When free is not fair: the case of vaccine donations

Comment authors used data gathered from 33 clinical trials and 19 cohort studies involving more than 20 000 patients and 102 different treatment regimens to show that initially isoniazid-resistant disease was associated with significantly poorer outcomes than was isoniazidsensitive disease. They used statistical methods to demonstrate that use of standard WHO first-line drug regimens in patients with isoniazid-resistant tuberculosis could lead to 60 000 new multidrug-resistant cases annually. This study should prompt clinicians to establish fully the drug-resistance pattern before prescribing an anti-tuberculosis regimen especially in places where the prevalence or incidence of resistance to isoniazid is high. An investigation by the European Respiratory Society and European Centre for Disease Prevention and Control of the effect of the European standards for tuberculosis care7–9 published in 2012 showed that adoption of this important document is still suboptimal and that more advocacy and training are necessary. In other words, publication of evidence-based standards or guidelines10 is important, but not sufficient to achieve high-quality diagnosis, treatment, and prevention of tuberculosis and latent tuberculosis infection.11,12 The findings of Gegia and colleagues2 are really useful to guide the upcoming WHO guidelines on tuberculosis treatment and the joint American Thoracic Society, Euopean Respiratory Society, US Centers for Disease Control and Prevention, and Infectious Diseases Society of America treatment guidelines on drug-resistant tuberculosis. 21049 Tradate (LD’A, GBM), Italy; Public Health Consulting Group, Lugano, Switzerland (LD’A, GBM); and Clinical Epidemiology and Medical Statistics Unit, Department of Biomedical Sciences, University of Sassari—Research, Medical Education, and Professional Development Unit, AOU Sassari, Sassari, Italy (GS) 1 2 3 4 5 6 7 8 9 10 11 12 WHO. Global Tuberculosis Report 2014. Geneva: World Health Organization, 2015. Gegia M, Winters N, Benedetti A, van Soolingen D, Menzies D. Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis. Lancet Infect Dis 2016; published online Nov 16. http://dx.doi.org/10.1016/S1473-3099(16)30407-8. Falzon D, Gandhi N, Migliori GB, et al; Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB. Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes. Eur Respir J 2013; 42: 156–68. Migliori GB, Sotgiu G, Gandhi NR, et al; Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB. Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis. Eur Respir J 2013; 42: 169–79. Espinal MA, Kim SJ, Suarez PG, et al. Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries. JAMA 2000; 283: 2537–45. Menzies D, Benedetti A, Paydar A, et al. Standardized treatment of active Tuberculosis in patients with previous preatment and/or with mono-resistance to Isoniazid: a systematic review and meta-analysis. PLoS Med 2009; 6: e1000150. Migliori GB, Zellweger JP, Abubakar I, et al. European union standards for tuberculosis care. Eur Respir J 2012; 39: 807–19. Van der Werf MJ, Sandgren A, D’Ambrosio L, Blasi F, Migliori GB. The European Union standards for tuberculosis care: do they need an update? Eur Respir J 2014; 43: 933–42. Sotgiu G, Beer N, Aliberti S, Migliori GB, van der Werf MJ. Fighting tuberculosis in the EU/EEA: towards the new European Union standards on tuberculosis care. Eur Respir J 2016; 48: 1278–81. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/ Centers for Disease Control/Infectious Diseases Society of America clinical practice guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis 2016; published online Aug 10. DOI: 10.1093/cid/ciw376. Falzon D, Jaramillo E, Schünemann HJ, et al. WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J 2011; 38: 516–28. Lönnroth K, Migliori GB, Abubakar I, et al. Towards tuberculosis elimination: an action framework for low-incidence countries. Eur Respir J 2015; 45: 928–52. *Lia D’Ambrosio, Giovanni B Migliori, Giovanni Sotgiu WHO Collaborating Centre for TB and Lung Diseases, Fondazione S Maugeri, IRCCS, Care and Research Institute, Via Roncaccio 16, When free is not fair: the case of vaccine donations On Oct 10, 2015, Médecins Sans Frontières (MSF) rejected Pfizer’s proposed donation of 1 million doses of its branded pneumococcal conjugate vaccine (PCV).1 The news caused a stir in the global health community; after all, free essential health goods might be considered something to be celebrated. This decision represents the latest development in a prolonged advocacy campaign spearheaded by MSF, which aims to reduce the cost of PCV, and presents a timely 128 opportunity to examine the case for vaccine donations. In their rejection of Pfizer’s offer, MSF cited several concerns related to the donation of pharmacological agents— namely, conditions attached to donation agreements, the sustainability of programmes dependent on donations, and the deleterious effect of donations on the incentive to reduce prices. To understand MSF’s concerns, the history of drug donation programmes should be explored. Perhaps the www.thelancet.com/infection Vol 17 February 2017 Comment most thoroughly documented case in the drug donation debate is the decision by Pfizer to donate fluconazole (Diflucan) for use in South Africa in 2000. To facilitate the treatment of HIV-related opportunistic infections, activists had lobbied for either a price reduction or the issue of a voluntary license to permit generic production of fluconazole. At the time, manufacturers in Thailand were marketing generic fluconazole for US$0·29 per unit, while Pfizer continued to dictate the cost of the same drug in South Africa, charging as much as $8·25 per unit.2 Pfizer subsequently delayed the delivery of Diflucan, causing local activists to illegally import 3000 capsules of generic fluconazole from Thailand to demonstrate the ease by which the drug could be provided to patients.3 In the months following Pfizer’s commitment to donate Diflucan, the company imposed the following conditions: clinical use would be limited to patients with cryptococcal meningitis, thereby excluding many patients with oral or oesophageal candidosis; the drug would only be available for patients in South Africa; and the donation agreement would expire after a period of approximately 2 years. Although some of these decisions were later retracted, a year passed before the first batch of donated Diflucan arrived in South Africa. During this period, Pfizer also remained a key litigant in a case against the South African government, which challenged legislation intended to make medicines more affordable.4 The Diflucan partnership has since been described as an “institutional compromise midwifed by conflict between public and private interests”.5 However, the motivation to engage in donation programmes, and the terms on which such programmes are negotiated, are clearly primarily determined by strategic financial considerations; Hank McKinnell, the then chief executive officer of Pfizer, revealed that “the marginal cost of our drugs is very low, so if we give away a drug to somebody who wouldn’t otherwise buy it, the profit impact of that action on us is just about zero”.6 The unpredictable nature of such profit-constrained philanthropy was central to MSF’s rejection of Pfizer’s proposed donation of branded azithromycin for the treatment of trachoma in Mali.6 Instead, MSF paid to import a generic version of the drug, thereby ensuring market competition and supply continuity. The misalignment of public health and private corporate www.thelancet.com/infection Vol 17 February 2017 priorities is arguably the most important criticism of donated pharmaceuticals: as Baker and Ombaka7 have explained, “market size and expected profits are the main drivers of entry of generic drugs”, whereas donations “capture market share, and thus demotivate generic entrants”. Such a strategy could have ramifications in the case of PCV, particularly given the anticipated entry of the Serum Institute of India’s tenvalent PCV at the affordable price of $2 per dose within the next 2 years.8 Further concerns include the ability of donation programmes to distort rational drug use and to disproportionately burden public health structures, particularly when such schemes are run in parallel to national systems for procurement and distribution.9 Finally, critics have cautioned that donation programmes tend to only meet a fraction of requirements. The decision by Boehringer Ingelheim to donate nevirapine for the prevention of vertical transmission of HIV in the early 2000s is a good example; the donation was limited to a particular subpopulation and distracted from the urgent need to reduce the cost of antiretroviral treatment for all patients who are HIV positive.10 One notable exception to this trend was Merck’s pledge to donate ivermectin “wherever needed for as long as needed” for the treatment of onchocerciasis.9 With these criticisms in mind, a donation of 1 million units of PCV is clearly an inadequate solution given the global burden of pneumococcal disease. Although vaccine donations could help a finite number of children, they do little to help the millions of children requiring immunisation against pneumococcal infection every year. Without a sustained commitment to price reductions, and healthy competition between pharmaceutical companies, vaccine donations will remain an ineffective remedy to the global burden of vaccine-preventable diseases. James Smith Médecins Sans Frontières, Geneva 1211, Switzerland [email protected] I declare no competing interests other than employment by Médecins Sans Frontières. 1 2 Cone J. There is no such thing as “free” vaccines: why we rejected Pfizer’s donation offer of pneumonia vaccines. 2016. http://www.doctors withoutborders.org/article/there-no-such-thing-“free”-vaccines-whywe-rejected-pfizer’s-donation-offer-pneumonia (accessed Oct 17, 2016). Pérez-Casas C, Chirac P, Berman D, Ford N. Access to fluconazole in less-developed countries. Lancet 2000; 356: 2102. 129 Comment 3 4 5 6 Mbali M. South African AIDS activism and global health politics. London: Palgrave Macmillan, 2013: 153–54. Mowjee T. Campaign to increase access to HIV/AIDS drugs. In: Clark J, ed. Globalising civic engagement: civil society and transnational action. London: Earthscan Publications, 2003: 72–74. Brown SA. Partnership prescriptions. In: Maclean SJ, Brown SA, Fourie P, eds. Health for some: the political economy of global health governance. New York, NY: Palgrave Macmillan, 2009: 219. Bakan J. The corporation: the pathological pursuit of profit and power. New York, NY: Free Press, 2005: 47. 7 8 9 10 Baker BK, Ombaka E. The danger of in-kind drug donations to the Global Fund. Lancet 2009; 373: 1218–21. MSF Access Campaign. The right shot: bringing down barriers to affordable and adapted vaccines. 2nd edn. Geneva: Médecins Sans Frontières Access Campaign, 2015: 76. Guilloux A, Moon S. Hidden price tags: disease-specific drug donations: costs and alternatives. Geneva: Médecins Sans Frontières, 2001. Pérez-Casas C, Herranz E, Ford N. Pricing of drugs and donations: options for sustainable equity pricing. Trop Med Int Health 2001; 6: 960–64. How long until routine Helicobacter pylori antimicrobial susceptibility testing? Three excellent consensus reports about the management of Helicobacter pylori infection and its treatment in adults have been published.1–3 Recommendations for eradication therapy are given, supported by many experts in the field. We agree with the reports that the goal of H pylori therapy should be eradication in at least 90% of treated patients. The three reports emphasise the increased resistance of H pylori to antimicrobials and the implication of resistance in treatment failures. Although culture-guided therapy is associated with higher eradication success rates as referred by two of the reports and corroborated by others,1,2,4,5 why is the main recommendation of the consensus papers not when possible, in all patients undergoing an endoscopy, a request for H pylori culture and its antimicrobial susceptibility or molecular determination of resistance must be performed? Antimicrobial susceptibility testing has been routinely done on most clinical bacterial isolates for over half a century. Why then did gastroenterologists resign themselves to saying susceptibility testing of H pylori is not currently clinically practical? In the 21st century, it is not acceptable to read that H pylori culture is troublesome and time-consuming. Most microbiology laboratories are able to culture H pylori from gastroduodenal biopsies. Every day these laboratories culture samples that are more troublesome, more timeconsuming, and more risky than H pylori. Most clinical laboratories can culture campylobacter from faeces, a microorganism that needs the same atmospheric requirements as H pylori, and similar staff training and laboratory costs. In 1999 our working group published a paper entitled “How long for the routine H pylori antimicrobial 130 susceptibility testing? The usefulness of the string test to obtain helicobacter for culture”,6 and 17 years later we are asking the same question. Since the commercial production of the string test (Entero-Test; HDC Corporation, Mountain View, CA, USA) ended, the only way to obtain H pylori strains is by endoscopy. Until 2013, Entero-test allowed the culture of H pylori without endoscopy;7 because of the interruption in the manufacture of the Entero-test, only a few institutions used it.6,8–11 Apart from the string test, our laboratory has cultured more than 17 000 samples of gastroduodenal biopsies and susceptibility testing was done in almost all positive cultures (>7800). It is surprising that despite the rampant increase of antimicrobial resistance, the idea is still being promulgated that the study of antimicrobial susceptibility is not useful in H pylori infection. As in all other bacterial infections, we encourage gastroenterologists and primary care physicians who treat patients infected with H pylori not to be content with knowing only if their patients are infected with H pylori. When doing an endoscopy in those patients, the biopsy should be sent to the microbiology laboratory for culture of H pylori, and if positive, susceptibility must be tested at least against the five most commonly used antimicrobials: amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin. It is time to break the myth that H pylori culture is troublesome and time-consuming. *Milagrosa Montes, Emilio Pérez-Trallero Microbiology Department, Hospital Universitario Donostia-Instituto Biodonostia, Paseo Dr Beguiristain, s/n 20014 San Sebastián, Gipuzkoa, Spain (MM, EP-T); and Medicine Faculty, University of the Basque Country, UPV/EHU, San Sebastián, Spain (EP-T) [email protected] www.thelancet.com/infection Vol 17 February 2017