NDI draft guidance comments: Industry has its say

Industry has been calling for FDA to create guidelines for filing new dietary ingredient notifications (NDINs) almost since the day after the Dietary Supplement Health and Education Act of 1994 (DSHEA) passed. The law mandated FDA notification for any new dietary ingredient (NDI) that enters the U.S. market after Oct. 15, 1994, the day DSHEA became law. As with other guidance documents, the NDI guidance will ultimately serve to describe FDA's current thinking on the matter, not to amend current law.

When FDA issued its "Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues" on July 1, 2011, 17 years after DSHEA passed, industry was quick to commend the agency for complying with FDA's Food Safety Modernization Act (FSMA). That act mandated FDA release an NDI Draft Guidance by within 180 days; FSMA was enacted Jan. 4, 2011.

As the comment period came to a close on Dec. 2, 2011--a 60 day extension from the original September deadline--it was clear industry praise had stopped. It's a good thing the document is only a draft because most say it is unworkable and illegal. Comments submitted by industry trade organizations, nonprofits, companies and lawyers all pointed to major flaws in the Draft Guidance. The overwhelming conclusion was that the Draft Guidance, as written, is not in line with DSHEA or FDA enforcement history. Most came to the conclusion that the Draft Guidance needs to be rewritten and reissued.

"We at NPA and the industry as a whole would like clarity from FDA on the NDI process," said John Gay, executive director and CEO, the Natural Products Association (NPA). "We did call upon and support the call for FDA to produce a guidance, but not this guidance. We as an industry need a guidance that is DHSEA compliant, and we will work with FDA to accomplish that goal."

The major industry organizations American Herbal Products Association (AHPA), Silver Spring, MD; the Council for Responsible Nutrition (CRN), Washington; the Consumer Healthcare Products Association (CHPA), Washington; NPA, Washington; and the United Natural Products Alliance (UNPA), Salt Lake Citycalled for FDA to withdraw the NDI Draft Guidance and issue a new guidance that it is consistent with the DSHEA, in comments filed separately. And they weren't the only ones.

In fact, Citizens for Health (CFH), Washington, collected 12,686 signatures in 10 days from industry members and consumers calling for Congress to withhold FDA appropriations until the agency withdraws the Draft Guidance. CFH representatives delivered the petition to the House, the Senate, FDA and President Obama on Dec. 2, 2011. CFH also submitted comments calling for FDA to withdraw the Draft Guidance.

In joint comments filed to the docket, CRN and CHPA said the Draft Guidance redefines the NDI notification process, contradicts the spirit of DSHEA and conflicts with nearly two decades of agency practice and policy. "It would impose significant and unnecessary new burdens on the dietary supplement industry without conferring safety benefits to consumers," the two trade groups said in the comments.

NPA said, "The NDI Draft Guidance completely eviscerates the food additive prohibitions that Congress so carefully placed in DSHEA and also contravenes the deep-rooted DSHEA policy in favor of consumer freedom of choice and support for smaller business."

CRN president and CEO Steve Mister, added, The Draft Guidance would essentially undo nearly two decades of agency practice and policy that began with DSHEAs passage. CRN and others in the industry have been calling on FDA to provide clarity through this Draft Guidance, and responsible industry fully supports a reasonable guidance that provides directions for filing NDI notices within the legal framework of DSHEA. However, this guidance does not answer that call."

Amin Talati LLC, a Chicago-based law firm active in the natural products industry, said the Draft Guidance reveals that FDA's interpretation contradicts the plain language of DSHEA and, therefore, violates the Administrative Procedures Act (APA). "FDA has made a complete about-face in re-interpreting the statute," the law firm wrote in its comments.

Sabinsa Corp., which supplies herbal extracts, cosmeceuticals, minerals and specialty fine chemicals as well as manufactures dietary supplements, asked FDA to either clarify a number of different points brought up by the document or withdraw it all together.

In its comments, dietary supplement manufacturer Atrium Innovations said the Draft Guidance would establish an unlawful premarket regulatory process contrary to both the letter and Congressional intent of DSHEA."We question why, after 17 years, FDA has promulgated such stringent guidelines, as we do not believe that a consumer safety crisis exists to merit such action by the agency," the company wrote in its comments. "This Draft Guidances unnecessarily burdensome, and costly requirements will have the additional consequence of stifling innovation in our industry, as well as limiting consumer access to currently available, traditionally used, safe and effective supplements."

Jarrow Formulas Inc. (JFI) has been an outspoken opponent of the Draft Guidance and also called for a rewrite in its comments. The [Draft] Guidance goes directly against the grain of U.S. hopes and goals at this point in our history, and is truly an escort to the guillotine for the supplement industry and a gross violation and disrespect of the will of the American people," said Jarrow Rogovin, founder, JFI.

JFI's comments were written by JFIs food and drug regulatory attorneys, Scott Polisky, Esq., and Susan Brienza, Esq. The comments submitted on behalf of JFI clearly show that the NDI Draft Guidance has been extremely low priority for 17 years; the FDA then worked under the 180-day Congressional mandate, and still didnt get it right," Brienza said. The Draft Guidance does not merely guide the industry in the filing of a more complete NDI notification, but instead seeks to impose a new regulation."

Polisky said JFI deserves the right to expand its comments, if and when FDA responds in a substantial manner to its 128-item Freedom of Information Act (FOIA) request, which was filed to FDA on Sept. 8, 2011. The FOIA request challenged certain assumptions and interpretations in Draft Guidance; solicited certain documents; and asked a number of questions regarding an NDI definition, probiotics, costs and more.

The FOIA request, the right of every American, asked key questions that still remain unanswered," according to JFI's submitted comments. JFI said FDA has only sent four "meager" responses to the company regarding the FOIA request, and said the agency has given no answers of substance. The submitted comments said FDA's lack of a response to the FOIA request was one of the reasons the company asked for a one-year comment period, a request that was not granted by FDA. JFI said it cannot fully submit comments until FDA adequately responds to the FOIA request.

Biggest issues

JFI may feel that it doesn't have all of the information it needs to comment fully on the Draft Guidance, but that didn't stop the company from voicing its issues with FDA's current thinking. And many in the industry joined them in submitting comments before the Dec. 2 deadline. While most companies and organizations filed comments separately, many saw the same problems.

JFI may feel that it doesn't have all of the information it needs to comment fully on the Draft Guidance, but that didn't stop the company from voicing its issues with FDA's current thinking. And many in the industry joined them in submitting comments before the Dec. 2 deadline. While most companies and organizations filed comments separately, many saw the same problems.

 Top concerns of industry, as noted in submitted comments, included:

Supplement focus

Every comment reviewed by Natural Products Insider took issue with the requirement for each new supplement with an NDI to file a notification. They argued it's contrary to DSHEA's language and legislative history. "Such a policy is not grounded in practical realities or science," CRN and CHPA wrote in their comments.

Attorney Marc Ullman, Ullman, Shapiro and Ullman, said FDA itself said DSHEA calls for ingredient, not supplement, notifications. In comments he submitted to FDA, he noted in a 1997 Final Rule, FDA itself estimated the number of NDIs that would be required each year would be 12 or fewer, not the thousands that would be necessary if notifications would be required for every single new supplement with a NDI or new combination of ingredients. In its cost-benefit analysis, FDA said the economic impact would not be significant because so few notifications would be submitted each year. He argued that if FDA thought DSHEA called for supplement notifications, it would have reported the economic effect to be much greater because, clearly, more than 12 new supplements with NDIs are launched each year.

Ullman said the Draft Guidance changes the law, which is not the purpose of a guidance. He said if FDA wanted to make NDI notifications required for supplements rather than ingredients, the agency would need to propose changes via notification in the Federal Register, which offers more scrutiny and review than a draft guidance.

Amin Talati said the Draft Guidance reverses FDA's longstanding, publicly accepted policy and practice of requiring notification for new dietary ingredients, not supplements that contain NDIs. The firm noted since 1994, FDA has acknowledged, with letters of non-objection, many NDI notifications submitted by ingredient suppliers for new ingredients. The firm said it could find no instance in which FDA, when objecting to a notification, cited a concern about lack of information about the other ingredients in formulation/finished product that would contain the new dietary ingredient. "Indeed, Congress could have, but chose not to apply the notification requirement to each and every dietary supplement containing the NDI," the firm wrote. "In the Draft Guidance, FDA inexplicably goes further, grafting on a requirement that Congress did not direct nor leave open to FDA the option to adopt."

Atrium Innovations said it believes the Draft Guidance's position that NDINs are required for each new productrather than for each new ingredientviolates DHSEA and FDA's historical regulatory policy. Atrium Innovations added that once an NDI is deemed safe by FDA (i.e., not rejected), no new submissions for other products that use that ingredient should be required.

Sabinsa echoed this concern and proposed FDA limit the notification to each new ingredient "without consideration for the dietary supplement in which it will be incorporated." Sabinsa noted in this scenario, the manufacturer or distributor of the ingredient would have the responsibility of submitting an NDIN.

The U.S. Pharmacopeial Convention (USP), Rockville, MD, also said it considers the requirement for a NDIN for every supplement with an NDI redundant and burdensome. It said if an NDIN has already been filed that complies to compendia monograph specifications, a manufacturer that meets those specifications should not need to submit another NDIN.

Chemical alteration

All the trade organizations also said FDA's view that a product would be considered chemically altered unless it used a limited number of processing techniques (Minor loss of volatile components, dehydration, lyophilization, milling, and formation of a tincture or a solution in water, a slurry, a powder, or a solid in suspension") is too narrow. When these processes were outlined in DSHEA, the organizations argued, Congress did not mean this to be an exhaustive list; rather, Congress intended this to be a few examples.

In its comments, the American Botanical Council (ABC), Austin, TX, said various solvents not noted in the Draft Guidance were marketed before the passage of DSHEA, and therefore should not trigger the need for NDINs.

Atrium Innovations also said this list is unnecessarily limited and any process used in food manufacturing should be OK for dietary ingredients, as long as the result is identical to a previously marketed product. "The Draft Guidance would have the industry turn the clock back to 1994 and disregard all innovation since or, at the very least, require expensive and complicated NDI submissions based on improvements in safety stability or environmental impact," the company wrote.

If FDA continues in its belief that solvents other than water and aqueous alcohol alters an ingredient chemically, Sabinsa asked FDA for its position on food-grade solvents listed as GRAS, such as carbon dioxide extraction. Sabinsa said maintaining the correct composition is the important thing and recommended FDA accept supercritical-extracted botanicals with no addition of solvents without an NDIN.

USP disagreed with FDA regarding its view that solvents other than aqueous ethanol and water chemically alter an ingredient. USP argued using hot water as a solvent may induce more chemical reactions (via hydrolysis) than another solvent, such as hexane or supercritical carbon dioxide. USP said its monographs limit the amount of residual solvents, and its Dietary Supplement Expert Committee (DSEC) decides the definition of "chemically altered" on a case-by-case basis. It suggested FDA make an exception to the NDIN requirement for botanical extracts that comply with USP monographs.

Old dietary ingredient list

ABC and NPA called for the agency to recognize a consolidated list of Old Dietary Ingredients (ODIs) created by industry trade organizations. ABC noted ODI lists were developed by AHPA, CRN and NPA, which were later consolidated by UNPA. UNPA said its ODI list was reviewed by its NDI Working Group, and the alliance submitted the list with comments it submitted to FDA. UNPA asked FDA to confirm its willingness to accept such authoritative lists to provide the agency and the industry with an invaluable resource.

While the Draft Guidance places the burden of proving an ingredient is not an NDI on industry, CRN, CHPA and APHA argued DSHEA places the burden on FDA to prove an ingredient is an NDI, and thus requires an NDIN.

Sabinsa broke from the pack by suggesting FDA revise the date that triggers an NDI for NDIs that have been on the market for a while without reported adverse effects. "Dietary ingredients have been in the U.S. market 'safely' post October 1994, but perhaps FDA should consider a more realistic date," the company wrote in its comments. "If this suggestion is accepted, consumer safety will be protected, and a number of NDI/supplement notification will be more manageable by FDA because the numbers will be less."

Sabinsa also asked for clarification, requesting FDA specifically address what type of documentation is needed for grandfathering an ingredient, if there is indeed not official grandfathered list.

Safety requirements

The Draft Guidance requires the same safety standards as food additives, CRN and CHPA said, which Congress did not intend. In fact, Congress deliberately removed dietary supplements from the food additive regulatory regime in DSHEA, they argued. NPA requested FDA be more flexible when it comes to showing safety data of NDIs when they have little history of use.

UNPA cited both court cases and DSHEA illustrating FDA's use of the food additive standard was unlawful. "FDA's proposal to merge the NDI safety standard into the food additive safety standard is without statutory basis and represents a major departure from FDAs NDI evaluation over the past 16 years," UNPA wrote in its comments. "UNPA requests FDA withdraw all reference to food additive safety standards and evaluation procedures, and re-propose a standard of safety within an appropriate level of evidence based on the reasonable expectation of safety standards laid down by DSHEA."

JFI had a lot to say about the safety issue in its comments. Brienza and Polisky said DSHEA states the proper standard for evaluating NDINs is "reasonable expectation of safety," with the burden of proof on FDA, not a risk-benefit analysis, which is used to ban supplements post market. They said Daniel Fabricant, Ph.D., Director, Division of Dietary Supplement Programs, FDA, has repeatedly invoked the "ephedra rule" as part of FDA's reasoning behind the Draft Guidance. The attorneys said the preamble to the ban on ephedrine alkaloids in dietary supplements states FDA conducted a risk-benefit analysis using the "unreasonable risk" standard. The unreasonable risk standard is appropriate only in a determination that a supplement is adulterated, they reiterated, not for an NDIN.

JFI's attorneys also said supplements have an extraordinary safety record when compared to every other FDA-regulated category and, thus, they said no justification exists for the Draft Guidances claimed concerns about safety as a justification for preventive controls. They also noted FDA has only issued six warning letters regarding NDINs in the 17 years since DSHEA (all concerning a steroid precursor, androstenedionenot a dietary ingredient). They said this further shows preventive controls are not necessary.

Sabinsa said it wants FDA to clarify if it expects the same safety information as is required for GRAS (generally recognized as safe) status. Specifically, the company wants to know what standard will apply: absence of significant risk relative or reasonable certainty of no harm.

Synthetic botanicals

Even though synthetic botanicals are not a constituant of an herb or botanical, they should still be considered a dietary ingredient, according to the trade groups. CRN and CHPA said FDA is proposing a ban on nature-identical synthetic botanicals in the absence of statutory authority. NPA argued FDA has allowed synthetic forms of vitamins, minerals and amino acids.

Sabinsa's comments also questioned FDA's hard line on synthetic versions. "Synthetics are pure molecules with the exact chemical structure of naturally occurring substances," the company wrote in its comments. "Therefore, synthetics have the exact same health benefits and safety concerns as the substances found in nature. Synthetics are also an excellent alternative to ongoing issues with supply and sustainability of natural products."

Probiotics

Probiotics are a lawful and viable category of dietary ingredients, Atrium Innovations asserted, and FDA should confirm fermentation advancements designed to improve culture yield and stability do not create an NDI, according to the company's comments.

JFI agreed that probiotics are dietary ingredients as defined by DSHEA, and have been shown to be safe and effective in foods such as cheeses and yogurt, as well as in supplements. Brienza and Polisky noted some probiotics have even been accepted by FDA as GRAS, which has a higher safety threshold than dietary supplements. They said the reclassification of probiotics as biologics is unreasonable and would put probiotics out of reach as dietary supplements, while putting them in an regulatory category where approval is all but impossible.

NPA asked FDA to differentiate probiotics from harmful pathogenic bacteria. NPA said probiotics offer health benefits and should be considered dietary ingredients, but the Draft Guidance does not confirm this.

Sabinsa said FDA should adopt the Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) definition of probiotics, which is "live microorganism, which when administered in adequate amounts confer a health benefit on the host."

Multiple NDI filings for the same dietary ingredient

AHPA said it believes separate notifications are not required, per DSHEA, when the initial NDIN provides a description of a dietary supplement or a range of dietary supplements that would include the NDI. NPA pointed out FDA's seemingly contradictory views on the matter, with in-person communication with FDA staff being at odds with what is written in the Draft Guidance.

Economic analysis

The Draft Guidance, if implemented in its current form, would devastate the supplement industry and further harm the U.S. economy, Brienza and Polisky said. They also said FDA failed to perform a proper economic impact analysis, while they said an analysis by an economics and law professor estimated up to $1 million as the cost of an NDIN, under the tests required by the Draft Guidance.

Atrium Innovations also argued in its comments that the Draft Guidance, as written, would stifle innovation and create a market that lacks product differentiation, thereby limiting consumer access and choice.

"One of the consequences of the implementation of the NDI Guidance could be less demand from the dietary supplement industry for innovative dietary ingredients and, therefore, less health benefits for U.S. consumers," Sabinsa wrote in its comments. It suggested FDA revise the Draft Guidance to encourage research of safe and innovative ingredients.

Intellectual Property (IP)

Admin Talati, in its comments, noted the new guidance and burdensome requirements on finished dietary supplements would raise significant intellectual property (IP) issues, as ingredient suppliers and finished product manufacturers would have to share confidential information and protected trade secrets. NPA also asked FDA to outline the precautions it will take to ensure IP related to NDIs.

Sabinsa also replicated concerns about potential IP issues. The company pointed out the Draft Guidance does not explain what kind of information will be considered as commercial trade secrets and how FDA will be able to keep this information confidential. Sabinsa asked FDA to outline its IP protection procedure in the next guidance it issues.

Additonal notes

While industry members were pretty much unanimous on many of the NDI Draft Guidance issues, some comments called out specific areas. NPA's comments included 11 points of concern, and along with the abovementioned issued, NPA addressed:

USP also had its own unique suggestions. It recommended NDIs that comply with compendial standards should be exempt from filling an NDIN. In its comments, the nonprofit said because USP monographs for dietary supplements include a threshold safety review and quality specifications pertaining to the quality, purity, identity and strength of the ingredient, FDA should recognize them as safe and able to enter the market without an NDIN.

USP said compendial standards can reduce regulatory and industry burden because they can show ingredients meet the same (equivalent or better) specifications for quality, purity, identity and strength, even if they are manufactured via different processes. Compendial quality standards can also address the concerns that different manufacturing processes might introduce different impurity profiles, USP said.

What now?

Now that the comment period for the Draft Guidance has closed, industry enters a wait-and-see period. FDA could either take industry suggestions and issue a new draft, issue a Final Guidance that incorporates some of industry's concerns, issue a Final Guidance without making major changes, or sit on the Draft Guidance without issuing a Final Guidance. It could takes months or years for the agency to issue a Final Guidance, if it does so at all. In a conference call with media in early December, Gay said it was NPA's job to not to let FDA forget about the Draft Guidance, and he said the organization plans to meet with the agency soon.

The industry as a whole has a responsibility to encourage FDA to release a new Guidance, be it another draft or a final document. With so many issues brought up in submitted comments regarding the agency's first attempt at a NDI guidance, industry should persist in its requests for movement on this issue. While we want to be sure FDA has adequate time to read, consider and address each comment that was filed, its best to not let it sit idle. FDA can still issue a guidance that follows DSHEA's language and intent, but it's good industry reminded them not to fall in love with the first draft.