If you liked the Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues of July, 2011, you will love the next draft guidance, if the April 2016 meeting[1] convened by the National Toxicology Program (NTP) provides any clues.
As you may recall, the July, 2011 draft guidance for an NDIN was particularly onerous in its mandate for extensive animal testing, the scope of which was at least on the level of a food additive petition, if not an IND. Because such demanding guidance was not in the spirit of the law[2] and particularly burdensome for the majority of dietary supplement manufacturers (most of whom are small or micro-market capitalized companies), the guidance was met with a firestorm of criticism from industry and Congress. Although (former) Commissioner Hamburg withdrew the draft guidance, it still remains on the FDA website and has been referenced in NDIN objection letters. Still, NDINs suffer a rejection rate of 66% from a net of 610 applications (from a gross of ~900).[3] Consumers and Industry must learn to deal with the fact that FDA has never looked favorably on dietary supplements or claims for any substance that does not come with an IND.[4]
It is the author’s belief that the April meeting, Addressing Challenges in the Assessment of Botanical Dietary Supplement Safety pre-sages the next attempt by FDA to curtail what it sees as an industry populated with a small, but reckless industry segment willing to pack most anything into a capsule or container and play off the willingness of a public to buy into splashy internet headline stories on “important new discoveries!” that report extrapolations of half-baked and unverified research as characterizing life-enhancing new products. Also, there is a large constituency within Congress and the public that feel the dietary supplement industry is unregulated and/or out of control. On the other side of this argument are responsible manufacturers and the public that have shown a certain tenacity and push back against unreasonable FDA-ODS[5] over-reach. Because of the strong feelings on both sides, FDA will have to launch its offensive from solid and familiar ground – this will be a two-pronged offensive, based on safety and truth- in-labeling demands. Naturally, this new offensive begs the question of why this tactic was not employed before, as it would be embarrassing to work on a pretext that has existed for the last 22 years? The answer is that the new emphasis is based on the findings of the National Toxicology Program, which forms the nexus of the now shared interests of these two agencies.
Although it is not the purpose of this article to embarrass the NIEHS, the NTP has conducted a series of ill-advised studies on natural products, but for our purposes here, a description of the study on non-decolorized whole leaf extract of Aloe Barbadensis Miller (i.e., aloe vera) will suffice. The NTP study showed carcinogenic effects of the extract in the intestine of male and female rats, which no one disputes; however, the issue is that the aloe extract used in the NTP study is not the aloe marketed to the public. That is, the NTP extract contained an aloin A content at approximately 6500 ppm, a figure that approximately doubles when the content of aloin B is considered, representing a total aloin content more than 1000 times greater than the industry standard.[6] This unfortunate example of erroneous study planning was undoubtedly a compelling antecedent to the April meeting at NIEHS.
Unfortunately, the slides from the April meeting have not been made available, although there is a 15+ hour video tape of the meeting in which the speakers make points as follows:
Traditional taxonomic classification (morphotypes) are sometimes passed over in favor of more accurate chemotype (chemometric) methods; for example, some plants such as chamomile, with three varieties (Roman, German and Chinese), look alike, but have different chemistry.
Identical varieties of plants may have far ranging quantitative differences in their constituents based on geographic location of growth (such as American Panax ginseng grown in Canada vs. mainland China) and local growth conditions (e.g., temperature, available minerals, sunlight, moisture).
Different parts of plants may contain quantitatively and qualitatively different profiles of biologically active substances.
Constituents of plants such as ginseng (now known to have 70+ ginsenosides) have competing activities which may produce a different response given the plant origin and extraction procedure, begging the question of what standards should be employed for assay?
Normally acutely fatal larkspur has within population diversity, with seasonal changes in toxicity, with some varieties non-toxic at certain times.
Biologically active constituents are often present at very low levels and the predominant constituents present at easily detectable levels may have very little to do with biologic activity.
The point to the above being that Nature has not seen fit to standardize plants or their constituents and we should not expect to grind up any batch of similarly looking weeds and seeds and expect the crude lot or any extraction to behave identically in a biological system. The message from the NIEHS is that in the future, it will overcome the mistakes made in previous naturals testing, by characterizing the constituents of the natural extractive and using only standardized extracts as test material. This new NIEHS mantra fits well within the mission of ODS, which may well demand that future dietary supplement products identify the biologically active constituents and be standardized for biological activity and, other potentially active constituents with possible competing (or potentiating) activities, be eliminated. Exacting qualitative and quantitative identification of constituents will easily fit within a paradigm for enforcement for accurate labeling and safety testing of the specific product, rather than a non-specific gamish.
What will be the “bottom line” for the interested parties? For ODS and those concerned about the “wild west” nature of the supplement community, there should be some comfort that the public is not being defrauded and safer supplements will be available. For the industry, this new level of scrutiny may result in the loss of all but large cap companies that can afford to complete the necessary research and, will usher in an era of pharmaceutical company dominance of the supplement business. For consumers, the supposedly ultimate beneficiaries of stringent new rules, the price for these benefits will be obvious at the checkout line.
[1] “Addressing Challenges in the Assessment of Botanical Dietary Supplement Safety,” convened by the National Toxicology Program (NTP). The workshop took place April 26-27 at the National Institutes of Health (NIH).
[2] “…(13) although the Federal Government should take swift action against products that are unsafe or adulterated, the Federal Government should not take any actions to impose unreasonable regulatory barriers limiting or slowing the flow of safe products and accurate information to consumers; (14) dietary supplements are safe within a broad range of intake, and safety problems with the supplements are relatively rare; …” Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 103rd Congress.
[3] Dr. Carra Welsh April 26, 2016. Net applications = those applications include those having been resubmitted after an initial rejection.
[4] George Burdock, “A Brief History of Health Claims” Tan Sheet, April 22, 2013.
[5] The newly formed Office of Dietary Supplements.
[6] Dentali, S. (2013) Toxicol. Sci. doi: 10.1093/toxsci/kft072