Thoughts about Draft Guidance and NDI Notifications

Alcrea Health believes in the principles behind the Draft Guidance—namely, ensuring consumer safety. However, we question why, after 17 years, FDA has published such stringent guidelines.  We do not believe that a consumer safety crisis exists to justify such action. Let’s take a look at the topics in question…

FDA’s Requirement for NDI Notification Based on Products Instead of Ingredients

The Draft Guidance requires submission of an NDI notification by each and every manufacturer or distributor for each and every product that contains an NDI, rather than relying on general safety information and dosage parameters per ingredient for all products.

Theoretically, any variation whatsoever to the ingredients of a dietary supplement containing an NDI would require a new NDI notification. This approach is unwarranted.  FDA has historically permitted notifications based on ingredients, not finished products. For example, bulk ingredient notifications from suppliers provided recommended ranges for safe use of the NDI in finished products manufactured by their customers 

Companies that rightfully bypassed this step, relying on a previous FDA acknowledgement for an ingredient, should not now be required to come forward and submit a notification. Such a result would generate a regulatory logjam with no benefit to the consumer.

Treatment of “Chemically-Altered”

Processes that would not render an ingredient “chemically-altered” is unnecessarily limited. It appears to be generated using 1994 standards without accounting for any processes developed or improved since.

By requiring excess NDI notifications in this way, FDA would drive up production costs and stifle innovation as manufacturers would forego new technologies.

Treatment of Probiotics

Probiotics are a lawful and viable category of dietary ingredients. However, the Draft Guidance’s treatment of probiotics created using advancements in fermentation media causes concern of unnecessary exclusion of safe and effective species or strains.

Advancements in fermentation or production processes designed to improve culture yield and stability do not create an NDI.

Treatment of Synthetic Herbal and Botanical Ingredients

We disagree with FDA’s proposed treatment of synthetic herbal and botanical ingredients.  DSHEA’s definition of a dietary supplement outlines the ingredients a product can contain, including a vitamin, a mineral, an herb or other botanical, an amino acid.

Because synthetic versions of vitamins, minerals, and amino acids are already permitted, it is arbitrary and illogical to exclude synthetic versions of herbs and other botanicals in the Draft Guidance. As such, we hope FDA reconsiders this position.

The Draft Guidance Creates “Homogenized Products” and Discourages Innovation

We believe that if the Draft Guidance is adopted in its current form, the resources required to submit redundant, product-based NDI notifications will limit innovation by creating an environment where pre-approved, “canned” products will become the norm due to a less resistant path to market. While unfortunate, we believe this is a practical reality. This policy would encourage a marketplace lacking product differentiation where the consumer will have limited access to health-promoting supplements, contrary to Congress’s intent as conveyed in DSHEA.

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Ingredient Spotlight: Magtein®

As the US population continues to age, there is a greater desire for supplements that can help support healthy memory and cognition.  One such novel product is Magtein®. Comprised of magnesium theronate, Magtein® has been shown to raise brain magnesium levels. Higher magnesium levels in the brain are associated with improved memory and cognitive functions.  Magnesium is an essential mineral that acts as a cofactor to over 300 enzymes involved in energy metabolism and biosynthesis. 

As a supplement, it can often be found in products that support healthy mental function. Until recently, magnesium’s use in brain function was not fully elucidated.  However, with the recent discovery of Magtein®, research is now showing that brain magnesium levels are associated with optimal neurological support.  Magtein® has been compared to other sources of magnesium; most were unable to effectively raise brain magnesium levels.

The Science behind it…

In one preliminary study, Magtein® was shown to help support short term synaptic facilitation and long term potentiation, as well as supporting healthy memory and cognition function in both young and aged animals. A human double blind placebo controlled trial has recently been started at the University of Southern California, with preliminary results expected in 6-8 months.

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Alcrea Health Executive Response to Multivitamin and Vitamin E Studies

Two recently published scientific articles have been picked up by the mainstream press and are being used to cast a negative light on dietary supplements. We would like to briefly explain the two studies and help to put their findings in context.


Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR. Dietary supplements and mortality rate in older women. Arch Intern Med. 2011;171(18):1625-33.

The first of the two articles was based on an analysis of data from the Iowa Women’s Health Study. This study, started in 1986, was designed to investigate associations between diet and lifestyle factors and the incidence of cancer in postmenopausal women. The current analysis examined the connection between supplement use and the risk of mortality in a cohort of over 38,000 women enrolled in the Iowa Women’s Health Study. The authors conclude that common vitamin and mineral supplementation by older women is of no benefit and is associated with an increased total mortality risk. The authors point out that the connection between supplementation and increased mortality risk was strongest for iron; however, they also found that supplemental multivitamins, folic acid, B6, magnesium, and zinc were associated with an increased risk of mortality. This has been portrayed by the media as new findings of the “deadly danger” of vitamins, and a further opportunity for those that believe the industry needs more regulation to advance their agenda. So, let’s put some things in context and better understand some key points about this study:

• This is an observational study spanning a 22 year time frame (1986-2008) and is not an intervention trial in which supplements were given. Observational studies are certainly not intended to determine cause and effect relationships.

• The use of supplements was obtained by subjects self-reporting their use at three times during the course of the study – 1986 (baseline), 1997, and 2004. In the authors’ analysis of mortality risk between the years of 1986 and 2004, if a subject reported supplement use during any of the 3 time points, they were considered to be a supplement user for the entire duration of the study. Certainly this methodology may not reflect long-term supplement use, as subjects could have discontinued or started supplementation that would not have been reflected in the analysis. Additionally, as the authors noted, supplement use changed dramatically during the course of the study. In 1986, self-reported supplement use was 62.7%, whereas in 2004 supplement use was 85.1%. Increased supplement use during the course of the study could have been the result of many factors, including self selection by subjects attempting to deal with failing health.

• The authors had to manipulate and adjust their analysis in order to find the negative associations that they reported. Supplement use at baseline was associated with a lower prevalence of diabetes, hypertension, and smoking as well as a lower BMI and hip:waist ratio. Supplement users were also more likely to have a lower intake of total calories, fat, and saturated fat and had a greater intake of grains, fruits and vegetable. When the data were analyzed and adjusted for age and energy intake, many of the supplements assessed were associated with a significantly decreased risk of mortality. It was not until the data were adjusted in an attempt to control for the variables associated with supplement use that the negative associations became statistically significant. However, in a statistical model it may be impossible to fully separate the healthful behaviors and characteristics that are associated with being a supplement user.

• The increased mortality risk from iron supplementation was mostly observed in subjects supplementing with greater than 200 mg/day. This level of supplementation is often associated with conditions such as anemia, for which there may already be an increased risk of mortality. This was not controlled for in the current study.

• The use of hormone replacement therapy was significantly greater in supplement users (13.5%) compared with nonusers (7.2%) during the duration of the study. While the authors attempted to adjust for this in their analyses, it certainly could have represented a confounding variable that could not have been sufficiently factored out of the analysis.

• Importantly, the manner in which the authors classified “nonusers” of supplements in their analyses is curious. They looked at 15 different supplement variables: multivitamins, vitamin A, beta-carotene, B6, folic acid, B complex, vitamin C, vitamin D, vitamin E, calcium, copper, iron, magnesium, selenium, and zinc. To assess the risk from a particular variable such as zinc, they compared the mortality in users of zinc supplements with the mortality in “nonusers” of zinc supplements. However, while the subjects in the “nonusers” of zinc category may not have been taking a standalone zinc product, many would have also been taking a multivitamin that contained zinc or supplements other than a standalone zinc product. As a result, in the analysis of risk for zinc users, the group against which they were being compared would have contained subjects who were consuming supplemental zinc. This point is not addressed in the study and could represent a serious limitation with respect to the interpretation of the data.

• It is interesting to note that very little attention is given to the fact that calcium supplementation was associated with a significant reduction in total mortality risk, cardiovascular mortality risk and cancer mortality risk.

These points highlight just a few of the questions and limitations that surround this study. The commentary accompanying the study is equally biased against supplementation and in general portrays supplementation in a negative light. We don’t believe that there is anything contained within this study that should cause one to stop taking their supplements, and in fact it raises more questions than it answers.

Vitamin E

The second recently published article was an analysis of data from the SELECT trial.

Klein EA, Thompson IM, Tangen CT, et al. Vitamin E and the risk of prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549-1556.

Similar to the multivitamin trial, the SELECT trial received significant negative media attention due to the reported finding of an increased risk of prostate cancer in those supplementing with vitamin E. The SELECT trial was a prospective randomized, placebo-controlled trial investigating if vitamin E, selenium, or the combination could reduce the risk of prostate cancer. Over 35,000 men at average risk for prostate cancer were randomized between 2001 and 2004 to participate in the study. Subjects were assigned to 400 IU/day dl-alpha-tocopherol (synthetic alpha-tocopherol), 200 μg selenium (from selenomethionine), the combination of the two, or placebo. A 2009 publication from the SELECT trial, with a median follow up of 5.5 years, revealed no statistically significant increase or decrease in prostate cancer risk among any of the groups. In 2008, the data and safety monitoring committee recommended that the study be discontinued because of “lack of efficacy for risk reduction…” The current publication is an analysis of the data taking in to account additional cases of prostate cancer in subjects through May, 2011. The authors reported a 17% increase in the risk of prostate cancer in the vitamin E group and did not find an increased risk in either the selenium or selenium plus vitamin E groups. A number of points should be understood in order to put these findings in context.

• The results of this study are in contrast to previously published randomized clinical trials including the Alpha-Tocopherol, Beta-Carotene trial (ATBC) and the Physicians Health Study II, which either found a reduced risk of prostate cancer or no change in risk.

• The results are also in contrast to previous trial including the CHAOS, HOPE, HOPE TOO and SPACE trials.

• It should be noted that the expert panel assembled by the American Institute for Cancer Research/World Cancer Research Fund (2007) examined a total of six cohort studies, 14 case-control studies, and one ecological study regarding the relationship between dietary and/or serum vitamin E and concluded that “there is limited evidence suggesting that foods containing vitamin E, and alpha-tocopherol supplements are protective” against the risk of prostate cancer. Importantly, none of these observational studies reported an increased risk of prostate cancer associated with vitamin E.

• A strange finding of the current study is that vitamin E was very specific for prostate cancer risk. No other increased risk of any other cancer, cardiovascular disease, diabetes or all-cause mortality was observed in the vitamin E group. The authors were not able to offer, nor does there appear to be any biological reasoning for the apparent specificity on prostate cancer risk. The authors also could not explain why there was no increased from the presence of selenium with vitamin E.

• No data on vitamin E levels were given so we don’t know the baseline vitamin E status of the subjects in any of the groups.

• Although the study was stopped in 2008, the current analysis includes cancers through 2011. We don’t know how many subjects continued taking supplements on their own and what impact the lack of supplementation over the past three years could have had on the outcome.

• Prostate cancer status was determined by self-reporting at 6-month intervals. The diagnosis was then centrally confirmed by the SELECT central pathology laboratory after obtaining the subject’s medical records. However, the authors state that 17% of the cancers were not centrally confirmed yet are still included in the analysis.

• The SELECT trial had an unusually small number of deaths from prostate cancer compared with what would be expected given the length of the study and number of participants.

• The form of vitamin E used was synthetic alpha-tocopherol and not natural-source alpha-tocopherol. We know that these forms of alpha-tocopherol are significantly different and are metabolized differently by the body.

As is the general rule, one should not rush to judgment based on the result of a single study, especially when it does not fit with the totality of the existing data. All of the evidence should be considered when making decisions about supplementation. Similar to the multivitamin study, many important questions remain unanswered in the most recent SELECT analysis.

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Ingredient Spotlight: Pterostilbene, Next Generation Resveratrol

We see great potential for creating custom nutritional supplements using the potent antioxidant pterostilbene, offering health benefits ranging from anti-aging, heart health, oxidative stress and memory.  Because of its better absorption and ability to last up to 7 times longer in the body than resveratrol, current science supports lower a daily dosage create an opportunity to include other key nutrients within the same supplement.

You may already know…

Resveratrol is a naturally occurring plant polyphenol commonly found in grape vines and skins.  Highly regarded as a powerful antioxidant, it plays supporting roles in normal cardiovascular and mitochondrial function.  Studies also indicate resveratrol may be supportive in maintaining the normal aging process by helping to prevent free radical damage that can lead to premature aging of cells.

But are you aware…

Pterostibene is a methylated resveratrol that is naturally occurring in berries.  Some advantages over resveratrol include:

  • Superior biological activity
  • Better oral bioavailability
  • Slower metabolism in the body

The enhanced activity of pterostilbene compared to resveratrol may be explained by structural differences.  Pterostilbene with two methoxy groups and one hydroxyl group has a greater ability to dissolve in fats, oils, lipids and non-polar solvents, and a higher potential for cellular uptake than resveratrol, which has three hydroxyl groups.

Pterostilbene also supports cardiovascular health.  In vivo studies demonstrate that pterostilbene possesses lipid and glucose lowering effects.

Two may be better than one!

Both pterostilbene and resveratrol support mitochondrial function and healthy aging by activating SIRT1, a key enzyme in a family of proteins that have been associated with influencing aging, energy efficiency, and alertness during low-calorie intake.

Researchers have suggested that these two compounds also work synergistically.  The combination of pterostilbene and resveratrol in a formulation may in fact be more effective than using these ingredients separately.

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Atrium Innovations Starts $5M Metabolic Syndrome Research

Atrium InnovationsResearch is an ongoing commitment everyone in the Atrium family is proud of. In fact, it is one of our core values and the key to Growing Together In Health. Investing in research allows us to continue to lead the way in developing and providing best-in-class supplements to help address today’s top health concerns. More than product development, we are investing in advancements to health management.

Better Health through Research

Our latest and largest research program to date, a $5 million multi-year commitment in collaboration with our strategic partner INAF (Institute for Nutraceuticals and Functional Foods), involves gaining a better understanding of Metabolic Syndrome and investigating the impact of nutrition on the prevention and treatment of the Silent Inflammation associated with this condition.

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Quality Matters!

Superior products begin with superior raw materials and every raw material that enters our building is inspected and quality control approved. All materials go through a rigorous inspection to ensure they meet predetermined standards that have been set for each raw material. As an additional step, we also meet face to face with raw material manufacturers on an annual basis as part of our Vendor Certification Program to ensure that we have a sound understanding of each material and can address any new advances that may have developed in the previous year. Unlike many other dietary supplement manufacturers, we have our own in-house microbiological laboratory that is partitioned off from the rest of our facility and operates using a separate air-flow system. Before ingredients can be used in any product, they are subjected to testing in our microbiology lab for contamination including total aerobic plate count, yeast, mold, E. coli and other potential pathogenic organisms including staphylococcus, salmonella and pseudomonas to ensure that the materials meet or exceed the requirements of the United States Pharmacopoeia (USP). Only after quality control approval has been granted can the raw material be released for use in one of our products.

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Things to Consider when Choosing a Contract Manufacturer (CMO)

With the growing popularity of nutritional and dietary supplements, the demand for quality manufacturers is on the rise. There are many companies producing these products so it is important that you review various aspects of each company before deciding who will best fit your needs not just immediately, but in the future as new projects present themselves.

1. Does the CMO have a commitment to product quality and the expertise necessary to differentiate/innovate products?

When looking to partner with a CMO, the first thing that most people look at are the product capabilities. If you are a company who is looking to grow and diversify your product or brand, then you may want to look at the types of forms and delivery systems offered and find out what type of support your potential manufacturing partner can offer you. If they have a knowledgeable team that can help create science based supplements, you can be sure you are getting a quality product. Also, you may want a team that can make suggestions on new and revised formulations as they pertain to ingredients, product form and delivery, and packaging choices. No matter what your needs are, you want to choose a partner who will work with you to ensure that you are getting the best product to fit your brand’s identity.

Alcrea’s Solution: We manufacture traditional tablets, capsules and powders. More innovative product options are available in CapliquesTM (two-piece liquid capsules), liquid sprays, and other liquids. There are opportunities to further customize your supplement by using colors, banding, printed logos, flavors, and delivery systems for an end product that is unique to your brand. On-staff PhDs and scientific experts are available to assist you in formulating your product and overseeing the quality control during the manufacturing process. We strive to deliver supplements to fit our clients’ needs, as our product development and technical team weigh in with ingredient suggestions for higher efficacy, lower cost, or other suggestions in accordance with the parameters you define for your product.

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Creating a Superior Vitamin D Supplement with VESIsorb® & Caplique®

VESIsorb® is a nano-colloid delivery system that enhances solubility and absorption of fat-soluble vitamins, such as Vitamin D. This process helps the body better utilize supplemental nutrients for maximized benefits:

  • Increased bioavailability of Vitamin D in liquid-filled Caplique®
  • Reduction of dosage size due to increased effectiveness
  • Better results for the consumer
  • Reduced costs as less raw materials needed

Why a Caplique®?

Traditionally, Vitamin D has been manufactured in tablet form. By exploiting the technology behind our liquid-filled capsule, you are already on your way to providing a product with greater bioavailability in its delivery. Since Capliques® are customizable, this dosage form also allows for many opportunities to fit your brand’s unique identity.

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