AHPA Backs NDI Filing For Kratom, Experts Question FDA Enforcement

2 / June 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.)

AHPA Backs NDI Filing For Kratom, Experts Question FDA Enforcement

Executive SummaryFDA regulation of kratom as an NDI is necessary to avoid untenable state regulations, says AHPA chief Michael McGuffin, adding the trade group’s support to kratom experts’ push to keep the herbal ingredient available. Experts also say salmonella issues currently linked to kratom could be an indirect result of FDA’s import alert as noncompliant suppliers filled continued demand.

The American Herbal Products Association adds its support to urging FDA to regulate kratom as it does other new dietary ingredients and preclude states from imposing inconsistent regulations that block sales of the herb due to “excessive hype” over its safety.

“The idea of having to understand 51 regulations, from FDA and each of the 50 states, is not tenable,” AHPA Executive Director Michael McGuffin said during an April 25 media briefing. He added that AHPA supports “strong federal management and regulation.

Asked if he is concerned that bans on sale of the herb, which typically is descried as having a mild, caffeine-like effect, in almost a dozen states will spread to others and which is known to help opioid addicts detox from their dependence, McGuffin said FDA should regulate kratom. “We are strongly supportive of appropriate regulation by the FDA and would discourage state-by-state approaches, simply to maintain order in commerce of [the] herb that is being used by people in 50 states,” he said.

States that have banned kratom sales include Alabama, Arkansas, Indiana, New Hampshire (to consumers under 18), Rhode Island, Tennessee, Vermont and Wisconsin as well as Washington, D.C. Additionally, some municipalities have acted on the substance; San Diego imposed a ban in November 2017 on the sale of kratom-containing products intended for human consumption.

Kratom experts Paula Brown, British Columbia Institute of Technology director of applied research, and Jack Henningfield, Pinney Associates VP of research, health policy and abuse liability, question FDA’s findings on kratom safety and the effectiveness of its import alert.

Firms are required to submit NDIs at least 75 days before marketing products containing the igredients but do not have to wait for FDA’s response before launching distribution or sales. However, FDA can order off the market products with NDIs that are the subjects of notifications it refuses to file. More commonly, FDA reports

finding dietary ingredients in supplements that should have but have not been subjects of NDI notifications submitted to the agency.

Other supplement industry trade groups agree with AHPA that kratom is an NDI that requires a notification to the agency showing its safety for the intended use, but the other groups say kratom has not been shown as t safe for use in supplements. Kratom has emerged as the most visible example of dietary ingredients that proponents say were used in the US food supply well before October 1994, the grandfather date for dietary ingredients already in use to be considered “old” and eligible for use in supplements without a notification before marketing, or that should be cleared by FDA in the NDI notification process. (Also see “Kratom: All Questions On Pre-DSHEA Ingredient Evidence In One Package” - Rose Sheet, 16 Oct, 2017.)

McGuffin said companies marketing kratom products must show good faith to comply with FDA’s NDI requirements.

AHPA encourages kratom marketers to “understand and meet all of the other regulations required for any herbal product sold as a dietary supplement, such as registering as a food facility, meeting the extensive good manufacturing practice rules, refraining from making any drug claims, and submitting to FDA all serious adverse event reports received in association with their kratom products,” he said.

The agency has refused to file two NDI notifications for mitragynine, a compound in kratom, meaning the submissions did not provide sufficient evidence for the substance’s safety for its intended use. (Also see “FDA Waves Stop Sign At Kratom Product Launch After Failed NDI Notification” - Rose Sheet, 26 Feb, 2018.)

Market Muddled As FDA, DEA ActJack Henningfield, vice president of research, health policy and abuse liability at Pinney Associates health care market consultancy, said the imposition of bans on kratom sales by states and municipalities is “predictable” following FDA’s and the Drug Enforcement Administration’s actions toward forcing kratom off the consumer health market.

“When the FDA declares that kratom is an addictive narcotic-like substance it is not surprising. I’m aware many health professionals with different agencies are considering what to do, because they are scratching their heads and getting mixed messages,” Henningfield said.

3 / June 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.)

In November 2017, FDA announced it completed a “comprehensive scientific and medical evaluation” that found mitragynine and another compound in kratom – hydroxymitragynine – are opioids. The agency said it would work with DEA to further evaluate the compounds as the DoJ agency considers whether and how the substances should be scheduled. DEA in 2016 proposed to schedule the ingredient as a controlled substance, but delayed finalizing scheduling the substance to allow for public comment following a wave of opposition, predominantly from kratom consumers and vendors but also from Capitol Hill. (Also see “DEA Takes Comments On Kratom, But Keeps Eye On Scheduling” - Rose Sheet, 14 Oct, 2016.)

In February, FDA reported that its testing of the chemical structures of the 25 most prevalent compounds in kratom found that all share the most structural similarities with controlled opioid analgesics, such as morphine derivatives. Agency scientists analyzed the kratom compounds’ chemical structures, using 3D computer technology showing how chemical constituents of a substance are structured at a molecular level, may behave inside the body and can potentially affect the brain to determine likely biologic targets, and produced a model that predicted 22 of the 25 compounds in kratom, including mitragynine, bind to µ-opioid receptors. The model and previously available experimental data confirmed that mitragynine and hydroxymitragynine are known to activate opioid receptors, FDA said.

The American Kratom Association trade group contends that no deaths FDA and some state agencies have reported as linked to kratom use can be classified as “caused” by the herb and while FDA’s analysis found kratom binds to the opioid receptor in the brain just as opioids do, naloxone also binds to the receptors. Naloxone is approved by FDA for an indications of complete or partial reversal of opioid overdose. Pittsburgh-based AKA says kratom binds to opioid receptors in the brain as naloxone does, not suppressing a user’s respiratory system. (Also see “FDA’s Opioid Label For Kratom Called Misbranding By Marketers” - Rose Sheet, 7 Feb, 2018.)

Henningfield, who also is an adjunct professor of behavioral neology at Johns Hopkins University School of Medicine and has worked with AKA in its response to FDA’s findings and DEA’s proposed scheduling, says science does not support labeling kratom or its alkaloids as dangerous, but that the neuropharmacology of mitragynine as well as surveys and “thousands” of comments submitted to FDA support that the ingredient provides benefits for anxiety, mood and minor pain and for helping opioid addicts detox from their dependency.

“The results of the surveys and recent research suggests kratom and its alkaloids may be among the promising next generation of safer treatments for pain and addiction, but also anxiety and minor depression,” he said in a same-day release.

He added during the briefing that a ban on sales of kratom as a consumer health product will take “life preservers away from people who are struggling in the ocean because they are not Coast Guard approved.”

Salmonella Muddies Market, TooKratom has garnered additional attention due to an outbreak of salmonella infections potentially linked to products containing the herb since early 2018. Seven supplement recalls have been made in association with salmonella contamination in kratom-containing products so far. (Also see “More Undeclared Allergens, Contaminated Kratom Prompt Supplement Recalls” - Rose Sheet, 9 Apr, 2018.)

FDA on April 2 exercised its mandatory recall authority over food products for the first time after Las Vegas firm Triangle Pharmanaturals LLC ignored two requests to recall contaminated kratom products. (Also see “Las Vegas Kratom Marketer Rolls Dice On FDA’s Mandatory Recall Authority” - Rose Sheet, 3 Apr, 2018.)

A ban on sales of the substance in states or by FDA will present a “deadly” option, says Henningfield. “If it’s banned in enough places and banned nationally and criminalized, then there will be only one place to go – illicit sources,” he said.

On salmonella contamination, McGuffin said AHPA “strongly recommends” that companies recognize “FDA’s public health mission comes first, so any company that is informed by the FDA that a voluntary recall is in order due to agency finding salmonella in a product needs to recognize this is a reflection of that priority.”

Contaminated Kratom Skirts Import Alert?During the briefing, Paula Brown, British Columbia Institute of Technology director of applied research and University of British Columbia adjunct professor of biology, said salmonella contamination “is not a reflection on kratom per se and underscores the need for FDA enforcement, not scheduling.”

Brown, also Canada Research chairwoman for photoanalytics, said the outbreak may highlight FDA’s “inconsistent enforcement” of the good manufacturing practices 2007 final rule for dietary supplements.

4 / June 2018 © Informa UK Ltd 2018 (Unauthorized photocopying prohibited.)

After FDA issued import alerts in 2012 and 2014 to stop shipments of kratom into the US, some firms making or marketing kratom products likely began finding additional suppliers of the herb. FDA enforcement or market changes in the supplement products space that have similar impacts on supply of an ingredient or product are known to generate “economic adulteration” – demand continues, supply dwindles and some suppliers might intentionally offer adulterated goods, such as salmonella-contaminated kratom, that previously would not have reached the market. (Also see “GAO Adulteration Report Points To Disconnect Among FDA Offices” - Pink Sheet, 5 Dec, 2011.)

“The import alert and failure to enforce [current] GMP regulations has forced kratom products into an illicit market where adulterated and substandard products may flourish while driving legitimate products out of the marketplace,” Brown said.

FDA dismisses assertions that its import alerts have any relation to the salmonella contamination of some kratom products that remain available. An agency representatives pointed out an import alert for kratom has been in place since 2012 and was expanded in 2014, three years before salmonella illnesses potentially associated with kratom became known in 2017.

“Any suggestion that these import alerts triggered a salmonella outbreak more than five years later is both

baseless and irresponsible,” the representative said, adding,”The FDA continues to warn all consumers not to use kratom.”

Moreover, like marketers of other FDA-regulated products in the US, any kratom marketers is responsible for ensuring its product complies with all relevant agency regulations, including prohibitions on adulteration, “such as by contamination with salmonella, and requirements including [current] GMP,” the rep said. “When products are brought into the country despite an FDA import alert, and these laws and requirements are not followed or ignored, public health is put at risk.”

FDA’s import alerts marked the start its attempt to prevent marketing of kratom products and attributed the alert to an increase in the shipments of supplements and bulk ingredients in capsules, whole leaves, processed leaves, leave resins, leave extracts and other forms. (Also see “Kratom Import Alert Clarifies FDA Deems The Botanical An Unsafe NDI” - Pink Sheet, 21 Mar, 2014.)

Henningfield said during the briefing that FDA should shift its focus from demonizing kratom to approaching it like other dietary ingredients. The agency could “take action as it is doing now when it finds batches or suppliers of kratom when it is contaminated, just like it does for lettuce, chicken or eggs. That’s where we need FDA, to help keep products pure, identify when there are problems and address the problems,” he said.