A note

1. Magnesium Sulfate for the Management ofEclampsia and Pre-eclampsia: Some Economic and Cost Reflections Andrew FarlowResearch Fellow in Economics, Oriel CollegeUniversity of Oxford Maternal Mortality day-conference, Oxford, June 2007

2. A note • This presentation is a requested response to the EngenderHealth/MacArthur Foundation background document ‘The Utilization of Magnesium Sulfate for the Management of Pre-eclampsia and Eclampsia’, June 2007. • Prepared, as requested, with an eye to research issues from an economics/social science perspective. Hence, a series of economics/social science lenses… and not a rounded approach to the issue of maternal mortality. • Many of the themes have resonance in many other areas: An opportunity to address cross-cutting issues?

3. Key themes identified in MacArthur background paper • Risk • Coordination • Health systems & health service providers • The need for context-sensitive solutions • Cost and supply • Provision and use of cost effectiveness evidence • Diagnostics/information/monitoring • Political processes (especially when they overlook some solutions in preference for other solutions) • Some of these may overlap in interesting ways: • risk/coordination with health system issues • diagnostics with cost effectiveness and risk • risk with cost and supply issues, etc.

4. Maternal Mortality per 100,000 live births in 2000 (2005 source) Source: WHO “The World Health Report 2005 – make every mother and child count” (2005) http://www.who.int/whr/2005/chap1-en.pdf

5. Causes of maternal mortalitya

6. Some background • Approximately 63,000 pregnant women die every year because of eclampsia and severe pre-eclampsia, which are also associated with a higher risk of newborn deaths.* • That is nearly 200 women every day. • Pre-eclampsia/eclampsia ranks second only to hemorrhage as a specific, direct cause of maternal death. • The risk that a woman in a developing country will die of pre-eclampsia or eclampsia is about 300 times that for a woman in a developed country. • Magnesium sulfate is the mainstay of treatment of pre-eclampsia and eclampsia in most developed countries. In other parts of the world diazepam and phenytoin (used for other types of seizures, including epilepsy) are more widely used. • * ‘Balancing the Scales: Expanding Treatment for Pregnant Women With Life-Threatening Hypertensive Conditions in Developing Countries, a Report on Barriers and Solutions to Treat Pre-eclampsia & Eclampsia’ EngenderHealth 2007 http://www.engenderhealth.org/files/pubs/maternal-health/EngenderHealth-Eclampsia-Report.pdf

7. Risk 1 • “There is no proof that evidence, no matter how clearly it is formulated and spoon-fed to clinicians, will change practice. Society would clearly benefit from better understanding of what drives physicians’ behavior and decision making.”(P4)* • “Clinicians’ perceptions of the dangers of magnesium sulphate may have contributed to the drug’s non-use. Respondents acknowledged that the international trials in which Zimbabwe collaborated showed clearly that the drug saves lives. They also noted, however, that the belief of many Zimbabwean clinicians in the drug’s effectiveness is tempered by their perception of its dangers to women.”(p7)** *Referring to Thorp J. O’, Evidence-based medicine – where is your effectiveness? BJOG 2007; 114:1-2) **Sevene E, et al. System and market failures: the unavailability of magnesium sulphate for the treatment of eclampsia and pre-eclampsia in Mozambique and Zimbabwe. BMJ 2005; 331:765-769.)

8. Risk 2 • “Physicians in Zimbabwe who participated in the Magpie Study expressed reservations about safety of use of magnesium sulfate in low-resource settings.” (p14) • “If the utilization of magnesium sulfate were expanded, in isolation from…other aspects of clinical practice, the safety of magnesium sulfate and the overall implications for lowering mortality are not known.” (p13) • These are clearly risk/risk perception issues. • “Some senior nurses feared that the intervention would increase the demand for out-patient and inpatient care.” (p12) • So ‘risk’ can also refer to risk of impact on local health budgets too? • This properly needs a risk (and incentive) lens.

9. Risk 3 • If magnesium sulfate is given to women already with preeclampsia…the clinician is already facing a high-risk situation. • If not being recommended for usage for mild to moderate preeclampsia, this means it is being recommended for sever cases only (p3). • What is the personal cost-benefit of those administering in terms of the risk they bear? What are their perceptions of that risk? • What is the global risk versus individual risk situation? • Is the globally efficient solution bearable by those at the local level? • How are they ‘insured’? Can their risk be better handled? • “Clinicians’ long use of other drugs to manage eclampsia” (p6). Is this part of a risk averse strategy, or the sign of some other failure?

10. Risk 4 • What is distribution of risk ‘across the players’ of a strategy that emphasizes the use of magnesium sulfate particularly for eclampsia, and that places less emphasis on its use for preeclampsia? (p14) • What about distribution of risk ‘across the players’ using a strategy of shorter (targeted?) courses of magnesium sulfate? (p14)* • The appropriate risk-based strategy is: For each possible impact, minimize risks; then find ‘optimal’ solution in ‘impact space’ (this may be context sensitive [see below]) • It may be a very ‘second best’-looking solution. • References to very limited drug budgets (p6), and hence priority given to first-line drugs: • Hints also at perceptions of personal (clinician/hospital manager) risk and trade-off of personal benefit v social benefit (latter could be high, even if clinician/manager benefit not high). *Weeks, AD, et al. Correspondence. The Lancet. Vol 360; October 26, 2002, p1329-1331.

11. Coordination issues • Magnesium sulfate absent in Nigeria. • Present in only 5%, 12%, and 25% of facilities in Burkina Faso, Tanzania, and Rwanda respectively (p4). • “Even after formal approval of the drug, difficulties with distribution and management gave the impression to clinicians that the drug was still unavailable. As a result, they continued to use alternative treatments and did not request magnesium sulphate from the Central Medical Stores or the pharmacy in their own health unit.” (p5) • Referring to case of Mozambique: “Central Medical Stores composed a list of purchases that included both the medicines listed in the formulary and other drugs that clinicians regarded as necessary. Magnesium sulphate had not been requested by clinicians, however, and was therefore not included.” (p5) • A coordination problem/prisoners’ dilemma? • ‘A’ does not do since has to rely on ‘B’, who does not do since has to rely on ‘C’ who does not do because does not think ‘A’ is going to do, etc. Magnesium sulphate not used because magnesium sulphate not used! • Also practical differences since an emergency drug, and distribution across a health system has (maybe?) all or nothing/coordination features?

12. Health system issues 1 • “There are several reasons to be circumspect when estimating degree to which mortality might be decreased by increasing availability of magnesium sulfate…A very significant portion of the maternal deaths from eclampsia reported from many developing countries are among women who had multiple seizures outside the hospital and those without prenatal care* Improvements in facility-based care are not likely to affect these women nor prevent their deaths….It is the standard practice in many countries to discharge women soon after childbirth.” (p13) *Sibai BM. Diagnosis, Prevention, and Management of Eclampsia. Am J Obstet Gynecol 2005;105(2):402-410 and Katz VL, et al. Preeclampsia into eclampsia: toward a new paradigm. Am J Obstet Gynecol 2000; 182:1389-96).

13. Health system issues 2 • “One of the most significant barriers to improving care of women with PE&E is the fact that fewer than 60% of women in some countries have access to services where preeclampsia could likely be diagnosed and fewer than 40% have access to professionals who could administer magnesium sulfate.”(p8)

14. Countries with a critical shortage of health service providers (doctors, nurses and midwives) Source: WHO World Health Report (2006)

15. Distribution of health workers by level of health expenditure and burden of disease Source: WHO World Health Report (2006)

16. Maternal mortality and skilled birth attendants Source: WHO “The World Health Report 2005 – make every mother and child count” (2005) http://www.who.int/whr/2005/chap1-en.pdf

17. Health systems issues 3 • Global shortage of about four million health-care workers. • The richer world sucking in these workers: • UK and Europe – Failures in domestic provision? • US – Lack of long-term human resource planning with an aging population? • Not to deny workers right to relocate to better themselves: Also have to make more attractive to stay in home country. • In addition, some recent studies have shown that efficiency of health workers in some resource-poor settings is heavily impaired by their need/incentive to work outside health sector to supplement income, absenteeism, and own ill-health (figures of efficiency as low as 25% in some settings).

18. Estimated deathsprevented by vaccination(deaths prevented in blue, lives not saved in grey)The point of inserting this in this presentation: The diseases at the top have cheap effective solutions*, in an area we have spent billions on, where all the issues are completely downstream. Yet coverage is highly imperfect, and many lives are still not saved.*In case of TB though, current BCG vaccine is not good enough even if cheap.

19. Health systems issues 4 • Two-thirds of all African children who die under the age of five could be saved by low-cost treatments such as: • Vitamin A supplements • Oral rehydration salts • Existing combination therapy drugs against malaria • Insecticide-treated bed-nets to combat malaria • A tenth of all the diseases suffered by African children are caused by intestinal worms: • These can be treated for 25 US cents per child • Again, the point is that there are many other areas with low-cost solutions where delivery is very imperfect. • There must therefore be common research themes.

20. Context sensitive solutions • Magnesium sulfate might be the ‘drug of choice’ (p2) and the “use of magnesium sulfate is now recommended worldwide…” (p15) But what about the local context? • “…before undertaking any intervention to improve the management of PE&E, a thorough understanding of the local situation is needed.” (p10) • We must avoid “applying a solution that is unnecessarily complex, expensive, fragile, or inconvenient.” (p9) • However, “Aasserud et al. conclude that: “The difficulties in obtaining information, combined with the wide and differing range of barriers between settings, makes it difficult to envisage any single intervention strategy…”(p13) • Trying to get our heads around the argument that there is “a lack of ‘commercial’ incentive.” How true is this? • Where is really at the heart of the problem?

21. Cost and supply issues 1 • One hypothesis for under-use is that magnesium sulfate may be too inexpensive to motivate mass manufacturing, licensing, production and distribution. (p4) • At the same time: “While magnesium sulfate is an inexpensive drug, the cost of this drug is ultimately a small factor in the overall cost of management of PE&E.” (p11) • What are the exact scale effects in manufacturing magnesium sulfate (say, if large bulk purchases were possible)? • Many cross-cutting examples where, to the contrary, lower COGS (Cost of Goods Sold) is requisite for success. What key differences? • Case of Hep B where importance of scale and appropriate technology (and appropriate holders of the technology) and good regulatory systems were key. [Hypothesis (p6), “complex mechanisms of drug approval” act as barrier… There are lessons from Hep B]. • TB vaccine investment case…. Driving down COGS is key to uptake of booster and prime-boost vaccine combinations. • Ditto, new generation malaria combination therapies. • Ditto pneumococcalvaccine (where poor cost pressure and technology decisions are harming potential impact).

22. Cost and supply issues 2 • “The cost of magnesium sulfate and the hospital care involved with providing it were seen as barriers in some countries. This problem of cost is reflected in the discrepancies between private and public facilities in the availability of treatment with magnesium sulfate.” (p8) • What comparative work has been done on public v private facilities, to draw out the key drivers of provision/delivery? • Role of product price mark-ups: Recent studies (GFHR) show that mark-ups on drugs are seen as a source of revenue for cash-strapped health systems. • In comparison, is magnesium sulfate sold in ways making this difficult? If so, what are the implications for revenue and incentives to use? • What pricing power is there? Does it depend on the sector (public or private) accounting for provision of magnesium sulfate or way it is sold, etc.? • Comparisons and contrasts with, say, way malaria drugs are sold? • Nature of it as only an ‘emergency’ drug?

23. Cost effectiveness issues 1 • Targeting to maximize cost effectiveness (p11): • 4 randomized trials comparing the use of magnesium sulfate versus no treatment (placebo) to prevent eclamptic seizures: 71 women with severe preeclampsia needed to be treated to prevent one case of eclampsia. • In a subset of these patients – those women with signs of imminent eclampsia (severe headaches, blurred vision, or upper abdominal pain) – 36 women required treatment to prevent one case of eclampsia.* *Sibai BM. Diagnosis, Prevention, and Management of Eclampsia. Am J Obstet Gynecol 2005;105(2):402-410).

24. Cost effectiveness issues 2 • Referring to Simon et al., “...it was calculated that the additional hospital care costs per woman receiving magnesium sulfate in high, middle, and low GNI countries were $65, $13, and $11, respectively. Many women with preeclampsia need to be treated to prevent one case of eclampsia. • If treatments were reserved for only women with severe preeclampsia, the incremental cost of preventing one case of eclampsia in high, middle, and low GNI countries were $12,942, $1179, and $263, respectively. • While the authors did not calculate the cost of preventing deaths, those costs would be considerably higher given that it is known that only up to about 14% of women who experience eclamptic seizures actually die.” (p11) • So, cost effectiveness evidence seems to need some more analysis? • Although magnesium sulfate is cheap, there are significant other cost hurdles. How/when do these bite?

25. Cost effectiveness issues 3 • “In low-resource settings, to what extent does magnesium sulfate ‘compete’ with other drugs, such as diazepam (which is also on the WHO’s Essential Drugs List)? Diazepam has many other clinical applications, including use as a pre-operative medication and for the treatment for epileptic convulsions. If staff at some hospitals believe that stocking Diazepam is easier to justify, how might this attitude be changed? (p14) • Diazepam and phenytoin have multiple uses, so while magnesium sulfate might dominate on simple cost effectiveness comparison basis, what happens if there is a more complex cost effectiveness /organisational comparison? • Similar issues in, e.g., malaria vaccine cost effectiveness measures, since tackling malaria involves a package of measures: • Wrong only to do cost effectiveness narrowly related to vaccine use; • Ditto for TB interventions.

26. Cost effectiveness issues 4 • “It should be noted, however, that if only eclampsia were treated with magnesium sulfate (and not preeclampsia) the use of magnesium sulfate would be an extraordinarily cost-effective intervention. Only two eclamptic women would need to be treated to save one life because maternal deaths are almost halved with the use of magnesium sulfate.” • “There are potentially additional factors in cost-effectiveness equations that are not factored into the above calculations. The Jamaican experience, cited below, suggests overall cost savings because of a reduction in bed-days.” (p11) • C.f. malaria/TB/HIV calculations where the economic costs to society are orders of magnitude higher when these sort of costs are measured. • Worth getting a better grasp on ALL avenues of cost effectiveness?

27. Cost effectiveness issues 5 • Second-best thinking on cost effectiveness. • Unrealistic to imagine in all cases that we do not have to accept compromise and trade-off (even deaths versus other things). • In the vaccine world, it has recently become an almost rule of law that advocacy needs better cost effectiveness evidence and huge effort has gone into gathering it. • Lessons from other initiatives to develop and deliver health products?

28. Cost effectiveness issues 6 • “What opportunities exist to collaborate or piggy-back with related efforts such as overall maternal mortality reduction initiatives or projects aimed at reducing maternal-to-fetal transmission of HIV?” (p14): • Again recent GFHR work • Plenty of practical examples in other areas. Any transferable lessons? • What is cost effectiveness evidence of this piggy-backing? • What past examples of piggy-backing worked? And why?

29. Monitoring/diagnosis issues 1 • “RCOG recommends monitoring patients receiving magnesium sulfate by regular assessment of the urine output, maternal reflexes, respiratory rate and oxygen saturation.”* (p3) • “Careful monitoring of blood pressure and measurement of urine protein are required. Laboratory studies of blood count, liver function, and kidney function should be obtained…Furthermore, monitoring and treatment should continue postpartum as appropriate.” (p3) • How costly is all this monitoring? How does it impact cost effectiveness and practicability of this intervention? *Re to RCOG, Royal College of Obstetricians and Gynaecologists, The Management of Severe Pre-Eclampsia. Guideline 2006 recommendations.

30. Monitoring/diagnosis issues 2 • Monitoring of condition that is relatively infrequent, and this causes resistance to doing so (p4). • How easy is it to get compliance with monitoring when patient and practitioner are less informed about risk/costs/benefits? • Patient and practitioner perceptions of what is of value to them: • MMV rice story • Patients asked why they did not turn up for malaria-related appointments. They explained they sat around for hours (at cost to them), only to be sent away almost immediately when seen by nurse/doctor. This generated a rumor of wasted time. • Better compliance when attendees were told a story they understood – that is was like searching rice grains for bad ones. All the good grains need nothing. Only the bad need attention. • Lesson: Manage expectations and educate even if it seems obvious to the ‘experts’ what is happening.

31. Monitoring/diagnosis issues 3 • How is cost effectiveness evidence impacted by diagnostics? • Besides, there is “An insufficient number of qualified clinicians to monitor the use of magnesium sulfate or even to prescribe the drug in peripheral hospitals”. • Again, lessons from other product fields. Those working on TB, malaria, and dengue (examples known to the author) realized at some point that cost and speed of product development and cost effectiveness of intervention and uptake were heavily impacted by state of diagnostics: • Gates funded Foundation for Innovative New Diagnostics, FIND, to tackle some of these issues (for TB and malaria and others); • Are there diagnostic issues in the case of pre-eclampsia and eclampsia that affect cost effectiveness, that need addressing and may also have been overlooked? • Mindful that this may not be comparable with the above cases. • Re to RCOG, Royal College of Obstetricians and Gynaecologists, • The Management of Severe Pre-Eclampsia. Guideline 2006 recommendations.

32. Political/international organization processes? • What really drives flows of resources and priority-setting globally? • Pneumococcalvaccine (GAVI/G8), combined $1.8bn to solve about 1%-2% of the total problem between now and 2030? • Evidence from distribution of resources across areas of R&D? • Intellectual Property debates (e.g. recent WHO initiatives like CIPIH): Maybe IP-based debates are easier for advocacy groups to push for, than delivery debates pushed for by delivery groups? • Sustainability of funding flows/initiatives after the first big-hit. Many recent initiatives have, or shortly will come up against, financial sustainability issues. Does the need to sustain funding have impact on advocacy and delivery issues? • Crowding out of lower profile initiatives? • How does advocacy and the politics of provision really work?

33. THANK YOUComments and feedbackalways welcome:andrew.farlow@oriel.ox.ac.uk