Rose Sheet Pharma intelligence rose.pharmaintelligence.informa.com December 2017 informa

NSF’s Cosmetics Verification Program Fizzles, While EWG’s Could See Second Boom JAMIE HAMMON [email protected] RYAN NELSON [email protected]

SF International has put its cos- The not-for-profit organization plans to metic product verification program conduct research in 2018 “to better under- N on hold less than a year after it stand the market interest in a robust, sci- launched, due to lack of interest. “We developed the ence-based product verification program,” The global independent standards, testing cosmetic product according to Coy. and certification organization introduced the verification service in April 2017. The program verification program earlier ‘EWG VERIFIED’ FLOURISHING was designed to review cosmetics companies’ IN COMPARISON regulatory and good manufacturing practices this year, and we realize The Environmental Working Group has had compliance, subject products to toxicological now that we may have markedly more success with its “EWG Veri- and contaminant testing, vet label claims and fied” platform, with more than 1,000 person- conduct periodic facility audits. been ahead of our time. We al-care products from 75+ brands qualifying Qualifying applicants would have been for the NGO’s mark to date. (Also see “’EWG free to sport the NSF Product Verified mark simply have not seen much Verified’ Personal-Care Safety Seal Builds On on their products, offering an added layer interest in the program,” ‘Skin Deep’ Platform” - Rose Sheet, 4 Nov, 2015.) of assurance to consumers, according to the While Coy suggests that NSF may have group. (Also see “NSF International Launches said NSF Cosmetics jumped the gun, it could be argued that Cosmetic Verification Program For ‘Consumer the group was late getting off the line, an- Assurance’” - Rose Sheet, 18 Apr, 2017.) Manager Casey Coy. nouncing its program some 18 months af- NSF said that “by selecting cosmetic ter EWG’s debuted. products that have been evaluated against From the outset, EWG Verified has proven the rigorous criteria of NSF International’s uct manufacturers. For example, its regula- popular with niche brands built on trending cosmetic product verification, consumers tory consulting team provides registration if ill-defined, largely unregulated concepts can be confident that products bearing the and notification services to help companies – “natural,” “green,” “sustainable.” Such com- NSF mark have been tested to meet the comply with California’s Safe Cosmetics Act, panies tend to cast themselves as uniquely quality and safety consumers expect.” the European Cosmetics Regulation and responsible and transparent, health-con- The group has since pressed pause on other such programs. scious actors and, thus, may have most to the initiative. It’s also available to assist with cosmetic gain from third-party verification in terms “We developed the cosmetic product product safety reports and product infor- of shoring up this positioning in the eyes of verification program earlier this year, and mation files required in the EU, and con- their target audiences. we realize now that we may have been ducts gap audits against other country- EWG lists Dolphin Organics, Aromatica ahead of our time,” said Casey Coy, cosmet- specific regulatory and quality system (touted as “Natural and safe, our promise to ics and personal care manager at NSF, in a standards, according to its website. you”), Cocoon Apothecary (“Nature makes Dec. 11 email to the Rose Sheet. Further, NSF reviews product labels and a comeback”), Davids Premium Natural “We simply have not seen much interest website claims to verify compliance with Toothpaste, Be Green Bath & Body, Finally in the program,” she added. regulations and ensure that ingredients Pure, Honestly pHresh and Conscious Skin- The group still offers a la carte testing ser- and test data are consistent with promo- care among brands that have earned its vices for cosmetics and personal-care prod- tional statements. mark on products. CONTINUED ON PAGE 1

BROUGHT TO YOU BY THE EDITORS OF ROSE SHEET AND TAN SHEET harma intelligence | DECEMBER 2017

Our selection of Rose Sheet content from the past month includes some of our most-viewed articles online and editors’ picks of top issues across the cosmetics and dietary supplement sectors.

Please visit rose.pharmaintelligence.informa.com for full access to our comprehensive, up-to-the-minute news coverage and analysis.

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COSMETICS COVER .NSF’s Cosmetics Verification Program Fizzles, While EWG’s Could See Second Boom 4 National Standard For Cosmetics Quality Nearing Finish Line With Retailer Buy-In 6 CIR: Industry Working On Producing Preservative PHMB Sensitization Data 8 Personal-Care Industry Leaders Issue Call For Green Chemistry Solutions 10 BASF Ingredient Case Begs For Verdict: Do REACH Animal Tests Violate Cosmetics Reg? 12 China Animal Testing Continues To Make Headaches For Beauty Brands

DIETARY SUPPLEMENTS 13 Dietary Supplement Sector Warnings Jump With FDA ‘Program Alignment’ 15 Form 483s: Supplement Firms’ Stage For Changing FDA Inspectors’ Views 16 Unusual Supplement Adverse Events Could Be ‘Canary’ Of Problem 17 Opioid-Withdrawal ‘Aids’ Warrant Immediate FDA, FTC Action – CSPI 19 Appropriators’ Interest Could Point To FDA Supplement Programs Funding Boost 20 FDA ‘Evolving’ Homeopathic Drug Enforcement With Risk-Based Approach

LEADERSHIP CORPORATE SALES ADVERTISING DESIGN SUPERVISOR Phil Jarvis, Richard Faint John Lucas, Elissa Langer Christopher Keeling Gayle Rembold Furbert

MANAGING EDITOR EXECUTIVE EDITOR EDITORIAL OFFICE Ryan Nelson Malcolm Spicer 52 Vanderbilt Avenue, 11th Floor REPORTER SENIOR REPORTER New York, NY 10017 Jamie Hammon Eileen Francis phone 240-221-4500, fax 240-221-2561

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2 | Rose Sheet | December 2017 © Informa UK Ltd 2017 COSMETICS

CONTINUED FROM PAGE 1 Participating companies could highlight Putting aside the timing of their veri- NSF’s credentials as an organization accred- fication program launches, it’s hard to ited by the American National Standards In- imagine that NSF’s name recognition is as “It’s been amazing to see stitute with a history of collaborating with strong as EWG’s among such companies the positive reaction. For the World Health Organization on water and their customers. While both NSF and quality and food safety issues, for example. EWG are committed to promoting pub- years brands have wanted The question remains though: Does lic and environmental health, their modi the average cosmetics consumer or main- operandi, industry relationships and the a stamp of approval stream brand loyalist need the “assurance” ways they interface with consumers are from EWG to show they that NSF’s mark is intended to provide? very different. Perhaps industry has already answered NSF’s consensus-based standards and are doing the best to that question. certification platforms generally lack the level of public visibility commanded by produce products free WALMART RECOMMENDATION EWG’s annual sunscreen ratings, its Guide from potentially dangerous COULD POSE DILEMMA to Healthy Cleaning, GMO-avoidance man- In a Dec. 15 email, EWG’s Jocelyn Lyle, vice ual, cosmetics legislative work, product chemicals.” – EWG’s president of development and online en- blacklists or unsafe chemical campaigns. gagement, expressed enthusiasm about It’s not uncommon for EWG’s initiatives to Jocelyn Lyle, vice president EWG Verified’s reception to date and opti- receive national media attention. of development and online mism about the program’s future. EWG has more than 54,000 Twitter fol- “It’s been amazing to see the positive lowers and 641,000 Facebook followers, engagement reaction,” she said. “For years brands have compared with NSF’s roughly 3,300 and wanted a stamp of approval from EWG to 6,000, respectively. EWG also has more show they are doing the best to produce than 50,000 Instagram followers, while NSF pert bodies such as the Cosmetic Ingredi- products free from potentially dangerous is without a presence on the photo- and ent Review (CIR) Expert Panel (US) and the chemicals.” video-sharing platform, a favorite among Scientific Committee on Consumer Safety The NGO expects interest in the verifica- younger consumers. (SCCS) (EU).” tion mark to continue to grow, particularly At the basis of EWG’s cosmetics safety As a non-voting liaison member of CIR’s in light of recent developments at mega- messaging and activism is the group’s Skin panel, FDA takes the group’s findings into retailer Wal-Mart Stores, Inc. Deep database, which houses information account in its cosmetics safety program, In September, Walmart said it would on close to 9,000 ingredients and hazard and SCCS’ opinions regularly shape the Eu- begin encouraging vendors to obtain assessments for more than 72,000 cosmetic ropean Commission’s rules for safe ingredi- the EWG Verified mark and/or Cradle to products. The group compares formula- ent use in the cosmetics sector. Cradle certification (silver level or bet- tions against roughly 60 sources of chemi- Loretz added, “Like its Skin Deep data- ter), administered by the nonprofit Cradle cal toxicity and regulatory information, ac- base, [EWG] does not use sound scientific to Cradle Products Innovation Institute. cording to the Skin Deep site. principles or peer-reviewed data as the (Also see ““Multi-Attribute” Cradle-To-Cra- EWG Verified products must score “green” basis for its claims.” Its analysis therefore “is dle Seal: The Ultimate In Sustainability?” - overall (1-2, denoting “low hazard”) on Skin fundamentally flawed, and the conclusions Rose Sheet, 27 Jun, 2011.) Deep’s 1-10 hazard scale and be free of ingredi- are not meaningful,” she asserted. According to the big-box retailer, the ents on the group’s “Unacceptable” list, which EWG has a passionate public follow- programs “lend credibility to green chem- includes various parabens, formaldehyde re- ing regardless, so it’s not surprising that a istry and safer substitutions” in line with its leasers, phthalates and other substances that growing number of self-styled “good-for- own sustainable chemistry commitments, regulatory authorities have deemed safe for you” startup brands, which purport to go launched in 2013. (Also see “Walmart Sus- cosmetic use at controlled levels. above and beyond mainstream industry tainable Chemistry Policy A “Big Deal,” But Large, established industry players tend standards, are aligning themselves with Raises Questions” - Rose Sheet, 17 Mar, 2014.) to take a deeply critical view of EWG’s Skin the organization and its hazard-based ap- EWG applauded the move, calling it Deep platform and the methodology that proach to cosmetics safety. “terrific news” for Walmart customers and informs its ingredient and product safety If the verification program that NSF has in their families. “This latest decision to not assessments. mind is a more “robust, science-based” sys- only embrace, but encourage companies In a December 2016 statement, the Per- tem in comparison, it could be promoted to to seek the EWG Verified seal further un- sonal Care Products Council’s Chief Toxi- larger, mainstream brands as an alternative derscores Walmart’s commitment to sus- cologist Linda Loretz observed that Skin to EWG’s mark that doesn’t compromise tainability and safer consumer products,” Deep “assumes certain ingredients are their scientific principles or disqualify prod- asserted the group’s co-founder and Pres- hazardous, despite the fact that they have ucts made with ingredients that regulatory ident Ken Cook. been found safe for use in cosmetics by ex- authorities agree are safe. According to Lyle, the Walmart endorse-

3 | Rose Sheet | December 2017 © Informa UK Ltd 2017 COSMETICS ment has generated significant new interest NSF DOUBLES DOWN ON NATIONAL where appropriate – such as FDA’s draft in EWG Verified “from companies of all sizes.” STANDARDS DEVELOPMENT guidance for cosmetics good manufactur- She continued, “Some of the biggest play- NSF’s verification program may be shelved, ing practices – as well as ISO quality stan- ers are already making huge movements to at least for now, but the group says it still dards and retailer requirements. meet our standards because of Skin Deep’s sees a need for quality and safety standards The idea is to combine all elements into powerful voice in better beauty.” in the personal-care industry. a single standard and auditing program for Lyle pointed to commitments from in- The organization collaborated with each category. Product certification will not dustry leaders in 2017 – namely Procter stakeholders to form the Global Retailer be part of the criteria, according to NSF. & Gamble Co. and Unilever – to disclose and Manufacturer Alliance in 2014 and now The first completed standard, for di- fragrance ingredients across product port- is stepping up efforts to help finalize the de- etary supplements, was expected to be folios, notwithstanding the fragrance sec- velopment of consensus-based standards available in 2015, but NSF says the pro- tor’s longstanding argument that giving up for industries including cosmetics, dietary cess has taken longer than expected due trade secrets could jeopardize innovation supplements and OTC drugs. to GRMA’s commitment to form a joint and fair competition. (Also see “P&G To Dis- Aimed at “strengthening safety, qual- committee with a balance of stakeholders close Fragrance Ingredients Portfolio-Wide By ity and trust throughout the supply chain” and to harmonize standards across sec- 2020” - Rose Sheet, 30 Aug, 2017.) and streamlining audits to reduce costs for tors as much as possible. “It makes us hopeful they [leading com- manufacturers, the standards are meant to The projected publication date for the OTC panies] are committed to not using harmful use US regulatory requirements as a base- drug, cosmetics and dietary supplement ingredients,” the EWG exec said. line while also incorporating FDA guidance standards is now the first quarter of 2018.

National Standard For Cosmetics Quality Nearing Finish Line With Retailer Buy-In

RYAN NELSON [email protected]

he Global Retailer and Manufacturer Supplement GMP Standards In Fine-Tuning Alliance aims to launch within the Phase” - Rose Sheet, 9 Dec, 2016.) T next three months voluntary Ameri- “The harmonization between the differ- can National Standards for cosmetics, di- “Once they get published ent groups was a key objective, and that’s etary supplements and OTC drugs that go we think this is going been taking the most time,” confirmed Mike beyond FDA’s expectations for good manu- Finamore, CEO of Gemini Pharmaceuticals, facturing practices to also address other to become not only an Inc. and president of the GRMA governance quality issues and retailer demands. board, in a Dec. 20 interview. The goal is to streamline audits for manu- industry standard but He noted the high number of manufac- facturers, thereby reducing complexity and something we look at turers with business in multiple product costs, while strengthening trust throughout categories – for example cosmetics as well the supply chain and promoting consumer going forward and are as dietary supplements and/or OTC drugs. confidence in certified brands. “So the more we could harmonize things NSF International, which is accredited by amazed that industry and get all parties on the same page, the the American National Standards Institute, existed without it.” better the primary purpose of the GRMA is facilitating the consensus-based stan- would be satisfied, which is to have really dards development process in accordance – Mike Finamore, president strong standards acceptable to retailers,” with ANSI guidelines and procedures. thereby casting a wide net that results in The independent standards creator, of GRMA governance board fewer audits and a reduced work schedule which also tests and certifies products, for companies, he said. announced the project in late 2014. It has GRMA has approached the standards’ de- since been working with retailers including publish by the end of the 2018 first quarter. velopment by using federal requirements Walmart, Walgreens, Costco and Wegmans, While the GRMA standard for dietary sup- for GMPs and/or related FDA guidance as a along with regulatory and industry reps plements initially was targeted for release in baseline, then layering in additional quality and other testing laboratories, to refine 2015, efforts to harmonize standards across considerations. initial blueprints and advance the category- sectors have resulted in delays, the orga- “What we’ve seen over time is that indi- specific standards, which now are slated to nization says. (Also see “Consensus-Based vidual auditing bodies have created their

4 | Rose Sheet | December 2017 © Informa UK Ltd 2017 COSMETICS own auditing standards based on [federal Manufacturers may not have been con- ated with the undertaking, may not pose regulations]. They really can’t get too far vinced that NSF’s name carries enough significant challenges from a big-picture away from what the CRF requires, but they weight with the average consumer to jus- standpoint. all had their own nuances” based on best tify the cost of investing in an NSF “Veri- For smaller companies with less experi- practices and other external guidelines, fied” mark. ence and fewer resources, earning the cer- Finamore explained. Firms may be more incentivized to tification could prove a harder row to hoe. Meanwhile, retailers have been working certify their operations to an American However, such enterprises could view the with preferred auditing organizations – National Standard, which must be de- investment as a stride toward compliance potentially requiring vendors to meet dif- veloped and approved as conforming with federal requirements down the line, ferent quality requirements depending on to ANSI Essential Requirements. ANSI, as multiple legislative proposals currently where their products are sold – or laboring which coordinates the process, notes on under consideration in Congress would di- to sort through the various auditing sys- its website that such standards “serve US rect FDA to establish GMPs for the cosmet- tems used by their vendors to determine interests well because all materially af- ics sector via rulemaking. (Also see “ICMAD what the information means for products fected stakeholders have the opportunity Stands By House Cosmetics Bill, But May Be sold in their stores. to work together to create them.” Ready To Negotiate” - Rose Sheet, 31 Oct, GRMA says its work will simplify matters American National Standards are volun- 2017.) by providing ANSI-approved gold stan- tary and only become mandatory “when, FDA took the International Organization dards for safety and quality assurance to and if, they are adopted or referenced by for Standardization’s ISO 22716 into ac- which companies can be certified. Fina- the government or when market forces count when updating its cosmetics GMPs more suggested that a grading scale will make them imperative.” draft guidance, which released in revised be included. Should retailers make certification to form in June 2013, and the GRMA used “So if retailers are doing a bidding pro- the GRMA cosmetics standard a de facto both documents as source materials for its cess and only A-graded vendors can bid, requirement for brands to have a presence standard. that’s a very strong incentive for everyone on their store shelves, a great number of Finamore is optimistic that the forthcom- to achieve that level,” he said. companies no doubt will come knocking ing American National Standards will meet on NSF’s door. with an enthusiastic reception. SMES IN PARTICULAR COULD While GMPs compliance in the dietary “We’re getting a lot of buy-in from the re- FACE CHALLENGES supplement and OTC drug sectors is man- tailers, and we’re seeing that although we NSF tried launching a cosmetic product ver- datory under federal law, FDA has issued haven’t yet published the standards people ification service in April 2017, which would just non-binding draft guidance for GMPs know what they’re getting into, the credibil- have assessed companies’ compliance with in the cosmetics sector. (Also see “ICCR Ush- ity of the group that’s putting this together regulatory mandates and GMPs, subjected ers Forth Updated Cosmetic GMP Guidelines and the desire for retailers to have this sort products to toxicological and contaminants From FDA” - Rose Sheet, 1 Jul, 2013.) of thing in place,” the exec said. testing and vetted product claims. Many cosmetics manufacturers, particu- “So we have this momentum, and once However, the program has been put on larly large firms and those with crossover they get published we think this is going to ice due to lack of industry interest. (Also see business into other product categories, become not only an industry standard but “NSF’s Cosmetics Verification Program Fizzles, may well be GMP-compliant already, so something we look at going forward and While EWG’s Could See Second Boom” - Rose certification to the more comprehensive are amazed that industry existed without Sheet, 19 Dec, 2017.) GRMA standard, and the costs associ- it,” he concluded.

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Rose Sheet delivers uniquely specialized coverage of regulatory, legislative, legal, scientific, business and marketing developments in the cosmetics and dietary supplements sector. rose.pharmaintelligence.informa.com

5 | Rose Sheet | December 2017 © Informa UK Ltd 2017 COSMETICS

CIR: Industry Working On Producing Preservative PHMB Sensitization Data

RYAN NELSON [email protected]

riglycerides and panthenol, pan- ally be in use in products that are intended included triglycerides, which function as tothenic acid and derivatives were to be sprayed. Indeed, one supplier submit- skin-conditioning and viscosity-increasing T among ingredient groups that re- ted a comment that their company would agents, among other roles. ceived final safety determinations at the Cos- not consider using this ingredient in such The ingredient group was determined metic Ingredient Review Expert Panel’s Dec. applications,” CIR notes. safe as used, along with panthenol, pan- 4-5 meeting, all deemed mostly safe as used, That said, CIR received a letter from Wom- tothenic Acid, and derivatives, present in with some caveats and cited data gaps. en’s Voices for the Earth in advance of the cosmetic products as hair- and skin-condi- In total, the industry-funded organiza- meeting expressing concern about PHMB’s tioning agents, humectants and solvents, tion’s team of independent experts issued inhalation toxicity potential. The NGO says according to the meeting recap. five final safety conclusions, six tentative re- it identified a number of cosmetic products Polysilsesquioxanes and ammonia and ports and two insufficient data announce- sold online that could expose consumers to ammonium hydroxide also are safe when ments. (Also see “Cosmetic Ingredient Review the ingredient via inhalation. used in accordance with current industry Report Status” - Rose Sheet, 14 Dec, 2017.) CIR says it’s aware of some PHMB-contain- practices and use concentrations, pro- The panel also tabled its draft final report for ing products reported to FDA through its vided that the latter ingredients are for- broad-spectrum preservative polyhexameth- Voluntary Cosmetic Registration Program mulated to be non-irritating, CIR’s experts ylene biguanide hydrochloride (INCI name: that may be sprays or powders, though this concluded. polyaminopropyl biguanide), noting a com- has not been confirmed. Persulfates received a split decision in mitment from industry to complete a 100-per- “The CIR executive director will develop an the CIR panel’s final report. The oxidizing son human repeated insult patch test (HRIPT) appropriate response to WVE’s concerns,” ac- agents are safe as used in hair colorants and to assess the ingredient’s allergenic potential. cording to the post-meeting announcement. hair lighteners, the group determined, but “The task force that will be overseeing CIR is inviting interested parties to com- available data are insufficient to assess their this project is being formed, and the Panel ment, provide information and/or request an safety in leave-on products and dentrifices, will receive ongoing updates relating to this oral hearing before the Expert Panel as soon according to the announcement. project,” including at its March 2018 meeting, as possible to help advance its work related to Tentative safety assessments covered CIR says in a post-meeting announcement. the tabled PHMB assessment. The organization zinc salts (safe when formulated to be non- CIR’s experts already received a quantita- notes that information may be submitted with- irritating), Hamamelis virginiana (witch tive risk assessment for PHMB from industry out identifying the source or the trade name of hazel)-derived Ingredients (safe when for- that “theoretically” supports use of the pre- a cosmetic product containing the ingredient. mulated to be non-irritating and non-sen- servative at concentrations of 0.1% or less, sitizing), and four other ingredient groups. which would align CIR’s guidelines for use REVIEWED INGREDIENTS The panel issued insufficient data -an with recommendations from the Scientific LARGELY SAFE AS USED nouncements for Ginkgo biloba-derived in- Committee on Consumer Safety in the EU. The five safety assessments finalized by the gredients and Eucalyptus globulus-derived (Also see “SCCS OKs Preservative PHMB At CIR Expert Panel at the December meeting ingredients. 0.1%, Leaving Room For EU Cosmetic Use” - Rose Sheet, 20 Jan, 2017.) However, the panel had concerns at its last meeting that an existing HRIPT study that factored in the QRA may not be adequately diverse. (Also see “CIR News In Brief: No Con- harma intelligence | clusion Reached On PHMB; Endocrine Activity Guidance; More” - Rose Sheet, 19 Sep, 2017.) The group also says it still needs consumer use data on pump and propellant hair sprays containing PHMB – which could represent Delivering uniquely specialized serious inhalation risks based on adverse coverage in the cosmetics and dietary events, including deaths, reported overseas supplements sector. for a chemically similar substance – in order to calculate an accurate margin of safety. rose.pharmaintelligence.informa.com “However, this ingredient might not actu-

6 | Rose Sheet | December 2017 © Informa UK Ltd 2017 COSMETICS

Cosmetic Ingredient Review Report Status REPORT INGREDIENT FUNCTION STATUS RULING Ammonia and Ammonium pH adjusters, fragrance, denaturant Final Safe as used (a) Hydroxide Persulfates Oxidizing agents Final Split (b) Polysilsesquioxanes Film formers, opacifying agents, nail-conditioning agents Final Safe as used Triglycerides Skin-conditioning agents, viscosity-increasing agents, fragrance, solvent Final Safe as used Panthenol, Pantothenic Acid, Hair-conditioning agents, skin-conditioning agent, humectant, solvent Final Safe as used and Derivatives Malic Acid and Sodium Malate Fragrance, pH adjuster, skin-conditioning agent, humectant Tentative Safe as used Mentha piperita (Peppermint)- Fragrance, skin-conditioning agents Tentative Split (c) Derived Ingredients Alkyl Sultaines Antistatic agents, surfactants, skin- and hair-conditioning agents Tentative Safe as used Zinc Salts Hair and skin-conditioning agents, astringents, preservatives, oral care, Tentative Safe as used (a) buffering agents, bulking agents, chelating agents, viscosity-increasing agents non-aqueous Alkane Diols Solvents Tentative Split (d) Hamamelis virginiana (Witch Astringents, skin-conditioning agents Tentative Safe as used (e) Hazel)-Derived Ingredients Ginkgo biloba-Derived Ingredients Skin-conditioning agents, antioxidants Draft Insufficient Data Eucalyptus globulus (Eucalyptus)- Abrasive, fragrance, skin-conditioning agent Draft Insufficient Data Derived Ingredients

(a) when formulated to be non-irritating (b) Safe as used in hair colorants and hair lighteners designed for brief discontinuous use followed by thorough rinsing from hair and skin. Available data are insufficient for determining the safety of these ingredients in leave-on products and dentifrices, which require concentration-of-use data and a no observed adverse effect level (NOAEL) for sensitization and urticarial reactions. (c) Safe as used when formulated to be non-sensitizing, with the exception of Mentha Piperita (Peppermint) Flower/Leaf/Stem Extract, Mentha Piperita (Peppermint) Flower/Leaf/Stem Water, and Mentha Piperita (Peppermint) Meristem Cell Culture, for which composition data, skin irritation data and sensitization data are needed to make a safety assessment. (d) Safe as used with the exception of 1,4-Butanediol, 2,3-Butanediol and Octanediol, which require concentration-of-use data and, in the cases of 2,3-Butanediol and Octanediol, 28-day dermal toxicity studies, developmental and reproductive toxicity data and mammalian genotoxicity studies. (e) when formulated to be non-irritating and non-sensitizing

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7 | Rose Sheet | December 2017 © Informa UK Ltd 2017 COSMETICS

Personal-Care Industry Leaders Issue Call For Green Chemistry Solutions

RYAN NELSON [email protected]

on-sensitizing preservatives, non- sensitizing fragrance raw materials N and naturally derived hair-condi- tioning agents are among green chemistry technology needs cited by leading person- al-care and household products firms in a call for entries from startups in an innova- tion competition. The Green Chemistry & Commerce Coun- cil is holding the competition, which will al- low up to 10 companies to present on the main stage at its 3rd Annual Green & Bio- Based Chemistry Technology Showcase and Networking Event, slated for May 8, 2018, the first day of GC3’s Innovators Roundtable in Kingsport, Tenn. GC3 describes itself as a cross-sectoral, business-to-business network of compa- nies and other organizations working col- laboratively to advance green chemistry GC3 currently is conducting stability and antimicrobial across sectors and supply chains. effectiveness testing on five finalist entries in a separate It grew out of a sustainable business and safer chemistry roundtable co-hosted in competition it launched in April 2017 to surface promising 2005 by the Lowell Center for Sustainable Production at the University of Massachu- early-stage preservative technologies for use in the setts, Lowell, where it now is based. personal-care and household products sectors. GC3’s members include Johnson & John- son, Procter & Gamble Co., L’Oreal USA, Inc., and Beiersdorf AG, which are named among firms attending the technology showcase Comments; Benefit Cosmetics Recall; More email list, but a broader announcement will event. In advance they’ve submitted a list of News In Brief” - Rose Sheet, 11 Dec, 2017.) be made in early 2018. specific green chemical and material tech- UV filters/light stabilizer ingredients with nologies “for which they are actively seeking low aquatic toxicity also make the list. NEW PRESERVATIVE SOLUTIONS new green chemistry solutions,” according to In addition to commanding the spotlight ON THE HORIZON? a notice on the GC3 website. at the GC3 event, winning applicants will Separately, GC3 is conducting stability and The list of wants includes biodegradable have the chance to network with GC3 com- antimicrobial effectiveness testing on five alternatives to chemicals such as sodium panies and potentially engage in joint de- finalist entries in a competition it launched lauryl ether sulfate, aka sodium laureth sul- velopment, licensing, investment and other in April 2017 to surface promising early- fate, as well as environmentally friendly sur- partnership opportunities. stage preservative technologies for use in factants (see table). GC3 says the event is attended by angel the personal-care and household products The GC3 members also are looking for an- and venture funds in addition to chemical sectors. (Also see “GC3 Preservatives Compe- timicrobials and preservatives that are non- suppliers, major consumer product manu- tition Deadline Nears With 15 Applicants So sensitizing at levels needed for preservation facturers and retailers. Far” - Rose Sheet, 10 Aug, 2017.) of personal care and household products. Startups must submit their applications The group says it received 48 submissions They’re also interested in “antimicrobials or by Feb. 16, 2018. Decisions are expected in in total. Category 1 sponsors, which include technologies that are non-biocidal” – i.e., March 2018, according to the notice. J&J, P&G, Beiersdorf, Colgate-Palmolive that do not require registration under the GC3 Co-Director Monica Becker said in Company, Unilever and Beautycounter, EU’s Biocidal Products Regulation. (Also see a Dec. 21 email that the group has done a as well as the Environmental Defense Fund “EU Endocrine Disruptor Guidance Open For “very soft launch” of the competition to its and Minnesota Pollution Control Agency, are

8 | Rose Sheet | December 2017 © Informa UK Ltd 2017 COSMETICS involved in the review and judging process. GC3 MEMBER-IDENTIFIED GREEN CHEMISTRY TECHNOLOGY NEEDS Dow Microbial Control, Lonza, Schülke, Symrise, and Thor are listed as Category 2 Technology Area: Raw materials for formulated consumer products (including personal- sponsors with potential partnership stakes care and household products) in winning technologies. They do not have a role in selecting finalists. Description: Results are expected in March, and GC3 Alternatives for cationic poly-electrolytes (quaternary ammonium derivatives or polyqua- is targeting April for an event to bring final- terniums), generally used as conditioning agents for skin and/or hair cleansing products, ists and potentially a handful of runners-up that are biodegradable and have low ecotoxicity together with its member manufacturers Antimicrobials and preservatives that are non-sensitizing at levels needed for preservation and chemical suppliers so they can present for personal care and household products their technologies and connect with pos- Antimicrobials or technologies that are non-biocidal (do not require registration per the sible partners. Biocidal Products Regulation [BPR, Regulation (EU) 528/2012]) Three to five cash prizes will be awarded Biodegradable alternatives for polyacrylate-based chemistry, generally used as rheology to winners from a pool of $175,000. modifiers or film formers New preservatives are in high demand due Biodegradable alternatives for sodium lauryl ether sulfate (SLES) to increasing regulation and consumer pres- sure that have rendered unusable numerous Biodegradable chelating agents for personal care and household products including dish- preservatives with time-tested efficacy. washing and laundry detergents There is skepticism from some corners of Chemistries to prepare ethanolamides without the use of ethylene oxide for improved safety industry that a preservative technology, let Fragrance raw materials that are non-sensitizing with a low risk of biodiversity loss alone multiple, will emerge from the GC3 Hair conditioning agents that are naturally derived challenge with real potential to be devel- oped for wide commercial use. Mineral oil alternatives that are biodegradable and/or natural origin oils In fairness, GC3 has made nothing in the Surfactants for laundry products that can remove hydrophobic soils way of promises to this effect, but specu- Surfactants that are amphiphilic, especially alternatives to ethoxylated materials lation regarding the fruit its competition Surfactants that are anaerobically biodegradable might bear is all but unavoidable. David Steinberg of Steinberg & Associ- Surfactants that are bio-based with low aquatic toxicity ates, which provides regulatory compliance UV filters/light stabilizer ingredients with low aquatic toxicity consulting for cosmetic and OTC drug man- ufacturers, has noted that preservatives must be pre-approved for use in cosmet- ists, “ethanolamines are made from the lighting the absence of perfectly lawful but ics under the EU’s Cosmetics Regulation, reaction of ethylene oxide and ammonia. distrusted or simply unfashionable ingredi- requiring costly safety testing that may be If that is what they mean, whoever can do ents. (Also see “Podcast: Preservatives Crisis seen as a questionable investment given this with the same economics would get Calls For Marketing Revolution” - Rose Sheet, the limited size of the personal-care market. the Nobel Prize in Chemistry.” 28 May, 2015.) The EU’s animal-testing ban for cosmet- He suggested in an email to the Rose Steinberg suspects that the same elements ics also poses development challenges, Sheet that the list of needs also lacks – “who wouldn’t know salt from sugar” – are though there may be workarounds for a specificity in places and definitions for more behind the green technology needs no- preservative intended for use in personal terms like “biodegradable,” as well as clar- tified to GC3 than industry chemists. care and other sectors not subject to the ity as to the testing standards against Pointing to the stated need for “mineral European Cosmetics Regulation. (Also see which solutions would be expected to oil alternatives that are biodegradable and/ “BASF Ingredient Case Begs For Verdict: Do prove themselves. or natural origin oils,” he said, “For cosmetics, REACH Animal Tests Violate Cosmetics Reg?” Generally, Steinberg takes a dim view of they already have been around for decades.” - Rose Sheet, 13 Dec, 2017.) the “green” chemistry groundswell insofar In other cases the needs read more Steinberg also has doubts about the as it may be reinforcing erroneous percep- like extravagances in wishful thinking, he newly announced green chemistry innova- tions – for example that “natural” substanc- suggested. tion competition and its capacity for gener- es are invariably safer than synthetics – and Clearly, however, leading personal-care ating solutions to the highlighted needs. contributing to the demonization of chemi- companies have a keen interest in answer- For example, the GC3 members seek cals that experts have determined safe for ing consumer demand for greener products “chemistries to prepare ethanolamides cosmetic use. and enough faith in the GC3 forum to back without the use of ethylene oxide for im- From his perspective, industry’s shrinking its projects financially. proved safety.” preservative palette is largely the fault of Or perhaps the stakes are high enough According to Steinberg, a former national cosmetics marketing departments, which that such firms can’t afford to leave any president of the Society of Cosmetic Chem- have driven the rise of “free of” claims high- stone unturned.

9 | Rose Sheet | December 2017 © Informa UK Ltd 2017 COSMETICS

BASF Ingredient Case Begs For Verdict: Do REACH Animal Tests Violate Cosmetics Reg?

RYAN NELSON [email protected]

he EU may be closer to resolving Banned Per Se" - Rose Sheet, 21 Sep, 2016.) legal uncertainties regarding the in- The court did not address the relation- T terplay of REACH and the Cosmetics “Until this case is resolved, ship between the Cosmetics Regulation Regulation, namely whether animal testing and REACH. mandated under the former regulation for companies registering Nor did European Ombudsman Emily substances exclusively used in cosmetics O'Reilly clarify in a July 2017 decision wheth- triggers the latter's marketing ban. substances used exclusively er animal data produced for REACH compli- A Dec. 12 decision from the European ance purposes can be used to support prod- Chemicals Agency Board of Appeal throws as cosmetics ingredients uct/ingredient safety under the Cosmetics the issue into high relief and could prompt under REACH will remain Regulation. (Also see "Animal-Tested Cosmetic Member State debate and action in the Ingredients In The EU: One Big Question Re- courts to rule on the matter once and for all. in a position of legal mains" - Rose Sheet, 26 Jul, 2017.) At the center of the controversy is a sub- She merely found no evidence of malad- stance manufactured by BASF Personal uncertainty, and so we ministration in a joint statement issued by Care and Nutrition GmbH – reaction mass would caution that only ECHA and the European Commission in Oc- of sodium hydrogen N-(1-oxooctadecyl)- tober 2014, which clarified that animal test- L-glutamate and stearic acid – registered non-animal approaches ing may be required under REACH for cos- under the EU's Registration, Evaluation, metic substances to assess risks to workers Authorization and Restriction of Chemicals be taken towards hazard and/or environmental hazards, or in cases regulation in the tonnage band of 100 to assessment.” – Julia Baines, where the substance is used for multiple 1,000 tons per year. purposes, not solely in cosmetics. In its registration dossier for the ingredient, science policy advisor for O'Reilly declined to weigh in on whether BASF proposed using a read-across adapta- REACH animal testing could in turn be used tion based on available animal test findings PETA International Science to fulfill the Cosmetics Regulation's safety for an analogous substance, rather than con- Consortium data requirements, stating, "It is for the ducting its own pre-natal developmental tox- Court of Justice to provide a definitive in- icity study to fulfill REACH data requirements. terpretation of EU law." ECHA rejected the chemical supplier's ics Regulation" and its interface with REACH. proposal in a decision adopted in Septem- Questions about the scope of the Cos- ECHA MAINTAINS HANDS-OFF ber 2016, roughly one year after it issued a metics Regulation's ban have arisen largely APPROACH TO COSMETICS REG draft decision on the matter. According to due to embedded language proscribing The present BASF case ultimately could ECHA, a new PNDT study is required. animal testing on ingredients "in order to serve as a litmus test, or the foundation for From the perspective of BASF and animal- meet the requirements of this regulation an authoritative court ruling, regarding the welfare advocates, the proposed adaptation [italics added]." The phrasing leaves open marketability of cosmetics-exclusive ingre- would spare the rats or rabbits needed for PNDT the ban's applicability to ingredients tested dients tested on animals under REACH. studies, consistent with REACH's "last resort" on animals to satisfy third-country require- After hearing from ECHA and BASF – as well principle for animal testing, and guarantee that ments, for example in China, or other EU as PETA International Science Consortium BASF's ingredient – registered exclusively for regulations, such as REACH. and European Coalition to End Animal Experi- use in cosmetics – isn't barred from the Euro- The European Court of Justice ruled on ments, which acted as interveners – ECHA's pean market under the Cosmetics Regulation. the third-country matter in September Board of Appeal annulled the decision reject- The Cosmetics Regulation has fully pro- 2016, determining that mandatory animal ing BASF's non-animal testing proposal and hibited the marketing of animal-tested cos- testing performed in China, for example, remitted it to ECHA for further action. metic products/ingredients in the European does not taint a cosmetic ingredient in such The issue is not that ECHA transgressed bloc since March 2013. (Also see "ECHA: Non- a way as to render it unmarketable in the necessarily in ordering an animal test to Animal Tests For Complex Toxicity Endpoints EU. However, the data derived from those assess reproductive toxicity, in lieu of the Not 'Foreseeable'" - Rose Sheet, 29 Nov, 2017.) tests cannot be used to substantiate safety read-across approach proposed by BASF, BASF noted in its exchanges with ECHA as required by the Cosmetics Regulation, but rather that ECHA breached its duty to that "there is still uncertainty with regard to the ECJ decided. (Also see "Landmark EU Rul- "state reasons" for the decision. the marketing ban laid down in the Cosmet- ing: Animal-Tested Cosmetic Ingredients Not According to ECHA, BASF's registration dos-

10 | Rose Sheet | December 2017 © Informa UK Ltd 2017 COSMETICS sier indicates the potential for worker exposure Regulation. Had it done so initially, and had to the substance in question. The substance Member State competent authorities unani- thus can be subject to required animal testing mously and expressly accepted its reason- under REACH in accordance with exceptions “It is obvious that a new ing, BASF would have been in a less legally outlined in the EC/ECHA joint statement, as decision by the ECHA uncertain position, the board says. well as a related factsheet on ECHA's website. Member State authorities were silent in "Consequently, the fact that the sub- competent body is needed July 2016 on ECHA's draft decision, propos- stance is registered exclusively for use as ing no amendments, according to back- an ingredient in cosmetic products is not with enhanced reasoning. ground information in the board's decision. relevant to the contested decision," the For ECHA the interface of According to Julia Baines, science policy ad- agency argues. "The exclusive use of the visor for the PETA International Science Consor- substance in cosmetic products cannot be the two legislations is clear tium, ECHA could choose to appeal the board's a reason for failing to meet the information ruling before the European General Court, a requirements under the REACH Regulation and it is explained in the constituent court of the Court of Justice. because workers may also be exposed to it." factsheet available,” an "A clarification from the court specifically The Board of Appeal points out, however, relating to the interpretation between the that ECHA made no mention of this factor agency press officer said. Cosmetics and REACH regulations is certain- (worker exposure) in its decision. ly warranted," she said in a Dec. 12 email. At this point, it may simply fall to ECHA to stances, the testing would have served no PISC does not have the standing to take redraft its decision, providing a more thor- purpose, the costs generated would have the issue to the EU courts itself, but a case ough explanation of why BASF's ingredient been unnecessary and animals sacrificed could be pursued by the EC, an EU Member requires animal testing based on the dan- unnecessarily," the appellate board notes. State or a cosmetics manufacturer or dis- gers it may pose to workers. At the same time, the board acknowledg- tributor, according to Baines. Indeed, an ECHA press officer said in a es that ECHA is "not competent to apply or In the interim, PISC is celebrating the Board Dec. 13 email that ECHA reads the board's implement Article 18(1)(b) of the Cosmetics of Appeal's decision, which for the time being decision as meaning that although the Regulation [the animal-testing marketing "saves hundreds of animals, including preg- relationship between the REACH Regula- ban]. It is also not competent to give a bind- nant females and their unborn offspring, from tion and the Cosmetics Regulation was ex- ing interpretation of this provision." being force-fed high concentrations of a cos- plained to BASF in behind-the-scenes con- This leaves ECHA in a precarious spot. metics ingredient," the organization says. versations, the contested decision itself did Baines added that "until this [BASF] case not contain that explanation. NEXT STOP: EU COURTS? is resolved, companies registering sub- "ECHA should have referred to ECHA’s In the previous ombudsman dispute, the stances used exclusively as cosmetics ingre- factsheet on the relationship between EC and ECHA indicated that they do not dients under REACH will remain in a posi- REACH Regulation and the Cosmetics Regu- believe REACH animal testing, when con- tion of legal uncertainty, and so we would lation in order to justify why the requested ducted as a last resort, should be seen as caution that only non-animal approaches vertebrate test is warranted," the rep said. an attempt to circumvent the Cosmetics be taken towards hazard assessment in or- He added, "It is obvious that a new deci- Regulation's prohibitions, as third-country der to avoid being potentially locked out of sion by the ECHA competent body is need- animal testing might be viewed. the EU market." ed with enhanced reasoning. For ECHA the They told the ombudsman that they are interface of the two legislations is clear and inclined to take the stance, accordingly, it is explained in the factsheet available." that companies may rely on REACH animal But it seems that all parties are interested testing data to substantiate the safety of in getting a more decisive position from cosmetics sold in the EU. ECHA on the usability of REACH animal data The EC and ECHA have issued no formal harma intelligence | to support the marketing of a cosmetic prod- statement to that effect, however, and they uct containing the tested ingredient with- don't seem eager to do so. out triggering the Cosmetics Regulation's In revisiting the BASF decision, ECHA Delivering uniquely animal-testing ban, particularly given that could lay out its rationale for why it lacks multiple references to the latter and its pro- the authority to interpret the Cosmetics specialized coverage in hibitions are woven into the text of REACH. Regulation, which would enable BASF to the cosmetics and dietary Minus such an interpretation and a cor- contest the "correctness" of those reasons, supplements sector. responding degree of legal certainty, "regis- according to the appeals board. trants could be obliged to cease marketing Or the agency could go further, setting rose.pharmaintelligence. substances for use in cosmetic ingredients forth an argument for why the REACH animal after complying with an Agency decision testing imposed on BASF would not lead to informa.com requiring animal testing. In these circum- a ban on the substance under the Cosmetics

11 | Rose Sheet | December 2017 © Informa UK Ltd 2017 COSMETICS

uct or isolated vegan claim than what many China Animal Testing Continues To online commenters view as a misleading cruelty-free message from the company Make Headaches For Beauty Brands overall, given its China business. From their perspective a cosmetics com- RYAN NELSON [email protected] pany can't both be cruelty-free and have a presence in China, a position that PETA has 'Oreal SA's L'Oreal Paris and the Estee exclude them anywhere," the brand says. long taken on L'Oreal and other leading Lauder Companies, Inc.'s MAC have MAC also notes that it continues to be multinationals. L been taking renewed fire on social a leading force in the movement toward a L'Oreal's website, like MAC's, includes an media in recent weeks as cruelty-free propo- "cruelty-free world," partnering for example FAQ page devoted to animal testing issues. nents that do business in China, where animal with the Institute for In Vitro Sciences to ad- And similar to MAC, L'Oreal says it does not testing typically is a prerequisite for foreign vance the use and acceptance of alternative test any of its products or ingredients on companies to sell cosmetics in the country. testing methods worldwide. animals and has been helping to drive the Australian singer Sia announced herself @ThisGirlThrives wasn't having it. "Unbe- development of non-animal test approach- as the new face of MAC's Viva Glam cam- lievably irresponsible of you to share this es for more than 30 years. paign via a Nov. 30 tweet, igniting a storm misinformation @Sia. @MACCosmetics sell "Since 1979, L'Oréal has been recon- of criticism from animal lovers. to China where animal testing is required structing human skin models in laborato- The eight-time Grammy nominee's lip- by law! MAC are absolutely NOT cruelty free ries to elaborate safety tests in vitro that stick will launch in early January, according and do not deserve that status." don’t involve animals. The group has thus to Team Sia, and "every single cent" will go to @EEboyle22 was similarly dismayed. "An been at the forefront of alternative meth- the MAC AIDS Fund, which provides financial international company like Mac who make ods for safety evaluation," it asserts. support to organizations around the world millions can afford to pull out of supplying L'Oreal notes the regulatory situation in that serve individuals living with HIV/AIDS. in China who endorse and support animal China and its rationale for playing there. "By The problem? Sia is a vocal animal wel- testing, however they are too egotistical to being present in China, L’Oréal can enable fare advocate who's teamed up with PETA do so and I doubt it will change any time the regulation to evolve. L’Oréal is the most on past campaigns and contributed hand- soon. For Sia to help move the blame of active company working with the Chinese somely to animal charities. Mac is a massive letdown." authorities towards a total elimination of Her partnership with MAC didn't sit well animal testing. As a result, the vast majority with some in the social media sphere. "MAC L'OREAL SHAMPOO'S '100% of products we sell in China are no longer WILLINGLY SELLS IN CHINA FOR $ WHERE VEGAN' CLAIM CHALLENGED tested on animals." ANIMAL TESTING IS MANDATORY. MAC Central to criticism leveled at L'Oreal Paris is Such considerations aside, "vegan," much TESTS ON ANIMALS. You're horrible for us- the brand's EverSleek Keratin Caring Sham- like "natural," is not a regulated term in the ing your platform to spread bad propagan- poo, which is sulfate-free, paraben-free and cosmetics sector, though many consumers da!" @_LeticiaLua tweeted at Sia Dec. 1. 100% vegan, according to its packaging. clearly have strong opinions about what it "Please delete this and promote a com- "Hey @Loreal," tweeted @JonaWeinhofen should mean. pany who is ACTUALLY against animal test- Nov. 26, "I guess no one has told you but to be L'Oreal's suggested definition of a vegan ing," snapped @231Tally the same day. 100% vegan you have to not test your horrible product – one that does not contain animal @Sia responded, tweeting, "Like MAC, I products on animals, not just make them free materials or byproducts and is not tested believe makeup shouldn't be tested on ani- of animal products. Buyers beware, this stamp in whole or in part on animals – seems to mals. MAC does not test on animals and is isn’t certified & product is NOT vegan friendly." align with consumer views overall, and it's advocating change in countries like China Others quickly piled on. "Did you see consistent with the standard used by Vegan where animal testing exists." L'oreal have stuck VEGAN badges on their Action, which administers the "Certified The artist refers interested persons to a disgusting products?? Like... someone for- Vegan" logo. related FAQ page of MAC's website, which got to mention them testing on animals False-advertising class actions against explains the brand's policy not to conduct doesn't equal vegan even without animal vegan product manufacturers haven't taken animal testing, while acknowledging that byproducts," tweeted @merij156. off like natural suits have, and arguably the some governments – namely China – test @L'OrealUSA responded, "To clarify, our vegan concept is better understood, with cosmetics on animals on a premarket ba- Ever Pure haircare products carry the 100% greater stakeholder consensus as to the sis to substantiate their safety (and require vegan claim. The packaging explains these term's denotations, compared with "natural." product owners to fund the testing). formulas are not tested on animals and also Still, it likely would behoove companies MAC markets products in China, with do not contain animal byproducts.” to take care in using vegan claims, leave marked success of late. (Also see "Lauder’s There's undoubtedly some confusion them off products available in China and GLAMGLOW Continues To Shine, MAC Improves among consumers, but at bottom, judging generally ensure that such assertions can In 'Outstanding' Q1" - Rose Sheet, 6 Nov, 2017.) by the Twitter stream, the L'Oreal bashing be supported if questioned by consumers "We love our fans and we never want to seems less to do with any particular prod- or targeted by plaintiffs.

12 | Rose Sheet | December 2017 © Informa UK Ltd 2017 DIETARY SUPPLEMENTS

Dietary Supplement Sector Warnings Jump With FDA ‘Program Alignment’

MALCOLM SPICER [email protected]

he number of FDA warning letters cal health; tobacco; and imports. (Also see to firms manufacturing and market- "FDA 'Program Alignment' Means Inspections T ing dietary supplements increased Consistency To Supplement Industry" - Rose by more than 30 to 81 during the year the Sheet, 17 May, 2017.) agency began assigning Office of Regula- tory Affairs inspectors to certain facilities BRAINALERT GMP, based on their areas of expertise. CLAIM PROBLEMS The "program alignment" ORA has im- BrainAlert is the latest supplement mar- plemented in 2017 sends inspectors more keter FDA warned about using unap- knowledgeable about FDA's supplement proved cognitive benefit claims, an area good manufacturing practices regulations, that the Federal Trade Commission also Part 111 of the agency's regulations in CFR prioritizes for enforcement. (Also see "Pre- 21, to plants, warehouses and other facili- vagen Study Data Withstand False Ad Com- ties operated by firms marketing vitamins, plaint By FTC, New York AG" - Rose Sheet, minerals or other nutritionals labeled as 5 Oct, 2017.) The Lynwood, Wash., firm's supplements. website, reviewed by FDA in August and "One of the outcomes of program align- again in December, promoted its name- ment is that we now have compliance of- sake supplement with claims including ficers dedicated specifically to a program, FDA inspectors say BrainAlert LLC's violative “Are you struggling with … seasonal de- whether drugs, devices, medical prod- claims for its namesake supplement include pression? … Then BrainAlert is the solu- ucts, human and animal foods. That will references on its website to published tion for you!” and "Studies have shown really give us a lot of synergy in working research with titles including "Effects of niacinamide to product an anti-anxiety with our respective centers and how we coenzyme Q10 in early Parkinson disease." effect,” according to the Dec. 14 warning go out about our approaches for many of letter from ORA's Seattle District. the public health challenges that we have The warning also notes that BrainAlert's to deal with," said Alonzo Cruz, director of to Eden’s Answers Inc./Sprigs Life Inc. website made additional claims for the FDA's Office of Regulatory Affairs, at a re- about drug claim and misbranding prob- product through references to published cent regulatory conference in Washington. lems for its natural pediatric and other research with titles including "Effects of Some in the industry have complained remedies (see box, p. 14). coenzyme Q10 in early Parkinson disease," that FDA inspectors unfamiliar with Part According to FDA's database, 81 warning and "L-acetylcarnitine treatment of mental 111 inappropriately and unfairly hold letters to firms marketing vitamins, miner- decline in the elderly." Additionally, incor- supplement firms to drug or food product als or nutritionals had been submitted in rect terms and formatting on the label ren- manufacturing regulations. FDA's assign- 2017 through Dec. 22, up from 49 in 2016. ders to the product misbranded. ment of inspectors with greater expertise The number of supplement firms warned BrainAlert also is the latest own-labeler on the regulations, though, could be turn- about claim, labeling, branding or GMP supplement marketer FDA has advised ing up compliance problems in the sector violations, with most cited for problems in about being responsible for its GMP com- that other ORA officials might have missed. multiple categories, in 2017 had reached 46 pliance and not relying on its contract "It's certainly been an exciting year with- in July. (Also see "Supplement Industry Warn- manufacturers and other suppliers to fulfill in ORA," Cruz said at a Food and Drug Law ings Near 2016 Total Midway Through 2017" its obligations under Part 111. (Also see "To- Institute conference on Dec. 6. "Program - Rose Sheet, 19 Jul, 2017.) tal Nutrition Latest Own-Label Supplement alignment really was an agency-wide ini- The agency in May, a year after begin- Marketer Warned On GMP Violations" - Rose tiative and really all centers were fully par- ning the program alignment initiative, an- Sheet, 31 Aug, 2017.) ticipatory in that process." nounced it had restructured each of its five Because BrainAlert distributes a "supple- The latest update to FDA's warning let- regional offices – Pacific, Central, Northeast, ment into interstate commerce in its final ter database includes three supplement Southwest, Southeast – into seven com- form for distribution to consumers," it "has marketers warned about GMP and other modity-specific programs: food products an overarching and ultimate responsibility violations -- BrainAlert LLC, Dynamic including supplements; biological prod- to ensure that all phases of the production Technical Formulations LLC and Maine ucts; bioresearch monitoring; pharmaceuti- of that product are in compliance with" Natural Health Inc. A fourth warning went cal quality; medical devices and radiologi- supplement GMP requirements, ORA states.

13 | Rose Sheet | December 2017 © Informa UK Ltd 2017 DIETARY SUPPLEMENTS

Its GMP deficiencies reflect common but containing selective androgen recep- tests and examinations to assure the iden- problems across the sector, including fail- tor modulators, SARMs, anabolic steroid- tity, purity, strength or composition of a ing to implement a system of controls for all like ingredients that have the potential to product, according to the Dec. 13 warning. stages of manufacturing, packaging, label- increase the risk of heart attack and stroke Dynamic Technical also failed to: ing and holding and to establish and follow and for which long-term effects are un- written procedures to fulfill requirements known. (Also see "SARMs Spells Latest 'Syn- •• prepare written master manufacturing related to product complaints. thetic Steroids' FDA Finds In Supplements" and batch production records; - Rose Sheet, 31 Oct, 2017.) •• establish specifications for every manu- SARMS TIP OF PROBLEMS The Roswell, Ga., firm's GMP deficiencies facturing point, step or stage where ORA's Atlanta District submitted a warning found during an inspection in May and control is necessary to the quality of a to Dynamic Technical Formulations after June included its quality control personnel product; the firm was among three that FDA asked failing to approve or reject all processes, identify each lot within each shipment to recall products labeled as supplements specifications, written procedures, controls, •• of components it receives and any lot of components it produces in a manner that allows tracing a lot to a supplier; HERBAL REMEDIES MAKE DEPRESSION, •• collect and hold reserve samples of ALLERGY CLAIMS each lot; •• document training. ORA's August inspection of Eden’s Answers Inc. and Sprigs Life Inc.'s facilities in Additionally, using SARMs in a product Beach City, Ohio, and a review of the firms' websites found drug claims for their renders it an unapproved and misbranded Pedia Para-Free, Lil’ Ones Breathe Easy, Respiratory Aid, Raw Elderberry and Honey new drug, the letter states. and Women’s Hormonal Help – Life Stage 2 herbal supplements. OUT-OF-SPEC COMPONENTS USED Lil’ Ones Breathe Easy, which is labeled with the ingredients chickweed, nettle and Maine Natural Health's GMP problems eyebright herbs, Burdock, echinacea and ginger roots and plantain leaf, was pro- found in an April and May inspection of its Warren, Maine, facility were failing to collect moted with claims including “Fights congestion and “Parents’ favorite for: Seasonal and hold samples, prepare written master Allergies, Colds, Flu, Congestion, Runny Nose, Sinus Infections,” according to the manufacturing records and establish man- Dec. 14 warning letter from ORA's Cincinnati District. ufacturing specifications at all points where control is necessary. Claims for Pedia Para-Free, labeled with ingredients black walnut hull, fennel seed, Additionally, the firm did not reject com- male fern and wormwood herbs and papaya, peppermint and sage leaf, included ponents with out-of-specification results “Parents’ favorite for: Pinworms, Tapeworm, Hookworm, Roundworm, Flatworm but used those materials in its supple- blood fluke, Giardia, Toxoplasma.” ments, ORA's East Division 1 said in the Dec. 13 warning. Women’s Hormonal Help – Life Stage 2 is labeled with ingredients angelica and Incorrect terms and formatting on labels wild yam roots, chaste tree berry, dong quai, damiana and red raspberry leaf, renders Maine Naturals' SO3 + D3 Fish Oil, blessed thistle, squaw vine and black cohosh, ginseng and licorice herbs. The SO3 Fish Oil, Recovery Whey Protein, Strong firms' claims for the product include “Customers’ favorite for: …Depression… Strength + Muscle and Pure Whey Protein supplements misbranded. Postpartum, Endometriosis.” Violative claims ORA found during a re- Women’s Hormonal Help and Respiratory Aid, which is promoted online with a view of the firm's website include "heart claim of “Customers’ favorite for: Cold, Flu, Infection, Inflammation, Mucus, Sinus disease is the leading cause of death in the US, which makes vitamin D an important Infection, Hay Fever,” are intended for treatment of conditions not amenable to nutrient” and "mega-3 fatty acids in fish oil self-diagnosis and do not state adequate directions for a laypersons' use, the … have shown beneficial results for a vari- warning states. ety of health problems … regular consump- tion of fish oil may help stave off disease.” Other misbranding problems with the firms' products include incorrect servings ORA also notes the also features "evidence size, servings per container and presentation of nutrition information on labels of intended use" as drugs for the firm's and failure to include the quantitative amount per serving size of all dietary products in its responses to consumer com- ingredients and to identify the part of the plant from which each botanical dietary ments, including “Looking for fish oil to help ingredient in a product is derived. my son’s eczema. … For your son, we recom- mend our omega-3 without Vit. D3.”

14 | Rose Sheet | December 2017 © Informa UK Ltd 2017 DIETARY SUPPLEMENTS

Form 483s: Supplement Firms’ Stage For Changing FDA Inspectors’ Views

EILEEN FRANCIS [email protected]

ietary supplement companies have a Supplement firms often go from form 483s window to dispel FDA's expectation to warning letters by missing FDA’s deadlines D they are “relatively clueless” about for responding, or because they don't care- FROM TESTING TO good manufacturing practice violations not- fully follow inspectors' directions. “Set forth REPROCESSING ed on form 483s following inspections, and to realistic time lines and that works both ways. avoid warning letters and re-inspections, say If you can do something within 20 days and lawyers familiar with FDA inspections. you are comfortable, make sure you do it in Young shared a list of supplement Manufacturers and other firms should 20 days. If it takes longer, explain why it’s go- firms' most common mistakes that respond immediately to form 483s with evi- ing to take longer and how long you think it’s prompt form 483s, but also acknow- dence, including photographs, that noted going to take,” said Feldstein, who specializes ledged that some manufacturers problems have been corrected, or that work in supplement inspection issues. and marketers commit "deliberate has begun to make corrections, said attor- If a firm disagrees with an inspector’s ob- neys Anthony Young and Alan Feldstein on servation, it should explain with documenta- prevarications" that end up costing Dec. 14 during the American Herbal Prod- tion backing up its position, he said. “We are them, such as misidentifying ucts Association's conclusion of a two-part talking about a collaborative process and ingredients to avoid investigation. webinar on GMP compliance and FDA in- responding adequately. Not answering or spection trends. taking an adversarial position will get you • Testing against non-validated Timely, substantive responses can sway nowhere.” samples; FDA Office of Regulatory Affairs officials AHPA Chief Information Analyst Merle from issuing a warning letter even when a Zimmerman suggested a firm's control over • Failing to follow inspectors' firm has not completed corrections in their whether it receives a warning begins during instructions after positives on standard operating procedures needed in an inspection. micro-screen tests; response to inspectors' findings, “The facilities have the opportunity the “If you provide evidence of those changes entire time from arrival of the inspector to • Laboratory contamination of test as you are doing them and it is good solid beginning to close out the report to make material with positive controls; evidence that you have changed SOPs and changes,” he said, adding that it helps "if you you are now releasing products under new can change something while the inspector is • SOPs not followed, or process SOPs, those kinds of things, giving that in- there and have them observe that change.” changes without SOP updates; formation to FDA in periodic submissions Additionally, appointing an employee • Absence of signed and dated usually does avoid a warning letter and also to accompany investigators, take copious makes FDA less anxious to come back and notes and ask questions demonstrates a entries in batch records; re-inspect you to see if you’re doing the firm approaches an inspection seriously • Reprocessing rejected materials things that you promised to do,” said Young, and will be on top of necessary changes. a partner at Kleinfeld, Kaplan & Becker LLP in without full investigation; Washington and general counsel for AHPA. LOSING SOME POINTS • Deviation from product-specific Common changes companies make after However, while impressing an ORA official GMPs and company records not they receive a 483 that help avoid a warn- about a firm's intentions helps, promises ing letter concern issues such as facility made but unfulfilled are sure to prompt warn- organized against GMPs; temperature, cleanliness and rodent con- ing letters. “If you say ‘we will comply’ and four • Failure to read certificates of trol, “those sorts of things in a facility we of- months later FDA hasn’t received anything, ten forget about,” said Feldstein, of counsel they will send a warning letter,” Young said. analysis allergen disclosures; with Collins Gann McClosley & Barry PLLC in Additionally, companies often do not ap- • Master manufacturing and Mineola, N.Y. ply corrections across a facility but only to a corresponding batch records not single area an FDA officials identified. “This ASSERTING SOME CONTROL is a real rookie mistake,” Young said. easily translated to GMPs; Supplement marketers and other partici- For example, when an inspector points • Supplement Fact labels differ from pants in the webinar asked about control out a company failed to identify an ingre- they have in avoiding a warning letter once dient on a product label, a firm often will MMR ingredient specs. they have received a form 483. simply correct the one error and overlook

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others on the same label and not review materials and websites. “Get that stuff off in November during the first part of AHPA's other products. your website. They are going to check be- webinar, discussing , FDA's shift in assigning “You have to take that teaching and apply it fore they close out inspection,” he said. officials to inspect regulated firms’ facilities to all your ingredients. You can’t just respond Similarly, outdated online or print mar- based on their expertise and the number to the ones in the 483 and expect to have keting materials with information that no of facilities inspected for compliance with completed the course work here,” Young said. longer tracks with product labeling also will GMPs. (Also see "FDA's Tighter Targeting For Another mistake is failure to remove all get inspectors' attention. GMP Inspections Still Leaves Consistency Gap" disease claims from products, marketing Zimmerman and Young also presented - Rose Sheet, 30 Nov, 2017.)

Unusual Supplement Adverse Events Could Be ‘Canary’ Of Problem EILEEN FRANCIS [email protected]

ost-market surveillance for a dietary that could influence that particular product verse events,” Kingston said. supplement should include identify- and what is happening with it." Marketers should consider a weight-of- P ing “sentinel" adverse events, low- “There could be quality control issues, evidence approach in evaluating sentinel incidence or unusual reports that can signal bacterial contamination that happens be- events. “Do you have other events coming major issues such as bacterial contamina- fore or after it leaves the plant,” Kingston through other venues, or scientific litera- tion or formula counterfeiting, according said. ture on it? Polymorphisms could be trigger- to toxicologist and industry consultant Rick Unusual, low-incidence events could be a ing it, such as another drug” Kingston said. Kingston. dynamic of a small, susceptible population “Identifying those canary-in-the-coal-mine “Sentinel events are essentially the ca- suffering from a certain disease or taking types of cases [could] indicate you might nary in the coal mine,” said Kingston during another supplement or a drug product that need to be educating consumers of the a recent Council for Responsible Nutrition is interacting with the supplement. These possibility of certain types of events.” webinar. and other community or population char- They often are a “small number of events acteristics are examples of variables that TREND ANALYSIS, that come through, but with high integrity cannot be controlled for in studies on prod- BENCHMARKING and can identify certain populations at risk,” ucts' safety. Supplement marketers' requirement to said the president of SafetyCall Internation- Kingston suggested nutrients' and other submit to FDA serious AE reports they re- al PLLC, which consults consumer product substances' interaction with cytochrome ceive from consumers or other parties is firms on post-market surveillance, product P450 genes, which produce enzymes in- not the same as post-market surveillance safety review and regulatory reporting for volved in the formation and breakdown of and there is much less guidance out there adverse events. molecules and chemicals within cells, is an to assist companies who want information During the Nov. 15 webinar also spon- emerging area of concern. on the best way to stay abreast of how their sored by Natural Products Insider, Kingston "I think that’s one of the biggest areas products are impacting people throughout discussed aggressive post-market surveil- we’re seeing right now. The product inher- their life cycle in the market. lance system focused on normalizing ad- ently by itself has really got an extremely Kingston suggested companies often re- verse event incidence rates, determining wide margin of safety, but because of the port AERs to FDA, within 15 day as required, expected events based on toxicology of way it acts in the body could have an im- but fail to use the data in post-market sur- products and design and identifying pre- pact on the P450 enzyme system and cause veillance. Yet, the marketer is ultimately re- dictable AEs and incidence rates. (Natural certain types of drugs to be metabolized sponsible for the product and unintended Products Insider is published by Informa Exhi- more rapidly or more slowly.” consequences of its use. bitions Inc., a division of Informa Inc., which Sentinel events from taking vitamins, “Companies are expected from a prod- also publishes the Rose Sheet.) minerals or supplements also can indicate uct liability perspective to be doing their He said companies often brush off report- a counterfeit product in the market, espe- own trend analysis and benchmarking, and ing AEs that deviate from expected incident cially for high-demand products sold at pre- when you are doing that, it leads to signal rates. "One of the most common responses mium prices. detection. If someone maliciously contami- I get from folks when we have a certain type “There is a significant amount of eco- nates your product, is your system designed of report that comes in and it seems highly nomic gain by counterfeiters if they can and set up to pick up those systems and act implausible, the first knee jerk response is, manufacture [a product] to look identical to appropriately? You have to be prepared to ‘Our product doesn’t do that.’ And it may the real product. This is something to think expect the unexpected,” Kingston added. not do that, but there could be other things about when you see uncharacteristic ad- Regarding an internal AE system, Kings-

16 | Rose Sheet | December 2017 © Informa UK Ltd 2017 DIETARY SUPPLEMENTS ton echoed many of the sentiments as acceptance study to see how a population products as a means to identify abnormal Nature’s Bounty Co. executive Christina would respond to use of one of your prod- patterns in reporting. Each product has a Romano, who also spoke during the webi- ucts, it will always be smaller than market distinct AE incidence rate, based on the nar about internal AE compliance systems. penetration. So, the effects noted in 50 market in which it is sold and the types of (Also see "Robust Internal AER Systems Follow subjects cannot predict all the effects in consumer it is attracting, he said. Supplement Lifecycle – Nature's Bounty Ex- thousands of individuals using a product Companies should also identify predict- pert" - Rose Sheet, 27 Nov, 2017.) and certainly those using it in varying con- able events and their expected incidence He also suggests firms limit their expec- ditions.” rates. “What do you expect to see, maybe tations from positive results in clinical stud- Additionally, companies should set nor- based on a previous product in the market- ies on their products. “If you do a consumer malized incidence rates for AE reports on place?” he said.

Opioid-Withdrawal ‘Aids’ Warrant Immediate Action – CSPI EILEEN FRANCIS [email protected]

ith FDA’s crackdown on certain can say is proof is in the pudding." line, CSPI asks FDA to prohibit the sale of forms of botanical ingredient According to CSPI's Director of Regulato- the substances it identified and others like W kratom underway, the Center ry Affairs Laura MacCleery, who penned the them on the grounds that they are unap- for Science in the Public Interest is asking letters, "None of the companies produced proved and/or misbranded drugs under the the agency along with the Federal Trade – or even, evidently, attempted to produce Food, Drug and Cosmetic Act. Commission to cast a wider enforcement – any adequate public scientific evidence” CSPI also is asking the FTC to file charges net to capture non-kratom dietary supple- when asked to do so. In a Dec. 11 blog post, against the marketers for false and unsub- ments promoted as opioid withdrawal aids. the watchdog group noted that one of the stantiated claims under the FTC Act and, “We urge the FDA and FTC to issue im- products identified in its research, Mida- where possible, obtain refunds for consum- mediate warning letters and bring enforce- trexone Opiate Withdrawal Aid, appeared er purchases. ment actions that require cessation of sales to have been pulled from the market after of these and other such products and allow CSPI prodded the company for information. MOMENTUM BUILDS ON inspectors to seize products,” the non-profit “It is both outrageous and shameful that KRATOM DEBATE consumer advocacy group writes in sepa- supplement manufacturers would seek to CSPI’s findings appear to signal a market- rate but similar letters to the agency and mislead patients and divert their efforts to ing trend amid the opioid addiction crisis, commission Dec. 8. overcome this devastating illness and their brought to light and publicized by recent ac- Over a two-week period in October and income toward entirely unproven rem- tions against kratom-containing supplements. November, CSPI identified eight non-kra- edies,” she says. FDA Commissioner Scott Gottlieb, in a tom dietary supplement products sold on- CSPI asserts in a statement on its web- Nov. 14 public health advisory, warned line and touted as addressing opioid with- site that the companies selling the prod- against use of dietary supplement botani- drawal symptoms for a cost of between $20 ucts are “unscrupulous” and are “exploiting cal kratom to ease withdrawal symptoms and $182 per month (see chart, p. 18.) The the ongoing opioid epidemic, diverting from opioid or opiate addiction and/or its products comprised vitamins, minerals and desperate patients from proven effective use in addition to drugs, which could have herbal ingredients. treatments to unproven ones, all in the dangerous interactions, he said. CSPI wrote each product marketer and service of their bottom lines.” He also stated there’s “clear data on the asked them to provide scientific studies The watchdog group notes one of the increasing harms associated with kratom.” showing that its products were more effec- companies included in its assessment – the (Also see "FDA Turns Kratom's Future In US Di- tive than a placebo, the group notes. “The Opiate Freedom Center – continues selling etary Supplement Market Into History" - Rose responses were often flip, cursory, riddled its product with withdrawal aid claims even Sheet, 14 Nov, 2017.) with pseudo-scientific jargon, or frighten- though it was recently targeted by the Na- Gottlieb added that while the agency ingly ill-informed,” CSPI tells FDA and FTC. tional Advertising Division of the Council of has imposed import alerts to stop kratom For example, the advocacy group says Mita- Better Business Bureaus in an investigation from entering the US and is working with done U4Life, LLC, the marketer of Mitadone in which it did not respond to NAD’s request the Drug Enforcement Administration to Anti Opiate Aid Plus, replied, “We don’t really for evidence to substantiate claims for the evaluate the product and determine how it have any scientific studies as such currently, formula. (Also see "Opiate Addiction Remedy should be scheduled by DEA as a controlled it takes years & millions of dollars to do that, Claims Could Face FTC Substantiation Test" - substance, the agency must do more, given however the product has been working to Rose Sheet, 6 Nov, 2017.) “the scope of this crisis.” help ease symptoms for most people that Suggesting the problem goes well be- The American Kratom Association, a have taken it along with their program, all we yond the eight products it identified on- group representing dietary supplement

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CSPI-Identified Supplements Marketed As Opioid-Dependence Aids RESPONSE TO CSPI’S REQUEST PRODUCT/MARKETER CLAIMS FOR SCIENTIFIC STUDIES

Mitadone Anti-Opiate “Help ease withdrawal symptoms associated with use “We don’t really have any scientific studies as such Aid Plus of oxycontin, morphine, oxycodone, opium, vicodin, currently, it takes years & millions of dollars to do that (Mitadone U4Life, LLC) Demerol, hydrocodone, lorcet, methadone, suboxone, however the product has been working to help ease heroin, tramadol & other such painkillers & opioids. symptoms for most people that have taken it along Helps eliminate cravings, symptoms & helps you quit.” with their program, all we can say is proof is in the pudding.”

TaperAid Complete “Helps those individuals who have decided to com- “Nope, only informal studies with the 170 people I’ve (TaperAid) pletely discontinue opioids.” shared it with so far.” “Used after the last opioid intake.” “Reduces withdrawal symptoms during the 3-5 day detox period.”

Vasovita 2.0 “Assists the body’s natural functional ability to sup- “We have data documenting highly significant differ- (Life Sciences port individuals who are taking opiates.” ences between the experimental group of 6 subjects Technologies and the control group of 6 subjects. Because Vasovita International) 2.0 is currently in a patent pending status, our attor- ney advises us not to release any further data at this time. We expect approval by the end of 2018.”

CalmSupport “An all natural supplement formulated to help ease No response (CalmSupport.com LLC) the symptoms of opiate withdrawal naturally and effectively.”

Natracet “All natural, non-addictive aid that may help with ad- No response (Medicus Holistic diction and withdrawal symptoms.” Alternatives LLC)

Midatrexone Opiate “East withdrawal symptoms.” Evasive answers Withdrawal Aid “Reduce opioid dependence.” Marketer No Longer Listed

Opiate Detox Pro “Opioid addiction ease.” “Scientific studies are very costly, so no, there is no NutraCore Health “Our ingredients are the most effective on the market study. Detox Pro is certainly not a miracle to with- Products, LLC for treating withdrawal symptoms.” drawal. Everyone still has symptoms, but what it does do is provide the body with essential nutrients that all users are depleted of. Especially the quatrefolic for the brain, and Methyl B12 for the cells. The body needs this rebuilding process to recover.”

Ultimate Recovery System “OFC supplements are formulated to support your No response (CRM Services Inc. DBA body’s own natural healing systems, which can in turn Opiate Freedom Center) ease withdrawal symptoms and shorten detox length. We designed our one-of-a-kind nutraceutical system to specifically supply the critical nutrients most often depleted by addiction to narcotics, prescription opi- oid painkillers, heroin.” “Made to help you ease withdrawal symptoms, shorten detox length, improve emotional well-being, provide nutritional support to the brain during detox.”

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manufacturers and marketers, is asking claims and false promises” of some dietary ity for Pinney Associates – who frequently FDA to recant the mid-November advisory supplements making unsubstantiated presents to FDA advisory panels on opi- on their ingredient, arguing the agency’s claims regarding assistance with opioid oids and addiction – says there may be a information is inaccurate and the ingre- withdrawal. place for supplement products and OTC dient is a tool in helping curb narcotics drugs that ease the symptoms of opioid abuse. The group also characterized FDA’s CRN: NO 'MAINSTREAM' EVIDENCE withdrawal, though only if companies stay conclusions on kratom has “secretive and LINKING SUPPLEMENTS TO away from making disease claims. unsubstantiated” as well as “irreconcilable TREATMENT “If you think about the different symp- and arbitrary.” (Also see "Kratom Supplement The Council for Responsible Nutrition re- toms, muscle and joint pain, nausea and Marketers Dispute FDA Warning, Ask For Re- leased a statement Dec. 12 addressing opi- diarrhea, headaches, feeling generally view" - Rose Sheet, 15 Nov, 2017.) oid-related claims among dietary supple- miserable. That’s where people in the early The FTC has publicized a number of re- ment firms, noting it is “not aware of any stages of withdrawal, where it isn’t terribly cent cases involving dietary supplements mainstream research” supporting the use severe, can often manage with an OTC,” he marketed as aids for opioid withdrawal. In of a supplement to treat opioid addiction. said in a Dec. 14 interview. September, the commission cut 5,379 re- “Even if research has been conducted He likened supplements and OTC drugs fund checks totaling more than $210,000 and published on this topic, the law pro- for withdrawal to taking chicken soup for to consumers who purchased Sunrise Nu- hibits marketers of dietary supplements the cold or flu. “You have a wide range of traceuticals LLC’s Elimidrol supplement, from promoting any dietary supplement things you can take for cold and flu – zinc advertised as an effective treatment for product that makes treatment claims. Bot- and supplements you can take. And it’s opiate addiction withdrawal. (Also see "Stur- tom line: dietary supplements provide hard to beat chicken soup for the flu. If you man Leads Nature's Bounty For New Owner: many positive benefits promoting better get really bad and you develop pneumo- Health And Wellness Industry News" - Rose health and wellness, but they don’t treat nia, you have to go to the hospital. But in Sheet, 28 Sep, 2017.) opioid addiction.” the meantime, I wouldn’t tell people ‘don’t FTC Acting Chair Maureen Ohlhausen Nonetheless, Jack Henningfield, VP of eat chicken soup because it’s not proven also has spoken out about the “phone research, health policy and abuse liabil- effective.’”

Appropriators’ Interest Could Point To FDA Supplement Programs Funding Boost

EILEEN FRANCIS [email protected]

ouse appropriators want details on to allocate increased funding” to the ODSP. FDA spending to regulate dietary The upgrade of the Center for Food Safety H supplement manufacturing and and Applied Nutrition’s supplement over- marketing, a request Council for Respon- sight unit to an office in 2016 was seen as sible Nutrition executive Mike Greene says enhancing dietary supplement regulation shows they're listening to industry con- by giving ODSP a higher profile for receiv- cerns and are considering a funding boost. ing FDA resources. (Also see "FDA Dietary In a letter to FDA Commissioner Scott Supplement Division Soon May Need Office Gottlieb dated Dec. 12, Reps. Andy Har- Accommodations" - Pink Sheet, 7 Dec, 2015.) ris, R-MD, Derek Kilmer, D-WA, and David However, CRN and other industry groups Young, R-IA, ask about the agency’s Office quickly saw the office designation as an “el- of Dietary Supplement Programs. Harris evation in name only,” said Greene, CRN's and Young are members of the Appropria- senior vice president for government re- tions' Agricultural subcommittee, which lations. “Part of our plan was to work over has oversight of FDA's budget. the next three years to try to raise aware- They said that to “better understand ness why the office of dietary supplements FDA’s priorities,” they request an assessment needs more money.” “of the most significant threats to public ODSP's annual funding has been around health related to products marketed as di- $6m, but should be in the range of $10m or etary supplements and how you would de- $11m, Greene said in an interview. ploy additional resources if Congress were The Trump administration’s fiscal 2018

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budget proposal would cut funding for FDA say while supplements are exempt from very simple fact that a lot of our arguments supplement industry oversight and other pre-market approval under an assumption and discussions that were made on the Hill food safety related programs by $83m to of safety, “FDA has well documented that this year were heard,” he said, noting CRN $1.3bn, a total that would require a $26m there are products that are contaminated, has met with Appropriations subcommit- increase in user fees. (Also see "Supplement either intentionally or unintentionally, with tees in the House and Senate with FDA Industry Oversight Among FDA Programs Tar- inherently unsafe ingredients, including ac- oversight regarding more funding for ODSP. geted For $86M Budget Cut" - Rose Sheet, 23 tive pharmaceutical ingredients." “One of the things we found in the cur- May, 2017.) The members commend FDA’s inspec- rent environment, was because there were tion of and enforcement actions against so many budget cuts across the board be- FDA 'HAS WELL DOCUMENTED' manufacturers with products containing ing proposed, it was difficult to navigate INDUSTRY'S PROBLEMS potentially harmful ingredients, pointing how we go about getting more funding” for The three House members request the out it has said it conducts roughly 500 in- the dietary supplement programs, Greene amount of funds allocated across the spections a year and issues around 70 to 80 said. The letter to Gottlieb “shows Congress agency for supplement sector enforcement warning letters on GMP violations. is continuing to work on other issues be- since ODSP was elevated from a division. “In order to better detect dangerous prod- sides bigger issues out there and that gives They also ask FDA for the numbers of: ucts in the market, FDA is encouraged to us a little bit of hope.” continue to invest resources into oversight The Pew Charitable Trust has worked •• enforcement actions FDA brought and inspection of manufacturing plants that with CRN in appealing for more money for against supplement manufacturers and produce dietary supplements. We have been supplement sector enforcement, inspec- marketers; pleased with the interagency collaboration tions specific to supplements and other •• supplement good manufacturing prac- and urge FDA to continue working with the regulatory activity, Greene said. tice inspections FDA has conducted; Department of Justice to remove illegal di- The lobbying included CRN and Ameri- •• full-time equivalent staff positions dedi- etary supplements from the market.” can Herbal Products Association members cated to supplement facility inspections; meeting with about 100 lawmakers or their REQUESTING A BOOST AMID CUTS staff to discuss issues facing the industry's •• supplement serious adverse events re- While CRN would not describe the three during CRN's annual day of Capitol Hill in ported to FDA. lawmakers necessarily as “friends” of indus- June. CRN said lawmakers on both sides They note “more than half of Americans try, the trade group believes they heard the were receptive to industry’s take on current take at least one dietary supplement each industry's lobbying message this year and issues, including funding of the ODSP. (Also day, with use particularly prevalent among “felt it was necessary to gather more infor- see "Making Nutritionals Eligible For Health older persons and in children.” mation” from FDA. Savings Accounts Whets Congress' Appetite" - However, Harris, Kilmer and Young also “We see this letter as a reflection of the Rose Sheet, 14 Jul, 2017.)

FDA ‘Evolving’ Homeopathic Drug Enforcement With Risk-Based Approach MALCOLM SPICER [email protected]

DA will put more teeth into its ho- enforcement and regulatory actions" in- Woodcock was quick to clarify, though, meopathic drug industry oversight cludes products with routes of administra- that FDA is not moving to requiring pre- F under a draft guidance that identi- tion other than oral and topical or intended market approval for the products, a recom- fies problems it will target for enforcement to be used for the prevention or treatment mendation some stakeholders in the phar- while allowing the products to remain avail- of serious or life-threatening diseases and ma and health care industries make. able without pre-market approval. conditions, the draft guidance states. "FDA does not intend to take action The draft guidance published Dec. 18 "It means that FDA is evolving its ap- against all homeopathic products that have states that FDA will use an enforcement proach to regulating homeopathic prod- not been FDA approved nor are we aim- approach similar to its oversight of conven- ucts to one that reflects the current mar- ing to remove all homeopathic products tional OTC and Rx drugs that are marketed ket and is consistent with FDA's other from the market. In fact, we recognize that following FDA evaluation or nonprescrip- risk-based regulatory approaches," said many homeopathics likely fall outside the tion products available under monographs. Janet Woodcock, director of the agency's risk-based categories described in the draft The list of problems with homeopathics Center for Drug Evaluation and Research, in guidance," the CDER director added. (see box below) where FDA will "prioritize a media briefing. Donald Ashley, director of CDER's Of-

20 | Rose Sheet | December 2017 © Informa UK Ltd 2017 DIETARY SUPPLEMENTS fice of Compliance, said FDA enforcement against products in those categories is im- peded by its current policy for homeopathic oversight, established in a 1988 compliance policy guide that defines the ingredients al- lowed for marketing in the US as those in- cluded in the Homeopathic Pharmacopeia of the United States’ monograph. The draft states that upon finalization of the "Drug Products Labeled as Homeopathic" guid- CDER Director CDER Office of Commissioner ance, the CPG will be withdrawn. Janet Woodcock: Compliance Director Scott Gottlieb: "The CPG is not a risk-based enforcement “FDA is evolving its Donald Ashley: “We are at an policy and I'll have to say we've actually approach to regulating “We’ve actually found it appropriate junction to found it challenging to be able to respond homeopathic products.” challenging to be able to adapt our regulation of to some of the higher-risk products that respond to some of the homeopathics.” we've encountered over the years, in par- higher-risk products.” ticular more recently in time," Ashley said during the briefing. Natural Products Association President "As a public health agency we must bal- The more-than 60 warning letters FDA and CEO Daniel Fabricant said while "ho- ance both allowing access to the alterna- has submitted to homeopathic firms over meopathic products have been used safe- tive treatments and protecting consumers the past 15 years aren't enough to rein in ly since the 1700s," FDA's enforcement who choose to use homeopathic products violative claims or manufacturing problems shift is needed. from those drugs that have potential to in the sector, he added. That's partly be- “Risk-based is generally good because it cause significant risks to patients," Gottlieb cause many of the products are manufac- keeps focus on fly-by-nights and scam art- said during the media briefing. tured outside the US. ists selling junk masquerading as natural "With this in mind we believe we are "We'll issue import alerts to make sure products, and those criminals should be at an appropriate junction to adapt our that problematic products are not allowed caught and penalized to the full extent of regulation of homeopathics to reflect the in the US," Ashley said. the law," Fabricant said in a statement. current complexity of the market." Woodcock pointed out that repeat offend- FDA made known its latest problem in ers would be enforcement targets under the the space in a same-day warning letter to 'APPROPRIATE JUNCTION' guidance. "We have a whole range of addi- Canadian firm Deserving Health Inter- TO CHANGE tional options for those that provide unsafe national Corp. on good manufacturing Recent problems with homeopathics, FDA products or have repeated problem," she said. problems violations in the production of Commissioner Scott Gottlieb said, are an im- The American Association of Homeo- its Symbio Muc Eye Drops 5X homeopathic petus for moving from the CPG to a risk-based pathic Pharmacists, which represents man- drug. Gottlieb noted that the firm also enforcement approach while maintaining ufacturers and other stakeholders, said in a makes a product containing an ingredi- consumer access to compliant products. statement that at a public hearing FDA con- ent that can result in penicillin contami- ducted in 2015, it encouraged the agency nation, penicillium notatum, but did not to do what it says the draft guidance de- address potential risks of the ingredient scribes, "take quick action against illegal or reaching its eye drops or other products. unsafe homeopathic medicines." “The CPG is not a risk-based Other problems FDA noted in announc- Abandoning the 1988 CPG, though, isn't ing the draft guidance include: necessary, AAHP says. "The AAHP is con- enforcement policy and I'll •• A September 2016 warning to consum- fident that the current Compliance Policy have to say we've actually Guide provides FDA with ample opportuni- ers about homeopathic teething tablets ty to take such action right now," said asso- found it challenging to be and gels containing belladonna after FDA ciation President Mark Land in a statement some contained elevated and inconsis- tent levels of the toxic substance with an to the Rose Sheet. able to respond to some unpredictable response in children under AAHP also said it expects the draft guid- of the higher-risk products 2. (Also see "FTC Homeopathic Disclaimer ance would not materially affect the vast Policy Should Prompt FDA Changes – Advo- majority of homeopathic drug products that we've encountered cacy Group" - Pink Sheet, 21 Nov, 2016.) available in the US due their "wide margin of safety and manufacturing according over the years, in particular •• FDA found Standard Homeopathic Co.'s to" FDA's drug GMP regulations. The trade more recently in time.” Hyland's Teething Tablets contained vary- group said it will submit "extensive com- ing amounts of belladonna and the firm ments to FDA" on the draft guidance. – Donald Ashley applied substandard control to manufac-

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turing the products. (Also see "Inspection, which contains strychnine, going into its the Federal Trade Commission, which AERs Prompt Hyland's Teething Tablets Re- products. "If you're working with strych- regulates advertising claims for OTC call" - Pink Sheet, 8 Nov, 2010.) nine you don't want to mess around with homepathics as it does for all consumer being sure of that," she said. products, in November 2016 published an In 2009, Matrixx Initiatives Inc. re- •• The comment period on the draft, dock- "Enforcement Policy Statement" stating moved its top-selling product, Zicam et FDA-2017-D-6580, closes 90 days after that OTC homeopathics need disclaim- nasal swabs, after FDA inspectors found its publication. ers about the lack of what the commis- hundreds of adverse event reports re- FDA published the draft after opening a sion considers a scientific basis for their ceived by the firm, but not forwarded to docket and conducting a two-day public claims. It published the statement a year the agency, indicating that users were hearing in 2015 on recommendations for after the comment period closed on a re- losing their sense of smell due to intra- changes to its homeopathic industry over- view of homeopathic advertising regula- nasal application of the ingredient zinc. sight. (Also see "FDA Examination Of Ho- tion it launched largely because of the (Also see "Zicam Lawsuits Multiply, But meopathic Regulation Looks Beyond Safety market’s shift from primarily Rx products Matrixx Is Confident History Will Repeat History" - Pink Sheet, 27 Apr, 2015.) CDER, prescribed for individual users to mass- Itself" - Pink Sheet, 29 Jun, 2009.) said Woodcock, "considered every one of market formulations sold nationwide. Woodcock also noted that FDA has the more than 9,000 comments" before (Also see "OTC Homeopathic Labels Must warned a homeopathic marketer about writing the draft guidance. Include Scientific Disclaimers – FTC" - Pink lax control of the amount of nux vomica, The draft guidance also comes after Sheet, 15 Nov, 2016.)

Homeopathic Market Regulatory Priorities

REGULATORY PRIORITIES EXAMPLES OF ENFORCEMENT PROMPTS

Products with reported MedWatch reports or other information submitted to FDA can indicate or signal a potential safety concerns. association between the product and an adverse event, medication errors or other safety issues.

Products for routes of Unapproved injectable drug products and unapproved ophthalmic drug products pose a greater risk of administration other than harm to users due to their routes of administration (e.g., bypassing some of the body’s oral and topical. natural defenses, differences in absorption) and the potential risk of harm from contamination.

Potentially significant safety concerns are raised by products that contain or purport to contain an Products that contain or purport infectious agent with potential to be pathogenic; a controlled substance; multiple ingredients that, to contain ingredients associated when used in combination, raise safety concerns due to possible interactions, synergistic effects or with potentially significant safety additive effects of the various ingredients; or ingredients that pose potential toxic effects, particularly concerns. when concentrated or in low dilution presentations (e.g., 1X, 2X, or 1C), or not adequately controlled in the manufacturing process.

Products intended to be used for Unapproved products for serious and/or life threatening diseases and conditions raise public health the prevention or treatment of concerns, in part, because they may cause users to delay or discontinue medical treatments that have serious and/or life-threatening been found safe and effective through the NDA or BLA approval processes. diseases and conditions.

Patient populations such as immunocompromised individuals, infants and children, the elderly and pregnant women may be at greater risk for adverse reactions associated with a drug Products for vulnerable product, even if it contains only small amounts of an ingredient, due to their varying ability to populations. absorb, metabolize, distribute, or excrete the product or its metabolites. These populations may also be at greater risk of harm by foregoing the use of medical treatments that have been found safe and effec- tive through NDA or BLA approval processes or under an OTC monograph.

If a product purports to be or is represented as a product recognized in the official US Pharmacopoeia, official Homoeopathic Pharmacopoeia of the US, official National Formulary or any Products deemed adulterated supplement to any of them but its strength, quality, or purity differs from the standards set forth in under the FD&C Act. that official compendium), or if there are significant violations of current good manufacturing practice requirements.

22 | Rose Sheet | December 2017 © Informa UK Ltd 2017