Entry to market of new medicines and medicines treating rare diseases: issues arising from value assessment processes in the European Union, the United Kingdom and Canada

To achieve access to new medicines within markets, manufacturers need to first receive marketing authorisation and subsequently seek funding from healthcare insurance. In countries where access to healthcare is free, the allocation of finite resources poses substantial challenges. Increasingly in these settings, health technology assessment (HTA) is used to inform funding decisions whilst seeking to promote healthcare financial sustainability and macro- and micro-economic efficiency. Variations in access to medicines can occur as countries implement HTA differently. These variations are further highlighted in medicines used to treat rare diseases, known as orphan medicines. Due to their high prices and high uncertainty about their clinical benefit, some HTA bodies have specialised assessment frameworks for orphan medicines to safeguard equity by considering additional dimensions of value beyond clinical- and/or cost-effectiveness. In this thesis, I explored how differences in HTA systems and processes may contribute to access variations of new medicines and medicines for rare diseases across settings. First, I outlined a conceptual framework that showed how HTA is operationalised; I also mapped HTA systems across 32 countries. Second, through a Delphi panel of European stakeholders, I identified features of HTA that facilitate access to new medicines. Third, I observed whether the presence of specialised assessment frameworks might translate to more favourable funding recommendations for and timely access to orphan medicines by comparing two settings where these medicines are treated differently. Finally, I evaluated whether HTA recommendations are aligned with funding decisions for orphan medicines in a decentralised healthcare setting where the HTA body has an advisory role. The main contributions of this thesis are fivefold: (i) it develops a conceptual framework that allows comparisons of HTA systems regardless of how well-developed they are; (ii) it generates evidence on the performance of HTA features, looking at HTA holistically, against different access metrics; (iii) it examines whether efforts to optimise access to orphan medicines across the market access pathway may translate into more favourable reimbursement decisions; (iv) it studies whether HTA recommendations are followed in funding decisions; and (v) it provides recommendations on what features of HTA need improvement to optimise patient access

Similarities and differences in Health Technology Assessment systems and implications for coverage decisions: evidence from 32 countries

Health technology assessment (HTA) systems across countries vary in the way they are set up, according to their role and based on how funding decisions are reached. Our objective was to study the characteristics of these systems and their likely impact on the funding of technologies undergoing HTA. Based on a literature review, we created a conceptual framework that captures key operating features of HTA systems. We used this framework to map current HTA activities across 32 countries in the European Union, the UK, Canada and Australia. Evidence was collected through a systematic search of competent authority websites and grey literature sources. Primary data collection through expert consultation validated our findings and further complemented the analysis. Sixty-three HTA bodies were identified. Most have a national scope (76%), are independent (73%), have an advisory role (52%), evaluate pharmaceuticals predominantly or exclusively (76%), assess health technologies based on their clinical and cost-effectiveness (73%) and involve various stakeholders as members of the HTA committee (94%) and/or through external consultation (76%). The majority of HTA outcomes are not legally binding (81%). Although all study countries implement HTA, the way it fits into decision-making, negotiation processes, and coverage and funding decisions differs significantly across countries. HTA is a dynamic and transformative process and there is a need for transparency to investigate whether evidence-based information influences coverage decisions

The Impact of External Reference Pricing within and across Countries

An assessment of the impact of external reference pricing (ERP) systems on important health system goals such as availability, affordability and diffusion/utilisation of pharmaceuticals; and an analysis of the impact that ERP systems have at the domestic and international levels, particularly considering their likely spillover effects

The Implementation of External Reference Pricing within and across Country Borders

An assessment of the way that 29 countries implement external reference pricing (ERP), which aims to contain medicine costs, using a systematic literature review-based process

International impact of external reference pricing: should national policy makers care?

Background: External reference pricing (ERP) is widely used to regulate drug prices. Although the literature has largely focused on the impact of ERP on a number of policy endpoints and its impact from a geographical perspective, a comparative study drawing on evidence from different settings does not exist to date. Methods: A systematic literature review was conducted on pre-defined endpoints on the impact of ERP across countries, such as price stability, price convergence and launch delays. Expert consultation was undertaken to analyse whether or not the international implications of ERP are considered during its design. Results: 46 studies were included in the analysis. Across countries, ERP may cause launch delays, price instability and lead to price convergence. However, these effects cannot be solely attributed to ERP, as there may be other factors at play, such as the size and the GDP of a country and other regulations in place, which can trigger these effects or reduce their effect. Nevertheless, the nature of ERP facilitates these unintended consequences and directly links them to it. Despite these cross-country implications being well known to decision-makers, they are not necessarily considered during the design of ERP. Conclusions: As the effects of ERP as a stand alone policy are very difficult to isolate in the presence of other regulatory measures implemented within countries and the presence of other extrinsic factors across countries, our findings are inconclusive. Still, there is an unquestionable unmet need related to the design of ERP systems to attain a positive impact internationally

Pricing of in-patent pharmaceuticals in the Middle East and North Africa: is external reference pricing implemented optimally?

In this paper we outline and compare pharmaceutical pricing policies for in-patent prescription pharma- ceuticals with emphasis on external reference pricing (ERP) in eleven countries across the Middle East and North Africa (MENA) region and explore possible improvements in their pricing systems. Primary and secondary evidence was used to inform our analysis. Comparative analysis of ERP systems across countries followed an analytical framework distilling ERP into twelve salient features, while ERP system performance was benchmarked against a framework of best practice principles across (a) objectives and scope, (b) administration and operations, (c) methods used, and (d) implementation. Results suggest that ERP is the dominant pricing method for in-patent pharmaceuticals. Although several good practice cases were identified, none of the eleven countries satisfy all best practice principles. ERP basket sizes vary sig- nificantly and are commonly composed using geographical proximity and low-price countries as criteria. Nine countries do not use the mean or median prices, but resort to using the lowest. Exchange rate fluc- tuations are routinely used to arrive at price reductions in local currency. Significant opportunities exist for MENA countries to develop their ERP regimes to achieve greater compliance with best practice princi- ples. Over the short-term, incremental changes could be implemented to several ERP salient features and can be achieved relatively easily, thereby enhancing the functionality and performance of national ERP systems. Countries in the region can also focus on the development of explicit value assessment systems, and minimize their dependence on ERP over the longer-term

Market access for medicines treating rare diseases: association between specialised processes for orphan medicines and funding recommendations

Access to medicines treating rare diseases (‘orphan medicines’) has proven challenging due to high prices and clinical uncertainty. To optimise market access to these medicines, some healthcare systems are implementing specialised pathways and/or processes during marketing authorisation (MA) and/or health technology assessment (HTA). Comparing one setting where these medicines are classed as “orphan” (Scotland) to another where they considered “non-orphan” (Canada), this study aims to explore whether the presence of specialised pathways and processes at MA and HTA levels is associated with more favourable funding recommendations and faster time to market access. A matched sample of 116 medicine-indication pairs with MA approval from 2001 to 2019 in Europe and Canada was identified, and publicly available sources were used for data extraction. Descriptive statistics were used for data analysis. All medicines were commercially marketed in both countries, except one instance in Scotland. In Scotland, more orphan medicines (68.1%) had a favourable HTA recommendation than in Canada (60.4%), while Canada issued more negative HTA recommendations (20.7%) than Scotland (15.5%). Low levels of agreement on HTA recommendations and the main reasons driving recommendations were found between settings. In both countries, medicines with specialised MA approval were less likely to receive negative HTA recommendations than medicines with standard MA. Time to market access was faster in Canada than Scotland, though medicines with specialised MA approval had slower timelines than medicines with standard MA approval in both countries. However, it is unclear whether the presence of orphan designation and HTA specialised processes alone could result in favourable funding recommendations without accounting for other healthcare system-related factors and differences in the decision-making processes across settings. Holistic approaches and better alignment of evidentiary requirements across regulators are needed to optimise access to orphan medicines

Do reimbursement recommendations by the Canadian Agency for Drugs and Technology in Health translate into coverage decisions for orphan drugs in the Canadian province of Ontario?

Objective: Unlike other high-income countries, Canada has no national policy for drugs treating rare diseases (‘orphan drugs’). However, in 2022, the Canadian government committed to creating a national strategy to make access to these drugs more consistent. Our aim was to study whether recommendations made by the Canadian Agency for Drugs and Technology in Health (CADTH) translated into coverage decisions for orphan drugs in Ontario, the largest Canadian province. This study is the first to look at this question for orphan drugs which are at the centre of policy attention. Methods: We included 155 orphan drug-indication pairs approved and marketed in Canada between 2002 and 2022. Cohen’s kappa was used to test agreement across HTA recommendations and coverage decisions in Ontario. Logistic regression was used to test which factors, relevant to decision-makers, might be associated with funding in Ontario. Results: We found only fair agreement between CADTH’s recommendations and coverage decisions in Ontario. Whilst a positive and statistically significant association between favourable HTA recommendations and coverage was found, more than half of drugs with a negative HTA recommendation were available in Ontario, predominately through specialised funds. Successful pan-Canadian pricing negotiations were a strong predictor of coverage in Ontario. Conclusions: Despite efforts to harmonise access to drugs across Canada, considerable room for improvement remains. Introducing a national strategy for orphan drugs could help increase transparency, consistency, promote collaborations and make access to orphan drugs a national priority

Access to personalised oncology in Europe

The development of personalised oncology (PO), where the right treatment is given to the right person at the right time determined by the use of biomarkers (a biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process or of a condition or disease), is predicted to lead to better outcomes and reduced risk of side effects for patients with cancer as well as reducing costs and improving efficiencies of healthcare systems. The European Federation of Pharmaceutical Industries and Associations (EFPIA) asked MTRG to conduct an evidence-based analysis to determine the use of personalised oncology products across Europe and to highlight barriers affecting patient access. The ultimate aim is for evidence highlighted in the report to be used to initiate discussions with policy-makers to work towards enhancing access to effective treatments and improving cancer-based health outcomes across Europe