Apr 14, 2014 - Why are functional foods and nutraceuticals so popular? The major ..... to further understand the adverse event, pharmacological effects on the.
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Human Clinical Trial for Nutraceuticals and Functional Foods Chin-Kun Wang
contents 22.1 22.2 22.3 22.4
Introduction ........................................................................................................................ 325 Discovery ............................................................................................................................ 326 Safety and Toxicity Evaluation ........................................................................................... 327 Clinical Trials ..................................................................................................................... 327 22.4.1 Sponsorship........................................................................................................... 327 22.4.2 Participating in Clinical Studies ........................................................................... 328 22.4.3 Institutional Review Boards ................................................................................. 328 22.4.4 Clinical Phases ..................................................................................................... 328 22.4.4.1 Phase 0 ................................................................................................. 329 22.4.4.2 Phase I ................................................................................................. 329 22.4.4.3 Phase II ................................................................................................ 329 22.4.4.4 Phase III............................................................................................... 330 22.4.4.5 Phase IV .............................................................................................. 330 22.4.5 Clinical Trial Design ............................................................................................ 331 22.4.6 Clinical Trial Protocol .......................................................................................... 331 22.4.7 Who Can Participate in a Clinical Study? ............................................................ 332 22.4.7.1 Eligibility ............................................................................................. 332 22.4.7.2 Participant Protection .......................................................................... 332 22.4.7.3 Safeguard ............................................................................................. 332 22.4.7.4 The Number of Participants Needed ................................................... 332 22.4.7.5 Follow-Up after Treatment in a Trial .................................................. 333 22.5 Summary ............................................................................................................................ 334 References ...................................................................................................................................... 334
22.1 IntroductIon Food is necessary and important for human beings. Except for providing the energy, health benefits have been greatly emphasized recently. Why are functional foods and nutraceuticals so popular? The major reason is the new challenge of noncommunicable diseases (NCDs) to human health. NCDs, also known as chronic diseases, are not transmitted from person to person. They are of long duration and generally slow progression. The four main types of NCDs are cardiovascular diseases (such as heart attacks and stroke), cancers, chronic respiratory diseases (such as chronic obstructed pulmonary disease and asthma), and diabetes.1 All age groups and all regions are affected by NCDs. NCDs are often associated with older age groups, but evidence shows that more than nine million of all deaths attributed to NCDs occur 325
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before the age of 60. Children, adults, and the elderly are all vulnerable to the risk factors that contribute to NCDs, whether from unhealthy diets, physical inactivity, exposure to tobacco smoke, or the effects of the harmful use of alcohol. To lessen the impact of NCDs on individuals and society, a comprehensive approach is needed which requires all sectors, including health, finance, foreign affairs, education, agriculture, planning, and others, to work together to reduce the risks associated with NCDs, as well as promote the interventions to prevent and control them.2,3 For the prevention and therapy of NCDs, conventional medicine is sometimes helpless and insufficient. Under the need of health, complementary and alternative medicine (CAM) shows its importance and new hope. Defining CAM is difficult because the field is very broad and constantly changing. The US National Center of CAM (NCCAM) defines CAM as a group of diverse medical and healthcare systems, practices, and products that are not generally considered part of conventional medicine. AQ 1 Conventional medicine (also called Western or allopathic medicine) is medicine as practiced by holders of medical doctor and doctor of osteopathic medicine degrees, and by allied health professionals, such as physical therapists, psychologists, and registered nurses. The boundaries between CAM and conventional medicine are not absolute, and specific CAM practices may, over time, become widely accepted.3 CAM practices are often grouped into broad categories, such as natural products, mind and body medicine, and manipulative and body-based practices. Although these categories are not formally defined, they are useful for discussing CAM practices. Some CAM practices may fit into more than one category. The natural products of CAM include use of a variety of herbal medicines (also known as botanicals), vitamins, minerals, and other “natural products.” Many are sold over the counter (OTC) as dietary supplements. (Some uses of dietary supplements—taking a multivitamin to meet minimum daily nutritional requirements or taking calcium to promote bone health—are not thought of as CAM.) The “natural products” of CAM also include probiotics—live bacteria (and sometimes yeasts) found in foods such as yogurt or in dietary supplements and live microorganisms (usually bacteria) that are similar to microorganisms normally found in the human digestive tract and that may have beneficial effects. Probiotics are available in foods (e.g., yogurts) or as dietary supplements. They are not the same thing as prebiotics—nondigestible food ingredients that selectively stimulate the growth and/or activity of microorganisms already present in the body. CAM includes many kinds of treatments. Functional foods and nutraceuticals are highly accepted and trusted because of their history and habitual use. “Complementary medicine” refers to the use of CAM together with conventional medicine. As for functional foods and nutraceuticals, they are good to assist to conventional medicine. However, based on the evidence, the related scientific intervention and related information, especially human clinical trials, are critically required.4–7
22.2 dIscovery Foods are the best medicine in the human history. Human foods include animals, plants, algae, microorganisms, and so on. To discover the health benefits, preclinical trials including in vitro, cell, and animal studies are used. However, the results are discovery and preclinical data. The cell system is fast and easy to know the reaction, and good to understand the detailed mechanism. Animal models are very practical to see the real response. Whether all the results can be completely responsive to the real situation in human being or not? Evidently, the answer is not so affirmative. However, the preclinical data are very worth for the advanced human clinical trial. In addition, the animal study can give a recommended dosage in the next human study.8 Basically, discovery is a scientific beginning and is also necessary for the new evidence. For new drugs development, the processed systems are well established, including the preclinical and various phases. In the preclinical discovery, molecular structure, best combination, screening design, cluster analysis, discriminant analysis, and factor analysis can be well obtained first. The dose-related response (regression) and pharmacological activity can also be provided by the animal study.9 The next step is to understand the genetic toxicity, animal toxicity, reproductive toxicity, carAQ 2 cinogenic toxicity, and the dose–relationship (regression). And further for absorption, distribution,
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disease state. For psychopharmacological agents, a fairly large sample size will be needed to discern the preliminary efficacy; for cancer trials, a relatively small number of patients may be sufficient to estimate the response rate. It is inherently clear that the results of the phase II trial will depend on the quality and adequacy of the phase I study. Likewise, the results from the phase II study are the basis for the expanded phase III trials.23 22.4.4.4 Phase III Adequate and well control are designed in this phase. The treatment is given to large groups of people (1000–3000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that allows it to be used safely. Usually this is a pivotal, placebo-controlled, and active control study. Further evaluation for the safety and efficacy, short term (weeks) and long term (one to two years) are required. Patients usually include the elderly AQ 6 (>65 years), or liver- or kidney-related patients. New drug application, commercialization, and valid evidence can be got in this phase.24 Because of the patient number and the trial duration, phase III trials are costly to run and more difficult to manage, especially for chronic medical conditions. Phase III studies are sometimes divided into phases IIIA and IIIB; placebo is used in the former and the market comparator is used in the latter. While phase III may remain blinded throughout the trial period, there are circumstances where open-label extension is carried out to confirm the efficacy. If efficacy becomes apparent at a certain point of the trial, the study may be terminated at an earlier stage through an interim utility AQ 7 analysis for example, BiDil® trial.25 More often than premature termination for good causes, many new chemical entities are terminated for development due to lack of efficacy through a utility analysis. This is undertaken to avoid the unnecessary suffering borne by the study subjects, besides the obvious economical consideration. Once the phase III trials are satisfactorily concluded, patient data from the multiple centers are pooled and analyzed for submission to appropriate regulatory authorities for review, along with a large body of information from preclinical investigation and manufacturing. Typically, two well-controlled phase III trials, at a minimum, are required for marketing. 22.4.4.5 Phase Iv AQ 8 After commercialized, to further understand the adverse event, pharmacological effects on the elderly, child, pregnant woman, morbidity, mortality, and also the new indication (new possible purpose). Phase IV trials may result in product recall or voluntary withdrawal from the market. Such AQ 9 examples included cerivastatin (Baycol), troglitazone (Rezulin), and rofecoxib (Vioxx) in the recent past.26 Some phase IV studies are not considered critical for marketing approval at the time of regulatory review, but clarification is important to warrant a postmarketing follow-up, for example, renal study for drugs that are primarily metabolized or drug interaction studies for drugs that are primarily excreted unchanged. Pediatric study, geriatric study, and gender effect study may also fall into this category, depending on the drug in question. There are phase IV studies that are required for labeling change such as the effects of juice, antacid or certain foods on oral medications, or boxed warning against adverse events. The drug company may also undertake phase IV study as a marketing strategy, in which head-to-head comparison with the competitor product is pursued. Prescription to OTC conversion is a commercial strategy undertaken by some drug makers after years of postmarketing surveillance demonstrating a high degree of drug safety. It is interesting to note that many phase IV studies are phase I in technical nature, but phase IV in terms of time sequence of study execution.27 Functional foods and nutraceuticals are not pure substances as the new drugs, and mostly are edible. In addition, the purpose of functional foods and nutraceuticals is not for disease therapy. They usually play the role on the health promotion, disease prevention, or therapy assessment. Phase II is usually recommended for the evaluation of nutraceuticals and functional foods. For further or advanced study, phases III and IV are required.28
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