Walter and Eliza Hall Institute of Medical Research — Grant for Iron Repletion RCT (January 2025)

Note: This page summarizes the rationale behind a GiveWell grant to the Walter and Eliza Hall Institute of Medical Research. WEHI staff reviewed this page prior to publication.

Published: October 2025

Summary

Background

Anemia is a condition in which a person's circulatory system is unable to transport enough oxygen to tissues throughout the body due to low hemoglobin levels.1 Iron deficiency is estimated to account for a large share of the global burden of anemia.2 According to Global Burden of Disease Study (GBD) 2021 estimates, anemia is the third leading cause of disability globally, representing 6% of all disability.3 It is therefore a major focus of guidelines and burden modeling from the World Health Organization (WHO), the Institute For Health Metrics and Evaluation (IHME), and other organizations. It is also a focus of public health programs in countries of all income levels, which are influenced by these guidelines and models.GiveWell has funded multiple programs aimed at addressing iron deficiency anemia through food fortification and supplementation.4

The cost-effectiveness of these programs depends heavily on IHME’s anemia burden estimates. However, we are uncertain about the accuracy of these estimates, as the prevalence of anemia is defined by statistical hemoglobin thresholds rather than the hemoglobin levels at which impairment occurs, and disability weights representing the burden of each severity of anemia are based on little evidence.5 This means IHME’s disability weights for anemia may not accurately reflect its true health burden. The WHO’s 2024 anemia guidelines highlight this evidence gap and call for new research to establish hemoglobin thresholds based on direct evidence on the relationship between hemoglobin level and impairments.6

What we think this grant will do

This grant will fund a double-blind, randomized, placebo-controlled trial assessing the burden of mild, moderate, and severe anemia in Bangladeshi women of reproductive age.7 The trial will be conducted by Sant-Rayn Pasricha's research team at the Walter and Eliza Hall Institute of Medical Research in collaboration with ICDDR,B in Rupganj Upazila, Bangladesh.

The study will assess the burden of mild, moderate, and severe anemia by measuring health outcomes in Bangladeshi women of reproductive age with iron deficiency who receive iron repletion. The team will screen women for signs of anemia. Women with mild or moderate anemia, or who have iron deficiency but not anemia, will be randomized to receive either intravenous iron (ferric carboxymaltose) or a saline placebo. Women that present with severe anemia will all receive intravenous iron for ethical reasons.8 The use of intravenous iron will allow for rapid correction of iron levels in one dose while avoiding the adherence challenges associated with oral supplementation.9

The researchers will measure multiple outcomes at 4 and 8 weeks after treatment:

• Primary outcome: Fatigue, measured using the FACIT (Functional Assessment of Chronic Illness Therapy) scale.10
• Secondary outcomes: Physical function, health-related quality of life, depression, cognitive performance, productivity, and other health markers.11

We expect this to provide direct empirical evidence on the health impact of anemia at different severity levels by comparing the improvements in women who receive iron treatment versus those who receive a placebo at each anemia severity level. In addition, it will provide evidence on the effects of non-anemic iron deficiency. By measuring how much health outcomes improve after iron repletion at different baseline hemoglobin levels, researchers can identify the causal impact of anemia and the hemoglobin thresholds at which significant functional impairments begin to occur. To our knowledge, this type of trial has not been done before.

By refining how we estimate the health burden of anemia, the trial could increase the accuracy of our future funding decisions for iron-related programs and anemia control more generally. In addition, we believe the findings may improve allocations to anemia control by other actors. We think the results from this study could drive change in two key ways:

1. Updating the hemoglobin thresholds used to more accurately define mild, moderate, and severe anemia.
2. Potentially identify additional health impacts of anemia not currently accounted for in burden estimates.

Why we made this grant

• We expect this study to have a strong chance of affecting our future grant decisions. We estimate the cost-effectiveness of this trial to be 24 times as cost-effective as direct cash transfers ('x cash'),12 and that the trial could influence around $20 million annually in room for more funding (RFMF) above or below our bar. We think this research has a high likelihood (roughly 75%) of leading to meaningful updates to our understanding of the cost-effectiveness of iron supplementation and fortification. This is significant because a RFMF analysis we conducted suggests there is approximately $152 million per year in potential funding opportunities for iron programs that could reach at least 4x cash, the minimum we used for estimating funding opportunities that may be affected by updates to our estimates from this grant, with $100 million currently above our 10x cash cost-effectiveness bar.
• The study may influence WHO anemia guidelines and IHME anemia burden modeling. WHO's 2024 anemia guidelines call for evidence linking hemoglobin levels to functional outcomes, and this trial aligns with that priority.13 Dr. Pasricha has previously collaborated with WHO on anemia guidelines and will form an advisory committee for the trial that includes WHO and IHME representatives, which we think increases the likelihood that the trial's findings will contribute to future guidance.14
• The study may impact how we estimate disability weights. This study represents our first attempt to empirically interrogate disability weights rather than rely solely on IHME data. If this study substantially changes our understanding of estimates of the morbidity burden of anemia, it could prompt us to empirically investigate disability weights in other areas of our grantmaking, such as fistula and clubfoot treatment.
• We think the research team is highly capable and that the trial is unlikely to be funded elsewhere. We believe the trial is well-designed and that Dr. Pasricha's team is highly qualified to conduct it. We also think this trial is unlikely to be funded elsewhere, as it is a large, relatively expensive study with benefits primarily accruing to countries outside Australia, where Dr. Pasricha's institution is based.15

Our main reservations

• We are uncertain about how much this trial's findings will impact GiveWell's funding decisions. Our value of information (VoI) analysis relies on uncertain assumptions, particularly about the amount of iron funding that could be affected by the trial results. While we very roughly estimate there are $152 million per year in potential funding opportunities for iron programs that could exceed a 4x cost-effectiveness bar, the minimum we used for estimating funding opportunities that may be affected by updates to our estimates from this grant, we have not assessed how many of these opportunities are relevant to our grantmaking strategy.
• The trial's external influence on WHO anemia guidelines and IHME burden estimates is uncertain. We think the trial has the potential to influence WHO anemia guidelines and IHME burden modeling. However, WHO representatives have indicated that this trial alone would not be sufficient to trigger an update to anemia thresholds.16 Similarly, IHME has told us that it would not update its anemia burden estimates based on this trial alone, though we think an update to WHO guidelines would likely lead to an IHME model update.17
• The findings may have limited external validity beyond the study population. This trial will be conducted in women of reproductive age in rural Bangladesh. While we think the findings will be broadly applicable to other low- and middle-income countries, there may be limitations to how well the results will generalize to other demographics and geographies. Experts we spoke with had differing views about the degree to which the study's findings could be extrapolated.18
• It will take approximately four years to get results from this study, during which GiveWell's priorities may shift away from anemia reduction programs. It is possible that our research priorities or GiveWell's broader focus areas may change before the trial results become available.

The organization

The Walter and Eliza Hall Institute of Medical Research is Australia's oldest medical research institute, founded in 1915. It focuses on medical research with the aim of improving health outcomes globally.19 The trial will be led by Dr. Sant-Rayn Pasricha, whose team at the Institute has substantial experience conducting similar research at the Bangladesh trial site.20 Dr. Pasricha was involved in developing WHO's anemia guidelines and has been acknowledged in WHO's 2024 anemia guidelines for his technical support and partnership during their development.21

ICDDR,B (International Centre for Diarrhoeal Disease Research, Bangladesh) is an international health research institution located in Bangladesh.22 It has extensive experience conducting clinical trials in Bangladesh.23 Dr. Pasricha will work with collaborators at ICDDR,B to carry out the trial.

The grant

This $3,828,632 grant will fund a randomized controlled trial (RCT) that aims to provide an empirical basis for estimating the burden of mild, moderate, and severe anemia. The trial will measure the functional impacts of anemia at different severity levels and generate evidence to update hemoglobin thresholds for defining anemia.

Trial design

The trial is a double-blind, randomized, placebo-controlled study that will assess the morbidity burden of mild, moderate, and severe anemia in Bangladeshi women of reproductive age with iron-deficiency anemia.24

Key elements of the trial design include:

• Participants: Women of reproductive age in Rupganj Upazila, rural Bangladesh, will be screened for iron-deficiency anemia of different severity levels (mild, moderate, severe) or for non-anemic iron deficiency. The target sample size is 524 women for mild anemia, 524 for moderate anemia, 524 for non-anemic iron deficiency.25 During screening, they also expect to identify approximately 57 women with severe anemia who will all receive iron treatment.26
• Intervention: Participants with mild or moderate anemia will be randomized to receive either IV iron (ferric carboxymaltose) or saline placebo. Women with severe anemia will all receive IV iron for ethical reasons.27 IV iron rapidly corrects iron status in one dose, has been used extensively, and is effective and safe.28 It also avoids the adherence challenges associated with oral supplementation because it is given as a single dose.
• Primary outcome: Fatigue, as measured by the FACIT scale (questionnaire) at 4 and 8 weeks after iron repletion.29
• Secondary outcomes: Additional measures reflecting health-related quality of life, physical function, depression, cognitive performance, productivity, physical activity, strength and aerobic capacity, and blood markers.30

How results will be used

The primary aim of the trial is to causally estimate the morbidity burden of mild, moderate, and severe anemia.31 We expect these findings can be used to:

1. Define new, evidence-based thresholds for defining anemia severity through an expert consultation process. An international panel of experts will determine what magnitude of improvements in fatigue, physical function, and other outcomes most closely match the Global Burden of Disease (GBD) health state descriptions for mild, moderate, and severe anemia. The baseline hemoglobin levels at which participants experience these functionally significant improvements after iron treatment (compared to placebo) could then inform new, evidence-based thresholds for defining anemia severity.
2. Identify additional health states associated with anemia that are not currently included in standard burden models.32 The trial will measure a variety of secondary outcomes that could indicate additional health impacts of anemia that aren't currently captured in GBD health state descriptions. It’s possible that IHME could incorporate these additional impacts to existing anemia burden estimates.33

We plan to incorporate the findings of this trial into our estimates of the morbidity burden of anemia (as measured in Years Lived with Disability, or YLDs), which are a key driver of the cost-effectiveness of iron fortification and supplementation interventions.34 We expect trial results to be available in approximately four years.

Budget for grant activities

The total cost of the trial is $3,828,632 USD.35

The budget covers approximately 4 years of trial design, implementation, and analysis work for conducting the study in Bangladesh, and includes a subgrant to ICDDR,B, the local implementing partner. The budget breakdown is:

• Personnel costs: $1,350,366
• Travel: $82,900
• Subgrant to ICDDR,B: $2,047,30836
• Indirect costs (20%): $348,058

The case for the grant

We expect this study to have a strong chance of affecting our future grant decisions

We estimate that this grant is approximately 24 times as cost-effective as unconditional cash transfers, which are GiveWell's benchmark for comparing programs. We think the trial will influence around $20 million annually in RFMF above or below our bar, with the majority of the expected value coming from creating funding opportunities in geographies that are currently below our cost-effectiveness threshold.

We also think this research has a strong likelihood (roughly 75%) of leading to meaningful updates to our iron supplementation and fortification CEAs, regardless of its broader impact on other actors. This is significant because a RFMF analysis we conducted as part of this analysis suggests there is approximately $152 million per year in potential funding opportunities for iron programs that we currently estimate could exceed a 4x cost-effectiveness bar, the minimum we used for estimating funding that may be affected by updates to our estimates from this grant.

We are highly uncertain about our estimate that the trial will influence $20 million, as we have not done work to estimate feasibility across contexts.37 However, our value of information (VoI) analysis suggests the trial would still meet our 10x cost-effectiveness bar even if we only influence around $8.5 million annually in RFMF above or below our bar.38

The study may influence WHO anemia guidelines and IHME anemia burden modeling

We think this trial could influence key external actors by influencing WHO anemia guidelines and IHME modeling of anemia burden. We include a +50% adjustment for the expected benefit that the trial influences external actors in our VoI analysis, though the extent and timeline of this impact are very uncertain.

WHO’s 2024 anemia guidelines call for evidence linking hemoglobin levels to functional outcomes and prefer thresholds based on such evidence rather than statistical methods currently in use, and this trial aligns with that priority.39 Dr. Pasricha’s team was commissioned to provide a main body of statistical evidence to inform discussions that led to the current WHO anemia thresholds.40 He will co-lead this new study, which is well-positioned to provide valuable new evidence for informing future thresholds.41 He plans to form an advisory committee for the trial that includes WHO representatives. We think this increases the likelihood that the trial’s findings will contribute to future guidance. However, WHO representatives have indicated that this trial alone will not be sufficient to trigger an update, as additional evidence from diverse demographics and locations would likely be required.42

If the trial impacts WHO guidelines, IHME is also likely to update its anemia burden estimates, as these are currently based on WHO anemia thresholds.43 IHME has told us that while a single study would not cause IHME to update its models, an update to WHO guidelines would likely trigger a change.44 IHME also told us that if the trial identifies new health impacts caused by anemia not currently captured in IHME’s estimates, these findings could also prompt updates to anemia burden estimates.45

We think the trial could also help improve the efficiency of global anemia control efforts, which receive substantial funding each year.46 By influencing WHO guidance and IHME modeling, we think the trial may lead to better targeting of resources, making existing programs more cost-effective.

The study may impact how we estimate disability weights

To compare morbidity due to different conditions, GiveWell typically uses “disability weights,” quantitative estimates of the magnitude of health loss associated with specific health outcomes, provided by IHME.47 Disability weights are used to calculate Years Lived with Disability (YLDs) for anemia, which we use in our CEA to estimate the amount of anemia morbidity a program may avert.

This study represents our first attempt to empirically interrogate disability weights rather than rely on IHME data. If this study substantially changes our understanding of estimates of the morbidity burden of anemia, it could cause us to try to empirically interrogate disability weights in other areas of grantmaking, such as fistula and clubfoot treatment.48

We think the research team is highly capable

We believe this trial is well-designed and that Dr. Pasricha’s team is highly capable of conducting it. The trial is appropriately powered, will be pre-registered, and has a single primary outcome to ensure methodological rigor. Dr. Pasricha’s team has substantial experience conducting similar research at the Bangladesh trial site, and the research team includes members with expertise in all aspects of study design.49

We think the trial is unlikely to be funded elsewhere

We also think this trial is unlikely to be funded elsewhere. It is a large, relatively expensive study with benefits primarily accruing to countries outside Australia, where Pasricha’s institution is based. The most likely alternative funder, the Australian National Health and Medical Research Council (NHMRC), appears unlikely to fund it.50

Risks and reservations

We are uncertain about how much this trial's findings will impact GiveWell's funding decisions

The Value of Information (VoI) analysis that suggests this grant is cost-effective (24x) relies on several speculative assumptions, including:

• Our RFMF analysis is highly speculative. We do not know how many of the locations we identified as relevant would actually be feasible for a GiveWell investment, and there are reasons to believe many of them would not be feasible.51
• Our VoI analysis is sensitive to changes in the cost-effectiveness of the countries included in the RFMF analysis.52 Since we have high uncertainty about the cost-effectiveness of the countries included in our RFMF analysis, this contributes to our uncertainty about the bottom line cost-effectiveness of this grant.
• We're also uncertain about the probability that the trial will yield positive and negative updates of specific magnitudes. We assume the trial has a high probability (75%) of meaningfully impacting our cost-effectiveness estimates for iron supplementation and fortification due to the fact that current anemia burden estimates are based on very little evidence, but these probabilities remain uncertain.
• The RFMF model relies on IHME estimates of anemia based on statistical hemoglobin thresholds rather than functional outcomes, which we are highly uncertain about.

The trial's external influence on WHO anemia guidelines and IHME burden estimates is uncertain

We include a +50% adjustment for the expected benefit that the trial influences external actors in our VoI analysis. This adjustment is highly subjective, and the actual impact of the trial on global anemia guidance remains difficult to predict.

While we think the trial has the potential to influence WHO anemia guidelines and IHME burden modeling, WHO representatives have indicated this trial alone would not be sufficient to trigger an update to anemia thresholds.53 Instead, they would require additional observational evidence from birth outcomes and studies across diverse demographics and locations.

Similarly, IHME has told us that it would not update its anemia burden estimates based on this trial alone. However, IHME’s models are based on WHO thresholds, so we think an update to WHO guidelines would likely lead to an IHME model update.54 The trial could also prompt IHME to incorporate additional health states caused by anemia if new morbidity impacts are identified, though the probability of this outcome is unclear.55

The findings may have limited external validity beyond the study population

This trial will be conducted in women of reproductive age in rural Bangladesh, a population that carries a disproportionately high burden of anemia. While we think the findings will be broadly applicable to other low- and middle-income countries (LMICs), there could be limitations to how well the results will generalize to other demographics and geographies.

Experts we spoke with disagreed about the degree to which the study’s findings could be extrapolated:

• Dr. Pasricha believes that iron deficiency symptoms appear similar in women and men, and he thinks they could be similar across countries, though cultural differences could impact how subjective measures are reported.56
• WHO representatives expressed more concern about potential external validity limitations that could be caused by differences in physical labor between men and women, and biological differences like pregnancy and menstruation.57

We considered conducting a multi-site trial to improve generalizability; this would have significantly increased costs.58 Given the cost trade-offs, we think it is reasonable to extrapolate from this study until more direct evidence emerges in other populations.

The results will take approximately four years, during which GiveWell's priorities may shift

It will take roughly four years to receive results from this trial. We are uncertain how the priorities of GiveWell and the nutrition team may change over this time. This raises the possibility that the results will not be as useful to us by the time they become available.

While we believe there is substantial room for more funding (RFMF) at a range of cost-effectiveness levels, we cannot predict how our assessment of iron interventions may evolve over the next four years, or if we may decide to shift our attention to other intervention areas instead. Despite this uncertainty, we think the trial results will be highly relevant to global anemia burden estimates and that our current cost-effectiveness thresholds suggest this investment is worthwhile.

Plans for follow up

• We plan to maintain regular contact with the trial team, and a GiveWell staff member will sit on the study advisory committee.
• Results are expected to be disseminated after about four years.
• Once GiveWell has these evidence-based thresholds, we will use individual-level distributions of hemoglobin levels in LMICs to determine how the new thresholds impact the prevalence of mild, moderate, and severe anemia.
• We will determine how these changes in prevalence impact the overall burden of anemia in women of reproductive age in a representative country (likely Bangladesh), and calculate an anemia burden adjustment factor that can easily be applied to other locations and demographics.
• If the trial identifies additional health outcomes caused by anemia that are not represented in the GBD health state descriptions for anemia, we will find GBD health states that correspond most closely to them and add the burden of those health states to our anemia-related CEAs.

Internal forecasts

For this grant, we are recording the following forecasts:

Confidence	Prediction	By time
60%	This research leads to decision-relevant updates to our iron supplementation and fortification CEAs (75% probability of updates * 80% probability of having results by end of Q3 2030)	End of Q2 2030
40%	We will have main results at the time predicted by the investigators	End of Q3 2029
80%	We will have main results by 2030	End of Q3 2030

Our process

• Dr. Pasricha developed and submitted a proposal to GiveWell to conduct this research.
• We conducted desk research and developed a room for more funding (RFMF) analysis and value of information (VoI) analysis and to quantify the potential cost-effectiveness of the grant.
• We spoke with four experts:
  • Sant-Rayn Pasricha
  • Nick Kassebaum, team lead for neonatal and child health modeling at IHME
  • Maria Nieves Garcia-Casal, a nutrition scientist at the WHO who led the development of WHO's 2024 anemia guidelines
  • Lisa Rogers, a nutrition scientist at the WHO who was involved with the development of WHO's 2024 anemia guidelines

Sources

Document	Source
Afolabi et al. 2024	Source
Field et al. 2021	Source
Gardner et al. 2023	Source
GiveWell, Evidence Action — Iron and Folic Acid (IFA) Supplementation in India (August 2022)	Source
GiveWell, Fortify Health – Support for Expansion (December 2021)	Source
GiveWell, VoI BOTEC for Walter and Eliza Hall Iron Repletion RCT, July 2025	Source
GloPID-R, National Health & Medical Research Council (NHMRC)	Source (archive)
Institute for Health Metrics and Evaluation, Global Burden of Disease Study 2021 Disability Weights, Data Release Information Sheet	Source
International Centre for Diarrhoeal Disease Research, Bangladesh, "About Us"	Source (archive)
International Centre for Diarrhoeal Disease Research, Bangladesh, Clinical Research	Source (archive)
National Health and Medical Research Council, International collaborative health research funding	Source (archive)
Pasricha, Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women	Source
Peña-Rosas et al. 2015	Source
Saini et al. 2022	Source
Salomon et al. 2012	Source
Science Direct, "The Delphi Method"	Source (archive)
Walter and Eliza Hall Institute, "About WEHI"	Source (archive)
WHO, Anemia fact sheet, 2023	Source (archive)
WHO, Guideline on haemoglobin cutoffs to define anaemia in individuals and populations, 2024	Source (archive)

• 1

  "Anaemia is a condition in which the number of red blood cells or the haemoglobin concentration within them is lower than normal. It mainly affects women and children.
  "Anaemia occurs when there isn’t enough haemoglobin in the body to carry oxygen to the organs and tissues." WHO anemia fact sheet 2023.

  "Anaemia is a condition in which the number of red blood cells (and consequently their oxygen-carrying capacity) is insufficient to meet the body's physiological needs." Field et al. 2021, Pg 9.

• 2

  “Chronic iron deficiency frequently turns into iron-deficiency anaemia. While iron deficiency is the most common cause of anaemia, other causes such as acute and chronic infections that cause inflammation; deficiencies of folate and of vitamins B 2 , B 12 , A, and C; and genetically inherited traits such as thalassaemia and drepanocytosis (sickle-cell anaemia) may be independent or superimposed causal factors (WHO 2001; WHO 2015a)." Peña-Rosas et al. 2015, Pg 7.

• 3

  “Anaemia affected more than 1.9 billion people and caused 52.0 million YLDs in 2021. This massive burden represented 5.7% of all YLDs in 2021, with only two level 3 GBD causes (low back pain and depressive disorders) responsible for more disability.”
  Gardner et al. 2023, p. 9.

• 4

  See:

  • Fortify Health: Since 2018, we’ve supported Fortify Health’s initiative to add iron to wheat flour in India.
  • Evidence Action’s Iron and Folic Acid Supplementation: In 2022, we made a grant to Evidence Action to provide technical assistance for iron and folic acid supplementation programs in India.

• 5

  “Establishing haemoglobin cutoffs for defining anaemia based on outcomes related to clinical symptoms or functional impairment was preferred but not possible for all age groups and trimesters of pregnancy. The evidence of an association between haemoglobin concentration and maternal and newborn health outcomes has been repeatedly reported, but the most relevant outcomes and precise cutoffs are still in development (22, 25–28); therefore, the statistical approach was used. The outputs of the statistical approach were haemoglobin values below which only a limited number of healthy individuals would be expected to have anaemia. This approach informed the evaluation and update of current cutoffs.”
  Guideline on haemoglobin cutoffs to define anaemia in individuals and populations, WHO 2024, p. 9.

• 6

  “To enable the definition of functional thresholds, research is needed on the haemoglobin concentrations below which clinical symptoms, increased risk of mortality, increased risk of morbidity, developmental impairment (cognitive, psychomotor, language, physical), and/or other conditions requiring further clinical investigation (e.g. genetic condition, nutritional deficiency, chronic bleeding) are observed to occur”
  Guideline on haemoglobin cutoffs to define anaemia in individuals and populations, WHO 2024, p. 11.

• 7

  "Trial design: Double-blind placebo-controlled individually randomised parallel-group superiority trial of iron treatment in Bangladeshi adult women (18-45 years) with iron deficiency anaemia, stratified by anaemia severity (mild/ moderate), coupled with a cohort of iron treated women with iron deficiency severe anaemia in a quasi-experimental pre-post treatment design." Pasricha, Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women.

• 8

  “Mild and moderate anaemic participants will be randomised to the intervention or control. Severe anaemic participants will not be randomised but will be treated with the intervention as treatment with placebo is not ethically acceptable”
  Pasricha, Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women, p. 4.

• 9

  “Newer intravenous iron preparations administered as a single rapid infusion are increasingly used.7 Intravenous ferric carboxymaltose is one such preparation; it is administered as a 20 mg/kg infusion to a maximum of 1000 mg over 15 min and has no identified safety issues except transient hypophosphataemia.”
  Afolabi et al. 2024, p. E1650.
  “Although the effect on overall anaemia did not differ, intravenous iron reduced the prevalence of iron deficiency to a greater extent than oral iron and was considered to be safe. We recommend that intravenous iron be considered for anaemic pregnant women in Nigeria and similar settings.”
  Afolabi et al. 2024, abstract.

• 10

  “The sample size is based on the FACIT-Fatigue Scale, which has an established
  minimal clinically important difference in trials of iron therapy of 3 and a standard deviation of ~10.36
  The sample size for each of the mild and moderate stratum will be 524 women (262 per treatment
  group, 1048 across both strata) including 10% loss to follow up (90% power, 5% two-sided alpha)
  which will enable detection of a 3-point treatment difference in change from baseline to 8 weeks in
  the FACIT total score assuming a standard deviation of 10, thus the trial will be sensitive to a
  standardised effect size of 0.3 (small effect). The sample size for the severe stratum is determined
  by recruitment achievable while the trial is open for the mild and moderate strata.”
  Pasricha, Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women, p. 6.

• 11

  See list and table of secondary and safety outcomes here: Pasricha, Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women, p. 5-6.

• 12

  This estimate of the value of direct cash transfers is out of date as of 2024. We are continuing to use this outdated estimate for now to preserve our ability to compare across programs, while we reevaluate the benchmark we want to use to measure and communicate cost-effectiveness.

• 13

  See more on hemoglobin and anaemia from WHO here: Guideline on haemoglobin cutoffs to define anaemia in individuals and populations, WHO 2024, p. 9-11. For example, they state "To enable the definition of functional thresholds, research is needed on the haemoglobin concentrations below which clinical symptoms, increased risk of mortality, increased risk of morbidity, developmental impairment (cognitive, psychomotor, language, physical), and/or other conditions requiring further clinical investigation (e.g. genetic condition, nutritional deficiency, chronic bleeding) are observed to occur."

• 14

  “WHO especially acknowledges Professor Sant-Rayn Pasricha from the Walter and Eliza Hall Institute of Medical Research, Australia, and Dr Maria Elena Jefferds and Dr Andrea Sharma from the United States Centers for Disease Control and Prevention (CDC), United States of America, for their technical support and partnership during the development of this guideline.”
  Guideline on haemoglobin cutoffs to define anaemia in individuals and populations, WHO 2024, p. vii.

• 15

  “This project has been designed to align with GiveWell research priorities. If we do not receive Givewell funding, we may seek competitive grant funding from the Australian National Health and Medical Research Council (NHMRC) (success rate 8-9%). NHMRC typically does not fund global health research, and even if we were to successfully obtain funding, this project would not commence until 2027, delaying the development of knowledge that would advance progress towards the 2030 global anaemia targets and improve health for women.”
  Pasricha, Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women, p. 8.

• 16

  Conversation with Maria Nieves Garcia-Casal and Lisa Rogers, the World Health Organization, December 9, 2024 (unpublished).

• 17

  Conversation with Nick Kassebaum, IHME, December 6, 2024 (unpublished).

• 18
  • “Based on clinical experience, men and women with anaemia/ iron deficiency anaemia experience similar symptoms i.e. fatigue, lethargy, shortness of breath, headache and restless leg syndrome (an iron deficiency related sleep disorder), with the symptoms driven by severity of anaemia. We are confident these data can be generalised across adult populations.

    In terms of different locations: we are focussing on iron deficiency anaemia which is the major cause of anaemia globally, and we would not expect that there would be differences in symptoms across populations. Some cultural differences may influence reporting of symptoms, we aim to overcome this through the use of a blinded parallel randomised trial and a pre-post design, and the use of objective outcomes such as exercise performance.” Response to GiveWell queries from Sant-Rayn Pasricha, p. 6 (unpublished).

  • We also spoke with Maria Nieves Garcia-Casal and Lisa Rogers, the World Health Organization, December 9, 2024 (unpublished).

• 19

  Walter and Eliza Hall Institute, "About WEHI"

• 20Pasricha’s team has substantial experience conducting similar research at this site in Bangladesh. The team includes members who are experienced in all aspects of the study’s design. More detail is available in the proposal, p. 1.
• 21“WHO especially acknowledges Professor Sant-Rayn Pasricha from the Walter and Eliza Hall Institute of Medical Research, Australia, and Dr Maria Elena Jefferds and Dr Andrea Sharma from the United States Centers for Disease Control and Prevention (CDC), United States of America, for their technical support and partnership during the development of this guideline.”
  Guideline on haemoglobin cutoffs to define anaemia in individuals and populations, WHO 2024, p. vii.

• 22

  International Centre for Diarrhoeal Disease Research, Bangladesh, "About Us"

• 23

  International Centre for Diarrhoeal Disease Research, Bangladesh, Clinical Research

• 24

  Pasricha, Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women

• 25
  • See Pasricha, Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women
  • We think it’s plausible that iron repletion could benefit women who are iron deficient but do not meet the current hemoglobin threshold for anemia. Expanding the trial to include this group could provide evidence on whether the hemoglobin cutoff for diagnosing anemia should be adjusted and whether the burden of non-anemic iron deficiency should be incorporated into our models.

• 26

  "Based on our assumptions, we anticipate identifying ~57 cases of severe anaemia with iron deficiency.” Response to GiveWell queries from Sant-Rayn Pasricha, p. 5 (unpublished).

• 27

  “Mild and moderate anaemic participants will be randomised to the intervention or control. Severe anaemic participants will not be randomised but will be treated with the intervention as treatment with placebo is not ethically acceptable”
  Pasricha, Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women, p. 4.

• 28

  “Newer intravenous iron preparations administered as a single rapid infusion are increasingly used.7 Intravenous ferric carboxymaltose is one such preparation; it is administered as a 20 mg/kg infusion to a maximum of 1000 mg over 15 min and has no identified safety issues except transient hypophosphataemia.”
  Afolabi et al. 2024, p. E1650.
  “Although the effect on overall anaemia did not differ, intravenous iron reduced the prevalence of iron deficiency to a greater extent than oral iron and was considered to be safe. We recommend that intravenous iron be considered for anaemic pregnant women in Nigeria and similar settings.”
  Afolabi et al. 2024, abstract.

• 29

  “The sample size is based on the FACIT-Fatigue Scale, which has an established
  minimal clinically important difference in trials of iron therapy of 3 and a standard deviation of ~10.36
  The sample size for each of the mild and moderate stratum will be 524 women (262 per treatment
  group, 1048 across both strata) including 10% loss to follow up (90% power, 5% two-sided alpha)
  which will enable detection of a 3-point treatment difference in change from baseline to 8 weeks in
  the FACIT total score assuming a standard deviation of 10, thus the trial will be sensitive to a
  standardised effect size of 0.3 (small effect). The sample size for the severe stratum is determined
  by recruitment achievable while the trial is open for the mild and moderate strata.”
  Pasricha, Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women, p. 6.

• 30

  Pasricha, Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women, p. 5-6.

• 31

  The trial will report results that are relevant to GBD health state descriptions for mild, moderate, and severe anemia. For example, the trial’s primary outcome of self-reported fatigue (FACIT scale) is relevant to the GBD health state descriptions for mild, moderate, and severe anemia (e.g., mild: “feels slightly tired and weak at times, but this does not interfere with normal daily activities”) Salomon et al. 2012, supplementary materials p. 17.

• 32

  "Beyond the symptoms implied by the health state descriptors included in the anaemia categorisation above (i.e. mostly fatigue, shortness of breath, concentration), anaemia may affect other domains of dysfunction not currently captured in these descriptors – for example, depression, anxiety, headache and other problems. It may be possible to create “combined disability weights” where these missing domains are incorporated. For example, if we create a new definition of ‘severe anaemia’ based on the original descriptors, but also find that women with severe anaemia also suffer from daily headache and depression, there are approaches to create a combined disability weight for severe anaemia that would incorporate proportions of these additional descriptors and their corresponding disability weights." Response to GiveWell queries from Sant-Rayn Pasricha, p. 5 (unpublished).

• 33

  Conversation with Nick Kassebaum, December 6, 2024 (unpublished).

• 34
  • 38% in our generic CEA of iron fortification, and 44% in our generic CEA of iron supplementation. These analyses are not yet published.

• 35

  Pasricha, Project Budget (unpublished)

• 36

  The subgrant to ICDDR,B covers local recruitment, data collection, participant follow-ups, and study implementation at the trial site in Rupganj Upazila, Bangladesh.

• 37

  We have not investigated the feasibility of opportunities in most of the locations included in the analysis, and there are reasons to believe many locations would not be feasible. For example, many of the countries in the RFMF analysis are in Africa, and we are not yet certain we would want to fund iron interventions in Africa. We have uncertainties about their impact in locations with high malaria pressure, and higher levels of inflammation may make iron interventions less effective. In addition, some locations may not have good implementing partners, or may present operational challenges. These are just a few examples of reasons why some locations identified in the RFMF analysis may not be attractive for GiveWell funding.

• 38

  The VoI analysis returns a cost-effectiveness of 23.6x. 23.6 / 10 = 2.36. 1 / 2.36 = 0.42. 0.42 * $20M = $8.5M.

• 39

  Guideline on haemoglobin cutoffs to define anaemia in individuals and populations, WHO 2024, p. 9-11

• 40

  “WHO especially acknowledges Professor Sant-Rayn Pasricha from the Walter and Eliza Hall Institute of Medical Research, Australia, and Dr Maria Elena Jefferds and Dr Andrea Sharma from the United States Centers for Disease Control and Prevention (CDC), United States of America, for their technical support and partnership during the development of this guideline.”
  Guideline on haemoglobin cutoffs to define anaemia in individuals and populations, WHO 2024, p. vii.

• 41

  “WHO especially acknowledges Professor Sant-Rayn Pasricha from the Walter and Eliza Hall Institute of Medical Research, Australia, and Dr Maria Elena Jefferds and Dr Andrea Sharma from the United States Centers for Disease Control and Prevention (CDC), United States of America, for their technical support and partnership during the development of this guideline.”
  Guideline on haemoglobin cutoffs to define anaemia in individuals and populations, WHO 2024, p. vii.

• 42

  Conversation with Maria Nieves Garcia-Casal and Lisa Rogers, December 9, 2024 (unpublished)

• 43

  “The Global Burden of Disease study directly applies the anaemia severity thresholds
  recommended by WHO.” Response to GiveWell queries from Sant-Rayn Pasricha, p. 1 (unpublished).

• 44

  Conversation with Nick Kassebaum, December 6, 2024 (unpublished)

• 45

  Conversation with Nick Kassebaum, December 6, 2024 (unpublished)

• 46

  We were not able to find estimates of global spending on anemia, but we identified one relevant estimate implying that global spending is likely in the hundreds of millions annually. We were unable to find a budget for India’s anemia control program, Anemia Mukt Bharat, but we did find the AMB funding for 12 of India’s 28 states. It is 7.4 billion Indian rupees, which is roughly $88M USD. This implies that total AMB spending may be ~$200M (28 / 12 * 88 = 205).
  “It was observed that the AMB budget increased over 3 years despite the COVID situation. It increased from INR 6184 million in FY 2019–2020 to INR 6293 million, a 2% increase in FY 2020–2021, and to INR 7433 million, an 18% increase in FY 2021–2022.”
  Saini et al. 2022, abstract.

• 47

  "Disability weights, which represent the magnitude of health loss associated with specific health outcomes, are used to calculate years lived with disability (YLD) for these outcomes in a given population. The weights are measured on a scale from 0 to 1, where 0 equals a state of full health and 1 equals death. This table provides disability weights for the 440 health states (including combined health states) used to estimate nonfatal health outcomes for the GBD 2021 study." Institute for Health Metrics and Evaluation, Global Burden of Disease Study 2021 Disability Weights, Data Release Information Sheet, p. 1.

• 48

  For example, we also rely on IHME disability weights in our cost effectiveness analyses for clubfoot and fistula. See here and here for more details.

• 49

  Pasricha, Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women, p. 1

• 50

  The proposal states that NHMRC “typically does not fund global health research”. However, this appears to contradict materials I found online, so I followed up with Pasricha about it. He explained that NHMRC has little funding available for global health research, and what gets funded is typically not basic science research like this (see quote from email at the bottom of this footnote).
  “This project has been designed to align with GiveWell research priorities. If we do not receive Givewell funding, we may seek competitive grant funding from the Australian National Health and Medical Research Council (NHMRC) (success rate 8-9%). NHMRC typically does not fund global health research, and even if we were to successfully obtain funding, this project would not commence until 2027, delaying the development of knowledge that would advance progress towards the 2030 global anaemia targets and improve health for women.”
  Randomised controlled stratified trial of iron therapy by anaemia severity: effects on functional outcomes in adult women, p. 8.
  “NHMRC:

  • supports international participation in its funded projects across the full breadth of health and medical research
  • supports Australian researchers to undertake research at institutions in other countries (including Europe through an Implementing Arrangement with the European Research Council)
  • engages in international research partnerships through bilateral and multilateral arrangements, such as the Global Alliance for Chronic Diseases and the e-ASIA Joint Research Program
  • participates in international networks such as GloPID-R.”

  National Health & Medical Research Council (NHMRC), GLOPID-R website.
  “NHMRC is part of the Global Alliance for Chronic Diseases (GACD), a collaboration of major international research funding agencies that support joint funding calls and research capacity building activities to address chronic, non-communicable diseases. NHMRC's CEO is a member of the Strategy Board and served as Chair in 2019 and 2020.
  The GACD funds, develops and facilitates innovative research collaborations between low-, middle- and high-income countries in the fight against chronic diseases. The alliance focuses on implementation research in low- and middle-income countries (LMICs) and in vulnerable and Indigenous populations in high-income countries (HICs).”
  International collaborative health research funding, NHMRC website.
  “NHMRC accepts open calls for clinical trials and cohort studies once a year. The overall budget allocated is small (A$70m across the whole scheme) and there are typically hundreds of applications and about 15 successful (success rate in 2023 ~10%). Of the grants funded, only ~1 per year has been in global health, with the rest set in Australia. We have been successful for this scheme in the past (e.g. our BRISC paper, NEJM) but it generally takes 2-3 years of trying to get a grant up given the very low success rate. The types of studies funded are generally quite different – think of them more as clean Phase III registration studies where a drug or policy is being brought into practice rather than an experimental medicine question trying to discern physiology, as we are doing. So yes, whilst we could submit this to NHMRC, it is not likely (based on probability alone!) that this would be funded.”
  Email from Sant-Rayn Pasricha to Stephan Guyenet, December 9, 2024 (unpublished)

• 51

  For example, many of the countries in the RFMF analysis are in Africa, and we are not yet certain we would want to fund iron interventions in Africa. We have uncertainties about their impact in locations with high malaria pressure, and higher levels of inflammation may make iron interventions less effective. In addition, some locations may not have good implementing partners, or may present operational challenges.

• 52

  For example, arbitrarily moving $63 million of RFMF from the 10-11x bucket to the 12-13x bucket lowers the cost-effectiveness of the VoI analysis from 24x to 17x.

• 53

  Conversation with Maria Nieves Garcia-Casal and Lisa Rogers, December 9, 2024 (unpublished)

• 54

  Conversation with Nick Kassebaum, December 6, 2024 (unpublished)

• 55

  Conversation with Nick Kassebaum, December 6, 2024 (unpublished)

• 56

  “Based on clinical experience, men and women with anaemia/ iron deficiency anaemia experience similar symptoms i.e. fatigue, lethargy, shortness of breath, headache and restless leg syndrome (an iron deficiency related sleep disorder), with the symptoms driven by severity of anaemia. We are confident these data can be generalised across adult populations.

  In terms of different locations: we are focussing on iron deficiency anaemia which is the major cause of anaemia globally, and we would not expect that there would be differences in symptoms across populations. Some cultural differences may influence reporting of symptoms, we aim to overcome this through the use of a blinded parallel randomised trial and a pre-post design, and the use of objective outcomes such as exercise performance.” Response to GiveWell queries from Sant-Rayn Pasricha, p. 6 (unpublished).

• 57

  Conversation with Maria Nieves Garcia-Casal and Lisa Rogers, December 9, 2024 (unpublished)

• 58

  For example, adding a site in Malawi would roughly double the trial cost to ~$7 million: “We could do this. The sites we have a lot of experience working with are Bangladesh (‘representing’ a site in South Asia), Malawi (sub Saharan Africa) and Viet Nam (South East Asia) which would be a perfect trio for this trial. At the very least, two sites, one in Bangladesh and Malawi would be extremely doable… However, I do think this would have a major impact on cost as it would require separate teams to be stood up in each site, and for the most difficult things (ethics, drug regulation, trial insurance) to be approved in each site. We would need each country to be the local sponsor… In terms of impact on cost – the impact in Australia would be perhaps one extra person so not devastating – but in country, it would be high because of replication of teams, even if each team is smaller and employed for a little less long."
  Email from Sant-Rayn Pasricha to Stephan Guyenet, January 1, 2025 (unpublished)