How solid is your substantiation? FDA has released a new guidance that reflects its current thinking on how it reviews evidence for health claims.

As President Bush's term winds down, the various agencies that have purview over the dietary supplement and general health industries have become more active in communicating with industry and the pubic at large. And the latest U.S. Department of Health and Human Services (HHS)-Food and Drug Administration (FDA) "Guidance for Industry" should be a must-read for every company in the dietary supplement industry ("Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims." Draft Guidance; June 2007).

In June, FDA published a document to convey its current thinking on the process for evaluating scientific evidence for health claims. This includes the meaning of the significant scientific agreement standard [SSA in 403(r)(3)] of the Federal Food, Drug and Cosmetic Act [(21 USC 343(r)3) and 21 CFR 101.14(c)], coupled with the scientific evidence to support a qualified health claim. The FDA used several previous documents to generate its current thinking, including: the Nutritional Labeling and Education Act of 1990 (NLEA 1990); the court ruling in Pearson v Shalala; the 1999 Guidance on Significant Scientific Agreement (64 Fed Reg 17494); the 2003 publication "Task Force Final Report on Consumer Health Information for Better Nutrition Initiative;" and the 2004 "Draft Guidance for Industry: Substantiation for Dietary Supplement Claims Made Under Section 403(r)(6) of the Act." In general, this new Draft Guidance attempts to string together common threads of earlier FDA-related publications and provide clarity for items that affect both the food and supplement industries. The examination of key parts of this document will help your company better understand how appropriately designed research could support company growth and lessen consumer-lead litigation.

While the FDA does state: "FDA guidance documents do not establish legal enforceable responsibilities," it should be noted that guidance documents are considered "should do," and therefore strongly represent suggested guidelines to be followed in order to avoid government litigation.

The New Evidence-Based Review System

The Evidence-Based Review is a systematic science-based evaluation of the strength of evidence to support a statement. This includes health claims and significant scientific agreement. The review encompasses--and this is what you really need to know--evaluation if the studies that you portend to be supportive have been designed so that the outcome is measurable in an objective manner. The application to the dietary supplement industry is clear in that the item being examined can be a whole food or a component of that food (i.e., tomato and lycopene). The second part that the FDA considers is if the study appropriately specified and measured the condition of the health claim. In other words, was the endpoint chosen for the study correct for the condition being studied (i.e., an objective marker or validated surrogate marker).

FDA also categorizes your substantiation by study type using the following hierarchy: the intervention study (the randomized, doubleblind, placebo-controlled trial), with or without a crossover, is considered to be the gold standard, followed by observational studies, cross-sectional studies, review articles, animal research and in vitro research. There are many facets of the randomized clinical trial, but most important, the quality of the study counts as much as the quantity of the data.

All studies should have clear outcome objectives. For example, a weight loss study should state in the objectives that the difference in weight (weight lost) is the primary objective. Thus, if the threshold is met you have achieved the primary objective. The "p" value for the placebo subtracted weight loss (the difference between the group on active product and that on placebo) has to be significant. In general, the pharma industry aims for a 5% weight loss.

If the study does not have a clear-cut, well-known endpoint, then a surrogate marker can be used. A validated surrogate marker is one that is well-established and accepted by the FDA's Center for Drug Evaluation and Research (FDA-CDER). Some examples are total serum cholesterol and blood pressure for cardiovascular disease, adenomatous colonic polyps for colon cancer and elevated blood sugar levels and insulin resistance for type 2 diabetes. Studies using surrogate endpoints should also be of the randomized clinical trial variety (have a placebo group). To sum up, the study design should be one that includes hard endpoints (body weight, body composition) enumerated in primary and secondary objectives (for the outcome), but if that is not possible the surrogate markers can be used. Combinations of hard endpoints and surrogate markers also support the strength of a study.

For intervention studies, the FDA will review the study and score it for strength based on the following types of questions:

* Were the study subjects healthy or did they have the disease (or condition) that is the subject of the health claim?

* Did the study include an appropriate control group?

* Was the study designed to measure the independent role of the substance (i.e., dietary supplement) in reducing risk of disease?

* Were the relevant baseline data significantly different between the active and placebo/control groups?

* How were the results from the intervention and control groups statistically analyzed?

* What type of biomarker was used?

* How long was the study conducted?

FDA has accepted studies as short as three-weeks in duration as a minimum duration for a surrogate end-point.

* If the intervention involved dietary advice, was there proper follow-up to ascertain whether the advice resulted in altered intake of the substance?

* Where were the studies conducted? The answer to this question is very important to FDA. For studies conducted outside of the U.S., the FDA has stated that differences in nutrition, diet and disease risk factors between the U.S. and the country where the study was held may mean that the results cannot be extrapolated to the U.S. population. David LaPay, MD, PhD, who is the senior advisor for Clinical Science/Health Coordinator for the FDA has stated "foreign studies must be well-designed and well-conducted, and study sites must be accessible for FDA GCP inspection."

FDA also has specific opinions about data capture. For example, it considers the 24-hour food diet recall to be useful for assessing the average intake of a group, but inadequate for assessing an individual's intake of a nutrient or substance. It also stresses the importance of a placebo/control group, specifies why there needs to be a "wash out" or "run-in" phase in crossover studies, and makes some suggestions as to how statistical methodology should be organized.

When FDA reviews the study or substantiation that you have for methodological quality, it will ask the following questions:

* Were the studies randomized and blinded, and was a placebo provided?

* Were inclusion/exclusion criteria and key information on the characteristics of the study population provided?

* Was subject attrition (dropouts, non-finishers) assessed, explained in the article reporting the study, and reasonable?

Each study type is reviewed for quantity (number of studies, number of subjects per group), methodological quality (as high, moderate or low) and outcomes. In general, the more consistent the results from research on your product, the better the rating you will get from FDA. Also, keep in mind that they review the study for relevance to the U.S. population.

Summary

FDA has provided the industry with a guide to the types of research that it is looking for in order for substantiation to be qualified. Research institutions, individual dietary supplement companies, trade journals and the politically active trade associations can now use this to help guide the growth of responsible industry rather than wait for more regulations to be enacted. You can use this Draft Guidance and this article as a guide to what questions you should be pondering when designing a clinical trial to support your product.

For more details on this Draft Guidance, contact the Center for Food Safety and Applied Nutrition (CFSAN) at 301-436-2367.

By Douglas Kalman, PhD, MS, RD, CCRC, FACN

Douglas Kalman, PhD, MS, RD, CCRC, FACN, is director of clinical nutrition at Miami Research Associates (MRA), Miami, FL, in the Nutrition and Endocrinology Division. MRA is a clinical service organization involved for over 10 years in phase II through post market trials for the pharmaceutical and nutraceutical industries. Mr. Kalman is also an active member of the American College of Sports Medicine, American College of Nutrition, the American Dietetic Association, the National Strength and Conditioning Association and the Association of Clinical Research Professionals. He is also the executive vice president and treasurer of the International Society of Sports Nutrition (ISSN). He can be reached at 305-666-2368; Fax: [phone]; E-mail: [e-mail]; Website: www.miamiresearch.com.