Evidence, process or context? Examining the factors that drive coverage decisions of pharmaceuticals by health technology assessment bodies in Europe

In Europe, Health Technology Assessment (HTA) bodies produce coverage decisions that guide public funding of pharmaceuticals. This thesis examines and weights those factors that drive HTA coverage decisions, focusing on the National Institute for Health and Clinical Excellence (NICE) in England and Wales, the Scottish Medicines Consortium (SMC), the Dutch College voor Zorgverzekeringen (CVZ), and the French Haute Autorité de Sante (HAS). To address the research question, a dataset of approximately 1000 HTA coverage decisions by NICE, SMC, CVZ and HAS from the period 2004-2009 was created, containing more than 30 clinical, economic, process and socio-economic factors extracted from published HTA reports. A three-category outcome variable was used, defined as the decision to ‘recommend’, ‘restrict’ or ‘not recommend’ a technology. Multivariate analyses were conducted to assess the relative contribution of the explanatory variables on coverage decisions both within and between HTA bodies. Results demonstrate that different combinations of clinical/economic evidence, process and socio-economic factors drive HTA coverage decisions by NICE, SMC, CVZ and HAS. In addition, the same factor may behave differently according to the nature of the coverage decision. The analysis further suggests there is a significant difference between HTA bodies in the probability of reaching a ‘restrict’ or ‘not recommend’ decision outcome relative to a ‘recommend’ outcome, adjusted for evidence, process and context factors. This thesis contributes to the understanding of factors driving HTA coverage decisions by examining multiple European HTA bodies, enhancing the comprehensiveness of the factors examined through descriptive and multivariate analyses and by identifying and weighting the key drivers of the coverage decisions made by the four HTA bodies between 2004 and 2009. This research further provides relevant insights to variation among HTA bodies in the determination of patient access to pharmaceuticals, and implications for collaboration between European HTA bodies

Untangling the complexity of funding recommendations: a comparative analysis of health technology assessment outcomes in four European countries

Objectives Health Technology Assessment (HTA) agencies produce recommendations that guide public funding of pharmaceuticals, based on various criteria. We explored factors that may contribute to explaining differences in coverage decisions by the National Institute for Health and Care Excellence (NICE) in England and Wales, the Scottish Medicines Consortium (SMC), the Dutch College voor Zorgverzekeringen (CVZ), and the French Haute Autorité de Santé (HAS). Methods A dataset of 977 HTA decisions made in 2004–2009 was created. A three-category outcome variable was used (decision to ‘recommend’, ‘restrict’ or ‘not recommend’ a technology). Multivariate analyses explored impacts of clinical, economic, process and socio-economic variables in their decision making. Results Relative to the CVZ and adjusting for a range of confounders, technologies were more likely to be recommended by NICE and HAS, and restricted or not-recommended by the SMC. Recommendation was significantly associated (p ≤ 0.10) with several variables: strength of clinical evidence (number of trials, use of active comparator-arm, demonstration of clinical superiority) orphan status and indication for cancer. Simultaneous assessment of multiple rather than single pharmaceuticals was associated with increased probability of restriction. Conclusions In this European multi-HTA study, appraisal outcomes differed significantly across HTA bodies. A range of evidence and non-evidence factors were associated with HTA decisions, confirming the value of comprehensive, multivariate analyses. Nevertheless, a large proportion of variance in HTA decisions remained unexplained, suggestin

Decision making by NICE: examining the influences of evidence, process and context

The National Institute for Health and Clinical Excellence (NICE) provides guidance to the National Health Service (NHS) in England and Wales on funding and use of new technologies. This study examined the impact of evidence, process and context factors on NICE decisions in 2004–2009. A data set of NICE decisions pertaining to pharmaceutical technologies was created, including 32 variables extracted from published information. A three-category outcome variable was used, defined as the decision to ‘recommend’, ‘restrict’ or ‘not recommend’ a technology. With multinomial logistic regression, the relative contribution of explanatory variables on NICE decisions was assessed. A total of 65 technology appraisals (118 technologies) were analysed. Of the technologies, 27% were recommended, 58% were restricted and 14% were not recommended by NICE for NHS funding. The multinomial model showed significant associations (p ≤ 0.10) between NICE outcome and four variables: (i) demonstration of statistical superiority of the primary endpoint in clinical trials by the appraised technology; (ii) the incremental cost-effectiveness ratio (ICER); (iii) the number of pharmaceuticals appraised within the same appraisal; and (iv) the appraisal year. Results confirm the value of a comprehensive and multivariate approach to understanding NICE decision making. New factors affecting NICE decision making were identified, including the effect of clinical superiority, and the effect of process and socio-economic factors

Relative efficacy and safety of simeprevir and telaprevir in treatment-naïve hepatitis C-infected patients in a Japanese population: a Bayesian network meta-analysis

Aim: Simeprevir (SMV) is an oral, once‐daily protease inhibitor for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. In phase II/III randomized controlled trials (RCT) conducted in Japan, SMV, in combination with peginterferon‐α and ribavirin (PEG IFN/RBV), demonstrated potent efficacy in HCV genotype 1‐infected patients relative to PEG IFN/RBV and was generally well tolerated. Telaprevir (TVR) in combination with PEG IFN/RBV is licensed for the treatment of HCV in Japan. In the absence of head‐to‐head comparisons of TVR and SMV in a Japanese population, we undertook a network meta‐analysis (NMA) to examine the relative efficacy and safety of SMV and TVR in combination with PEG IFN/RBV. Methods: A systematic review identified SMV and TVR RCT in Japanese treatment‐naïve patients. Bayesian NMA was performed assuming fixed study effects. Results: Three studies met our inclusion criteria: two SMV and one TVR. SMV showed a higher mean odds ratio (OR) of achieving SVR versus TVR (OR, 1.68 (95% credible interval 0.66–4.26)). SMV showed a lower mean OR of discontinuation: overall, 0.35 (0.12–1.00); and due to AE, 0.87 (0.23–3.34) versus TVR. SMV showed a lower mean OR of experiencing anemia 0.20 (0.07–0.56) and rash 0.41 (0.17–0.99) but a higher mean OR of experiencing pruritus 1.26 (0.46–3.47) versus TVR. Conclusion: In this indirect treatment comparison, SMV, in combination with PEG IFN/RBV, showed a favorable risk–benefit profile compared with TVR with PEG IFN/RBV in Japanese treatment‐naïve HCV patients

Fatigue during treatment for hepatitis C virus : results of self-reported fatigue severity in two Phase IIb studies of simeprevir treatment in patients with hepatitis C virus genotype 1 infection

Background: Fatigue is a common symptom of chronic hepatitis C virus (HCV) infection and a frequent side-effect of peginterferon/ribavirin (PR) therapy for HCV. This study evaluated the impact of adding the oral HCV NS3/4A protease inhibitor simeprevir to PR on patient-reported fatigue and health status among patients with chronic HCV genotype 1 infection enrolled in the Phase IIb PILLAR and ASPIRE trials [NCT00882908; NCT00980330]. Methods: Treatment-naïve patients (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) were randomized to simeprevir plus PR (simeprevir/PR) or placebo plus PR (placebo/PR). In PILLAR, duration of PR treatment in the simeprevir/PR groups was determined using response-guided therapy (RGT) criteria. PR could be terminated at Week 24, instead of Week 48, if HCV RNA was <25 IU/mL by Week 4 and then undetectable at Weeks 12, 16, and 20. In both studies, patients completed the Fatigue Severity Scale (FSS) and EQ-5D quality-of-life questionnaire in their native language at baseline and throughout the studies up until Week 72. Results: During the first 24 weeks of treatment, mean FSS total score was increased to a similar degree compared with baseline among patients receiving simeprevir/PR or placebo/PR in both studies indicating increased fatigue severity. Mean FSS scores returned to values comparable with baseline among patients receiving simeprevir/PR after Week 24 in PILLAR (after treatment completion for the majority of patients) and in ASPIRE (after Week 48), consistent with RGT enabling early termination of all treatment at Week 24 in 82.2% of simeprevir/PR-treated patients in the PILLAR study. Similar results were observed for EQ-5D, with simeprevir/PR-treated patients experiencing less time with worse health problems according to EQ-5D scores compared with placebo/PR groups in both studies, and more rapid improvement in health status associated with shorter treatment duration in the PILLAR study. Conclusions: Combination of simeprevir with PR did not increase patient-reported fatigue severity or health status impairments beyond that reported by patients treated with PR alone. Many patients treated with simeprevir/PR returned to pretreatment fatigue and health status levels sooner due to increased treatment efficacy that enabled shorter duration of all therapy, compared with PR alone

Mycobacterium avium subsp. paratuberculosis isolated from wild red deer ( Cervus elaphus ) in Northern Italy

Paratuberculosis (or Johne’s disease) is an infectious disease which affects mainly ruminants and it is caused by Mycobacterium avium subsp. paratuberculosis (MAP). During a culling program (years 2011–2015) aimed at controlling the red deer (Cervus elaphus) population in Stelvio National Park (Italian Alps), where paratuberculosis was already described in this species, 382 tissue samples from the Lombardy Region and 102 fecal specimens from the Autonomous Province of Bolzano were analyzed by PCR. Of these, 77 samples (20.16%) from the Lombardy area and 19 specimens (18.63%) from the Bolzano area resulted PCR positive. The cultural test was carried out on PCR positive samples (n = 96), enabling the isolation of 19 MAP field strains which were genotyped using MIRU-VNTR typing and Short Sequence repeats (SSRs). Our results suggest that all isolates share an identical VNTR profile corresponding to the INMV1 genotype. The only variation was on the locus SSR2, but the utility of this last locus has already been questioned because of its instability. Overall, these data suggest a common clonal origin and host adaptation during the diffusion of paratuberculosis in this population. Finally, this profile is the same as that which has already been described in the cattle population in Northern Italy, suggesting a possible inter-species disease transmission pattern from wildlife to domestic ruminants and vice versa