Article
Reference
Getting cytisine licensed for use world-wide: a call to action
WALKER, Natalie, et al.
Abstract
Getting cytisine licensed for use world-wide: a call to action.
WALKER, Natalie, et al . Getting cytisine licensed for use world-wide: a call to action. Addiction , 2016, vol. 111, no. 11, p. 1895-1898
DOI : 10.1111/add.13464 PMID : 27426482
Available at:
http://archive-ouverte.unige.ch/unige:116794
Disclaimer: layout of this document may differ from the published version.
Getting cytisine licensed for use world-wide: a call to action
Most tobacco users live in low and middle income countries where stop smoking medicines are unavailable or
unaffordable. There is an urgent need for action by key stakeholders to get cytisine licensed worldwide so that its life-saving potential can be realised.
Effective tobacco cessation medicines are needed in low- and middle-income countries (LMICs), where most tobacco users live, but are often unavailable or unaffordable [1].
Cytisine (an alkaloid found in some plants belonging to the Leguminosae family) could be a solution to this prob- lem. Cytisine, like varenicline, is a partial agonist at nicotinic acetylcholine receptors (nAChRs) [2] with high affinity for the alpha-4 beta-2 nAChRs subtype, and aids cessation by reducing the severity of withdrawal and the satisfaction associated with tobacco use [3]. However, there are a number of key differences between the two medications (Table 1).
Evidence for cytisine’s efficacy and effectiveness comes from several sources. Four systematic reviews (five trials, undertaken in central/eastern Europe, n = 3250) have found cytisine to be superior to placebo for short- and long-term abstinence from smoking [7–10], with a pooled relative risk at≥6 months of 3.29 (95% confidence inter- vals = 1.84–5.90) [8]. A New Zealand non-inferiority trial (n= 1310) found that cytisine was more effective than combination nicotine replacement therapy (NRT) at increasing 6-month quit rates [11]. Cytisine is well toler- ated when taken according to the recommended dose: ad- verse events reported in trials are typically non-serious and self-limiting gastrointestinal and sleep disturbances [7–11].
Cytisine is cheaper than varenicline (Table 1), nortriptyline (~US$95 for a 12-week course), NRT (~US$112–685 for an 8–10-week course) and bupropion (~US$228–521 for a 12-week course) [4]. Cytisine is affordable (even in LMICs) [12], it has the lowest cost per quality-adjusted life-year of all smoking cessation medications [13] and may be more cost-effective than varenicline [14].
Since the 1960s cytisine has been available as a prescription-only or non-prescription smoking cessation treatment in central/eastern Europe. Cytisine is manufactured according to the principles of European Union (EU) Good Manufacturing Practice standards by two companies: Sopharma (Bulgaria) and Aflofarm (Poland), yet cytisine is currently authorized only by regu- latory authorities for smoking cessation in four EU coun- tries (Bulgaria, Poland, Latvia, Lithuania) and 13 non-EU countries (Azerbaijan, Armenia, Belarus, Georgia,
Kazakhstan, Kyrgyzstan, Moldova, Russia, Serbia, Tajikistan, Turkmenistan, Uzbekistan, Ukraine). Many LMICs will not licence cytisine unless it isfirst licensed in a reference country (namely Australia, Austria, Belgium, Canada, Denmark, Germany, Finland, Iceland, France, Ireland, Luxemburg, Holland, New Zealand, Norway, Swe- den, Switzerland, United States, United Kingdom, Japan, Italy, Spain, Portugal) or is on the World Health Organization (WHO) Essential Medicines List.
If cytisine is effective, cost-effective, affordable and well tolerated, why is it not licensed more widely? [4,13,15] A key reason is that Sopharma and Aflofarm have not sought regulatory approval actively outside central/eastern Europe. This could be because regulatory authorities such as the UK Medicines and Healthcare Products Regulatory Agency (MHRA), the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) may require further placebo-controlled trials of cytisine to be undertaken in western European and/or North American populations. However, there is little incentive for pharma- ceutical companies to conduct such research, as cytisine is a generic drug. Potential investors may not see the oppor- tunity for substantial return unless a patent can be attached; this would almost certainly increase the cost to consumers [15]. Interestingly, Extab has recently obtained the rights from Sopharma to market a ‘new patent- protected version of Tabex (cytisine)’outside central and eastern Europe, and is currently seeking regulatory approval in the United States, Japan and other major mar- kets (Archived by WebCite® at http://www.webcitation.
org/6iOWMRTDu). Extab’s website states: ‘Following discussions with FDA and MHRA, a further large-scale clinical trial is in planning’ (Archived by WebCite® at http://www.webcitation.org/6iOWaLk4z). If regulatory approval is obtained, it remains unknown where the new version of Tabex will be priced in the market.
What can be done now to promote wider marketing authorization and availability of the existing low-cost cytisine? Without pharmaceutical industry investment, tri- als required by the MHRA, EMA and FDA will rely upon public good funding to progress; such funding is difficult to obtain in a highly competitive research environment and is often insufficient to cover the costs of studies that would meet regulatory standards. For many LMICs, where cytisine has the potential to have the greatest impact, there are addi- tional barriers to accessing tobacco cessation products. For example, tobacco cessation is not listed among the WHO
‘best buys’—a priority list of cost-effective interventions to
tackle non-communicable diseases (NCDs) [16]—despite be- ing a leading risk factor in the WHO target of a 25% relative reduction in NCD mortality by 2025 [17]. Furthermore, tobacco control is key to achieving Goal 3 (Good Health and Well-Being) of the United Nations Sustainable Develop- ment Goals (Archived by WebCite® at http://www.
webcitation.org/6iOWjGvM2). To date, international health donors have shown limited interest in tobacco cessation.
In response, we propose the following:
1 We recommend to regulatory authorities that further placebo-controlled trials of cytisine in its current form are unnecessary (sufficient placebo-controlled trial data exist and additional long-term safety data would become available through post-marketing surveillance) and unethical (people motivated to quit will be denied a cessation treatment if randomised to placebo).
2 We encourage companies to explore alternative regula- tory routes to licensing of cytisine, such as the‘well- established use’procedure in Europe [18].
3 We plan to facilitate access to all relevant trial data. The website www.stop-tabac.ch/cytisine contains the origi- nal trial articles and English translations (where needed). An up-to-date evidence summary for cytisine is available at this website (Archived by WebCite® at http://www.webcitation.org/6iOWsmKdp), and clinical study reports from the two most recent trials [11,19]
can be obtained from the trial authors.
4 We encourage the WHO to update its position on tobacco cessation to include cytisine.
5 We advocate that all governments signatory to the WHO Framework Convention on Tobacco Control prior- itize implementation of Article 14.
6 We encourage donors to support wider provision of low- cost tobacco cessation interventions (such as cytisine) in LMICs.
If cytisine became available more widely, the presence of an in-class competitor to varenicline (which comes off patent in 2020) could exert a downward pressure on the price of both drugs. There is urgent need for action by key stakeholders to get cytisine licensed worldwide so that its life saving potential can be realized.
Declaration of interests
The editorial was drafted initially by N.W., with input from all co-authors on subsequent versions. N.W. will act as guarantor. N.W., C.B. and J.B. have been involved in a
clinical trial in which cytisine was supplied at no cost by the manufacturer, Sopharma/Extab Ltd, Bulgaria. N.W., C.B. and J.S. have also accessed cytisine tablets for pharmacokinetic/pharmacodynamic studies, which have been provided free of charge from Aflofarm, Poland and/or Sopharma/Extab Ltd, Bulgaria. In all instances the companies have had no role in the study design, data col- lection, analysis and writing and interpretation of the study findings. N.W. has had funding for her research in the past 3 years from the University of Auckland, the Health Research Council of New Zealand, the National Health and Medical Research Council of Australia, the Auckland Medical Research Foundation, the University of Malaya, Social Code Ltd, Waitemata District Health Board, the Heart Foundation of New Zealand and the New Zealand Ministry of Health. She has also received support for travel, accommodation, conference fees, honoraria and/or expenses from the Heart Foundation of New Zealand, the Society for Research into Nicotine and Tobacco and the University of Malaya. C.B. has had funding for his research, consultancy or travel as a speaker in the past 3 years from the Health Research Council of New Zealand, Moffit Cancer Centre, Commonwealth University of Virginia, University of Hong Kong, National University of Taiwan, University of Malaya and the New Zealand Ministry of Health. J.B.
has undertaken fee-paid work commissioned for the Uni- versity of Otago, Curtin University, University of Queens- land, University of Sydney and the Pharmaceutical Society of New Zealand. She has been a paid speaker for the Pharmaceutical Society of New Zealand and received funding from the University of Auckland and University of Auckland UniServices. She has also received support for travel and conference fees and/or expenses from the Auckland Medical Research Foundation, the Maurice and Phyllis Paykel Trust, the University of Otago/International Scientific Acupuncture and Meridian Symposium, the Pharmaceutical Society of New Zealand and the National Institute of Complementary Medicine (Australia). She has also received royalties from Elsevier/Churchill Livingstone and the Authors’Licensing and Copyright Association. H.
M.R. has received investigator-led research funding and honoraria for speaking at educational meetings from Pfizer Inc. He has also received honoraria from Johnson and Johnson for speaking at educational meetings and an advi- sory board meeting. P.T. has undertaken paid consultancy for Aflofarm, a manufacturer of cytisine. M.R. has no con- flicts of interest to declare. J.-F.E. has no conflicts of interest Table 1 Cytisine compared to varenicline.
Half-life Treatment period Cost for full course (US$) [4]
Cytisine 4.8 hours [5] Titrated down over 25 days $15–20
Varenicline 17 hours [6] Titrated up over 12 weeks $474–501
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to declare. K.S. has received research funding from Pfizer (GRAND 2014) to conduct a smoking cessation trial. R.J.
C. has had funding for his research in the past 3 years from the National Health and Medical Research Council of Australia and is supported by a Cancer Institute New South Wales Early Career Research Fellowship (GNT14/ECF/1- 46). J.M.C.M. has been awarded a Pfizer Independent Grant for Learning and Change (IGLC), managed by Global Bridges (Healthcare Alliance for Tobacco Dependence Treatment) and hosted at the Mayo Clinic, to support free smoking cessation treatment training in addiction/mental health care units in Brazil (grant IGLC 13513957). P.S.
has no conflicts of interest to declare. J.S. has had funding for her research in the past 3 years from the University of Auckland, Auckland Medical Research Foundation and the New Zealand Education and Research Foundation.
She received research funding from Britannia Pharmaceu- ticals in 1997 to undertake research. She has also attended CME dinners sponsored by Reckitt Benckiser, Sanofi, Janssen Cilag, AlphaPharm and Invidior and was sup- ported to travel to the International Harm Reduction Asso- ciation conference in 2005 by Schering Plough. She has co-supervised a PhD student who had received funding from Janssen-Cilag, Eli Lilly, Astra Zeneca, Roche Diagnos- tics and Douglas Pharmaceuticals, but was not named on any of these grant applications. Her personal investments may include shares in pharmaceutical companies as part of a managed portfolio. She was awarded a University of Auckland Hood Fellowship in 2007. The Lion Foundation http://www.lionfoundation.org.nz/, a gambling charity which derives its money from gambling machines, is one of the major donors to this fund. She has received funding from the Alcohol Advisory Council (ALAC) of New Zealand to conduct a literature review. A.L.A.C. received a hypoth- ecated levy on the consumption of alcohol. She is a Co- Principle Investigator on an investigator-initiated project funded by the Health Promotion Agency (NZ) which is a Crown Agency (http://www.hpa.org.nz/who-we-are). The HPA is funded from Vote Health, the levy on alcohol pro- duced or imported for sale in New Zealand (hypothecated funding) and part of the problem gambling levy. N.A.R.
has received a research grant and been a consultant (accepting no honorarium) to Pfizer.
Keywords Affordable, cost-effective, cytisine, regulatory approval, smoking cessation, treatment.
NATALIE WALKER1, CHRIS BULLEN2, JOANNE BARNES3, HAYDEN MCROBBIE4, PIOTR TUTKA5, MARTIN RAW6, JEAN- FRANÇOIS ETTER7, KAMRAN SIDDIQI8, RYAN J. COURTNEY9, JOÃO MAURICIO CASTALDELLI-MAIA10, PETER SELBY11, JANIE SHERIDAN12& NANCY A. RIGOTTI13 National Institute for Health Innovation and Centre for Addiction Research, School of Population Health, University of Auckland,
Auckland, New Zealand,1National Institute for Health Innovation, School of Population Health, University of Auckland, Auckland, New Zealand,2School of Pharmacy, University of Auckland, Auckland, New Zealand,3Queen Mary University of London, London, UK,4 Department of Pharmacology, Centre for Innovative Research for Medical and Natural Sciences, University of Rzeszów, Rzeszów, Poland,5 UK Centre for Tobacco Control Studies, University of Nottingham, Nottingham, UK,6Faculty of Medicine, University of Geneva, Geneva, Switzerland,7Department of Health Sciences, University of York, York, UK,8National Drug and Alcohol, Research Centre, University of New South Wales, Sydney, Australia,9Department of Neuroscience, Medical School, Fundação do ABC, Santo André, Brazil,10Departments of Family and Community Medicine, Psychiatry and Public Health Sciences, University of Toronto, Toronto, Canada,11School of Pharmacy and Centre for Addiction Research, University of Auckland, Auckland, New Zealand12and Harvard Medical School, Tobacco Research and Treatment Center, Massachusetts General Hospital, Boston, USA13
References
1. Piné-Abata H., McNeill A., Murray R., Bitton A., Rigotti N., Raw M. A survey of tobacco dependence treatment services in 121 countries.Addiction 2013;108: 1476–84.
2. Coe J. W., Brookes P. R., Vetelino M. G., Wirtz M. C., Arnold E.
P., Huang J.et al.Varenicline: an alpha4beta2 nicotinic recep- tor partial agonist for smoking cessation.J Med Chem 2005;
48: 3474–7.
3. Tutka P., Zatonski W. Cytisine for the treatment of nicotine ad- diction: from a molecule to therapeutic efficacy.Pharmacol Rep 2006;58: 777–98.
4. Prochaska J., Das S., Benowitz N. Cytisine, the world’s oldest smoking cessation aid.BMJ 2013;347: f5198.
5. Jeong S.-H., Newcombe D., Sheridan J., Tingle M. Pharmaco- kinetics of cytisine, an α4β2 nicotinic receptor partial agonist, in healthy smokers following a single dose.Drug Test Anal 2014; DOI: 10.1002/dta.1707.
6. Obach R., Reed-Hagen A., Krueger S., Obach B. J., O’Connell T. N., Zandi K. S. et al. Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist,in vivoandin vitro.Drug Metab Dispos 2006;
34: 121–30.
7. Etter J. F. Cytisine for smoking cessation: a literature review and a meta-analysis.Arch Intern Med 2006;166: 1553–9.
8. Hajek P., McRobbie H., Myers K. Efficacy of cytisine in helping smokers to quit: systematic review and meta analysis.Thorax 2013;68: 1037–42.
9. Cahill K., Stead L. F., Lancaster T. Nicotine receptor partial ag- onists for smoking cessation. Cochrane Database Syst Rev 2012;18: CD006103.
10. McRobbie H., Hajek P., Bullen C., Feigen V. Rapid review of non-NHS treatments for smoking cessation. London: National Institute of Clinical Excellence (NICE); 2006.
11. Walker N., Howe C., Glover M., McRobbie H., Barnes J., Nosa V.et al.Randomized comparison of cytisine versus nicotine for smoking cessation.N Engl J Med 2014;371: 2353–62.
12. West R., Raw M., McNeill A., Stead L., Aveyard P., Bitton J.
et al.Healthcare interventions to promote and assist tobacco cessation: a review of efficacy, effectiveness and affordability E-mail: [email protected]
for use in national guideline development.Addiction 2015;
110: 1388–403.
13. Stapleton J. The case for licensing cytisine now for smoking cessation is overwelming [Letter].BMJ 2013;347: f5736.
14. Leaviss J., Sullivan W., Ren S., Everson-Hock E., Stevenson M., Stevens J. W.et al.What is the clinical effectiveness and cost- effectiveness of cytisine compared with varenicline for smoking cessation? A systematic review and economic evalu- ation.Health Technol Assess2014;18: 1–119.
15. Aveyard, P., West, R. Cytisine and the failure to market and regulate for human health.Thorax2013;68: 989.
16. World Health Organization and World Economic Forum, From burden to‘best buys’: reducing the economic impact of non-communicable diseases in low- and middle-income
countries. 2011. Geneva: World Health Organization and World Economic Forum (www.who.int/nmh/publications/
best_buys_summary) (accessed 21 March 2016).
17. Kontis V., Mathers C., Rehm J., Stevens G., Sheild K., Bonita R.
et al.Contribution of six risk factors to achieving the 25 x 25 non-communicable disease mortality reduction target: a modelling study.Lancet 2014;384: 427–37.
18. Borg J., Laslop A., Pani L., Maciulaitis R., Melchiorri D. Reflec- tions on decisions made on the well-established use of medicinal products by EU Regulators and the ECJ.Sci Pharm 2014;82: 655–63.
19. West R., Zatonski W., Cedzynska M., Lewandowska D., Pazik J., Aveyard P. et al. Placebo-controlled trial of cytisine for smoking cessation.N Engl J Med 2011;365: 1193–200.
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