Drug Information Association Pharmacovigilance and Risk Management Strategies 2017: Overview of the Generic Drug Program and Surveillance.

The US Food and Drug Administration's (FDA's) generic drug program has dramatically increased the availability of affordable, high quality generic drugs. The foundation of generic drug approvals is a two-tiered regulatory framework of pharmaceutical equivalence and bioequivalence. Intrinsic to both of these is consideration of the clinical relevance of formulation and bioequivalence data to support an inference of therapeutic equivalence, based on clear evidence that there are no significant differences between the generic drug and the brand name drug. These analyses allow FDA to determine that the generic drug will perform in the patient in the same way, with the same safety and efficacy profiles, as the brand name drug. Allowable differences and the precise definition of what is meant by equivalence are critical to maintaining the quality, efficacy, and safety of generic drugs. The FDA Office of Generic Drugs' (OGD's) Clinical Safety Surveillance Staff (CSSS) has developed investigative processes that complement the broader FDA safety efforts that focus on the potential impact of allowable differences and equivalence determinations for generic drugs. Two recent examples of the CSSS's processes include a clonidine transdermal system and lansoprazole oral disintegrating tablet. Ongoing efforts of the CSSS result in improvements to the FDA's review processes and the quality of generic drugs in the US market.

Impact of differing glucose-lowering regimens on the pattern of association between glucose control and survival.

AIMS: To characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose-lowering regimens with differing risks of hypoglycaemia. METHODS: Data were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose-lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all-cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time-dependent covariable. RESULTS: There were 6646 deaths in a total follow-up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (≥7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95-1.12); sulphonylurea, aHR 1.11 (95% CI 0.99-1.25); insulin, aHR 1.47 (95% CI 1.25-1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94-1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13-1.35) and including insulin, aHR 1.28 (95% CI 1.18-1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all-cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia. CONCLUSIONS: The pattern of mortality risk across the range of HbA1c differed by glucose-lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk.

Comparative Risk Assessment of Formulation Changes in Generic Drug Products: A Pharmacology/Toxicology Perspective.

This review highlights general toxicology concerns caused by formulation differences between generic and innovator drugs. It underscores the importance of a scientific, clinically oriented, evidence-based comparative safety evaluation procedure for generic drugs and discusses representative case studies from a pharmacology-toxicology perspective. For consideration by generic drug industry stakeholders, this article provides an overview of comparative risk assessments for generic drug products.

International Guidelines for Bioequivalence of Locally Acting Orally Inhaled Drug Products: Similarities and Differences.

International regulatory agencies have developed recommendations and guidances for bioequivalence approaches of orally inhaled drug products (OIDPs) for local action. The objective of this article is to discuss the similarities and differences among these approaches used by international regulatory authorities when applications of generic and/or subsequent entry locally acting OIDPs are evaluated. We focused on four jurisdictions that currently have published related guidances for generic and/or subsequent entry OIDPs. They are Therapeutic Goods Administration (TGA) in Australia, Health Canada (HC) in Canada, European Medicines Association (EMA) of European Union (EU), and the Food and Drug Administration (FDA) in the United States of America (USA). The comparisons of these bioequivalence (BE) recommendations are based on selection of reference products, formulation and inhaler device comparisons, and in vitro tests and in vivo studies, including pharmacokinetic (PK), pharmacodynamics (PD), and clinical studies. For the in vivo studies, the study design, choices of dose, subject inclusion/ exclusion criteria, study period, study endpoint, and equivalence criteria are elaborated in details. The bioequivalence on multiple-strength products and waiver options are also discussed.

Development of performance matrix for generic product equivalence of acyclovir topical creams.

The effect of process variability on physicochemical characteristics and in vitro performance of qualitatively (Q1) and quantitatively (Q2) equivalent generic acyclovir topical dermatological creams was investigated to develop a matrix of standards for determining their in vitro bioequivalence with reference listed drug (RLD) product (Zovirax®). A fractional factorial design of experiment (DOE) with triplicate center point was used to create 11 acyclovir cream formulations with manufacturing variables such as pH of aqueous phase, emulsification time, homogenization speed, and emulsification temperature. Three more formulations (F-12-F-14) with drug particle size representing RLD were also prepared where the pH of the final product was adjusted. The formulations were subjected to physicochemical characterization (drug particle size, spreadability, viscosity, pH, and drug concentration in aqueous phase) and in vitro drug release studies against RLD. The results demonstrated that DOE formulations were structurally and functionally (e.g., drug release) similar (Q3) to RLD. Moreover, in vitro drug permeation studies showed that extent of drug bioavailability/retention in human epidermis from F-12-F-14 were similar to RLD, although differed in rate of permeation. The results suggested generic acyclovir creams can be manufactured to obtain identical performance as that of RLD with Q1/Q2/Q3.

Mortality and other important diabetes-related outcomes with insulin vs other antihyperglycemic therapies in type 2 diabetes.

CONTEXT: The safety of insulin in the treatment of type 2 diabetes mellitus (T2DM) has recently undergone scrutiny. OBJECTIVE: The objective of the study was to characterize the risk of adverse events associated with glucose-lowering therapies in people with T2DM. DESIGN AND SETTING: This was a retrospective cohort study using data from the UK General Practice Research Database, 2000-2010. PATIENTS: Patients comprised 84 622 primary care patients with T2DM treated with one of five glucose-lowering regimens: metformin monotherapy, sulfonylurea monotherapy, insulin monotherapy, metformin plus sulfonylurea combination therapy, and insulin plus metformin combination therapy. There were 105 123 exposure periods. MAIN OUTCOME MEASURES: The risk of the first major adverse cardiac event, first cancer, or mortality was measured. Secondary outcomes included these individual constituents and microvascular complications. RESULTS: In the same model, and using metformin monotherapy as the referent, the adjusted hazard ratio (aHR) for the primary end point was significantly increased for sulfonylurea monotherapy (1.436, 95% confidence interval [CI] 1.354-1.523), insulin monotherapy (1.808, 95% CI 1.630-2.005), and insulin plus metformin (1.309, 95% CI 1.150-1.491). In glycosylated hemoglobin/morbidity subgroups, patients treated with insulin monotherapy had aHRs for the primary outcome ranging from 1.469 (95% CI 0.978-2.206) to 2.644 (95% CI 1.896-3.687). For all secondary outcomes, insulin monotherapy had increased aHRs: myocardial infarction (1.954, 95% CI 1.479-2.583), major adverse cardiac events (1.736, 95% CI 1.441-2.092), stroke (1.432, 95% CI 1.159-1.771), renal complications (3.504, 95% CI 2.718-4.518), neuropathy (2.146, 95% CI 1.832-2.514), eye complications (1.171, 95% CI 1.057-1.298), cancer (1.437, 95% CI 1.234-1.674), or all-cause mortality (2.197, 95% CI 1.983-2.434). When compared directly, aHRs were higher for insulin monotherapy vs all other regimens for the primary end point and all-cause mortality. CONCLUSIONS: In people with T2DM, exogenous insulin therapy was associated with an increased risk of diabetes-related complications, cancer, and all-cause mortality. Differences in baseline characteristics between treatment groups should be considered when interpreting these results.

Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study.

BACKGROUND: Results of intervention studies in patients with type 2 diabetes have led to concerns about the safety of aiming for normal blood glucose concentrations. We assessed survival as a function of HbA(1c) in people with type 2 diabetes. METHODS: Two cohorts of patients aged 50 years and older with type 2 diabetes were generated from the UK General Practice Research Database from November 1986 to November 2008. We identified 27 965 patients whose treatment had been intensified from oral monotherapy to combination therapy with oral blood-glucose lowering agents, and 20 005 who had changed to regimens that included insulin. Those with diabetes secondary to other causes were excluded. All-cause mortality was the primary outcome. Age, sex, smoking status, cholesterol, cardiovascular risk, and general morbidity were identified as important confounding factors, and Cox survival models were adjusted for these factors accordingly. FINDINGS: For combined cohorts, compared with the glycated haemoglobin (HbA(1c)) decile with the lowest hazard (median HbA(1c) 7.5%, IQR 7.5-7.6%), the adjusted hazard ratio (HR) of all-cause mortality in the lowest HbA(1c) decile (6.4%, 6.1-6.6) was 1.52 (95% CI 1.32-1.76), and in the highest HbA(1c) decile (median 10.5%, IQR 10.1-11.2%) was 1.79 (95% CI 1.56-2.06). Results showed a general U-shaped association, with the lowest HR at an HbA(1c) of about 7.5%. HR for all-cause mortality in people given insulin-based regimens (2834 deaths) versus those given combination oral agents (2035) was 1.49 (95% CI 1.39-1.59). INTERPRETATION: Low and high mean HbA(1c) values were associated with increased all-cause mortality and cardiac events. If confirmed, diabetes guidelines might need revision to include a minimum HbA(1c) value. FUNDING: Eli Lilly and Company.

Generic drugs--safe, effective, and affordable.

This article discusses the history and evolution of the process for generic drug evaluation and approval in the United States, with emphasis on locally acting dermatologic products. The requirements for in vivo bioequivalence (BE) testing and the statistical criteria for BE are discussed, and an example of a topical antifungal dermatologic product is used to demonstrate the BE determination for locally acting drugs. Other factors in the dispensing of prescription medications that are not within the Food and Drug Administration regulatory authority are also mentioned.

Switching from premixed insulin to glargine-based insulin regimen improves glycaemic control in patients with type 1 or type 2 diabetes: a retrospective primary-care-based analysis.

BACKGROUND: Insulin glargine (glargine) and premixed insulins (premix) are alternative insulin treatments. This analysis evaluated glycaemic control in 528 patients with type 1 (n = 183) or type 2 (n = 345) diabetes, after switching from premix to a glargine-based regimen, using unselected general practice (GP) data. METHODS: Data for this retrospective observational analysis were extracted from a UK GP database (The Health Improvement Network). Patients were required to have at least 12 months of available data, before and after, switching from premix to a glargine-based regimen. The principal analysis was the change in HbA1c after 12 months of treatment with glargine; secondary analyses included change in weight, bolus usage and total daily insulin dose. Inconsistent reporting of hypoglycemic episodes precludes reliable assessment of this outcome. Multivariate analyses were used to adjust for baseline characteristics and confounding variables. RESULTS: Both cohorts showed significant reduction in mean HbA1c 12 months after the switch: by -0.67% (p < 0.001) in the type 1 cohort and by -0.53% (p < 0.001) in the type 2 cohort (adjusted data). The size of HbA1c improvement was positively correlated with baseline HbA1c; patients with a baseline HbA1c > or = 10% had the greatest mean reduction in HbA1c, by -1.7% (p < 0.001) and -1.2% (p < 0.001), respectively. The proportion of patients receiving co-bolus prescriptions increased in the type 1 (mean 24.6% to 95.1%, p < 0.001) and type 2 (mean 16.2% to 73.9%, p < 0.001) cohorts. There was no significant change in weight in either cohort. Total mean insulin use increased in type 2 diabetes patients (from 0.67 +/- 1.35 U/Kg to 0.88 +/- 1.33 U/Kg, p < 0.001) with a slight decrease in type 1 diabetes patients (from 1.04 +/- 2.51 U/Kg to 0.98 +/- 2.58 U/Kg, p < 0.001). CONCLUSION: In everyday practice, patients with type 1 or type 2 diabetes inadequately controlled by premix insulins experienced significant improvement in glycaemic control over 12 months after switching to a glargine-based insulin regimen. These findings support the use of a basal-bolus glargine-based regimen in patients poorly controlled on premix.

Improved glycaemic control by switching from insulin NPH to insulin glargine: a retrospective observational study.

BACKGROUND: Insulin glargine (glargine) and insulin NPH (NPH) are two basal insulin treatments. This study investigated the effect on glycaemic control of switching from a NPH-based regimen to a glargine-based regimen in 701 patients with type 1 (n= 304) or type 2 (n= 397) diabetes, using unselected primary care data. METHODS: Data for this retrospective observational study were extracted from a UK primary care database (The Health Improvement Network). Patients were required to have at least 12 months of data before and after switching from NPH to glargine. The principal analysis was the change in HbA(1c) after 12 months treatment with glargine; secondary analyses included change in weight and total daily insulin dose. Inconsistent reporting of hypoglycemic episodes precludes reliable reporting of this outcome. Multivariate analyses were used to adjust for baseline characteristics and confounding variables. RESULTS: After adjustment, both diabetic cohorts showed statistically significant reductions in mean HbA(1c) 12 months after the switch, by 0.38% (p < 0.001) in type 1 patients and 0.31% (p < 0.001) in type 2 patients. Improvement in HbA1c was positively correlated with baseline HbA(1c); patients with baseline HbA(1c) > or = 8% had reductions of 0.57% (p < 0.001) and 0.47% (p < 0.001), respectively. There was no significant change in weight or total daily insulin dose while on glargine. The majority of patients received a basal-bolus regimen prior to and after the switch (mean 79.3% before and 77.2% after switch in type 1 patients, and 80.4% and 76.8%, respectively in type 2 patients, p > 0.05). CONCLUSION: In routine clinical practice, switching from NPH to glargine provides the opportunity for improving glycaemic control in diabetes patients inadequately controlled by NPH.

Evaluation of the costs and outcomes from changes in risk factors in type 2 diabetes using the Cardiff stochastic simulation cost-utility model (DiabForecaster).

AIMS: The aim of this study was to determine the mean costs and outcomes associated with modifiable risk factors in patients with type 2 diabetes and to determine equivalent changes to these risk factors in terms of financial costs and health outcomes. METHODS: The Cardiff Stochastic Simulation Cost-Utility Model (DiabForecaster), which evolved from the Eastman model, was used to follow a cohort of 10 000 patients over 20 years. RESULTS: Costs were affected most significantly by changes in the total cholesterol to HDL cholesterol (Total-C:HDL-C) ratio and in HbA(1c). Unit increases in Total-C:HDL-C increased discounted costs by pound 200 per patient; for ratios > 8 units, unit increases led to cost increases of pound 300 per patient. Unit increases in HbA(1c) increased per patient discounted costs from pound 200 (5-6%) up to pound 2900 (10-11%). Similar patterns were observed for QALYs. Estimates of equivalence showed that a 1% reduction in HbA(1c) was equivalent to an 0.4 increment in QALYs, which was equivalent to a reduction of 44 mmHg in SBP, 18.2 mg/dL in HDL, 100 mg/dL in total cholesterol or 1.8 units of Total-C:HDL-C ratio. A 1% reduction in HbA(1c) was also equivalent to pound 108 less cost, which was equivalent to a 13.0 mmHg decrease in SBP or a 0.57 unit decrease in the Total-C:HDL-C ratio. CONCLUSIONS: This model provides reliable utility estimates for diabetic complications and may eliminate uncertainty in cost-effectiveness analyses of treatment. These data also provide a novel way of comparing the value of treatments that have multiple effects.

Anticoagulation in patients with non-valvular atrial fibrillation: an evaluation of stability and early factors that predict longer-term stability on warfarin in a large UK population.

OBJECTIVE: To determine the proportion of patients with non-valvular atrial fibrillation (NVAF) treated with warfarin that achieved a 6-month period within the target INR range (stability). To then evaluate any associations between stability and outcome and to determine whether stability can be predicted by clinical factors at an early stage in warfarin treatment. METHODS: This study was a record linkage study in 1513 patients with NVAF treated with warfarin for a minimum of 6-months, carried out in a large UK population. The main outcome measures were stability (defined as six months within the target INR range [2.0-3.0]), thromboembolic and bleeding event rates and mortality. Secondary outcome measures were the predictive value of baseline characteristics and other treatment variables. RESULTS: Stability was achieved in 52% of the study group. Standardised mean survival was significantly higher in the group who achieved stability (Delta = 16.91 months, p < 0.001) with a hazard ratio of 4.36 (p < 0.001). The stable group had a lower rate of both thromboembolic events (0.8% vs. 2.3% per patient year) and bleeds recorded on inpatient diagnoses (0.4% vs. 1.2% per patient year). Failure to achieve stable control was associated with age (Odds Ratio [OR] 1.011 (95% Confidence Interval [CI] 1.001-1.021)) and morbidity at baseline (OR 1.015; 95% CI 1.007-1.022). An increase in mean time between visits (OR 0.939; 95% CI 0.926-0.952) and the percentage time in range (OR 0.889; 95% CI 0.879-0.900) was associated with a decrease in the chance of instability. Greater variability in INR was also associated with a failure to achieve stability (OR 1.518; 95% CI 1.427-1.615). Receiver Operator Characteristic (ROC) analysis using data from the first three months of treatment demonstrated good discrimination of stability using age and morbidity at baseline and percentage time in range and frequency of visits during the first three months of treatment (area under curve [AUC] 0.780; standard error [SE] 0.012; 95% CI 0.757-0.803). CONCLUSIONS: Many patients never achieved a period of 6-months stability and were at increased risk of thromboembolic events and bleeds. Age, morbidity at baseline and variability of INR control in the first three months could be used to predict instability using warfarin. This study infers that patients should be treated more intensively in the early stages of warfarinisation in order to improve outcome.

Pulse pressure predicts cardiovascular risk in patients with type 2 diabetes mellitus.

BACKGROUND: Pulse pressure (PP), a marker of arterial stiffness, is a better predictor of coronary heart disease (CHD) risk than systolic blood pressure (SBP) or diastolic blood pressure (DBP) in older adults. Whether this is also true in subjects with type 2 diabetes, who are at increased risk for cardiovascular disease, is unknown. METHODS: Data on 2911 type 2 diabetic subjects relating to blood pressure (BP), other risk factors, and cardiovascular events were abstracted from The Cardiff Diabetes Database. Logistic regression was used to assess the relationship among BP components and the risk of CHD, cerebrovascular (CVD), and peripheral vascular (PVD) events after correction for age, gender, cholesterol, and smoking status. RESULTS: In the 4-year follow-up period there were 574 CHD, 168 CVD, and 157 PVD events. Both PP and SBP, but not DBP, were positively associated with the risk of all event types. However, PP emerged as the best predictor of CHD events, and SBP as the best predictor of CVD and PVD events. Total and HDL-cholesterol were the most important variables associated with PP after age. CONCLUSIONS: In summary, PP is a better predictor of CHD events than SBP in persons with type 2 diabetes, but the converse is true for CVD and PVD.

Impact of hypoglycaemia on quality of life and productivity in type 1 and type 2 diabetes.

AIM: To characterise the impact of increasing severity and frequency of hypoglycaemia on utility, quality of life, primary care resource use and productivity (time away from normal activities) in people with both Type 1 and Type 2 diabetes. METHODS: A postal survey was sent to 3200 people with diabetes. Self-reported episodes of mild, moderate, severe and nocturnal hypoglycaemia were quantified from a list of signs and symptoms. A number of instruments were used to explore the effect of frequency and severity of hypoglycaemia on quality of life and productivity. RESULTS: There were 861 respondents for whom diabetes type was identifiable. Of these respondents, 629 (73%) experienced some form of hypoglycaemia, 516 (60%) non-exclusively experienced mild or moderate hypoglycaemia, 57 (7%) experienced severe hypoglycaemia and 191 (22%) experienced nocturnal hypoglycaemia. Quality of life and health-related utility decreased as the frequency and severity of hypoglycaemia increased. The use of primary care resources and lost productivity increased as the severity and frequency of hypoglycaemia increased. These associations were independent in multivariate analysis. CONCLUSIONS: These findings suggest hypoglycaemia impacts heavily on the well-being, productivity and quality of life of people with diabetes, and that every effort should be made to minimise hypoglycaemia while aiming for good glycaemic control.

The routine collation of health outcomes data from hospital treated subjects in the Health Outcomes Data Repository (HODaR): descriptive analysis from the first 20,000 subjects.

OBJECTIVES: Health technology assessment requires data covering many different facets of treatment. A new resource, the Health Outcomes Data Repository (HODaR), is described and evaluated for its use in the pharmaceutical research and development process. METHODS: Data were collated for subjects treated at Cardiff and Vale National Health Service (NHS) Hospitals Trust, United Kingdom. Inpatients are surveyed 6 weeks postdischarge by postal survey, whilst outpatients are handed a survey pack when they attend. Survey data cover sociodemographics, resource use, production losses, and quality of life. Electronic hospital data are available for all responders, and linked with survey returns. Sample characteristics, coverage of disease areas, and a more detailed description of data values for diabetes are described. RESULTS: Survey responses relating to 16,188 admissions and 4476 outpatient attendances were available relating to around 2000 different diagnoses. Over 5000 pharmacy items and 400,000 biochemistry test results were available. Analysis of utility data showed a broad coverage of diseases. For patients with diabetes the pattern of EQ-5D scores across subgroups is not clear. Health service resource use showed a linear relationship with respect to number of comorbidities. CONCLUSIONS: HODaR represents a new approach to accessing patient data, and gathers both routine and survey-based data. Although linking survey data to routine hospital systems is a complex task, which produces some limitations, it can produce health outcomes data at relatively low cost. Its performance within the pharmaceutical research and development process needs to be further evaluated in order to assess its most appropriate role.