihyperglycemic medications. Increased body mass index is associated with an increased risk of multiple cancers based on observational epidemiological data, and is closely associated with increased levels of endogenous insulin, insulin-like growth factors, inflammatory cytokines, and other factors that can have downstream pro-cancer growth effects. The role of hyperglycemia in cancer development is less clear, but an association cannot be ruled out, as current observational data additionally suggest an increased cancer risk in people with diabetes. There is currently insufficient evidence that antihyperglycemic medications may be definitively associated with an increased cancer risk owing to a lack of data from large-scale randomized study designs. Similarly, there is also insufficient evidence showing a positive impact of these medications on cancer development. Clinicians can continue to confidently prescribe all FDA-approved antihyperglycemic medications for the management of hyperglycemia according to established practice guidelines. In patients who have an elevated cancer risk or positive family history of cancer, the cautious selection of antihyperglycemic medications is both prudent and warranted. The AACE additionally advocates for the improved treatment and management of obesity, early cancer screening in patients at increased risk, increased research collaboration, and improved study designs to address outstanding concerns surrounding the diabetes-cancer relationship.

Qualitative assessment of the brief pain inventory (BPI) “pain at its worst in the last 24 hours” item to support assessment of pain as a clinical trial endpoint in metastatic castrate resistant prostate cancer (mCRPC) per FDA labeling standards.

e16018 Background: Pain is common in men with mCRPC and can substantially impair function and quality of life. For assessment of pain as a clinical trial endpoint, substantial validation work has been conducted on the BPI “pain at its worst in the last 24 hours” item, but additional qualitative study of patient understanding of this item is necessary to fully meet FDA labeling standards. Methods: Twenty-six patients with mCRPC in a non-randomized expansion cohort (N=144) of phase II study XL184-203 were interviewed to confirm their comprehension of the BPI “pain at its worst in the last 24 hours” item, and elicit their interpretation of points on the 0-10 response scale to establish levels of intra-patient pain rating consistency. Patient descriptions were evaluated and further compared with previously identified associations between pain severity and pain interference ratings. Results: Patients (median age = 68; range 44-81) had ECOG performance status of 0 (38%) and 1 (62%). Nearly all patients answered the question as intended – by considering the past 24 hours (72%; 18% did not specify); including non-cancer related pain (96%); and reporting pain experienced with analgesia (100%). Patients described pain of “2” as relatively mild, noticeable, and not limiting; pain of “5” as moderate and limiting activity; and pain of “8” as severe and more or less incapacitating. Interpretation of the response scale was highly consistent both among patients and in comparison to levels of pain severity and interference identified in previous large statistical analyses. Conclusions: This study provides important qualitative support for the use of the BPI “pain at its worst in the last 24 hours” item to assess pain per FDA labeling standards in men with mCRPC. Consistent with prior qualitative work, these results confirm this item is well understood by patients. The interpretation of the response scale is remarkably consistent among patients, as well as with results from large statistical analyses, demonstrating the reliability of this item to assess patient-reported pain in cancer trials.

Abstract P5-17-01: Bevacizumab (B) in the adjuvant treatment of breast cancer - first toxicity results from Eastern Cooperative Oncology Group trial E5103.

Abstract Background: A previous feasibility trial (E2104 – Ann Oncol 23(2):331–7,2012) suggested incorporation of B into anthracycline-containing adjuvant therapy was feasible but ongoing cardiac monitoring was required to define the true impact of B on cardiac function. Methods: Patients (pts) were assigned 1:2:2 to one of three treatment arms. In addition to doxorubicin and cyclophosphamide followed by weekly paclitaxel, patients received either placebo (Arm A – AC&amp;gt;T) or B during chemotherapy (Arm B - BAC&amp;gt;BT), or B during chemotherapy followed by B monotherapy (15 mg/kg q3wk) for an additional 10 cycles (Arm C – BAC&amp;gt;BT&amp;gt;B). Randomization was stratified and B dose adjusted for choice of AC schedule (classical q3wk − 15 mg/kg; dose dense(dd) q2 wk − 10 mg/kg). When indicated, radiation and hormonal therapy were administered concurrently with B (for Arm C pts). The primary cardiac endpoint was the incidence of clinically apparent cardiac dysfunction (CHF)defined as symptomatic decline in left ventricular ejection fraction (LVEF) to below the lower limit of normal (LLN) or symptomatic diastolic dysfunction as assessed by independent review. Cumulative toxicity data as of Jan 23, 2012 are presented. Results: From 11.07 to 2.11, 4994 pts were enrolled. Median age was 52; 80% received ddAC. Chemotherapy associated toxicities including myelosuppression (Grade 4 neutropenia 16/20/19%) and neuropathy (Grade ≥ 3 8/8/8%) were similar across all arms. Grade ≥ 3 hypertension/thrombosis/proteinuria/hemorrhage was reported by 7/3/&amp;lt;1/&amp;lt;1% of B-treated pts. 99 pts developed CHF, most commonly reported at the post-AC or post-T evaluation. After a median follow-up of 26 months, the cumulative incidence of clinical CHF at 15 months from randomization in Arm A/B/C was 1.0/1.7/2.9% respectively. Median age of CHF pts was 57; median baseline LVEF of CHF pts was 60. Conclusion: Incorporation of B into anthracycline and taxane containing adjuvant therapy results in a significant but small increase in clinical CHF. The rate of clinical CHF is similar to that predicted by E2104 (2.5–2.9%) and reported In the FDA label for anthracycline pre-treated pts(3.8%). No unexpected toxicities were encountered. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-17-01.

De-adoption of epidermal growth factor receptor (EGFR) inhibitors following recommendations for KRAS testing to guide treatment of metastatic colorectal cancer (mCRC).

191 Background: KRAS mutation status is a predictive biomarker for resistance to EGFR antibodies among mCRC pts, and is recommended for use by ASCO and the FDA. Little is known about the uptake of clinical recommendations in oncology practice. We sought to study the effect of ASCO and FDA guidelines on the use of EGFR antibodies among a commercially insured population. Methods: The LifeLink Health Plan Claims Database (formerly the PharMetrics Patient-Centric Database) was used to create a cohort of &gt;18 yo mCRC pts treated between 2004-2010. We identified treatment and diagnosis using ICD-9 or HCPCS (J) codes. We defined 1st-line therapy as any chemotherapy +/- bevacizumab given after the pt had a claim for mCRC, excluding pts treated with EGFR antibodies in the 1st line. 2nd-line therapy was defined as the initiation of a new chemotherapy agent (irinotecan/oxaliplatin) +/- EGFR antibody. We examined pts in two-month time intervals and calculated the fraction of pts in each interval who received EGFR antibody at any point beyond their 1st-line treatment. Chi 2 tests were used to compare treatment rates at the time points shown in the Table. Results: 5,099 pts received 2nd-line therapy of which 2,603 pts received an EGFR antibody. Median age was 61 years, with 57% males. 59% received an EGFR antibody as a single agent. The remainder received this in combination with one or more of the following agents: fluorouracil 13.5%, irinotecan 36.7%, oxaliplatin 3.9%, and bevacizumab 6.1%. Rates of EGFR antibody use are outlined in the Table. Conclusions: The utilization of EGFR antibodies for mCRC treatment decreased following the presentation of clinical trial data, publication of ASCO guidelines and FDA label change. These data suggest that oncologists respond rapidly to new evidence and professional guidelines, and readily accept the use of predictive biomarkers in clinical practice. [Table: see text]

Physician response to financial incentives when choosing drugs to treat breast cancer

This paper considers physician agency in choosing drugs to treat metastatic breast cancer, a clinical setting in which patients have few protections from physicians' rent seeking. Physicians have explicit financial incentives attached to each potential drug treatment, with profit margins ranging more than a hundred fold. SEER-Medicare claims and Medispan pricing data were formed into a panel of 4,503 patients who were diagnosed with metastatic breast cancer and treated with anti-cancer drugs from 1992 to 2002. We analyzed the effects of product attributes, including profit margin, randomized controlled trial citations, FDA label, generic status, and other covariates on therapy choice. Instruments and drug fixed effects were used to control for omitted variables and possible measurement error associated with margin. We find that increasing physician margin by 10% yields between an 11 and 177% increase in the likelihood of drug choice on average across drugs. Physicians were more likely to use drugs with which they had experience, had more citations, and were FDA-approved to treat breast cancer. Oncologists are susceptible to financial incentives when choosing drugs, though other factors play a large role in their choice of drug.

PRM120 Pathways to Effective Clinro Dossier Development

To highlight some of the common areas that require particular attention when preparing clinical outcome assessment (COA) dossiers, suitable for FDA regulatory label claims, with a particular focus on clinician-reported outcome (ClinRO) measures. The FDA has provided guidance for the use of Patient-Reported Outcome (PRO) measures for relevant endpoints in clinical trials to support label claims (FDA, 2009). Although several authors have indicated that the standards used to evaluate PRO's will apply to all COA's (Burke, 2011; Gwaltney, 2012), the FDA have not published guidelines on ClinRO measures to support label claims. This is surprising given that the ratio of label claims based on ClinRO's is approximately three ClinRO's to every PRO measure (Burke, 2010). We conducted a review of the literature to ascertain the general level of use of ClinRO's and to find examples of widely used ClinRO's. The available evidence for these ClinRO's was then assessed by the standards of the PRO guidance, specifically in relation to content and construct validity, reliability and other psychometric properties. The literature review revealed that ClinRO's are common endpoints in clinical trials. However, it was also apparent from the sample of ClinRO's reviewed, that they fail to meet the evaluative standards prescribed by the FDA particularly in being “well defined and reliable”. ClinRO's used as endpoints in clinical trials to support FDA label claims may lack the required evidence set out in the FDA PRO guidance document. Specifically, many ClinRO's have been developed by clinicians, and widely accepted by clinical peers, without undergoing psychometric evaluation. If the FDA were to evaluate ClinRO's to the same standards as PRO's, the ratio of label claims between ClinRO's and PROs may decrease significantly.

Integration of a standardized pharmacogenomic platform for clinical decision support at Boston Children's Hospital

The Clinical Pharmacogenomics Service (CPS) at Boston Children's Hospital (BCH) was established to use genomic information to make pediatric medications safer. Nearly one-quarter of outpatients are prescribed one or more drugs with genetic information in the FDA label [1]. However, there are still important barriers that must be overcome for routine pharmacogenomic (PGx) clinical use: (1) identification of clinically significant variants, (2) knowledge of variant genotype prior to prescribing medication, and (3) integration with current electronic health record (EHR) systems. To tackle these challenges at BCH, the CPS decided to standardize thiopurine S-methyltransferase (TPMT) testing hospital-wide. TPMT is best known for its role in the catalyzing the S-methylation of the thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine. Approximately 13% of Caucasians and African Americans are heterozygous and have reduced TPMT activity, while approximately 0.3% are completely deficient. Defects in the TPMT gene can lead to decreased methylation and excessive levels of the toxic thioguanine nucleotides, particularly with azathioprine and 6-mercaptopurine, and are at risk for bone marrow suppression. Although the FDA drug label recommends testing for TPMT deficiency prior to dosing and the PharmGKB CPIC group published a guideline [2] with a recommended dosing strategy and interpretation, testing is not universal because these guidelines are difficult to translate into a clinical decision support (CDS) system and integrate with the EHRs. We developed models and specifications to execute PGx CDS rules based on a patient's genotype. Rules are modeled at four levels of abstraction: (1) unstructured (narrative), (2) semi-structured, (3) structured, and (4) executable. As genomic sequencing becomes routine, standardized methods to interpret the data and make clinical decisions are paramount. In conjunction with the BCH DNA Diagnostic Laboratory, we streamlined the TPMT testing process to fit into the usual clinical routine (including ordering, testing in-house and return of results to the clinician). We consolidated all genetic sequencing testing into a single clinical workflow (blood to report) that is run, analyzed and interpreted in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory using the codified CDS rules. The interpretation reports are generated automatically directly from the genotype calls and then manually reviewed for accuracy. Once cleared by the laboratory director, the reports are uploaded into the EHR (Cerner). Specialty flow sheets enable providers to easily view the allele status and interpretation report. We intend to expand the PGx platform to include additional drug/gene pairs.

Comparison of Analytical Nutrient Values to Food Label Values in Select Breakfast Cereals

USDA determines nutrient values for selected foods in the U.S. diet to update the USDA National Nutrient Database for Standard Reference. Label data are sometimes used for breakfast cereals when analytical data are unavailable. According to labeling regulation 21CFR 101.9(g), Table 1. FDA Label Regulations [2] Class I. Added in fortified or fabricated foods Rule: Analytical > label 21CFR 172.5 General provisions for direct food additives – “The quantity of the substance added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other Table 4. Class IIb intrinsic nutrients to limit: analytical results as percent of label values Bran Flakes With Raisins Crisp Toasted Rice Frosted Corn Flakes Multigrain Flakes With Oat Clusters Oat Rings Toasted Oat Shapes With Marshmallows FDA Rule analytical values for fortification must be at least equal to label values, while naturally occurring nutrient values must be at least 80% of label values for “beneficial” (e.g., protein, dietary fiber, potassium, magnesium) or no more than 120% of label values for “nutrients to limit” (e.g., total fat, sugar, sodium). Manufacturers typically add overages to fortified foods to ensure that their products meet the FDA regulations. Six types of ready-to-eat breakfast cereals, selected based on consumption data and other factors, were analyzed as part of Figure 1. Percent difference between analytical and label values for iron technical effect in food.” Thus, the amount of allowed overage is not specified. Class II. Naturally occurring a) Beneficial (vitamins, minerals, protein, total carbohydrate, dietary fiber, polyunsaturated or monounsaturated fat) Rule: Analytical > 80% of label b) Nutrients to limit (calories, sugar, total fat, saturated fat, cholesterol, or sodium) Rule: Analytical 120% of label values for three of the l b t di d lt ll b l 120% i d RESULTS & DISCUSSION Fortification nutrients: The RTE cereals studied were all fortified with vitamins A, D, B6, B12, thiamin, riboflavin, niacin, and iron. Cereal manufacturers typically add amounts greater than the labeled amount in order to account for losses during processing and storage. These overages are demonstrated in this study’s results, shown in Table 2. Th j it f f tifi t l l t th th l b l l (105 228%) of L ab el

Androgen deprivation therapy (ADT) use in Medicare beneficiaries with nonmetastatic (M0) prostate cancer (PC) in the United States.

e15169 Background: ADT is well-established for metastatic PC but is also used in men with less advanced PC. Patterns of ADT use in the M0 PC setting have not been well-described. Methods: Medicare claims in 2005 for men aged ≥66 years (yrs) were assessed for use of gonadotropin-releasing hormone agonists or bilateral orchiectomy. The cohort was limited to men who, during the 15 months (mos) prior to their first 2005 ADT claim, had continuous Parts A + B coverage, a diagnosis code for PC, no claims for metastases (except lymph nodes), and no claims for ADT. Follow-up (f/u) was from ADT initiation to 3 yrs, death, or change in Medicare coverage. Regimen duration was defined by combining claim service count and dosage with FDA label dosing. Because ADT has biologic activity beyond the recommended regimen duration, active dose time was calculated by adding 3 and 6 mos to claims for regimens &lt;6 mos and ≥6 mos, respectively. Interruption was defined as ≥180 days from end of active dose time to next ADT claim. Results: We identified 3246 M0 PC patients aged ≥66 yrs who initiated ADT in 2005 but describe results in the 2161 who had 3 full yrs of f/u (data for the entire cohort were similar). Nearly 70% received only 1 type of ADT agent during f/u (25% had 2 types, 5% had 3 or 4 types), and 73% started on a 3-or 4-month regimen. The distribution of patients by first ADT type (and by type received at any point) was: leuprolide injection: 54% (67%); goserelin implant: 36% (43%); triptorelin injection: 6% (19%); leuprolide implant: 2% (4%); orchiectomy: &lt;1% (1%); and histrelin implant: 0% (3%). Use of &gt;1 type of ADT agent was more common in men who began with goserelin (45%) or triptorelin (53%) versus leuprolide (≤24%). At three years after ADT initiation, 36% received ADT for the entire 36-month period, 15% for 24-35 mos, 17% for 12-23 mos, and 32% for &lt;12 mos. Interruption in active therapy occurred in only 13%. Conclusions: Most elderly men with M0 PC initiating ADT in 2005 started on a 3- or 4-month leuprolide or goserelin regimen. Though these agents remained the most commonly used throughout f/u, switching was common (30% used &gt;1 type during f/u). ADT was continued for at least 2 yrs in nearly half and extended to 3 yrs in over one-third of the cohort.