Regulatory Comment to Docket No. FDA-2016-N-2523 Request for Comment on the Status of Vinpocetine
Date: November 7, 2016
Background:
Vinpocetine is often described as a semi-synthetic alkaloid discovered during the late 1960s. It is typically derived from carboline alkaloids found in periwinkle (Vinca minor) leaves and it is similar in structure and pharmacology to a very closely related analog isolated from Tabernaemontana rigida, Tabernaemontana riedelii, Vinca erecta and Vinca minor., The first clinical studies on the cerebrovascular hemodynamic properties of vinpocetine occurred in the 1970s, and it was first introduced as a drug under the trade name Cavinton® in 1978 by pharmaceutical formulator Gedeon Richter Nyrt in Hungary. The scientific literature contains numerous human clinical studies and animal investigations on the pharmacological and biochemical actions of vinpocetine. These include antioxidant effects, menopause, eye disorders, kidney impairment, stroke,, uncontrolled micturition, reductions in platelet aggregation,,, antiulcer activity, phosphodiesterase-1 inhibition, cerebrovascular vasodilation,, hearing defects of neurological origin,,,, and other brain disorders. , Vinpocetine is also known as 14-Ethoxycarbonyl-(3alpha, 16alpha-ethyl)-14,15-eburnamine, apovincaminate acid, Cavinton®, cezayirmeneksesi (Turkish), Crioceras longiflorus, ethyl apovincaminate, Eusenium®, Intelectol®, kavinton, myrtle vincapervinc, periwinkle, RGH-4405, TCV-3b, vinRx, vintoperol, and Voacanga Africana. It has since been used widely in Japan, Germany, Russia, Poland, and Hungary for the treatment of cerebrovascular-related pathologies. Vinpocetine has never been approved for use as a drug in the United States (U.S.) by the U.S. Food and Drug Administration (FDA) for any condition. It has been lawfully marketed in the U.S. as a dietary ingredient for use in dietary supplements, a category of food in the U.S. Vinpocetine has become popular for its protective effects on the nervous system and therefore has been marketed for brain health, boost memory, support attention, promote alertness, and other structure function claims in the U.S. over the past 19 years.
Issue:
FDA notified stakeholders of an unprecedented administrative proceeding initiated by the Agency under 21CFR 10.25(b) to determine the regulatory status of vinpocetine (ethyl apovincaminate) in the Federal Register on September 7, 2016 (81 FR 61700). Vinpocetine has never been an approved drug in the U.S. It has been lawfully marketed as a dietary ingredient for use in dietary supplements. In fact, vinpocetine holds the distinction of having five (5) New Dietary Ingredient (NDI) notifications filed with FDA’s Center for Food Safety and Applied Nutrition (CFSAN). By 1994, companies manufacturing and distributing dietary ingredients for use in dietary supplements had to submit NDI notifications to FDA CFSAN if the ingredient was intended to be sold in a dietary supplement and was something never before introduced into the diet. The first submission to the FDA docket for NDIs (FDA-95S-0316) after its creation occurred in July 1995. Part of FDA’s review of a submitted NDI is to investigate its current regulatory status as a drug. FDA NDI team members will look up an ingredient in FDA’s Document Archiving, Reporting, and Regulatory Tracking System (DARRTS) and report back as to whether an Investigation New Drug (IND), New Drug Application (NDA), or orphan drug has ever been filed for the ingredient and whether it is still active or inactive. Because FDA classified its first vinpocetine NDI submission in 1997 as “filed without comment”, any DARRTS query by FDA’s James Tanner and Robert J. Moore would have yielded either a null return or an “inactive” drug application status. While FDA may have received an IND application for the compound known as vinpocetine at some point (NPA is unable to confirm), the IND status in FDA’s DARRTS would have indicated vinpocetine’s status as “inactive” at the time of the evaluation of all five NDI submissions. An alternate explanation is that FDA personnel failed to perform such a DARRTS search. In any case, FDA has classified five NDI notifications to date as AKL (“acknowledgement”) letters, meaning vinpocetine was filed without comment each time. These five vinpocetine submissions also do not suggest that they were pure natural extracts or metabolites from a botanical source.
- Amrion, Inc. (filed July 8, 1997)
- Leiner Health Products (filed October 20, 1998)
- Leiner Health Products (filed March 24, 1999)
- General Nutrition Corporation (April 16, 1999)
- Pharmavite Corporation (May 12, 1999)
By submitting five separate NDI notifications for vinpocetine, the FDA had a total of 375 days (75 days x 5 submissions) to review whether it was a drug ingredient and how it fits under the definition of dietary ingredient in 201(ff)(1) of the Federal Food, Drug, and Cosmetic Act (FFDCA). FDA’s acknowledgement of these five NDIs suggests that 1) synthetically made vinpocetine fits under the definition of a dietary ingredient in Section 201(ff)(1) [21 USC §321(ff)(1)], 2) vinpocetine submissions contained reasonable expectations of safety to the consumer, and 3) vinpocetine can be lawfully marketed and sold in the U.S. To date, vinpocetine contains 19 years of lawful historical safe use in the U.S. alone as a food and 38 years of safe use in Europe as a drug/functional food. FDA and the European Union considers 25 years of widespread use to be the minimum to establish a history of safe use, according to their definition., As NPA is unaware of any chemical changes to vinpocetine over the past 38 years, this dietary ingredient has demonstrated sufficient historical safe use worldwide and domestically as a lawfully marketed dietary ingredient for use in dietary supplements.
Issue:
NPA maintains a significant interest in the FDA’s use of an administrative proceeding to attempt to alter the regulatory status of an FDA-acknowledged dietary ingredient for use in dietary supplements.
Action:
- Vinpocetine Fits Under 201(ff)(1)(F) in Addition to 201(ff)(1)(E) of the FFDCA
- FDA Wrote “NDL” Letters in Response to NDI Notifications for Other Ingredients in 1999
- NPA Supports the Lawful Marketing of Vinpocetine in the U.S. and Possesses Sufficient Historical Use
- FDA Does Not Have Authority to Re-Evaluate Vinpocetine’s Regulatory Status as a Dietary Ingredient Unless There is a Safety Issue
- FDA Failed to Submit an Economic Impact Analysis to the Office of Management and Budget Regarding this Cost to the Industry and Regulatory Alternatives
- NPA Urges FDA to Use Their Mandated Authority Based Upon Safety
