Undertaking research is a daunting task, so it is important to know the proper steps.
By Douglas Kalman
Have you ever turned on the television only to see a commercial or brief infomercial for a product that just sounds to good to be true? From widgets to robotic housecleaners, even products designed to reduce belly fat, the claims for efficacy keep on coming. Sure there’s the Federal Trade Commission (FTC) and the Better Business Bureau (BBB), which monitor advertising and can be alerted to questionable advertisements, but these agencies are only one small part of the equation in keeping a system of checks and balances. These entities also rely on industry itself to self-regulate, but unfortunately this is where the supplement industry falls short of its responsibilities. Think about it: if the supplement industry considered self-regulating, it would ensure the media and the public of truth in advertising and thus products that deliver on their promises.
With this in mind, the time has come to examine some dietary supplements and related health products that have utilized the model of clinical research in order to substantiate claimed efficacy. The following is not an endorsement of any products or the research models used for their claimed substantiation, but rather a suggested model for the industry to consider. In addition, it is apparent that the Food and Drug Administration (FDA) is considering the basic pharmaceutical model of clinical trials for product substantiation of either safety, efficacy and both. If you read any of the judicial findings or actions taken by any of the regulatory agencies, in addition to examining the Draft Guidance for Substantiation (November 2004), the aforementioned is apparent.
Oral Supplementation for Osteoarthritis
Dietary supplements are not intended to treat, cure or prevent any disease as denoted by the FDA mandated warning on all marketed products. This, however, does not mean that dietary supplements cannot be used to increase the quality of life in those that may have a specific condition. For example, if a product aids in increasing mobility of someone that has osteoarthritis (OA), then it is not a disease-modifying agent (per se). Thus, this may be one avenue to pursue when developing a nutraceutical for the open marketplace.
One such product that has been developed both as an oral agent and as a topical cream is Celadrin (Imagenetix, San Diego, CA.). Celadrin is a cetylated fatty acid-based product. The topical version of Celadrin also contains menthol (listed as the active agent on the label). It is important to first examine the only published full-length study on the oral product in order to see what is claimed to be substantiation for marketing support. There are at least three published papers on the topical version of this product (only one including the newer menthol-containing design), however, these will not be discussed within this article.
Any good study will utilize a randomized, double-blind, placebo-controlled design in order to determine if the product in question is any better than a placebo. In 2002, the Journal of Rheumatology (a leading journal) published a study titled “Cetylated Fatty Acids Improve Knee Function in Patients with Osteoarthritis.” This study examined Indian patients (subjects with previously diagnosed OA) at two separate medical clinics, while following the same inclusion, exclusion and study criteria. Evaluations over the 68-day intervention period included physician assessment, range of motion testing and a standard OA quality of life questionnaire.
At the 30-day mark, subjects receiving the oral-CFA, but not the placebo achieved significant improvement in almost all parameters measured (except for knee extension); this remained essentially unchanged at the end of the study. The quality of life measurement used in this study is considered amongst the valid techniques to assess change in OA—Lequensne Algofunctional index, or LAI. The other standard used in this type of research (but not in this study) is the Western Ontario McMaster Osteoarthritis Index (WOMAC). This study demonstrated that under standardized conditions (controlling for diet and medication usage), Indian subjects with OA improved their ability to move their knees (improved range of motion) and their quality of life in as little as 30-days with no further improvement by the end of the study (and no loss of positive change either).
One could say that by demonstrating improvement in qualify of life, and under randomized, double-blind, placebo-controlled fashion, that the product was indeed efficacious. But it should also be noted that currently there is only one study for this oral product and that there should always be a push for at least two well-designed clinical trials for substantiation. However, this is a good start.
If one wanted to replicate this basic study design in the U.S., (Note: One should always study a product in the target market group they wish to sell it in), there are a couple of items that may strengthen the design. First off, researchers should consider using the WOMAC and Brief Pain Inventory scales to determine the improvement in quality of life. They should also consider measuring specific interleukins and other markers of inflammation to uncover the potential mechanism of action of the product. Also, researchers should consider using a larger sample size, one that is heterogeneous and consistent with where the where the product will be sold. A basic foundation of product substantiation appears to be in place for Celadrin. Now researchers must take additional steps to strengthen that foundation of efficacy. (Note: This commentary is not on the legal interpretation of substantiation, just the basis of the study design and findings).
Why do Studies Fail?
Studies fail to meet their primary objective for many reasons. First of all, the design may be flawed, i.e., the question being asked may not be the best one. In addition, it may very well be that the product being tested does not work. Keep in mind that a product may not work in a study if the dose picked is not optimal (doses should be based on prior animal or human studies, not on a theoretical basis). The product also may not work if the agent is not clean; the wrong isomer is being used or if the product was extracted from the wrong part of a plant. For example, let’s look at the recent echinacea study published in the New England Journal of Medicine (July 28, 2005;353(4):341-8). This study used what was thought to be a sub-optimal dosage of the herbal and perhaps a species of echinacea that does not have uniformity of positive results in clinical trials. Thus, a false negative outcome may have been the result of faulty study design.
There are many other reasons a study might lead to a negative outcome. This is why you may want to enlist the help of a consultant or clinical research organization (CRO), which have actually worked in clinical trials (not just someone who reads many published studies) because they are well versed in study design and supervision.
Coming in the April issue…
In the next column, we will construct a plausible framework for the research and development of dietary supplements when a company wants to make claims. If this framework is followed, your product intellectual property (IP) will be real, valuable and able to be protected. NW
References furnished upon request.