Commentary: Evidence versus influence in the WHO procedure for approving essential medicines: misoprostol for maternal health Colin Millard senior lecturer , Allyson M Pollock professor of public health research and policy , Petra Brhlikova senior lecturer Global Health Policy and Innovation Unit, Queen Mary, University of London, London, UK In 2002, the World Health Organization changed its procedures for revising the model list of essential medicines as part of a shift to a more transparent and evidence based approach. 1 Barbui and Purgato’s analysis highlights how poor quality applications unaccompanied by a systematic review of evidence may lead to the WHO expert committee prioritising reviews of medicines with limited value. Another problem is that the influence of civil society organisations in the application and review process can apparently trump evidence. A case in point is misoprostol, a synthetic analogue of naturally occurring prostaglandin E1 that was, after six attempts, added to the essential medicine list in 2011 for the prevention of postpartum haemorrhage when oxytocin is not available or cannot be safely used. However, an application to include the drug for the treatment of postpartum haemorrhage was rejected at the same time because it “could divert the attention from or reduce attempts to implement oxytocin availability, a superior treatment.” The drug of choice for preventing and treating postpartum haemorrhage is oxytocin, followed by ergometrine, both of which are heat sensitive and require parenteral administration. Because misoprostol is stable at room temperature and can be administered orally, sublingually, rectally, and vaginally it has been presented as an ideal alternative in low resource settings, where most maternal deaths from haemorrhage occur. However, the evidence in support of using misoprostol is weak despite the large number of trials. Over 10 years, four successive versions of a Cochrane review of the safety and efficacy of the use of prostaglandins in the prevention of postpartum haemorrhage concluded that misoprostol is not as effective in reducing blood loss as oxytocin and has more side effects, although it adds that misoprostol may be used where no injectable uterotonic is available. 2 A further separate Cochrane review of the safety of postpartum misoprostol compared with other uterotonics and placebos in 2013 concluded that it increases the risk of fever in doses ≥600 μg. 3 Ten applications have been made to add misoprostol to the essential medicines list, six for postpartum haemorrhage (table⇓). The decision to add misoprostol to the list in 2011 was based on evidence from four randomised controlled trials conducted in low resource settings, 4-7 which the WHO expert committee said showed that misoprostol was effective and safe when used by traditional birth attendants trained to use it at home deliveries. However, a subsequent review of the four papers showed that the evidence in support of misoprostol in such situations was weak, identifying deficiencies in exclusion criteria, intervention and controls, temporality, and use of outcomes. 89 Vested interests The WHO website provides information on applications, including supporting letters. Apart from the submitting organisations, the only supporting documents for the four applications in 2003 and 2005 were from the Population Council. However, the four applications in 2009 and 2011 were endorsed by 89 organisations and individuals working in maternal health (fig 1⇓). 10 This change came about primarily through the activities of the three American civil society organisations that made the applications: Gynuity Health Projects (GHP), Venture Strategies for Health Development (VSHD), and its partner organisation Venture Strategies Innovations (VSI). These organisations have received substantial financial backing for their postpartum haemorrhage programmes and have used those funds to promote the use of misoprostol in developing countries, either through research or through registration and roll-out programmes. 11-14 According to information provided on its website, Gynuity’s programme began in 2004; the second phase commenced in 2009 with a five year grant from the Gates Foundation of $25m (£15m; €19m). VSHD was established in 2000, the year that misoprostol came off patent, with the aim of making misoprostol widely available for postpartum haemorrhage; its partner organisation VSI took over these activities in 2008. According to VSI’s biennial reports it received $2.3m in grants and Correspondence to: C Millard colin.millard@qmul.ac.uk For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe BMJ 2014;349:g4823 doi: 10.1136/bmj.g4823 (Published 31 July 2014) Page 1 of 4 Analysis ANALYSIS