Biopharmaceutics Risk Assessment-Connecting Critical Bioavailability Attributes with In Vitro, In Vivo Properties and Physiologically Based Biopharmaceutics Modeling to Enable Generic Regulatory Submissions.

Quality risk assessment following ICH Q9 principles is an important activity to ensure optimal clinical efficacy and safety of a drug product. Typically, risk assessment is focused on product performance wherein critical material attributes, formulation variables, and process parameters are evaluated from a manufacturing perspective. Extending ICH Q9 principles to biopharmaceutics risk assessment to identify factors that can impact in vivo performance is an upcoming area. This is evident by recent regulatory trends wherein a new term critical bioavailability attributes (CBA) has been coined to identify such factors. Although significant work has been performed for biopharmaceutics risk assessment for new molecules, there is a need for harmonized biopharmaceutics risk assessment workflow for generic submissions. In this manuscript, we attempted to provide a framework for performing biopharmaceutics risk assessment for generic regulatory submissions. A detailed workflow for performing biopharmaceutics risk assessment includes identification of initial CBA (iCBA), their confirmatory evaluation followed by definition of the control strategy. Tools for biopharmaceutics risk assessment, i.e., bio-discriminatory dissolution method and physiologically based biopharmaceutics modeling (PBBM) were discussed from a practical perspective. Furthermore, a case study for CBA evaluation using PBBM modeling for an extended-release product for regulatory submission has been described using the proposed workflow. Finally, future directions of integrating CBA evaluation, biopharmaceutics risk assessment to the FDA Knowledge Aided Structured Assessment (KASA) initiative, the necessity of risk assessment templates, and knowledge sharing between industry and academia are discussed. Overall, the work described in this manuscript can facilitate and provide guidance for biopharmaceutics risk assessment for generic submissions.

Side Effects of Antihypertensives Induced by Switching to Different Generic Medications: Case Reports.

Generic medication is a product that contains the same active substance and pharmaceutical characteristics as brand-name medications. Generic medications are cost-effective and comparable to brand-name medications in terms of clinical endpoints. However, the use of generic medications instead of brand-name medications is a debatable issue among patients and healthcare providers. Two patients with essential hypertension experienced side effects after switching to different generic antihypertensives (one generic medication to another generic medication). Adverse drug reactions, including, hypersensitivity, side effects, and intolerance, should be identified through present and past medical history and clinical characteristics. The adverse drug reactions in both patients were more likely to be side effects of the medications after switching to different generic antihypertensives produced by different companies (patient 1: enalapril and patient 2: amlodipine). The side effects were possibly caused by the different inactive ingredients or excipients. These two case reports emphasise the importance of monitoring adverse drug reactions throughout the course of treatment and communicating with patients prior to switching to a new generic medication.

Efficacy and Safety of Generic Dasatinib in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase: A Multicenter Prospective Study in China.

BACKGROUND: Brand-name dasatinib was approved for newly diagnosed chronic myeloid leukemia-chronic phase (CML-CP) patients due to its deeper and faster molecular response than imatinib. Generics, as the alternative, low-cost forms, are much in demand. This study aimed to evaluate the efficacy and safety of generic dasatinib (Yinishu) as a first-line treatment in CML-CP. MATERIALS AND METHODS: This was a prospective, multicenter, single-arm study from May 2016 to October 2018 with a 2-year follow-up analysis. All patients were given 100 mg/d (initial dose) of the generic dasatinib once a day. The primary endpoint was the major molecular response (MMR) calculated based on the BCR-ABL1 gene mutation rate of ≤ .1% at 12 months. RESULTS: Among 55 patients in CP observed for at least 3 months, 80.4% achieved MMR at 12 months. The cumulative MR4.5 was 58.2% by 24 months. Responses occurred rapidly, with 69.1% of patients achieving complete cytogenetic response (CCyR) by 3 months and 70.9% achieving CCyR by 6 months. The estimated 2-year PFS and OS were both 96%, with a median follow-up time of 24 months. Grade 3 neutropenia occurred in 8.5% of patients, and thrombocytopenia occurred in 11.9% of patients. Nonhematologic toxicity was usually mild and manageable. Pleural effusion occurred in 20.3% of patients, and only 1 patient (1.7%) had a grade 3 pleural effusion. No grade 4 adverse events were observed. CONCLUSION: Generic dasatinib is an effective option for newly diagnosed CML-CP patients, producing an MMR early in a greater number of patients during their therapy.

Comparing real-life carbamazepine exposure between innovator and generic formulation.

BACKGROUND: Carbamazepine is an anticonvulsant largely used in the treatment of epilepsy. The use of generic antiepileptic drugs (AEDs) is controversial because of the eventual possibility to loss seizures control. The aim of our study was to compare the concentration over dose ratio of two products containing carbamazepine, the innovator (Tégrétol®-NOVARTIS) and the generic (Taver®-MEDOCHEMIE). METHODS: It is a retrospective study (2009-2016) including 32 patients treated with carbamazepine. Patients were treated initially by innovator then switched to generic or vice versa. All patients have at least one level of carbamazepine plasma concentration (C0) with the innovator or the generic formulation. Monitoring of carabamazepine was made using immunoassay method (ARCHITECT-ABOTT®). RESULTS: The mean age of our patients was 28.4 years and ranged from 2 to 55 years. The sex ratio M/F was 1.46. The mean ratio C0/dose for the innovator group was 0.723 (min/max: 0.017/1.73), and the mean ratio C0/dose for the generic group was also 0.607 (min/max: 0.064/1.68). There was no statistically significant difference between both groups (P=0.16). CONCLUSION: Our results confirm the difference between the innovator and the generic formulation of carbamazepine. So, switching from innovator to generic seems to be safe and exposure to carbamazepine remains the same.

Cost-effectiveness analysis of branded and authorized generic celecoxib for patients with chronic pain in Japan.

OBJECTIVES: The aim of this study was to examine the cost-effectiveness of branded and authorized generic (AG) celecoxib for chronic pain patients with osteoarthritis (OA), rheumatoid arthritis (RA), and low back pain (LBP), using real-world cost information for loxoprofen and pharmacotherapy for gastrointestinal bleeding. METHODS: This cost-effectiveness analysis was performed as a long-term simulation using the Markov model from the Japanese public healthcare payer's perspective. The analysis was conducted using loxoprofen with real-world weighted price by branded/generic distribution (hereinafter, loxoprofen with weighted price) as a comparator. In the model, we simulated the prognosis of patients with chronic pain by OA, RA, and LBP treated with loxoprofen or celecoxib, over a lifetime period. RESULTS: A cost-increase of 129,688 JPY (1,245.00 USD) for branded celecoxib and a cost-reduction of 6,268 JPY (60.17 USD) for AG celecoxib were recognized per patient in lifetime horizon, compared to loxoprofen with weighted price. No case was recognized to reverse the results of cost-saving by AG celecoxib in one-way sensitivity analysis. The incremental cost-effectiveness ratio of branded celecoxib attained 5,403,667 JPY/QALY (51,875.20 USD/QALY), compared to loxoprofen with the weighted price. CONCLUSION: The current cost-effectiveness analysis for AG celecoxib revealed its good value for costs, considering the patients' future risk of gastrointestinal injury; also, the impact on costs due to AG celecoxib against loxoprofen will be small. It implies that the disadvantage of AG celecoxib being slightly more expensive than generic loxoprofen could be offset by the good cost-effectiveness during the prognosis.

Acceptability of generic versus innovator oral medicines: not only a matter of taste.

Optimum use of generic products would require equivalence, not only in terms of quality, safety, and efficacy in clinical studies, but also patient acceptability to not jeopardize treatment success because of non-adherence which would de facto limit the potential cost saving anticipated by their use. Although acceptability is a requirement for the authorization of pediatric innovator products, a survey of European Union (EU) regulatory authorities showed that few have a formal process for assessing patient acceptability of generic products during the registration processes. The current International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) focus on unifying guidance for the development and scrutiny of generics but should include acceptability alongside the other factors being considered for harmonization.

Efficacy and safety of generic exenatide injection in Chinese patients with type 2 diabetes: a multicenter, randomized, controlled, non-inferiority trial.

AIMS: This study aimed to compare the efficacy and safety of generic exenatide with branded exenatide Byetta® in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on monotherapy or combination therapy of metformin and insulin secretagogues. METHODS: A multicenter, randomized, controlled, non-inferiority trial was performed. A total of 240 patients with T2DM and glycated hemoglobin (HbA1c) ≥ 7% (53 mmol/mol) to ≤ 9.0% (75 mmol/mol) on monotherapy or combination therapy of metformin and insulin secretagogues for at least 3 months were randomized into generic exenatide or branded exenatide groups with a 1:1 ratio for 16 weeks of treatment. The primary endpoint was the change in HbA1c levels from baseline at week 16, with a non-inferiority margin of - 0.35% (- 3.83 mmol/mol) (lower bound of one-sided 95% confidence interval (CI) > - 0.35% (- 3.83 mmol/mol)). Secondary endpoints included the proportion of participants achieving HbA1c < 7% (53 mmol/mol), the changes in fasting plasma glucose (FPG), 2-h postprandial glucose (2hPG) following a standard meal, 7-point self-monitoring blood glucose (SMBG) profiles, body weight change from baseline at week 16 and the change in HbA1c levels from baseline at week 8. Safety issues were also evaluated. RESULTS: After 16 weeks of treatment, HbA1c levels decreased significantly from baseline in the two groups, with a reduction of - 1.10% ± 1.31% (- 12.0 mmol/mol ± 14.3 mmol/mol) in the generic exenatide group and - 1.08% ± 1.11% (- 11.8 mmol/mol ± 12.1 mmol/mol) in the branded exenatide group (both P < 0.001). The least-squares mean difference of HbA1c reduction between the two groups was - 0.03% (- 0.33 mmol/mol), with a lower one-sided 95% CI limit of - 0.27% (- 2.95 mmol/mol), which was higher than the prespecified non-inferiority margin of - 0.35% (- 3.83 mmol/mol). Moreover, there were no significant differences in the proportion of participants achieving HbA1c < 7% (53 mmol/mol) and the changes in FPG, 2hPG, 7-point SMBG profiles and body weight at week 16 and the change in HbA1c levels from baseline at week 8 (all P > 0.05) between the two groups. The incidence of adverse events, including the incidence of hypoglycemia (18.3% and 17.5%, respectively), was similar for the generic and branded exenatide groups (P > 0.05). CONCLUSIONS: In patients with T2DM inadequately controlled on monotherapy or combination therapy of metformin and insulin secretagogues, add-on treatment with generic exenatide demonstrated non-inferiority to branded exenatide in terms of improvements in HbA1c after 16 weeks of treatment. Furthermore, the two drugs were also similar for other efficacy endpoints and safety profile. Trial registration Chinese Clinical Trial Registry: ChiCTR-IPR-15006558, Date registered May 27, 2015.

Compared efficacy and tolerance of the neuromuscular blockade induced by brand-name (Nimbex®) and generic (Cisatrex®) of cisatracurium in mechanically ventilated critically ill patients: a crossover double-blind randomized study.

INTRODUCTION: use of generic drugs is common. However, there is still concern among patients and physicians that brand name drugs are more efficient. The aim of the study was to compare efficacy and tolerance between two forms of cisatracurium: brand name versus generic name. METHODS: it´s a crossover, randomized, double-blind physiological trial. Patients admitted for hypoxemic acute respiratory failure with PaO2/FIO2 < 200mmHg despite optimized ventilation and sedation thus requiring non-depolarizing neuromuscular blocking agents (NMBAs), were enrolled. Patients received consecutively, in a random order, cisatracurium brand name (Nimbex®) and generic (Cisatrex®) over two-hour period separated by one-hour washout period. Neuromuscular function was monitored by a calibrated train-of-four (TOF) stimulation device. Paralysis time delay to reach TOF of 2/4, recovery kinetics and tolerance were monitored. The number needed to demonstrate a significant difference in time delays to reach a TOF of 2/4 between the two forms of cisatracurium was estimated at 22 patients. RESULTS: twenty-two patients were included. Eight (36.4%) had acute respiratory distress syndrome; 8(36.4%), acute exacerbation of chronic obstructive pulmonary disease and 3(13.6%), status asthmaticus. Median [IQR] SAPS II at admission, 28.5 [22, 41]. PaO2/FIO2, 121 [81, 156] mmHg. Paralysis time delays were respectively, 80 [50, 112] vs. 87 [65, 115] minutes, in Nimbex® group and Cisatrex® group; (p=0.579). Within the recovery period, the between two-studied drugs´ difference in TOF was at 0.25±0.96; p=0.64. There were no significant hemodynamic differences. CONCLUSION: the present study revealed no significant differences in efficacy nor in tolerance between cisatracurium brand name Nimbex® and generic name Cisatrex® in hypoxemic ventilated patients.

Adherence and Persistence with DPP-4 Inhibitors Versus Pioglitazone in Type 2 Diabetes Patients with Chronic Kidney Disease: A Retrospective Claims Database Analysis.

BACKGROUND: Adherence and persistence with diabetes medication play an important role in glycemic control and may differ by medication class. However, there is a lack of research comparing diabetes medications in patients with renal impairment, despite the challenges and higher burden associated with managing this population. OBJECTIVE: To compare adherence and persistence among patients with type 2 diabetes mellitus (T2DM) and nondialysis chronic kidney disease (CKD) treated with dipeptidyl peptidase-4 (DPP-4) inhibitors versus pioglitazone. METHODS: This retrospective cohort study used Truven MarketScan administrative claims databases from 2009 to 2015. One-year adherence for patients with T2DM and nondialysis CKD who initiated therapy with either a DPP-4 inhibitor or pioglitazone was measured by proportion of days covered (PDC) following an initial dispensing, and PDC ≥ 0.80 was coded as adherent. Persistence was calculated as the days between the index date and last day with the index medication on hand, based on the end of the last days supply or the end of follow-up (i.e., 365 days), whichever occurred first. Multivariate logistic regression and Cox proportional hazards models were used to estimate confounder-adjusted differences between the groups for adherence and persistence. RESULTS: The final cohort included 9,019 patients (DPP-4 inhibitors: 7,002; pioglitazone: 2,017). In the adjusted analysis, DPP-4 inhibitor users demonstrated a 1.41 (95% CI = 1.25-1.59) higher odds of being adherent compared with pioglitazone users. Overall adjusted HR for persistence was 0.74 (95% CI = 0.69-0.79), which favored DPP-4 inhibitors compared with pioglitazone. Relative to 2010, persistence with pioglitazone decreased in 2011-2012 and then increased in 2013-2014. In the subgroup analysis, DPP-4 inhibitors first had lower (2010: OR = 0.78, 95% CI = 0.70-0.87; 2011-2012: OR = 0.60, 95% CI = 0.54-0.66) and then similar (2013-2014: OR = 1.03, 95% CI = 0.88-1.19) hazards of nonpersistence compared with pioglitazone. CONCLUSIONS: Among patients with T2DM and nondialysis CKD, the use of DPP-4 inhibitors was associated with better adherence compared with pioglitazone. However, following the approval of generic pioglitazone and associated lower cost sharing after 2012, the magnitude of difference in adherence between the medication classes reduced. Similarly, safety warnings in 2011 and approval of generic products in 2012 may have affected pioglitazone persistence, leading to first higher and then similar hazards for nonpersistence with pioglitazone as compared with DPP-4 inhibitors. These shifts in the results for pioglitazone warrant further investigation and close monitoring of the population initiating this medication. DISCLOSURES: No funding was received for this study. The authors have no conflicts of interest to disclose. An abstract for this study was presented as a podium presentation at the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) 2019 Annual Meeting; May 18-22, 2019; New Orleans, LA.

Generic Drugs Not as Safe as FDA Wants You to Believe.

Food and Drug Administration (FDA) rules for the production of prescription drugs are very rigorous and, if followed, guarantees a safe drug supply. For many years, foreign manufacturers have produced substandard generic products and active pharmaceutical ingredients and shipped them into the United States. If the FDA had inspected them with the same rigor as they do domestic manufacturers, they would have found many of these egregious deviations from ethical manufacturing much earlier. Although the FDA is finally stepping up the number of inspections, their current processes still rely on preannounced inspections with long time horizons, so quality issues can be temporarily corrected and documents altered or destroyed.

Comparative Outcomes of Treatment Initiation With Brand vs. Generic Warfarin in Older Patients.

The anticoagulant response to warfarin, a narrow therapeutic index drug, increases with age, which may make older patients susceptible to adverse outcomes resulting from small differences in bioavailability between generic and brand products. Using US Medicare claims linked to electronic medical records from two large hospitals in Boston, we designed a cohort study of ≥ 65-year-old patients. Patients were followed for a composite effectiveness outcome of ischemic stroke or venous thromboembolism, a composite safety outcome, including major hemorrhage, and a 1-year all-cause mortality outcome. After propensity score fine-stratification and weighting to account for > 90 confounders, hazard ratios comparing brand vs. generic warfarin initiators (95% confidence intervals) for the effectiveness, safety, and all-cause mortality outcomes, were 0.97 (0.65-1.46), 0.94 (0.65-1.35), and 0.84 (0.62-1.13), respectively. Results from subgroup analyses of patients with atrial fibrillation, CHADS-VASc score ≥ 3, and HAS-BLED score ≥ 3 were consistent with the primary analysis.

Low quality of some generic cardiovascular medicinal products represents a matter for growing concern.

AIMS: Generic medicinal products (GMPs) are low-priced copies of off-patent medicines that reduce healthcare costs and broaden access to healthcare. Thus, healthcare authorities, professionals, and providers recommend their use. In recent years, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved hundreds of GMPs based on specific bioequivalent trials. The question is whether the brand name drugs and GMPs or the different GMPs similar in purity, efficacy, and safety. METHODS AND RESULTS: We have reviewed the progressive increasing recalls and warning letters of cardiovascular GMPs issued recently by the FDA/EMA. Both Agencies found numerous irregularities in the purity, safety, effectiveness, and current good manufacturing practices in some GMPs widely used in cardiovascular therapy. This evidence and the recent identification of nitrosamine impurities classified as probable human carcinogens in several angiotensin receptor blockers confirm that the presence of low-quality/substandard GMPs represents a serious public health problem with significant impact on national clinical and economic burden. CONCLUSION: A global strategy that unifies the efforts of all the stakeholders, including drug manufacturers, healthcare providers, governments, health professionals, patients, and judicial systems are needed to protect the drug chain supply and ensure that only high-quality GMPs are available for use.

Did Generic Clopidogrel Commercialization Affect Trends of ER Consultations and Hospitalizations in the Population Treated with Clopidogrel?

BACKGROUND: Clopidogrel has been widely used to prevent atherothrombotic events. Since 2011, pharmacists have offered their patients the opportunity to switch to generic clopidogrel, an economic alternative. Whether bioequivalence of generic cardiovascular drugs translates into clinical equivalence at a population level remains unclear and needs to be further documented. OBJECTIVE: We aimed to evaluate the impact of generic clopidogrel commercialization on adverse events (AEs): hospitalizations or emergency room (ER) consultations. METHODS: This is an interrupted time series analysis using the Quebec Integrated Chronic Disease Surveillance System. We included all patients ≥ 66 years old who were users of the brand-name clopidogrel or a generic version (n = 6) 24 months before and up to 12 months after generics commercialization. Rates of AEs were computed, and periods before and after generics commercialization were analyzed by segmented regression models along with exploratory analyses (generic vs. brand name). Sensitivity analyses were also performed using stratification of the time series by (1) sex, (2) the number of prevalent cardiovascular comorbidities, and (3) socioeconomic status. RESULTS: Time series were constituted of 89,525 clopidogrel users (mean age 78 years, 45% women, 71% ischemic heart disease, 34% stroke). For all users, there was a mean rate of 157 AEs per 1000 user-months, stable trend before (-0.1% [95% confidence interval -0.3 to 0.1] and after (0.0% [- 0.5 to 0.6]) generics commercialization. In exploratory analyses, once generic clopidogrel versions were commercialized, rates of AEs were 19.2% (95% CI 11.7-26.7) higher for generic versus brand-name users. This difference persisted up to 1 year. Sensitivity analyses yielded similar results. CONCLUSIONS: The population treated with clopidogrel had similar rates of hospitalizations or ER consultations before and after generics commercialization. However, differences in rates of hospitalizations or ER consultations between generic and brand-name clopidogrel users may represent a drug safety signal which remains to be validated. Using a different study design, permitting adjustment for potential confounders, could be useful in this regard.

The requirements for manufacturing highly active or sensitising drugs comparing Good Manufacturing Practices.

BACKGROUND: To date there exist no internationally recognised Good Manufacturing Practices (GMP) that clearly outline universally accepted standards for manufacturing highly active or sensitising ingredients. The pharmaceutical industry is faced with a twofold problem: determining which drugs need dedicated production areas and identifying the different regulations required in different countries. The aim of this paper is to find, by comparing the current regulations of the various Regulatory Agencies, the differences between containment requirements for the production of highly active or sensitising ingredients. METHODS: An analysis of the following Regulatory Agencies' GMPs was performed: Europe (EMA), China (CFDA), Mexico (COFEPRIS), United States (FDA), Canada (Health Canada) Brazil (ANVISA), India (CDSCO), PIC/S and WHO in order to examine the differences in terms of  containment requirements set by the different Regulatory Authorities for the manufacture of highly active or sensitising ingredients. RESULTS: Our analysis found that the majority of Regulatory Agencies require that beta-lactams (sensitising materials) be produced in dedicated and segregated facilities. For "certain" highly active pharmaceutical ingredients (APIs), COFEPRIS, FDA, HC, EMA, PIC/S and WHO require that they be produced in facilities similar to those required for beta-lactams, while CDSCO, CFDA and ANVISA require that production takes place in segregated areas. Further differences between the Agencies  have emerged regarding classes of highly APIs that require dedicated production. CONCLUSION: A study of GMP adopted by Regulatory Agencies has uncovered significant differences, in particular concerning containment requirements for the production of APIs. For this reason, the harmonisation of GMP following  up-to-date quality standards based on cutting-edge science which are globally applicable is fundamental and will benefit companies and patients alike. Pharmaceutical companies would not be obliged to follow requirements enforced by the State in which they intend to manufacture a product, and patients would benefit from high-quality drugs regardless of their place of production.

Comparison of Incident Cardiovascular Event Rates Between Generic and Brand l-Thyroxine for the Treatment of Hypothyroidism.

OBJECTIVE: To determine whether levothyroxine (L-T4) preparation (generic vs brand) affected hospitalization for cardiovascular events. PATIENTS AND METHODS: We performed a retrospective analysis using a large administrative claims database, OptumLabs Data Warehouse, creating two 1-to-1 propensity score-matched cohorts initiating generic or brand L-T4. Patients were followed for a mean of 1.0±1.2 years (range, 0-9.3 years). We included 87,902 propensity score-matched patients (43,951 patients per cohort) initiating generic or brand L-T4. Variables included in matching were age, sex, race/ethnicity, residence region, selected comorbidities, and Charlson-Deyo comorbidity score. Patients with previous use of any thyroid preparation, amiodarone, or lithium were excluded. Primary outcomes were the event rates for hospitalizations for incident atrial fibrillation, myocardial infarction, congestive heart failure, or stroke. RESULTS: In the generic L-T4 cohort, 35,242 (80.2%) were women and 7327 (16.7%) were 65 years of age or older; in the brand L-T4 cohort, 34,633 (78.8%) were women and 8092 (18.4%) were 65 years of age or older. We found no differences in event rates (events per 1000 person-years) for 4 outcomes comparing generic and brand L-T4 therapy: (1) atrial fibrillation (1.82 vs 2.19; hazard ratio [HR], 1.22; 95% CI, 0.90-1.65; P=.19); (2) myocardial infarction (2.12 vs 1.83; HR, 0.86; 95% CI, 0.64-1.17; P=.35); (3) congestive heart failure (2.27 vs 2.00; HR, 0.88; 95% CI, 0.66-1.18; P=.41); and (4) stroke (3.10 vs 2.38; HR, 0.77; 95% CI, 0.59-1.00; P=.05). Stratification by age group revealed no differences. CONCLUSION: In patients with newly treated hypothyroidism, cardiovascular event rates were similar for generic and brand L-T4.

Single-centre retrospective observational study comparing trough blood concentration and safety of teicoplanin formulations.

Teicoplanin formulations are marketed as antibiotic mixtures with several compounds that share the same core structure. Recent studies conducted in vitro have reported differences in the composition ratio of different teicoplanin products. In this retrospective study, we examined the trough blood concentration of the originator brand and a generic teicoplanin product. Target patients were retrospectively assigned to the originator (Targocid) or generic group. The groups were matched 1:1 using propensity scores. The initial trough blood concentration analysis identified 44 matches. In both groups, the median dosing day for the first measurements was 4, respectively. The initial trough blood concentration of the originator group was significantly higher (mean ± SD, 16.3 ± 4.5 mg/L) than that of the generic group (12.8 ± 4.7 mg/L; 95% CI, -5.4 to -1.6). A significant difference was observed in the frequency of serum creatinine elevation in the study of the frequency of adverse events using Common Terminology Criteria for Adverse Events (originator group, 41.9% vs generic group, 20.9%). In cases where discontinuation was necessary due to side effects, there were three patients in the originator group and one patient in the generic group. This study found that trough blood concentration differed between formulations. Therefore, correction might be necessary while monitoring drug concentration in the blood. Trough blood concentrations are used as surrogate markers for efficacy and safety, so further studies on differences in efficacy and safety between formulations are required.

Exploring knowledge and perceptions on generic drugs of final year pharmacy school students in Greece.

Objectives: The economic crisis in Greece has triggered an extensive public debate about the use of generic drugs (generics). Despite their cost-saving potential, generic market penetration remains very low. This raises questions on awareness of, perception on and preference for generics by health-care professionals and patients. This is a descriptive study on the level of knowledge and attitudes towards generics of final year pharmacy school students in Greece. Methods: An electronic questionnaire was distributed to 173 senior pharmacy school students in three Universities in Greece. Responses were submitted electronically. Results: The majority of students knew that generics contain the same active ingredient as the originator products and are cheaper. Students were somehow concerned with safety and efficacy of generics. The majority of students agreed that pharmacists should probably recommend the use of generics, and indicated that prescribing and dispensing practices would largely depend on the profit margin. Despite more than half of the students expressing a positive attitude towards generics, they were inadequately educated on their features. Conclusion: It is critical to improve knowledge of and preference for generics amongst health-care professionals from early on if to build the trust required to increase generic market penetration and achieve measurable savings in pharmaceutical expenditure.

Patient-Reported Experiences with a Relicensed Generic: Thioguanine for the Treatment of Inflammatory Bowel Diseases.

BACKGROUND AND AIM: Patient-reported outcomes and experiences are indicative of the impact and the quality of care. Thioguanine, a generic drug initially developed for leukemia, has been explored and relicensed as a certified treatment for patients with inflammatory bowel diseases (IBD). The patients' perception of this treatment has not been evaluated before. In this study, we aimed to assess self-reported experiences with thioguanine for IBD. METHODS: Questionnaires were sent out to members of the Dutch National Crohn's and Colitis patient organization. The Treatment Satisfaction with Medicines Questionnaire (SATMED-Q) was used to address questions regarding the satisfaction and impact of thioguanine therapy on the disease and their daily life. Furthermore, data on demographics, disease and (historical) treatment characteristics were collected. Open-ended questions were used for additional comments to the questionnaire. RESULTS: A total of 173 organization members (73% female) reported to be previous or current users of thioguanine. A total of 74% were satisfied with the effectiveness of thioguanine, whereas 5% were not. Eighty percent of the respondents were satisfied with the quality of care. A good or excellent impact on daily life was reported by 54%. A neutral or bad impact on daily life was reported by 40% and 6%, respectively. Improvement of disease activity was reported by 58%. This remained stable or worsened in 39% and 3%, respectively. CONCLUSION: In this self-report survey, among thioguanine treated patients with IBD who had failed with traditional therapies, 80% reported satisfaction with medical care and 74% with the effectiveness of the therapy. In the evaluation of new or rediscovered therapies, patient-reported outcomes and experiences should be considered as a key instrument.

Treatment persistence and adherence and their consequences on patient outcomes of generic versus brand-name statins routinely used to treat high cholesterol levels in Spain: a retrospective cost-consequences analysis.

BACKGROUND: High blood lipoprotein concentrations are one of the major risk factors for cardiovascular diseases. Drug therapy is the base of treatment; statins in particular. Both brand-name and generic presentations are available for statin therapy of high cholesterol levels. Factors that may influence their use in routine medical practice include, among others, patient persistence and adherence to treatment as prescribed by physicians. The aim of this retrospective analysis was to provide real-world evidence of treatment persistence and adherence and their consequences on economic and patient outcomes of generic versus brand-name statins routinely used to treat high cholesterol levels in Spain. METHODS: Existing real-world electronic medical records abstracted from a database of two regions in Spain were analyzed. The analysis compared generic versus brand-name statins data from subjects' who started treatment between July 1, 2010 and June 30, 2012. Treatment persistence, adherence expressed as medication possession ratio (MPR), healthcare resource utilization and their costs were analyzed together with patient's at-goal rates of low-density-lipoprotein-cholesterol (LDL-c), incidence of any major cardiovascular event (CVE) and all-cause mortality during a 5-year follow-up period. Multivariate analyses were applied. RESULTS: A total of 13,244 records were included. Persistence was lower with generics; adjusted hazard ratio -HR- [95% confidence interval]: 0.86 [0.82-0.91], p < 0.001) and MPR was also lower: 61.5% vs. 65.1% (p < 0.001). Less patients with generics reached their LDL-c goal: 39.2% [38.3-40.2%] vs. 42.0% [40.2-43.7%]; adjusted odds ratio; 0.87 [0.80-0.95], p = 0.003. Compared to brand-name statins, the observed probability of occurrence of a CVE; HR: 1.31 [1.15-1.50], p < 0.001, and also all-cause deaths; HR: 1.36 [1.15-1.62], was significantly higher with generics; p < 0.001 in both cases. Adjusted mean total healthcare cost per patient was also higher with generic than with brand-name statins: €9118 (9059-9176) vs. €7980 (7853-8808) [adjusted difference: €1137 (997-1277), p < 0.001]. CONCLUSION: This retrospective cost-consequences analysis found poorer treatment persistence and adherence in patients who first started therapy with generic instead of brand-name statins in routine medical practice in Spain. Also, patients receiving generics were more unlikely to reach LDL-c goals, showed increased probability of having CVE and all-cause mortality at a higher cost to payers.