Barriers for Access to New Medicines: Searching for the Balance Between Rising Costs and Limited Budgets
- 1Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
- 2Health Economics Centre, University of Liverpool Management School, Liverpool, United Kingdom
- 3Division of Clinical Pharmacology, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden
- 4School of Pharmacy, Sefako Makgatho Health Sciences University, Pretoria, South Africa
- 5Mechanism of Coordinated Access to Orphan Medicinal Products (MoCA), Brussels, Belgium
- 6Ecorys, Rotterdam, Netherlands
- 7Department for Health Evidence, Radboud University Medical Center, Nijmegen, Netherlands
- 8Department of Drug Management, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
- 9Division of Health Policy and Insurance Research, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, United States
- 10EURORDIS-Rare Diseases Europe, Paris, France
- 11Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
- 12HCD Economics, The Innovation Centre, Daresbury, United Kingdom
- 13KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium
- 14Department of Pharmacology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
- 15Global Health and Development Group, Imperial College, London, United Kingdom
- 16Department of Pathology, Forensic Medicine and Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania
- 17NHS Lothian, Edinburgh, United Kingdom
- 18IQVIA, Brussels, Belgium
- 19Department of Pharmacy, Faculty of Medicine, University of Medicine, Tirana, Albania
- 20Hauptverband der Österreichischen Sozialversicherungsträger, Vienna, Austria
- 21Department of Biomedical Sciences, Faculty of Medicine, University of Botswana, Gaborone, Botswana
- 22Department of Social Pharmacy, College of Pharmacy, Federal University of Minas Gerais, Av. Presidente Antônio Carlos, Belo Horizonte, Brazil
- 23SUS Collaborating Centre – Technology Assessment & Excellence in Health (CCATES/UFMG), College of Pharmacy, Federal University of Minas Gerais. Av. Presidente Antônio Carlos, Belo Horizonte, Brazil
- 24Department of Social Pharmacy and Pharmacoeconomics, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria
- 25Health Insurance Organisation (HIO), Nicosia, Cyprus
- 26State Agency of Medicines, Tartu, Estonia
- 27IRDES, Paris, France
- 28Wissenschaftliches Institut der AOK (WIdO), Berlin, Germany
- 29EOPYY-National Organization for the Provision of Healthcare Services, Athens, Greece
- 30School of Economics and Political Science, University of Athens, Athens, Greece
- 31Department of Health Services, Ministry of Health, Reykjavík, Iceland
- 32Pharmaceutical Drug Department, Azienda Sanitaria Locale of Verona, Verona, Italy
- 33Department of Pharmacology and Pharmacognosy, School of Pharmacy, University of Nairobi, Nairobi, Kenya
- 34Division of Biology and Public Health, Mokwon University, Daejeon, South Korea
- 35UBT - Higher Education Institute, Prishtina, Kosovo
- 36Department of Pharmacology and Therapeutics, Faculty of Health Sciences, University of Namibia, Windhoek, Namibia
- 37Department of Pharmacology and Therapeutics, Ekiti State University, Ado-Ekiti, Nigeria
- 38Norwegian Institute of Public Health, Oslo, Norway
- 39Agency for Health Technology Assessment and Tariff System (AOTMiT), Warsaw, Poland
- 40HTA Consulting, Cracow, Poland
- 41Ministry of Health and Social Welfare, Banja Luka, Bosnia and Herzegovina
- 42Department of Social Pharmacy, Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina
- 43Public Health and Management Department, Faculty of Medicine, “Carol Davila”, University of Medicine and Pharmacy Bucharest, Bucharest, Romania
- 44National Research Institution for Public Health, Moscow, Russia
- 45ZEM Solutions, Belgrade, Serbia
- 46Health Insurance Institute, Ljubljana, Slovenia
- 47Faculty of Medicine, Slovak Medical University in Bratislava, Bratislava, Slovakia
- 48Drug Territorial Action Unit, Catalan Health Service, Barcelona, Spain
- 49Vall d'Hebron University Hospital, Fundació Institut Català de Farmacologia, Barcelona, Spain
- 50Department of Medicine Solna, Karolinska Institutet and Clinical Pharmacology Karolinska University Hospital, Stockholm, Sweden
- 51Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden
- 52Raleigh Fitkin Memorial Hospital, Manzini, Swaziland
- 53Division of Population Health, Health Services Research and Primary Care, Centre for Primary Care, University of Manchester, Manchester, United Kingdom
- 54NIHR Greater Manchester Patient Safety Translational Research Centre, School of Health Sciences, University of Manchester, Manchester, United Kingdom
Introduction: There is continued unmet medical need for new medicines across countries especially for cancer, immunological diseases, and orphan diseases. However, there are growing challenges with funding new medicines at ever increasing prices along with funding increased medicine volumes with the growth in both infectious diseases and non-communicable diseases across countries. This has resulted in the development of new models to better manage the entry of new medicines, new financial models being postulated to finance new medicines as well as strategies to improve prescribing efficiency. However, more needs to be done. Consequently, the primary aim of this paper is to consider potential ways to optimize the use of new medicines balancing rising costs with increasing budgetary pressures to stimulate debate especially from a payer perspective.
Methods: A narrative review of pharmaceutical policies and implications, as well as possible developments, based on key publications and initiatives known to the co-authors principally from a health authority perspective.
Results: A number of initiatives and approaches have been identified including new models to better manage the entry of new medicines based on three pillars (pre-, peri-, and post-launch activities). Within this, we see the growing role of horizon scanning activities starting up to 36 months before launch, managed entry agreements and post launch follow-up. It is also likely there will be greater scrutiny over the effectiveness and value of new cancer medicines given ever increasing prices. This could include establishing minimum effectiveness targets for premium pricing along with re-evaluating prices as more medicines for cancer lose their patent. There will also be a greater involvement of patients especially with orphan diseases. New initiatives could include a greater role of multicriteria decision analysis, as well as looking at the potential for de-linking research and development from commercial activities to enhance affordability.
Conclusion: There are a number of ongoing activities across countries to try and fund new valued medicines whilst attaining or maintaining universal healthcare. Such activities will grow with increasing resource pressures and continued unmet need.
Spending on medicines is a concern across all countries due to changing demographics and lifestyles leading to increased medicine use, stricter targets for treating patients, rising patient expectations and the continued launch of new premium priced medicines (1–6). The costs of medicines are a particular issue in low and middle income countries (LMICs) where they can account for up to 70% of total healthcare expenditure (7, 8), exacerbated by high and growing prevalence of non-communicable diseases (NCDs) such as diabetes and hypertension. The growing prevalence of NCDs in LMICs leads to issues of affordability (9), with funding of medicines for patients with cancer and immune diseases such as rheumatoid arthritis a particular challenge due to their costs (10–13). High income countries are also struggling to fund new premium priced medicines in all or some populations (3, 14). This situation will worsen with continuing unmet need (4) leading to continued debates regarding the possible funding of new high priced medicines in different disease areas.
Total expenditure on medicines among OECD countries in 2015 was over US$800 billion and rising as a result of appreciable increases in expenditure on new medicines for hepatitis C and in oncology (15). Concerns with the potential budget impact of second generation direct acting antivirals (DAAs) resulted in restrictions on their use despite their undoubted effectiveness (16–19). There were also intense price negotiations across countries with for instance the authorities in France initially faced with the cost of sofosbuvir at 756 times its cost of production, i.e., potentially over 99.8% gross profit, before negotiations (20). However, prices in some countries, e.g., Egypt, were discounted up to 99% from the US prices to support affordability (16, 17, 20). Overall, prices were substantially lower for second generation DAAs in LMICs to help with affordability (21).
The increased expenditure on cancer medicines has been augmented by prices for new cancer medicines rising by up to 10-fold during the last decade (22, 23). As a result, expenditure on medicines for patients with cancer now dominate pharmaceutical expenditure in developed markets (24). The increasing prevalence of patients with cancer, coupled with rising prices (25–28), has seen world-wide sales of medicines for cancer reach $107billion in 2015, an increase of 11.4% since 2014 (29). Expenditure on cancer medicines will rise further with new cancer cases anticipated to rise to 21.4 million per year by 2030 (22, 30) coupled with the appreciable pipeline of new potential premium priced oncology drugs with more than 500 companies actively pursuing new oncology medicines in over 600 indications (29).
The increasing expenditure on new premium priced medicines in recent years, including those for cancer, is despite their questionable therapeutic value, with most new medicines revealing limited or no health gain vs. existing therapies when appraised by independent drug information journals (Table 1) (33–37).
This is certainly the case for new cancer medicines as there is limited health gain for most alongside uncertain evidence (25, 38–42). However, high prices have been facilitated by pharmaceutical companies seeking orphan status for their new cancer medicines. This is despite the cost of goods for a number of new cancer medicines as low as 1% of originator prices (43, 44).
There have also been concerns with funding for new medicines for patients with orphan diseases given increasing prices and uncertain evidence (33, 34, 45, 46), again exacerbated by the emotive nature of the disease area (37). In view of the number of medicines for orphan diseases currently available and in development, it is likely that global spending on orphan medicines will reach US$178billion per year by 2020 (47), equalling the amount spent on medicines for patients with cancer. There may though be some overlap with a number of new antineoplastic medicines designated as orphan status. However, concerns with the requested prices for medicines for orphan diseases, and their potential budget impact, has to be balanced against incentives for pharmaceutical companies to develop new medicines to address unmet need (48, 49). We are also aware that the prices for a number of medicines for orphan diseases are sustainable (50), and that sales of medicines for orphan diseases can be limited, e.g., sales of Pfizer's Elelyso® (taliglucerase alfa) for type 1 Gaucher disease had a net revenue of only US$48million in 2016 (47). We have also seen the establishment of European Reference Networks for patients with rare diseases to accelerate research in the area of orphan diseases, which coupled with a greater role of patients and registries, could help with appropriate pricing models (47, 51, 52). However, this remains to be seen.
Adaptive pathways have also been proposed to accelerate the introduction of innovative medicines in Europe (53, 54). However, there are considerable concerns among European payers in this regard, and these will continue.
The increasing impact of personalized medicine within a number of therapeutic fields is also a major challenge with regard to the developmental chain for new medicines. This includes evidence generation through clinical research, optimization of novel treatment approaches, adaptation of tools for assessment, reimbursement mechanisms, costs, and monitoring of outcomes (55–58). For example, the use of health technology assessments (HTA) to reveal the added values of treatments in personalized medicine is challenging, which in turn may well have an impact on reimbursement processes. There are also concerns with the funding of new gene therapies at ~US$1.3million per dose, although limited sales to date (47).
Concurrent with these developments, we have seen health authorities instigate educational and other activities as part of developing a comprehensive model to better manage the entry of new medicines where there have been concerns with their potential safety and/ or expenditure in routine clinical care. This was the case with dabigatran with increased acquisition costs over warfarin coupled with concerns with potentially excessive bleeding and deaths arising from inappropriate use, exacerbated by issues with the commercial activities of the company (3, 59, 60). There was typically no excessive bleeding and no excessive deaths in countries and regions that had instigated educational and other activities to enhance the appropriate use of dabigatran post launch (59, 61).
We are also seeing the growth in managed entry agreements (MEAs) and other mechanisms to lower the price of new medicines to enhance their chances of reimbursement (62–66). In addition, the development of multiple criteria decision analysis (MCDA) tools for valuing new medicines especially those for orphan diseases (2, 67–72).
Alongside this, health authorities across countries have instigated a variety of measures and initiatives to improve prescribing efficiency to release valuable resources. These include measures to direct physicians toward prescribing well proven and effective medicines, enhance the prescribing of generics versus originators and patented products in a class and biosimilars, as well as actively pursue disinvestment of technologies where pertinent (73–79). Strengthening pro-generic and biosimilar policies, as well as increasing transparency, are especially important in LMICs to enhance access to medicines (80, 81). The prescribing of generics is growing across countries as more originators lose their patents, helped by prices of generics as low as 2% of originator prices (82–85). However, we are aware that any quality, safety and efficacy concerns with generics need to be addressed before savings can be fully realized (86, 87).
Given ongoing concerns and barriers to the funding of new medicines with increasing resource pressures, the aim of this paper is to consider potential ways to optimize the use of new medicines balancing rising costs with increasing budgetary pressures. This includes potential approaches to the funding of research and development (R & D) for new medicines. The situation in LMICs can be more challenging with issues of affordability and access even to essential medicines. As a result, we hope to stimulate future debates in this crucial area.
We present a narrative review of pharmaceutical policies and implications, as well as possible developments, based on key publications and initiatives known to the co-authors who are experts in this research and practice area. This is principally from a health authority perspective as many of the co-authors are senior level decision makers and advisers in their country. We have used this approach before in a number of previous publications to provide direction and stimulate debate (2, 33, 55, 75, 88–91).
We do not discuss specifically pricing and reimbursement policies across countries as this has been undertaken by others (34, 92–94). We also do not discuss ongoing initiatives to increase the prescribing of low cost generics or biosimilars, or disinvestment practices, as these initiatives have also already been covered by the co-authors and others in a number of published studies (75, 76, 78, 79, 95–98). We also do not discuss issues of adherence to medicines, which is of particular concern with medicines for patients with NCDs, with non-adherence negatively impacting on morbidity, mortality and costs (99–104), as these issues are outside the scope of this paper. We are also aware of access programmes especially in African countries for key medicines for infectious diseases and NCDs (9, 105, 106). However, again this is outside the scope of this paper although this will be briefly mentioned when discussing different pricing approaches as well as potential ways forward.
There are a number of ongoing approaches to enhance the funding for new valued medicines especially among higher income countries given ongoing budgetary constraints. These include developing new models to optimize their managed entry including issues of MEAs and post launch registries; developing and testing MCDA approaches; and developing new financing approaches. These will now be discussed in detail building on recent publications to give future direction with a particular emphasis on medicines for cancer and orphan diseases (34, 94, 107–111).
New Models to Optimize the Managed Entry of New Medicines
Payers and their advisers across Europe and wider have developed new models to optimize the managed entry of new medicines in response to ever increasing costs of new medicines, which build on initial initiatives in Stockholm, Sweden, and across Europe (112, 113). The models have subsequently been refined based on activities surrounding the launch of dabigatran to help prevent potential excessive bleeding (Figure 1) (3, 59), with further iterations since then. These models are typically based on three pillars: pre-, peri-, and post launch activities (3, 33, 34, 114–116).
Figure 1. Ongoing model to optimize the managed entry of new drugs across Europe incorporating national and regional stakeholder groups (Reproduced with kind permission of Frontiers in Pharmacology) (3, 59).
We are aware that there is appreciable variation in the uptake and utilization of new medicines across countries as seen for instance with physicians in the UK typically more conservative in adopting new medicines than colleagues in Italy, Spain or the US (117–120). Generally, critical factors in the uptake and utilization of new medicines across sectors include issues of involvement in clinical trials, influence and impact of drug and therapeutic committees (DTCs), cost of the new medicines to hospitals including potential budgets and any discounts, as well as pharmaceutical industry and patient pressures (115, 117, 121–128). Introducing a more structured approach (Figure 1) seeks to address a number of these issues and concerns.
Pre-launch activities include horizon scanning and budgetary planning, with peri-launch activities including assessing the role and value of new medicines using robust methodologies as well as appraising proposed MEAs (34, 115, 129). Post launch activities including evaluating the effectiveness and safety of new medicines in routine clinical practice via registries and other approaches as well as assessing prescribing against agreed guidelines (Figure 1). The following sub-sections contain further details.
Pre-launch activities include horizon scanning for new medicines to prepare for the future. Horizon scanning for medicines is defined as “identifying new medicines or new uses of existing medicines that are expected to receive marketing authorization from the Regulatory Authority in the near future and estimating their potential impact on patient care” (113, 130, 131), with activities growing across countries and regions (131–137). This includes recent proposals for cross country collaboration in Horizon Scanning (137). A recent publication from Sweden has shown good sensitivity for such analyses especially in the oncology/immunomodulating areas (138).
Horizon scanning activities can include budget forecasts in all or some populations to help fund their utilization within agreed budgets (115, 116, 136, 139). They typically consist of a number of sequenced approaches (Figure 2).
• Number of potential patients for the new medicine and disease severity
• Intended use of the new medicine, i.e., add-on to existing medicines, a replacement for existing treatments or an innovative approach
• Likely health gain of the new medicine vs. existing standards including any potential safety issues, i.e., potential to critically improve patient outcomes
• Current clinical development status, i.e., Phase II or III
• Estimated budget impact based on likely costs—especially if likely comparators will soon lose their patent
• Potential for off-label use and its budget impact
• Potential to result in re-organization of healthcare for the disease area
• Possible high media/ public interest.
Horizon scanning activities often start up to 24 to 36 months before likely European Medicines Agency (EMA) marketing authorization. They include providing data to regional and national payers on the findings from Phase II studies and ongoing Phase III trials, with more complete data provided nearer marketing authorization by regulatory agencies such as the EMA (133, 136, 137). However, providing horizon scanning data just before marketing authorization may be too late for some healthcare systems to effectively react with increased budgets for new valued medicines (142).
We are also seeing the growth in budget impact analyses (BIAs) to help estimate the potential financial implications of new technologies and their possible impact on future spending (116, 143). The key components of any BIA should include the following: (i) the budget holders' perspective; (ii) the defined time horizon for the analysis, e.g., up to 36 months post launch; (iii) clear identification of the setting; (iv) budget estimates expressed as undiscounted cost differences between any new medicine and the current situation; (v) estimates taking into account potential trade-offs in healthcare resources based on possible variations in the effectiveness of the new medicine; and (vi) sensitivity analyses taking into account the uncertainty surrounding future care (116, 144). Drug utilization studies using patient level data enhance the robustness of forecasted budgets through reducing uncertainty as seen for instance in Brazil when documenting the cost of atypical antipsychotics in the public healthcare system (145). Robust patient level data is also used to develop forecasts for the potential spend on new medicines in Stockholm County Council, Sweden, helped by expert groups and interaction with pharmaceutical companies (136, 139).
It is increasingly recognized that a more integrative approach is needed in the future to enhance the usefulness of peri-launch activities, including increased use of HTA techniques, which will require new skills (142). In addition, considering smart data systems and greater international collaboration to improve the efficiency and usefulness of horizon scanning activities and outputs (142).
Independent willingness-to-pay and other preference elucidation studies can also be conducted at this time to help authorities in their pricing negotiations, especially if such data is taken into account during pricing negotiations as seen currently in Brazil (146, 147).
The development of any potential quality indicators to improve the prescribing of the new medicine post launch should also ideally be considered pre-launch and not several years after launch, which has typically been the case in the past (148). The same applies to the development of any patient registry for new medicines especially for patients with orphan diseases (3, 47), which can be part of ongoing measures to enhance physician adherence to any prescribing guidelines. Specific biomarkers to better target patients for new therapies should also be highlighted given the growth in pharmacogenomics (55).
Countries have typically adopted different approaches to the pricing and reimbursement of new medicines (34, 92, 94, 141, 149, 150). These can be classified into those that first assess the level of innovation of new medicines against existing standards before negotiating prices, such as Austria, France, and Germany (34, 92, 115, 151, 152), as opposed to those countries that base reimbursement and funding decisions on economic criteria such as cost/quality adjusted life year (QALY), with or without threshold levels, as seen for instance in Belgium, Sweden and the United Kingdom (33, 34, 92, 110, 153, 154). Other countries apart from European countries that also increasingly include economic criteria in their pricing and reimbursement decision making include Australia, Brazil, Canada, Korea, and New Zealand (2, 92, 146, 155, 156). Currently though, only a minority of countries such as Poland, Slovakia, and the United Kingdom use economic principles to set threshold levels (63, 92), although some countries such as Belgium provide guidance (110). There are suggestions by some authors that any proposed levels should be lowered for long term sustainability (157). However, the lack of standard methodologies for determining possible thresholds, with the WHO recently stating it does not recommend three times GDP per capita as being relatively cost effective (158), appears to have provided manufacturers with a means to justify higher prices (159).
Whichever method is used, all incorporate approaches to assess the value of new medicines based on HTA principles and techniques with variable levels of uncertainty, with the concept of value based pricing (VBP) increasingly utilized (34, 66, 141, 160). However, whilst VBP is a well-established concept, there is no universal definition and its implementation has been challenging (129, 158, 161, 162). Having said this, VBP typically means the use of strategies designed to link prices of a perceived medicine with its perceived value (153, 158, 163), with issues such as the cost-effectiveness of a new medicine just one of the key considerations for reimbursement alongside issues of affordability and budget impact (66, 158, 161). Such considerations are particularly important in LMICs (164).
As a result of increasing resource pressures, we are likely to see the continued role of robust comparative effectiveness analysis along with BIAs in reimbursement decisions (158), especially with limited perceived innovation with most new medicines (Table 1). This will also require more independent BIAs being performed to help assess issues of affordability of new medicines given concerns with bias if BIAs are performed by commercial organizations (165). In addition, acknowledging differences between payers and companies, with companies typically seeking prices that may not be consistent with VBP on the basis that their new medicine, such as those for cancer and orphan diseases, should be treated differently (36, 49, 153). These concerns can be eased by companies providing data to suggest in which sub-populations their new medicine will provide most benefit, which should be aided by the increasing availability of biomarkers (55, 166), as well as more closely aligning requested prices with the additional health gain of their new medicine (25, 39, 49). The alternative is for healthcare sectors to impose restrictions themselves on the use of new and expensive medicines to stay within agreed budgets (115), which may be more arbitrary potentially adversely impacting on care provision. Alongside this, prices and/ or discounts for patented medicines will have to be increasingly re-evaluated as comparators become available as either low cost generics or biosimilars.
We are also likely to see increased cross border and regional collaboration among countries to enhance their pricing negotiations (46, 167–170). The number of MEAs, also called risk sharing arrangements, will also grow with pharmaceutical companies wishing reimbursement for their new medicines (65). This is because reimbursement is essential in most countries otherwise there will be limited funding and utilization of any new medicine.
There is also an ongoing proposal from the European Commission to strengthen joint cooperation on HTA beyond 2020 (171–173). Whilst such an approach is welcome to reduce duplication of activities, which is especially important among European countries with limited resources, a number of concerns have been identified with the proposal as originally set out. These include making sure that any European Coordination Group has the final say on any joint assessment report, which includes safety data and relative effectiveness assessments, rather than the Commission (as recommended in the proposal). This is important since there are concerns with pushing for acceptance of early assessments with greater uncertainty with available data extending from concerns with adaptive pathways (53, 54). In addition, there must be continued flexibility to allow national decision makers to be actively involved when using any joint report for their reimbursement decisions given ongoing differences in the availability and affordability of medicines between European countries (171).
Other ways to influence prices of medicines, and hence their affordability, include revising wholesaler and pharmacy mark-ups where needed (33, 174). Wholesaler margins typically vary between 2 and 8% of the pharmacy retail price in Europe, although mark-ups as high as 24% have been seen for a small number of medicines (174). For instance, the mark-up in Croatia was 8.5% of ex-factory prices, and in Greece there were up to 130 wholesalers at one stage vs. for instance twenty in the UK and three in Denmark with mark-ups as high as 7.8% before falling to 5.4% (175, 176). Pharmacy mark-ups have typically ranged between 18 and 25% among European countries, although mark-ups have been as low as 12% and as high as 50% (174). Whether a mark-up is based on a percentage of the base price (which can result in unduly high or low absolute amounts) or a flat fee, or a combination of both, is better, is an ongoing discussion across countries. Given the current political situation within countries, this has to be decided at the national level by each Member State in the European Union and other countries. Such debates are increasing especially with the continued launch of expensive new medicines in ambulatory care coupled with the increasing availability of low cost generics.
Managed entry agreements
MEAs can be divided into (a) financial schemes typically involving discounts, rebates, or price volume agreements and (b) performance based schemes including outcome guarantee schemes (63, 91, 110, 150). Schemes involving (usually confidential) discounts, rebates, or price: volume agreements, are increasingly seen in practice as they are easier to administer (150, 155, 177). Outcome or performance based agreements are seen as more problematic since they increasingly require robust and sophisticated systems to collect the data and many confounders may influence the outcomes in real life (63, 66, 110). This can potentially be addressed through clear definitions of the data to be collected, open and agreed standards for outcomes to be measured, clear and transparent decision making rules, openness of the information collected, as well as clarifying early in the process who owns and funds any patient registries that will be used (108). Such schemes can be linked to coverage with evidence schemes; however, these can also be problematic in Europe with limited incentives for companies to collect additional data and difficulties with delisting new medicines from reimbursement lists based on their value rather than safety (108, 110). Overcoming the latter may well require strengthening of health authorities' abilities to uphold negative funding decisions (108). In addition, in the case of oncology, performance based schemes have typically been based on surrogate markers rather than clinically relevant outcome measures (178). This can be a concern if there is no clear link between the surrogate markers used and improved overall survival, which is a key goal of treatment (25, 179, 180). As a result, we are now seeing disillusionment and an ensuing decline in the use of this particular type of MEA (181). However, they have proven beneficial under the right circumstances (182), and we may see their use increasing again as the use of “real world” evidence generation grows (66, 183, 184). Outcome based schemes may also achieve lower prices in practice than indication based pricing schemes with their many challenges (185).
Overall despite these concerns, we are likely to see continuing growth in MEAs to enhance access to new medicines, especially new oncology medicines, as countries struggle to stay within budgets with ever increasing prices (62, 65, 107, 150). However, there is increasing agreement that MEAs should not become the norm for introducing new medicines (111). The need for MEAs is symptomatic of unsustainable prices and their use fosters a lack of transparency. Overall, new medicines should be priced at sustainable levels for all key stakeholder groups, and the use of MEAs should be the exception rather than the norm aimed particularly for new medicines with anticipated high expenditure and uncertain longer-term clinical benefits (111).
Having said this, experience in implementing MEAs does vary substantially across Europe. It is recognized that there is considerable scope for countries to share their experiences recognizing though that publications assessing such schemes may be limited due to data protection concerns (63, 150). It is essential going forward that all key stakeholder groups should also ask themselves whether confidential discounts within public health care systems should be continued (63), and whether legislative measures could be introduced to force companies to disclose discount levels (167). This is important as it is not clear who is really benefiting from existing MEA schemes especially in countries where there are substantial co-payments for medicines based on list rather than discounted prices (63). In the future, countries need to establish clear objectives for any agreed MEA as well as seek to introduce a monitoring framework alongside assessing the financial burden of their implementation. Such information will help health authorities fully evaluate the role of MEAs in the future.
Indication-based pricing for new medicines
We are aware that there are proposals to incentivise pharmaceutical companies to invest in ongoing research for new indications for existing treatments to reduce the reliance on new medicines (186). There have also been calls for indication specific pricing to expand the use of existing medicines (187, 188). However, there are concerns about the availability of robust information systems to track this, similar to concerns with outcome based MEAs (188).
In addition, some companies already promote the off-label use of their medicines, as well as increase the number of indications post launch, to extend their patent life, and hence profitability (189–191). This is after they have secured optimal prices for their new medicine based on the greatest value in a given population. Extending the patent life has been enhanced by the issuing of supplementary protection certificates (SPCs) (192).
However, such activities can cause concern especially in countries such as the UK with high international non-proprietary name (INN) prescribing once the first indication loses its patent. Doctors in the UK were threatened with legal action if they prescribed pregabalin by INN name for neuropathic pain rather than the originator, with the neuropathic pain indication still patent protected (190). This is because high INN prescribing is routine in the UK apart from a minority of situations (193, 194).
These issues and concerns will need to be resolved before indication-based pricing becomes a realistic option. However, this has to be balanced against decreasing times for patent protection with stricter regulatory requirements for new medicines which SPCs can help address (192).
Differential pricing between countries as well as cross border collaboration with pricing negotiations
An alternative to confidential discounts to enhance the chances of reimbursement for new premium priced medicines, especially among LMICs where affordability is an issue, is variable pricing based on countries' ability to pay (111, 195). The European Pharmaceutical Industry Federation (EFPIA) recently considered the possibility of tiered pricing for European countries struggling to fund new medicines, although this has not been taken further (2). This may be because such considerations will be complex given for instance free movement of services and goods in Europe (196) and potentially difficult within the confines of external reference pricing despite its many challenges and concerns (111, 197–199).
There are also concerns that such strategies may decrease transparency between pharmaceutical companies and health authorities (200), that such arrangements amount to developed countries subsidizing medicines for LMICs, and that companies may not have strong incentives to re-evaluate tier prices in the absence of competition (195). There may though be situations where tiered pricing is an option to address affordability issues for new valued medicines; however, there is a need to stimulate competition in the long term to ensure continued availability and affordability of new medicines (2, 195).
Other approaches include LMICs taking advantage of public health intellectual property flexibilities, and LMICs working with pharmaceutical companies and others to make sure essential medicines are made routinely available (30, 195, 201). Private public partnerships between government and the pharmaceutical industry are growing among LMICs to decrease costs and increasing availability. In South Africa, the Biovac Institute will in the future locally manufacture the hexavalent vaccine, which protects against six life-threatening infections, with an estimated medium term saving of 15% (202, 203). Partnerships are also growing in Brazil to increase access to biosimilars and medicines for HIV (204, 205). In addition, pharmaceutical companies are making medicines for patients with NCDs available for as little as US$1/patient/ month to address issues of affordability (9). This is happening in Kenya, and we will be monitoring the findings (105, 206). Janssen has also recently signed an agreement to lower the prices of medicines for TB in South Africa (106). It is likely such arrangements will grow in the future.
Alongside this, there is likely to be greater cross-border and regional collaborations among European countries to lower the prices of new medicines during negotiations especially for cancer and orphan diseases (46, 111, 168–170, 207).
Valuing new cancer medicines
There have been initiatives by different stakeholder groups, including different cancer organizations, to try to quantify the level of benefit of new cancer medicines given ongoing funding concerns and little correlation to date between reimbursed prices and increased effectiveness (25, 208–212). However, there have been concerns with the use of surrogate markers such as response rates and disease free survival especially in patients with solid tumors (25, 39, 40, 179, 180). This has resulted in proposals to introduce more stringent assessment criteria such as minimal improvements in survival rates before granting premium prices for new cancer medicines (25, 34, 42, 213–216). Suggested minimal improvements include 3 to 6 months additional survival compared with current standards, although others have suggested less (215, 217). Alongside this, looking more critically at important factors for patients, and critically assessing the evidence alongside requested prices for decision making if only surrogate endpoint data is available (213, 216). Having said this, EUnetHTA believe surrogate endpoints in oncology are acceptable for accelerated or conditional marketing authorization approval; however, their utility for reimbursement and funding decisions will vary across countries (218).
There are also increased calls for moderation in the pricing of new cancer medicines as the continued increase in requested prices is becoming unsustainable (219–221). Such calls are enhanced by currently limited correlation between the degree of spend on cancer care and overall survival rates (222, 223). This is part of a general considerations on issues of fairer pricing with for instance the WHO recently launching the “Fair Price Forum” (158). There are also calls for proactive engagement by health authorities and governments in determining the potential initial price for a new cancer medicine based on the perceived health gain vs. current standards and improving negotiation skills during pricing discussions (111). Such discussions could also include whether the definition for orphan disease status needs refining into those medicines for genuine orphan diseases vs. companies using orphan disease status to increase requested prices for their new oncology medicines, which has resulted in very high prices especially for combinations (47).
Alongside this, there needs to be greater scrutiny regarding the existing spend on cancer medicines with greater understanding of opportunity costs across the different components of cancer care, as well as encouraging greater involvement of NGOs and others in helping to fund cancer medicines especially in LMICs, similar to the situation for treatments for HIV/ AIDS, cancer and NCDs (10, 105, 107, 128, 224, 225).
There also needs to be greater re-evaluation of reimbursed prices, including potential discounts, as more standard medicines in oncology become available as low cost generics or biosimilars. This is increasingly essential to fund increased volumes and new valued oncology medicines to improve care within finite resources.
Post Launch Activities
Post launch activities (Figure 1) include (i) monitoring the effectiveness and safety of new medicines in routine clinical practice using information in either patient registries or Electronic Health Records, (ii) evaluating ongoing MEAs and (iii) monitoring physicians prescribing against agreed guidance or quality indicators (3, 116, 141, 148).
Examples of studies monitoring the effectiveness and/ or safety of new medicines, as well as monitoring prescribing against agreed guidance, are contained in Table 2.
It is likely that the use of real world data (RWD) will grow to support reimbursement and funding decisions with increasing use of electronic health records (183), enhanced in Europe through initiatives such as GetReal, which is a 3-year project involving the Innovative Medicines Initiative (IMI), pharmaceutical companies, academia, HTA agencies, payers, regulators, patient organizations as well as commercial organizations in generating patient level data (184). This is particularly important with medicines for orphan diseases where only limited data may be available at launch. However, ownership of RWD is a critical issue (108).
It is also likely that we will see greater historical data to help appraise the role and value of new medicines for orphan diseases with the full implementation of the European Reference Network (50, 52).
There are also ongoing activities particularly among LMICs to improve the activities and influence of drug and therapeutic committees (DTCs) to enhance the rational use of medicines especially in their hospitals as this can be variable (126, 240, 241). These activities can be enhanced by introducing legislation and other activities to increase the role of DTCs as currently seen in South Africa (240, 242). This builds on activities among Western countries to improve the rational use of medicines generally and post launch, including the interface (125). There is also ongoing research within Stockholm, Sweden, to document the impact of DTCs on influencing the use of new medicines given ongoing resource pressures. Overall Sweden, including Stockholm Country Council, has been one of the leading countries to co-ordinate such activities to improve the managed entry of new medicines, providing direction to other countries (136). This will continue.
Norway also provides an example of hospitals coming together for joint pricing negotiations for new and established medicines to improve affordability, for example low prices are now being paid for infliximab biosimilar and medicines for cancer (243). As mentioned, we are also seeing a growth in cross-border and regional collaborations to improve pricing negotiations for new medicines, which will continue (46, 168, 169, 207).
There is also ongoing research among European payers and their advisers to seek additional ways to enhance the rational use of medicines to help ensure available funds are prioritized for valued medicines. This together with the implications will be reported in future publications to further improve rational use.
Care is needed though when introducing new initiatives as expectations may not always be realized. This was seen in both Abu Dhabi and Korea when introducing policies to enhance competition and use of generics within their healthcare systems (244, 245).
Multiple Criteria Decision Analysis (MCDA) Tools Especially for Patients With Cancer and Orphan Diseases
We are also seeing the growth in MCDA tools as a potential way to enhance structured, transparent and explicit approaches to reimbursement and funding decisions, resulting in guidance from different groups (33, 71, 246, 247). This also includes guidance to LMICs on potential ways to implement MCDAs to enhance transparency and standardization in funding decisions for new medicines (248). MCDA is an extension of decision theory that supports decision makers who have multiple (possibly conflicting) objectives by decomposing the decision objectives into key criteria (249). MCDA does not replace judgement, but rather identifies, collects and structures the information required by those making judgements to support the deliberative process.
Several public agencies and health insurers (such as G-BA in Germany, NICE in England and Wales and PBAC in Australia) are already using or proposing MCDA approaches in healthcare decision making, including prioritization of resources and activities (e.g., in Thailand), given concerns with uncertainty and rising prices, and this is likely to grow (247, 250–254). In most MCDAs, criteria such as disease severity, likely health outcomes including the safety profile, effectiveness, likely total costs/ budget impact, and activities surrounding the implementation of the new medicine, are mostly used to enhance decision making in addition to the quality of the evidence (33, 69, 255). Overall, it is increasingly believed MCDA can be used to support the HTA process; however, methodological challenges still remain (254, 256).
There are also ongoing initiatives, such as in the Netherlands and the UK, to use structured deliberative MCDA as opposed to the classic algorithmic MCDA in appraising new health technologies. In this approach, an in-depth consideration of a broad range of criteria takes place, including a critical assessment of available evidence. This requires relevant stakeholders to be explicit about their judgment regarding each criterion, and the impact on decisions. It is argued that structured deliberative MCDA improves the quality, consistency and transparency of decisions, and is likely to be applied more in the future. We will be monitoring these developments and their implications for reimbursement and funding decisions for new premium priced medicines.
It is perhaps not surprising that most MCDAs have been proposed for medicines for patients with cancer and orphan diseases given the level of uncertainty surrounding a number of these medicines, high requested prices, the heterogeneous nature of key stakeholders, and the emotive nature of the disease area (2, 67, 68, 72, 257). A number of the suggestions to improve reimbursement negotiations for new medicines for orphan diseases followed the controversy surrounding the reimbursement for enzyme replacement therapy for the symptomatic treatment of Fabry disease in the Netherlands at an incremental cost/ quality adjusted life-year of €3.3 million (37). A similar situation was seen with alglucosidase alfa to treat Pompe's disease. The estimated cost/ QALY was €0.3–0.9 million for the classic form of Pompe's disease up to €15 million/ QALY for the non-classic form (37). One of the principal MCDAs that evolved from this experience was the development of a Transparent Value Framework (TVF) for new medicines for orphan diseases (258–260) driven by MoCA (Mechanism for Co-ordinated Access to Orphan Medicinal Products). The TVF (Table 3) consists of four elements of value together with the extent to which each criterion is met, with the findings subsequently used as a possible basis for pricing negotiations (259, 260).
Table 3. The transparent value framework [adapted from (260)].
It must be recognized though that the TVF is a non-prescriptive and non-binding value framework, which means that EU member states still have the responsibility for reimbursement decisions with regard to new medicines for orphan diseases in their country.
Having said this, the MoCA process is continuing with the TVF to provide a mechanism for joint discussions in this crucial area among all key stakeholder groups in Europe (259, 261) given current disparities in the availability of medicines for rare diseases across Europe (262). Such developments could also aid EURORDIS in its objective to have 3 to 5 times more therapies for rare diseases approved per year than currently by 2025 and three to five times cheaper to enhance access and affordability (50). This may be helped by improvements in genomics to aid diagnosis and discussions around fair pricing, potentially helped by joint purchasing and pricing negotiations, to re-balance current disparities in the availability of medicines for orphan diseases across countries (14, 47, 50, 169, 262). This can start with early dialogue between all key stakeholder groups as part of Horizon Scanning activities (section Pre-launch Activities), coupled with discussions on registries to improve information about orphan diseases and new medicines post launch. In addition, discussions about realistic pricing expectations among all key stakeholder groups starting pre-launch (49, 50, 263, 264).
Possible Different Models for Financing New Medicines
New ways of addressing and financing new medicines are also being discussed given the extent of unmet need. A number of proposals have been suggested to finance R&D and new medicines given increasing concerns with issues of access and affordability (108). These include issues of acceptable value as well as de-linking the costs of R&D from a medicine's price, with basic research currently being predominantly undertaken in universities or funded by public sources (108, 265–268). De-linking models have been postulated for new cancer medicines in addition to new antimicrobials (267, 269). The situation with antibiotics is especially critical given the scarcity of new antibiotics in development to combat rising resistance rates with their appreciable impact on morbidity, mortality, and costs (270). The Drugs for Neglected Disease Partnership has been seen as a potential model for future de-linkage activities (108).
We are also seeing initiatives such as the Triple Helix model for innovation involving partnerships between universities, industry and governments (108, 271). An example of this is the development of new innovations in radiotherapy involving the Karolinska Institutet in Sweden together with other universities, private companies, and the government (108).
Potential new approaches also include a combination of push and pull incentives. Push mechanisms involve for instance direct investments in basic research and product development (272), which can include public sector research grants or research institutions (273). Pull mechanisms provide confidence in future sales and possible profitability through giving assurance on potential sales (272). Such approaches can stimulate research activities leading to the launch of new medicines in areas of need such as new medicines to treat rare orphan diseases or neglected diseases (272).
Health Impact Bonds (HIBs) have also been proposed, implemented for instance by a government determining suitable health programmes for finance and engaging intermediary stakeholders to help market potential investment opportunities (274). The programmes would be administered by healthcare providers, with external evaluators responsible for monitoring their progress (274). The first HIB was a program run in California for patients with asthma based on attaining over a 2-year period a 30% reduction in emergency room visits and a 50% reduction in asthma-related hospitalisations (274).
Additional possibilities include establishing a megafund as a single financial entity to invest in multiple biomedical projects (275). The intention is that by having one megafund, which entails a large portfolio of biomedical projects during different stages of drug development, the risk associated with attrition rates can be decreased to improve access and availability of new medicines. Such approaches have been proposed for new oncology medicines as well as medicines for rare diseases (275–277).
Lastly, annuity payments have been proposed for new gene therapies in view of their requested prices and limited uptake to date with such costs (47, 109, 278). We are already seeing companies offering installment payment plans to lung cancer patients to spread the costs (107).
There is ongoing research among payers and their advisers in Europe to discuss these and other potential approaches to improve financing and access to new valued medicines whilst maintaining sustainability of healthcare systems. This will be reported in the future.
We are aware that we have principally concentrated on the perspective of payers and their advisers. However, we believe this is appropriate especially among European and South American countries and Korea given their crucial role in the funding and utilization of new medicines.
There is continued unmet need for new medicines especially for disease areas such as cancer, immunological diseases and orphan diseases. However, there are concerns with ever increasing prices along with funding increased medicine volumes with growing rates of patients with infectious diseases and NCDs worldwide. This requires co-ordinated activities by all key stakeholder groups to seek to fund new valued medicines whilst maintaining or attaining universal access to healthcare, with health considered a goal for all individuals. Co-ordinated activities among payers have been successful with limiting increases in expenditure in Europe (279); however, new approaches are now needed given increasing resource pressures alongside continual unmet need.
A number of approaches have been discussed to help fund new valued medicines overcoming current barriers. This includes developing new models to optimize the managed entry of new medicines starting up to 36 months before likely EMA approval through horizon scanning activities. In addition, more stringent assessment of the actual role and value of new medicines to ensure funding is directed to those new medicines that are the most valued in all or sub-populations, as well as greater involvement of patients in key areas. This will be closely monitored. As part of this, we are likely to see continued growth in MEAs to help with the financing of new medicines although there are concerns with these including continuing confidential discounts. This is likely to lead to increased discussions whether such discounts should continue within public healthcare systems. There are also likely to be clearer objectives around any proposed MEAs in the future as well as greater monitoring of their outcomes, including any administrative financial burden, to guide future schemes, and this will be followed up in future research projects.
We are also likely to see new initiatives especially in higher income countries around MCDAs for new medicines such as the TVF for orphan diseases and possibly new cancer medicines. Ongoing activities with the MoCA and EURODIS will also be closely monitored to see if this improves access to new medicines for orphan diseases in the future. Any MCDA for new cancer medicines are likely to include effectiveness/outcome criteria given current concerns with surrogate markers and limited additional overall survival for a number of new cancer medicines. Alongside this, there is likely to be increasing re-evaluation of prices and discounts for existing patented medicines, especially high priced medicines, once the comparators used in the evaluations become available as low cost generics or biosimilars. This will also be closely monitored given concerns with increasing expenditure on cancer medicines and issues of sustainability.
We are also likely to see continued growth in cross-border and regional collaborations to enhance pricing negotiations especially surrounding new medicines for orphan diseases (170). In addition, greater generation of real world evidence around new medicines given the continued growth in electronic healthcare systems to inform future treatment decisions. This will also be the subject of future research projects involving some of the co-authors. There will also continue to be ongoing research around different approaches to the financing of new medicines especially from the standpoint of payers and their advisers, and we will also be reporting on this in the near future.
The principal issue for a number of LMICs are concerns with the availability and access to essential medicines as defined by the WHO and others. This includes for instance ensuring increased access to appropriate medicines for patients with NCDs including cancer as well as enhancing their appropriate use, which involves enhancing adherence rates where these are a concern (10, 101, 225). Alongside this, accelerating moves toward universal health care. These are essential first steps before LMICs actively consider funding new treatments, unless these are funded by donors such as those for HIV and multidrug resistant TB, given the limited health gain with most new medicines. Alongside this, instigating improved systems management to reduce out-of-stock situations in public healthcare facilities, as well as greater accountability and transparency in decision making, building on current initiatives (81, 242). We will also be monitoring this in the future. We will also see the growth of HTAs among LMICs evaluating the cost-effectiveness and value for money of new interventions to improve evidence-based decision-making. This though will require legislation and policies as well as making suitable resources available (280).
We are already seeing DTC activities grow in LMICs to improve the quality and efficiency of prescribing, and this will continue alongside initiatives to improve physician education regarding the use medicines. As a result helping to reduce any inappropriate influence of pharmaceutical company activities (281). Alongside this, we are likely to see increased activities to monitor the appropriate use of medicines especially among LMICs given concerns with inappropriate prescribing leading to increased costs and for instance higher antimicrobial resistance rates (239, 240, 242). This is already happening for instance across Africa (282), and will increasingly include monitoring of prescribing against national treatment guidelines, and any other authoritative guidelines, building on current initiatives (239, 283).
There will also need to be greater scrutiny of the quality of medicines, especially generics, among a number of LMICs to improve their acceptance and use.
Moves to introduce fairer prices for medicines, including potential consortia, will also grow to improve access to key medicines as LMICs strive toward universal access, and this will also be the subject of future research projects.
BG, AB, PVB, WO, CR, AF, AHi, APM and SS contributed to the initial hypothesis for the paper. BG, AB, PVB, WO, CR, AF, SB, AHi, APM, SS, AK, MG, JG, AT, TB, AS, IH, RS, AM, AG, GP, ZMi, GA, OL, CS, GS, VK, JY, EM, RJ, MO, H-Y K, AJ, FK, JF, OM, MP, MW, VM-P, IM, DM, TN, JF, DT, CZ, ED, JM, RM, BW, ZMa, SC and AHa contributed to the final paper.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We would like to thank Konstantīns Logviss for his helpful comments regarding funding medicines for orphan diseases.
1. Garattini S, Bertele V, Godman B, Haycox A, Wettermark B, Gustafsson LL. Enhancing the rational use of new medicines across European health care systems. Eur J Clin Pharmacol. (2008) 64:1137–8. doi: 10.1007/s00228-008-0537-z
2. Godman B, Malmstrom RE, Diogene E, Gray A, Jayathissa S, Timoney A, et al. Are new models needed to optimize the utilization of new medicines to sustain healthcare systems? Expert Rev Clin Pharmacol. (2015) 8:77–94. doi: 10.1586/17512433.2015.990380
3. Malmstrom RE, Godman BB, Diogene E, Baumgartel C, Bennie M, Bishop I, et al. Dabigatran - a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs. Front Pharmacol. (2013) 4:39. doi: 10.3389/fphar.2013.00039
4. Kaplan W, Wirtz V, Mantel-Teeuwisse A, Stolk P, Duthey P, Laing R. Priority Medicines for Europe and the World. 2013 Update. Available online at: http://www.who.int/medicines/areas/priority_medicines/MasterDocJune28_FINAL_Web.pdf
5. Irazola VE, Gutierrez L, Bloomfield G, Carrillo-Larco RM, Dorairaj P, Gaziano T, et al. Hypertension prevalence, awareness, treatment, and control in selected LMIC communities: results from the NHLBI/UHG Network of Centers of Excellence for Chronic Diseases. Global Heart (2016) 11:47–59. doi: 10.1016/j.gheart.2015.12.008
6. International Diabetes Federation. IDF Diabetes Atlas. 8th ed. (2017). Available online at: http://www.diabetesatlas.org
7. Cameron A, Ewen M, Ross-Degnan D, Ball D, Laing R. Medicine prices, availability, and affordability in 36 developing and middle-income countries: a secondary analysis. Lancet (2009) 373:240–9. doi: 10.1016/S0140-6736(08)61762-6
9. Mbui JM, Oluka MN, Guantai EM, Sinei KA, Achieng L, Baker A, et al. Prescription patterns and adequacy of blood pressure control among adult hypertensive patients in Kenya; findings and implications. Expert Rev Clin Pharmacol. (2017) 10:1263–71. doi: 10.1080/17512433.2017.1371590
10. Atieno OM, Opanga S, Martin A, Kurdi A, Godman B. Pilot study assessing the direct medical cost of treating patients with cancer in Kenya; findings and implications for the future. J Med Econ. (2018) 21:878–87. doi: 10.1080/13696998.2018.1484372
11. Putrik P, Ramiro S, Kvien TK, Sokka T, Pavlova M, Uhlig T, et al. Inequities in access to biologic and synthetic DMARDs across 46 European countries. Ann Rheum Dis. (2014) 73:198–206. doi: 10.1136/annrheumdis-2012-202603
12. Kostic M, Djakovic L, Sujic R, Godman B, Jankovic SM. Inflammatory Bowel Diseases (Crohn s Disease and Ulcerative Colitis): Cost of Treatment in Serbia and the Implications. Appl Health Econ Health Policy (2017) 15:85–93. doi: 10.1007/s40258-016-0272-z
13. Goldstein DA, Clark J, Tu Y, Zhang J, Fang F, Goldstein R, et al. A global comparison of the cost of patented cancer drugs in relation to global differences in wealth. Oncotarget (2017) 8:71548–55. doi: 10.18632/oncotarget.17742
14. Kwon H-Y, Kim H, Godman B. Availability and affordability of drugs with a conditional approval by the European Medicines Agency; Comparison of Korea With Other Countries and the implications. Front Pharmacol. (2018) 9:938. doi: 10.3389/fphar.2018.00938
15. OECD. Health at a Glance 2017 - OECD Indicators. Available online at: https://read.oecd-ilibrary.org/social-issues-migration-health/health-at-a-glance-2017_health_glance-2017-en#page1
17. de Bruijn W, Ibanez C, Frisk P, Bak Pedersen H, Alkan A, Vella Bonanno P, et al. Introduction and utilization of high priced HCV medicines across Europe; implications for the future. Front Pharmacol. (2016) 7:197. doi: 10.3389/fphar.2016.00197
20. Phelan M, Cook C. A treatment revolution for those who can afford it? Hepatitis C treatment: new medications, profits and patients. BMC Infect Dis. (2014) 14(Suppl. 6):S5. doi: 10.1186/1471-2334-14-S6-S5
24. ACS Chemical - Neurosciences. New 2016 Data and Statistics for Global Pharmaceutical Products and Projections through 2017. Available online at: https://pubs.acs.org/doi/pdfplus/10.1021/acschemneuro.7b00253
29. IMS Institute for Healthcare Informatics. Global Oncology Trend Report. A Review of 2015 and Outlook to 2020. (2016). Available online at: https://morningconsult.com/wp-content/uploads/2016/06/IMS-Institute-Global-Oncology-Report-05.31.16.pdf
30. Chalkidou K, Marquez P, Dhillon PK, Teerawattananon Y, Anothaisintawee T, Gadelha CA, et al. Evidence-informed frameworks for cost-effective cancer care and prevention in low, middle, and high-income countries. Lancet Oncol. (2014) 15:e119–31. doi: 10.1016/S1470-2045(13)70547-3
33. Godman B, Oortwijn W, de Waure C, Mosca I, Puggina A, Specchia ML, et al. Links between Pharmaceutical R&D Models and Access to Affordable Medicines. A Study for the ENVI COMMITTEE. Available online at: http://www.europarl.europa.eu/RegData/etudes/STUD/2016/587321/IPOL_STU(2016)587321_EN.pdf
34. WHO. Access to New Medicines in Europe: Technical Review of Policy Initiatives and Opportunities for Collaboration and Research. Available online at: http://www.euro.who.int/__data/assets/pdf_file/0008/306179/Access-new-medicines-TR-PIO-collaboration-research.pdf?ua=1
37. Simoens S, Picavet E, Dooms M, Cassiman D, Morel T. Cost-effectiveness assessment of orphan drugs: a scientific and political conundrum. Appl Health Econ Health Policy (2013) 11:1–3. doi: 10.1007/s40258-012-0004-y
40. Davis C, Naci H, Gurpinar E, Poplavska E, Pinto A, Aggarwal A. Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13. BMJ (2017) 359:j4530. doi: 10.1136/bmj.j4530
41. Grössmann N, Wild C. Between January 2009 and April 2016, 134 novel anticancer therapies were approved: what is the level of knowledge concerning the clinical benefit at the time of approval? ESMO Open (2017) 1:e000125. doi: 10.1136/esmoopen-2016-000125
42. Del Paggio JC, Azariah B, Sullivan R, Hopman WM, James FV, Roshni S, et al. Do contemporary randomized controlled trials Meet ESMO thresholds for meaningful clinical benefit? Ann Oncol. (2017) 28:157–62. doi: 10.1093/annonc/mdw538
43. Hill A, Gotham D, Fortunak J, Meldrum J, Erbacher I, Martin M, et al. Target prices for mass production of tyrosine kinase inhibitors for global cancer treatment. BMJ Open (2016) 6:e009586. doi: 10.1136/bmjopen-2015-009586
44. Hill A, Redd C, Gotham D, Erbacher I, Meldrum J, Harada R. Estimated generic prices of cancer medicines deemed cost-ineffective in England: a cost estimation analysis. BMJ Open (2017) 7:e011965. doi: 10.1136/bmjopen-2016-011965
45. Pauwels K, Huys I, Casteels M, Larsson K, Voltz C, Penttila K, et al. Are products with an orphan designation for oncology indications different from products for other rare indications? A retrospective analysis of European orphan designations granted between 2002-2012. Orphanet J Rare Dis. (2017) 12:36. doi: 10.1186/s13023-017-0578-4
47. Brau R, Tzeng I. Orphan Drug Commercial Models. Available online at: https://www.lifescienceleader.com/doc/orphan-drug-commercial-models-0001
48. Simoens S, Huys I. Market access of Spinraza (Nusinersen) for spinal muscular atrophy: intellectual property rights, pricing, value and coverage considerations. Gene Ther. (2017) 24:539–41. doi: 10.1038/gt.2017.79
50. EURODIS. Breaking the Access Deadlock to Leave No One Behind. A Contribution by EURORDIS and Its Members on Possibilities for Patients' Full and Equitable Access to Rare Disease Therapies in Europe. (2018). Available online at: https://www.eurordis.org/sites/default/files/reflexion-paper.pdf
52. European Commission. European Reference Networks. Available online at: https://ec.europa.eu/health/sites/health/files/ern/docs/2017_brochure_en.pdf
53. Ermisch M, Bucsics A, Vella Bonanno P, Arickx F, Bybau A, Bochenek T, et al. Payers' views of the changes arising through the possible adoption of adaptive pathways. Front Pharmacol. (2016) 7:305. doi: 10.3389/fphar.2016.00305
54. Vella Bonanno P, Ermisch M, Godman B, Martin AP, Van Den Bergh J, Bezmelnitsyna L, et al. Adaptive pathways: possible next steps for payers in preparation for their potential implementation. Front Pharmacol. (2017) 8:497. doi: 10.3389/fphar.2017.00497
55. Godman B, Finlayson AE, Cheema PK, Zebedin-Brandl E, Gutierrez-Ibarluzea I, Jones J, et al. Personalizing health care: feasibility and future implications. BMC Med. (2013) 11:179. doi: 10.1186/1741-7015-11-179
56. Rosenthal ET, Evans B, Kidd J, Brown K, Gorringe H, van Orman M, et al. Increased identification of candidates for high-risk breast cancer screening through expanded genetic testing. J Am Coll Radiol. (2017) 14:561–8. doi: 10.1016/j.jacr.2016.10.003
57. George A, Riddell D, Seal S, Talukdar S, Mahamdallie S, Ruark E, et al. Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients. Sci Rep. (2016) 6:29506. doi: 10.1038/srep29506
58. Leopold C, Vogler S, Habl C, Mantel-Teeuwisse AK, Espin J. Personalised medicine as a challenge for public pricing and reimbursement authorities - A survey among 27 European countries on the example of trastuzumab. Health Policy (2013) 113:313–22.
59. Godman B, Malmstrom RE, Diogene E, Jayathissa S, McTaggart S, Cars T, et al. Dabigatran - a continuing exemplar case history demonstrating the need for comprehensive models to optimize the utilization of new drugs. Front Pharmacol. (2014) 5:109. doi: 10.3389/fphar.2014.00109
61. Sinigoj P, Malmstrom RE, Vene N, Ronquist-Nii Y, Bozic-Mijovski M, Pohanka A, et al. Dabigatran concentration: variability and potential bleeding prediction in “real-life” patients with atrial fibrillation. Basic Clin Pharmacol Toxicol. (2015) 117:323–9. doi: 10.1111/bcpt.12417
62. Pauwels K, Huys I, Vogler S, Casteels M, Simoens S. Managed entry agreements for oncology drugs: lessons from the european experience to inform the future. Front Pharmacol. (2017) 8:171. doi: 10.3389/fphar.2017.00171
63. Ferrario A, Arāja D, Bochenek T, Catić T, Dankó D, Dimitrova M, et al. The implementation of managed entry agreements in Central and Eastern Europe: findings and implications. Pharmacoeconomics (2017) 35:1271–85. doi: 10.1007/s40273-017-0559-4
64. Ferrario A, Kanavos P. Dealing with uncertainty and high prices of new medicines: a comparative analysis of the use of managed entry agreements in Belgium, England, the Netherlands and Sweden. Soc Sci Med. (2015) 124:39–47. doi: 10.1016/j.socscimed.2014.11.003
65. Ferrario A, Kanavos P. Managed Entry Agreements for Pharmaceuticals: The European Experience. EMiNet, Brussels (2013). Available online at: http://eprints.lse.ac.uk/50513/
66. Annemans L, Panie L. Dynamic Outcomes Based Approaches to Pricing and Reimbursement of Innovative Medicines (2017). Available online at: https://www.eurordis.org/sites/default/files/FIPRA.pdf
67. Schey C, Krabbe PF, Postma MJ, Connolly MP. Multi-criteria decision analysis (MCDA): testing a proposed MCDA framework for orphan drugs. Orphanet J Rare Dis. (2017) 12:10. doi: 10.1186/s13023-016-0555-3
68. Hughes-Wilson W, Palma A, Schuurman A, Simoens S. Paying for the Orphan Drug System: break or bend? Is it time for a new evaluation system for payers in Europe to take account of new rare disease treatments? Orphanet J Rare Dis. (2012) 7:74. doi: 10.1186/1750-1172-7-74
69. Angelis A, Kanavos P. Multiple Criteria Decision Analysis (MCDA) for evaluating new medicines in Health Technology Assessment and beyond: the advance value framework. Soc Sci Med. (2017) 188:137–56. doi: 10.1016/j.socscimed.2017.06.024
70. Angelis A, Montibeller G, Hochhauser D, Kanavos P. Multiple criteria decision analysis in the context of health technology assessment: a simulation exercise on metastatic colorectal cancer with multiple stakeholders in the English setting. BMC Med Inform Decis Mak. (2017) 17:149. doi: 10.1186/s12911-017-0524-3
71. Marsh K, IJzerman M, Thokala P, Baltussen R, Boysen M, Kalo Z, et al. Multiple criteria decision analysis for health care decision making–emerging good practices: Report 2 of the ISPOR MCDA emerging good practices task force. Value Health (2016) 19:125–37. doi: 10.1016/j.jval.2015.12.016
72. Zelei T, Molnár MJ, Szegedi M, Kaló Z. Systematic review on the evaluation criteria of orphan medicines in Central and Eastern European countries. Orphanet J Rare Dis. (2016) 11:72. doi: 10.1186/s13023-016-0455-6
73. Gustafsson LL, Wettermark B, Godman B, Andersen-Karlsson E, Bergman U, Hasselstrom J, et al. The ‘wise list’- a comprehensive concept to select, communicate and achieve adherence to recommendations of essential drugs in ambulatory care in Stockholm. Basic Clin Pharmacol Toxicol. (2011) 108:224–33. doi: 10.1111/j.1742-7843.2011.00682.x
74. Eriksen J, Gustafsson LL, Ateva K, Bastholm-Rahmner P, Ovesjo ML, Jirlow M, et al. High adherence to the ‘Wise List’ treatment recommendations in Stockholm: a 15-year retrospective review of a multifaceted approach promoting rational use of medicines. BMJ Open (2017) 7:e014345. doi: 10.1136/bmjopen-2016-014345
75. Godman B, Wettermark B, van Woerkom M, Fraeyman J, Alvarez-Madrazo S, Berg C, et al. Multiple policies to enhance prescribing efficiency for established medicines in Europe with a particular focus on demand-side measures: findings and future implications. Front Pharmacol. (2014) 5:106. doi: 10.3389/fphar.2014.00106
77. Lemos LLP, Guerra Junior AA, Santos M, Magliano C, Diniz I, Souza K, et al. The assessment for disinvestment of intramuscular interferon beta for relapsing-remitting multiple sclerosis in Brazil. Pharmacoeconomics (2018) 36:161–73. doi: 10.1007/s40273-017-0579-0
78. Parkinson B, Sermet C, Clement F, Crausaz S, Godman B, Garner S, et al. Disinvestment and value-based purchasing strategies for pharmaceuticals: an international review. Pharmacoeconomics (2015) 33:905–24. doi: 10.1007/s40273-015-0293-8
79. Guerra-Junior AA, Pires de Lemos LL, Godman B, Bennie M, Osorio-de-Castro CGS, Alvares J, et al. Health technology performance assessment: real-world evidence for public healthcare sustainability. Int J Technol Assess Health Care (2017) 33:279–87. doi: 10.1017/S0266462317000423
80. Nguyen TA, Knight R, Roughead EE, Brooks G, Mant A. Policy options for pharmaceutical pricing and purchasing: issues for low- and middle-income countries. Health Policy Plan. (2015) 30:267–80. doi: 10.1093/heapol/czt105
81. Vian T, Kohler JC, Forte G, Dimancesco D. Promoting transparency, accountability, and access through a multi-stakeholder initiative: lessons from the medicines transparency alliance. J Pharm Policy Pract. (2017) 10:18. doi: 10.1186/s40545-017-0106-x
82. Woerkom M, Piepenbrink H, Godman B, Metz J, Campbell S, Bennie M, et al. Ongoing measures to enhance the efficiency of prescribing of proton pump inhibitors and statins in The Netherlands: influence and future implications. J Comp Effect Res. (2012) 1:527–38. doi: 10.2217/cer.12.52
83. Cameron A, Mantel-Teeuwisse AK, Leufkens HG, Laing RO. Switching from originator brand medicines to generic equivalents in selected developing countries: how much could be saved? Value Health (2012) 15:664–73. doi: 10.1016/j.jval.2012.04.004
84. Godman B, Baker A, Leporowski A, Morton A, Baumgärtel C, Bochenek T, et al. Initiatives to increase the prescribing of low cost generics; the case of Scotland in the international context. Med Res Arch. (2017) 5:1–34.
85. Kaplan WA, Ritz LS, Vitello M, Wirtz VJ. Policies to promote use of generic medicines in low and middle income countries: a review of published literature, 2000-2010. Health Policy (2012) 106:211–24. doi: 10.1016/j.healthpol.2012.04.015
86. Fadare JO, Adeoti AO, Desalu OO, Enwere OO, Makusidi AM, Ogunleye O, et al. The prescribing of generic medicines in Nigeria: knowledge, perceptions and attitudes of physicians. Expert Rev Pharmacoecono Outcomes Res. (2016) 16:639–50. doi: 10.1586/14737167.2016.1120673
87. Khan B, Godman B, Babar A, Hussain S, Mahmood S, Aqeel T. Assessment of active pharmaceutical ingredients in the registration procedures in Pakistan: implications for the future. GaBI J. (2016) 5:154–63. doi: 10.5639/gabij.2016.0504.041
88. Godman B, Abuelkhair M, Vitry A, Abdu S, Bennie M, Bishop I, et al. Payers endorse generics to enhance prescribing efficiency: impact and future implications, a case history approach. GABI J. (2012) 1:69–83. doi: 10.5639/gabij.2012.0102.017
89. Godman B, Wettermark B, Bishop I, Burkhardt T, Fürst J, Garuoliene K, et al. European payer initiatives to reduce prescribing costs through use of generics. GABI J. (2012) 1:22–7. doi: 10.5639/gabij.2012.0101.007
91. Adamski J, Godman B, Ofierska-Sujkowska G, Osinska B, Herholz H, Wendykowska K, et al. Risk sharing arrangements for pharmaceuticals: potential considerations and recommendations for European payers. BMC Health Serv Res. (2010) 10:153. doi: 10.1186/1472-6963-10-153
92. Paris V. Belloni A. Value in Pharmaceutical Pricing. Available online at: http://www.oecd-ilibrary.org/social-issues-migration-health/value-in-pharmaceutical-pricing_5k43jc9v6knx-en
93. WHO. WHO Guideline on Country Pharmaceutical Pricing Policies. Available online at: http://apps.who.int/medicinedocs/documents/s21016en/s21016en.pdf
94. WHO Europe. Medicines Reimbursement Policies in Europe. Available online at: http://www.euro.who.int/__data/assets/pdf_file/0011/376625/pharmaceutical-reimbursement-eng.pdf?ua=1
95. Godman B, Shrank W, Andersen M, Berg C, Bishop I, Burkhardt T, et al. Comparing policies to enhance prescribing efficiency in Europe through increasing generic utilization: changes seen and global implications. Expert Rev Pharmacoecon Outcomes Res. (2010) 10:707–22. doi: 10.1586/erp.10.72
96. Moon JC, Godman B, Petzold M, Alvarez-Madrazo S, Bennett K, Bishop I, et al. Different initiatives across Europe to enhance losartan utilization post generics: impact and implications. Front Pharmacol. (2014) 5:219. doi: 10.3389/fphar.2014.00219
97. Brett J, Elshaug AG, Bhatia RS, Chalmers K, Badgery-Parker T, Pearson S-A. A methodological protocol for selecting and quantifying low-value prescribing practices in routinely collected data: an Australian case study. Implement Sci. (2017) 12:58. doi: 10.1186/s13012-017-0585-9
101. Nielsen JO, Shrestha AD, Neupane D, Kallestrup P. Non-adherence to anti-hypertensive medication in low- and middle-income countries: a systematic review and meta-analysis of 92443 subjects. J Hum Hypertens. (2017) 31:14–21. doi: 10.1038/jhh.2016.31
102. Cramer JA, Benedict A, Muszbek N, Keskinaslan A, Khan ZM. The significance of compliance and persistence in the treatment of diabetes, hypertension and dyslipidaemia: a review. Int J Clin Pract. (2008) 62:76–87. doi: 10.1111/j.1742-1241.2007.01630.x
103. Nashilongo MM, Singu B, Kalemeera F, Mubita M, Naikaku E, Baker A, et al. Assessing adherence to antihypertensive therapy in primary health care in Namibia: findings and implications. Cardiovasc Drugs Ther. (2017) 31:565–78. doi: 10.1007/s10557-017-6756-8
104. Rampamba EM, Meyer JC, Godman B, Kurdi A, Helberg E. Evaluation of antihypertensive adherence and its determinants at primary healthcare facilities in rural South Africa. J Comp Effect Res. (2018) 7:661–72. doi: 10.2217/cer-2018-0004
105. Sandoz. Kenya is first country to launch ‘Novartis Access’, expanding affordable treatment options against chronic diseases (2015) Available online at: https://www.sandoz.com/news/media-releases/kenya-first-country-launch-novartis-access-expanding-affordable-treatment
106. Medical Brief. SA Signs Deal With Janssen to Lower Price of TB Medicine (2018). Available at URL: https://www.medicalbrief.co.za/archives/sa-signs-deal-janssen-lower-price-tb-medicine/
107. La Mola F, Liu C, de Salaberry J. Paying for the Cure - Transforming the Financing of Novel Therapies. Available online at: https://www.lek.com/sites/default/files/insights/pdf-attachments/Paying-for-the-cure_3.pdf
108. European Commission. Innovative Payment Models For High-Cost Innovative Medicines. Available onlone at: https://ec.europa.eu/health/expert_panel/sites/expertpanel/files/docsdir/opinion_innovative_medicines_en.pdf
109. Jorgensen J, Kefalas P. Annuity payments can increase patient access to innovative cell and gene therapies under England's net budget impact test. J Mark Access Health Policy (2017) 5:1355203. doi: 10.1080/20016689.2017.1355203
110. KCE. How to Improve the Belgian Process for Managed Entry Agreements? (2017). Available online at: https://kce.fgov.be/sites/default/files/atoms/files/Download%20the%20synthesis%20in%20English%20%2840%20p.%29.pdf
111. WHO. Informal Advisory Group on the Availability and Affordability of Cancer Medicines (2018). Available online at: http://apps.who.int/iris/bitstream/handle/10665/272961/WHO-EMP-IAU-2018.04-eng.pdf
112. Godman B, Wettermark B, Hoffmann M, Andersson K, Haycox A, Gustafsson LL. Multifaceted national and regional drug reforms and initiatives in ambulatory care in Sweden: global relevance. Expert Rev Pharmacoecon Outcomes Res. (2009) 9:65–83. doi: 10.1586/1473722.214.171.124
113. Wettermark B, Godman B, Eriksson C, van Ganse E, Garattini S, Joppi R, et al. Einführung neuer Arzneimittel in europäische Gesundheitssysteme (Introduction of new medicines into European healthcare systems). GGW (2010) 10:24–34.
114. Godman B, Acurcio F, Guerra Junior AA, Alvarez-Madrazo S, Faridah Aryani MY, et al. Initiatives among authorities to improve the quality and efficiency of prescribing and the implications. J Pharma Care Health Syst. (2014) 1:1–15. doi: 10.4172/jpchs.1000113
115. Godman B, Paterson K, Malmstrom RE, Selke G, Fagot JP, Mrak J. Improving the managed entry of new medicines: sharing experiences across Europe. Expert Rev Pharmacoecon Outcomes Res. (2012) 12:439–41. doi: 10.1586/erp.12.44
116. Godman B, Joppi R, Bennie M, Jan S, Wettermark B. Managed introduction of new drugs. In Elseviers M, Wettermark B, Almarsdottir AB, Andersen M, Benko R, Bennie M, Eriksson I, Godman B, Krska J, Poluzzi E, Taxis K, Vlahovic-Palcevski V, Stichele RV editors. Drug Utilization Research: Methods and Applications. Chichester: John Wiley & Sons (2016). p. 210–21.
119. Richards PSM. Extent and Causes of International Variations in Drug Usage. A Report for the Secretary of State for Health. Available online at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/216249/dh_117977.pdf; 2012
120. Packer C, Simpson S, Stevens A. International diffusion of new health technologies: a ten-country analysis of six health technologies. Int J Technol Assess Health Care (2006) 22:419–28. doi: 10.1017/S0266462306051336
122. Spurling GK, Mansfield PR, Montgomery BD, Lexchin J, Doust J, Othman N, et al. Information from pharmaceutical companies and the quality, quantity, and cost of physicians' prescribing: a systematic review. PLoS Med. (2010) 7:e1000352. doi: 10.1371/journal.pmed.1000352
123. Dunn AG, Braithwaite J, Gallego B, Day RO, Runciman W, Coiera E. Nation-scale adoption of new medicines by doctors: an application of the Bass diffusion model. BMC Health Serv Res. (2012) 12:248. doi: 10.1186/1472-6963-12-248
125. Bjorkhem-Bergman L, Andersen-Karlsson E, Laing R, Diogene E, Melien O, Jirlow M, et al. Interface management of pharmacotherapy. Joint hospital and primary care drug recommendations. Eur J Clin Pharmacol. (2013) 69(Suppl. 1):73–8. doi: 10.1007/s00228-013-1497-5
126. Lima-Dellamora Eda C, Caetano R, Gustafsson LL, Godman BB, Patterson K, Osorio-de-Castro CG. An analytical framework for assessing drug and therapeutics committee structure and work processes in tertiary Brazilian hospitals. Basic Clin Pharmacol Toxicol. (2014) 115:268–76. doi: 10.1111/bcpt.12215
127. Vogler S, Zimmermann N, Habl C, Mazag J. The role of discounts and loss leaders in medicine procurement in Austrian hospitals - a primary survey of official and actual medicine prices. Cost Effect Resour Alloc. (2013) 11:15. doi: 10.1186/1478-7547-11-15
129. Vogler S, Zimmermann N. In Coordination with the Pharmaceutical Pricing and Reimbursement Information (PPRI) network and the World Health Organization (WHO). Glossary of Pharmaceutical Terms (2016). Available online at: http://whocc.goeg.at/Literaturliste/Dokumente/MethodologyTemplate/Glossary_Update2016_final.pdf
131. Wild C, Simpson S, Douw K, Geiger-Gritsch S, Mathis S, Langer T. Information service on new and emerging health technologies: identification and prioritization processes for a European union-wide newsletter. Int J Technol Assess Health Care (2009) 25(Suppl. 2):48–55. doi: 10.1017/S0266462309990687
134. Nachtnebel A, Breuer J, Willenbacher W, Bucsics A, Krippl P, Wild C. Looking back on 5 years of horizon scanning in oncology. Int J Technol Assess Health Care (2016) 32:54–60. doi: 10.1017/S0266462316000052
135. Simpson S, Hillier J, Gutierrez-Ibarluzea I, Kearney B, Norderhaug I, Fay AF, et al. A Toolkit for the Identification and Assessment of New and Emerging Health Technologies. Birmingham: EuroScan.
136. Eriksson I, Wettermark B, Persson M, Edstrom M, Godman B, Lindhe A, et al. The early awareness and alert system in Sweden: history and current status. Front Pharmacol. (2017) 8:674. doi: 10.3389/fphar.2017.00674
137. KCE REPORT 283. horizon Scanning for Pharmaceuticals: Proposal for the Beneluxa Collaboration. Available online at: http://www.beneluxa.org/sites/beneluxa.org/files/2017-07/Horizon%20scanning_ScientificReport_full.pdf
138. Eriksson I, von Euler M, Malmström RE, Godman B, Wettermark B. Did we see it coming? An evaluation of the Swedish early awareness and alert system. Appl Health Econ Health Policy (2018). doi: 10.1007/s40258-018-0434-2
139. Wettermark B, Persson ME, Wilking N, Kalin M, Korkmaz S, Hjemdahl P, et al. Forecasting drug utilization and expenditure in a metropolitan health region. BMC Health Serv Res. (2010) 10:128. doi: 10.1186/1472-6963-10-128
140. Nachtnebel A, Geiger-Gritsch S, Hintringer K, Wild C. Scanning the horizon: development and implementation of an early awareness system for anticancer drugs in Austria. Health Policy (2012) 104:1–11. doi: 10.1016/j.healthpol.2011.11.003
141. Kahveci R, Oortwijn W, Godman B, Koç EM, Tibet B. Role of Health Technology Assessment in Pharmaceutical Market Access in Developed Countries in Pharmaceutical Market Access in Developed Countries. Koçkaya G, Wertheimer A editors (2018). Available online at: http://books.seedmedicalpublishers.com/index.php/seed/catalog/view/Pharmaceutical_MA_developed/PDF/747.ch15
142. Oortwijn W, Sampietro-Colom L, Habens F, Trowman R. How can health systems prepare for new and emerging health technologies? The role of horizon scanning revisited. Int J Technol Assess Health Care (2018) 34:254–9. doi: 10.1017/S0266462318000363
143. Sullivan SD, Mauskopf JA, Augustovski F, Jaime Caro J, Lee KM, Minchin M, et al. Budget impact analysis-principles of good practice: report of the ISPOR 2012 Budget Impact Analysis Good Practice II Task Force. Value Health (2014) 17:5–14. doi: 10.1016/j.jval.2013.08.2291
144. van de Vooren K, Duranti S, Curto A, Garattini L. A critical systematic review of budget impact analyses on drugs in the EU countries. Appl Health Econ Health Policy (2014) 12:33–40. doi: 10.1007/s40258-013-0064-7
145. Barbosa WB, Costa JO, de Lemos LLP, Gomes RM, de Oliveira HN, Ruas CM, et al. Costs in the treatment of schizophrenia in adults receiving atypical antipsychotics: an 11-year cohort in Brazil. Appl Health Econ Health Policy (2018) 16:697–709. doi: 10.1007/s40258-018-0408-4
146. Godoi IP, Santos AS, Reis EA, Lemos LL, Brandao CM, Alvares J, et al. Consumer Willingness to Pay for Dengue Vaccine (CYD-TDV, Dengvaxia(R)) in Brazil; implications for future pricing considerations. Front Pharmacol. (2017) 8:41. doi: 10.3389/fphar.2017.00041
147. Weernink MGM, Janus SIM, van Til JA, Raisch DW, van Manen JG, Ijzerman MJ. A systematic review to identify the use of preference elicitation methods in healthcare decision making. Pharm Med. (2014) 28:175–85. doi: 10.1007/s40290-014-0059-1
148. Campbell SM, Godman B, Diogene E, Furst J, Gustafsson LL, MacBride-Stewart S, et al. Quality indicators as a tool in improving the introduction of new medicines. Basic Clin Pharmacol Toxicol. (2015) 116:146–57. doi: 10.1111/bcpt.12295
149. Godman B, Campbell S, Suh HS, Finlayson AE, Bennie M, Gustafsson LL. Ongoing measures to enhance prescribing efficiency across Europe: implications for other countries. J Health Tech Assess. (2013) 1:27–42.
150. Vogler S, Paris V, Ferrario A, Wirtz VJ, de Joncheere K, Schneider P, et al. How can pricing and reimbursement policies improve affordable access to medicines? Lessons learned from European countries. Appl Health Econom Health Policy (2017) 15:307–21. doi: 10.1007/s40258-016-0300-z
151. Sermet C, Andrieu V, Godman B, Van Ganse E, Haycox A, Reynier JP. Ongoing pharmaceutical reforms in France: implications for key stakeholder groups. Appl Health Econom Health Pol. (2010) 8:7–24. doi: 10.2165/11313900-000000000-00000
152. Godman B, Bucsics A, Burkhardt T, Haycox A, Seyfried H, Wieninger P. Insight into recent reforms and initiatives in Austria: implications for key stakeholders. Expert Rev Pharmacoeconom Outcomes Res. (2008) 8:357–71. doi: 10.1586/14737126.96.36.1997
154. Svensson M, Nilsson FO, Arnberg K. Reimbursement decisions for pharmaceuticals in Sweden: the impact of disease severity and cost effectiveness. Pharmacoeconomics (2015) 33:1229–36. doi: 10.1007/s40273-015-0307-6
156. Griffiths EA, Hendrich JK, Stoddart SD, Walsh SC. Acceptance of health technology assessment submissions with incremental cost-effectiveness ratios above the cost-effectiveness threshold. ClinicoEconom Outcomes Res. (2015) 7:463–76. doi: 10.2147/CEOR.S87462
159. Santos AS, Guerra-Junior AA, Godman B, Morton A, Ruas CM. Cost-effectiveness thresholds: methods for setting and examples from around the world. Expert Rev Pharmacoeconom Outcomes Res. (2018) 18:277–88. doi: 10.1080/14737167.2018.1443810
160. Kawalec P, Tesar T, Vostalova L, Draganic P, Manova M, Savova A, et al. Pharmaceutical regulation in central and Eastern European countries: a current review. Front Pharmacol. (2017) 8:892. doi: 10.3389/fphar.2017.00892
162. Pharmaceutical Executive. UK: Is Value Based Assessment the New Value Based Pricing? (2014). Available online at: http://www.pharmexec.com/uk-value-based-assessment-new-value-based-pricing
164. Marseille E, Larson B, Kazi DS, Kahn JG, Rosen S. Thresholds for the cost-effectiveness of interventions: alternative approaches. Bull World Health Organ. (2015) 93:118–24. doi: 10.2471/BLT.14.138206
165. Faleiros DR, Alvares J, Almeida AM, de Araujo VE, Andrade EI, Godman BB, et al. Budget impact analysis of medicines: updated systematic review and implications. Expert Rev Pharmacoeconom Outcomes Res. (2016) 16:257–66. doi: 10.1586/14737167.2016.1159958
166. Antonanzas F, Rodriguez-Ibeas R, Juarez-Castello CA. Personalized medicine and pay for performance: should pharmaceutical firms be fully penalized when treatment fails? Pharmacoeconomics (2018) 36:733–43. doi: 10.1007/s40273-018-0619-4
168. Press Release. Ireland to Open Negotiations With Belgium, the Netherlands, Luxembourg and Austria on Drug Pricing and Supply – Minister Harris. Available online at: http://health.gov.ie/blog/press-release/ireland-to-open-negotiations-with-belgium-the-netherlands-luxembourg-and-austria-on-drug-pricing-and-supply-minister-harris/
169. European Observatory. How Can Voluntary Cross-Border Collaboration in Public Procurement Improve Access to Health Technologies in Europe? Available online at: http://www.euro.who.int/__data/assets/pdf_file/0009/331992/PB21.pdf?ua=1
170. Ferrario A, Humbert T, Kanavos P, Pedersen HB. Strategic procurement and international collaboration to improve access to medicines. Bull World Health Organ. (2017) 95:720–2. doi: 10.2471/BLT.16.187344
171. ESIP. Regulation on Health Technology Assessment Position Paper of the European Social Insurance Platform (ESIP). (2018). Available online at: https://www.esip.eu/publications-intranet?idf=137&preview=332
172. European Commission. Strengthening of the EU cooperation on Health Technology Assessment (HTA), Inception Impact Assessment. (2016). Available online at: http://ec.europa.eu/smart-regulation/roadmaps/docs/2016_sante_144_health_technology_assessments_en.pdf
173. European Commission. Proposal for a Regulation of the European Parliament of the Council on Health Technology Assessment Amending Directive 2011/24/EU (2018/0018(COD). (2018). Available online at: file:https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:52018PC0051
174. Kanavos P, Wouters O. Competition Issues in the Distribution of Pharmaceuticals, Session III of the OECD Global Forum on Competition, Paris. (2014). Available online at: http://eprints.lse.ac.uk/56006/1/__lse.ac.uk_storage_LIBRARY_Secondary_libfile_shared_repository_Content_Wouters,%20O_Competition%20issues_Wouters_Competition%20issues_2014.pdf
176. Vogler S, Habl C, Bogut M, Voncina L. Comparing pharmaceutical pricing and reimbursement policies in Croatia to the European Union Member States. Croatian Med J. (2011) 52:183–97. doi: 10.3325/cmj.2011.52.183
177. Rotar AM, Preda A, Loblova O, Benkovic V, Zawodnik S, Gulacsi L, et al. Rationalizing the introduction and use of pharmaceutical products: The role of managed entry agreements in Central and Eastern European countries. Health Policy (2018) 122:230–6. doi: 10.1016/j.healthpol.2018.01.006
178. Toumi M, Jaroslawski S, Sawada T, Kornfeld A. The use of surrogate and patient-relevant endpoints in outcomes-based market access agreements: current debate. Appl Health Econom Health Policy (2017) 15:5–11. doi: 10.1007/s40258-016-0274-x
179. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet (2014) 384:164–72. doi: 10.1016/S0140-6736(13)62422-8
180. Prasad V, Kim C, Burotto M, Vandross A. The strength of association between surrogate end points and survival in oncology: a systematic review of trial-level meta-analyses. JAMA Intern Med. (2015) 175:1389–98. doi: 10.1001/jamainternmed.2015.2829
182. Clopes A, Gasol M, Cajal R, Segu L, Crespo R, Mora R, et al. Financial consequences of a payment-by-results scheme in Catalonia: gefitinib in advanced EGFR-mutation positive non-small-cell lung cancer. J Med Econom. (2017) 20:1–7. doi: 10.1080/13696998.2016.1215991
183. Annemans L. The Use of Real World Data Throughout an Innovative Medicine's Lifecycle. (2017). Available online at: https://www.inami.fgov.be/SiteCollectionDocuments/real_world_data.docx
184. IMI GetReal. New Methods for RWE Collection Synthesis. (2018). Available online at: http://www.imi-getreal.eu/
185. Yeung K, Li M, Carlson JJ. Using performance-based risk-sharing arrangements to address uncertainty in indication-based pricing. J Manag Care Special Pharm. (2017) 23:1010–5. doi: 10.18553/jmcp.2017.23.10.1010
186. Nayroles G, Frybourg S, Gabriel S, Kornfeld A, Antonanzas-Villar F, Espin J, et al. Unlocking the potential of established products: toward new incentives rewarding innovation in Europe. J Mark Access Health Pol. (2017) 5:1298190. doi: 10.1080/20016689.2017.1298190
188. Persson U, Norlin JM. Multi-indication and combination pricing and reimbursement of pharmaceuticals: opportunities for improved health care through faster uptake of new innovations. Applied Health Econom Health Pol. (2018) 16:157–65. doi: 10.1007/s40258-018-0377-7
190. Godman B, Wilcock M, Martin A, Bryson S, Baumgärtel C, Bochenek T, et al. Generic pregabalin; current situation and implications for health authorities, generics and biosimilars manufacturers in the future. GaBI J. (2015) 4:125–35. doi: 10.5639/gabij.2015.0403.028
191. Staton T. Pfizer adds another $325M to Neurontin settlement tally. Total? $945M. Available online at: http://www.fiercepharma.com/story/pfizer-adds-another-325m-neurontin-settlement-tally-total-945m/2014-06-02
192. European Commission. Study on the Economic Impact of Supplementary Protection Certificates, Pharmaceutical Incentives and Rewards in Europe. Available online at: https://www.copenhageneconomics.com/dyn/resources/Publication/publicationPDF/5/445/1527517171/copenhagen-economics-2018-study-on-the-economic-impact-of-spcs-pharmaceutical-incentives-and-rewards-in-europe.pdf
193. Leporowski A, Godman B, Kurdi A, MacBride-Stewart S, Ryan M, Hurding S, et al. Ongoing activities to optimize the quality and efficiency of lipid-lowering agents in the Scottish national health service: influence and implications. Expert Rev Pharmacoeconom Outcomes Res. (2018) 2018:1–12. doi: 10.1080/14737167.2018.1501558
194. Godman B, Bishop I, Finlayson AE, Campbell S, Kwon HY, Bennie M. Reforms and initiatives in Scotland in recent years to encourage the prescribing of generic drugs, their influence and implications for other countries. Expert Rev Pharmacoeconom Outcomes Res. (2013) 13:469–82. doi: 10.1586/14737167.2013.820956
195. Moon S, Jambert E, Childs M, von Schoen-Angerer T. A win-win solution?: A critical analysis of tiered pricing to improve access to medicines in developing countries. Global Health (2011) 7:39. doi: 10.1186/1744-8603-7-39
196. Rémuzat C, Tavella F, Toumi M. Differential Pricing for Pharmaceuticals: Overview of a Widely Debated Pricing Concept and Key Challenges. ISPOR. (2015). Available online at: file:///C:/Users/mail/Desktop/My%20documents/Ongoing%20papers/Frontiers%20PH%20New%20Medicines/Remuzat%20et%20al%202015.pdf
197. Leopold C, Vogler S, Mantel-Teeuwisse AK, de Joncheere K, Leufkens HG, Laing R. Differences in external price referencing in Europe: a descriptive overview. Health Policy (2012) 104:50–60. doi: 10.1016/j.healthpol.2011.09.008
198. Carone G, Schwierz C, Xavier A. Cost-Containment Policies in Public Pharmaceutical Spending in the EU. Available online at: http://ec.europa.eu/economy_finance/publications/economic_paper/2012/pdf/ecp_461_en.pdf
200. KE International. Resurrecting the Ghost of Høsbjør Past: Global Fund Seeks to Establish Global Framework on Tiered Pricing Enforced by WTO Rules. Available online at: http://keionline.org/node/19792014
201. Baker B. Industry-Led Tiered-Pricing or Country-Led, Real Equitable Access – the Global Fund's Task Force Proposal Get Worse Instead of Better. (2014). Available online at: http://infojustice.org/wp-content/uploads/2014/03/Baker-Global-Fund-Tiered-Pricing-03282014.pdf
202. Medical Brief. SA Takes First Step Towards Producing its Own Vaccines Again. (2018). Available online at: https://www.medicalbrief.co.za/archives/sa-takes-first-step-towards-producing-vaccines/
203. Walwyn DR. Why Manufacturing a Key Vaccine in South Africa is so Important. (2018). Available online at: https://theconversation.com/why-manufacturing-a-key-vaccine-in-south-africa-is-so-important-94380
204. Kershaw A. Transforming the Brazilian Domestic Pharma Industry Through PDPs. (2015). Available online at: https://ihsmarkit.com/research-analysis/transforming-the-brazilian-domestic-pharma-industry-through-pdps.html
205. GSK. GSK and Brazil's Fiocruz Form Partnership for New R&D Effort and Increased Vaccine Access. (2009). Available online at: https://www.gsk.com/en-gb/media/press-releases/gsk-and-brazil-s-fiocruz-form-partnership-for-new-rd-effort-and-increased-vaccine-access/
206. Novartis. Novartis Access. Available online at: https://www.novartis.com/about-us/corporate-responsibility/expanding-access-healthcare/novartis-access
207. Mihajlovic J, Dolk C, Tolley K, Simoens S, Postma MJ. Reimbursement of targeted cancer therapies within 3 different European health care systems. Clin Ther. (2015) 37:474–80. doi: 10.1016/j.clinthera.2014.12.005
208. Bentley TGK, Cohen JT, Elkin EB, Huynh J, Mukherjea A, Neville TH, et al. Validity and Reliability of Value Assessment Frameworks for New Cancer Drugs. Value Health (2017) 20:200–5. doi: 10.1016/j.jval.2016.12.011
209. Cherny NI, Sullivan R, Dafni U, Kerst JM, Sobrero A, Zielinski C, et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol. (2015) 26:1547–73. doi: 10.1093/annonc/mdv249
210. Ellis LM, Bernstein DS, Voest EE, Berlin JD, Sargent D, Cortazar P, et al. American society of clinical oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. (2014) 32:1277–80. doi: 10.1200/JCO.2013.53.8009
211. Schnipper LE, Davidson NE, Wollins DS, Tyne C, Blayney DW, Blum D, et al. American society of clinical oncology statement: a conceptual framework to assess the value of cancer treatment options. J Clin Oncol. (2015) 33:2563–77. doi: 10.1200/JCO.2015.61.6706
214. Henshall C, Sampson L, Eichler H-G, Lemgruber A, Longson C, O'Rourke B, et al. Understanding the role and evidence expectations of health technology assessment and coverage/payer bodies: what are they looking for, and how and why does this differ from what regulators require? Ther Innovat Regul Sci. (2013) 48:341–6. doi: 10.1177/2168479013512488
217. Dreicer JJ, Mailankody S, Fahkrejahani F, Prasad V. Clinically meaningful benefit: real world use compared against the American and European guidelines. Blood Cancer J. (2017) 7:645. doi: 10.1038/s41408-017-0009-8
218. EUnetHTA. Endpoints used in Relative Effectiveness Assessment: Surrogate Endpoints. (2015). Available online at: https://www.eunethta.eu/wp-content/uploads/2018/03/surrogate_endpoints.pdf
219. Tefferi A, Kantarjian H, Rajkumar SV, Baker LH, Abkowitz JL, Adamson JW, et al. In support of a patient-driven initiative and petition to lower the high price of cancer drugs. Mayo Clin Proc. (2015) 90:996–1000. doi: 10.1016/j.mayocp.2015.06.001
220. Editorial. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood (2013) 121:4439–42. doi: 10.1182/blood-2013-03-490003
221. Ghinea H, Kerridge I, Lipworth W. If We Don't Talk About Value, Cancer Drugs Will Become Terminal for Health Systems. Available online at: http://theconversation.com/if-we-dont-talk-about-value-cancer-drugs-will-become-terminal-for-health-systems-44072
224. Hoen E't. Access To Cancer Treatment. A Study of Medicine Pricing Issues With Recommendations for Improving Access to Cancer Medication. Available online at: https://www.oxfam.org/sites/www.oxfam.org/files/file_attachments/rr-access-cancer-treatment-inequality-040215-en.pdf
225. Jakupi A, Godman B, Martin A, Haycox A, Baholli I. Utilization and expenditure of anti-cancer medicines in Kosovo: findings and implications. Pharmacoeconomics (2018). doi: 10.1007/s41669-017-0066-8
226. Larock AS, Mullier F, Sennesael AL, Douxfils J, Devalet B, Chatelain C, et al. Appropriateness of prescribing dabigatran etexilate and rivaroxaban in patients with nonvalvular atrial fibrillation: a prospective study. Ann Pharmacother. (2014) 48:1258–68. doi: 10.1177/1060028014540868
227. Troncoso A, Diogene E. Dabigatran and rivaroxaban prescription for atrial fibrillation in Catalonia, Spain: the need to manage the introduction of new drugs. Eur J Clin Pharmacol. (2014) 70:249–50. doi: 10.1007/s00228-013-1593-6
228. Piccinni C, Raschi E, Poluzzi E, Puccini A, Cars T, Wettermark B, et al. Trends in antiarrhythmic drug use after marketing authorization of dronedarone: comparison between Emilia Romagna (Italy) and Sweden. Eur J Clin Pharmacol. (2013) 69:715–20. doi: 10.1007/s00228-012-1377-4
229. Cars T, Lindhagen L, Malmstrom RE, Neovius M, Schwieler J, Wettermark B, et al. Effectiveness of drugs in routine care: a model for sequential monitoring of new medicines using dronedarone as example. Clin Pharmacol Ther. (2018) 103:493–501. doi: 10.1002/cpt.751
231. Raaschou P, Simard JF, Holmqvist M, Askling J. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden. BMJ (2013) 346:f1939. doi: 10.1136/bmj.f1939
232. Iannone F, Gremese E, Atzeni F, Biasi D, Botsios C, Cipriani P, et al. Longterm retention of tumor necrosis factor-alpha inhibitor therapy in a large italian cohort of patients with rheumatoid arthritis from the GISEA registry: an appraisal of predictors. J Rheumatol. (2012) 39:1179–84. doi: 10.3899/jrheum.111125
233. Dos Santos JB, Almeida AM, Acurcio FA, de Oliveira Junior HA, Kakehasi AM, Guerra Junior AA, et al. Comparative effectiveness of adalimumab and etanercept for rheumatoid arthritis in the Brazilian public health system. J Compar Effect Res. (2016) 5:539–49. doi: 10.2217/cer-2016-0027
234. Garcia-Doval I, Cohen AD, Cazzaniga S, Feldhamer I, Addis A, Carretero G, et al. Risk of serious infections, cutaneous bacterial infections, and granulomatous infections in patients with psoriasis treated with anti-tumor necrosis factor agents versus classic therapies: prospective meta-analysis of Psonet registries. J Am Acad Dermatol. (2017) 76:299–308.e16. doi: 10.1016/j.jaad.2016.07.039
235. Marra LP, Araujo VE, Oliveira GC, Diniz LM, Guerra Junior AA, Acurcio FA, et al. The clinical effectiveness of insulin glargine in patients with Type I diabetes in Brazil: findings and implications. J Compar Effect Res. (2017) 6:519–27. doi: 10.2217/cer-2016-0099
237. Gomes RM, Guerra Junior AA, Lemos LL, Costa Jde O, Almeida AM, Alvares J, et al. Ten-year kidney transplant survival of cyclosporine- or tacrolimus-treated patients in Brazil. Expert Rev Clin Pharmacol. (2016) 9:991–9. doi: 10.1080/17512433.2016.1190270
238. Frisk P, Aggefors K, Cars T, Feltelius N, Loov SA, Wettermark B, et al. Introduction of the second-generation direct-acting antivirals (DAAs) in chronic hepatitis C: a register-based study in Sweden. Eur J Clin Pharmacol. (2018) 74:971–8. doi: 10.1007/s00228-018-2456-y
239. Nakwatumbah S, Kibuule D, Godman B, Haakuria V, Kalemeera F, Baker A, et al. Compliance to guidelines for the prescribing of antibiotics in acute infections at Namibia's national referral hospital: a pilot study and the implications. Expert Rev Anti-Infect Ther. (2017) 15:713–21. doi: 10.1080/14787210.2017.1320220
240. Matlala M, Gous AG, Godman B, Meyer JC. Structure and activities of pharmacy and therapeutics committees among public hospitals in South Africa; findings and implications. Expert Rev Clin Pharmacol. (2017) 10:1273–80. doi: 10.1080/17512433.2017.1364625
241. Tiroyakgosi C, Matome M, Summers E, Mashalla Y, Paramadhas BA, Souda S, et al. Ongoing initiatives to improve the use of antibiotics in Botswana: University of Botswana symposium meeting report. Expert Rev Anti-Infect Ther. (2018) 16:381–4. doi: 10.1080/14787210.2018.1467756
242. Meyer JC, Schellack N, Stokes J, Lancaster R, Zeeman H, Defty D, et al. Ongoing initiatives to improve the quality and efficiency of medicine use within the public healthcare system in South Africa; a preliminary study. Front Pharmacol. (2017) 8:751. doi: 10.3389/fphar.2017.00751
243. Matusewicz W, Godman B, Pedersen HB, Furst J, Gulbinovic J, Mack A, et al. Improving the managed introduction of new medicines: sharing experiences to aid authorities across Europe. Expert Rev Pharmacoeconom Outcomes Res. (2015) 15:755–8. doi: 10.1586/14737167.2015.1085803
244. Kwon HY, Kim H, Godman B, Reich MR. The impact of South Korea's new drug-pricing policy on market competition among off-patent drugs. Expert Rev Pharmacoeconom Outcomes Res. (2015) 15:1007–14. doi: 10.1586/14737167.2015.1083425
245. Abuelkhair M, Abdu S, Godman B, Fahmy S, Malmstrom RE, Gustafsson LL. Imperative to consider multiple initiatives to maximize prescribing efficiency from generic availability: case history from Abu Dhabi. Expert Rev Pharmacoeconom Outcomes Res. (2012) 12:115–24. doi: 10.1586/erp.11.90
246. Thokala P, Devlin N, Marsh K, Baltussen R, Boysen M, Kalo Z, et al. Multiple criteria decision analysis for health care decision making–an introduction: report 1 of the ISPOR MCDA emerging good practices task force. Value Health. (2016) 19:1–13. doi: 10.1016/j.jval.2015.12.003
248. Inotai A, Nguyen HT, Hidayat B, Nurgozhin T, Kiet PHT, Campbell JD, et al. Guidance toward the implementation of multicriteria decision analysis framework in developing countries. Expert Rev Pharmacoeconom Outcomes Res. (2018) 18:585–92. doi: 10.1080/14737167.2018.1508345
249. Broekhuizen H, Groothuis-Oudshoorn CG, van Til JA, Hummel JM, IJzerman MJ. A review and classification of approaches for dealing with uncertainty in multi-criteria decision analysis for healthcare decisions. Pharmacoeconomics (2015) 33:445–55. doi: 10.1007/s40273-014-0251-x
252. Reddy BP, Kelly MP, Thokala P, Walters SJ, Duenas A. Prioritising public health guidance topics in the National Institute for Health and Care Excellence using the Analytic Hierarchy Process. Public Health. (2014) 128:896–903. doi: 10.1016/j.puhe.2014.07.003
253. Youngkong S, Baltussen R, Tantivess S, Mohara A, Teerawattananon Y. Multicriteria decision analysis for including health interventions in the universal health coverage benefit package in Thailand. Value Health (2012) 15:961–70. doi: 10.1016/j.jval.2012.06.006
254. Wahlster P, Goetghebeur M, Kriza C, Niederlander C, Kolominsky-Rabas P. Balancing costs and benefits at different stages of medical innovation: a systematic review of Multi-criteria decision analysis (MCDA). BMC Health Serv Res. (2015) 15:262. doi: 10.1186/s12913-015-0930-0
255. Tanios N, Wagner M, Tony M, Baltussen R, van Til J, Rindress D, et al. Which criteria are considered in healthcare decisions? Insights from an international survey of policy and clinical decision makers. Int J Technol Assess Health Care (2013) 29:456–65. doi: 10.1017/S0266462313000573
259. EURODIS. Mechanism of Coordinated Access to orphan medicinal products (MoCA). Available at URL: https://www.eurordis.org/content/moca
260. MOCA. Process on Corporate Social Responsibility in the Field of Pharmaceuticals Platform on Access to Medicines in Europe Working Group on Mechanism of Coordinated Access to Orphan Medicinal Products (MoCA-OMP). Available online at: http://download2.eurordis.org.s3.amazonaws.com/moca/history/WG%20MoCA-OMP%20Transparent%20Value%20Framework.pdf
261. Bucsics A. Payer Experience in MoCA. Available online at: http://download2.eurordis.org.s3.amazonaws.com/moca/presentations/PRES-2016-05%20Payer%20Experience%20in%20MoCA%20%28Bucsics%29.pdf
265. Prata WM, Silvestre RG, Godman B, Martin A, Dias CZ, Dias EM, et al. A critical look at innovation profile and its relationship with pharmaceutical industry. Int J Sci Res Manag (IJSRM). (2017) 5:934–5948. doi: 10.18535/ijsrm/v5i7.20
268. KEI. Delinkage. Available online at: http://delinkage.org/overview/
269. Outterson K, Gopinathan U, Clift C, So AD, Morel CM, Rottingen JA. Delinking investment in antibiotic research and development from sales revenues: the challenges of transforming a promising idea into reality. PLoS Med. (2016) 13:e1002043. doi: 10.1371/journal.pmed.1002043
270. O'Neill J. Securing New Drugs for Future Generations: The Pipeline of Antibiotics. The Review of Antimicrobial Resistance. Available online at: https://amr-review.org/sites/default/files/SECURING%20NEW%20DRUGS%20FOR%20FUTURE%20GENERATIONS%20FINAL%20WEB_0.pdf
272. Batson A, Meheus F, Brooke S. Chapter 26: innovative financing mechanisms to accelerate the introduction of HPV vaccines in developing countries. Vaccine (2006) 24(Suppl 3):S3/219–25. doi: 10.1016/j.vaccine.2006.05.042
273. Mueller-Langer F. Neglected infectious diseases: are push and pull incentive mechanisms suitable for promoting drug development research? Health Econom Policy Law (2013) 8:185–208. doi: 10.1017/S1744133112000321
276. Lo AW. Can Financial Engineering Engineering Help Cure Cancer? (2016). Available online at: https://bfi.uchicago.edu/sites/default/files/file_uploads/Lo-can-financial-engineering-cure-cancer.pdf
278. Marsden G, Towse A, Pearson SD, Dreitlein W, Henshall C. GENE THERAPY: Understanding the Science, Assessing the Evidence, and Paying for Value. (2018). Available online at: https://www.ohe.org/news/new-publication-gene-therapy-understanding-science-assessing-evidence-and-paying-value
279. Espin J, Schlander M, Godman B, Anderson P, Mestre-Ferrandiz J, Borget I, et al. Projecting pharmaceutical expenditure in EU5 to 2021: adjusting for the impact of discounts and rebates. Appl Health Econom Health Policy (2018). 16:803–17. doi: 10.1007/s40258-018-0419-1
280. Siegfried N, Wilkinson T, Hofman K. Where From and Where to for Health Technology Assessment in South Africa. Chapter 4 South African Health Review. (2017). Available online at: http://www.hst.org.za/publications/South%20African%20Health%20Reviews/4_Where%20from%20and%20where%20to%20for%20health%20technology%20assessment%20in%20South%20Africa.pdf
281. Fadare JO, Oshikoya KA, Ogunleye OO, Desalu OO, Ferrario A, Enwere OO, et al. Drug promotional activities in Nigeria: impact on the prescribing patterns and practices of medical practitioners and the implications. Hospital Pract. (2018) 46:77–87. doi: 10.1080/21548331.2018.1437319
282. Massele A, Burger J, Katende-Kyenda NL, Kalemeera F, Kenaope T, Kibuule D, et al. Outcome of the first Medicines Utilization Research in Africa group meeting to promote sustainable and rational medicine use in Africa. Expert Rev Pharmacoeconom Outcomes Res. (2015) 15:885–8. doi: 10.1586/14737167.2015.1088386
283. Niaz Q, Godman B, Massele A, Campbell S, Kurdi A, Kagoya HR, et al. Validity of World Health Organisation prescribing indicators in Namibia's primary healthcare: findings and implications. Int J Qual Health Care (2018). doi: 10.1093/intqhc/mzy172
Keywords: managed entry, health policy, pharmaceuticals, financing, cancer, orphan diseases, new models
Citation: Godman B, Bucsics A, Vella Bonanno P, Oortwijn W, Rothe CC, Ferrario A, Bosselli S, Hill A, Martin AP, Simoens S, Kurdi A, Gad M, Gulbinovič J, Timoney A, Bochenek T, Salem A, Hoxha I, Sauermann R, Massele A, Guerra AA Jr, Petrova G, Mitkova Z, Achniotou G, Laius O, Sermet C, Selke G, Kourafalos V, Yfantopoulos J, Magnusson E, Joppi R, Oluka M, Kwon H-Y, Jakupi A, Kalemeera F, Fadare JO, Melien O, Pomorski M, Wladysiuk M, Marković-Peković V, Mardare I, Meshkov D, Novakovic T, Fürst J, Tomek D, Zara C, Diogene E, Meyer JC, Malmström RE, Wettermark B, Matsebula Z, Campbell S and Haycox A (2018) Barriers for Access to New Medicines: Searching for the Balance Between Rising Costs and Limited Budgets. Front. Public Health 6:328. doi: 10.3389/fpubh.2018.00328
Received: 15 August 2018; Accepted: 26 October 2018;
Published: 05 December 2018.
Edited by:Mihajlo Jakovljevic, Lund University, Sweden
Reviewed by:Jonathan Spiteri, University of Malta, Malta
Simon Grima, University of Malta, Malta
Magdalena Syrkiewicz-Switala, Medical University of Silesia, Poland
Copyright © 2018 Godman, Bucsics, Vella Bonanno, Oortwijn, Rothe, Ferrario, Bosselli, Hill, Martin, Simoens, Kurdi, Gad, Gulbinovič, Timoney, Bochenek, Salem, Hoxha, Sauermann, Massele, Guerra, Petrova, Mitkova, Achniotou, Laius, Sermet, Selke, Kourafalos, Yfantopoulos, Magnusson, Joppi, Oluka, Kwon, Jakupi, Kalemeera, Fadare, Melien, Pomorski, Wladysiuk, Marković-Peković, Mardare, Meshkov, Novakovic, Fürst, Tomek, Zara, Diogene, Meyer, Malmström, Wettermark, Matsebula, Campbell and Haycox. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Brian Godman, Brian.firstname.lastname@example.org