Getting on the Right Path

When it comes to research, development and adverse events, it makes the most sense for dietary supplement companies to take the high road.

By Douglas Kalman

Have you ever heard the saying: “In order to make an omelet, some shells are going to have to be broken…”? No, this is not a column on the virtues of breaking an eggshell or how to whip up the best omelet this side of the Atlantic, but if you apply this saying to clinical research and acknowledge what is occurring on the political side of the natural products/nutraceuticals industry, it is obvious that eggs are being cracked on the path to creating a new system for regulating the dietary supplement industry.

To some degree, the new paradigm being endorsed by many politically active trade associations is following in the footsteps of the pharmaceutical industry. The facets being discussed in the popular media and within trade journals relate to clinical research and dietary supplements, presenting an opportunity to discuss the meanings of research studies, adverse events, ad-verse event reporting and product development. These exact areas are of particular importance and hopefully are of interest to you, the reader.

At First…

In the pharmaceutical industry and as promulgated by The Code of Federal Regulations 21 (CFR 21), with additional guidelines and guidance from FDA, there is a set pathway for the development of a pharmaceutical product. The pathway involves discovery, identification of the agent, in vitro research, safety and dose finding/
ranging studies, safety studies, efficacy studies, safety and efficacy studies and post-market surveillance studies.

In the dietary supplement industry, however, no such pathway for product development has been formally de-tailed. Some companies design products via theoretical nutrition, others conduct “in-house” non-controlled studies; there are also “copy cat” formulators who do no science, but instead borrow it from others (violation of the Lanham Act?). Some of the more responsible companies sponsor some form of an independent study (pilot or larger) at a local university or partner with a contract research organization (CRO).

As a result, there is not a high barrier for developing a finished good, since at this time there is no federal regulation demanding pre-market approval (New Dietary Ingredients—NDIs—must be submitted to the FDA for review of the safety data during the 75-day review period). Therefore, perhaps the dietary supplement and nutraceuticals industry should consider per-adoption of a product development flow similar to that already recognized by FDA. This would involve reworking the pre-clinical and phase I-III designs to meet the needs of the industry and what appears to be forthcoming legislation.

Let’s assume that a product has one or more ingredients and that it is DSHEA 1994 compliant. So perhaps the following suggested steps should be taken in order to: a) demonstrate the safety of the product; b) demonstrate that the products work in the intended population (target audience); c) cover many potential legal issues; d) have direct scientific substantiation for marketing; e) get a tax break for Research and Development via I.R.S. Tax Code 174; and f) gain more loyal consumers via being known as a company with integrity.

Adoption of the Pharmaceutical
Paradigm: New Definitions

Phase I. The traditional view of a phase I study is that this is where the pharmacology of the drug is determined. The studies will use healthy volunteers to learn the absorption, distribution, metabolism and excretion of the drug (“ADME”). In the realm of supplements, maybe the industry should think about adopting this phase as a dose-ranging study. In other words, perhaps the first study could be one where it is determined how the product is handled by the body. The accumulation of safety data during this phase is also of importance. This also applies to multi-ingredient products.

Phase 2. This is the clinical investigation portion of the development program. This is where one would use the target population for the product. This study is used to assess the safety and tolerability in carefully controlled doses. The supplement industry could slightly alter the phase II definition to translate into open-label pilot clinical trials with the product intended for marketing and within the intended consumer group. Safety data should also be accumulated throughout this phase.

Phase 3. Within the pharmaceutical sector, this is the formal clinical and pivotal trial. It is a randomized double-blind, placebo-controlled clinical trial (“RDBCT”). This is the study that confirms the efficacy of the product. The dietary supplement/nutraceuticals sector could make use of this paradigm by adding a RDBCT to a product-specific master file (product-specific dossier).

The good news is, if you complete the three phases of research on your particular product, then you would have at least three product-specific studies of different designs to detail the dose of your product, the safety and the efficacy in the intended target audience. Once phase III studies are completed within the pharmaceutical arena, a product dossier is submitted to FDA for marketing approval.

The supplement industry may want to accumulate these types of trials prior to marketing a product. In addition, it is recommended that a second phase III study be undertaken to strengthen the product dossier, especially if product specific claims (marketing) are going to be made. In the pharmaceutical arena, the phase IV studies are often designed as product comparator trials (i.e., Relafen vs. Celebrex), and/or smaller RDBCT are undertaken in order to continue accumulating safety, efficacy and marketing data.

The supplement industry should also consider this approach—product comparator trials in the intended target audience. For example, sponsor a CRO to run a weight loss trial of your product versus either a pharmaceutical agent (i.e., product X versus Meridia) or a competing supplement product. If your product is just as effective or more effective than the prescription/supplement product and the safety data are strong, then the additional evidence for your product dossier and intellectual property files would be nothing less than impressive.

It should be noted that within the weight loss category, GlaxoSmithKline (GSK) recently submitted a letter to the FDA effectively asking it to consider obesity as a disease and to bar supplements from being marketed for weight loss especially among those with a body mass index (BMI) equal to or above 30 kg/m2. Thus, if the FDA agrees with GSK, the supplement audience for weight loss products may be limited to those with a BMI of less than 30.

Adverse Events

According to the International Code of Harmonization Guidelines (ICH), an adverse event is any event that is not a pre-existing condition and that was not noted at baseline (baseline of the study). Some refer to an adverse event as any untoward sign or symptom either clinical or biological in nature. An example of an adverse event (AE) would include a person participating in a study on a cholesterol lowering medication, who develops a head cold during the study. The relationship of that AE to the study product is determined by the principal investigator and not fully determined until the study is completed and the statistical analysis is undertaken. The point is that while head colds occur, if one occurs during the study, it is considered an AE, thus the reality is that unrelated AE’s are noted during studies and get reported to FDA or to the public if the data is published.

The ICH defines a serious adverse event (SAE) as an “an untoward medical occurrence that results in: 1) death; 2) hospitalization or prolongation of an existing hospitalization or a visit to the emergency room; 3) is life threatening; or 4) results in a permanent disability, or congenital anomaly/birth defect. It is important to understand that just because a SAE may occur in a study of your product, it does not mean that the SAE would always be considered product related. For example, if a person was in a glucosamine study and was in a car accident that resulted in the individual being admitted to the hospital, the event would be classified as a SAE. It is important to note that all AE’s are rated for potential severity and potential relationship to the study agent—this is a most important aspect of AE/SAE analysis.

It is essential to consider the previously mentioned scenarios and ICH definitions simply because it is likely that some sort of regulation as it is re-lates to reporting AEs within the diet-ary supplements industry will occur. The NPA (formly NNFA), CRN and other trade associations are working “within the Beltway” to make sure that the right definitions and most appropriate system make it to Congress. It is interesting to note that over-the-counter (OTC) medications are included in the present pending legislation on AE reporting. All clinical studies should always capture AEs and these should be analyzed statistically for their relationship to product/placebo and rate of occurrence (if possible).

In putting together a true research and development team for product creation, even if you are creating a finished product with ingredients that are DSHEA appropriate, one would still want the proper pedigree of actual first hand research rather than borrowed science to substantiate the product. This includes the three or four phases of research discussed previously, as well as capturing any and all AEs.NW