Putting the Nutritional Supplement Industry to the Test: Looking for Transparency

Frederick H. Fern Marina Plotkin @RickFern_HB @MarinaPlotkin_HB [email protected] [email protected] Putting the Nutritional Supplement Industry to the Test

. Objectives:  Recent Activity by NY Attorney General  DNA Barcoding Issues  Regulatory Scheme  Increased FDA Scrutiny, Recent FDA Guidance and Litigation  Best Practices for Industry

. Contribute $122B to the U.S. economy . $37B sales in the U.S. in 2014 . Projected $180 billion globally by 2020 . 65,000 supplements on the market . 68% of Americans consume dietary supplements

. February 2, 2015 . Cease and desist letters sent . Four retailers ordered to remove certain store-brand products from New York stores

. AG requested documents concerning authenticity, purity and marketing of herbal supplements sold in NYS since January 1, 2013 from:

1) NBTY Inc. (New York) 2) Nature’s Way Products Inc. (Utah) 3) Pharmavite, LLC (California) 4) Nutraceutical Corp. (Utah)

. November 2013 New York Times article referred to the 2013 study . “DNA Barcoding Detects Contamination and Substitution in North American Herbal Products”

What was tested?

. 78 bottles of popular, store-brand herbal supplements from:  Walmart  Target  Walgreens  GNC

. DNA Barcoding to determine the presence of the genetic materials of the plants listed on the label  Technique to characterize species of plant  Using a short DNA sequence from genome . AG has not disclosed details of testing methods

. Is DNA Barcoding an appropriate method of testing botanical extracts?  Extraction process degrades DNA  No complete library of DNA barcodes for validation  No single technology adequate

. 21% of tests confirmed labeled ingredients . 35% of tests identified DNA barcodes from plants not on label  GNC Ginseng tested negative for any DNA from ginseng plant  Walgreens’ Ginseng contained powdered garlic and rice . Raw data not released . Transparency?

. Two recent studies -- DNA barcoding is not an adequate method by itself  FDA data and an Australian research consortium, both presented at Oxford International Conference on the Science of Botanicals at the University of Mississippi . FDA data on five popular botanical ingredients – Soy, Valerian, Yohimbe, St John’s wort, and Ginkgo  Vastly different results from high-performance liquid chromatography analysis versus DNA barcoding

http://www.nutraingredients-usa.com/Research/Data-confirms-that-DNA-barcoding-alone-not-suitable-for-finished-dietary-supplement- products

. More successful if carried out on raw herbal materials before processing . More successful if carried out on dried or powdered raw material versus the final extract or tincture . Cannot differentiate between plant parts (root versus leaf, for example) . Cannot differentiate between plants within the same species . Excipients/fillers could give a false negative . No reference libraries for DNA sequences . Unsuitable as a stand-alone tool . Should be “part of a multi-faceted approach” (Natural Products Association)

Litigation Landscape . Consumer class actions filed against all four targeted retailers . In re: Herbal supplements marketing and sales practices litigation  Currently 73 associated cases  Consolidated in MDL – U.S.D.C. N.D.Il.  Economic damages; no personal injury alleged

. GNC products are safe and compliant . What did GNC agree to? . Will GNC’s terms become the standard for future agreements with other retailers? . Effect on the industry?

. Harris Beach assisted trade organization in setting up meeting with AG to discuss industry education . Natural Products Association (NPA) and AG issue joint statement:  Product safety  Authenticity  Transparency . Will other industry trade organizations follow suit?

. NBTY, one of the nation’s largest manufacturers of popular herbal supplements agreed to conduct advanced genetic testing (DNA barcoding) to help:  Confirm authenticity  Ensure purity  Educate consumers on chemical contents . The agreement affects several popular brands including Solgar, Nature’s Bounty and Sundown Naturals. . This is the third agreement with a supplement maker negotiated by the NYS AG

. NBTY will invest $250,000 in herbal authenticity genetic research and education . “I am pleased that NBTY has joined GNC and Nature’s Way and agreed to increase transparency, improve quality control, and do more to protect consumers, and I urge the rest of the herbal supplements industry to do the same.”

. AGs sent letters to Congress and FDA for stronger oversight of the industry . May 26, 2015 letter from New York AG/Indiana AG to FDA urging cGMP reforms

. The Dietary Supplement and Health Education Act of 1994 (DSHEA)  Amended the FD&C Act by defining “dietary supplement” and “new dietary ingredient”  Mandated the New Dietary Ingredient Notification  Without the New Dietary Ingredient Notification, the new dietary ingredient is deemed adulterated

. FDA issued regulations to implement the FD&C Act’s premarket notification (1997)  21 CFR 190.6

. FDA Food Drug Modernization Act (FSMA, 2011)  Required FDA to publish guidance

. August 2016, FDA issued best practices for NDIs in a draft guidance document

. While only a draft – helpful to interpret the FDA’s position

Any one of the following:

 Vitamin  Mineral  Amino Acid  Herb or Other Botanical  Dietary substance to supplement the diet by increasing the total dietary intake  Concentrate, metabolite, constituent, extract or combination of any ingredient above

. Synthetically produced substances  Synthetic vitamins, minerals, and amino acids qualify as dietary ingredients

 Per FDA, a synthetic copy of an herb or botanical does not qualify as a dietary ingredient unless used as a lawfully marketed ingredient in the conventional food supply

. A dietary ingredient that was not marketed in the U.S. before October 15, 1994 . Dietary ingredients marketed prior to October 15, 1994 do not require NDI notification . There is no current authoritative list of dietary ingredients marketed prior to October 15, 1994 . FDA draft guidance proposed to develop a list of grandfathered ingredients exempt from NDI notification

. When the NDI has been present in the food supply in a form that is not chemically altered . Examples of chemical alteration:  A process that makes or breaks chemical bonds (example - hydrolysis)  Changing the chemical or molecular composition or structure (examples – chromatography, distillation, filtration)  Use of solvents other than water or aqueous ethanol  High temperature baking or cooking

. Manufacturers of dietary supplements containing ingredients introduced after October 15, 1994 are required to notify the FDA at least 75 days before marketing . NDI notification must provide evidence of safety, such as historical use . However, FDA approval is not required before the marketing of dietary supplements

. Manufacturers must substantiate that the NDI will reasonably be expected to be safe under the labeled conditions of use  History of safe use in humans  Similar conditions of use . Additional animal and human studies may be required when the historical use is significantly different from the proposed use

. Since February 2015, FDA sent hundreds of warning letters to supplement companies regarding adulterated and/or misbranded products and cGMP violations . FDA increasing holds on products imported into NY area

. “Graviola Extract product is not generally recognized as safe and effective for [tranquilizer and sedative] referenced uses and, therefore, the product is a “new drug” under section 201(p) of the Act” . “Your products are intended for prevention or treatment of one or more diseases that are not amenable to self-diagnosis and treatment; therefore, it is impossible to write adequate directions for a layperson to use”

. “You failed to establish and follow written procedures to fulfill the requirements related to product complaints” . “Your product label does not identify the product as a dietary supplement” . “The label fails to declare the common or usual name for the ingredient OsetoGene™ and FOS”

. Examined ED visits for adverse events associated with dietary supplements over 10 years from 63 hospitals  More than 23,000 ED visits for adverse events annually  Average of 2,100 hospitalizations annually (estimated) . Specific product categories implicated:  Multivitamins (33.6%)  Iron (11.8%)  Supplements for weight loss (10.4%), and  Supplements for sleep, sedation, or anxiolysis (8.8%)

. FDA must be notified regarding ingredients not marketed prior to October 15, 1994 . NDI notification must be filed at least 75 days before ingredient is sold or offered for sale . Compliance with 21 U.S.C. § 350(b)

Due diligence . Review contract manufacturer’s documentation including:  Employee training procedures/policies  SOPs  Recent FDA audits/compliance history . Negotiate agreements with manufacturers to ensure compliance with cGMPs . Compliance programs  Review Certificate of Analysis for each shipment  Finished product testing  Onsite audits

. Confirm all mandated information appears on label in correct location, order and manner . Ensure substantiation of claims . Review ingredients for existing IP protections

. Adverse Event Reports  The “responsible party” is required to review and report Serious Adverse Events (SAE)  SAEs must be reported  Mild and moderate adverse effects may be reported  Records of all adverse events must be maintained for six years  Foreign jurisdictions have different reporting obligations

. Be prepared for the eventuality of litigation with counsel

. Maintain knowledge of industry, relevant regulations, and latest regulatory agencies’ actions

1. Is FDA approval required before marketing of dietary supplements?

2. Is FDA notification required before marketing of dietary supplements?

3. Do dietary ingredients marketed prior to October 15, 1994 require NDI notification?

4. True or false: DNA barcoding is more successful if carried out on raw as opposed to processed herbal materials.

5. What percentage of Americans utilize supplements?

Questions?

Frederick H. Fern Marina Plotkin @RickFern_HB @MarinaPlotkin_HB [email protected] [email protected] 212-313-5402 212-313-5409