The Impact of Brexit on Pharmaceuticals and HTA

The Impact of Brexit on Pharmaceuticals and HTA PharmacoEconomics Open (2018) 2:87–91 https://doi.org/10.1007/s41669-018-0072-5 COMMENTARY Paula K Lorgelly Published online: 20 March 2018 The Author(s) 2018 a customs union and the EU propose a ‘common regulatory We are living in uncertain times. The exit of the United area’ on the island of Ireland, effectively keeping Northern Kingdom (UK) from the European Union (EU) (hereafter, Ireland in the customs union). Changes are already taking Brexit) will have significant impacts on the health care place in the pharmaceutical sector due to this uncertainty, system, life sciences and the pharmaceutical industry. particularly the prospect of ‘no deal’ [4]; below I set out a Health technology assessment (HTA) will not go unaf- number of the issues that could arise post-Brexit with fected. The cost of medicines and health care more gen- respect to the HTA of pharmaceuticals for adoption and erally will increase, the role of the National Institute for reimbursement in the UK National Health Service (NHS), Health and Care Excellence (NICE) as a leading global as well as possible wider global implications. It is HTA agency could be challenged, and the evidence base acknowledged that this is but a minor issue in the context with which we do HTA will be impacted. This editorial of the effect of Brexit on health and the health care system discusses these issues and attempts to find some opportu- [5, 6], but it is an area in which a significant number of UK nities amongst the challenges that HTA faces post-Brexit. health economists specialise, thus is relevant to the disci- pline [7]. 1 Uncertain Times 2 Health Care Will Cost More Many health economists have written about uncertainty and its impact on HTA [1–3], but few have written in the Depending on the extent to which the UK is involved in the face of uncertainty. Brexit has created one of the most EU’s public health activities after Brexit [particularly the uncertain times in the UK across a number of industries relationship with the European Medicines Agency, (EMA), and sectors, including the pharmaceutical industry. see below], pharmaceutical companies (as a minimum) As I write this much is known although little is agreed may need to set up a base in both the UK and the EU to test about the details of the UK’s exit from the EU. It is likely and release batches [8]; for some this could involve moving that the UK will leave the single market and its associated their EU headquarters from the UK [4]. There will be an free movement of goods and people, although as the UK is additional level of licensure and of regulatory require- still in the early stages of negotiations with the EU nothing ments. These will add to pharmaceutical companies’ cost is certain (for example, February 2018 saw Labour moot base, increasing the cost of producing pharmaceuticals. Likewise, if the UK is not a member of the EMA, then the & Paula K Lorgelly Medicines and Healthcare products Regulatory Agency plorgelly@ohe.org (MHRA) would either have to duplicate the function or Office of Health Economics, 105 Victoria Street, London (more unlikely) adopt the EMA decisions. The MHRA is a SW1E 6QT, UK 88 P. Lorgelly significant contributor to the EMA, undertaking, amongst 2017), coupled with the fourth hurdle of NICE approval, other activities, 40% of all testing and amassing a third of may deter the industry. Further magnifying this is the their income by delivering EMA contracts. The loss of this proposal that NICE charge for its technology appraisal work to other Member States will result in a loss of income (TA) and highly specialised technologies (HST) guidance to the MHRA. Some of this will be picked up with an as a cost-recovery model [15], although this has been increase in the workload due to non-cooperation with the temporarily suspended in light of the other issues that need EMA; under a fee-for-service system, this would further to be addressed in a life sciences strategy with respect to increase the cost of supplying medicines in the UK [9]. Brexit. The growing influence of NHS England in adoption The extent of various trade deals and the possible impo- decisions, via the budget threshold assessment, also does sition of customs duties and changes in the supply chain will not incentivise early launch in the UK market [16, 17]. also add to the cost of production. Under perfect competition, cost increases would be passed on to the purchaser, either just in the UK or globally, whilst a monopoly supplier would 4 NICE to Become Less Relevant? absorb some of the costs. More of an issue is that as the cost of doing business increases in a small country, where prices It was recently announced that the EMA will move from cannot rise as they are constrained by the likes of the Phar- London to Amsterdam, providing medicines regulation and maceutical Price Regulation Scheme (PPRS), companies approval for Europe from temporary accommodation as of will relocate and reconsider their supply. the 30th of March 2019. The relocation of the EMA to A departure from the single market will also significantly Amsterdam is particularly significant as the Netherlands impact parallel trade. Currently with parallel trade, if third has a robust HTA system [18, 19]. parties can purchase branded medicines in the rest of the EU at Both NICE and its Dutch counterpart [the National Health lower prices, they can then resell for a profit in the UK at a Care Institute, Zorginstituut Nederland (ZiN)] were lead lower price than others in the UK market. Parallel trade has partners in founding the European Network for Health been shown to lower the cost of pharmaceutical prices [10]; Technology Assessment (EUnetHTA). ZiN now provides thus without access to such a trade environment, health care the secretariat for EUnetHTA, which is well established. costs could increase. The Healthcare Distribution Association It was announced in July 2017 that the EMA and EUnetHTA estimates that parallel trade directly saved the NHS €986.2 will provide parallel advice to support decision making on million during the period 2004–2009 [11]. There are also marketing authorisation and reimbursement [20]. This par- further issues with respect to medicines shortages, which may allel consultation will be via either an individual route (with have long run health effects and associated costs. For a dis- individual country HTA agencies) or a consolidated route cussion of those issues see Maignen et al. [12]. {with the HTA Early Dialogue Working Party (EDWP), Higher costs will not be easily absorbed into the NHS; which currently includes NICE [21]}. It is unclear if NICE the now infamous Vote Leave’s campaign slogan that £350 will continue to take part in this parallel process (and million a week will be returned to the NHS upon leaving specifically the EDWP), despite being involved in the initial the EU will not happen. The health (and social care) budget pilots of parallel advice and having a history of successful is already pushed to breaking. There are also supply side scientific advice and parallel advice with the MHRA. While consequences; EU migrant staff, particularly in social care, membership of EUnetHTA is not dictated by a country’s are already leaving [13]. membership in the EU, if the UK decides not to adopt the EMA decisions, any involvement in EUnetHTA could be of limited benefit. More recently, the European Commission 3 The UK Will Not Be an Early Launch Market also proposed to strengthen cooperation in HTA in the EU, suggesting new regulations for common European HTA The UK has traditionally been an early launch market for methods, sharing data and expertise, and common proce- pharmaceuticals, partly because UK prices are often used dures across the EU [22]. As the UK will not be an EU as a reference price for other countries [14] and also Member State, NICE and the other HTA agencies in the UK because NICE assessments are held in high esteem. Brexit [the Scottish Medicines Consortium (SMC) and the All could change this. If the UK does not collaborate with the Wales Medicines Strategy Group (AWMSG)] will have a EMA, that is the UK does not accept the marketing limited role to play in this new strategy. authorisation approval of the EMA, then access to the UK It is important to reflect on the changing environment of market will require an additional authorisation process (and HTA globally and the influence of NICE. NICE still sub- expense) via the MHRA. The fact that the UK market is a scribes—as it has for the last 20 years—to its cost per mere 2.4% of global pharmaceutical sales (compared with quality-adjusted life year (QALY) approach with a focus 21.5% for all of Europe) (IMS World Review Analyst on the health care perspective. Other agencies like ZiN The Impact of Brexit on Pharmaceuticals and HTA 89 have, arguably, been more innovative in reviewing and Brexit will also affect the evidence base in terms of data, changing their guidelines [23], while multi-criteria decision both data sharing and data protection. Clinical trial data analysis (MCDA) [24, 25] and value frameworks [26] and other personal data like health records are currently highlight that there is more to HTA than an incremental governed by the EU Data Protection Directive and the UK cost-effectiveness ratio (ICER). NICE is well aware of this, Data Protection Act 1998. As of May 2018, the General but constrained by NHS England and the Department of Data Protection Regulation EU/2016/679 will come into Health in making significant change. force. As this is a regulation, it will need to be legislated for when the UK leaves the EU, which could introduce some changes. A significant issue for HTA could be the 5 The Evidence Base Will Change sharing of data once the UK leaves the EU. The 1998 Act states that ‘personal data shall not be transferred outside the Many of us in research will be acutely aware of the European Economic Area unless there is adequate protec- uncertainty that Brexit has had on research funding, and tion’. This could cause problems for not just clinical trial specifically the UK’s eligibility and access to programmes data but also real world evidence (RWE). RWE is gaining like Horizon 2020 and the Innovative Medicines Initiative traction in HTA [19], and the UK as a post-launch study (IMI), which have been particularly supportive of research site to collect such data could become less attractive. An in health economics. If such programmes continue with additional issue with data sharing is the EMA’s role in limited UK involvement, then the applicability of project monitoring the safety and efficacy of pharmaceuticals. If outcomes to the UK setting and the generalisability and there was limited cooperation between the UK/MHRA and transferability of these results could find the UK lagging the EMA, which is additionally hindered by constraints behind other EU countries when it comes to trialling and around data sharing, then patient safety and public health adopting new methodologies and research techniques. The would be at risk [12]. knowledge exchange between the UK and the EU is mutually beneficial [27], and is important for supporting the (social) science base. 6 Possible Opportunities Clinical trial research will be particularly affected by leaving the EU. Leave campaigners argued that the EU Every cloud has a silver lining, but in truth it is difficult to Clinical Trials Directive (EC) No. 2001/20/EC damaged find the opportunities for HTA in Brexit. The UK market medical research and innovation in the UK as it increased the could be promoted to industry by offering early engage- administrative burden and cost of running trials, which saw a ment and a fast-track stream-lined MHRA and NICE par- reduction in trials taking place in Europe. The new Clinical allel approval process. The HTA process could become Trials Regulation 536/2014 will harmonise the application value-led, specifically involving NHS England in discus- and authorisation processes. Sponsors will be required to sions on access agreements and promote flexible pricing register trials, and there will be greater transparency and an and reimbursement arrangements like outcome-based accessible database of results. Implementation of the regu- payments [28] and multi-indication pricing [29]. This, lation has been delayed until after March 2019 and will however, will not be affordable without an increase in NHS therefore not be captured in the European Union (With- funding, and necessitates evaluating what such innovations drawal) Bill (previously known as the Great Repeal Bill), so in HTA and market access are worth in terms of patient it is unclear what new legislation would look like. Ideally it benefit and a buoyant life sciences industry. would allow the UK to fully participate in the EU system; low standards would not attract the pharmaceutical indus- try who require trials to meet Food and Drug Administration 7 Deal or No Deal (FDA) or EMA requirements. Under a scenario of limited cooperation, a pharmaceutical company would register their It is important to point out that while there are many ‘deals’ trial in the EU, which would give them access to all EU to be negotiated, there is a possibility—given statements countries, but should they wish to recruit UK patients, they from Prime Minister May that ‘no deal is better than a bad would need to seek additional authorisation in the UK. A deal’ [30] —that come March 2019, Britain will not have reduction in the number of UK patients in trials means British secured a trade deal with the EU. It will then fall under the patients will not get to benefit from these innovations early, World Trade Organization’s (WTO) terms. Without a free and the evidence base that is submitted for marketing trade agreement (FTA), tariffs would apply. In addition, authorisation and market access may not be representative of important questions over the legality of the FTAs with non- the UK patient population, challenging the validity of the EU countries would need addressing, specifically the HTA outcome. grandfathering of trade deals and what implications this has 90 P. Lorgelly 4. The Economist, Pharmaceutical firms trigger contingency plans on rules of origin [31]. At its worst, it could affect the for a no-deal Brexit. 2017. https://www.economist.com/news/ supply chain of pharmaceuticals, as there may be legal and britain/21731409-industry-long-production-timelines-cannot- regulatory gaps in those pharmaceutical regulations that afford-wait-any-longer-pharmaceutical-firms?fsrc=rss. may not be covered by the European Union (Withdrawal) 5. Dayan M, How will our future relationship with the EU shape the NHS? 2017: Nuffield Trust. http://www.nuffieldtrust.org.uk/ Bill [12]. research/brexit-relationship-eu-shape-nhs. 6. Fahy N, Hervey T, Greer S, Jarman H, Stuckler D, Galsworthy M, McKee M. How will Brexit affect health and health services 8 Final Thoughts in the UK? Evaluating three possible scenarios. Lancet. 2017;390(10107):2110–8. 7. Kaambwa B, Frew E. Health economics in the UK: capacity, I suspect some of what I have written above will eventuate constraints and comparisons to US health economists. Int Rev in the coming weeks, months and years; I do not wish to Econ Educ. 2013;12:1–11. take a bet on which scenario will materialise as I lost 8. Acha V. Breaking up the band: European regulatory cooperation in a post-Brexit world. Br J Pharm. 2017;2(1):1–5. money on that fateful day in June 2016. However, one can 9. Hatswell AJ. How do we avoid disaster when exiting the Euro- only hope that the Brexit effect on HTA is a short- to pean Medicines Agency? Making the most of Brexit in phar- medium-term phenomenon, and the strength and growth maceutical regulation. Ecancermedicalscience. 2017;11:ed67. that the discipline experienced during the UK austerity 10. Ganslandt M, Maskus KE. Parallel imports of pharmaceutical products in the European Union. 2001. The World Bank. http:// phase bodes well for this coming experience. As an emi- apps.who.int/medicinedocs/documents/s17518en/s17518en.pdf. nent professor once said to me, ‘austerity means that they 11. Enemark U and Pedersen M, Parallel import of pharmaceuticals [the government] need health economists even more to in Denmark, Germany, Sweden and the UK, 2004–2009, an ensure they are getting value for money’. Maybe that will analysis of savings. 2011, CAST–Centre for Applied Health Services Research and Technology Assessment Odense: be true of Brexit. Maybe there will be a mass migration of University of Southern Denmark. health economists to Canada or indeed for many of us back 12. Maignen F, Berdud M, Hampson G, Lorgelly P. Public health and to our country of birth, be that the continent or further economic implications of the United Kingdom exiting the EU and afield. Perhaps, just perhaps, HTA will benefit globally. the single market. OHE Consulting Report, Office of Health Economics, 2017. https://www.ohe.org/system/files/private/ publications/Executive%20report%20-%20final.pdf. Acknowledgements The author would like to thank Adrian Towse 13. Costa-Font J. The National Health Service at a critical moment: and Mike Drummond for discussions and reviews of early drafts. The when Brexit means hectic. J Soc Policy. 2017;46(4):783–95. author would also like to acknowledge the patience of Tim Wrightson 14. Re´muzat C, Urbinati D, Mzoughi O, El Hammi E, Belgaied W, for bearing with the author’s uncertainty regarding when the right Toumi M. Overview of external reference pricing systems in time to finalise the paper was; at times it was like the protracted Europe. J Mark Access Health Policy. 2015;3(1):27675. Brexit negotiations, but hopefully with a better outcome. 15. National Institute for Health and Care Excellence, Charging for NICE technology appraisal and highly specialised technologies Compliance with Ethical Standards guidance: a document for consideration and comment by the life sciences industries’ associations. 2016. https://www. Funding No funding was received to write this paper. remapconsulting.com/wp-content/uploads/2016/09/NICE-TA- and-HST-cost-recovery-for-industry-associations-August-2016- Conflict of interest The author reports no conflicts of interest; the FINAL.pdf. author voted remain. 16. Ogden J. How will NICE’s budget impact test affect new drug availability? Prescriber. 2017;28(8):9–12. Open Access This article is distributed under the terms of the 17. Buckland D. Brexit and the EMA: what’s next for the UK? Creative Commons Attribution-NonCommercial 4.0 International Prescriber. 2017;28(5):49–51. License (http://creativecommons.org/licenses/by-nc/4.0/), which per- 18. Wilsdon T, Fiz E, Haderi A. A comparative analysis of the role mits any noncommercial use, distribution, and reproduction in any and impact of health technology assessment: 2013. Washington medium, provided you give appropriate credit to the original DC: Charles River Associates; 2014. author(s) and the source, provide a link to the Creative Commons 19. Makady A, van Veelen A, Jonsson P, Moseley O, d’Andon A, De license, and indicate if changes were made. Boer A, Hillege J, Klungel O, Goettsch W. Using real-world data (RWD) in health technology assessment (HTA) practice: a comparative study of 5 HTA agencies. Value Health. References 2017;20(9):A401. 20. European Medicines Agency. Parallel consultation with regula- 1. Briggs A, Sculpher M, Buxton M. Uncertainty in the economic tors and health technology assessment bodies. 2017 1st February 2018]; Available from: http://www.ema.europa.eu/ema/index. evaluation of health care technologies: the role of sensitivity jsp?curl=pages/regulation/general/general_content_001857. analysis. Health Econ. 1994;3(2):95–104. jsp&mid=WC0b01ac0580a11c96. 2. Philips Z, Bojke L, Sculpher M, Claxton K, Golder S. Good 21. EUnetHTA and EMA, Guidance for parallel consultation, EMA/ practice guidelines for decision-analytic modelling in health 410962/2017. 2017. http://www.ema.europa.eu/docs/en_GB/ technology assessment. Pharmacoeconomics. 2006;24(4):355–71. document_library/Regulatory_and_procedural_guideline/2017/ 3. Eckermann S, Willan AR. Expected value of information and 07/WC500230375.pdf. decision making in HTA. Health Econ. 2007;16(2):195–209. The Impact of Brexit on Pharmaceuticals and HTA 91 22. European Commission, Proposal for a regulation of the European 27. Varnai P, Rentel M, Dave A, De Scalzi M, Timmerman W, Parliament and of the Council on health technology assessment Rosemberg-Montes C, Simmonds P. The impact of collaboration: and amending Directive 2011/24/EU. 2018. https://ec.europa.eu/ the value of UK medical research to EU science and health 2017. health/sites/health/files/technology_assessment/docs/com2018_ Technopolis Group. http://www.cancerresearchuk.org/about-us/ 51final_en.pdf. we-develop-policy/we-work-with-government/exiting-the-eu/uk- 23. Versteegh M, Knies S, Brouwer W. From good to better: new and-eu-research. Dutch guidelines for economic evaluations in healthcare. Phar- 28. Carlson JJ, Sullivan SD, Garrison LP, Neumann PJ, Veenstra DL. macoeconomics. 2016;34(11):1071–74. Linking payment to health outcomes: a taxonomy and examina- 24. Thokala P, Devlin N, Marsh K, Baltussen R, Boysen M, Kalo Z, tion of performance-based reimbursement schemes between Longrenn T, Mussen F, Peacock S, Watkins J. Multiple criteria healthcare payers and manufacturers. Health Policy. decision analysis for health care decision making—an introduc- 2010;96(3):179–90. tion: report 1 of the ISPOR MCDA Emerging Good Practices 29. Persson U, Norlin J. Multi-indication and combination pricing Task Force. Value Health. 2016;19(1):1–13. and reimbursement of pharmaceuticals: opportunities for 25. Marsh K, IJzerman M, Thokala P, Baltussen R, Boysen M, Kalo´ improved health care through faster uptake of new innovations. Z, Lo¨nngren T, Mussen F, Peacock S, Watkins J. Multiple criteria Appl Health Econ Health Policy. 2018. Feb 22. https://doi.org/10. decision analysis for health care decision making—emerging 1007/s40258-018-0377-7. good practices: report 2 of the ISPOR MCDA Emerging Good 30. Prime Minister’s Office. The government’s negotiating objectives Practices Task Force. Value health. 2016;19(2):125–37. for exiting the EU: PM Speech. 2017 17th January 2017; 26. Garrison LP, Neumann PJ, Willke RJ, Basu A, Danzon PM, Available from: https://www.gov.uk/government/speeches/the- Doshi JA, Drummond MF, Lakdawalla DN, Pauly MV, Phelps governments-negotiating-objectives-for-exiting-the-eu-pm- CE. A health economics approach to US value assessment speech. frameworks—summary and recommendations of the ISPOR 31. Holmes P, Rollo J, Winters LA. Negotiating the UK’s post-Brexit Special Task Force report [7]. Value Health. 2018;21(2):161–5. trade arrangements. Natl Inst Econ Rev. 2016;238(1):R22–30. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png PharmacoEconomics - Open Springer Journals

The Impact of Brexit on Pharmaceuticals and HTA

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PharmacoEconomics Open (2018) 2:87–91 https://doi.org/10.1007/s41669-018-0072-5 COMMENTARY Paula K Lorgelly Published online: 20 March 2018 The Author(s) 2018 a customs union and the EU propose a ‘common regulatory We are living in uncertain times. The exit of the United area’ on the island of Ireland, effectively keeping Northern Kingdom (UK) from the European Union (EU) (hereafter, Ireland in the customs union). Changes are already taking Brexit) will have significant impacts on the health care place in the pharmaceutical sector due to this uncertainty, system, life sciences and the pharmaceutical industry. particularly the prospect of ‘no deal’ [4]; below I set out a Health technology assessment (HTA) will not go unaf- number of the issues that could arise post-Brexit with fected. The cost of medicines and health care more gen- respect to the HTA of pharmaceuticals for adoption and erally will increase, the role of the National Institute for reimbursement in the UK National Health Service (NHS), Health and Care Excellence (NICE) as a leading global as well as possible wider global implications. It is HTA agency could be challenged, and the evidence base acknowledged that this is but a minor issue in the context with which we do HTA will be impacted. This editorial of the effect of Brexit on health and the health care system discusses these issues and attempts to find some opportu- [5, 6], but it is an area in which a significant number of UK nities amongst the challenges that HTA faces post-Brexit. health economists specialise, thus is relevant to the disci- pline [7]. 1 Uncertain Times 2 Health Care Will Cost More Many health economists have written about uncertainty and its impact on HTA [1–3], but few have written in the Depending on the extent to which the UK is involved in the face of uncertainty. Brexit has created one of the most EU’s public health activities after Brexit [particularly the uncertain times in the UK across a number of industries relationship with the European Medicines Agency, (EMA), and sectors, including the pharmaceutical industry. see below], pharmaceutical companies (as a minimum) As I write this much is known although little is agreed may need to set up a base in both the UK and the EU to test about the details of the UK’s exit from the EU. It is likely and release batches [8]; for some this could involve moving that the UK will leave the single market and its associated their EU headquarters from the UK [4]. There will be an free movement of goods and people, although as the UK is additional level of licensure and of regulatory require- still in the early stages of negotiations with the EU nothing ments. These will add to pharmaceutical companies’ cost is certain (for example, February 2018 saw Labour moot base, increasing the cost of producing pharmaceuticals. Likewise, if the UK is not a member of the EMA, then the & Paula K Lorgelly Medicines and Healthcare products Regulatory Agency plorgelly@ohe.org (MHRA) would either have to duplicate the function or Office of Health Economics, 105 Victoria Street, London (more unlikely) adopt the EMA decisions. The MHRA is a SW1E 6QT, UK 88 P. Lorgelly significant contributor to the EMA, undertaking, amongst 2017), coupled with the fourth hurdle of NICE approval, other activities, 40% of all testing and amassing a third of may deter the industry. Further magnifying this is the their income by delivering EMA contracts. The loss of this proposal that NICE charge for its technology appraisal work to other Member States will result in a loss of income (TA) and highly specialised technologies (HST) guidance to the MHRA. Some of this will be picked up with an as a cost-recovery model [15], although this has been increase in the workload due to non-cooperation with the temporarily suspended in light of the other issues that need EMA; under a fee-for-service system, this would further to be addressed in a life sciences strategy with respect to increase the cost of supplying medicines in the UK [9]. Brexit. The growing influence of NHS England in adoption The extent of various trade deals and the possible impo- decisions, via the budget threshold assessment, also does sition of customs duties and changes in the supply chain will not incentivise early launch in the UK market [16, 17]. also add to the cost of production. Under perfect competition, cost increases would be passed on to the purchaser, either just in the UK or globally, whilst a monopoly supplier would 4 NICE to Become Less Relevant? absorb some of the costs. More of an issue is that as the cost of doing business increases in a small country, where prices It was recently announced that the EMA will move from cannot rise as they are constrained by the likes of the Phar- London to Amsterdam, providing medicines regulation and maceutical Price Regulation Scheme (PPRS), companies approval for Europe from temporary accommodation as of will relocate and reconsider their supply. the 30th of March 2019. The relocation of the EMA to A departure from the single market will also significantly Amsterdam is particularly significant as the Netherlands impact parallel trade. Currently with parallel trade, if third has a robust HTA system [18, 19]. parties can purchase branded medicines in the rest of the EU at Both NICE and its Dutch counterpart [the National Health lower prices, they can then resell for a profit in the UK at a Care Institute, Zorginstituut Nederland (ZiN)] were lead lower price than others in the UK market. Parallel trade has partners in founding the European Network for Health been shown to lower the cost of pharmaceutical prices [10]; Technology Assessment (EUnetHTA). ZiN now provides thus without access to such a trade environment, health care the secretariat for EUnetHTA, which is well established. costs could increase. The Healthcare Distribution Association It was announced in July 2017 that the EMA and EUnetHTA estimates that parallel trade directly saved the NHS €986.2 will provide parallel advice to support decision making on million during the period 2004–2009 [11]. There are also marketing authorisation and reimbursement [20]. This par- further issues with respect to medicines shortages, which may allel consultation will be via either an individual route (with have long run health effects and associated costs. For a dis- individual country HTA agencies) or a consolidated route cussion of those issues see Maignen et al. [12]. {with the HTA Early Dialogue Working Party (EDWP), Higher costs will not be easily absorbed into the NHS; which currently includes NICE [21]}. It is unclear if NICE the now infamous Vote Leave’s campaign slogan that £350 will continue to take part in this parallel process (and million a week will be returned to the NHS upon leaving specifically the EDWP), despite being involved in the initial the EU will not happen. The health (and social care) budget pilots of parallel advice and having a history of successful is already pushed to breaking. There are also supply side scientific advice and parallel advice with the MHRA. While consequences; EU migrant staff, particularly in social care, membership of EUnetHTA is not dictated by a country’s are already leaving [13]. membership in the EU, if the UK decides not to adopt the EMA decisions, any involvement in EUnetHTA could be of limited benefit. More recently, the European Commission 3 The UK Will Not Be an Early Launch Market also proposed to strengthen cooperation in HTA in the EU, suggesting new regulations for common European HTA The UK has traditionally been an early launch market for methods, sharing data and expertise, and common proce- pharmaceuticals, partly because UK prices are often used dures across the EU [22]. As the UK will not be an EU as a reference price for other countries [14] and also Member State, NICE and the other HTA agencies in the UK because NICE assessments are held in high esteem. Brexit [the Scottish Medicines Consortium (SMC) and the All could change this. If the UK does not collaborate with the Wales Medicines Strategy Group (AWMSG)] will have a EMA, that is the UK does not accept the marketing limited role to play in this new strategy. authorisation approval of the EMA, then access to the UK It is important to reflect on the changing environment of market will require an additional authorisation process (and HTA globally and the influence of NICE. NICE still sub- expense) via the MHRA. The fact that the UK market is a scribes—as it has for the last 20 years—to its cost per mere 2.4% of global pharmaceutical sales (compared with quality-adjusted life year (QALY) approach with a focus 21.5% for all of Europe) (IMS World Review Analyst on the health care perspective. Other agencies like ZiN The Impact of Brexit on Pharmaceuticals and HTA 89 have, arguably, been more innovative in reviewing and Brexit will also affect the evidence base in terms of data, changing their guidelines [23], while multi-criteria decision both data sharing and data protection. Clinical trial data analysis (MCDA) [24, 25] and value frameworks [26] and other personal data like health records are currently highlight that there is more to HTA than an incremental governed by the EU Data Protection Directive and the UK cost-effectiveness ratio (ICER). NICE is well aware of this, Data Protection Act 1998. As of May 2018, the General but constrained by NHS England and the Department of Data Protection Regulation EU/2016/679 will come into Health in making significant change. force. As this is a regulation, it will need to be legislated for when the UK leaves the EU, which could introduce some changes. A significant issue for HTA could be the 5 The Evidence Base Will Change sharing of data once the UK leaves the EU. The 1998 Act states that ‘personal data shall not be transferred outside the Many of us in research will be acutely aware of the European Economic Area unless there is adequate protec- uncertainty that Brexit has had on research funding, and tion’. This could cause problems for not just clinical trial specifically the UK’s eligibility and access to programmes data but also real world evidence (RWE). RWE is gaining like Horizon 2020 and the Innovative Medicines Initiative traction in HTA [19], and the UK as a post-launch study (IMI), which have been particularly supportive of research site to collect such data could become less attractive. An in health economics. If such programmes continue with additional issue with data sharing is the EMA’s role in limited UK involvement, then the applicability of project monitoring the safety and efficacy of pharmaceuticals. If outcomes to the UK setting and the generalisability and there was limited cooperation between the UK/MHRA and transferability of these results could find the UK lagging the EMA, which is additionally hindered by constraints behind other EU countries when it comes to trialling and around data sharing, then patient safety and public health adopting new methodologies and research techniques. The would be at risk [12]. knowledge exchange between the UK and the EU is mutually beneficial [27], and is important for supporting the (social) science base. 6 Possible Opportunities Clinical trial research will be particularly affected by leaving the EU. Leave campaigners argued that the EU Every cloud has a silver lining, but in truth it is difficult to Clinical Trials Directive (EC) No. 2001/20/EC damaged find the opportunities for HTA in Brexit. The UK market medical research and innovation in the UK as it increased the could be promoted to industry by offering early engage- administrative burden and cost of running trials, which saw a ment and a fast-track stream-lined MHRA and NICE par- reduction in trials taking place in Europe. The new Clinical allel approval process. The HTA process could become Trials Regulation 536/2014 will harmonise the application value-led, specifically involving NHS England in discus- and authorisation processes. Sponsors will be required to sions on access agreements and promote flexible pricing register trials, and there will be greater transparency and an and reimbursement arrangements like outcome-based accessible database of results. Implementation of the regu- payments [28] and multi-indication pricing [29]. This, lation has been delayed until after March 2019 and will however, will not be affordable without an increase in NHS therefore not be captured in the European Union (With- funding, and necessitates evaluating what such innovations drawal) Bill (previously known as the Great Repeal Bill), so in HTA and market access are worth in terms of patient it is unclear what new legislation would look like. Ideally it benefit and a buoyant life sciences industry. would allow the UK to fully participate in the EU system; low standards would not attract the pharmaceutical indus- try who require trials to meet Food and Drug Administration 7 Deal or No Deal (FDA) or EMA requirements. Under a scenario of limited cooperation, a pharmaceutical company would register their It is important to point out that while there are many ‘deals’ trial in the EU, which would give them access to all EU to be negotiated, there is a possibility—given statements countries, but should they wish to recruit UK patients, they from Prime Minister May that ‘no deal is better than a bad would need to seek additional authorisation in the UK. A deal’ [30] —that come March 2019, Britain will not have reduction in the number of UK patients in trials means British secured a trade deal with the EU. It will then fall under the patients will not get to benefit from these innovations early, World Trade Organization’s (WTO) terms. Without a free and the evidence base that is submitted for marketing trade agreement (FTA), tariffs would apply. In addition, authorisation and market access may not be representative of important questions over the legality of the FTAs with non- the UK patient population, challenging the validity of the EU countries would need addressing, specifically the HTA outcome. grandfathering of trade deals and what implications this has 90 P. Lorgelly 4. The Economist, Pharmaceutical firms trigger contingency plans on rules of origin [31]. At its worst, it could affect the for a no-deal Brexit. 2017. https://www.economist.com/news/ supply chain of pharmaceuticals, as there may be legal and britain/21731409-industry-long-production-timelines-cannot- regulatory gaps in those pharmaceutical regulations that afford-wait-any-longer-pharmaceutical-firms?fsrc=rss. may not be covered by the European Union (Withdrawal) 5. Dayan M, How will our future relationship with the EU shape the NHS? 2017: Nuffield Trust. http://www.nuffieldtrust.org.uk/ Bill [12]. research/brexit-relationship-eu-shape-nhs. 6. Fahy N, Hervey T, Greer S, Jarman H, Stuckler D, Galsworthy M, McKee M. How will Brexit affect health and health services 8 Final Thoughts in the UK? Evaluating three possible scenarios. Lancet. 2017;390(10107):2110–8. 7. Kaambwa B, Frew E. Health economics in the UK: capacity, I suspect some of what I have written above will eventuate constraints and comparisons to US health economists. Int Rev in the coming weeks, months and years; I do not wish to Econ Educ. 2013;12:1–11. take a bet on which scenario will materialise as I lost 8. Acha V. Breaking up the band: European regulatory cooperation in a post-Brexit world. Br J Pharm. 2017;2(1):1–5. money on that fateful day in June 2016. However, one can 9. Hatswell AJ. How do we avoid disaster when exiting the Euro- only hope that the Brexit effect on HTA is a short- to pean Medicines Agency? Making the most of Brexit in phar- medium-term phenomenon, and the strength and growth maceutical regulation. Ecancermedicalscience. 2017;11:ed67. that the discipline experienced during the UK austerity 10. Ganslandt M, Maskus KE. Parallel imports of pharmaceutical products in the European Union. 2001. The World Bank. http:// phase bodes well for this coming experience. As an emi- apps.who.int/medicinedocs/documents/s17518en/s17518en.pdf. nent professor once said to me, ‘austerity means that they 11. Enemark U and Pedersen M, Parallel import of pharmaceuticals [the government] need health economists even more to in Denmark, Germany, Sweden and the UK, 2004–2009, an ensure they are getting value for money’. Maybe that will analysis of savings. 2011, CAST–Centre for Applied Health Services Research and Technology Assessment Odense: be true of Brexit. Maybe there will be a mass migration of University of Southern Denmark. health economists to Canada or indeed for many of us back 12. Maignen F, Berdud M, Hampson G, Lorgelly P. Public health and to our country of birth, be that the continent or further economic implications of the United Kingdom exiting the EU and afield. Perhaps, just perhaps, HTA will benefit globally. the single market. OHE Consulting Report, Office of Health Economics, 2017. https://www.ohe.org/system/files/private/ publications/Executive%20report%20-%20final.pdf. Acknowledgements The author would like to thank Adrian Towse 13. Costa-Font J. The National Health Service at a critical moment: and Mike Drummond for discussions and reviews of early drafts. The when Brexit means hectic. J Soc Policy. 2017;46(4):783–95. author would also like to acknowledge the patience of Tim Wrightson 14. Re´muzat C, Urbinati D, Mzoughi O, El Hammi E, Belgaied W, for bearing with the author’s uncertainty regarding when the right Toumi M. Overview of external reference pricing systems in time to finalise the paper was; at times it was like the protracted Europe. J Mark Access Health Policy. 2015;3(1):27675. 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PharmacoEconomics - OpenSpringer Journals

Published: Mar 20, 2018

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