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Traditional randomized clinical trials not suitable for nutritionals
Researchers agree that supplements should be vetted differently than pharmaceuticals.
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“Randomized clinical trials are very good for testing drugs, but when we’re talking about individual foods or dietary patterns, the way these studies are conducted are not a gold standard,” Jeffrey Blumberg, PhD FASN, FACN, CNS, said at the Ocular Nutrition Society symposium, held during Vision Expo East this spring.
“With a randomized clinical trial (RCT) you have a nonexposed or placebo group,” Blumberg said. “This doesn’t work for a nutrient trial. Your participants have probably eaten before you’ve seen them. You can theoretically introduce a nutrient deficiency, but that’s unethical.”
“Nutrient levels are rarely considered in trial inclusion criteria,” Morris and colleagues wrote in the Journal of the American Medical Association. “Further, trial volunteers are typically healthy behavior-seeking individuals and are unlikely to have low nutrient intake. More probably, intake levels are already at the level for optimal functioning, and further supplementation provides no additional benefit.”
“In order to conduct a RCT that adequately tests the efficacy of a nutrient for a specific chronic disease, it will usually be important to ensure an adequate contrast in intake between the intervention and the control groups,” Blumberg and colleagues wrote in Nutrition Review. “The control intake is an approximate analog of the placebo control in drug RCTs. However, since sufficiently low intakes are associated with significant disease in some body systems, doing so can lead to serious ethical problems, particularly if the disease outcome is serious and/or irreversible.
Jeffrey
Blumberg
“In contrast to observational studies, which typically assess nutrient exposures ranging from low to high, most RCTs of nutrient effects have employed a control group receiving an intake typical of the population, oftentimes near the recommended daily allowance, and certainly above the thresholds for many deficiency states, while the intervention group receives even more,” he continued.
Another approach
Blumberg suggested the use of evidence-based nutrition (EBN) instead of evidence-based medicine (EBM).
“EBN thus departs from the situation of EBM, where, for most interventions, the use of a no-intake control group is usually quite appropriate,” he stated. “In EBM, the hypothesis is that adding an intervention ameliorates a disease, whereas in EBN it is that reducing the intake of a nutrient causes (or increases the risk of) disease. This distinction is critical. No one proposes in EBM that a disease is caused by the absence of its remedy; whereas for nutrients the hypothesis is precisely that malfunction is caused by deficiency.
“A hypothesis about disease causation can rarely, if ever, be directly tested in humans using the RCT design,” he continued in Nutrition Review. “This is because in the RCT the disease/dysfunction occurs in at least some of the study participants, and the investigators must ensure that this will happen. Instead where EBN must operate is with respect to two related, but different questions: In addition to disease X, does the inadequate intake of nutrient A also contribute to other diseases? At what level of intake of nutrient A is risk of all related disease minimized or all related functions optimized?”
Nutrients are ‘pansystemic’
Another issue with testing nutrients vs. drugs is that drugs principally target a single system, while nutrients are “pansystemic in their effect,” Blumberg said in his presentation.
Drug studies look for a large and targeted effect, he said. However, “nutrients don’t work that way. Their effects are usually modest, but aggregated across multiple systems over long periods of time.”
For example, with a negative calcium balance of 30 mg/d, an individual will lose 10% of his or her bone density mass per year and have osteoporosis in 30 years, he said.
A challenge in designing a RCT for a nutrient is deciding what different outcomes you will be looking at and teasing out the one you need, Blumberg said.
“Different conditions require different levels of nutrients,” he said. “What is the right dose for the outcome you’re interested in?
“You must look at intake or baseline status before you provide the intervention,” he continued in his presentation. “It’s like doing a clinical trial with a new antihypertensive drug and not measuring blood pressure at baseline.”
Blumberg said a study of nutrients must consider the health status of the people in the study, their lifestyle, their baseline nutrient intake and status, and their susceptibility to the outcome.
RCTs ‘impractical’ for nutritionals
“RCT models are impractical in human nutrition. If someone has a cancerous condition, a RCT can help determine over a short duration whether the drug product improved that condition,” Arhangelsky wrote in The Emord Blog. “The drug might claim to ‘treat osteoporosis,’ for example. So you test patients with that condition, after 6 months you examine bone density and the results could help establish efficacy.
“A dietary supplement may claim to reduce risk of contracting certain cancers,” he continued. “Imagine performing a clinical study that can produce statistically significant results for that claim. How would you test? How large would the population size need to be? How long would the study last? You are testing against the population generally, trying to establish that the dietary ingredient reduces the incidence of cancers over a lifetime.”
Arhangelsky stated that there would be numerous problems in attempting to conduct such a study.
“We cannot predict with accuracy who will develop cancer, so the population size must be substantial,” he wrote. “We would need to test subjects over a lifetime (or at least many years), and that fact alone is financially prohibitive. Even assuming costs were not unreasonably high for studies of that duration, we would need substantial compliance with the protocol over that span. As the duration of a study increases, we lose the ability to control for confounders or variables. We cannot, for example, control a subject’s exact diet over 20 years.”
He also noted that a randomized clinical trial for a dietary supplement would be “near impossible” because the cost would be overwhelming, and the U.S. Food and Drug Administration could still reject the data.
FDA guidance
The FDA has proposed a new guidance for requiring investigational new drug applications for human studies of supplements when they are intended to prevent “damage to an organ, part, structure or system of the body such that it does not function properly (e.g. cardiovascular disease) or a state of health leading to such dysfunctioning (e.g. hypertension).”
“This is treating nutrients exactly like drugs,” Blumberg said. “If it comes forth, it’s going to inhibit a lot of nutrition human intervention studies. It will be too hard to do these studies in the U.S.
“I’m not suggesting the standard of proof should be lowered,” he added. ‘I’m saying that requiring an RCT-type level of evidence when this design is ill suited or not available impedes the application of nutrition research to public health issues.
“So is it prudent to proceed without definitive proof?” Heaney and colleagues asked in Nutrition Today. “In answering that question, we stress that we do not suggest that the standards of proof should be relaxed for nutrients. Rather, we question whether we need as much proof of efficacy for a nutrient policy decision as we do for approval of powerful, expensive and potentially dangerous pharmaceutical agents. We suggest that a solution to this quandary can best be sought by shifting the decision context from one of irrefutable proof to one of probable harm.
“I would argue that we can make nutrient-related decisions at a level of certainty different than required for drugs,” he concluded. “If we’re going to move forward, we have to integrate all strategies in research and use scientific judgment.”
Other researchers and scientists have expressed similar doubts in randomized clinical trials and their efficacy regarding nutrients.
“Clinical trials are both costly and important for substantiation of nutrient effects on health,” Morris wrote. “The public health may be better served by initially conducting trials in individuals with insufficient nutriture and, if effective, further testing the effectiveness in those with adequate nutrient levels.”
“Because deliberately reducing intake to deficient levels in humans is ethically impermissible, the RCT will often not be available as a means of elucidating many potential nutrient-disease relationships,” Blumberg said. “The general principles of EBN can provide a sufficient foundation for establishing nutrient requirements and dietary guidelines in the absence of RCTs for every nutrient and food group… A general approach to acting in the absence of ultimate certainty should include a broader consideration of other research strategies along with revised estimates of the certainty level of the evidence and the confidence needed to act in support of public health.” – by Chelsea Frajerman and Nancy Hemphill, ELS