FDA is inhibiting innovation in the dietary supplement space. This was the refrain from many speakers and participants in the agency’s Public Meeting on Responsible Innovation in Dietary Supplements, held May 16 in College Park, Maryland.
While FDA’s approach to new dietary ingredients (NDIs) was the focus of the all-day meeting, all areas of FDA’s oversight of dietary supplements came into discussion. One session looked at Health Canada’s regulation of such products in hopes its successful aspects could help improve FDA’s approach.
Spotlight on ingredients
A requirement in the Dietary Supplement Health and Education Act (DSHEA) mandates distributors and manufacturers notify FDA at least 75 days before introducing an NDI into interstate commerce. This NDI notification (NDIN) must provide “a history of use or other evidence of safety establishing that the dietary ingredient when used under the conditions recommended or suggested in the labeling of the dietary supplement will reasonably be expected to be safe.”
Under Canadian regulation, natural health products (NHPs), including dietary supplements, can only contain ingredients listed in the Natural Health Products Ingredients Database (NHPID), which includes both medicinal and non-medicinal ingredients. Additions or modifications to the list of approved ingredients can be proposed via a specific form, which NNHPD would evaluate for approval.
During her presentation, Manon Bombardier, Ph.D., director general of Health Canada’s Natural and Non-prescription Health Products Directorate (NNHPD), which regulates NHPs, explained each product must be approved by her agency, which then assigns the product a unique Natural Product Number (NPN) and enters the information into its Licensed Natural Health Products Database.
“Products that don’t have an NPN number are illegal in Canada,” she said.
Several dietary supplement industry speakers in the meeting supported the idea of some level of mandatory product registration in the United States.
Industry attorney Scott Bass, head of the Global Life Sciences team for Sidley Austin LLP, opened the meeting’s first panel by calling for mandatory listing of dietary supplement products.
“I am incredulous when I hear people say they are willing to put a product on the internet or in a store, but they are not willing to tell the government they are selling it,” he said. “There is no way we can have adequate enforcement, a working NDI system or incentives for better science or innovation unless FDA knows what’s on the market.”
Bass, who led the drafting of DSHEA at the request of former Sen. Orrin Hatch (R-Utah), stated the supplement industry has not accepted its responsibility on the safety front.
“Other than grandfathered products and foods that genuinely were consumed as normal foods [before 1994], everything else should go through an NDI [notification process],” he argued. “That’s what we intended when we wrote the law and all of this talk about exception…is in my mind off the mark.”
“Old dietary ingredients” marketed before Oct. 15, 1994 are exempt from the NDIN requirement, although FDA has never approved a list of grandfathered ingredients. DSHEA also exempted from the requirement a dietary supplement that “contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered.”
Bass stated FDA is inhibiting innovation and endangering consumer safety by the way it is interpreting the NDI provision of the law. He noted FDA has said that dietary supplements can only include substances already present in foods and food components that humans eat as part of their usual diet.
“Does anybody here think that any innovative product can meet that definition? I don’t,” he said.
Innovation requires protection
One of industry’s major requests of FDA relative to NDIs and innovation is for more protection of intellectual property (IP). In the United States, an innovator of a novel ingredient or supplement product that requires notification must submit proprietary information, such as chemistry (identity and purity), manufacturing processes and safety data. This data represents a substantial investment. However, a company wanting to put out a “me too” or copycat ingredient/product could steal the submitted data and submit a “successful” NDIN without making the same investment as the innovator made.
Under DSHEA, FDA must make an NDI notification public with the exception of “trade secrets or otherwise confidential, commercial information.”
Health Canada allows for a master file to support product license applications. This enables manufacturers of ingredients or raw materials to supply proprietary information, such as manufacturing details and technical specifications to the NNHPD without exposure to other applicants.
Nana Bafi-Yeboa, a manager in NNHPD’s product evaluation bureau, noted the master file can keep certain pieces of information confidential, but there isn’t a way to mask the identity of the ingredient on the product label.
“If [the information] is within context of the master file, that is confidential,” he noted. “The issue, then, in practical terms is whether someone else can represent that ingredient in a way that appears to be similar to yours and have enough publicly available information to substantiate the safety and efficacy of the ingredient.”
He added if a copycatting company somehow managed to satisfy the license requirements for an ingredient protected with a master file, it would be the IP holder’s responsibility to police any patent or trademark infringements. Ultimately, he reminded while Canadian officials protect certain information in the master file, the regulator’s primary responsibility is to gauge the safety and efficacy of a product seeking a license.
FDA vs. ‘Synbots’
Industry also has requested FDA identify a pathway to market for synthetic copies of dietary ingredients. Many presenters noted FDA has been fine with some synthetic ingredients, such as certain vitamins, but the issue of so-called “synthetic botanicals” has been the subject of heavy debate between industry and regulators.
Cara Welch, Ph.D., special assistant to the Deputy Commissioner of Policy, Legislation and International Affairs at FDA, opened the meeting with the agency’s take on ingredient definitions, including synthetics: “There is no such thing as a synthetic herb or botanical, just in case you were curious about that.”
However, she didn’t totally rule out the use of synthetic copies of nutritional compounds. “To be clear, I think synthetic substances can be dietary substances if the synthetic version of which is in the diet.” She also noted FDA was interested in different viewpoints from the stakeholder panelists.
“Maybe there is new terminology that we can come up with and agree on and define so that all parties can agree to the functionality of these ingredients,” said Larisa Pavlick, vice president of global regulatory and compliance for the United Natural Products Alliance (UNPA).
Pavlick, a former FDA investigator, claimed the genesis for FDA’s policy on synthetic alternatives to botanical constituents was erroneously driven by a safety issue with ephedra and ephedra alkaloids nearly 18 years ago. She suggested the safety and health issues tied to ephedra supplement use might not have been due to the presence of synthetic alkaloids, but to misuse of the products.
She further noted in addition to synthetic vitamins, the agency allows synthetics substances in food (additives), drugs and cosmetics. “We have the ability to have approval in some of these other commodity categories,” Pavlick noted. “I think it’s time to modernize the approach to synthetic compounds used in dietary supplement products, regardless of their source.”
Bombardier said under Canadian law, a synthetic duplicate of a natural substance, including vitamins and minerals, can be listed as acceptable if the synthetic’s activity is the same as the natural version..
A place for probiotics?
One nagging nuance in FDA’s latest draft guidance on the NDIN process (2016) is the absence of a specific category for probiotics, an already large and rapidly growing area of the dietary supplement industry. There is no official definition of probiotics in existing U.S. food law, and FDA refers to such ingredients as “bacterial micoorganisms” or “live microorganisms” in its draft NDI guidance.
FDA stated bacterial microorganisms must meet one of the statutory definitions of a dietary ingredient before they can be used in dietary supplements.
Panelist George Paraskevakos, executive director of the International Probiotics Association (IPA), reasoned the likely category for probiotics would be “dietary substances for use by man to supplement the diet by increasing the total dietary intake.”
He noted many probiotics were present in the food supply well before the passage of DSHEA and should be defined and have a specific category in FDA’s forthcoming NDI guidance.
“We know FDA has a partial list of organisms, which have come from safety assessments, GRAS [generally recognized as safe], but I think the list is not comprehensive,” he said, noting IPA and IFAC (International Food Additives Council) can help FDA make a more thorough food list.
Such a list would help officially grandfather from the NDIN requirement well-established probiotic species with safe histories of use, but Paraskevakos recommended strains within the species of such a list would not need to go through the NDIN process. “Safety assessments would still need to happen even though there would be a grandfathering process,” he noted.
He also backed master files as an NDI solution. “Master files or dossiers would provide FDA with enough information to avoid unnecessary notifications but also reduce the burden and resources of FDA and industry.”
Canada’s Natural Health Products Regulation uses and defines the term probiotics, which have their own line item on the list of “included Natural Health Product Substances.” Bombardier explained products containing these substances are subject to a probiotic monograph, a standard Health Canada established to specify all the conditions probiotic products can claim on NHP license applications. NNHPD verifies all the information meets the monograph (proper and common names, source material, conditions of use, dose, dosage form, risk assessment).
“If all the requirements of the monograph are met and appear on the label as such, the company receives a license for that product,” she explained.
The use of such monographs has helped improve a more timely and efficient processing of NHP applications, Bombardier noted.
Pathways to market
In the United States, companies are free to market their dietary supplements whenever they’ve satisfied the statutory and regulatory requirements. For the most part, this does not require any premarket review and approval. The NDIN process is the only opportunity for FDA to review the safety of certain dietary supplements before they are marketed, and this requirement is merely a notification before marketing.
Once the company submits the NDIN, it can start marketing 75 days later. Historically, FDA has objected to the majority of NDINs. A company may decide to ignore an FDA objection letter if it believes it met the statutory requirements and take an ingredient to market, but it risks potential enforcement by FDA.
After a product is on the market, FDA must take steps to remove the product if it believes it is illegal, such as with products adulterated due to the presence of a substance that is not a dietary ingredient. However, the burden is on agency to establish a product is adulterated, and it may have to eventually prove its case in court.
In Canada, there are three pathways to NHP licensing, with each class representing different risk levels.
“The level of evidence that’s required to support the efficacy and safety of these products is based on risk,” Bombardier explained. “We have lower risk, medium and high risk depending on the level of risk of the ingredients, the intended use, if it requires some assistance from health professionals.”
The three-class system is based on monographs. Class one products comply with all requirements of a single existing monograph, such as with probiotics; the information is verified, and the license is issued within 60 days.
“If the product is supported by two or more monographs entirely, it is still reviewed and the timeline there is 90 calendar days,” Bombardier said, explaining class two product licensing. “If anything goes beyond the monograph, if it is a new ingredient or new condition of use we have not seen before, or if we don’t have the data so it has to be provided by the applicant, it requires a full review by our scientist, including [Bafi-Yeboa’s] team, it’s 210 days to get the [class three] license.”
She said the classification system provides flexibility for companies to fast-track products to market that contain NHPID-listed ingredients and meet existing standards, but it also provides regulators a chance to conduct a full science and safety review of new ingredients. She reported more than 150,000 NHPs have been approved to date.
Comparing agency sizes, resources and challenges
Bombardier said NNHPD has about 150 employees and a budget of about CAD14million (US$10.4 million). This is just for the premarket side, however, and she did not have the equivalent data handy for the post-market side.
The Office of Dietary Supplement Programs (ODSP) at FDA has a mere 24 employees and an annual budget of $7.3 million. However, FDA departments other than ODSP handle various aspects of dietary supplement oversight, and FDA has reported overall agency spending on dietary supplement activities was $17.5 million in 2018.
Bafi-Yeboa noted the Natural Health Products Regulation wasn’t passed until 2004, which offered Health Canada a chance to observe DSHEA’s successes and failures. “We had that 10 years to really look at what was working and what could be improved.”
Still, Canadian health officials had to make many adjustments to its policies and practices when analyses found lax reviews approved many incomplete and erroneous applications. NNPHD had trusted companies’ assertions that their class one products met monographs, but a 2017 audit of application files found 70 percent did not meet requirements for safety and efficacy. Bombardier said NNHPD adjusted its process to perform line-by-line reviews of each application regardless of class.
Post-market enforcement has also been a challenge for Health Canada, as it has for FDA. Bombardier reported 46 inspections of licensed Canadian NHP manufacturers have been conducted since the regulations became effective in 2016. She said all sites inspected have had quality issues, including documentation errors and omissions; non-existent or poorly trained quality assurance personnel; insufficient or missing specifications; lack of proper testing, including stability; and inadequate methodologies.
Similar issues have been found in dietary supplement cGMP (current good manufacturing practice) inspections by FDA, which has conducted hundreds of inspections each year (591 in fiscal year 2018) since the compliance phase-in started in 2008.
Adulteration and managing internet sales imports are additional challenges, Bombardier acknowledged. She said Health Canada works with the Canada Border Services Agency (CBSA) to police imported NHPs to ensure compliance with Canadian regulations. In April 2019, FDA and U.S. Customs and Border Protection (CBP) signed an agreement to better screen and detect illegal import products, including adulterated dietary supplements.
“As much as you can introduce things on the premarket side, unless you have the ability to balance all that out and verify on the post-market side, you really don’t have the type of rigor that you need, in my opinion, to make a difference on adulteration,” Bafi-Yeboa said.