December 21, 2009
by Jayesh Chaudhary, BPharm, MS
Determining the primary question to be asked in a clinical trial of a dietary supplement is critical to its success. Ask a wrong question and you end up with the wrong answer, no answer or an answer that has no market or regulatory value. A complex human trial can be compared with a simpler scientific experiment consisting of a substrate (the patient or disease state), the reagent (the supplement or the intervention) and the endpoint (the outcome). Of course, clinical research has an added dimension of medical ethics that is absent from other research. In any study the scientist must smartly choose the correct substrate and watch for the mostly likely endpoint to prove a certain property of the reagent. In other words, selection of the wrong subject population and impractical clinical endpoints may result in failure of the clinical trial objectives.
How does one take these critical decisions regarding claim selection/definition and substantiation? First, look at what happens in conventional drug discovery and development, which provides lessons for planning effective clinical trials for dietary supplements. Next, consider all research decisions from the point of view of the investigator and, more importantly, the trial subject (the patient) in addition to the sponsors interests.
Prior Data Available for Trial Design
When a drug molecule enters Phase II clinical research, a trial phase that is comparable in its objective to typical nutraceutical trials, a lot is already known about the molecule from preclinical work. For most molecules entering Phase II, the target site of action, exact indication, disease sub-type, stage/severity of disease, probable safe and effective dose, expected duration of therapy, onset of action and half life of the drug in the body are known factors. The concept of the new drug already exists and needs to be proven in humans (Proof of Concept Study). The safety of the new chemical entity (NCE) in healthy humans in terms of maximum tolerable dose (MTD), likely adverse effects, etc., are also known through Phase I trials. The safety of the drug in patients is studied in further Phase II/III trials.
A systematic review of available data about folklore; identity, quality and strength of ingredients; and biological effects will help compile a respectable Investigators Brochure (IB) which will not only reassure IRBs, but also stimulate the imagination of investigators. They can suggest outcomes patients long for and value, which should therefore be measured or counted. For example, if a product facilitates epithelial healing (effect), and is shown to reduce the time required for re-epithelialization (efficacy), patients must find earlier or faster relief of symptoms (effectiveness).
For this discussion, let us consider only supplements that go beyond a nutritional benefit and are chosen to be studied for hard claims. While current regulations in most countries will allow only normal structure/function or quality-of-life type of claims, it is common practice to study the effect of nutraceuticals on a disease state. In the eyes of the regulators, even a clinically proven therapeutic product can not be labeled as a drug until it goes through the IND-NDA process consisting of several phases of human trials. Yet, it is often beneficial to have supplement studies done under an Investigational New Drug (IND) Application to FDA or local authorities to lend the study some credibility and improve quality of the research.
In comparison to NCEs, a typical herbal supplement that enters a human clinical study for the first time is not armed with much data. A lot can be dug out from folklore or traditional use of herbal remedies; but, a lot is often lost in translation from a traditional medical book to a modern clinical research protocol. Finding someone trained in both sciencescomplementary and alternative medicine (CAM) and clinical pharmacologycan fill the void due to inadequate preclinical data. In the event that the supplement or ingredient is lacking in both ethnobotanical and in vitro/in vivo animal data, the task of choosing the correct label claim for the clinical trial becomes even more challenging. Such trials are just based on popular use without an established basis.
The Need for Exploratory Clinical Trials
In such situations, the first clinical trial of a lesser-studied nutraceutical becomes purely exploratory; not much is to be expected from such a trial in terms of marketable outcomes. While such studies may not yield marketable outcomes, their scientific value is immense in guiding further focused, well-powered studies. The primary question of such an exploratory study could read, for example: Does a high dose of the Investigational Product (IP) reduce fasting blood glucose in type II diabetics? The study will enroll a general diabetic population and follow up frequently to get an idea of onset of action and point when maximal response may be achieved. Since the dose is not known from earlier studies, subjects will be exposed to a relatively high dose in order to elicit some response, if it exists at all. The expected outcome from such a study is the birth of a claim statement or the hypothesis for the next study. This pilot study lays a strong foundation for the next confirmatory or proof-of-concept (PoC) study. In supplement parlance, the claim definition study paves the way for a claim substantiation study. This transforms a known or observed effect (feature) into a claim of efficacy (benefit). Later, a Large Simple Trial can establish the effectiveness (realizable benefit) of the product as it will be used when marketed.
Questions for a Proof of Concept Study
The primary question for the PoC could be something like: Does x mgs daily of the IP reduce the fasting blood glucose levels of recently diagnosed non-obese type II diabetics to less than 120 mg/dl in two months? This question assumes there will be no change in patients diet, exercise and diabetic medication during the course of the study. Further sub-questions could be: Does this effect occur in patients with elevated blood lipids also?, Do diabetics on sulfonylureas benefit as much with this herbal supplementation as do diabetics on other medication?, etc. It would be good to have indicative answers to those sub-questions from the exploratory pilot study. This is known as sub-group analysis.
Secondary questions could then be: Does the IP lower elevated triglycerides and low-density lipoprotein (LDL) in the diabetic population also? or Does the IP reduce elevated nitrotyrosine in this population? Glucose management along with reduction of nitrotyrosine, an important cardiovascular disease marker, would be the ultimate proof of the dual powers of a diabetes supplement that most drugs would shudder to even think about. A single well-designed study can help substantiate multiple related claims. Research sponsors must select a research partner (hospital or CRO) that is well-versed with dietary supplement regulations (FDA, FTC guidelines) as well as the supplement market, and also with the art of medical writing. At the moment, few companies are making claims based on onset of action and time for maximal response. Such statements could read: fastest acting curcumin or clinically proven to improve quality of life significantly in less than one month as compared to two months
Consider the Variables
Clearly the choice of questions that can be asked in clinical research is unlimited, but not all from a single small study. Each question (intended claim) may warrant a different set of study population or lay specific restrictions on the type of recruits. Strong evidence requires statistical significance and, thus, a large enough sample of a homogeneous population. Each unrelated claim requires a specific population.
Claims involving objective research outcomes such as blood glucose and other quantifiable clinical or lab values are always more desirable for initial studies as compared with subjective efficacy variables, such as pain and feeling of well-being. Proving a hypothesis based on objective variables requires simpler designs (controlled studies are always better, but non-comparator studies are also possible) and smaller sample sizes. While some lab tests can be substantially more expensive than simple clinical questionnaires, it is always desirable to design claim statements bases on objective lab tests.
There will always be a tussle between advocates for soft claims (general benefit or improved well-being in patients with only mild disorders) and harder claims (significant improvement in quantifiable values of severe cases). While marketing and legal may decide on soft claims, the clinical research planner may still choose a harder claim to test in the research study. Depending on confidence levels from prior data, one may take on ambitious clinical endpoints or first prove the easiest marketable claim and then embark on more challenging studies.
Safety is a much-ignored variable and most dietary supplement companies fail to leverage the relative safety of their natural products to their advantage. Statements such as clinically proven to help lose 2 pounds per month and three times safer than can add to a brands claims portfolio.
One of the stronger factors in deciding primary claims in clinical trials is available study budgets. It is unfortunate that financials often play a greater role in shaping trial design and sample size than is desirable. Cost constraints coupled with overambitious marketing goals often seal the fate of the study even before it starts. If it is difficult to conduct a confirmatory study on a sizeable sample within the limitations of time and budget in North America, then one should actively to consider offshoring it to Asia. Both India and China are already hot clinical trial destinations for big pharma as well as start-up biotechs. There is no reason why cost and quality-conscious nutraceutical firms should not look that way.
Investing in an experienced research partner (CRO) early in the program can help companies design good human studies. Conducting these studies in the most scientific manner required is another subject.
Jayesh Chaudhary is founder and CEO of Vedic Lifesciences, a CRO specializing in nutraceutical claim substantiation trials. He can be reached at [email protected] or +91-98-210-86665.
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