As the World Health Organization prepares to release a review of its guidelines for ready-to-use therapeutic foods, disputes over existing research, data, and metrics in determining the effectiveness of alternative RUTF formulas threaten to prevent progress in increasing treatment for severe acute malnutrition, or SAM, which kills an estimated 1 million children under 5 each year.
In 2019, WHO began the review to determine whether the agency could endorse cheaper and locally available formulas, particularly plant-based RUTFs. To garner endorsement, they would have to be found to be equally effective in fighting SAM as milk-based recipes such as Plumpy’Nut, which is made by French company Nutriset, the largest manufacturer of RUTFs.
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But after a two-year review process, WHO says that despite some promising trial results from alternate recipes that others want to see scaled, there isn’t enough evidence for the agency to change its guidelines to endorse nonmilk recipes.
Currently, at least half of the proteins in an RUTF must come from milk, as stipulated by a joint United Nations statement in 2007. That statement was also the official endorsement of community-based management of acute malnutrition, or CMAM, which revolutionized treatment for wasting — or low weight for height — by making it available outside a hospital setting and thereby increasing access vastly.
However, nearly 15 years after that programmatic change, millions of children around the world still lack access to lifesaving care, and progress on preventing wasting has fallen short, according to recent data published by The Lancet.
“It’s difficult to say how you would rank weight gain if you were including it in a composite benefit with other benefits, and so it’s difficult to put a dollar value on a kilo gain.”— Dr. Jay Berkley, professor of pediatric infectious diseases, KEMRI Wellcome Trust Research Programme
Expanding the pool of approved RUTFs could help fill the coverage gap. But researchers, nutrition experts, and physicians don’t always agree on how to evaluate the efficacy of plant-based RUTFs or what trade-offs in current metrics — such as the rate of weight gain — could safely be made in favor of reducing product cost and expanding access to treatment.
An estimated 20% to 25% of wasted children receive CMAM, but those figures are based on prevalence data instead of incidence data, said Jeremy Shoham, a co-founder of nutrition organization N4D. Many children experience SAM for less than a year, but they can have it multiple times.
“That probably means we’re only reaching about 10% of children with CMAM at the moment. That’s a lot better than the 1% we were before CMAM and RUTF were developed,” Shoham said. “But still pretty sad after 20 years, isn’t it? And the major reason for CMAM not being scaled up in low-income countries is cost to governments.”
Cost, therefore, is a chief topic of concern.
When WHO began its review, its original call for proposals listed three stated objectives: determine whether formulas with alternative proteins or those that have less than 50% of proteins from milk are as effective and safe as the original formula; determine whether alternative formulas are equal to the original in terms of environmental factors such as household acceptability, equity, accessibility, and sustainability; and measure the cost-effectiveness of alternate formulas in terms of production and program delivery in different settings.
Alternative plant-based RUTF recipes have experimented with a range of proteins, including soy, maize, sorghum, whey, and flaxseed oil, in place of the milk in RUTFs such as Plumpy’Nut.
“Milk accounts for well over 50% of the ingredient cost,” said Dr. Steve Collins, founding director at Valid Nutrition, who helped develop CMAM. “It’s always imported, and so that means that the manufacture of these products in sub-Saharan Africa — and a lot of other countries, actually, who are affected by acute malnutrition haven’t got a massive milk industry … is really difficult because you’ve got to import the most expensive ingredient.”
Collins has publicly acknowledged he could be seen as having a conflict of interest in advocating for approval of plant-based recipes because some alternate formulas have been developed by his organization. But he, like others Devex spoke with on background, said he simply wants to see WHO run a fair review of existing data and encourage further research and innovation to reduce the private sector barrier to entry in the RUTF market, which could ultimately lead to a decrease in cost and an increase in the reach of treatment for SAM.
Amid a lack of data, disagreements over metrics
The WHO guideline review examined six studies on the efficacy of alternative RUTF formulas that currently exist, pooling the data to determine whether plant-based recipes could be considered as effective as milk-based ones.
Three of those studies were done by Valid, and the results for the first two were deemed inferior to those for WHO’s current recipe. But the third recipe, refined after those earlier studies and trialled in Malawi, was more promising. It was sorghum-based, enriched with amino acids, and deemed “non-inferior” to milk-based products in terms of recovery and mortality, but it had a slightly inferior rate of weight gain. It was superior in the treatment of anemia and restoration of body iron stores.
Collins pointed out that pooling the data from early, failed recipes was “bound to come to a result that [alternate recipes] don’t work.” “It’s totally madness,” he said.
The Valid recipe was produced over the course of a 14-year research project, with the amino acid mix developed by Japanese company Ajinomoto.
“Cost is important, but it’s also the effectiveness which is important. So there’s no point in having a cheap product … if it’s not effective in terms of recovery of children.”— Zita Weise Prinzo, evidence and program guidance technical officer, WHO
Valid retains the right to use and distribute the formulation, and Collins said he wants to eventually see manufacturing of RUTFs domestically in any country that could support it, although regional production would likely have to come first as a product worked to reach scale. Private sector companies have been dissuaded from getting into the RUTF market because it has been difficult for them to scale up production.
According to WHO, the yet-to-be-published meta review found that RUTFs with less than 50% protein coming from dairy products were “comparatively less effective” based on weight gain, recovery, and weight for age.
Because weight gain was a key metric in the review process, Zita Weise Prinzo, evidence and program guidance technical officer in WHO’s nutrition department, said the failure of the Valid amino acid recipe in meeting the milk-based benchmark meant it could not be endorsed.
“We’re very supportive of these new formulations, which should be continued in research settings and evaluation settings,” Weise Prinzo said. “We would need more information about what the ideal weight gain is or the different risks that children are in. But we’re not questioning weight gain. If you want the child to recover, weight gain is clearly an important outcome. There’s no question about that. We’re not questioning that as an outcome; we’re just saying that there are other outcomes that we will be looking at in the future.”
She said that WHO supports local production of RUTFs, which could lower costs, and that the agency also wants more data to be able to measure how long children stay recovered from SAM.
But getting that additional data is difficult. Weise Prinzo said the Valid recipe that showed promise in Malawi needs to be trialed elsewhere to build a more diverse evidence base for WHO to examine in a future guideline review. But governments are hesitant to program a product that has not been endorsed by WHO, leaving development, trials, and scaling of a potentially cheaper plant-based RUTF recipe in a Catch-22.
No randomized controlled trial was ever done to determine that Plumpy’Nut’s formulation and rate of weight gain were ideal before it was adopted as the WHO standard. And while rate of weight gain is the primary way of determining the efficacy of an RUTF, there are other factors that ought to be considered, said Dr. Jay Berkley, a professor of pediatric infectious diseases with the KEMRI Wellcome Trust Research Programme who works on child survival in relation to undernutrition.
“To me, in general, weight is a proxy measure for all kinds of health things that are going on,” Berkley said. “Weight is a good predictor of health outcomes, but it’s not an actual health outcome.”
According to Collins, moving to the CMAM approach of SAM treatment halved the rate of weight gain in recovering children but increased coverage of treatment, so it has ultimately been considered a success. Weight gain was reduced because products were often shared among multiple children in a household, decreasing the speed at which children recovered.
Berkley said there are not enough studies that have followed children for a long enough period of time to determine how important the rate of weight gain is in health over the course of a child’s lifetime. It doesn’t make sense to “close the door” on any RUTF formulations, he said, without conducting longer-term research.
“If you think that weight is a predictor of outcomes, then you would think that increasing weight quickly would then reduce the chances of bad things happening. But there’s no real linear association between those two things. If you feed children rapidly, they remain susceptible to infectious diseases for quite a long time afterwards. So you're not necessarily immediately reducing their risk,” Berkley said.
“It’s difficult to say how you would rank weight gain if you were including it in a composite benefit with other benefits, and so it’s difficult to put a dollar value on a kilo gain. That's quite difficult, except if you can relate it to a reduction in actual health events. But very, very few trials or assessments of nutrition interventions have health events as their outcome.”
“To require a recipe to be perfect and say, ‘Oh, it doesn’t do great for weight gain’ — you’re ignoring the cost, the coverage implications.”— Dr. Steve Collins, founding director, Valid Nutrition
No cost-effectiveness study
Because there’s been a lack of competition at scale for Plumpy’Nut, its cost has remained virtually unchanged over 10 years. A study run by Valid on the use of its alternate recipe in Malawi saw costs reduced by 29%, showing a financial benefit of the decentralized production of RUTFs.
With its guideline review, WHO did not conduct a cost-effectiveness study, as stipulated in the original scope. Weise Prinzo said that WHO had the money to run such a study — turning down further financial support from the Eleanor Crook Foundation, which provided funds for the review process — but that it was not necessary because none of the alternative formulas examined were found to be as effective as milk-based ones.
“Cost is important, but it’s also the effectiveness which is important. So there’s no point in having a cheap product … if it’s not effective in terms of recovery of children,” Weise Prinzo said. “First we have to demonstrate that it works. And then, is it cheaper as well? So we did try to scope for cost-effectiveness studies in general, of any of these products, and they haven’t really been done.”
She added: “It’s not that we changed the scope of the guideline. It’s not that we dropped something.”
But others disagree. Collins said the review cannot be considered complete without the cost-effectiveness data.
“Our position is we just want them to follow their own process and let the data get a good hearing,” he said.
Weise Prinzo said WHO wants to see everyone involved “work closely together” to obtain better data and improve RUTF efficacy rather than trying to “undermine the process.”
Dr. Alan Jackson, who has been involved in WHO guidelines for SAM since the first ones were developed in 1981, was one of the independent experts in WHO’s guideline development group on RUTFs. He echoed concerns over the lack of sufficient evidence evaluating efficacy of alternative formulas and said the group of nutritionists, doctors, and public health experts did its best with the data that was available as part of the review.
“I consider that the review was carried out according to the rules that had been set down by WHO for the guideline process and that the conclusions that were reached were in accord with that process. The limitations — any limitations that there are — are as likely to be in and around the nature and the quality of the data available to the committee to review rather than the process itself,” Jackson said.
“Where I have had concerns, I have raised them. And so far as I know, my understanding goes, WHO has done its best to address the concerns that I have raised,” he added.
Jackson declined to detail those concerns on the record.
The COVID-19 pandemic did pose some challenges to the review, he said, prohibiting members from coming together in Geneva to discuss sometimes contentious topics in person. Despite this, he said every member of the group had an opportunity to express their views and have them heard by other members.
Jackson said the committee examined data to determine whether products other than milk-based RUTFs were efficacious enough to justify changing the WHO standard, and it considered a number of other factors, such as whether recipients would accept the products, manufacturing would be possible in the necessary locations, and the products would be affordable. But just because a product showed some promising outcomes wouldn’t necessarily merit a change in WHO RUTF guidelines, he said.
Collins, however, argued it needs to be easier for programs with strong monitoring and evaluation to use alternative RUTF formulas, instead of relying solely on expensive randomized controlled trials for evidence. He said the world can’t afford to wait several more years for another review to encourage innovation while treatment remains out of reach for so many children with SAM.
“To require a recipe to be perfect and say, ‘Oh, it doesn’t do great for weight gain’ — you’re ignoring the cost, the coverage implications. You’re ignoring the benefits of anemia, you’re ignoring the benefits to the environment of low-carbon, nonmilk recipes. You’re ignoring the benefits to the local food value chains,” Collins said. “These recipes have to be evaluated in their entirety. And that is where I'm saying there’s a major barrier here in the use of evidence. We’re putting up higher and higher levels or barriers to stop data from turning into practice.”
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