By Todd Harrison, Venable LLP04.05.24
On March 5, the U.S. Food and Drug Administration (FDA) announced the availability of a final guidance for industry titled “Dietary Supplements: New Dietary Ingredient Notification Procedures and Timeframes” (March 2024 Guidance). The guidance finalizes Section V (“NDI Notification Procedures and Timeframes”) of the 2016 revised draft guidance as well as several related questions from other sections.
FDA said it intends to continue to break up the revised draft 2016 guidance and publish other individual sections as the agency completes its review and analysis of these sections. For example, FDA just recently (Apr. 3) published a draft guidance on New Dietary Ingredient Notification Master Files for Dietary Supplements and has indicated that it intends to finalize certain recommendations in the revised draft 2016 guidance regarding safety and identity information. It is obviously useful to get clarity from the government on how to comply with the Federal Food, Drug, and Cosmetic Act (FDCA) and the underlying regulations. I also appreciate the heads up as to FDA’s plans.
Indeed, Section 413 (21 U.S.C. 350b), which defines the term “new dietary ingredient” only imposes a notification requirement. Under this provision, the manufacturer or distributor of an NDI, or of the dietary supplement that contains the NDI, must submit a premarket NDIN to FDA that contains certain information at least 75 days before marketing its product.
There is a limit on what must be provided. Industry is required only to provide “the basis on which [it] has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe” (section 413(a)(2) of the FDCA). In other words, as FDA itself has pointed out, there is no minimum safety requirement. See 62 FR 49886 (Sept. 23, 1997) at 49890. The manufacturer or distributor only must make a showing as to why it considers that consumption of an NDI will be safe for consumers. Id. at 49888.
Indeed, FDA’s remedy if it does not believe an ingredient meets the statutory standard for safety is to either gain voluntary compliance or seek an injunction in court prohibiting the ingredient’s introduction into interstate commerce. Nowhere in the law does FDA have the ability to refuse a submission or state that it’s incomplete, nor does it have the ability to extend the 75-day requirement without the submitter’s agreement.
FDA’s role in this process is clear. As spelled out in 21 CFR 190.6, FDA must acknowledge receipt of an NDIN and notify the submitter of the date of receipt. FDA’s regulations spell out that the date of receipt is the date the agency receives the notification. See 21 CFR 190.6(c). This is so that manufacturers know when the 75-day notice period expires. See 62 FR 49886 at 49890. Furthermore, 90 days after the filing date of the notification, FDA must place all information in the notification on public display, except for information that is trade secret or otherwise confidential commercial information. See 21 CFR 190.6(e).
To be clear, when an NDIN is filed, it should be complete. However, an NDIN is filed when it is submitted. The statute does not provide for a preapproval process, such as the one that exists for drugs, under which FDA may refuse to file a new drug application (NDA) or supplemental NDA submitted to the Center for Drug Evaluation and Research under 21 CFR 314.101(d)(1)-(9). Moreover, FDA does not have the authority to create such a process.
It is not even clear what “complete” means or could mean in the future. While the agency gives examples in Section IV. B.—”What are examples of omissions that cause an NDIN to be incomplete?”—not all these examples appear to be based on requirements.
For example, the March 2024 Guidance states that the provision of contact information that is inaccurate and does not permit FDA to establish contact with the notifier can cause an NDIN to be incomplete. However, it is not clear what “contact information” means. Under 21 CFR 190.6, there is only the requirement to provide FDA with the notifier’s name and complete address. Is that what FDA means? It does not appear to be, given the agency’s language choice.
This conclusion, however, is inconsistent with the language in the statute. It seems intended to avoid the agency’s burden by switching aspects of the statute, which states if an ingredient is an NDI that requires notification and the notification is not filed, the ingredient is adulterated as a matter of law.
However, once filed, it is FDA’s burden to establish the ingredient does not have a reasonable expectation of safety. FDA may not like this aspect of DSHEA but the new dietary ingredient notification provisions of the act are clear, and FDA does not have the ability through regulation or guidance to change it.
Second, at least 75 days before being introduced or delivered for introduction into interstate commerce, the manufacturer or distributor of the dietary ingredient or dietary supplement must provide FDA with information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe.
There is no requirement related to “completeness.” Indeed, the preamble to the final rule 21 CFR 190.6 explains that the manufacturer or distributor is not required to do a complete literature search. See 62 FR 49886 at 49888. The regulation only requires a filer to provide the basis on which it has concluded that a dietary ingredient will reasonably be expected to be safe.
Once the manufacturer or distributor has filed an NDIN, the burden shifts to the government. FDA must acknowledge receipt and review the NDIN to determine whether it complies with the applicable statutory and regulatory requirements. As stated, even if an FDA response letter raises identity or safety concerns regarding a particular NDI, the notifier may still proceed to market after the 75-day period is over, as FDA’s remedy is to seek judicial relief by establishing that the ingredient does not have a reasonable expectation of safety.
While FDA should review the submission, it does not have the ability to refuse to file the submission except in limited circumstances, nor can it stall the clock by requesting additional safety information. While FDA should review an NDIN for safety concerns, its options are limited to either gaining voluntary compliance or seeking judicial relief if it has serious concerns regarding safety.
With that said, FDA can refuse to file a notification if the ingredient does not meet the definition of a dietary supplement under the statute or if it is precluded. But it cannot simply reject the notification or stall the clock because it does not necessarily agree with the safety information being provided.
That said, it is important to recognize that dietary supplements are generally safe, as Congress stated almost 30 years ago. Let’s be clear here: I’m not talking about those “dietary supplements” that illegally contain active ingredients found in FDA-approved prescription drugs, nor am I talking about designer drugs masquerading as dietary supplements, as I believe FDA has the ability to reject such a notification because it does not meet the definition of a dietary supplement under the FDCA.
Instead, I’m referring to those products that comply both with the current good manufacturing practices for dietary supplements and the applicable labeling requirements when the notifier has provided FDA with its basis for concluding the ingredient has a reasonable expectation of safety.
However, FDA has not heeded Congress’s request. Instead, FDA has stated it needs more time to study and analyze these issues. In the meantime, other critical legal issues remain unaddressed. For example, FDA has yet to define the phrase “substantial clinical investigations” so industry may determine when an ingredient that was not first marketed as a dietary supplement may still be used as or in a dietary supplement if the ingredient has not undergone “substantial clinical investigation.” Rather than stand up a system that appears to go beyond its regulatory authority, FDA should focus on these larger issues.
Notably, however, the March 2024 Guidance does not reflect the next logical step, which would have been to finalize the agency’s thinking as reflected in Section IV.C.2. of the revised draft 2016 guidance, that companies do not need to submit an NDIN for a new dietary supplement that contains the same NDI(s) covered by the same company’s prior submission if certain criteria are met.
For this reason, and without explanation, it appears that industry can no longer assume that if the conditions of use for the dietary supplement you plan to market are within the conditions of use evaluated in your original notification and FDA did not object to that notification, you may market the supplement without submitting another notification. It is hard to see the good in this approach.
Furthermore, the guidance appears to go further than the prior draft regarding how changes in manufacture can turn a pre-DSHEA ingredient into an NDI. FDA now asks that botanicals grown under controlled, specific conditions to concentrate or increase specific constituents to be identified.
It is difficult to understand this ask when the agency does not make a connection to safety or give an example as to what it is looking for. Thus, FDA continues to stray from the task at hand, which is to clarify the applicable statutory and regulatory requirements.
With that said, I recognize that FDA is concerned about the number of NDINs that have been submitted, but there is a better solution that will gain acceptance by industry as a whole while providing FDA with the necessary tools to determine what is actually in the marketplace and whether there really is a safety issue lurking out there that generally does not exist for these safe products.
To this end, my next article will offer a practical process that would be acceptable to both FDA and industry while safeguarding consumers from intentionally unsafe ingredients.
About the Author: Todd Harrison is Partner with Venable, which is located in Washington, D.C. He advises food and drug companies on a variety of FDA and FTC matters, with an emphasis on dietary supplement, functional food, biotech, legislative, adulteration, labeling and advertising issues. He can be reached at 575 7th St. NW, Washington, D.C. 20004, Tel: 202-344-4724; E-mail: taharrison@venable.com.
FDA said it intends to continue to break up the revised draft 2016 guidance and publish other individual sections as the agency completes its review and analysis of these sections. For example, FDA just recently (Apr. 3) published a draft guidance on New Dietary Ingredient Notification Master Files for Dietary Supplements and has indicated that it intends to finalize certain recommendations in the revised draft 2016 guidance regarding safety and identity information. It is obviously useful to get clarity from the government on how to comply with the Federal Food, Drug, and Cosmetic Act (FDCA) and the underlying regulations. I also appreciate the heads up as to FDA’s plans.
Re(defining) FDA’s Role?
However, the system being set up regarding new dietary ingredients (NDIs) and NDI notifications (NDINs) seems to be heading in the wrong direction. FDA appears to be transforming through guidance the notification requirement under section 413(a)(2) of the Dietary Supplement Health and Education Act of 1994 (DSHEA) into a substantive requirement that may be used to bar entry to the marketplace against the express intent of Congress.Indeed, Section 413 (21 U.S.C. 350b), which defines the term “new dietary ingredient” only imposes a notification requirement. Under this provision, the manufacturer or distributor of an NDI, or of the dietary supplement that contains the NDI, must submit a premarket NDIN to FDA that contains certain information at least 75 days before marketing its product.
There is a limit on what must be provided. Industry is required only to provide “the basis on which [it] has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe” (section 413(a)(2) of the FDCA). In other words, as FDA itself has pointed out, there is no minimum safety requirement. See 62 FR 49886 (Sept. 23, 1997) at 49890. The manufacturer or distributor only must make a showing as to why it considers that consumption of an NDI will be safe for consumers. Id. at 49888.
Indeed, FDA’s remedy if it does not believe an ingredient meets the statutory standard for safety is to either gain voluntary compliance or seek an injunction in court prohibiting the ingredient’s introduction into interstate commerce. Nowhere in the law does FDA have the ability to refuse a submission or state that it’s incomplete, nor does it have the ability to extend the 75-day requirement without the submitter’s agreement.
FDA’s role in this process is clear. As spelled out in 21 CFR 190.6, FDA must acknowledge receipt of an NDIN and notify the submitter of the date of receipt. FDA’s regulations spell out that the date of receipt is the date the agency receives the notification. See 21 CFR 190.6(c). This is so that manufacturers know when the 75-day notice period expires. See 62 FR 49886 at 49890. Furthermore, 90 days after the filing date of the notification, FDA must place all information in the notification on public display, except for information that is trade secret or otherwise confidential commercial information. See 21 CFR 190.6(e).
No Preapproval Authority
The March 2024 Guidance, however, does not follow this framework. Instead, the March 2024 Guidance states in Section IV.A. that “The date when FDA receive a complete NDIN is the date of that notification’s filing,” (emphasis added). It goes on to state that “A complete NDIN is a notification that contains all the information required by 21 CFR 190.6.”To be clear, when an NDIN is filed, it should be complete. However, an NDIN is filed when it is submitted. The statute does not provide for a preapproval process, such as the one that exists for drugs, under which FDA may refuse to file a new drug application (NDA) or supplemental NDA submitted to the Center for Drug Evaluation and Research under 21 CFR 314.101(d)(1)-(9). Moreover, FDA does not have the authority to create such a process.
It is not even clear what “complete” means or could mean in the future. While the agency gives examples in Section IV. B.—”What are examples of omissions that cause an NDIN to be incomplete?”—not all these examples appear to be based on requirements.
For example, the March 2024 Guidance states that the provision of contact information that is inaccurate and does not permit FDA to establish contact with the notifier can cause an NDIN to be incomplete. However, it is not clear what “contact information” means. Under 21 CFR 190.6, there is only the requirement to provide FDA with the notifier’s name and complete address. Is that what FDA means? It does not appear to be, given the agency’s language choice.
Shifting Burden
What this language means is important because the guidance also states in Section IV.B. that an “incomplete NDIN” does not satisfy the notification requirement found in Section 413(a)(2) of the FDCA. Thus, “if the dietary supplement containing the NDI is marketed in reliance on an incomplete NDIN, it is deemed to be adulterated….”This conclusion, however, is inconsistent with the language in the statute. It seems intended to avoid the agency’s burden by switching aspects of the statute, which states if an ingredient is an NDI that requires notification and the notification is not filed, the ingredient is adulterated as a matter of law.
However, once filed, it is FDA’s burden to establish the ingredient does not have a reasonable expectation of safety. FDA may not like this aspect of DSHEA but the new dietary ingredient notification provisions of the act are clear, and FDA does not have the ability through regulation or guidance to change it.
What’s Required and What’s Not?
Specifically, under section 413(a)(2), there are only two requirements. First, there must be 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.Second, at least 75 days before being introduced or delivered for introduction into interstate commerce, the manufacturer or distributor of the dietary ingredient or dietary supplement must provide FDA with information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe.
There is no requirement related to “completeness.” Indeed, the preamble to the final rule 21 CFR 190.6 explains that the manufacturer or distributor is not required to do a complete literature search. See 62 FR 49886 at 49888. The regulation only requires a filer to provide the basis on which it has concluded that a dietary ingredient will reasonably be expected to be safe.
Once the manufacturer or distributor has filed an NDIN, the burden shifts to the government. FDA must acknowledge receipt and review the NDIN to determine whether it complies with the applicable statutory and regulatory requirements. As stated, even if an FDA response letter raises identity or safety concerns regarding a particular NDI, the notifier may still proceed to market after the 75-day period is over, as FDA’s remedy is to seek judicial relief by establishing that the ingredient does not have a reasonable expectation of safety.
While FDA should review the submission, it does not have the ability to refuse to file the submission except in limited circumstances, nor can it stall the clock by requesting additional safety information. While FDA should review an NDIN for safety concerns, its options are limited to either gaining voluntary compliance or seeking judicial relief if it has serious concerns regarding safety.
With that said, FDA can refuse to file a notification if the ingredient does not meet the definition of a dietary supplement under the statute or if it is precluded. But it cannot simply reject the notification or stall the clock because it does not necessarily agree with the safety information being provided.
What is FDA’s Authority Under the Law?
Rather, the FDCA provides numerous ways to address adulterated dietary supplements. For example, FDA may initiate an in rem action to seize violative products, such as adulterated dietary supplements, when introduced into or while held for sale after their shipment in interstate commerce. See section 304(a)(1) of the FDCA Act (21 U.S.C. 334(a)(1)). The agency may also order the administrative detention of dietary supplements found during, among other things, an inspection if an FDA officer or qualified employee has “reason to believe that such article[s are] adulterated or misbranded.” See section 304(h)(1)(A) of the FDCA (21 U.S.C. 334(h)(1)(A)).
Moreover, should FDA have safety concerns, then the agency could monitor the relevant databases for adverse events reported to have occurred in individuals following consumption of dietary supplements containing this ingredient and issue a safety communication if appropriate.That said, it is important to recognize that dietary supplements are generally safe, as Congress stated almost 30 years ago. Let’s be clear here: I’m not talking about those “dietary supplements” that illegally contain active ingredients found in FDA-approved prescription drugs, nor am I talking about designer drugs masquerading as dietary supplements, as I believe FDA has the ability to reject such a notification because it does not meet the definition of a dietary supplement under the FDCA.
Instead, I’m referring to those products that comply both with the current good manufacturing practices for dietary supplements and the applicable labeling requirements when the notifier has provided FDA with its basis for concluding the ingredient has a reasonable expectation of safety.
Historic Struggles
FDA has been struggling with how to deal with dietary supplements for quite some time (and I’m not even referring to the time before DSHEA was passed, which is another story). The 2024 Guidance finalizes Section V (“NDI Notification Procedures and Timeframes”) of the FDA’s 2016 revised draft guidance, which in turn replaced a predecessor draft guidance from 2011 on the same topic (the 2011 Guidance). The 2011 Guidance came about because over 13 years ago, Congress recognized the need for clarification regarding when a manufacturer or distributor of a dietary ingredient or dietary supplement should submit an NDIN and ordered FDA to provide clarifying guidance.1However, FDA has not heeded Congress’s request. Instead, FDA has stated it needs more time to study and analyze these issues. In the meantime, other critical legal issues remain unaddressed. For example, FDA has yet to define the phrase “substantial clinical investigations” so industry may determine when an ingredient that was not first marketed as a dietary supplement may still be used as or in a dietary supplement if the ingredient has not undergone “substantial clinical investigation.” Rather than stand up a system that appears to go beyond its regulatory authority, FDA should focus on these larger issues.
Clarity and Still Uncertainty
I acknowledge that the March 2024 Guidance appears to be offering certain concessions to industry by finalizing the language that industry may submit a single NDIN that covers safety data for a range of conditions of use and covers multiple products. This question originally was not in Section V of the revised draft 2016 guidance but in Section IV.C.1., which indicates that the agency is making a point in incorporating it in the March 2024 Guidance.Notably, however, the March 2024 Guidance does not reflect the next logical step, which would have been to finalize the agency’s thinking as reflected in Section IV.C.2. of the revised draft 2016 guidance, that companies do not need to submit an NDIN for a new dietary supplement that contains the same NDI(s) covered by the same company’s prior submission if certain criteria are met.
For this reason, and without explanation, it appears that industry can no longer assume that if the conditions of use for the dietary supplement you plan to market are within the conditions of use evaluated in your original notification and FDA did not object to that notification, you may market the supplement without submitting another notification. It is hard to see the good in this approach.
Furthermore, the guidance appears to go further than the prior draft regarding how changes in manufacture can turn a pre-DSHEA ingredient into an NDI. FDA now asks that botanicals grown under controlled, specific conditions to concentrate or increase specific constituents to be identified.
It is difficult to understand this ask when the agency does not make a connection to safety or give an example as to what it is looking for. Thus, FDA continues to stray from the task at hand, which is to clarify the applicable statutory and regulatory requirements.
With that said, I recognize that FDA is concerned about the number of NDINs that have been submitted, but there is a better solution that will gain acceptance by industry as a whole while providing FDA with the necessary tools to determine what is actually in the marketplace and whether there really is a safety issue lurking out there that generally does not exist for these safe products.
To this end, my next article will offer a practical process that would be acceptable to both FDA and industry while safeguarding consumers from intentionally unsafe ingredients.
About the Author: Todd Harrison is Partner with Venable, which is located in Washington, D.C. He advises food and drug companies on a variety of FDA and FTC matters, with an emphasis on dietary supplement, functional food, biotech, legislative, adulteration, labeling and advertising issues. He can be reached at 575 7th St. NW, Washington, D.C. 20004, Tel: 202-344-4724; E-mail: taharrison@venable.com.
