text:
Trastuzumab emtansine for treating HER2-positive advanced breast cancer after trastuzumab and a taxane
Technology appraisal guidance [TA458] Published date: 19 July 2017 Last updated: 20 November 2017
6 Appraisal committee members and NICE project team
Clinical effectiveness (NICE technology appraisal guidance 371)
Cost effectiveness (NICE technology appraisal guidance 371)
Pharmaceutical Price Regulation Scheme (PPRS)
Cancer Drugs Fund reconsideration
Summary of appraisal committee's key conclusions
The appraisal committee reviewed the data available on the clinical and cost effectiveness of trastuzumab emtansine, having considered evidence on the nature of human epidermal growth factor receptor 2 (HER2)-positive, unresectable, locally advanced or metastatic breast cancer and the value placed on the benefits of trastuzumab emtansine by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
4.1 The committee discussed with patient experts the nature of the condition and the perceived benefits of trastuzumab emtansine for patients. It heard that metastatic breast cancer is a debilitating condition that can affect women of all ages and leads to premature death. The committee heard from the patient experts that patients and their families often highly value what may seem to others even relatively short extensions to life, as long as the person's quality of life is maintained. The committee noted that patients are particularly concerned about unpleasant side effects associated with treatment. The clinical experts explained that trastuzumab emtansine is both an effective treatment and also well tolerated, with fewer side effects than some of the other options. The committee recognised that patients value the availability of more treatment options and that trastuzumab emtansine would be welcomed by patients and their families.
4.2 The committee discussed with the clinical experts the current clinical management of HER2‑positive metastatic breast cancer. It was aware that NICE recommends trastuzumab plus paclitaxel as a first-line treatment for people who have not received chemotherapy for metastatic breast cancer and in whom anthracycline treatment is inappropriate (see NICE's guidance on the use of trastuzumab for the treatment of advanced breast cancer). After disease progression, NICE recommends second- and third-line treatment with non-targeted therapies such as capecitabine or vinorelbine, which can be combined with continued trastuzumab therapy if disease progression is within the central nervous system alone (see NICE's guideline on advanced breast cancer). The committee heard from the clinical experts that trastuzumab plus chemotherapy has become the standard first-line treatment in clinical practice, but more recently in England patients may receive pertuzumab in addition to trastuzumab and docetaxel, which is funded by the Cancer Drugs Fund. It further heard that after disease progression on trastuzumab (that is, in the second-line setting) clinical practice varies, but most patients will continue trastuzumab plus chemotherapy (capecitabine or vinorelbine) or receive lapatinib plus capecitabine. The committee noted that continued trastuzumab therapy was not offered by all cancer centres, and that lapatinib plus capecitabine was available in England through the Cancer Drugs Fund. The committee heard from the clinical experts that contrary to NICE guidance, single-agent chemotherapy (for example, capecitabine or vinorelbine) is not routinely used for patients whose disease progressed on first-line treatment. The committee concluded that local access to treatments and the availability of treatments through the Cancer Drugs Fund led to some variation in clinical practice so that no single pathway of care could be defined.
4.3 The committee considered the likely position of trastuzumab emtansine in the treatment pathway of HER2‑positive, unresectable, locally advanced or metastatic breast cancer and the key comparators for trastuzumab emtansine in clinical practice. It noted that the clinical experts expect that trastuzumab emtansine would be used as second-line therapy (that is, instead of continued trastuzumab plus chemotherapy or lapatinib plus capecitabine) because trastuzumab emtansine has been shown to be more clinically effective than the alternative second‑line agent, lapatinib plus capecitabine, in EMILIA. The committee concluded that based on current clinical practice, trastuzumab plus capecitabine, trastuzumab plus vinorelbine and lapatinib plus capecitabine were relevant comparators at this stage of the disease.
4.4 The committee discussed which sources of trial data were appropriate for the second-line setting, in which trastuzumab emtansine is likely to be used. The committee was aware that 36% of patients in EMILIA and 0% of patients in TH3RESA received trastuzumab emtansine as second-line therapy for locally advanced or metastatic disease. Given these proportions, the committee concluded that EMILIA was the most relevant source of clinical evidence for its decision-making in this appraisal.
4.5 The committee discussed whether the results from EMILIA were generalisable to clinical practice, noting that patients in England may receive pertuzumab plus trastuzumab plus docetaxel in the first-line setting. It heard from the company that 9.5% of patients in EMILIA had previously received pertuzumab therapy (10.3% of patients in the trastuzumab emtansine group, 8.7% of patients in the lapatinib plus capecitabine group) but the committee considered this proportion too small to determine whether the effect of trastuzumab emtansine differed in patients who had previously received pertuzumab. In addition, the committee heard from the clinical experts that there was no evidence on whether or not pertuzumab can modify the effect of subsequent treatment with trastuzumab emtansine. However, the clinical experts indicated that trastuzumab emtansine demonstrated a clinical benefit after trastuzumab, and that trastuzumab and pertuzumab have similar mechanisms of action, so the effect of trastuzumab emtansine would not be expected to differ after trastuzumab or after pertuzumab plus trastuzumab. The committee concluded that it was currently unknown whether previous pertuzumab would alter the clinical effectiveness of subsequent treatment with trastuzumab emtansine, but there was no positive evidence that this was the case.
4.6 The committee also noted the evidence review group's (ERG's) concern that none of the patients in EMILIA had an Eastern Cooperative Oncology Group (ECOG) performance status of 2, whereas in clinical practice around one third of patients would have an ECOG performance status of 2. The committee appreciated that patients enrolled in clinical trials may be younger and with better performance status than those in routine clinical practice, and so might have better outcomes. The committee agreed that the population in EMILIA was otherwise reasonably representative of patients in the UK. It concluded that the results of EMILIA were suitable for assessing the clinical effectiveness of trastuzumab emtansine in clinical practice.
4.7 The committee considered the clinical effectiveness of trastuzumab emtansine as a second-line treatment. It was aware that in EMILIA, patients in the trastuzumab emtansine group had improved survival compared with patients in the lapatinib plus capecitabine group, irrespective of the line of therapy. However, the committee noted that subgroup analyses suggested a lesser benefit in patients who received second‑line treatment (in whom the difference in effect was not statistically significant) than in the overall population. The committee was aware that the analysis may not have been powered to show a difference in treatment effect in the subgroup. In addition, the committee heard from the clinical experts that there is no biologically plausible reason for the effect to differ according to the number of previous treatments patients had received. The committee concluded that the subgroup analysis was not reliable enough to inform a decision about the clinical effectiveness of trastuzumab emtansine as a second-line treatment.
4.8 The committee took note of the patient expert's concern about the tolerability of treatment and discussed the adverse events in EMILIA that led patients to stop treatment, which it considered to be a reasonable proxy for tolerability. The committee understood that fewer patients stopped treatment because of an adverse event in the trastuzumab emtansine group than in the lapatinib plus capecitabine group (5.9% and 17% of patients respectively). It also heard from the company that the most common adverse event that resulted in patients stopping trastuzumab emtansine was a decreased platelet count (2% of patients). The committee concluded that trastuzumab emtansine had been shown to have a satisfactory adverse event profile in EMILIA.
4.9 The committee considered the Bayesian mixed treatment comparison used by the company to estimate hazard ratios for trastuzumab emtansine relative to the comparators for which no head-to-head evidence existed. The committee agreed that CEREBEL, an open-label trial comparing the incidence of central nervous system metastases in patients with HER2‑positive metastatic breast cancer treated with lapatinib plus capecitabine or trastuzumab plus capecitabine, and the study by Martin et al. (2011), should be included in the base-case analysis to use all available evidence and that the ERG's random effects model would better reflect the heterogeneity between the trials than the company's fixed effect model.
4.10 The committee considered the company's economic model used to estimate the cost effectiveness of trastuzumab emtansine and how it captured the main aspects of the condition. It noted that the company used a 3‑state model and chose a time horizon of 10 years for its base case. The committee agreed that the model structure was consistent with other models used for the same disease. The committee noted that the ERG preferred a 15‑year time horizon because a small proportion of patients were still alive at 10 years and data for these patients would not be included in a model with a 10‑year horizon. The committee agreed that in principle a lifetime time horizon should be used to capture all long-term costs and health effects. It concluded that the company's model was appropriate to estimate the cost effectiveness of trastuzumab emtansine, but that a 15‑year time horizon should be used.
4.11 The committee considered the utility values used in the company's model. It noted that in the progression-free state, the company applied a higher utility value for trastuzumab emtansine than for its comparators. The company considered that the favourable side effect profile of trastuzumab emtansine supports using a distinct utility value for trastuzumab emtansine. The committee questioned whether utility values should differ for each treatment because the clinical experts indicated that most adverse events resolve within a few weeks, whereas in the model the utility values were applied throughout the entire progression-free state. In addition, the committee considered that applying a higher utility value for trastuzumab emtansine could result in treatment benefit being double-counted and overestimated, because the utility decrements for adverse events already capture part of this benefit. In response to the appraisal consultation document for NICE technology appraisal guidance 371, the company clarified that the utility decrements for adverse events were not applied separately in the model, but were incorporated into the utility values in the progression-free state, and therefore were applied only once. The committee heard from the ERG that, although the modelling of adverse events had limitations, the benefit of trastuzumab emtansine from reducing adverse events was not double-counted in the model. The committee acknowledged the additional evidence submitted by the company in response to the appraisal consultation document. It noted that the evidence suggested that in EMILIA, patients who received trastuzumab emtansine felt better and reported being less troubled by side effects than those who received lapatinib plus capecitabine. The committee was aware that EMILIA was an open-label trial, which may have introduced bias in the outcomes reported by patients, but noted the additional evidence on wellbeing and side effects presented by the company. The committee concluded that a marginally higher utility value for trastuzumab emtansine in the progression-free state could be accepted in this appraisal.
4.12 The committee noted that in its cost-effectiveness analysis, the company assumed clinical equivalence between capecitabine and vinorelbine, and between trastuzumab plus capecitabine and trastuzumab plus vinorelbine. The committee discussed with the clinical experts whether this assumption was clinically plausible. The clinical experts indicated that any chemotherapy would produce additional benefit when combined with trastuzumab. They stated that the precise clinical difference between capecitabine and vinorelbine had not been established in clinical trials, although in their opinion it would be reasonable to assume no difference. The committee concluded that, although it would be preferable to base the comparison on data from well-conducted clinical trials, the assumption of no difference between capecitabine- and vinorelbine-based regimens in the model could be justified for this appraisal.
4.13 The committee considered the adverse events associated with trastuzumab emtansine in relation to the economic modelling. It noted that the model incorporated utility decrements for only 3 adverse events and costs for 2 adverse events. The committee was concerned that this did not capture many adverse events associated with trastuzumab emtansine, including decreased platelet counts. The committee was aware that when the ERG included the costs of the adverse events that occurred frequently in EMILIA, this had little impact on the cost-effectiveness estimates. However, it concluded that the model should have incorporated both the decrease in utility and the increased costs associated with adverse events.
4.14 The committee considered the cost-effectiveness results for trastuzumab emtansine. It noted the company's suggestion that lapatinib plus capecitabine should be excluded from the analysis because the incremental cost-effectiveness ratio (ICER) for lapatinib plus capecitabine compared with capecitabine alone was £49,800 per quality-adjusted life year (QALY) gained, which the company considered to be above the acceptable maximum ICER normally regarded by NICE to represent cost-effective treatments. The committee was aware that excluding a technology based on its cost effectiveness in relation to a maximum ICER does not comply with the NICE reference case, which recommends a fully incremental cost–utility analysis. The committee agreed that there was no reason on this occasion to depart from the NICE reference case. It concluded that the cost effectiveness of trastuzumab emtansine should be evaluated in an incremental analysis comparing all technologies including lapatinib plus capecitabine.
4.15 The committee discussed the most plausible ICERs for trastuzumab emtansine without the patient access scheme. It agreed that lapatinib plus capecitabine, trastuzumab plus capecitabine and trastuzumab plus vinorelbine were in routine use in clinical practice in the NHS and should be included in the analysis. It also agreed that the analysis should use a 15‑year time horizon and incorporate the decrease in utility and increased costs associated with treating adverse events. The committee noted that in both the company's and ERG's base case, trastuzumab plus capecitabine and trastuzumab plus vinorelbine were more costly and less effective than lapatinib plus capecitabine (that is, they were dominated). The company's base-case ICER for trastuzumab emtansine compared with lapatinib plus capecitabine was £167,200 per QALY gained. The committee noted that the ERG's base-case ICER was very similar at £166,400 per QALY gained. At its first meeting, the committee agreed that the most plausible ICER was above the ICER range that would normally be considered a cost-effective use of NHS resources.
4.16 At its second meeting, the committee considered the revised cost-effectiveness results incorporating the patient access scheme submitted in response to the appraisal consultation document (which are commercial in confidence). It expressed disappointment that the patient access scheme did not reduce the ICER to a level close to one that could be accepted as a cost-effective use of NHS resources. The committee concluded that the size of the discount in the patient access scheme meant that it was still unable to recommend trastuzumab emtansine for treating HER2‑positive, unresectable, locally advanced or metastatic breast cancer after trastuzumab and a taxane.
4.17 The committee considered whether trastuzumab emtansine represents an innovative treatment. It acknowledged that trastuzumab emtansine is a novel antibody–drug conjugate combining the HER2-targeted anti-tumour activity of trastuzumab with a cytotoxic agent. It also noted that trastuzumab emtansine prolonged survival, with less toxicity than lapatinib plus capecitabine. However, the committee considered that all benefits of a substantial nature relating to treatment with trastuzumab emtansine had been captured in the QALY calculation, including the favourable adverse event profile and increased progression-free and overall survival.
4.18 The committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met.
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
The treatment is licensed or otherwise indicated for small patient populations.
In addition, when taking these criteria into account, the committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.
4.19 The committee considered the criterion for short life expectancy. It agreed that the best estimate of expected survival using current standard NHS treatment was demonstrated in the control groups of the trials. The committee noted that in EMILIA, the median overall survival of patients in the lapatinib plus capecitabine group was 25.1 months. The committee noted the company's response to the appraisal consultation document suggesting that lapatinib plus capecitabine should not be considered a comparator in the context of life-extending treatments at the end of life because it is only available through the Cancer Drugs Fund. The committee was aware that it should be guided by established practice in the NHS when identifying the appropriate comparators, irrespective of how these are funded. The committee noted that lapatinib plus capecitabine was the comparator treatment in EMILIA, and after discussion with clinical experts the committee agreed that lapatinib plus capecitabine was a clinically relevant comparator in the second-line setting. Lapatinib plus capecitabine was also the relevant comparator for trastuzumab emtansine in the incremental cost-effectiveness analysis. After further consideration, the committee did not change its view that the evaluation of expected survival with current standard of care should be based on that of patients receiving lapatinib plus capecitabine. However, the committee did note the comment from the company that if lapatinib plus capecitabine is to be a comparator, evidence on survival from sources other than EMILIA should be taken into account. Specifically, the comment highlighted that in a clinical trial of lapatinib plus capecitabine compared with capecitabine alone (Cameron et al. 2010) the median survival with lapatinib plus capecitabine was 75 weeks (18.8 months). The committee considered evidence from this trial, together with other trials for lapatinib plus capecitabine in patients with advanced breast cancer. It noted that patients who received lapatinib plus capecitabine in EMILIA appeared to have lived longer than those who received it in other trials, in which median survival on this treatment generally fell below 24 months. However, the committee did not have details of the patient characteristics at baseline in these trials, so it could not compare them directly with EMILIA or determine the extent to which they were generalisable to clinical practice. The committee also noted that the mean survival with lapatinib plus capecitabine estimated by the company in its cost-effectiveness analysis was 30.4 months. The committee found it difficult to evaluate this conflicting evidence, but after review of the reported median survival from several trials of lapatinib plus capecitabine, it was prepared to accept that trastuzumab emtansine fulfilled this criterion. It also accepted that trastuzumab emtansine fulfilled the other 2 end-of-life criteria, namely a small patient population (approximately 1,200) and a survival gain of at least 3 months. The committee therefore concluded that trastuzumab emtansine fulfilled the criteria for end-of-life consideration.
4.20 Based on the considerations in section 4.19, the committee discussed whether trastuzumab emtansine represents a cost-effective use of NHS resources. It agreed that, even taking into account additional weights applied to QALY benefits for a life-extending treatment at the end of life, the ICER incorporating the patient access scheme remained well above the range that could be considered a cost-effective use of NHS resources. The committee concluded that trastuzumab emtansine could not be recommended for treating HER2-positive, unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane.
4.21 The committee met after an appeal against the final appraisal determination for this appraisal, which was upheld. The appeal panel had concluded that 'the 2014 PPRS should have been taken into account, or, alternatively and sufficiently for this appeal, that the possibility of the PPRS being relevant had not been sufficiently considered and its irrelevance established'. The committee noted that, after this appeal, NICE had sought a view from the Department of Health about whether it should take account of the payment mechanism set out in the 2014 PPRS agreement in its technology appraisals. In the Department of Health's view, 'the 2014 PPRS does not place obligations on, nor create expectations of, NICE other than where these are explicitly stated in that agreement'. The Department of Health noted paragraph 4.9 of the PPRS which states that 'the basic cost-effectiveness threshold used by NICE will be retained at a level consistent with the current range and not changed for the duration of the scheme', and stated that 'the PPRS contains no other provisions which require NICE to adopt a particular approach or method for technology appraisals, or to make an adjustment to its considerations to take account of the payment arrangements set out in the scheme agreement'. The committee understood that, in response to the appeal decision, NICE developed a position statement about the relevance of the 'PPRS payment mechanism' of the 2014 PPRS to assessing the cost effectiveness of new branded medicines. This took into account the views obtained from the Department of Health. It was subsequently refined in a targeted consultation with the Department of Health, the Association of the British Pharmaceutical Industry (ABPI), and NHS England. The NICE position statement concluded that 'the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee noted the response from the ABPI, an association with 57 pharmaceutical company members, which stated that the ABPI had no comments on the substance of the position statement, and welcomed the statement. The committee also noted the ABPI comment that: 'Indeed, any other interpretation may increase the risk of legal challenge from other companies'. The committee was, however, aware that the company continued to believe that it was 'unfair to disregard the consideration of PPRS payments within the appraisal process' and was 'deeply disappointed' by the conclusion of the position statement. Company representatives at the meeting stated that the company's opinion was that the NICE position statement should state that 'the 2014 PPRS payment mechanism should, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines', and that it should apply to all technology appraisals, not just to the appraisal of trastuzumab emtansine. The committee concluded that the 2 sole negotiators for the PPRS, that is the Department of the Health and the ABPI, fully supported the NICE position statement, but that the company disagreed with it.
4.22 The committee discussed what the NICE position statement meant for its consideration of cost effectiveness. It noted the company's suggestion that the failure of NICE to identify a solution was not sufficient reason for the committee to disregard the impact of the 2014 PPRS on its appraisal of trastuzumab emtansine. The company representatives stated that the company's view was that the committee should disregard the NICE position statement, and either accept the 'pragmatic solution' suggested in the company's formal response (see section 4.25), or itself devise some other mechanism to incorporate the PPRS into its evaluation of cost effectiveness. The committee reminded itself that its role was limited to making recommendations to NICE about the clinical and cost effectiveness of treatments for use within the NHS, in line with the guide to the methods of technology appraisal (2013). This states that the committee should not recommend treatments that are not cost effective. It also recalled paragraph 6.2.14 of the guide, which states that: 'The potential budget impact of the adoption of a new technology does not determine the appraisal committee's decision'. The committee concluded that it was not responsible for devising new methods for estimating cost effectiveness and, further, it had neither the remit nor the expertise to do so. Furthermore, it understood that the position statement had been issued as guidance to all NICE technology appraisal committees to ensure consistency of decision-making. It therefore took the view that the NICE position statement should not be disregarded without clear and coherent reasons for doing so.
4.23 The committee discussed whether the PPRS could potentially be relevant to assessing opportunity costs that underlie a NICE appraisal; that is, would NHS adoption of trastuzumab emtansine, or other branded medicines that were not cost effective, come without additional cost to society, and without reducing spending on other more cost-effective treatments. It noted that the rationale for the NICE position statement was that it was not clear how payments made under the 2014 scheme were being applied in providing NHS services. The payments were not mandated to be allocated to local drug budgets and so would not automatically or routinely allow local commissioners or NHS England to revise their assessment of the opportunity costs of branded medicines. The committee also noted NHS England's question and answer document for the NHS on the Pharmaceutical Price Regulation Scheme (PPRS), which states that 'the agreement makes no provision for what happens to the PPRS payments, so there is no commitment for the Department of Health to make any additional payments to the NHS'. Moreover, the committee was aware that any rebates for drug costs are paid quarterly, so even if the PPRS payments were repaid to the NHS, and directly to local commissioners, who have finite budgets, decisions would have to be made to temporarily reduce funding other health services until the PPRS payments are received, which would incur opportunity cost. In addition, there would be no rebate for administration or other follow-on medical costs incurred from introducing a new technology. The committee also understood that, under the terms of the 2014 PPRS, when the allowed growth rate is exceeded, companies will make a cash payment of a percentage applied to sales covered by the PPRS payment during the relevant quarter (excluding products launched after 1 January 2014), and that percentage will be equal for all companies. Therefore, the committee considered that the opportunity cost would not only be borne by the NHS, but also by other companies who have joined the 2014 PPRS, and would have to contribute a larger share to the rebate based on how much the allowed spend was exceeded because of trastuzumab emtansine prescribing. The committee concluded that, as it stands, the 2014 PPRS does not remove the opportunity cost from funding treatments that are not considered to be cost effective according to the normal methods of technology appraisals, and that the precise and full costs of introducing a new technology into the NHS were not covered or rebated through the PPRS.
4.24 The committee noted that the essence of the position statement was that NICE did not consider that the 2014 PPRS enabled rebates to be transparently attributed to the acquisition cost of individual branded medicines at the time of the appraisal, and so could not identify a way in which the 2014 PPRS could fit within NICE's framework of appraising cost effectiveness. However, the statement did provide for potential exceptions to the general position of NICE. The committee referred to the guidance in the guide to the methods of technology appraisal (2013) on considering prices for technologies in cost-effectiveness analyses. Specifically, it noted paragraph 5.5.2 which states that the public list prices for technologies should be used in the reference case analysis or alternatively, and when nationally available, price reductions, provided that these are transparent and consistently available across the NHS, and the period for which the specified price is available is guaranteed. Because of the role of the committee and the basis for the position statement, the committee concluded that it would only be able to apply the exception provided for in the position statement if the PPRS mechanism could be shown to reduce the cost of the technology to the NHS, and still be in keeping with paragraph 5.5.2 of the guide.
4.25 The committee discussed the company's proposal that the committee issues positive guidance on trastuzumab emtansine conditional on the following:
The company remains within the 2014 PPRS scheme.
The spend level within the 2014 PPRS scheme remains above the agreed growth levels.
Guidance is reviewed at the start of the 2019 PPRS scheme.
The committee noted that the company's proposal did not show how the PPRS rebate mechanism can be applied directly to the cost to the NHS of trastuzumab emtansine, in a way that could be incorporated into a cost-effectiveness analysis. It also heard from NICE that accepting this proposal would potentially be unlawful for a number of reasons. Firstly, the committee would be overriding current guidance on the assessment of the cost effectiveness of health technologies and, by not applying its published methods of technology appraisal, this implies that NICE would not be fulfilling its statutory functions. This would also be incongruous with the 2014 PPRS itself, which states that 'the basic cost-effectiveness threshold used by NICE will be retained at a level consistent with the current range and not changed for the duration of the scheme', indicating that NICE should continue to assess cost effectiveness. Secondly, accepting the proposal would potentially impact on the financial position of other pharmaceutical companies, with the potential legal implications referred to in the ABPI's response to consultation on the NICE position statement (see section 4.21). Thirdly, there is already a mechanism within the existing process for companies to propose special pricing arrangements to be taken into account in technology appraisals; patient access schemes. These have to be approved by the Department of Health, which is also responsible for the 2014 PPRS. The committee noted that the company could have used this mechanism to apply a price discount in line with what it believed would be the true cost of trastuzumab emtansine to the NHS, in the context of the 2014 PPRS. Accepting the company's proposal would, therefore, transcend the existing framework. In summary, the committee was not satisfied that the company's proposal demonstrated that the impact of the PPRS rebate could be traced back to the opportunity cost of trastuzumab emtansine within the existing NICE guide to the methods of technology appraisal (2013), and NICE's statutory functions. Because of this, the committee concluded that the company's proposal did not represent an exception that might lead it to depart from the general position in the NICE statement.
4.26 In conclusion, the committee did not hear anything that it could consider to be reasonable grounds to disregard the NICE position statement in this appraisal. The committee agreed that it may consider the 2014 PPRS if specific proposals are put forward, if these fit within the methods and processes of technology appraisal and are consistent with NICE's statutory functions. However, it did not consider that such proposals had been put forward in this appraisal. Therefore, the committee concluded that the 2014 PPRS did not affect its previous recommendations about trastuzumab emtansine.
4.27 This appraisal was a Cancer Drugs Fund reconsideration of NICE's technology appraisal guidance on trastuzumab emtansine for treating HER2‑positive, unresectable, locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane. In its revised submission, the company included:
an additional 2 years' follow-up data from EMILIA, which was used to model overall survival
a complex patient access scheme in which the NHS would pay for trastuzumab emtansine up to the first 14 months of treatment for each patient, and the company would pay for trastuzumab emtansine for any patients remaining on treatment beyond 14 months (which was subsequently amended after the first committee meeting)[1] and
an updated model incorporating new data and using some of the committee's preferred assumptions (see sections 4.10 to 4.20):
extending the model time horizon from 10 to 15 years
incorporating the follow-up costs of left ventricular ejection fraction monitoring
correcting the utility values for adverse events (although the ERG suggested that these may still be incorrect)
using the actual dose of trastuzumab emtansine and lapatinib plus capecitabine rather than the planned dose
revising the parameters for the probabilistic sensitivity analysis and
estimating the post-progression treatment costs.
Clinical management of HER2‑positive advanced breast cancer
4.28 The committee heard from the clinical experts that trastuzumab emtansine is an effective treatment, which improves overall survival by several months compared with other HER2‑directed treatments. The clinical experts recognised that trastuzumab emtansine is not suitable for everyone, but noted that it is particularly well tolerated in many people compared with other treatments. The committee heard that the other treatment options have a worse toxicity and side effect profile than trastuzumab emtansine. It also heard that, on average, after 6 months of capecitabine treatment people start to have major side effects, which reduce treatment effectiveness and cause people to stop treatment. This also applies to the combination therapies, trastuzumab plus capecitabine and lapatinib plus capecitabine. People whose disease responds well to trastuzumab emtansine have improved quality of life as well as longer life. The clinical experts noted that they can assess whether trastuzumab emtansine is effective or limited by toxicity within 3 cycles. Treatment normally continues until disease progression. The clinical experts stated that the next line of treatment after trastuzumab emtansine would depend on the person's treatment history, but options were limited at this stage, and often this would be palliative care.
4.29 The patient experts described the benefits of treatment with trastuzumab emtansine. They stated that as well as the treatment stopping the progression of the condition, quality of life is better with trastuzumab emtansine than with other treatments. They noted that the side effects are minimal so they no longer need to be admitted to hospital or confined to bed after treatment. The patient experts stated that trastuzumab emtansine has removed some of the fear associated with their disease and has given them quality time with family and friends. They also emphasised that trastuzumab emtansine has helped them to live their lives fully and continue working, 2 factors that are very important and highly valued by patients, especially because many are relatively young women with caring responsibilities. They stated that if the drug were not available there would be no other suitable treatments for them.
4.30 The committee acknowledged the comments from patients after consultation, in particular that 115,000 people have signed a Breast Cancer Now petition urging NICE and Roche to ensure that trastuzumab emtansine remains available for patients in England. The committee appreciated how important it is for effective treatments for breast cancer to be available, but noted that its role was to consider the clinical and cost effectiveness of this technology at the price set by the company (including any nationally agreed access arrangements). Nevertheless, the committee acknowledged that it was relevant that the treatment had been provided to patients in the NHS in England for 3 years so that patients and clinicians would view a negative recommendation as 'taking away' an existing NHS funded treatment. Although it could be argued that the opportunity cost issues are not the same for a previously funded drug as for one that requires new NHS investment, the NICE methods guide does not have any specific mechanisms or advice which apply to this situation.
4.31 The committee noted that the company had excluded some of the comparators listed in the original appraisal from the incremental analysis in the revised submission. The committee assumed that vinorelbine had been excluded because it was expected to be dominated (less effective and more costly) by capecitabine. The company also excluded lapatinib plus capecitabine from the cost-effectiveness analysis because lapatinib was removed from the Cancer Drugs Fund in January 2015. The company stated that it has independent audit data to suggest that lapatinib plus capecitabine no longer represents current practice in England. The committee heard that lapatinib was removed from the Cancer Drugs Fund because the evaluation score (which considers clinical effectiveness, toxicity and drug cost for the Cancer Drugs Fund) for lapatinib plus capecitabine was considered to be too low to keep it in the Fund. The committee heard from the Cancer Drugs Fund clinical lead that drugs that had been removed from the Cancer Drugs Fund were no longer commissioned in England. The committee noted that lapatinib plus capecitabine was removed after trastuzumab emtansine became available. Since then, trastuzumab emtansine has become part of NHS clinical practice, and has replaced the comparator treatments listed in the original scope. The committee noted the company's opinion that trastuzumab plus capecitabine should be considered as the main comparator for trastuzumab emtansine. Responses from other consultees and commentators supported this view. The committee heard from the clinical expert and the Cancer Drugs Fund clinical lead that if trastuzumab emtansine were not available, trastuzumab plus capecitabine was likely to be offered to patients with HER2-positive advanced breast cancer who had relapsed after first-line trastuzumab-based therapy. The committee noted that trastuzumab plus capecitabine does not have a marketing authorisation for this indication but was aware that according to section 6.2 of the NICE guide to the methods of technology appraisal, comparators without a marketing authorisation for the relevant indication can be considered as comparators by the committee if they are part of established practice in the NHS. It also noted that based on the results of the network meta-analysis, trastuzumab plus capecitabine showed similar clinical effectiveness to lapatinib plus capecitabine. Overall the committee concluded that based on what it had heard from experts at the committee meeting and in light of the consultation comments, trastuzumab plus capecitabine is the most relevant comparator.
The company's revised economic model
4.32 The committee considered the company's updated economic model submitted for the Cancer Drugs Fund reconsideration and the subsequent updates in response to the ERG's critique. It also considered the ERG's exploratory analyses. It acknowledged that the final version of the model from the company took into account the ERG's concerns about the plausibility of the methods used in the probabilistic sensitivity analysis in the model. The company:
used patient-level data to calculate vial use
excluded an additional adjustment for wastage
updated the patient access scheme[1] and
updated the probabilistic sensitivity analysis in line with the ERG's suggestions.
The committee heard from the ERG that the patient access scheme and other amendments had been accurately incorporated in the model. The committee agreed that the company's changes were plausible. It also noted that the updated probabilistic sensitivity analysis in the final version was validated by the ERG. In general the ERG was satisfied with the updated analysis, but it also tested alternative prior distributions to determine the sensitivity of the economic model. As a result, the cost-effectiveness results presented by the company and the ERG were very similar.
Calculation of treatment costs
4.33 The committee considered the company's economic model and the ERG's critique. The committee noted that the company initially estimated average vial use using the average dose from EMILIA, but also used patient-level data to calculate vial use after a request from the ERG. The committee noted that using patient-level data increased the ICER compared with the company's base case, but it recognised that this did not account for dose reductions or treatment breaks. The committee heard that there is vial sharing in oncology centres that have centralised intravenous drug preparation. This reduces the amount of wastage, but cannot stop it completely. The committee noted that the company's revised economic model assumed no wastage because it used patient-level data to calculate vial use, although the previous version of the model assumed that 50% of any drug remaining in a vial after the dose is drawn up is re-used and 50% is wasted. The committee concluded that some wastage needs to be included in the calculation of trastuzumab emtansine treatment costs, because assuming no wastage is not plausible.
End-of-life considerations
4.34 The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. The committee noted that the updated median overall survival in the EMILIA intention-to-treat population was 25.9 months for people randomised to lapatinib plus capecitabine (it was 25.1 months at the time of the original appraisal), and 29.9 months for those randomised to trastuzumab emtansine. The committee recognised that during NICE's original appraisal of trastuzumab emtansine, evidence from other trials of lapatinib plus capecitabine in advanced breast cancer was also considered. The original appraisal committee noted that patients who received lapatinib plus capecitabine in EMILIA appeared to live longer than those who received it in other trials, in which median survival generally fell below 24 months. The committee also considered the evidence submitted by the company for life expectancy with trastuzumab plus capecitabine. It heard from the company that there are limited data available on the life expectancy of patients with metastatic breast cancer receiving trastuzumab with capecitabine as second-line treatment. However, data from the CEREBEL study (Pivot et al. 2015) suggests that it is likely to be around 24 months. The committee took into account that patients with metastatic disease who are eligible for trastuzumab emtansine had already progressed on first-line therapy and were in the advanced stages of the disease. Therefore the committee agreed to uphold the end-of-life decision from the original appraisal. It was aware that it was now looking at a different comparator from the one on which the original decision had been made (lapatinib plus capecitabine), but judged that any difference in survival between lapatinib plus capecitabine and trastuzumab and capecitabine was likely to be marginal, taking into account the results of the network meta-analysis (see section 4.31). The committee therefore concluded that trastuzumab emtansine fulfilled the criteria for a life-extending, end-of-life treatment for HER2-positive advanced breast cancer.
4.35 The committee noted that the updated evidence available since the original appraisal confirms that trastuzumab emtansine is clinically effective, with a statistically significant survival benefit compared with lapatinib plus capecitabine. Despite only indirect evidence of its effectiveness compared with trastuzumab plus capecitabine, there was no reason to consider that the relative benefits would not be comparable. Based on what the committee heard from experts at the committee meeting and in light of the consultation comments, it concluded that trastuzumab plus capecitabine is the most relevant comparator. Based on the clinical and cost-effectiveness analyses, including the updated complex patient access scheme, the most plausible ICER for trastuzumab emtansine compared with trastuzumab plus capecitabine was within the range that would normally be considered cost effective if the end-of-life criteria apply. The committee therefore concluded that trastuzumab emtansine could be recommended for use in the NHS for treating HER2-positive advanced breast cancer.
Appraisal title: Trastuzumab emtansine for treating HER2‑positive advanced breast cancer after trastuzumab and a taxane
Key conclusion (Cancer Drugs Fund reconsideration of TA371)
Trastuzumab emtansine is recommended, within its marketing authorisation, as an option for treating human epidermal growth factor receptor 2 (HER2)‑positive, unresectable, locally advanced or metastatic breast cancer in adults who previously received trastuzumab and a taxane, separately or in combination. Patients should have either received prior therapy for locally advanced or metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. Trastuzumab emtansine is recommended only if the company provides it in line with the commercial access agreement with NHS England.
The updated evidence available since the original appraisal confirms that trastuzumab emtansine is clinically effective, with a statistically significant survival benefit compared with lapatinib plus capecitabine. Despite only indirect evidence of its effectiveness compared with trastuzumab plus capecitabine, there was no reason to consider that the benefits would not be comparable. Based on the clinical and cost-effectiveness analyses, including an updated complex patient access scheme (that was subsequently replaced by a commercial access agreement), the most plausible ICER for trastuzumab emtansine compared with trastuzumab plus capecitabine was within the range that would normally be considered cost effective if the end-of-life criteria apply.
1.1, 4.35
Cancer Drugs Fund reconsideration of TA371
The company's revised submission included:
an additional 2 years follow-up data from EMILIA, which was used to model overall survival and
a complex patient access scheme.
After consultation an updated model was submitted, in which the company:
excluded an additional adjustment for wastage and
updated the patient access scheme and
The committee considered that based on what it heard from experts at the committee meeting and in light of the consultation comments, trastuzumab plus capecitabine is the only relevant comparator.
It also recognised that during NICE's original appraisal on trastuzumab emtansine, the original appraisal committee noted that patients who received lapatinib plus capecitabine in EMILIA appeared to live longer than those who received it in other trials, in which median survival generally fell below 24 months. The committee also considered the evidence submitted by the company for life expectancy with trastuzumab plus capecitabine. It heard from the company that data from the CEREBEL study (Pivot et al. 2015) suggests that it is likely to be around 24 months. The committee took into account that patients with metastatic disease eligible for trastuzumab emtansine had already progressed on first-line therapy, and were in the advanced stages of the disease. Therefore the committee agreed to uphold the end-of-life decision from the original appraisal. The committee therefore concluded that trastuzumab emtansine fulfilled the criteria for a life-extending, end-of-life treatment for HER2‑positive advanced breast cancer.
Taking into account all factors, including the end-of-life criteria and the commercial access agreement that replaced the updated complex patient access scheme, trastuzumab emtansine could be recommended for use in the NHS for treating HER2-positive advanced breast cancer.
4.27, 4.32, 4.34, 4.35
[1] The complex patient access scheme was subsequently replaced by a commercial access agreement. See section 2 for further details.


Guests nine years old and under are permitted to wear costumes in the parks of Walt Disney World. There are only two events during the year where guests older than nine years old are allowed to wear a costume in the parks of Walt Disney. The first is during Star Wars Weekends in Hollywood Studios which typically occurs in May and June of each year. The other time is at Mickey's Not So Scary Halloween Party which is a hard ticket event in the Magic Kingdom that is typically held in September and October each year. You could wear a Princess Crown for example because various hats and head coverings are permitted (Mouse Ears are OK too).
I hope that your next vacation in Walt Disney World is truly amazing and even magical!


The report also went on to add that there were "no signs of destruction or casualties" except for the two soldiers who died due to "unprovoked firing" by the Indian army. While Hindus prefer remaining in India, an overwhelming majority of Muslims in Kashmir - from 75 to 95 percent, according to one poll - would rather join Pakistan.
Emmerdale spoilers: Will Adam Barton kill Holly's drug dealer?
F1 Ferrari, Vettel: "Domani servirà una buona partenza"
I don't have any comment beyond that", said former House Speaker Newt Gingrich, a top supporter. She added that the late-night rant was "unhinged" and proved he is "temperamentally unfit" for the Oval Office, a line of attack she's used before.
Mrs. Clinton led Mr. Trump by 15 points among women, compared to a 5-point lead among women in the August poll. In a separate poll that included alternative party candidates, Mrs Clinton led the field by 4%. The Detroit News-WDIV poll surveyed 500 likely MI voters on Sept 27-28. Its margin of sampling error is plus or minus 3 percentage points. National opinion polls have differed this year in how they measure support for Clinton and Trump.
For the 2016-2017 flu season , the Center for Disease Control suggests receiving the flu shot as opposed to the nasal spray flu vaccine due to the changing virus. According to Arthur Reingold , an epidemiology expert at the University of California-Berkeley and a member of the CDC's immunization advisory committee, last week's push to get people vaccinated is partly about keeping those numbers up.
Secondo le prime informazioni, dei feriti intossicati e leggermente ustionati 4 sono stati portati al Niguarda, 4 al Fatebenefratelli e 2 all'ospedale Città Studi. Fortunatamente a quell'ora il locale era chiuso al pubblico. Ora sono in corso indagini da parte della polizia e i rilievi dei vigili del fuoco. La zona in cui è avvenuta l'esplosione è molto vicina al centro e alle vie trafficate di Milano .
It has been a topsy-turvy start to the season at Old Trafford, with Community Shield glory and three successive Premier League wins followed by three straight defeats in all competitions. 'Every game I know more about my players, especially the ones that are on the pitch'. We want to get that win and come back feeling fresh. "It was hard, we had chances in the first half but we didn't take them and they were organised with people behind the ball", said Mourinho.
L'azienda ha convocato i sindacati a un incontro per lunedì 3 ottobre alle ore 16,30. "L'auspicio è che inizino ad arrivare le risposte che chiediamo per risolvere la situazione, per la quale resta preoccupazione", conclude Bollini. Richiesta che fu accolta: l'assemblea decise di dare mandato al cda di ricapitalizzare con 10 milioni di euro. Spiragli di luce per la Braccialini, l'azienda fiorentina specializzata in borse di alta moda .
Tropical storm force winds extend over 200 miles from the center. The storm is now moving toward the west at seven miles per hour, but is expected to turn toward the northwest on Saturday. Forecasters expect it to resume its westward motion later today, followed by a turn toward the west-northwest by tonight. Forecasters cautioned those in Florida to keep an eye on Matthew and said it was too soon to say the USA was out of the woods.
CALIFORNIA 28, No. 18 Utah 23: Davis Webb threw four touchdown passes and California stopped Zach Moss from the 1-yard line on the final play to win its second straight matchup against a ranked opponent. While the Vols whooped it up with their small, orange-clad contingent in a corner of the Sanford Stadium, Georgia straggled off the field in disbelief.
All'origine del caso di violenza familiare una lite divampata tra padre e figlio e causata dalla decisione del figlio di sospendere le cure a cui veniva sottoposto da tempo presso il centro di Igiene mentale di Trento. Gli uomini dell'Arma hanno così ricostruito con le testimonianze ed i rilievi sul posto la dinamica, sottoponendo l'aggressore all'arresto per tentato omicidio.


text:
Shaun Dellenty
In 2014, whilst running the Twin Peaks UK Festival, I was approached by a man who told me that he had had a magical experience and thanked me for everything I did for Twin Peaks fans. We chatted for a while, and as I watched him go, I knew we'd stay in touch and he would be a real positive energy in my life.
Fast forward 6 years, and I was completely right. Shaun Dellenty is a dear friend and confidant, and his 'must be read to be believed journey' has taken him all the way from the Yorkshire Dales and Emmerdale to 10 Downing Street. It's my pleasure to introduce this inspiring man to you.
Lindsey Bowden (LB)
Hi Shaun, it's a real pleasure to have you on the blog. How are you? Keeping safe in these trying times?
Shaun Dellenty (SD)
Hi Lindsey, many thanks for inviting me to take part and I hope you are well and staying safe. My husband, Mike, Schnauzer (our dog), and I are thankfully safe and well, although our family and friendship groups have sadly not gone untouched by the virus. Not being able to support those we love in person is particularly challenging, but we are grateful for our health, our home, and for being able to access food and online services. Thank goodness we have the ability to communicate face to face via phones and computers, can you imagine how different this experience would have been if we were all still using Bakelite telephones and queuing with bags of change outside red phoneboxes to keep in touch? I had just returned from working in Mumbai when lockdown started and have been keeping in touch with friends there via Facetime; if in the UK we think one hour of exercise a day feels limiting, their experience has been far more isolating.
Humbling words there Shaun and you're completely right. We've had a pretty relaxed lockdown here compared to others. Shaun your career has been varied to say the least, actor, educator, advocate and author. Let's start with your acting, where did that all begin for you?
Varied indeed! Apart from a natural leaning towards creativity, which I think was always there, I have two people to thank for my acting career: singer/actor Anita Harris and my middle school teacher Mr. Biebrach. My parents took me to see Peter Pan at the Oxford Playhouse when I was four; apart from feeling overwhelmed by how magical it all was, I decided there and then that one day I would be on the stage. Unfortunately, when I arrived at school it became clear that I was a shy little boy. It wasn't until I was ten years old that Mr Peter Biebrach encouraged me onstage as the character, the Journalist in a school production of War of the Worlds. Having astutely clocked my shyness he wisely informed me that acting was akin to wearing a mask, one I could hide behind. As a kid who already knew he was gay from an early age, I was already developing some survival strategies to conceal my true nature, in response to familial and societal prejudice. Playing a character became a coping strategy, giving me respite from who I was, and my confidence grew as a result. In secondary school I became known for mimicry, often noisily acting out TV comedy sketches from Kenny Everett and The Young Ones to distract from who I was and to gain social approval with the 'cool kids.' In secondary school I was blessed with a supportive drama teacher Sheila Hill, who encouraged me towards the acting profession. I was part of a two-year pilot of an accredited drama course at secondary school, so by the time I walked out of formal education aged seventeen due to sustained homophobic bullying, I wanted to get 'out there' and perform, rather than train formally. Initially I did a lot of extra work, just to listen, observe, and to learn the ropes technically. I also did some amateur dramatics but ultimately found it unfulfilling as the emphasis fell too heavily upon applause and acclaim rather than the creative process itself. In my mid-twenties (whilst also training to be a primary school teacher) I worked as a presenter, corporate host, and stand-up comedian performing hundreds of live shows. I also wrote a few one-man shows and was repeatedly informed by audiences that I was able to deliver difficult and challenging content and messages in a way that drew people in, rather than throwing them out, this would prove to be a key skill in my advocacy work later in life but I learned it telling rather risqué jokes onstage! The two halves of my professional life collided when I began performing and directing Theatre In Education (T.I.E.). After a year in full-time teaching, I left to pursue my acting career and was lucky to get picked up by an agent. I got my Equity card and for the next five years I was very blessed with a wide range of work, ranging from national Shakespeare tours, voiceovers, TV presenting work, adverts, and television, including soaps.
Shaun Dellenty in Emmerdale
I love how we all have that one teacher who made such an impact. I had one in school and one is drama school who are both still dear friends. As you say, you featured in some great stage shows as well as high profile TV shows, including Emmerdale, which you are still known for. Can you talk a bit about working on one of the UK's top soaps?
It's twenty years ago since I last appeared as Dr. Steven Rawson but occasionally in pubs I still get asked if I was in Emmerdale, despite the fact I look very different now! Working on a successful soap is a very different discipline to stage work and requires real stamina in terms of maintaining energy levels and line learning at often no notice. It is surreal to walk onto a set featuring actors and characters you have seen on screen since you were a kid, and then act alongside them with nothing but a short camera rehearsal. I remember when my episodes were first broadcast, I was still undertaking teacher supply work in a local school and they asked me to open the village fete and sign autographs in a sweaty tent full of cakes and oddly shaped vegetables! I still have a bag of Emmerdale fan mail somewhere, it started arriving before I had even filmed a scene! The whole team were hugely welcoming, and it was a very positive experience. A friend of mine actually worked as the announcer on regional ITV (where I was based) and I for a laugh he introduced one of my episodes live by saying 'look out for the hot Doctor in this episode' which was sweet. I also fulfilled a lifelong ambition by getting my name for the first time in the Radio Times thanks to Emmerdale. Working on Crimewatch was a whole different experience though and I was once attacked by an elderly woman with a handbag in Rugby and reported to the police simply because I had appeared in Crimewatch that week. I guess we've got to admire her community spirit!
That's hilarious! Was there a certain point that you thought your acting may be developing into another career?
It was my father who suggested that I train as a teacher to maintain financial stability, and he was absolutely right. Inevitably as you get older your priorities change and in 2000 at the end of a twelve-year rural Midlands based relationship, I made a snap decision to move to London to reboot my life. Independent for the first time, I needed to sustain myself financially and found myself teaching more and more. Around this time my agent ungraciously did a bunk with all the money, leaving me without monies due or indeed an agent. He was subsequently Equity blacklisted, but I never got my money back and it left a bad taste in the mouth at a time when I was quite vulnerable. At this point I auditioned for and was offered a presenting job on a nightly news show, it was set to be my biggest break and I was thrilled that I would also have creative input. The set was built, and the first location reports filmed; then the evening prior to the filming of the first show I had an apologetic phone call from the producer to say that Sky TV had bought out the channel and had cancelled all existing commissions. I was pretty crushed. The following day a primary school in South London asked me to stay on and teach for a year and I ended up as Deputy Head and staying for sixteen; that marked the end of my professional acting career. I fell from acting into teaching and school leadership quite organically, although as a school-based professional one never really stops acting. On one occasion a Channel Four programme for schools I had filmed was shown to children by one of my class teachers. As I walked in with a message for the class, several of the children got very worried that I was apparently able to appear in their television and physically in their classroom simultaneously! Teaching is a profession in which my acting, presenting, and sometimes even my voiceover skills could all be kept alive, due to the demands of the job. The skills I had developed as a presenter also bore fruit as I unexpectedly moved into LGBT+ advocacy on the world stage.
Shaun Dellenty at the Excellence in Diversity Awards
Ha! I can imagine the kids reaction seeing you on TV and in front of them. I love that innocence! So, you've just mentioned your LGBT+ work. Can you talk a little about how you become an advocate for the LGBT+ community?
I certainly never sought or planned to become an advocate for any community, LGBT+ or otherwise. As a teenager, growing up in the 1980s under the prejudicial law Section 28, I like many others experienced homophobic bullying from my peers and teachers, in addition to suffering from familial and societal rejection. With some kids at school telling me I deserved to get AIDS and die, purely for being me, I came very close to ending my own life aged 17. Even as a gay primary school leader, I was closeted until 2009 due to experiencing homophobia within the profession and from some parents. In late 2009 my school undertook pupil surveys with our primary aged pupils. When the data was crunched, we were appalled to learn that 75% of our pupils were experiencing homophobic bullying on a daily basis, in and around the school; 98% heard the word 'gay' deployed as a negative term or put down, as in 'that's so gay.' It didn't matter whether they identified as LGBT+ or not (some did by the way and others had LGBT+ parents and friends) the homophobia was targeted at any child who simply didn't fit perceived social 'norms'. Appalled by our data I 'came out' as gay to my whole school community in an assembly, ostensibly to provide an authentic point of connection with the potential lifelong impact of bullying and prejudice and to provide a role model to any students, parents, and staff who were LGBT+ themselves. Men working in primary schools was still quite taboo, even in 2009. Had our bullying data related to racism, we would not as a leadership team have hesitated to plan our response; yet as our data related to 'gay stuff' and we hesitated-out of fear. I realised that the words 'lesbian, gay, bisexual or transgender' had never been spoken during my professional training as a teacher, nor in any subsequent professional conversations or staff training sessions. Despite this I knew all too well the impact of LGBT+ bullying and felt compelled to act on our bullying data; I contacted some of the leading LGBT charities such as Stonewall and asked if they provided teacher training or age-appropriate curricula for primary schools, but I was told no, due to a fear of parental/press reprisal. I then wrote a compassionate LGBT+ inclusion teacher training strategy called 'Inclusion For All' aimed initially at primary schools and subsequently for faith and secondary schools and teacher training faculties. I delivered it first in my own school with great success and interest and ten years on I 've personally delivered to over 65,000 UK educators. My work immediately went viral and as a result national and international organisations including Stonewall, Amnesty International, Church of England, Kidscape, Show Racism The Red Card, NSPCC, teacher trade unions, and politicians visited and worked with me to develop their own LGBT+ inclusion offers. I have now taken my training around the world, into Parliaments and had the privilege of working the entire Isle of Man education system to make it LGBT+ friendly. I led a national social media and blogging campaign on tackling the use of the word 'gay' as a negative term and campaigned for LGBT+ educators to be supported to out at work, should they choose to be. My work has been reported around the world in newspapers, magazines and on television. It continues to be an unexpected but mainly joyous journey, with several major awards along the way, however making schools and our wider communities safe for all, not just some naturally diverse human beings is the only reward I seek.
Shaun Dellenty at Southwark Cathedral
It's an incredible journey Shaun, and one that I'm sure many people will relate to. You really hit a large audience when you founded the charity, Inclusion for All. For those who aren't sure, what is Inclusion for All and what was the ethos of the charity?
Inclusion For All grew into a small charitable organisation as a result of the national and international interest in my training offer. Inclusion For All and latterly Celebrating Difference (a revised version of my training offer launched as a business in 2016) is rooted in the realisation that as human beings we all experience bias and prejudice. Historically, our education system has told stakeholders 'not to be prejudiced' and even banned specific racist or homophobic words. This is all very well, but what schools fail to do is to encourage young people (and indeed staff and parents) to explore and bring non-judgmental curiosity to our potential for prejudice from an early age in order to work positively and pro-actively with them throughout our lives in order to prevent us from damaging other human beings; this is the core of my approach. As we are learning to co-exist with a virus and work pro-actively to diminish its impact, so we must aspire to work to co-exist with our prejudice and bias to avoid hurting our fellow human beings, however different from us they might seem on first impressions.
100% agree, it all starts with educating the younger generation. Your work within the LGBT+ community has grown to astounding heights, to the point that you were named one of the 100 most influential LGBT+ people in the U.K. and designated a 'Point of Light' by the U.K. Prime Minister for services to both LGBT+ and education communities. That must have been an incredible high point for you?
Thank you for your kind words, yes, a week in May 2016 was a week I will never forget! I was awarded the Mayor of Southwark's Highest Civic Honour at Southwark Cathedral and given the Freedom of Southwark. The following day I travelled to Leeds for the national Excellence In Diversity Awards and was named 'Education Champion 2016' and whilst at the ceremony (and quite honestly after one too many glasses of champagne) I took a call from the Cabinet Office inviting me to a reception in the garden of 10 Downing Street later that week. On my arrival at Downing Street I was told I was to be presented with a 'Points of Light Award' by the Prime Minster for services to education and LGBT+ communities. Let's just say he wasn't my Prime Minister, but as it was not a political award, but one awarded to people around the world doing compassionate things I was very grateful, even if I had to bite my tongue a few times in conversation afterwards-time and a place and all that! As a child who had suffered under Section 28 at school, which essentially precluded teachers from talking about the existence of LGBT+ people in school, it was startling to find myself in 2009 being honoured by a Conservative Prime Minister for doing just that, and in primary schools. I was also given a letter of recommendation for my work signed by the PM. My work was then tweeted from the Number 10 account to millions of followers, resulting in a significant amount of online hate, but I am used to that, and at the ripe old age of 52 there is really not a lot people can write that I haven't heard before. This year The Bishopsgate Institute in London asked me to curate a public archive of my ten years of international LGBT+ inclusion work which will also serve as my public legacy when I am long gone. It is a huge privilege and the archive will feature some of the awards and letters from politicians and celebrities I have accrued along the way.
Shaun Dellenty at 10 Downing Street
What a legacy you have Shaun. So, all of this work, as you mention spanning ten years, climaxed in the publishing of your first book Celebrating Difference. The book is a guide book almost of inclusion in education. Can you talk about the process of how you were approached for this book, the journey, and the path it has led you to?
I can. Bloomsbury Publishing had been following my social media accounts for some time as well as articles I'd written for The Huffington Post and The Guardian etc. In 2017 I was tweeted by my (now) editor Hannah who asked if I was interested in writing a book about my life journey and, by then, tried and tested approach to compassionate LGBT+ inclusion. We met for coffee and she kindly heard me speak at Amnesty International. It was clear that she got the bigger picture of my work; I simply wish the world was a kinder place and want to help facilitate that. Although it was my first experience of working with an editor (on a book at least) I saw how vital it is to work with an editor with whom one can form a relationship based upon mutual respect and understanding; this allowed me to respond and react to her feedback with an open mind and heart. From the start it was agreed that the first section of the book would ground my training approach in lived experience in the form of a summarised autobiography, before going on to describe (in the form of a handbook) my six tier approach to compassionate LGBT+ inclusion, utilising case study, research, impact study and first-hand accounts to make the book as accessible as possible, without reading like some dull and lifeless academic tome, which I find a real turn off! I hope in the end we succeeded. The book was certainly well received, even being recommended in the House of Lords in April 2019. As you know yourself Lindsey, to find oneself signing books after years of asking others to sign books, is surreal, but rather lovely too.
Celebrating Difference by Shaun Dellenty
It is very surreal yes. I've done it in London and Los Angeles and it felt almost outer-body!
Exactly! My advice to any budding writer is to write down what is in your heart and mind and then give yourself a good distance from it before reading it back. As a meditator I am very aware of my judging and comparing minds and this proved extremely helpful when it came to self-editing. Lots of people say ' I think I have a book in me but I am not sure how to get started' my advice is just to get started and if you don't like what you write at the beginning, well that is what editing is for. Just get writing; life is too fragile, too brief not to at least try. These lockdown days and months are the perfect opportunity to externalise thoughts and feelings and ultimately no one needs to read it except you, it's your choice.
Shaun, his husband Mike, with myself at his book launch
Absolutely. I think any writer would agree. We all sit and stare at the computer, but as soon as you start to writing something, that's when the dialogue naturally comes. So Shaun, now you travel the world delivering training and also making personal appearances for your work which must be hugely rewarding?
It is hugely rewarding to be invited to travel and meet and train new people in new places, I never could have anticipated in my life when I was a bullied little asthmatic gay sci-fi geek that one day politicians, Archbishops, even pop stars would be seeking my input and help, or that I would be invited to help facilitate change across whole countries-what an immense privilege. My international book talks and training sessions also enable me to gain a more holistic view of the experiences of LGBT+ and other minorities globally, who often don't enjoy the privileges we currently do in the UK. It is heart-breaking to hear of LGBT+ children rejected by their parents, thrown out of schools, of those murdered for simply being transgender, or of teachers sacked for being in a same-sex relationship. A ten-year accumulation of these negative experiences could potentially take me down, or cause me to feel hopeless, instead they instill me with an even greater passion to nurture a kinder and more compassionate world in my own small way.
So with all of this incredible experience , could you see yourself ever returning to acting?
Do you know, I would love to return to some kind of performing. My last gig was a stand-up slot with Zoe Lyons at the legendary Royal Vauxhall Tavern in 2007. I miss the creative process a lot and as I get older, I certainly do feel the pull back to the creative process and even the stage. It would be interesting to explore whether the unique set of experiences I have gained via my LGBT+ life journey and ten years of advocacy could somehow be woven into a one-man show moving forward, it has also been suggested that the first chapter of my book would make a film script and I would like to explore ways of collaborating to take this forward. Watch this space I guess!
Follow Shaun Dellenty on Twitter @ShaunDellenty and Instagram @shaundellenty_lgbtauthor. Visit Shaun's website at www.shaundellenty.com
Follow Lindsey Bowden on Instagram @lindseybowden76 and Twitter @lindseybowden76
Celebrating Difference is available in iTunes and at https://www.amazon.co.uk/Celebrating-Difference-Shaun-Dellenty/dp/1472961501
Follow Shaun's journey at htthttps://www.facebook.com/shaundellentycelebratingdifference/

redpajama_set_name: RedPajamaCommonCrawl


Researching, we're researching the answer to this question now. Copy this code and use at checkout. Coupon Detail 2 Free Deluxe Samples With 35 Order for Beauty Insiders. Does Dorco USA or Sephora have better PayPal support?..
Where TO find michaels coupons deals. Otherwise, sign up for email updates and they will often text you mobile coupons. Each week they publish a 40 off coupon for one item. They are frequently open extended hours..
Priced Purchase Exp. 06/30 * Online: Use Office Depot Coupon Code In-store: In-store Office Depot Printable Coupon 20 Off Your Qualifying Purchase of 125 Or More Exp. Share Expires 08/25/18 Get Coupon Code sales offers 2 Used Today Current Coupons, Promo Codes, and Special Offers Check out the current Office Depot and Office Max coupons and promo codes here!


Arthur's message made the crucial connection between the Gospel and the Law. Knowing that the Gospel and the Law are inseparable is the basis for proclaiming that the Law is for today! The Law is one of the primary ways the Father speaks to His people. However, as Arthur said, "What good does it do for Him to speak to you if you're not going to take what He speaks to you and do something with it?" In other words, what good is the Father's Truth if you are not living by it?
Arthur gave an illustration of how many of us have been affected by the lawless denominations that we attended. What we have been taught becomes a filter through which new information flows and the new information becomes tainted when the filter is not truth. For example, many of us were taught that Paul circumcised Timothy to please the religious Jews. However, when lawless people teach the Bible, they do not have the background experience or the mindset of a person who keeps the Law. Therefore, the Law is not taken into consideration when discussing the actions of Paul.
Paul understood the Covenant of Circumcision and he required Timothy to be circumcised as the Law required. Paul circumcised Timothy so that nothing would be lacking in Timothy. Paul was taught by Yeshua and Paul knew that Yeshua did not come to establish a new Law. The Law of Christ/Messiah is the same as the Law of God/YeHoVaH. There is only One Kingdom, One Law, and One Lawgiver. Yeshua came to preach the Kingdom of YeHoVaH, not the Kingdom of Messiah!
Yeshua came to do the will of His Father. He kept the Laws of Elohim and told us to do the same.
For whosoever shall do the will of my Father, which is in heaven, the same is my brother, sister, and mother.
Resolve to Endure to the END!
Our Father loves us and forgives our sins when we ask for forgiveness and repent. We are to emulate our Father's character. As Arthur exhorted us, we should always leave room for reconciliation; we should always leave room for restoration, no matter what a person does. Many of us have made grave mistakes and were grateful to be forgiven and have our relationships restored.
A case in point, Floyd's paternal grandparents were married for 44 years and got divorced. According to Floyd, his grandfather was a gambler, drinker, womanizer, and smoked a cigar. His grandmother got a divorce because her husband was "keeping company" with another woman for years. They were divorced for nearly 2 years.
When Floyd's grandfather realized the errors of his ways, he repented and asked for forgiveness. Floyd's grandmother showed grace towards her estranged husband, forgave him, and they were remarried. According to Floyd, his grandparents remained peacefully married for 3-4 years until the death of his grandfather.
This was a new day for the in-house and online community. A microphone was set up with a camera focused on the Saints from the congregation during the Q & A Session! I was elated because I was a part of the Online Community for at least 3 years before we moved to South Carolina to be a part of the ministry. During those years, I earnestly wanted to see my Sisters and Brothers that were testifying, asking questions, and making comments at the microphone. There was no camera on them, so I cataloged their voices in my mind. I would try to match the voices to the people when we came to Charlotte for the Feasts.
I remember our first Passover in Charlotte. It was my first time seeing Arthur and his family. I was marveling at how much they all looked alike. It took me a while to get the names of the four younger sons correct! While I was watching them take a family photo, I heard a gentleman laugh. I knew that laugh! I followed sound of the laugh across the room and around some furniture. I introduced myself and began a conversation with the Brother that regularly spoke at the microphone during the House of Israel services.
Today, I felt like a yearning from the past was fulfilled.
A couple with an adolescent daughter joined us today. The wife looked a bit familiar and I noticed that we kept making eye contact during the service. After the congregation received the Aaronic blessing, I joined them in the food line. I realized that she and I had met two years ago at the former HOI building on Hill Road! She had attended with two of her friends. I remembered the three ladies very well because we had talked at great length that particular day.
The couple and their daughter drove more than two hours to join us at House of Israel. We had a wonderful time fellowshipping. Sister Saint and me joined another group of Sisters and talked about the troubles we have witnessed when there is no order in one's life. We all agreed that order comes from being obedient to the Law.
Brother Saint joined a group of three other Brothers. Their conversation was highly animated with each of them taking turns "holding court".
I wanted their daughter to meet the other four young girls that were attending today. I looked around the room and couldn't find them. The Sisters that direct the children and youth activities were still fellowshipping and eating, so the girls wouldn't be upstairs in the Children's Room. So, I asked a few of the Sisters had they seen the troupe of young girls. One suggested that I look outside. I looked; no girls were outdoors on the lawn. Then an astute Sister said, "Check the bathroom!" Then I remembered that one Sabbath, I had seen several young girls in the Restroom area talking and fellowshipping! Sure enough, I found them. I introduced the new girl and they bonded immediately.
When it was time for that family to go home, the young girls were trying to get a commitment from their new friend's father to come next week. He said, "We will see you soon!" Even I hoped that we would see that family again soon!


text:
Бигор је насеље у граду Подгорици у Црној Гори. Према попису из 2003. било је 85 становника (према попису из 1991. било је 99 становника).

Демографија
У насељу Бигор живи 67 пунолетних становника, а просечна старост становништва износи 43,5 година (40,6 код мушкараца и 46,2 код жена). У насељу има 30 домаћинстава, а просечан број чланова по домаћинству је 2,83.

Становништво у овом насељу веома је хетерогено, а у последња три пописа, примећен је пад у броју становника.

Референце

Спољашње везе
 Мапе, аеродроми и временска ситуација локација (-{Fallingrain}-)
 Гугл сателитска мапа (-{Maplandia}-)
 План насеља на мапи (-{Mapquest}-)

Главни град Подгорица
Насељена места у Црној Гори
Википројект географија/Насеља у Црној Гори

redpajama_set_name: RedPajamaWikipedia


text:
Olivet College RN-BSN Program Already Making an Impact
Nov 29, 2018 | General, OC at Work, Olivet College, Student Stories
This summer, Olivet College launched its RN-BSN program, designed to increase the number of bachelor-level nursing graduates in the Battle Creek region. As the first class of students began this fall, the program has already begun to make an impact in the community and workforce.
The RN-BSN program is in partnership with Kellogg Community College (KCC) and focuses on a blended-delivery, community-based learning model. The curriculum is grounded in the liberal arts and upholds a flexible approach for licensed registered nurses. The program is designed to provide a balance of evidence-based delivery models to assure that students feel supported through their family-work-life responsibilities, while learning and earning a bachelor of science in nursing degree.
The program is led by Lorraine Manier, DNP, who is passionate about nursing, leadership and teaching and is inspired to make a positive difference in the world in as many ways as possible.
"The Olivet College RN-BSN program is designed to meet students at their current level as registered nurses with associate degrees and support them through a curriculum that will develop critical thinking skills matching the expectation of the baccalaureate nurse," Dr. Manier explained. "The learning style of all students is considered and embedded in this program, with the intent of developing nursing leaders at the patient's bedside and beyond. Furthermore, the program will prepare students for graduate degrees in nursing."
Dr. Manier credits much of her success in the nursing field to her own college professors, mentors and advisers. She understands the positive impact of a relationship-based education and utilizes an individualized approach to teaching to ensure every student in the program is successful.
Casie Hudson, a member of the inaugural RN-BSN class, directly connects with Dr. Manier's teaching philosophy. Casie's inspiration to serve as a nurse also stems from her desire to do good in the world, and it's the close relationship she has with her professors that's helping her reach her goals.
"I chose Olivet because it fits well with my own personal beliefs and morals. As an RN, my job and life goal is to make a difference in lives of others and Olivet College does that every day," Casie said. "I love the small community feel of the program and how the teachers really care about their students."
Designed for Professional Learners
Another student pursuing his BSN, Rick Wilson, directly connects with the relationship-based model of the program — but that's not the only way the program is helping students succeed. Rick discovered his passion for nursing later in life after spending time in psychology, real estate and insurance.
"The hybrid of online and classroom instruction allows me to truly learn," Rick said. "I was slated to attend another program this fall, but the OC RN-BSN program is a much better fit for my learning style. I find classes thought-provoking and interactive, and the knowledge we are learning is directly applicable to my professional role."
Further, Rick shared that the class recently had the chance to attend the Michigan American Nurses Association Annual Conference. He noted that these unique learning opportunities are directly tied to small class sizes, a staple in OC's program.
RN-BSN student Nicole Stone-Matako echoed that classes are not only small and comprehensive, but also cater to the working nurse. "I chose Olivet College because it was close to home, offered flexible class times and upholds a strong reputation," she explained. "OC is focused on real life and motivation. Class sizes are small and the teachers are fantastic, open, available and flexible."
The Olivet College BSN degree completion program requires the completion of 120 semester hour credits. The program has no hidden prerequisites or requirements and all general education requirements are embedded in the nursing courses to be completed. The total credits required for the BSN degree are earned through a combination of upper-division nursing courses, credits transferred from the associate degree in a nursing-granting institution or other colleges attended, and "flexible credits" that may be earned in a variety of ways.
"I am committed to the RN-BSN program's success through ensuring that the student's educational experience remains the primary focus. Together we will improve the health care outcomes of the community in which we serve," Dr. Manier said.
OC's RN-BSN program offers a 50 percent tuition reduction to cohorts spring 2019, summer 2019 and fall 2019 through the duration of the degree with the commitment of maintaining program completion within five semesters. Learn more about the Olivet College Bachelor of Science in Nursing by contacting Jim Weidman, director of admissions for adult professionals and graduate programs, at 269.749.6612 or jweidman@olivetcollege.edu.


Details: The Mizuno WaveKnit R2 was able to receive welcoming reviews from consumers who desired a road shoe that offered form-fitting support and lightweight performance. The upper unit and the midsole were elements that were focused as they apparently did what was expected of a neutral shoe. There were a few concerns with the sizing scheme being too small, but that's an issue that can easily be remedied by a sizing adjustment.