Dr. Richard L. Wynn is Professor of Pharmacology at the University of Maryland Dental School. He holds a BS degree in Pharmacy and a PhD degree in Pharmacology. More »He chaired the Department of Pharmacology at the University of Maryland Dental School from 1980 to 1995. He is the lead author of the Drug Information Handbook for Dentistry, a co-author on many other dental drug publications, an author of over 300 refereed scientific journal articles, a consultant to the Academy of General Dentistry, a featured columnist, and a featured speaker presenting more than 500 courses in continuing dental education. One of his primary interests continues to be keeping dental professionals informed of all aspects of drug use in dental practice.

Supplement/Natural Products Safety - the Food and Drug Administration's Newly Proposed Guidelines

The 2011 proposed guidelines clarify the level of evidence the FDA would use to assess safety of supplements. Safety of a given supplement would be evaluated according to its documented history of use, the proposed daily dose and the recommended duration of use. The proposed guidelines are available at: http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/DietarySupplements/ucm257563.htm (accessed February 25, 2012)

The following is a summary of how the proposed guidelines would work - based on safety testing recommendations for new dietary ingredients (NDIs).

If the dietary ingredient was marketed in the US prior to passage of the DHESA (October 1994), and there have been no changes to the manufacturing process of the dietary ingredient, then the documented history of use would be sufficient for evidence of safety. This then leads in to a number of scenarios for any new dietary ingredient (NDI).

Scenario #1

If the documented historical use of the ingredient is "long term daily" and the proposed use of the NDI is also long term daily, but the proposed use leads to intake levels that are the same or less than levels consumed historically, then documented history of use should be sufficient for evidence of safety.
If the documented historical use of the ingredient is "long term daily" and the proposed use of the NDI is also long term daily, but the proposed use leads to intake levels that are greater than the levels consumed historically, then safety testing would be recommended.
If the documented historical use of the ingredient is "long term daily" and the proposed use of the NDI is intermittent, but the proposed use leads to intake levels that are the same or less than levels consumed historically, then documented history of use should be sufficient for evidence of safety.
If the documented historical use is "long term daily" and the proposed use of the NDI is intermittent, but the proposed use leads to intake levels that are greater than the levels consumed historically, then safety testing would be recommended.

Scenario #2

If the documented historical use of the ingredient is "intermittent" and the proposed use of the NDI is also intermittent, but the proposed use leads to intake levels that are the same or less than levels consumed historically, then documented history of use should be sufficient for evidence of safety.
If the documented historical use of the ingredient is "intermittent" and the proposed use of the NDI is also intermittent, but the proposed use leads to intake levels that are greater than the levels consumed historically, then safety testing would be recommended.
If the documented historical use is "intermittent" and the proposed use of the NDI is long term daily, but the proposed use leads to intake levels that are the same or less than levels consumed historically, then documented history of use should be sufficient for evidence of safety.
If the documented historical use is "intermittent" and the proposed use of the NDI is long term daily, but the proposed use leads to intake levels that are greater than the levels consumed historically, then safety testing would be recommended.

Scenario #3

If there is no history of documented use of the ingredient and the proposed use of the NDI is long term daily, then safety testing would be recommended.
If there is no history of documented use of the ingredient and the proposed use of the NDI is intermittent, then safety testing would be recommended.

The terms used in the above scenarios are defined as follows:

Daily use of the historically consumed material refers to ingestion at least once a day, every day, for at least three months in a row or for more than 90 days in a year.

Long term daily use refers to consumption of the substance every day by men, women and children throughout life, unless the notification specifies otherwise.

Intermittent use is any use that is less frequent than that defined as daily use. Intermittent use, thus, can be either daily, but finite in duration or non-daily and lifetime in duration.

In the above scenarios in which the safety studies are recommended, examples of those safety studies are the following:

A two-study genetox battery (bacterial mutagenesis and in vitro cytogenetics) that includes a test for gene mutations in bacteria, either an in vitro mouse lymphoma thymidine kinase+/- gene mutation assay (preferred) or another suitable in vitro test with cytogenetic evaluation of chromosomal damage using mammalian cells.
A 14-day range-finding oral study to establish a maximum tolerated dose (MTD) in an appropriate animal model.
A 90-day sub-chronic oral study (same species as the range-finding study) to establish an MTD and a No Observed Adverse Effect Level (NOAEL) for use in calculating the margin of safety.
A repeat-dose tolerability study in humans (30-90 day duration).
A one-year chronic toxicity study in an appropriate animal model or a two-year carcinogenesis study in rodents.
A one-generation rodent reproductive study.
A teratology (risk of birth defects) study (rodent or non-rodent).

The published perspective in the New England Journal of Medicine mentioned at the beginning of this newsletter includes a commentary on the proposed guidelines and is entitled Perspective: assessing supplement safety - the FDA's controversial proposal, by Dr. Pieter A. Cohen, from Cambridge Health Alliance, Somerville, MA and Harvard Medical School, Boston, (New England J Medicine 2012; 366(5):389-91).

As part of his commentary, Dr. Cohen mentions that Americans spend $28 billion annually on supplements, with more than 100 million Americans consuming those dietary supplements.

The DSHEA law from 1994 stipulates that for new ingredients (those introduced since 1994), manufacturers must provide the FDA with evidence supporting a "reasonable expectation of safety." According to Dr. Cohen, this has not been enforced.

Since DSHEA became law, the number of dietary supplements increased from an estimated 4,000 marketed products to more than 55,000. Of the new 51,000 products, the FDA has received safety data submissions from approximately 170 new supplement ingredients. Thus, many new products have been introduced without any assessment of safety. To address the lack of safety data submissions, the proposed new guidelines are designed to help assess safety of any new dietary ingredient.

According to Dr. Cohen, industry supporters have petitioned the FDA arguing that the guidance is overly stringent and should be withdrawn. They argue that the guidelines hold supplements to similar safety standards as food additives, which was not Congress's intent when DSHEA was formulated. They also argue that DSHEA does not hold established (pre-1994) supplement ingredients to the same safety standards as food additives.

To counter that argument, Dr. Cohen states that "the industry's argument is flawed with respect to new supplement ingredients." Additionally, "The FDA's legal authority over new products is generally greater than that over established products." DSHEA explicitly requires the FDA to assess the reasonable expectation of safety of new ingredients and it can only be done with experimental data.

Quality Control Standards for Supplement Manufacturers

The following describes the quality control standards of Good Manufacturing Practice (GMP) in effect as a result of the 2007 guidelines.

The FDA guidelines require that domestic and foreign manufacturers of vitamins, herbs and other dietary supplements follow standards to show that their products are labeled properly and not contaminated. The guidelines ensure the quality of dietary supplements so that consumers can be confident that the new products they purchase contain what is on the label.

The standards lay out practices to ensure quality during manufacturing, labeling and storage of dietary supplements. They list requirements for quality control procedures, the design of manufacturing plants along with the testing of ingredients and final products. The guidelines became effective for the large manufacturers in June 2008 and for small companies in June 2010. The guidelines also stipulate that manufacturers are required to report adverse effects caused by their products.

Under the rules of GMP, the FDA can now inspect manufacturing plants for compliance. Companies must keep records showing that supplement ingredients have been tested. At the present time, these records do not have to be submitted to the FDA. Manufacturers are responsible for devising scientifically defensible tests for the purity of ingredients. If a company violates the rules of GMP, the FDA has the authority to fine the firm and ask for a voluntary withdrawal of a product.

These guidelines can be found at:

http://www.fda.gov/Food/DietarySupplements/default.htm (accessed Feb 25, 2012)

When these standards for quality control were passed, it was recognized, at that time, that GMP did not assure product safety. Hence, the guidelines of 2011 have been proposed to fill in that gap.

Stay tuned!