Patient access schemes in Asia-pacific markets: current experience and future potential

Objectives Patient access (or risk-sharing) schemes are alternative market access agreements between healthcare payers and medical product manufacturers for conditional coverage of promising health technologies. This study aims to identify and characterize patient access schemes to date in the Asia-Pacific region. Methods We reviewed the literature on patient access schemes over the last two decades using publicly available databases, Internet, and grey literature searches. We extracted key features of each scheme identified, including the drug, clinical indication, stakeholders involved, and details of the scheme. We categorized schemes according to a previously published taxonomy of scheme types and by country. Results We identified 3 schemes in South Korea, 5 in New Zealand, and 98 in Australia. Most (97.2%; n = 103) schemes focused on pharmaceuticals, few on medical technologies. More than half of the schemes related to treatments for cancer and inflammatory diseases such as rheumatoid arthritis. The majority (77.4%; n =82) involved pricing arrangements. Evidence generation schemes were rarely used. About half (41.8%; n = 41) of schemes in Australia were hybrid by nature, consisting of pricing arrangements with a conditional treatment continuation component. Conclusions Australia has the most experience with patient access schemes and its experience may provide useful insights for other Asia-Pacific countries. The main targets are pharmaceuticals likely to have high budget impact (due to high per-patient costs and/or large volumes of use), and pharmaceuticals that may be adopted more widely than indicated. With the proliferation of high-cost medicines, the use of schemes may increase to address rising cost pressures, consumer demands, and uncertainties, while attempting to provide patient access to innovative care within finite budgets. Future research is warranted to evaluate the performance of patient access schemes.


Introduction
Many countries and insurance schemes are pursuing universal health coverage with the goal of ensuring that all people have access to needed health services without suffering financial hardship [1,2]. However, healthcare systems grapple with the challenges of funding clinically beneficial health services and medicines while ensuring that financing systems are sustainable.
In an effort to improve the efficiency of rising healthcare expenditures, many systems evaluate whether expected additional health benefits of a new technology justify its additional cost compared to existing treatments (cost-effectiveness or 'value-for-money') [3][4][5]. Healthcare systems in the Asia-Pacific region that require proof of value-for-money in coverage of medical technologies include Australia, New Zealand, Thailand, South Korea, and Taiwan [6][7][8][9][10]. Even in systems that do not explicitly consider cost, there is often a focus on the magnitude of health benefits, which are informally weighed against cost. Traditionally, coverage decisions on medical technologies such as medicines and devices have been binary in nature; based on evidence available at launch and the price set by the manufacturer, payers decide whether or not to reimburse a product. In recent years, various types of conditional coverage decisions have emerged. Patient access schemes (also known as managed entry schemes or risk-sharing agreements) are alternative market access agreements, typically between payers and manufacturers, to enable provisional or conditional coverage of promising health technologies [4,5,11]. There are three broad categories of schemes [5]. First, outcome-based schemes (also known as performancebased or effectiveness guarantee schemes) in which the price, level, or nature of reimbursement are tied to clinical or intermediate endpoints measured in the future and ultimately related to patients' quality or quantity of life. Second, evidence generation schemes in which a positive coverage decision is conditioned upon the collection of additional evidence through clinical studies, which might result in continued, expanded, or withdrawn coverage. Third, financially-based schemes negotiate company contributions to the cost of a product (e.g., discounts or rebates, price-volume agreements, utilization caps) for a particular patient or population without linking reimbursement to health outcomes.
Interest in patient access schemes is growing due to increasing cost pressures, the need to balance the interests of patients, clinicians, manufacturers, and other stakeholders, and uncertainties due to incomplete information at the time that decisions must be made. The necessary evidence to demonstrate incremental effectiveness and cost-effectiveness of a new technology is often not available at the time of launch [12]. Therefore, uncertainties exist about whether the technology will deliver the promised health gains in routine clinical practice. Clinical and cost-effectiveness uncertainties result in budget uncertainties [12]. In addition, costs of innovative products may bankrupt households and threaten sustainability of systems. Patient access schemes offer an important option for systems to allow (some) patients (early) access to promising technologies that systems may not otherwise fund. At the same time, these schemes may reduce the financial risks that payers face in making decisions based on limited evidence, and in some cases, they facilitate collection of more evidence to support future decisions [4,5,11].
Little is known about experiences with patient access schemes in Asia-Pacific countries. The purpose of this study was to identify and categorize patient access schemes in this region. The results of this study will enhance understanding of the roles of patient access schemes in emerging Asia-Pacific markets and inform policy developments for enabling patient access to promising technologies.

Methods
We reviewed the literature on patient access schemes. We searched in PubMed and Google Scholar for English-language articles published through July 2012 using the following terms; 'conditional coverage', 'conditional reimbursement', 'managed entry', 'risk sharing', 'risk sharing agreement', 'risk sharing, pharmaceuticals', 'risk sharing scheme', 'coverage with evidence', 'valuebased pricing, pharmaceuticals', 'patient access scheme', 'pay back schemes', 'performance-based, pharmaceuticals', 'outcome-based reimbursement, pharmaceuticals', 'reimbursement mechanisms, pharmaceuticals', and 'outcome guarantee'. We scanned titles and abstracts to select relevant articles to review. The reference lists of relevant articles were also reviewed for studies fitting our criteria that our search strategy may have missed. We also added relevant unpublished or 'grey literature' (reports, conference presentations, payer websites) that were identified during our search.
We extracted key features of the schemes: the technology, disease area, country, payer, manufacturer, scheme type, and agreement details (when reported). We categorized the schemes according to a published taxonomy [5] of scheme types: (1) outcome-based schemes, (2) evidence generation schemes, and (3) financially-based schemes. These scheme types have generally been termed "risk sharing schemes" or "patient access schemes" by payers or pharmaceutical companies. Consistent with the literature [13], we classified schemes with a "conditional treatment continuation" component that limits continued subsidy of medicines to patients who demonstrate a pre-specified adequate clinical response as outcome-based schemes. We deliberately included financially-based schemes, in contrast to previous reviews of patient access schemes that focused on outcome-based schemes only [13]. Although financially-based schemes do not directly address uncertainties in clinical outcomes, they can address uncertainties in cost-effectiveness and/or budget impact estimates. Their use is increasing rapidly because they may be more feasible than outcome-based schemes that require more information and are administratively burdensome. We did not limit our search to any country. We report on schemes identified in Asia-Pacific markets.

Search results
Using the search terms in PubMed and Google Scholar, we found 2229 articles published between 1998 and July 2012. Reviewing article titles and abstracts, we excluded commentaries and articles that did not describe specific patient access schemes. Next, we reviewed the references of remaining articles and grey literature sources for additional examples of patient access schemes. Our search identified 299 schemes described in 146 publicly available sources (92 scientific articles, 18 electronic articles, 14 reports, 9 websites, and 13 conference presentations). From these we selected the 106 examples from the Asia-Pacific region.

Participating countries
We identified 106 patient access schemes in 3 countries from the Asia-Pacific region (Table 1). Public payers were involved in all schemes. Most (92.5%; n = 98) have taken place in Australia (Table 2) [14][15][16][17][18][19][20][21]. The Australian Pharmaceutical Benefits Advisory Committee (PBAC) is an expert committee that reviews incremental effectiveness and cost-effectiveness of medicines for coverage under the Pharmaceutical Benefits Scheme. The PBAC has formally assessed evidence of cost-effectiveness since 1993 [4]. The Medical Benefits Advisory Committee is an equivalent committee that evaluates medical devices for coverage under the Medical Benefits Scheme.
Apart from Australia, we found 5 schemes in New Zealand and 3 in South Korea. Table 3 summarizes the schemes [22][23][24][25]. These countries also have established a formal process for health technology assessment. Similar to Australia, New Zealand has a national health insurance for its people. The pharmaceutical management agency was established in 1993 to make decisions about drug coverage. The agency considers a number of factors, including the clinical need, clinical benefits and risks, cost-effectiveness, and budget impact of new drugs [26]. South Korea is the first country in Asia to officially adopt economic evaluation for making drug reimbursement decisions since January 2008. The Health Insurance Review Agency is responsible for reviewing the cost-effectiveness and budget impacts of new drugs for reimbursement under South Korea's National Health Insurance [27].

Types of medical products
Almost all patient access schemes focused on pharmaceuticals (97.2%; n = 103), few on medical technologies. More than half of schemes covered treatments for noncommunicable diseases, predominantly cancer (n = 31) and inflammatory diseases (n = 29) such as rheumatoid arthritis. Schemes in Australia were largely established for technologies with high budget impact due to high cost per patient (e.g., adalimumab, which costs approximately $20,000 per patient-year) or large volumes of use (e.g., dabigatran for prevention of stroke or systemic embolism), as well as for products that may be used beyond their approved indications (e.g., entecavir that is subsidized only for chronic hepatitis B in adults with evidence of active liver inflammation). Similarly, New Zealand targeted new products with high cost per-patient or large volumes of use. Instead of individual drugs, the schemes in South Korea targeted the entire class of older medications with high budget impact due to large volumes of use (e.g., hyperlipidemia medications).

Outcome-based schemes
Nearly two-thirds of schemes in Australia (63.3% n = 62; Table 2) included a "conditional treatment continuation" component that limits continued subsidy of high-cost medicines to patients who demonstrate an adequate clinical response. These schemes specify strict criteria for both initial and continued access. For example, the scheme for adalimumab for rheumatoid arthritis requires confirmation of clinical improvement at 3 months (measured by reductions in the total number of affected joints and in levels of inflammation markers) for continued subsidy [28]. In the scheme for bosenten in Australia, price was directly linked to the observed survival of patients treated with bosentan to confirm the clinical benefits (i.e., survival) and cost-effectiveness assumed at the time of assessment [29].

Evidence generation schemes
We found three schemes with an evidence generation component in Australia, all focused on medical technologies: positron emission tomography, deep brain stimulators, and endovascular aneurysm repair (Table 2). In all three cases, the Australian government agreed to provide interim funding for access to the technology and to support collection of relevant clinical (and cost) information [15]. The manufacturers did not share the financial costs to generate evidence.

Financially-based schemes
Financially-based schemes involving price reductions, price-volume agreements, or utilization caps were the most common risk-sharing schemes across the Asia-Pacific region (77.4%; n = 82). We identified 3 in South Korea, 5 in New Zealand, and 74 schemes in Australia. Forty-one of 74 schemes in Australia were hybrid schemes that involved both pricing arrangements and conditional treatment continuation.

Discussion
In attempts to provide access to promising technologies, many countries are assessing the potential applicability of patient access schemes for their markets; these schemes typically involve novel arrangements between payers and manufacturers. We reviewed the literature on patient access schemes in the last two decades, with a focus on experiences in the Asia-Pacific region. We found a few schemes from South Korean and New Zealand, and many more schemes in Australia. Though different in their development and implementation, these schemes have arisen in response to cost pressures, demands from key stakeholders, and the inherent uncertainties in the health value and estimated budget impact of medical products in real-world settings. Pharmaceuticals account for nearly all identified schemes. The preponderance of pharmaceutical schemes may reflect the different evidence profiles at product launch, the higher budget impact of pharmaceuticals versus devices, and/or the different intellectual property and patent environments. There do not appear to be guidelines on when patient access schemes are applied or which type of scheme is most appropriate in a given circumstance. However, our findings suggest that the main targets are pharmaceuticals likely to have high budget impact due to high per-patient acquisition costs and/or potential large volumes of use, and pharmaceuticals likely to be used beyond their approved indications.
In the Asia-Pacific region, Australia has the most experience with patient access schemes. This may reflect the negotiating power and extensive experience in technology assessment, due to the design of the regulatory, institutional, and policy structures for medicines benefit decisions in the Australian publicly-funded national healthcare system [4,6]. High-cost medicines for treatment of cancer and inflammatory diseases were the targets of more than half of the schemes in Australia. Typical outcome-based schemes, in which the price or level of reimbursement is tied to achieving intermediate or final clinical endpoints, have rarely been used in Australia, with bosentan being the only example. Implementing outcome-based schemes is complex: they require detailed longitudinal information on patient clinical status (e.g., disease severity and progression, comorbidities) [30]; they require substantial financial, human, and infrastructure resources for monitoring of patients and financial transactions related to treatments [31]; and they require a mechanism for adjusting price or level of reimbursement when explicit clinical endpoints are not reached. Instead, Australia limits continued subsidy of high-cost medicines to patients who demonstrate an adequate response, known as "conditional treatment continuation" policies, which are often coupled with pricing arrangements, that is, hybrid schemes. Initial access is also restricted to a small pool of patients largely based on disease severity and non-responsiveness to less expensive therapeutic alternatives. Criteria restricting both initial and continued access aim to maximize value-formoney and control costs. While some evidence suggests that such policies can cap spending [28,32], whether they achieve value-for-money or if patients who need the medicines actually gained access should be investigated. Further, strict initial and continued access criteria are ethically challenging as individual patients may just missed the arbitrary threshold for access [33,34].
Evidence generation schemes were also rarely used in the Asia-Pacific region, possibly due to the complexity in tracking patient outcomes and the additional costs and administrative burden involved to operate these schemes.
In contrast, we found that financially-based schemes were common, possibly due to fewer operational challenges. Price-volume agreements and utilization caps have been in place for more than a decade in Australia [19]. Typically, product prices are reduced if sales exceed pre-agreed volumes, or expenditures refunded by the manufacturer if government expenditures exceed a pre-agreed cap or threshold. Price-volume agreements can shift cost considerations from the payer to the manufacturer, which is important especially if there are concerns that (i) new medicines will be prescribed to a wider population than envisaged, (ii) the patients prescribed the drug will not always be those most likely to gain the greatest benefit [4,11,35], and/or (iii) the product does not result in the expected clinical benefits. Expectations are that manufacturers will target promotion in accordance with approved prescribing requirements. Details of patient access schemes (e. g., capped prices, negotiated volumes) are generally unavailable to the public [19].
Our study has several limitations. The review focused on the Asia-Pacific region; however, the investigators were limited to the English language literature; schemes that were described only in other languages have not been included. Given the sensitive nature of contracts in this field, it is likely information on schemes remains unpublished. Manufacturers will be reluctant to disclose details about patient access schemes if such information will be available to other countries that use external reference pricing. We thus are likely to have underestimated the total number of patient access schemes in Asia-Pacific countries. Nevertheless, this study provides insights about what types of products are commonly targets for patient access schemes and about recent experiences in the Asia-Pacific region that may inform the development of future schemes.
Although beyond the scope of this review, we noted that industry-sponsored patient assistance programs were implemented in several countries to improve access to medicines. For instance, the Glivec International Patient Assistance Program, implemented since 2001 in 81 low and middle-income countries (including China, India, Indonesia, Thailand, and Vietnam), has provided access to imatinib for patients with specific types of leukemia or gastrointestinal cancer [36]. The MUSANDA patient assistance program, implemented in the United Arab Emirates, supports access to ranibizumab for agerelated macular degeneration. Although payers are usually not involved in industry-sponsored patient assistance programs, these programs can provide interim access to innovative medicines while payer-industry patient access schemes are under negotiation; they can complement payer-industry patient access schemes by providing treatments for individual patients who are unable to self-fund treatments and who have no third-party payer; or they can become a vehicle for implementing a payer-industry patient access scheme, as has happened for coverage of imatinib in Thailand [37].
Globally, forecasts estimate that spending on new biologic agents will outpace overall spending growth on medicines and represent about 20% of the estimated US $1.2 trillion total pharmaceutical market by 2017 [38]. The recent availability of sofosbuvir, a new, curative treatment for hepatitis C, a disease that is highly prevalent in many low and middle-income countries, highlights the need for innovation in medicines financing. Refined patient access schemes may constitute muchneeded innovations in financing arrangements that provide equitable and affordable access for those who need the new medicines. Payers have an incentive to develop strategies that can help control costs while ensuring patient access to medical products that benefit health. Patient access schemes may also mitigate the negative impacts of uncertainties in cost-effectiveness and budget impact estimates, and shift payer and manufacturer focus to improving patient outcomes in real-world settingsthe ultimate goal of medical care. Payers have different ranges of authority over pricing, access, and evidence generation; some are more limited in the types of coverage decisions or access schemes they can consider, which may explain some of the variation in use of schemes between countries. Manufacturers are likely to prefer patient access schemes over a denial of coverage or explicitly reduced pricing, in part because patient access schemes can keep the real reimbursement prices confidential allowing them to tier prices by markets without the threat of external reference pricing [5,13].
There is little evidence on whether patient access schemes achieve their intended goals; they are a relatively recent development and the details of such agreements are usually confidential. However, key stakeholders appear willing to at least discuss types of schemes that can enable patient access to needed medicines [4,31,33]. Future studies should generate evidence on whether patients who need the medicines actually receive and benefit from them; whether schemes make high quality care more affordable for households and systems; whether they provide incentives for manufacturers to continue to invest in products that meet unmet needs; and whether data collected as part of the schemes confirm estimated cost-effectiveness or long-term benefits. Such evidence about potential benefits and costs is needed to inform the adoption of patient access schemes globally. Other factors that may affect their adoption center around operational challenges such as administrative burden and difficulty in tracking patient outcomes in healthcare delivery and financing systems [4,5,13,28,[30][31][32][33][34]39], as well as the transparency and perceived fairness of the complex decisions on the establishment of patient access schemes and criteria for access [33,34]. Research is needed to compare costs of administration and operation on the payer side and effects on pricing strategies globally on the pharmaceutical company side between patient access schemes and upfront discounts in drug prices.

Conclusions
Patient access schemes offer an important option for healthcare systems to allow patient access to promising technologies that may not otherwise be funded. Our study adds to existing knowledge by identifying and characterizing published patient access schemes in the Asia-Pacific region. Financially-based access schemes are most common. Australia tends to couple conditional treatment continuation with financial arrangements to provide further assurance. The main targets of patient access schemes are pharmaceuticals likely to have high budget impact due to high perpatient costs and/or large volumes of use, and pharmaceuticals that may be adopted more widely than indicated. With the rapid proliferation of high-cost medicines, these schemes may increasingly be used to enable access to innovative care within finite budgets. Future research is needed to generate evidence about the effectiveness and economic, administrative, and company pricing policy consequences of patient access schemes.
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