Role of patient-reported outcomes and other efficacy endpoints in the drug approval process in Europe (2008-2012)

The present study aimed at systematically reviewing the role and extent of patient-reported outcomes (PROs) usage within the package of scientific evidence considered for marketing authorization (MA). All regulatory information published by the European Medicines Agency (EMA) for products authorized between January 2008 and December 2012 and appearing in the European Public Assessment Report (EPAR) database was examined for efficacy endpoints. The endpoints here considered included: PROs, clinician reported outcomes (CROs), and laboratory reported outcomes (LROs). LROs were the most frequently reported endpoints. Out of the 180 products here selected, 99 (55%), 67 (37%), and 30 (17%), respectively, used LROs, CROs and PROs as primary endpoints (PEs). PROs as any endpoints were used in 82 (46%) products. Out of these, PROs were documented as PE in 30 (37%), with 27 (33%) products having used PROs both as primary and non-PEs. PRO usage was most frequently identified with nervous system and antineoplastic agents. During the study period, the use of all the three types of endpoints appeared to be static. Both the regulatory bodies and the industry should ensure complete and clear reporting of all endpoints used, including PROs, to improve transparency.Peer reviewedFinal Published versio

High Prevalence of Neuropathic Pain Component in Patients with Low Back Pain : Evidence from Meta-Analysis

BACKGROUND: Low back pain (LBP) is a complex syndrome which includes a nociceptive (NcP) component, a neuropathic (NeP) component, or a mixture of components (mixed pain). The NeP component (NePC) in LBP is defined as the presence of NeP with or without an NcP. OBJECTIVE: This meta-analysis aimed at assessing the pooled prevalence of NePC in patients with LBP and at identifying the factors causing significant heterogeneity in reported prevalence. STUDY DESIGN: Meta-analysis. METHODS: A systematic literature search was carried out, with inclusion of all epidemiological studies describing the NeP prevalence levels in LBP patients while using standard diagnostic methods. The "pooled prevalence rate (PPR)" of NePC, either on its own or in combination with NcP, was calculated. A pre-specified subgroup analysis was carried out, considering LBP duration, presence of leg pain, diagnostic method(s), and questionnaire(s) used. RESULTS: The meta-analysis included 20 studies relating to a total of 14,269 LBP patients, of whom 7,969 patients (55.8%) were identified as presenting with NePC. The pooled PR (95% CI) of NePC in patients with LBP was 0.47 (0.40 - 0.54), while the pooled PR of NcP was 0.56 (0.48 - 0.63). Higher NePC pooled PR values were identified in LBP with leg pain as compared to uncomplicated LBP (respectively: 0.60; 0.47 - 0.73 vs 0.27; 0.23 - 0.31; Pinteraction < 0.01). LIMITATIONS: The quality of the included studies was assessed using ad-hoc criteria. Due to the limited number of available studies, one may need to be cautious in reaching conclusions about the impact of disease duration on NePC prevalence values. We pooled studies which used a range of different diagnostic methods, with putatively different sensitivity/specificity diagnosing levels. CONCLUSIONS: Overall, high NePC prevalence levels were here identified in LBP patients. As the pain is a subjective phenomenon and there is no gold standard for the diagnosis of NePC, there is the possibility that the pooled effect estimate may alter depending upon the diagnostic method used. KEY WORDS: Neuropathic pain, nociceptive pain, low back pain, symptom-based questionnaire, chronicity.Peer reviewedFinal Published versio

Cost Effectiveness and Budget Impact of Siponimod Compared to Interferon Beta-1a in the Treatment of Adult Patients with Secondary Progressive Multiple Sclerosis with Active Disease in Switzerland

OBJECTIVE The study aim was to evaluate the cost effectiveness and budget impact of siponimod compared to interferon beta-1a for adult patients with secondary progressive multiple sclerosis (SPMS) with active disease, from a Swiss health insurance perspective. METHODS We conducted an analysis using a Markov cohort model with a cycle length of 1 year, life-long time horizon, and discount rate of 3% for cost and health outcomes. We used a matching-adjusted indirect comparison to estimate clinical outcomes using data from the EXPAND randomised controlled trial of siponimod vs placebo and the Nordic SPMS randomised controlled trial of interferon beta-1a vs placebo as the basis for estimates of disability progression and relapse outcomes. We used 6-month confirmed disability progression results to estimate disability progression in the base-case analysis. We calculated quality-adjusted life-years (QALYs) based on an external study that administered the EQ-5D-3L questionnaire to European patients with multiple sclerosis. We included costs (Swiss Franc (CHF), year 2020) of drug acquisition/administration, adverse events and disease management. We also performed a budget impact analysis to estimate the cost over the first 3 years of introducing siponimod. RESULTS For the base case, siponimod resulted in mean incremental costs of CHF 84,901 (siponimod: CHF 567,838, interferon beta-1a: CHF 482,937) and mean incremental QALYs of 1.591 (siponimod: 7.495, interferon beta-1a: 5.905), leading to an incremental cost-effectiveness ratio of CHF 53,364 per QALY gained. In the probabilistic sensitivity analysis, the probability of the cost effectiveness of siponimod assuming a willingness-to-pay threshold of CHF 100,000 per QALY gained was 90%. Siponimod was projected to result in drug administration costs for siponimod of CHF 23,817,856 in the first 3 years after introduction, accompanied by large cost offsets in drug acquisition of other multiple sclerosis drugs. Considering drug administration, monitoring and adverse event management costs, it was estimated to result in additional healthcare costs in Switzerland of CHF 2,177,021. CONCLUSIONS In the base-case analysis, we found that siponimod may be cost effective for treating Swiss adult patients with SPMS with active disease. The results of the cost-effectiveness analyses are valid under the assumption that the efficacy of siponimod and the comparators on disability progression for the overall SPMS population would be the same in the active SPMS population. CLINICAL TRIAL IDENTIFIER NCT01665144. This economic evaluation was based on the EXPAND trial

Ruboxistaurin for the Treatment of Diabetic Peripheral Neuropathy: A Systematic Review of Randomized Clinical Trials

BackgroundDiabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus. Protein kinase C (PKC) inhibitor's has been thought to be a potential disease modifying drug's in DPN as it slows or reverse neuropathy's progression. To assesses the efficacy and safety of ruboxistaurin on the progression of symptoms, signs, or functional disability in DPN.MethodsA systematic review of the literature databases like PubMed, ProQuest, EBSCO, EMBASE, and Cochrane Central was performed up to August 2012. We included randomized controlled trials (RCTs) comparing PKC inhibitor ruboxistaurin (RBX) with control and lasting at least 6 months. Our primary outcome measure was change in neurological examination, measured by neurological total symptom score (NTSS) and vibration detection threshold (VDT). Secondary outcome measures were total quality of life (QoL), skin microvascular blood flow and others.ResultsSix RCTs were included in review. Change in neurological function assessed by NTSS was reported in six studies, out of which significant difference between the RBX and placebo group seen in four studies favouring treatment group while remaining two studies reported no significant difference. VDT was assessed in only one study in which no significant difference seen between RBX and placebo group. Two studies reported significant improvement in QoL data. Safety data was reported in only two studies in which none of side effect was related to RBX.ConclusionRBX had effects on DPN in some studies, but the evidence is not enough for meta-analysis and firm conclusion

Anti-Counterfeit Technologies: A Pharmaceutical Industry Perspective

Growth of international free trade and inadequate drug regulation have led to the expansion of trade in counterfeit drugs worldwide. Technological protection is seen to be the best way to avoid this problem. Different technologies came into existence like overt, covert, and track and trace technologies. This review emphasises ideal technological characteristics, existing anti-counterfeit technologies, and their adoption in different countries. Developed countries like the USA have implemented RFID while the European trend is towards 2D barcodes. The Indian government is getting sensitised about the extent of the problem and has formulated rules mandating barcodes. Even the pharmaceutical companies have been employing these technologies in order to detain illegitimate drugs in their supply chain

Agreement between Framingham Risk Score and United Kingdom Prospective Diabetes Study Risk Engine in Identifying High Coronary Heart Disease Risk in North Indian Population

BackgroundThe aim of the study is to evaluate the concurrence between Framingham Risk score (FRS) and United Kingdom Prospective Diabetes Study (UKPDS) risk engine in identifying coronary heart disease (CHD) risk in newly detected diabetes mellitus patients and to explore the characteristics associated with the discrepancy between them.MethodsA cross-sectional study involving 489 subjects newly diagnosed with type 2 diabetes mellitus was conducted. Agreement between FRS and UKPDS in classifying patients as high risk was calculated using kappa statistic. Subjects with discrepant scores between two algorithms were identified and associated variables were determined.ResultsThe FRS identified 20.9% subjects (range, 17.5 to 24.7) as high-risk while UKPDS identified 21.75% (range, 18.3 to 25.5) as high-risk. Discrepancy was observed in 17.9% (range, 14.7 to 21.7) subjects. About 9.4% had high risk by UKPDS but not FRS, and 8.6% had high risk by FRS but not UKPDS. The best agreement was observed at high-risk threshold of 20% for both (κ=0.463). Analysis showed that subjects having high risk on FRS but not UKPDS were elderly females having raised systolic and diastolic blood pressure. Patients with high risk on UKPDS but not FRS were males and have high glycosylated hemoglobin.ConclusionThe FRS and UKPDS (threshold 20%) identified different populations as being at high risk, though the agreement between them was fairly good. The concurrence of a number of factors (e.g., male sex, low high density lipoprotein cholesterol, and smoking) in both algorithms should be regarded as increasing the CHD risk. However, longitudinal follow-up is required to form firm conclusions

Microvascular Complications and Their Associated Risk Factors in Newly Diagnosed Type 2 Diabetes Mellitus Patients

The study was aimed at assessing the prevalence of microvascular complications and associated risk factors in newly diagnosed type 2 diabetes mellitus patients. A cross-sectional study was conducted in a public tertiary care hospital. All the recruited patients underwent extensive examination for the presence of microvascular complications like neuropathy, retinopathy, and nephropathy. Prevalence of any complication was 18.04%. Prevalence of neuropathy, retinopathy, and nephropathy was found to be 8.2%, 9.5%, and 2.8%, respectively. Triglycerides (OR, 1.01; P = 0.011) and old age (OR, 1.06; P ≤0.01) were significantly associated with any complication. Triglycerides were significantly associated with neuropathy (OR, 1.01; P = 0.05) and retinopathy (OR, 1.01; P =0.02). Being male posed high risk for nephropathy (OR, 0.06; P =0.01). These results are suggesting need of regular screening for microvascular complications

Evaluating the impact of early vs delayed ofatumumab initiation and estimating the long-term outcomes of ofatumumab vs teriflunomide in relapsing multiple sclerosis patients in Spain

Objectives To evaluate the impact of early (at first-line) vs delayed (3-year delay) ofatumumab initiation and long-term clinical, societal, and economic outcomes of ofatumumab vs teriflunomide in relapsing multiple sclerosis (RMS) patients from a Spanish societal perspective. Methods A cost-consequence analysis was conducted using an Expanded Disability Status Scale (EDSS)-based Markov model. Inputs were sourced from ASCLEPIOS I and II trials and published literature. Results At the end of 10 years, compared with first-line teriflunomide treatment, early first-line ofatumumab initiation was projected to result in 35.6% fewer patients progressing to EDSS ≥7 and 27.8% fewer relapses. The ofatumumab cohort required 7.3% reduced informal care time and had 19% fewer disability-adjusted life years (DALYs) than the teriflunomide cohort. A 3-year delay in ofatumumab treatment (3-year teriflunomide + 7-year ofatumumab) was projected to result in 32.2% more patients progressing to EDSS ≥7, 20.2% more relapses, 5.4% increased informal care time, and 16.6% more DALYs compared with early ofatumumab initiation. Early ofatumumab initiation was associated with total annual cost savings (excluding disease-modifying-therapies’ acquisition costs) of €35,328 ($34,549; conversion factor 1€=$1.02255) and €24,373 ($23,836) per patient vs teriflunomide and 3-year delayed ofatumumab initiation, respectively. Conclusions This study highlights the benefits of early initiation of high-efficacy therapy such as ofatumumab vs its delayed initiation for improving the outcomes in RMS patients (having characteristics similar to those of patients included in the ASCLEPIOS trials). Ofatumumab treatment was projected to provide improved long-term clinical, societal, and economic outcomes vs teriflunomide treatment in RMS patients from a Spanish societal perspective. The therapeutic benefits of ofatumumab in relapsing multiple sclerosis (RMS) patients have been reported in the ASCLEPIOS I and II trials. Using an Expanded Disability Status Scale-based Markov model, this study aimed to assess the impact of early (ie, at first-line, as the first treatment after diagnosis) vs delayed (ie, 3-year delay) ofatumumab initiation in RMS patients from a Spanish societal perspective. In addition, the long-term clinical, societal, and economic outcomes of ofatumumab vs teriflunomide treatment were assessed. Evidence from this study suggests that early initiation of a high-efficacy therapy such as ofatumumab, compared with its delayed initiation, is an effective and cost-saving strategy for improving outcomes in RMS patients. Furthermore, patients receiving ofatumumab for 10 years are projected to experience comparatively better outcomes (clinical, societal, and economic) than those receiving teriflunomide.</p