Risk Assessment of RYR Food Supplements: Perception vs. Reality

This guidance describes how the FDA evaluates patient-reported outcome (PRO) instruments used as effectiveness endpoints in clinical trials. It also describes our current thinking on how sponsors can develop and use study results measured by PRO instruments to support claims in approved product labeling (see appendix point 1). It does not address the use of PRO instruments for purposes beyond evaluation of claims made about a drug or medical product in its labeling. By explicitly addressing the review issues identified in this guidance, sponsors can increase the efficiency of their endpoint discussions with the FDA during the product development process, streamline the FDA's review of PRO endpoint adequacy, and provide optimal information about the patient's perspective of treatment benefit at the time of product approval. A PRO is a measurement of any aspect of a patient's health status that comes directly from the patient (i.e., without the interpretation of the patient's responses by a physician or anyone else). In clinical trials, a PRO instrument can be used to measure the impact of an intervention on one or more aspects of patients' health status, hereafter referred to as PRO concepts, ranging from the purely symptomatic (response of a headache) to more complex concepts (e.g., ability to carry out activities of daily living), to extremely complex concepts such as quality of life, which is widely understood to be a multidomain concept with physical, psychological, and social components. Data generated by a PRO instrument can provide evidence of a treatment benefit from the patient perspective. For this data to be meaningful, however, there should be evidence that the PRO instrument effectively measures the particular concept that is studied. Generally, findings measured by PRO instruments may be used to support claims in approved product labeling if the claims are derived from adequate and well-controlled investigations that use PRO instruments that reliably and validly measure the specific concepts at issue. The glossary defines many of the terms used in this guidance. In particular, the term instrument refers to the actual questions or items contained in a questionnaire or interview schedule along with all the additional information and documentation that supports the use of these items in producing a PRO measure (e.g., interviewer training and instructions, scoring and interpretation manual). The term conceptual framework refers to how items are grouped according to subconcepts or domains (e.g., the item walking without help may be grouped with another item, walking with difficulty, within the domain of ambulation, and ambulation may be further grouped into the concept of physical ability). FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidance documents describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance documents means that something is suggested or recommended but not required. First publication of the Draft Guidance by the Food and Drug Administration- February 2006.

Red yeast rice (RYR) is a widely available dietary supplement used by millions of patients as an alternative therapy for hyperlipidemia. It contains 14 active compounds called monacolins that inhibit hepatic cholesterol synthesis. Although studies have suggested that some formulations of RYR may be effective and safe for lipid lowering, monacolin levels are not standardized among marketed products and are generally not published on labels. We evaluated monacolin levels in 12 commercial RYR formulations and tested for citrinin, a mycotoxin that is nephrotoxic in animals. Each formulation of RYR was labeled "600 mg/capsule" of active product. Analyses for monacolins and citrinin were performed between August 2006 and June 2008 using high-performance liquid chromatography with mass spectroscopy-mass spectroscopy detection. Laboratory analyses of RYR products were conducted by ConsumerLab.com, White Plains, New York. There was marked variability in the 12 RYR products in total monacolins (0.31-11.15 mg/capsule), monacolin K (lovastatin) (0.10-10.09 mg/capsule), and monacolin KA (0.00-2.30 mg/capsule). Four products had elevated levels of citrinin. We found striking variability in monacolin content in 12 proprietary RYR products and the presence of citrinin in one-third of the formulations tested. Although RYR may have potential as an alternative lipid-lowering agent, our findings suggest the need for improved standardization of RYR products and product labeling. Until this occurs, physicians should be cautious in recommending RYR to their patients for the treatment of hyperlipidemia and primary and secondary prevention of cardiovascular disease.