Current european regulatory perspectives on insulin analogues

Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions

Clinical effectiveness, cost-effectiveness and acceptability of low-intensity interventions in the management of obsessive–compulsive disorder: the Obsessive–Compulsive Treatment Efficacy randomised controlled Trial (OCTET)

Background: The Obsessive–Compulsive Treatment Efficacy randomised controlled Trial emerged from a research recommendation in National Institute for Health and Care Excellence obsessive–compulsive disorder (OCD) guidelines, which specified the need to evaluate cognitive–behavioural therapy (CBT) treatment intensity formats. Objectives: To determine the clinical effectiveness and cost-effectiveness of two low-intensity CBT interventions [supported computerised cognitive–behavioural therapy (cCBT) and guided self-help]: (1) compared with waiting list for high-intensity CBT in adults with OCD at 3 months; and (2) plus high-intensity CBT compared with waiting list plus high-intensity CBT in adults with OCD at 12 months. To determine patient and professional acceptability of low-intensity CBT interventions. Design: A three-arm, multicentre, randomised controlled trial. Setting: Improving Access to Psychological Therapies services and primary/secondary care mental health services in 15 NHS trusts. Participants: Patients aged ≥ 18 years meeting Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for OCD, on a waiting list for high-intensity CBT and scoring ≥ 16 on the Yale–Brown Obsessive Compulsive Scale (indicative of at least moderate severity OCD) and able to read English. Interventions: Participants were randomised to (1) supported cCBT, (2) guided self-help or (3) a waiting list for high-intensity CBT. Main outcome measures: The primary outcome was OCD symptoms using the Yale–Brown Obsessive Compulsive Scale – Observer Rated. Results: Patients were recruited from 14 NHS trusts between February 2011 and May 2014. Follow-up data collection was complete by May 2015. There were 475 patients randomised: supported cCBT (n = 158); guided self-help (n = 158) and waiting list for high-intensity CBT (n = 159). Two patients were excluded post randomisation (one supported cCBT and one waiting list for high-intensity CBT); therefore, data were analysed for 473 patients. In the short term, prior to accessing high-intensity CBT, guided self-help demonstrated statistically significant benefits over waiting list, but these benefits did not meet the prespecified criterion for clinical significance [adjusted mean difference –1.91, 95% confidence interval (CI) –3.27 to –0.55; p = 0.006]. Supported cCBT did not demonstrate any significant benefit (adjusted mean difference –0.71, 95% CI –2.12 to 0.70). In the longer term, access to guided self-help and supported cCBT, prior to high-intensity CBT, did not lead to differences in outcomes compared with access to high-intensity CBT alone. Access to guided self-help and supported cCBT led to significant reductions in the uptake of high-intensity CBT; this did not seem to compromise patient outcomes at 12 months. Taking a decision-making approach, which focuses on which decision has a higher probability of being cost-effective, rather than the statistical significance of the results, there was little evidence that supported cCBT and guided self-help are cost-effective at the 3-month follow-up compared with a waiting list. However, by the 12-month follow-up, data suggested a greater probability of guided self-help being cost-effective than a waiting list from the health- and social-care perspective (60%) and the societal perspective (80%), and of supported cCBT being cost-effective compared with a waiting list from both perspectives (70%). Qualitative interviews found that guided self-help was more acceptable to patients than supported cCBT. Professionals acknowledged the advantages of low intensity interventions at a population level. No adverse events occurred during the trial that were deemed to be suspected or unexpected serious events. Limitations: A significant issue in the interpretation of the results concerns the high level of access to high-intensity CBT during the waiting list period. Conclusions: Although low-intensity interventions are not associated with clinically significant improvements in OCD symptoms, economic analysis over 12 months suggests that low-intensity interventions are cost-effective and may have an important role in OCD care pathways. Further research to enhance the clinical effectiveness of these interventions may be warranted, alongside research on how best to incorporate them into care pathways

Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation

Background: Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium–glucose co-transporter 2 (SGLT2) inhibitors. Objective: To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin. Sources: MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions. Methods: Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers. Results: We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP). Limitations: There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking. Conclusions: Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Boehringer Ingelheim, Bracknell, UK). Funding: The National Institute for Health Research Health Technology Assessment programme

Evaluating long-term outcomes of NHS stop smoking services (ELONS):a prospective cohort study

Background  NHS Stop Smoking Services (SSSs) provide free at the point of use treatment for smokers who would like to stop. Since their inception in 1999 they have evolved to offer a variety of support options. Given the changes that have happened in the provision of services and the ongoing need for evidence on effectiveness, the Evaluating Long-term Outcomes for NHS Stop Smoking Services (ELONS) study was commissioned.  Objectives  The main aim of the study was to explore the factors that determine longer-term abstinence from smoking following intervention by SSSs. There were also a number of additional objectives.  Design  The ELONS study was an observational study with two main stages: secondary analysis of routine data collected by SSSs and a prospective cohort study of service clients. The prospective study had additional elements on client satisfaction, well-being and longer-term nicotine replacement therapy (NRT) use.  Setting  The setting for the study was SSSs in England. For the secondary analysis, routine data from 49 services were obtained. For the prospective study and its added elements, nine services were involved. The target population was clients of these services.  Participants  There were 202,804 cases included in secondary analysis and 3075 in the prospective study.  Interventions  A combination of behavioural support and stop smoking medication delivered by SSS practitioners.  Main outcome measures  Abstinence from smoking at 4 and 52 weeks after setting a quit date, validated by a carbon monoxide (CO) breath test.  Results  Just over 4 in 10 smokers (41%) recruited to the prospective study were biochemically validated as abstinent from smoking at 4 weeks (which was broadly comparable with findings from the secondary analysis of routine service data, where self-reported 4-week quit rates were 48%, falling to 34% when biochemical validation had occurred). At the 1-year follow-up, 8% of prospective study clients were CO validated as abstinent from smoking. Clients who received specialist one-to-one behavioural support were twice as likely to have remained abstinent than those who were seen by a general practitioner (GP) practice and pharmacy providers [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.2 to 4.6]. Clients who received group behavioural support (either closed or rolling groups) were three times more likely to stop smoking than those who were seen by a GP practice or pharmacy providers (OR 3.4, 95% CI 1.7 to 6.7). Satisfaction with services was high and well-being at baseline was found to be a predictor of abstinence from smoking at longer-term follow-up. Continued use of NRT at 1 year was rare, but no evidence of harm from longer-term use was identified from the data collected.  Conclusions  Stop Smoking Services in England are effective in helping smokers to move away from tobacco use. Using the 52-week CO-validated quit rate of 8% found in this study, we estimate that in the year 2012–13 the services supported 36,249 clients to become non-smokers for the remainder of their lives. This is a substantial figure and provides one indicator of the ongoing value of the treatment that the services provide. The study raises a number of issues for future research including (1) examining the role of electronic cigarettes (e-cigarettes) in smoking cessation for service clients [this study did not look at e-cigarette use (except briefly in the longer-term NRT study) but this is a priority for future studies]; (2) more detailed comparisons of rolling groups with other forms of behavioural support; (3) further exploration of the role of practitioner knowledge, skills and use of effective behaviour change techniques in supporting service clients to stop smoking; (4) surveillance of the impact of structural and funding changes on the future development and sustainability of SSSs; and (5) more detailed analysis of well-being over time between those who successfully stop smoking and those who relapse. Further research on longer-term use of non-combustible nicotine products that measures a wider array of biomarkers of smoking-related harm such as lung function tests or carcinogen metabolites