Implementing health technology assessment in Ghana to support universal health coverage: building relationships that focus on people, policy, and process.

Ghana is one of the few African countries to enact legislation and earmark significant funding to establish universal health coverage (UHC) through the National Health Insurance Scheme, although donor funds have declined recently. Given a disproportionate level of spending on medicines, health technology assessment (HTA) can support resource allocation decisions in the face of highly constrained budgets, as commonly found in low-resource settings. The Ghanaian Ministry of Health, supported by the International Decision Support Initiative (iDSI), initiated a HTA study in 2016 to examine the cost-effectiveness of antihypertensive medicines. We aimed to summarize key insights from this work that highlights success factors beyond producing purely technical outputs. These include the need for capacity building, academic collaboration, and ongoing partnerships with a broad range of experts and stakeholders. By building on this HTA study, and with ongoing interactions with iDSI, HTAi, WHO, and others, Ghana will be well positioned to institutionalize HTA in resource allocation decisions and support progress toward UHC.

Moderating the impact of patent linkage on access to medicines: lessons from variations in South Korea, Australia, Canada, and the United States.

BACKGROUND: The inclusion of patent linkage mechanisms in bilateral and plurilateral trade and investment agreements has emerged as a key element in the United States' TRIPS-Plus intellectual property (IP) negotiating agenda. However, the provisions establishing patent linkage mechanisms in several agreements appear to reflect a degree of ambiguity, potentially enabling some flexibility in their implementation. In this study, we reviewed the features of the prototypic patent linkage mechanism established by the Hatch-Waxman Act in the United States, and compared these with the implementation of systems in three countries whose agreements with the US include patent linkage obligations. From these analyses, we draw lessons for moderating the impact of these mechanisms on access to generic medicines. METHODS: We reviewed the features of the patent linkage mechanism in the US, and undertook a detailed analysis of relevant treaty provisions and the manner of implementation in Canada, Australia, and South Korea. RESULTS: A key difference between the US implementation of patent linkage and that of its trading partners is the disparate treatment afforded to biologics. Because of the significant differences in the regulatory frameworks applying to small molecule and biologic medicines in the US, the Hatch- Waxman provisions do not apply to biologics and they are not subject to patent linkage. By contrast, the regulatory frameworks in Canada, Australia and South Korea do not reflect similar distinctions and thus patent linkage mechanisms also capture biologics. Additional variations in implementation, mainly the result of constructive ambiguities in the respective treaty texts, offer potential opportunity for mitigating the adverse impact of patent linkage provisions on market entry of generic medicines. Practical measures include ensuring the availability of an accessible, transparent and easily searchable database of patent information; avoiding automatic stays of generic marketing approval where possible; and requiring certification by rights holders to prevent abuse of the system. CONCLUSIONS: Where countries accept treaty obligations to establish patent linkage mechanisms, the impact on access to generic medicines may be moderated to a degree by retaining and exploiting constructive ambiguities in the treaty text and addressing practical aspects of implementation.

The Trans Pacific Partnership Agreement, intellectual property and medicines: Differential outcomes for developed and developing countries.

The final text of the Trans Pacific Partnership Agreement (TPP), agreed between the 12 negotiating countries in 2016, included a suite of intellectual property provisions intended to expand and extend pharmaceutical company exclusivities on medicines. It drew wide criticism for including such provisions in an agreement that involved developing countries (Vietnam, Peru, Malaysia, Mexico, Chile and Brunei Darussalam) because of the effect on delaying the introduction of low-cost generics. While developing nations negotiated transition periods for implementing some obligations, all parties would have eventually been expected to meet the same standards had the TPP come into force. While the TPP has stalled following US withdrawal, there are moves by some of the remaining countries to reinvigorate the agreement without the United States. The proponents may seek to retain as much as possible of the original text in the hope that the United States will re-join the accord in future. This article presents a comparative analysis of the impact the final 2016 TPP intellectual property chapter could be expected to have (if implemented in its current form) on the intellectual property laws and regulatory regimes for medicines in the TPP countries. Drawing on the published literature, it traces the likely impact on access to medicines. It focuses particularly on the differential impact on regulatory frameworks for developed and developing nations (in terms of whether or not legislative action would have been required to implement the agreement). The article also explores the political and economic dynamics that contributed to these differential outcomes.

The International Decision Support Initiative Reference Case for Economic Evaluation: An Aid to Thought.

BACKGROUND: Policymakers in high-, low-, and middle-income countries alike face challenging choices about resource allocation in health. Economic evaluation can be useful in providing decision makers with the best evidence of the anticipated benefits of new investments, as well as their expected opportunity costs-the benefits forgone of the options not chosen. To guide the decisions of health systems effectively, it is important that the methods of economic evaluation are founded on clear principles, are applied systematically, and are appropriate to the decision problems they seek to inform. METHODS: The Bill and Melinda Gates Foundation, a major funder of economic evaluations of health technologies in low- and middle-income countries (LMICs), commissioned a "reference case" through the International Decision Support Initiative (iDSI) to guide future evaluations, and improve both the consistency and usefulness to decision makers. RESULTS: The iDSI Reference Case draws on previous insights from the World Health Organization, the US Panel on Cost-Effectiveness in Health Care, and the UK National Institute for Health and Care Excellence. Comprising 11 key principles, each accompanied by methodological specifications and reporting standards, the iDSI Reference Case also serves as a means of identifying priorities for methods research, and can be used as a framework for capacity building and technical assistance in LMICs. CONCLUSIONS: The iDSI Reference Case is an aid to thought, not a substitute for it, and should not be followed slavishly without regard to context, culture, or history. This article presents the iDSI Reference Case and discusses the rationale, approach, components, and application in LMICs.

Costs to Australian taxpayers of pharmaceutical monopolies and proposals to extend them in the Trans-Pacific Partnership Agreement.

Intellectual property (IP) protections proposed by the United States for the Trans-Pacific Partnership Agreement (TPPA) have sparked widespread alarm about the potential negative impact on access to affordable medicines. The most recently leaked draft of the IP chapter shows some shifts in the US position, presumably in response to ongoing resistance from other countries. While some problematic provisions identified in earlier drafts have been removed or mitigated, major concerns remain unresolved. Three of the greatest concerns for Australia in the recent draft include provisions that would further entrench secondary patenting and evergreening, lock in extensions to patent terms and extend monopoly rights over clinical trial data for certain medicines. Data from the 2013 Pharmaceutical Patents Review, and from various submissions made to it, show that pharmaceutical monopoly protections already cost Australian taxpayers hundreds of millions of dollars each year. Provisions still being considered for the TPPA would further entrench and extend costly monopolies, with serious implications for the budget bottom line and the sustainability of the Pharmaceutical Benefits Scheme.

Intussusception risk and disease prevention associated with rotavirus vaccines in Australia's National Immunization Program.

BACKGROUND: Estimates of the risk of intussusception (IS) associated with currently licensed rotavirus vaccines (RV1 [Rotarix; GSK] and RV5 [RotaTeq; Merck]) diverge. Contemporaneous introduction of both vaccines in Australia enabled a population-based assessment of risk. METHODS: Confirmed cases of IS in infants aged 1 to <12 months were identified from national hospitalization databases, supplemented by active hospital-based surveillance, from July 2007 through June 2010. Vaccination histories were verified by the Australian Childhood Immunisation Register, which was also used to identify age-matched controls. Self-controlled case series and case-control methods were used to assess the risk of IS associated with both vaccines in prespecified periods after vaccination. The estimated burden of vaccine-attributable IS was compared with estimated reductions in gastroenteritis hospitalizations. RESULTS: Based on 306 confirmed cases of IS, the relative incidence of IS in the 1-7-day period after the first vaccine dose, was 6.8 (95% confidence interval, 2.4-19.0; P < .001) for RV1, and 9.9 (95% confidence interval, 3.7-26.4; P < .001) for RV5. There was a smaller increased risk 1-7 days after the second dose of each vaccine. The case-control analysis gave similar results. We estimate an excess of 14 IS cases and >6500 fewer gastroenteritis hospitalizations in young children annually in Australia after vaccine introduction. CONCLUSIONS: We found a similarly increased risk of IS after both vaccines, but the balance of benefits and risks at population level was highly favorable, a finding likely to extend to other settings despite varying incidence of IS and potentially higher morbidity and mortality from both gastroenteritis and IS.

Simulated value-based insurance design applied to statin use by Medicare beneficiaries with diabetes.

OBJECTIVE: To examine cost responsiveness and total costs associated with a simulated "value-based" insurance design for statin therapy in a Medicare population with diabetes. METHODS: Four-year panels were constructed from the 1997-2005 Medicare Current Beneficiary Survey selected by self-report or claims-based diagnoses of diabetes in year 1 and use of statins in year 2 (N = 899). We computed the number of 30-day statin prescription fills, out-of-pocket and third-party drug costs, and Medicare Part A and Part B spending. Multivariate ordinary least squares regression models predicted statin fills as a function of out-of-pocket costs, and a generalized linear model with log link predicted Medicare spending as a function of number of fills, controlling for baseline characteristics. Estimated coefficients were used to simulate changes in fills associated with co-payment caps from $25 to $1 and to compute changes in third-party payments and Medicare cost offsets associated with incremental fills. Analyses were stratified by patient cardiovascular event risk. RESULTS: A simulated out-of-pocket price of $25 [$1] increased plan drug spending by $340 [$794] and generated Medicare Part A/B savings of $262 [$531]; savings for high-risk patients were $558 [$1193], generating a net saving of $249 [$415]. CONCLUSIONS: Reducing statin co-payments for Medicare beneficiaries with diabetes resulted in modestly increased use and reduced medical spending. The value-based insurance design simulation strategy met financial feasibility criteria but only for higher-risk patients.

Towards Better Pharmaceutical Provision in Europe-Who Decides the Future?

Significant progress has been achieved in human health in the European Union in recent years. New medicines, vaccines, and treatments have been developed to tackle some of the leading causes of disease and life-threatening illnesses. It is clear that investment in research and development (R&D) for innovative medicines and treatments is essential for making progress in preventing and treating diseases. Ahead of the legislative process, which should begin by the end of 2022, discussions focus on how Europe can best promote the huge potential benefits of new science and technology within the regulatory framework. The challenges in European healthcare were spelled out by the panellists at the roundtable organised by European Alliance for Personalised Medicine (EAPM). Outcomes from panellists' discussions have been summarized and re-arranged in this paper under five headings: innovation, unmet medical need, access, security of supply, adapting to progress, and efficiency. Some of the conclusions that emerged from the panel are a call for a better overall holistic vision of the future of pharmaceuticals and health in Europe and a collaborative effort among all stakeholders, seeing the delivery of medicines as part of a broader picture of healthcare.

Hydroxyzine Initiation Following Drug Safety Advisories on Cardiac Arrhythmias in the UK and Canada: A Longitudinal Cohort Study.

INTRODUCTION: Regulatory advisories on hydroxyzine and risk of QT prolongation and Torsade de pointes (TdP) were issued in the UK in April 2015 and Canada in June 2016. We hypothesized patients with risk factors for QT prolongation and TdP, compared with those without risk factors, would be less likely to initiate hydroxyzine in the UK and in British Columbia (BC), Canada, following advisories. METHODS: We conducted a longitudinal study with repeated measures, and evaluated hydroxyzine initiation in a UK cohort and a concurrent BC control cohort (April 2013-March 2016) as well as in a BC advisory cohort (June 2014-May 2017). RESULTS: This study included 247,665 patients in the UK cohort, 297,147 patients in the BC control cohort, and 303,653 patients in the BC advisory cohort. Over a 12-month post-advisory period, hydroxyzine initiation decreased by 21% in the UK (rate ratio 0.79, 95% confidence interval 0.66-0.96) relative to the expected level of initiation based on the pre-advisory trend. Hydroxyzine initiation did not change in the BC control cohort or following the Canadian advisory in the BC advisory cohort. The decrease in hydroxyzine initiation in the UK in the 12 months after the advisories was not significantly different for patients with risk factors compared with those without risk factors. CONCLUSION: Hydroxyzine initiation decreased in the UK, but not in BC, in the 12 months following safety advisories. The decrease in hydroxyzine initiation in the UK was not significantly different for patients with versus without risk factors for QT prolongation and TdP.

Influence of drug safety advisories on drug utilisation: an international interrupted time series and meta-analysis.

OBJECTIVE: To evaluate the association between regulatory drug safety advisories and changes in drug utilisation. DESIGN: We conducted controlled, interrupted times series analyses with administrative prescription claims data to estimate changes in drug utilisation following advisories. We used random-effects meta-analysis with inverse-variance weighting to estimate the average postadvisory change in drug utilisation across advisories. STUDY POPULATION: We included advisories issued in Canada, Denmark, the UK and the USA during 2009-2015, mainly concerning drugs in common use in primary care. We excluded advisories related to over-the-counter drugs, drug-drug interactions, vaccines, drugs used primarily in hospital and advisories with co-interventions within ±6 months. MAIN OUTCOME MEASURES: Change in drug utilisation, defined as actual versus predicted percentage change in the number of prescriptions (for advisories without dose-related advice), or in the number of defined daily doses (for dose-related advisories), per 100 000 population. RESULTS: Among advisories without dose-related advice (n=20), the average change in drug utilisation was -5.83% (95% CI -10.93 to -0.73; p=0.03). Advisories with dose-related advice (n=4) were not associated with a statistically significant change in drug utilisation (-1.93%; 95% CI -17.10 to 13.23; p=0.80). In a post hoc subgroup analysis of advisories without dose-related advice, we observed no statistically significant difference between the change in drug utilisation following advisories with explicit prescribing advice, such as a recommendation to consider the risk of a drug when prescribing, and the change in drug utilisation following advisories without such advice. CONCLUSIONS: Among safety advisories issued on a wide range of drugs during 2009-2015 in 4 countries (Canada, Denmark, the UK and the USA), the association of advisories with changes in drug utilisation was variable, and the average association was modest.

Postmarket Safety Communication for Protection of Public Health: A Comparison of Regulatory Policy in Australia, Canada, the European Union, and the United States.

In the wake of the withdrawal of the nonsteroidal anti-inflammatory drug rofecoxib, regulators worldwide reconsidered their approach to postmarket safety. Many have since adopted a "life cycle" approach to regulation of medicines, facilitating faster approval of new medicines while planning for potential postmarket safety issues. A crucial aspect of postmarket safety is the effective and timely communication of emerging risk information using postmarket safety advisories, commonly issued as letters to healthcare professionals, drug safety bulletins, media alerts, and website announcements. Yet regulators differ in their use of postmarket safety advisories. We examined the capacity of regulators in the United States, Europe, Canada, and Australia to warn about postmarket safety issues through safety advisories by assessing their governance, legislative authority, risk communication capabilities, and transparency.

Comparative effectiveness research and evidence-based health policy: experience from four countries.

CONTEXT: The discussion about improving the efficiency, quality, and long-term sustainability of the U.S. health care system is increasingly focusing on the need to provide better evidence for decision making through comparative effectiveness research (CER). In recent years, several other countries have established agencies to evaluate health technologies and broader management strategies to inform health care policy decisions. This article reviews experiences from Britain, France, Australia, and Germany. METHODS: This article draws on the experience of senior technical and administrative staff in setting up and running the CER entities studied. Besides reviewing the agencies' websites, legal framework documents, and informal interviews with key stakeholders, this analysis was informed by a workshop bringing together U.S. and international experts. FINDINGS: This article builds a matrix of features identified from the international models studied that offer insights into near-term decisions about the location, design, and function of a U.S.-based CER entity. While each country has developed a CER capacity unique to its health system, elements such as the inclusiveness of relevant stakeholders, transparency in operation, independence of the central government and other interests, and adaptability to a changing environment are prerequisites for these entities' successful operation. CONCLUSIONS: While the CER entities evolved separately and have different responsibilities, they have adopted a set of core structural, technical, and procedural principles, including mechanisms for engaging with stakeholders, governance and oversight arrangements, and explicit methodologies for analyzing evidence, to ensure a high-quality product that is relevant to their system.

Evidence-based decision-making within Australia's pharmaceutical benefits scheme.

In Australia, most prescription drugs are subsidized through the Pharmaceutical Benefits Scheme (PBS), one of several government programs in which evidence-based decision making is applied to the funding of health technologies. PBS processes are intended to ensure "value for money" for the Australian taxpayer and to support affordable, equitable access to prescription medicines; they are not intended as a mechanism for cost containment. The inclusion of a drug on the national formulary depends on the recommendation of the Pharmaceutical Benefits Advisory Committee (PBAC), which considers not only the comparative effectiveness but also the comparative cost-effectiveness of drugs proposed for listing. While some decisions have been controversial, the PBS retains strong public support. Moreover, evidence does not suggest that the consideration of cost-effectiveness has created a negative environment for the drug industry: Australia has a high penetration of patented medicines, with prices for some recently approved drugs at U.S. levels.

Financial costs associated with monopolies on biologic medicines in Australia.

Objectives The aim of the study was to estimate the potential savings to the Pharmaceutical Benefits Scheme (PBS) and the Repatriation Pharmaceutical Benefits Scheme (RPBS) in 2015-16 if biosimilar versions of selected biologic medicines (biologics) had been available and listed on the PBS. Methods The research involved retrospective analysis of Australian Medicare expenditure data and PBS price data from 2015-16 for biologics, for which biosimilar competition may be available in future, listed on the PBS. Results Australian Government expenditure on biologics on the PBS and RPBS was estimated at A$2.29 billion dollars in 2015-16. If biosimilar versions of these medicines had been listed on the PBS in 2015-16, at least A$367million dollars would have been saved in PBS and RPBS subsidies. Modelling based on price decreases following listing of biosimilars on the PBS suggests that annual PBS outlays on biologics could be reduced by as much as 24% through the timely introduction of biosimilars. Conclusions Biologic medicines represent a large proportion of government expenditure on pharmaceuticals. Reducing the length of monopoly protections on these medicines could generate savings of hundreds of millions of dollars per year. What is known about the topic? Biologics take up an increasing share of pharmaceutical expenditure, but no previous published studies have examined Australian Government expenditure on biologics or the potential savings from reducing the duration of monopoly protection. What does this paper add? This paper provides new evidence about Australian Government expenditure on biologics and potential savings for selected medicines that are still subject to monopoly protection and thus are not yet subject to biosimilar competition. In 2015-16 Australian Government expenditure on biologics through the PBS and RPBS was estimated at A$2.29 billion dollars. If biosimilar versions of these medicines had been listed on the PBS at that time, at least A$367million dollars would have been saved. What are the implications for practitioners? Reducing the duration of monopoly protection on biologic medicines could save hundreds of millions of dollars annually that could be redirected to other areas of the healthcare system.

The Trans Pacific Partnership Agreement and access to HIV treatment in Vietnam.

In the Trans Pacific Partnership (TPP) Agreement negotiations, the USA successfully pursued intellectual property (IP) provisions that will affect the affordability of medicines, including anti-retrovirals (ARV) for HIV. Vietnam has the lowest GDP per capita of the 12 TPP countries and in 2013 provided ARVs for only 68% of eligible people living with HIV. Using the current Vietnamese IP regime as our base case, we analysed the potential impact of a regime making full use of legal IP flexibilities, and one based on the IP provisions of the final, agreed TPP text. Results indicate that at current funding levels 82% of Vietnam's eligible people living with HIV would receive ARVs if legal flexibilities were fully utilised, while as few as 30% may have access to ARVs under the TPP Agreement - more than halving the proportion currently treated.

Prices for innovative pharmaceutical products that provide health gain: a comparison between Australia and the United States.

OBJECTIVES: Pricing polices used in many countries are often viewed in the United States as a mechanism of price constraint. Support for this contention has arisen from pricing studies which demonstrate that the United States pays higher prices for many pharmaceutical products. No study to date, however, has examined the prices paid for pharmaceuticals that provide significant health gain, which might be expected to be lower where price constraints were operating. This study aimed to examine prices paid by federal government programs and agencies in Australia and the United States for pharmaceutical products that provide significant health gain. METHODS: Products identified by the US Food and Drug Administration and the Canadian Patented Medicines Prices Review Board as likely to confer significant health gains between 1999 and 2004 were identified. Australian and USfederal government prices ($US) and US average manufacturer prices (AMP), which do not include discounts or rebates, during the second quarter of 2006 were compared. RESULTS: Of 22 products for which comparisons were possible, Australian prices were higher than the US Federal Supply Schedule (FSS) prices for 14 (64%) products. When compared with AMP, Australian prices were higher for eight of the 22 products. Overall, Australian prices were higher on average by 4.2% when compared with the FSS and lower by 14.4% when compared with the AMP. CONCLUSION: These results suggest that Australian prices for medicines representing significant advances in therapy are similar to those paid under key US programs despite fundamental differences in policy contexts.

What is fair? Choice, fairness, and transparency in access to prescription medicines in the United States and Australia.

The importance of prescription drugs to modern medical practice, coupled with their increasing costs, has strengthened imperatives for national health policies that ensure safety and quality, facilitate affordable access, and promote rational use. Australia has made universal and affordable prescription drug coverage a priority for decades, within a policy framework that emphasizes equity and increasing transparency in coverage design and payment decisions. By contrast, the U.S. lacks such a national policy. Furthermore, federal Medicare reforms aimed at making appropriate drug coverage affordable and accessible employs two icons of the U.S. perception of fairness--the right to choose and the right to challenge coverage design limits--that mask the limited nature of the assistance. As the U.S. seeks to impose its values and priorities on other nations through the negotiation of bilateral and regional trade agreements, it becomes important to consider the two national experiences, in order to avoid trading illusory notions of fairness for true population equity.

High-Expenditure Pharmaceutical Use Among Children in Medicaid.

BACKGROUND AND OBJECTIVES: Medication use may be a target for quality improvement, cost containment, and research. We aimed to identify medication classes associated with the highest expenditures among pediatric Medicaid enrollees and to characterize the demographic, clinical, and health service use of children prescribed these medications. METHODS: Retrospective, cross-sectional study of 3 271 081 Medicaid-enrolled children. Outpatient medication spending among high-expenditure medication classes, defined as the 10 most expensive among 261 mutually exclusive medication classes, was determined by using transaction prices paid to pharmacies by Medicaid agencies and managed care plans among prescriptions filled and dispensed in 2013. RESULTS: Outpatient medications accounted for 16.6% of all Medicaid expenditures. The 10 most expensive medication classes accounted for 63.9% of all medication expenditures. Stimulants (amphetamine-type) accounted for both the highest proportion of expenditures (20.6%) and days of medication use (14.0%) among medication classes. Users of medications in the 10 highest-expenditure classes were more likely to have a chronic condition of any complexity (77.9% vs 41.6%), a mental health condition (35.7% vs 11.9%), or a complex chronic condition (9.8% vs 4.3%) than other Medicaid enrollees (all P < .001). The 4 medications with the highest spending were all psychotropic medications. Polypharmacy was common across all high-expenditure classes. CONCLUSIONS: Medicaid expenditure on pediatric medicines is concentrated among a relatively small number of medication classes most commonly used in children with chronic conditions. Interventions to improve medication safety and effectiveness and contain costs may benefit from better delineation of the appropriate prescription of these medications.