Comment

Further, WHO and Russia have published a strategy for cooperation that mentions mass gatherings medicine, but the focus is on general epidemic emergency response and does not mention specific plans for the upcoming World Cup.12 By contrast, to strengthen health-system preparedness in Poland and Ukraine during the runup to the Union of European Football Associations European Football Championship Finals (Euro 2012), a daily health surveillance system was established through multicountry collaborations between local organising committees, WHO, and international public health organisations.13 Russia deserves the same. Instead of political isolation, Russia should be able to benefit from the experience of international experts. For nearly a century, Russia has largely existed apart from western technological and economic flows, and even the fall of the Soviet Union did not eliminate the tendency of western policy makers and commentators to view Russia as an antagonist rather than as a partner. The upcoming 2018 World Cup offers a chance to repair this tumultuous relationship: international collaboration during mega-event preparations creates space in which new connections and institutions can grow. The first step must be to end Russia’s political and economic isolation. It is difficult to convince Russians of the west’s friendly intentions while sanctions persist.14 Indeed, western sanctions have only served to boost President Vladimir Putin’s approval ratings, and allowed him to marginalise Russia’s moderates and opposition figures under the guise of defending the nation from international aggression.15 Unless current western attitudes change, it seems likely that Russia will prepare for the 2018 FIFA World Cup without the benefit of international collaboration—a situation that will increase health risks for all.

Sven Daniel Wolfe Department of Geography, University of Zurich, CH-8057 Zurich, Switzerland [email protected] I declare no competing interests. 1

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Abubakar I, Gautret P, Brunette G, et al. Global perspectives for prevention of infectious diseases associated with mass gatherings. Lancet Infect Dis 2012; 12: 66–74. Steffen R, Bouchama A, Johansson A, et al. Non-communicable health risks during mass gatherings. Lancet Infect Dis 2012; 12: 142–49. Memish ZA, Alrabeeah AA. Jeddah declaration on mass gatherings health. Lancet Infect Dis 2011; 11: 342–43. Memish ZA, Stephens G, Al Rabeeah A. Mass gatherings medicine. Lancet Infect Dis 2012; 12: 10. Memish ZA, Stephens GM, Steffen R, Ahmed QA. Emergence of medicine for mass gatherings: lessons from the Hajj. Lancet Infect Dis 2012; 12: 56–65. Johansson A, Batty M, Hayashi K, Al Bar O, Marcozzi D, Memish ZA. Crowd and environmental management during mass gatherings. Lancet Infect Dis 2012; 12: 150–56. Müller M. What makes an event a mega-event? Definitions and sizes. Leisure Studies 2015; published online Jan 13. DOI:10.1080/ 02614367.2014.993333. Russia 2018 Local Organising Committee. Annual report 2012. http://www.fifa.com/mm/document/tournament/loc/02/07/81/59/2012annual-report_eng.pdf (accessed Jan 25, 2015). Russian Federal Government. Decree no 518. June 20, 2013 (in Russian). http://www.minsport.gov.ru/documents/518.pdf (accessed Jan 10, 2015). Khan K, McNabb SJ, Memish ZA, et al. 2012. Infectious disease surveillance and modelling across geographic frontiers and scientific specialties. Lancet Infect Dis 2012; 12: 222–30. WHO. The Russian Federation aims for smoke-free Winter Games—new tobacco control measures are showing effects. February, 2014. http:// www.who.int/features/2014/russia-antitobacco-law/en/ (accessed Jan 21, 2015). WHO Regional Office for Europe. Strategy of national cooperation. World Health Organization and Ministry of Health of the Russian Federation. 2014–2020. http://www.who.int/countryfocus/cooperation_strategy/ccs_ rus_russian.pdf (accessed Jan 23, 2015). Smallwood CAH, Arbuthnott KG, Banczak-Mysiak B, et al. Euro 2012 European football championship finals: planning for a health legacy. Lancet 2014; 383: 2090–97. Levada. Russia’s foreign policy: orientation and critiques, 2015. Levada Center poll on popular attitudes towards other nations and international criticism towards Russia. Levada Jan 13, 2015 (in Russian). http://www. levada.ru/13-01-2015/vneshnyaya-politika-rossii-orientiry-i-kritika (accessed Jan 14, 2015). Levada. January approval ratings, 2015. Levada Center poll conducted regularly since 1999. Levada Jan 28, 2015 (in Russian). http://www.levada.ru/28-012015/yanvarskie-reitingi-odobreniya-i-doveriya (accessed Jan 28, 2015).

Rare diseases and effective treatments: are we delivering? See Editorial page 746

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Rare diseases afflict millions of individuals: they cause loss of life and impose a huge physical, psychological, and socioeconomic burden on patients and their families. There are almost 7000 rare diseases (defined in the European Union as diseases that affect fewer than five people per 10 000), although fewer than 100 rare diseases account for about 80% of affected patients.1,2 For most rare diseases there are no effective treatments.

In 2000, the orphan drugs regulation enacted by the European Union provided incentives for pharmaceutical companies to bring orphan medicinal products to the market; and since then 106 drugs have been approved for specific rare diseases.3 On the one hand, their therapeutic benefits have been substantial or spectacular; on the other hand, the prices of these new drugs have ranged from high to astronomical.4–6 Despite www.thelancet.com Vol 385 February 28, 2015

the small numbers of patients, rare diseases seem to have become commercially attractive for industry. Patients with rare diseases have made a remarkable contribution to research efforts. A notable example is a drug designed for a subgroup of patients with cystic fibrosis who have a G551D-CFTR mutation. The publicly funded basic research that led to the identification of the CFTR gene and its mutations provided the rationale for developing ivacaftor, which, in turn, was the product of a close collaboration between the cystic fibrosis community and industry; the Cystic Fibrosis Foundation contributed substantial resources and played a key part in coordinating clinical studies crucial for approval of the drug.7 The price of ivacaftor was set at US$294 000 (€226 000) per year for each patient. In 2014, the Cystic Fibrosis Foundation sold part of its ivacaftor royalties, but the price of the drug has not changed. The very patients who assumed the risks of participating in clinical trials must now confront the high cost of ivacaftor, whether through their insurers or otherwise, and national health services must do the same for their citizens. Increased recognition by governments and by health services of the problems faced by patients with rare diseases has been a major advance, and an important component has been to incentivise the development of orphan drugs. However, these incentives have to some extent backfired. Pharmaceutical companies have decided to compensate for the small number of patients who can benefit from an orphan drug by setting exorbitant prices. Unlike with anti-cancer drugs, where in most cases the total cost for treatment with expensive drugs is limited by either success or death, many rare diseases are congenital or long term, which means that drug costs accumulate with time. With current prices, the total cost for a patient with cystic fibrosis on ivacaftor for 30 years, or for a patient with paroxysmal nocturnal haemoglobinuria receiving eculizumab for 20 years, is about $8 million. Such costs are unsustainable, even for health services that have met them hitherto.8 Therefore, we make three proposals about what can be done. First, a firm diagnosis and rigorous adherence to clinical indications for therapy are imperative for patients with a rare disease. In this respect, the prescription for a new and expensive drug should be validated by a designated centre with expertise in the care of patients with that rare disease. Second, a diagnosis-based, regularly updated registry with high-quality data should be in place for each rare www.thelancet.com Vol 385 February 28, 2015

disease for which an expensive drug is available. This registry will make it possible to assess the efficacy of the drug in larger numbers of patients, since the drug might have been licensed on the basis of few patients and short periods of time. Such a registry will also allow assessment of the clinical course of patients who take the drug compared with patients who do not receive it. Moreover, the registry will provide comprehensive and unbiased data on unwanted effects of the drug. For these purposes it is essential that the registry be kept by an independent body. Third, the cost of orphan drugs should be negotiated systematically. The costs incurred during the development of an orphan drug should be documented; the number of eligible patients should be estimated; and a reasonable margin of profit should be allowed. On this basis, agreement about the cost of the drug should be reached. In this respect, the European Union, were it to act as one, would be in a position to negotiate the price of orphan drugs from a position of moral and economic strength. There are sound reasons for these proposals. A medicine is not a consumer good that we can take or leave depending on price. The health profession has adhered to the moral imperative that, as long as there is an effective treatment for a patient with a certain disease, we must administer that treatment. For millennia human societies have translated moral imperatives into laws. Hyry and colleagues9 have recently argued that whenever it is possible to treat a rare disease, to do so should be a legal requirement. Therefore, rejecting an effective orphan drug on economic grounds is not an option: we must use the law, the power of persuasion, and also our creativity to work towards price reduction. The rare diseases community is no longer alone in this endeavour. In July, 2014, the US Senate challenged the company that produces the hepatitis C drug sofosbuvir at a cost of $1000 per tablet to justify this price; the Senate stated the principle that for any drug there must be proportionality between production cost and pricing.10 There would be considerable room for manoeuvre, in our opinion, if this principle were applied to new drugs for rare diseases.

BSIP VEM/Science Photo Library

Comment

Cystic fibrosis

Lucio Luzzatto, Carla E M Hollak, Timothy M Cox, Arrigo Schieppati, Christoph Licht, Helena Kääriäinen, Giampaolo Merlini, Franz Schaefer, Steven Simoens, Luca Pani, Silvio Garattini, *Giuseppe Remuzzi Istituto Toscano Tumori, Florence, Italy (LL); Department of Endocrinology and Metabolism, Academic Medical Center,

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Comment

Amsterdam, the Netherlands (CEMH); University Department of Medicine, University of Cambridge, Cambridge, UK (TMC); IRCCS Istituto di Ricerche Farmacologiche Mario Negri, 24126 Bergamo, Italy (AS, SG, GR); Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy (AS); Division of Nephrology, The Hospital for Sick Children, Toronto, Canada (CL); European Platform for Patients’ Organizations Science and Industry, Brussels, Belgium (HK); Amyloidosis Research and Treatment Center, Department of Molecular Medicine, University of Pavia, Italy (GM); Pediatric Nephrology Division, Heidelberg University Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany (FS); KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (SS); and AIFA Italian Medicine Agency, Rome, Italy (LP) [email protected]

See Online for appendix

This paper reflects the discussion that emerged during an International Workshop on Orphan Drugs on March 25, 2014. We thank the Menarini Foundation, in particular Alessandro Casini, for their support and an unrestricted grant. We thank all the participants at the workshop (appendix) for their contribution to the discussion. 1

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Commission of the European Communities. Communication on rare diseases: Europe’s challenges COM(2008) 679. Nov 11, 2008. http://ec.europa.eu/ health/ph_threats/non_com/docs/rare_com_en.pdf (accessed Jan 21, 2015). Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products (consolidated version .7/8/2009). http://ec.europa.eu/health/files/eudralex/vol-1/reg_2000_141_ cons-2009-07/reg_2000_141_cons-2009-07_en.pdf (accessed Jan 21, 2015). Hillmen P, Hall C, Marsh JC, et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004; 350: 552–59. Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet 2009; 373: 759–67. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368: 2169–81. O’Sullivan BP, Orenstein DM, Milla CE. Pricing for orphan drugs: will the market bear what society cannot? JAMA 2013; 310: 1343–44. Picavet E, Annemans L, Cleemput I, Cassiman D, Simoens S. Market uptake of orphan drugs—a European analysis. J Clin Pharm Ther 2012; 37: 664–67. Hyry HI, Stern AD, Cox TM, Roos JC. Limits on use of health economic assessments for rare diseases. QJM 2014; 107: 241–45. Wyden R, Grassley CE. United States Senate Committee on Finance. July 11, 2014. http://www.finance.senate.gov/imo/media/doc/WydenGrassley%20Document%20Request%20to%20Gilead%207-11-141.pdf (accessed Jan 21, 2015).

Schieppati A, Henter JI, Daina E, Aperia A. Why rare diseases are an important medical and social issue. Lancet 2008; 371: 2039–41.

LTH NHS Trust/Science Photo Library

Home-based management of patients with atrial fibrillation

Published Online November 17, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)62013-4 See Articles page 775

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Globally, a challenge for clinicians is treatment of a growing number of patients who develop atrial fibrillation in conjunction with existing chronic disorders.1 Evaluations of approaches to manage chronic disease are important for improving both patient-centred outcomes and use of health-care resources. In The Lancet, Simon Stewart and colleagues2 report results of a randomised trial of an atrial fibrillation-specific management strategy (SAFETY) versus standard management. The SAFETY intervention is a nurse-led, home-based management approach that has shown positive outcomes in patients with heart failure3 and aims to reduce all-cause unplanned recurrent admission and prolong survival in individuals with chronic atrial fibrillation. Stewart and colleagues’ investigation builds on findings of a previous small study of a home-based intervention for patients with atrial fibrillation with or without heart failure4 by enrolling a larger sample of patients (n=335) and focusing on individuals with a diagnosis of atrial fibrillation without pre-existing left-ventricular systolic dysfunction or valvular disease. Completion of this study shows the feasibility of delivering a comprehensive home-based intervention within the Australian healthcare system to patients with atrial fibrillation and multiple comorbidities, and this outcome is meaningful in itself.

Stewart and colleagues assessed two primary outcomes that are of concern to clinicians, administrators, and policy makers—all-cause mortality and all-cause unplanned readmission. They measured these coprimary outcomes as event-free survival and the proportion of actual versus maximum days alive and out of hospital. No difference was recorded between the SAFETY intervention and standard management with respect to median eventfree survival (hazard ratio 0·97, 95% CI 0·76–1·23), and a small effect size in favour of SAFETY (0·22, 95% CI 0·21–0·23; p=0·039) was reported for days alive and out of hospital. In view of these findings, why did such a carefully developed and comprehensive intervention not lead to greater differences between the well-matched groups? If the primary outcome measures in Stewart and colleagues’ study had been patient-centred, might we view the value of the SAFETY intervention from a different perspective? For example, of 485 unplanned readmissions in patients allocated to the SAFETY intervention, 223 (46%) were unrelated to cardiovascular causes and, therefore, were possibly not amenable to the intervention. 49 deaths were reported, but the causes were not recorded and, as the authors note, the study was underpowered to detect relevant differences between interventions with respect to mortality. With no information about causes of death, we cannot establish if the deaths were preventable www.thelancet.com Vol 385 February 28, 2015

Rare diseases and effective treatments: are we delivering?

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