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Evidence Synthesis and Methodology

HTA methods are evolving continuously, in response to the increasing complexity of clinical development programmes and decision-making processes. The HTA team are involved in methodological research which will underpin the practice of HTA in Ireland. A key element of HTA is the comparative effectiveness assessment of all relevant competing interventions, reflecting all of the available evidence. Formal evidence synthesis methods include systematic review and meta-analysis, extending to network meta-analysis (NMA) where the comparison of more than two interventions is of relevance, or where interventions were not previously trialled against one another. NMA allows the simultaneous estimation of comparative effectiveness of multiple interventions using an evidence base of trials that individually may not compare all intervention options, but form a connected network of comparisons. Evidence synthesis methods are used to obtain estimates of comparative effectiveness together with measures of uncertainty, both necessary for informed decision-making. The Evidence Synthesis research team has close collaborative links with the Centre for Health Decision Science (CHeDS).

Neoadjuvant Treatments for Malignant or Metastatic melanoma: A Cochrane Systematic Review

Collaborators:
Cochrane Skin Group, University of Nottingham; Department of Dermatology St James Hospital; Discipline of Radiation Therapy, Trinity College Dublin.

Status: Ongoing

Summary:
Awarding Body: Health Research Board Historically Stage IIIc and IV melanoma has been associated with a very poor survival prognosis and available treatments have little impact on the disease course. Various clinical options have been explored, including combinations of surgical procedures, chemotherapy, immunotherapy, vaccines, radiotherapy, in both neoadjuvant and adjuvant settings. Since 2011, there has been an increase in the availability of systemic treatments which improve the prognosis of patients with melanoma, and now there is an emphasis on determining the optimal clinical use of these agents. Treatments such as immunotherapies and targeted treatments have demonstrated efficacy in advanced disease but their utility is constrained by heterogeneity in patient response and the development of tumour resistance over time. It is thought that these agents may be more effective in earlier stages of disease, prior to changes in the tumour microenvironment which facilitate tumour escape mechanisms, and this forms the underlying therapeutic hypothesis for neoadjuvant therapy. There is a considerable body of literature relating to neoadjuvant treatment in melanoma, but there are no high-quality systematic reviews or meta-analyses published to quantify the treatment effects of the various regimens. In order to assess the benefit of newer agents, it is important to systematically analyse the evidence on benefits of neoadjuvant treatments used for melanoma. This review will provide physicians, researchers and patients with a systematic evaluation of the current evidence base for neoadjuvant treatment, and will serve to provide comparative evidence for the relative efficacy of neoadjuvant treatment with a new generation of therapies.

Gorry C, McCullagh L, O’Donnell H, Barrett S, Schmitz S, Barry M, Curtin K, Beausang E, Barry R, Coyne I. Neoadjuvant treatment for malignant and metastatic cutaneous melanoma.
Cochrane Database of Systematic Reviews 2018, Issue 3. Art. No: CD012974.
DOI: 10.1002/14651858.CD012974.


Systematic Review and Network meta-analysis of treatments for advanced melanoma

Collaborators:
National Centre for Pharmacoeconomics Department of Statistics Trinity College Dublin, Materials and Surface Science Institute (MSSI), University of Limerick

Status: Ongoing

Summary:
There have been a large number of new and novel drugs licensed for the treatment of metastatic melanoma since 2010. No randomised controlled trials exist to compare most of these treatment options in terms of clinical efficacy or safety and there is significant uncertainty surrounding the optimal use of these agents, and their relative effectiveness. The purpose of this systematic review is to identify all relevant sources of efficacy information, in order to synthesise the outcomes in a network meta-analysis, to produce measures of relative efficacy for the included treatments. These measures will be implemented in a cost-effectiveness model to estimate the relative cost-effectiveness of these new agents in the Irish setting.


Regorafenib for colorectal cancer

Collaborators:
National Centre for Pharmacoeconomics, Materials and Surface Science Institute (MSSI) University of Limerick, Royal College of Surgeons Ireland, National Cancer Registry of Ireland

Status: Ongoing

Summary:
Awarding Body: Health Research Board – Applied Partnership Award 2016. (Part of the Utility of High-Tech Drug Analysis to the Decision Maker project)
This is a proof-of-concept study to evaluate how drugs dispensed through the High-Tech drug scheme are informing health outcomes using the multi-kinase inhibitor regorafenib for colorectal cancer as an example. Using outcome data (all and cause-specific mortality) from the National Cancer Registry Ireland (NCRI) and linking with prescription data from High-Tech scheme, the database will be analysed to:

  • Develop a methodological approach to the synthesis of the evidence contained in the existing large databases together with randomized controlled trial data.
  • To investigate overall survival associated with regorafanib treatment and identify potential confounding variables (including age, demographics, drug compliance, tumour characteristics at diagnosis).
  • To reweight the linked observational data to account for confounders and match the RCT cohort.
  • To extrapolate the individual patient level overall survival established in our cohort to a lifetime horizon using survival analysis extrapolation techniques.

To estimate the mean overall survival in our population and compare this to the mean overall survival estimated from (i) the clinical trial data and (ii) an NCRI derived control cohort who have received best supportive care.


Comparative efficacy of disease-modifying therapies for patients with relapsing remitting multiple sclerosis

Collaborators:
National Centre for Pharmacoeconomics, St. Vincent’s University Hospital Department of Neurology, Trinity College Dublin Department of Statistics.

Status: Complete

Summary:
Multiple sclerosis (MS) is a chronic, autoimmune, disabling disease of the central nervous system. Relapses and disability progression are the clinical hallmarks of MS and the two most commonly assessed clinical endpoints used to evaluate therapeutic interventions in clinical trials. The efficacy of disease-modifying therapies (DMTs) on these clinical endpoints has been demonstrated in clinical trials over the last two decades, however few trials have assessed the comparative effectiveness of DMTs. We conducted a systematic review and Bayesian network meta-analysis considering all placebo-controlled and comparative trials of DMTs, to evaluate their comparative efficacy in reducing the risk of relapse and disability progression in MS.

Publications:
Comparative efficacy of disease-modifying therapies for patients with relapsing remitting multiple sclerosis: Systematic review and network meta-analysis. Fogarty E, Schmitz S, Tubridy N, Walsh C, Barry M. Multiple Sclerosis and Related Disorders 2016;9: 23-30

Multi-criteria decision analysis (MCDA)

Collaborators:
National Centre for Pharmacoeconomics

Status: Complete

Summary:
Decisions on reimbursement of health interventions in many jurisdictions are informed by HTAs. Historically, the focus of these has often been cost effectiveness or cost utility, while other criteria were considered informally. More recently, there has been an increasing interest in the formal incorporation of additional criteria using multi-criteria decision analysis (MCDA). Such an approach has not yet formally been part of decision-making policy in Ireland.
A list of potential criteria was identified based on the literature, national guidelines and experience of the national HTA agency (NCPE). Information on each of these criteria was sought for every pharmacoeconomic evaluation conducted in Ireland up to July 2015. A logistic regression was fitted to the data to identify influential parameters. Thirteen criteria were considered in the analysis. Model selection suggests that the incremental cost-effectiveness ratio and quality of evidence could be important drivers of reimbursement recommendations in Ireland. Less important drivers suggested include the year of assessment, the level of uncertainty, as well as safety and tolerability. The analysis demonstrates that recommendations for or against the reimbursement of technologies in Ireland are not only driven by cost effectiveness. This highlights the need for more formal inclusion of criteria in the process, to improve transparency and ensure consistency.

Publications:
Schmitz S, McCullagh L, Adams R, Walsh C. Identifying and Revealing the Importance of Decision-Making Criteria for Health Technology Assessment: A Retrospective Analysis of Reimbursement Recommendations in Ireland. PharmacoEconomics (2016) 34:925. DOI 10.1007/s40273-016-0406-z.

Value-of-Information Analysis: Choice of Thromboprophylaxis after Total Hip Replacement

Collaborators:
National Centre for Pharmacoeconomics, Trinity College Dublin Department of Statistics

Status: Complete

Summary:
The objective was to demonstrate the benefits of using value of information analysis in decreasing uncertainly associated with the reimbursement decision. Further, to examine the viability of applying these techniques as part of the formal HTA process for reimbursement purposes within the Irish healthcare system.
The evaluation was conducted from the Irish health payer perspective. A bespoke lifetime cost-effectiveness model evaluated the cost effectiveness of rivaroxaban, dabigatran etexilate and enoxaparin sodium for the prophylaxis of venous thromboembolism after total hip replacement. The partial expected value of perfect parameter information (EVPI) was calculated for the 3 model parameter subsets; probabilities, preference weights and direct medical costs. Results indicated that, at a payer threshold of €45,000 per QALY, assuming a 10 year decision time horizon, the population level EVPI associated with the decision was €11.96 million and the direct medical costs subset had the highest partial value (€9.00 million). In order to decrease uncertainty a more detailed costing study was undertaken. In the subsequent analysis, the 10 year population EVPI decreased to €3.58 million and the population value associated with the direct medical costs fell to €1.72 million. This substantially reduced potential opportunity loss could influence a decision maker’s confidence in making a reimbursement decision. Subsequent to this research, value of information analysis has been incorporated into the national agreed HTA guidelines in Ireland.

Publications:
McCullagh L, Walsh C, Barry M , Value-of-Information Analysis to Reduce Decision Uncertainty Associated with the Choice of Thromboprophylaxis after Total Hip Replacement in the Irish Healthcare Setting., PharmacoEconomics, 30, (10), 2012, p941 - 959.