Designing and executing a clinical trial that meets scientific and marketing requirements can be a tall order. Lots of variable exist, and often a meaningful clinical study result is a moving target. So study design requires significant expertise in the therapeutic area, and an understanding of market dynamics.

Here are four main questions to ask.

1.) What are the rationale and central questions to the study? There are a number of questions that need answers, but in general, clinical studies should start with one or two central questions, and a reason for why the material should be studied. This results in the development of primary and secondary endpoints. Are you trying to see whether a nutritional product can improve joint pain in baby boomers, or muscle pain in athletes? Because the study design may be completely different for what may appear to be very similar studies.

How the product will be perceived by the market post-study is also important. What study endpoints will allow for solid marketing claims? If your product has a significant effect in the study, will it help to differentiate your product against the leaders in the category? In the drug industry, studies on new products are compared against the “standard of care,” and the approach for supplement clinicals can take the same approach, particularly if the product is not very well differentiated in other ways.  Are there new mechanisms of action or emerging markers that can be added as secondary endpoints, which would help to differentiate your product?

Accumulation of data to support safety and global regulatory acceptance such as GRAS determinations should always be an objective, so any efficacy study is also a great opportunity to inexpensively accumulate safety data.

2.) What is the dose? Often, this is the most challenging and critical question across all drug and nutrition clinical studies. For many products that are complex mixtures of active compounds, pharmacokinetics or bioavailability is unknown or untenable, making dosing a wild guess. In cases where there are only a couple active compounds, bioavailability should be assessed before moving on to clinical efficacy trials.

In cases where bioavailability cannot be easily determined, a dose-response study (using multiple doses) should be performed. Ideally, a dose-response study observes a small effect at a lower dose, and a greater effect at a higher dose. In other cases, a linear dose-response relationship should not be assumed; a higher dose may not work as well (or reveal safety issues) compared to a lower dose.

Market considerations, such as cost per day and number of capsules should also be included in this evaluation. While a randomized, placebo-controlled clinical trial is wonderful to have, if the product never reaches the shelf (or the dose is too high for the consumer to stomach) then the best-designed study is like a tree falling in the woods.

3.) How many subjects are needed for the study to be adequately powered? A minimum requirement today for nutritional products is that the changes in the group taking the active dose must be significantly different than the changes in the placebo or control group. It makes no sense to design and invest in a study that will show no difference between your product and a sugar pill. For some subjective measures such as pain, the placebo effect and inter-individual variation can be very high, due to the subjective and ever-changing nature of pain perception. In this case, the number of subjects required to get reliable statistical separation between the active versus control groups is relatively high. For other endpoints, such as blood concentrations of actives in pharmacokinetic studies, placebo effects are almost nil, and therefore a lower ‘n’ is likely to result in significant changes versus controls.

4.) What is the budget and timeline? Research is an investment, one that can be expensive and time-consuming. For example, if the therapeutic area and endpoints include testing of blood markers, then the drawing, processing and testing of blood samples is a major cost center in the research budget.  Common blood markers such as blood lipids are relatively easy using standard kits, while other less standard markers can require method development and increase costs, and may provide unreliable data that needs to be repeated.

A university-based study offers the independence and clout of world-class clinical studies, but the prestige can be balanced with increased costs and more uncertainty in the timeline, particularly when your study is relatively small and relies on shared resources. While a contract research organization is often faster than a university, this option can also come with greater costs. A research services contract with a detailed protocol and time-based milestones is critical to have in place.

Ethical approval (typically through an Institutional Review Board, or IRB) is also required for all human studies. Some research centers can get IRB approval within a month, while others are mired in bureaucracy and generally take six months or more.

Recruiting also contributes to the study timeline. If you are excluding a lot of lifestyle factors, then your available population is low, and getting the required number of subjects can be costly if not impossible.  Many clinical studies never get off the ground when recruiting is not taken into account.

Lastly, it is critical to do the homework up front and ask a lot of questions. Make sure you have someone in your corner, who speaks the language and is looking out for your best interests. Only then can you ensure the returns on your research investment are maximized.

By: Blake Ebersole

This article was previously published in Natural Products Insider, June 2015.

Heart health, gut microbiota and diet are closely linked in ways we are just beginning to understand. It is well-known that diet can alter microflora balance and tip the scales toward a pro-inflammatory status affecting heart health, but new research has uncovered other interesting links between gut and heart health. A 2015 study published in Metabolism found women with and without metabolic syndrome who produced equol, a gut bacteria metabolite resulting from soy consumption, enjoyed cardiovascular benefits from consuming soy nuts.¹ However, non-equol producers experienced no improvement. This suggests the possibility that in order to enjoy the cardiovascular benefits from soy, a certain balance or type of gut bacteria is required.

Many nutritional interventions appear to work regardless of gut microbiota. A 2015 randomized, controlled clinical trial published in the journal Hypertension by a university group in London, found the primary active constituents of beet root are the nitrates like betain.² In this study, 250 ml of beet root juice (compared to a placebo of nitrate-free beet juice) reliably lowered blood pressure in hypertensive patients, as well as improved endothelial function by 20 percent (p<0.001). Remarked the authors, “This is the first evidence of durable BP reduction with dietary nitrate supplementation in a relevant patient group.”

But juicers might want to keep the fiber. A study in the American Journal of Clinical Nutrition following 7,216 men and women for eight years found baseline consumption of fruits and fiber was associated with a significantly lower death rate, and those consuming the highest level of fruits (>210 g/d) had a 41-percent lower risk of mortality, which was mainly associated with cardiovascular disease.³

The questions around cardioprotective effects of whole grains continues. The Dietary Guidelines for Americans recommends at least half of our grain consumption come from whole grains, but study findings tend to be inconsistent. In a well-designed controlled crossover study in the Journal of Nutrition, which was co-authored by researchers from Nestlé and General Mills, an increase of 140 g/d in whole grain consumption did not result in significant effects in blood pressure, fecal measurements or gut microbiology.⁴

Studies like this one lead to more questions than answers, such as whether the “gold standard” randomized controlled trial is adequate to measure effects of interventions such as whole grains, especially when it is difficult to control every possible mitigating factor (such as the elimination of whole grains from subjects’ diet during the washout period). Perhaps the type of whole grain was a factor as well, but some also suggest that a lack of effect also illustrates why simply eating a balanced diet according to prevailing nutrition recommendations may not be sufficient to impact health, especially as we age.

Lest we forget that diet does not exist in a vacuum, there are a number of psychological and social factors that impact nutrition and cardiovascular outcomes. In the Cardiovascular Risk in Young Finns Study published in Circulation, 1,089 children were followed for 27 years, which resulted in a fantastic dataset.⁵ Higher ratings of emotional, parental health and self-control behavior patterns in children resulted in a significantly better cardiovascular risk rating as adults. Although the study did not focus on specific nutritional aspects, it may be worth our time as an industry to consider ways to integrate dietary interventions with lifelong behaviors that optimize health outcomes.

Reams of evidence suggest polyphenols support cardiovascular health. A recent six-week controlled clinical trial in Portugal was published in the American Journal of Clinical Nutrition, which compared the effects of two olive oils containing different levels of polyphenols on proteomic biomarker scores related to coronary artery disease.⁶ The findings were surprising: the olive oil lower in polyphenols was slightly more effective than the enriched olive oil. Could there be other compounds in olive oil other than polyphenols responsible for its well-known health benefits?

Regardless, the research on polyphenols continues, with berries as the main focus. Ongoing trials on polyphenols from colored berries and flowers, based on a search of ClinicalTrials.gov, include the following: a study on a hibiscus extract beverage on cardiovascular and endothelial health, which completed in February 2015; another study on a chokeberry extract in former smokers, to complete in May; and another study on cranberry extract in obese, insulin-resistant humans at Pennington Biomedical Research Center, anticipated to complete in July.

On berries, a study published in Italy in April 2015 found that a formulation of white mulberry leaf extract, berberine and red yeast rice both lowered low-density lipoprotein (LDL) and raised high-density lipoprotein (HDL) cholesterol in humans with high cholesterol not already on statins.⁷ This formulation was compared to a similar one without mulberry, but with astaxanthin, folic acid, policosanol and CoQ10. Based on the complexity of the formulations, it is difficult to conclude much about the contributions of each ingredient; however, the authors suggested that the mulberry extract might have made the difference for the high-performing formulation.

Future research is expected to add to our increasing knowledge of how to reach the heart through the gut.

References:

1.       Acharjee S et al. “Effect of soy nuts and equol status on blood pressure, lipids and inflammation in postmenopausal women stratified by metabolic syndrome status.” Metabolism. 2015 Feb;64(2):236-43. DOI: 10.1016/j.metabol.2014.09.005.

2.       Kapil V et al. “Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study.” Hypertension. 2015 Feb;65(2):320-7. DOI: 10.1161/HYPERTENSIONAHA.114.04675.

3.       Buil-Cosiales P et al. “Fiber intake and all-cause mortality in the Prevención con Dieta Mediterránea (PREDIMED) study.” Am J Clin Nutr. 2014 Dec;100(6):1498-507. DOI: 10.3945/ajcn.114.093757.

4.       Ampatzoglou A et al. “Increased whole grain consumption does not affect blood biochemistry, body composition, or gut microbiology in healthy, low-habitual whole grain consumers.” J Nutr. 2015 Feb;145(2):215-21. DOI: 10.3945/jn.114.202176.

5.       Pulkki-Råback L et al. “Cumulative effect of psychosocial factors in youth on ideal cardiovascular health in adulthood: the Cardiovascular Risk in Young Finns Study.” Circulation. 2015 Jan 20;131(3):245-53. DOI: 10.1161/CIRCULATIONAHA.113.007104.

6.       Silva S et al. “Impact of a 6-wk olive oil supplementation in healthy adults on urinary proteomic biomarkers of coronary artery disease, chronic kidney disease, and diabetes (types 1 and 2): a randomized, parallel, controlled, double-blind study.” Am J Clin Nutr. 2015 Jan;101(1):44-54. DOI: 10.3945/ajcn.114.094219.

7.       Trimarco V et al. “Effects of a New Combination of Nutraceuticals with Morus alba on Lipid Profile, Insulin Sensitivity and Endotelial Function in Dyslipidemic Subjects. A Cross-Over, Randomized, Double-Blind Trial.” High Blood Press Cardiovasc Prev. 2015 Apr 14.

By: Blake Ebersole

This article was first published in Natural Products Insider in June 2015