Kratom: All Questions On Pre-DSHEA Ingredient Evidence In One Package

"Kratom illustrates the promise and the peril of dietary supplement regulation," says Jack Henningfield, Pinney Associates consultant and an expert on abuse liability of various substances. Kratom firms agree NDI notifications are needed for ingredients made from separate kratom alkaloids, but say the botanical itself has decades of safe use in the US.

The numerous questions that complicate proving to FDA that a dietary ingredient was marketed in the US before October 1994 are asked not only about ingredients that are not available, but also about some commonly used today, such as the botanical kratom.

At a recent public meeting on evidence to identify "old dietary ingredients," those available before the grandfather date – Oct. 15, 1994 – set by the Dietary Supplement Health and Education Act, and on processes for compiling a list of those ingredients that FDA will recognize as authoritative, kratom market representatives said the ingredient is an example of the reason the agency and the industry are asking those questions.

"Kratom illustrates the promise and the peril of dietary supplement regulation," said Jack Henningfield, vice president of Research, Health Policy, and Abuse Liability at Pinney Associates and professor of behavioral biology in Johns Hopkins University School of Medicine.

Kratom, available in formats including dried/crushed leaves, powder, capsules, tablets, liquids and gum/resin, also has attracted Drug Enforcement Administration attention and currently is raising safety questions among state and local officials unfamiliar with the properties of the ingredient extracted from a tropical deciduous and evergreen tree in the same biological family as coffee and native in Southeast Asia, where its leaves long have been used for therapeutic purposes. Two recent deaths medical examiners in Florida and New York attributed to kratom in preliminary findings following investigations criticized as incomplete prompted an industry association to explain the ingredient in a media briefing on Oct. 12 (see sidebar).

Henningfield and Upstream Consulting principal C.M. "Mac" Haddow, representing the American Kratom Association, spoke during the public comment period of FDA's meeting on Oct. 3 to explain kratom's history in the US and inquire about proof needed to document that the herb extracted from a plant in the coffee family was available pre-DSHEA. (Also see "Compiling Pre-DSHEA Ingredient List Relies On Bridging FDA-Industry Gap" - HBW Insight, 4 Oct, 2017.)

Haddow, a longtime Capitol Hill lobbyist, pointed out to FDA officials, supplement industry stakeholders and public health advocates at the meeting that kratom is among the many herbal ingredients that were available in the US before October 1994 and have longer histories in foreign countries.

However, kratom and some other vitamin, mineral and supplement ingredients were not products offered in mainstream US marketplaces and their uses before being introduced here are culturally established but with little if any official records of commerce or production.

Kratom's use in the US is known to have started in the 1970s after refugees and other immigrants from Southeast Asia and US military members returning from serving in Vietnam brought the herb with them, Haddow said.

"Can anyone document that? Not today, because we know there was no documentation," he said.

Documentation, Profile And More

Documentation of sales or other evidence of availability that is acceptable to FDA isn't the only question the agency has on whether a dietary ingredient was marketed in the US pre-DSHEA. Like kratom, other herbals are prompting multiple question from FDA.

On documentation, for instance, do records or other information indicate sales for use as a dietary ingredient of a certain ingredient or products containing it? It's not clear so far whether FDA will agree that evidence of an ingredient's pre-DSHEA presence in the US will be sufficient unless the information shows its use as a dietary ingredient.

Use of kratom, available in dried/crushed leaves, powder, capsules, tablets, liquids and gum/resin, in the US is known to have started in the 1970s.

Information on pre-DSHEA domestic use of some herbals could show their histories as oral medicinal remedies, though the products were not regulated as drugs, said American Herbal Products Association President Michael McGuffin.

"Some might argue 'yes, but those were marketed as drugs.' My view, AHPA's view is that any oral use establishes use in the United States prior to the date," said McGuffin during a discussion of the status of kratom and other herbals long used in other countries and brought to the US prior to 1994.

"They were medicines but they were also being consumed in a manner that was a home medicine and traditional therapeutic ingredient. We think all of those are old dietary ingredients," he added.

The ODI/NDI status for kratom, like other ingredients, also could swing on how it is produced, another issue unsettled between FDA and the industry. The agency's point is different extraction and manufacturing processes implemented since 1994 may render ingredients that do not fit the same chemical profiles as the substances of the same name used pre-DSHEA.

While industry stakeholders agree that different processes used for the same ingredient could generate different end products, they are not aligned with FDA on how firms can show whether ingredients are chemically altered from predecessor substances.

Similarly, ingredients used in formulations that differ from pre-DSHEA products could be deemed NDIs by FDA. That is, alkaloids of a botanical may not have the same chemical profile as the host plant.

Notification Guidance Off-Shoot

FDA's consideration of standards and protocols for an authoritative list of pre-DSHEA dietary ingredients is an off-shoot of its work on guidance for submitting new dietary ingredient notifications.

Dietary ingredients available pre-DSHEA are eligible for use in dietary supplements marketed in the US without submitting to FDA evidence supporting reasonable expectation of safety for the intended use. Conversely, for ingredients that FDA deems as becoming available in the US after October 1994, marketers must notify FDA with proof of those substances' safety at least 75 days before offering products containing the ingredient.

Clearance from the agency is not required before marketing NDI-containing supplements, but FDA is authorized to enforce against marketing of products that it questions following its evaluations of NDI notifications.

The first NDI notification draft guidance in 2011 did not mention an industry-sourced list as authoritative identification, but its absence was a huge obstacle to FDA and the industry agreeing on suitable guidance for NDI notifications. The agency broached the idea in its second draft guidance in 2016, opened a docket for comments – FDA-2017-N-4625 – and conducted the meeting to start the process. It is accepting comments through Dec. 4. (Also see "‘Old’ Ingredient List On FDA Table Could Spur New Supplement Launches" - HBW Insight, 14 Aug, 2017.)

Finalizing the NDI guidance is a separate docket, FDA-2011-D-0376, and the comment period is closed.

The Council of Responsible Nutrition see firms' use of constituents of ODIs as a big part of the industry's challenge to compiling a pre-DSHEA list FDA will acknowledge. "This is the issue that has dragged this thing out of the closet and caused so much tension," said Duffy Mackay, CRN's vice president for regulatory and scientific affairs.

Ingredients separated from the extracted botanical aren't in an ODI's profile, Mackay said at the meeting. "It cannot piggyback just because it's present in the botanical," he said, but also noted that some constituent ingredients might also have been available pre-DSHEA or could have been notified as NDIs.

The kratom industry group, Haddow said, agrees with FDA that some alkaloids should be submitted to the agency in NDI notifications before firms launch products containing those substances. "The separation of these classes of products is essential to maintain consume access to products and to fulfill the mission of DSHEA," he said.

The herb kratom, though, is not an NDI, Haddow added. "It is unfair take to take a broad stroke and brush and say all kratom proacts are therefore classified that way when you have this body of evidence that is currently available that demonstrates safe use by millions of Americans today."

Yesterday's Use Not From Affidavits Today

Even if an ingredient does not raise red flags about potential effects from different formulations or manufacturing processes or from separate alkaloids being used, firms realize they could face long odds in convincing FDA about an ingredient's history of use in the US.

Those odds are stretched partly because FDA has said it will not accept as evidence sworn affidavits made since 1994 about an ingredient's pre-DSHEA use without separate evidence supporting the oaths.

"The challenge is that the important date is 23 years old and if no affidavits were taken contemporaneously at that time, how do you fill the gap to have someone who says, 'yes, this happened pre-DSHEA and I'm prepared to state that'? How do we get around this problem?" said United Natural Products Alliance President Loren Israelsen.

The problem, said Steve Tave, FDA's dietary supplement programs chief, can be overcome, though the solution still includes providing evidence from before 1994.

"We did not rule it out. What we said was an affidavit unsupported by contemporary documentation is not likely" to clear FDA's threshold, Tave said.

Henningfield, who submitted comments in 2016 for the kratom group on the DEA's proposal to schedule the active materials in the botanical as controlled substances, recommended that FDA provide guidance on the type of documentation acceptable to support post-1994 affidavits. (Also see "DEA Proposal To Schedule Kratom Stirs Wave Of Opposition" - HBW Insight, 8 Dec, 2016.)

"Some ex-US data is garbage, some US data are garbage, but some ex-US data are great," he said.

Standards for documentation "would allow somebody like me working with clients to say, 'OK, here's what we've got to do to get the affidavits that would satisfy the FDA as being reasonable evidence."

Used in Southeast Asia "for a century or more to treat minor aches, pains and so forth to help people get through the work day," kratom has been show in studies as an effective substitute for some Rx pain medicine, said Henningfield, an expert on drugs of abuse, addiction and the assessment of the abuse liability of various substances.

"It's clear that there are a lot of people that are perfectly happy with alternatives that are not drugs and have strong safety records," he said.

From the editors of the Tan Sheet. Our dietary supplement industry coverage now is published in the Rose Sheet, with articles emailed to readers daily and available on this page of the Rose Sheet website.