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Regulatory Focus™ > News Articles > 2020 > 6 > Integrating master files in the NDI notification process to facilitate innovation in dietary supplem

Integrating master files in the NDI notification process to facilitate innovation in dietary supplements

Posted 05 June 2020 | By Haiuyen Nguyen 

Integrating master files in the NDI notification process to facilitate innovation in dietary supplements

This article discusses the application of master files to the new dietary ingredient notification process to protect intellectual property of ingredient manufacturers and incentivize submission of NDI notifications. The author describes an NDI master file model, based on the US drug master file, as a proposal for consideration by the US Food and Drug Administration.
 
Introduction
Innovation grows industries, and it is no different for the dietary supplement industry. Estimated US sales for the industry reached $48.8 billion in 2019 and its growth has hovered around 5%-6% in recent consecutive years.1 Some of that success is likely attributable to innovation of products. New products, in part, emerge from formulations of new dietary ingredients (NDIs), which are ingredients that came to market after 15 October, 1994, in accordance with the Dietary Supplement Health and Education Act (DSHEA). Under the law, marketers must affirm the safety of an NDI and submit a detailed notification for review by the United States Food and Drug Administration (US FDA) at least 75 days before the NDI becomes accessible to consumers.2
 
Since the enactment of DSHEA, the number of supplement products on the US market proliferated from 4,000 to around 80,000 in 2019, according to FDA estimates,3 and the agency has received just over 1,100 NDI notifications.4 Diverse companies have submitted NDI notifications for numerous botanical-derived ingredients, such as sea buckthorn extract, algal DHA, astaxanthin, huperzine A, and resveratrol. Other notified NDIs comprise microorganisms, including various species of Bifidobacterium (bifidum, breve, lactis, longum) and Lactobacillus (acidophilus, bulgaricus, casei, fementum, reuteri, rhamnosus, plantarum) and their various strains; enzymes, such as peptidase, pepsin, and seaprose; and a host of dietary substances from conjugated linoleic acid to krill oil to zeaxanthin.4
 
The statistics indicate it is possible that notifications have not been submitted for all NDIs on the market. There may be many reasons for that, including a lack of clarity on exactly what an NDI is and in which cases an NDI notification must be filed (there are exemptions to the notification requirement). Industry and FDA have expressed differing views on these and other NDI-related issues since 2011,5-9 when the agency issued a draft guidance on NDI notifications, and even after the draft guidance was revised in 2016.10 Although FDA does not have final guidance in place, it recognizes that NDI notification issues may present obstacles to dietary supplement innovation and proclaims the agency is examining new approaches to NDIs.11
 
Intellectual property incentive
FDA should consider intellectual property protection as it explores incentives for companies to submit NDI notifications. Development of new ingredients requires substantial investment. Significant resources go into establishing a manufacturing process that produces a consistent, stable ingredient and generating scientific data to support the safety of the ingredient under the intended conditions of use. Companies making these investments want assurance that they can protect NDI-related intellectual property throughout the notification process, and long after, to have a competitive edge in the marketplace as a return on investment.

A master file is an elective submission to FDA that contains data deemed proprietary by a company, such as a drug ingredient manufacturer.12 The master-file submission procedure is already used extensively in the drug industry. Adding a master file component to the NDI notification process could protect the intellectual property of NDI manufacturers and facilitate the supplement industry and FDA in fulfilling NDI-related goals and, ultimately, promote consumer access to safe dietary supplements.
 
Drug companies submit master files for a myriad drug components, including active pharmaceutical ingredients (APIs) and packaging; these drug master files (DMFs) are referenced by multiple sponsors in the context of new drug applications (NDAs) and other applications. The DMF owner, or holder, has the discretion to authorize any third party to reference its DMF by issuing a letter of authorization (LOA). LOAs, along with a list of authorized parties, are submitted with the DMF.

This authorization permits the authorized party to reference the master file, but not to review its contents, and FDA reviews the relevant parts of the master file in accordance with the LOA. Implementation of the DMF has allowed API manufacturers, for instance, to protect intellectual property related to their APIs, while seamlessly facilitating the drug approval process by reducing the need to submit information of the same type across different NDAs. In Canada, natural health product master files (NHP-MF) are commonly referenced in product licensing applications. The NHP-MF submission procedures and requirements are similar to those for DMFs in the US.
 
As with drug and natural health product companies, dietary supplement companies could benefit from the addition of the master file to the premarket process, that is, the NDI notification. Implementation of an NDI master file (NDI-MF) system avails dietary ingredient manufacturers of the option to seek protection of intellectual property generated through research and development of an NDI, such as information regarding manufacturing, processing and safety.

Once the NDI-MF has been submitted to FDA, it may be referenced, with permission from the NDI-MF holder, by those submitting NDI notifications. The entire NDI notification process is streamlined if NDI-MF data can be referenced by multiple submitters of NDI notifications, and the paperwork burden is reduced because it is possible to submit NDI notifications in an abbreviated manner. An NDI-MF may be referenced by various ingredient manufacturers that desire to include the proprietary NDI in a novel ingredient blend, or by supplement manufacturers that plan to use the proprietary NDI in a new formulation outside the conditions of use established in the NDI-MF. In both hypothetical situations, the NDI notifications submitted to FDA may simply reference the NDI-MF and be abbreviated.
 
It would also be advantageous for FDA to accept master files. The agency would play a vital role in protecting intellectual property and likely face fewer instances of duplicative notifications, which slow down review efficiency, once master files are in place. FDA has responded positively to supplement industry calls to incorporate NDI master files into the NDI notification process.13

In its 2016 revised draft guidance, the agency explains that a company may submit a confidential NDI master file, incorporate the contents of the master file into an NDI notification, and authorize other firms to reference the master file in notifications.14 Furthermore, firms relying on the master file should provide documentation, such as a signed letter, that specifies the relevant parts of the master file included in the authorization. However, although FDA elaborated on the NDI master file concept in guidance, it did not clarify a submission process or how firms might identify existing NDI master files.
 
Industry-proposed framework for NDI master files
Existing and long-standing approaches to master files may be adapted for NDIs. The DMF system has persisted since the 1940s, evolved over time, and served as a model for a framework for the NDI-MF. A supplement industry proposal tailored for NDIs contains all the key elements shared among master file systems, including initial administrative review of submissions and assignment of a master file number by FDA, authorization procedures and requirements, master file updates and closure, and public availability of master file information (Table).
 
Table. Key elements of a proposed NDI master file framework
 20-6_Nguyen_NDI-MF_RM_3-Table.png

Conclusion
The NDI-MF is an optional and useful tool for the dietary supplement industry as well as FDA. Other industries have successfully used master files to protect intellectual property. Borrowing from major elements of the DMF, the supplement industry has adapted a framework for NDI-MFs. FDA should consider the industry’s proposal and implement a system for accepting and reviewing NDI-MFs as part of NDI notifications to facilitate innovation in dietary supplements.
 

Abbreviations
API, active pharmaceutical ingredients; DHA, docosahexaenoic acid; DMF, drug master file; DSHEA, Dietary Supplement Health and Education Act; FDA, Food and Drug Administration; LOA, letter of authorization; NDA, new drug application; NDI, new dietary ingredient; NDI-MF, new dietary ingredient master file; NHP-MF, natural health product master file.
 
References
  1. Polito R. Off the map and outside the model: Economic and epidemic matters make predictions difficult. Nutrition Business Journal. April 2020.
  2. Federal Food, Drug, and Cosmetic Act. 21 USC 350b: New dietary ingredients. https://www.govinfo.gov/content/pkg/USCODE-2010-title21/html/USCODE-2010-title21-chap9-subchapIV-sec350b.htm. 2010 edition. Accessed 30 March 2020.
  3. Sharpless N. Opening remarks. Public meeting to discuss responsible innovation in dietary supplements. May 16, 2019. Food and Drug Administration, Center for Food Safety and Applied Nutrition, College Park, MD. https://www.fda.gov/food/workshops-meetings-webinars-food-and-dietary-supplements/public-meeting-discuss-responsible-innovation-dietary-supplements. Last updated 6 June 2019. Accessed 30 March 2020.
  4. Food and Drug Administration. Submitted 75-day premarket notifications for new dietary ingredients. https://www.fda.gov/food/new-dietary-ingredients-ndi-notification-process/submitted-75-day-premarket-notifications-new-dietary-ingredients. Posted 15 May 2020. Accessed 30 March 2020.
  5. Council for Responsible Nutrition. CRN/CHPA comments to Docket No. FDA-2011-D-0376 76 Fed. Reg. 39111 (July 5, 2011) draft guidance for industry—Dietary supplements: New dietary ingredient notifications and related Issues. https://www.crnusa.org/regulation-legislation/crn-comments-legal-action#NDI. Posted 2 December 2011. Accessed 30 March 2020.
  6. Council for Responsible Nutrition. CRN submits comments to FDA, Docket FDA-2009-P-0298 —Defining a “Dietary Ingredient.” https://www.crnusa.org/crn-submits-comments-fda-docket-fda-2009-p-0298-defining-dietary-ingredient. Posted 29 June 2011. Accessed 16 April 2020.
  7. Council for Responsible Nutrition. CRN calls on FDA to reverse its current position on synthetic botanicals. https://www.crnusa.org/crn-calls-fda-reverse-its-current-position-synthetic-botanicals-0. Posted 22 October 2012 Accessed 16 April 2020.
  8. Council for Responsible Nutrition. Comments submitted on behalf of CRN on Docket No. FDA-2011-D-0376; Draft guidance for industry: Dietary supplements: New dietary ingredient notifications 76 Fed. Reg. 3911, by Steptoe & Johnson LLP. https://www.crnusa.org/comments-submitted-behalf-crn-docket-no-fda-2011-d-0376-draft-guidance-industry-dietary-supplements. Posted 2 May 2013. Accessed 16 April 2020.
  9. Council for Responsible Nutrition. CRN submits comments to FDA on ‘Draft guidance for industry: Dietary supplements: New dietary ingredient notifications and related issues’ Docket No. FDA-2011-D-0376. https://www.crnusa.org/crn-submits-comments-fda-draft-guidance-industry-dietary-supplements-new-dietary-ingredient.
  10. CRN Comments to Dietary Supplements: New Dietary Ingredient Notifications and Related Issues: Revised Draft Guidance for Industry [FDA-2011-D-0376] (December 12, 2016). regulations.gov website.https://www.regulations.gov/document?D=FDA-2011-D-0376-1994. Accessed 30 March 2020.
  11. Food and Drug Administration. Statement from FDA commissioner Scott Gottlieb, MD, on the agency’s new efforts to strengthen regulation of dietary supplements by modernizing and reforming FDA’s oversight. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-agencys-new-efforts-strengthen-regulation-dietary. 11 February 2019. Accessed 31 March 2020.
  12. Food Drug Administration. Drug master files (DMFs). https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs. Posted 31 March 2020. Accessed 31 March 2020.
  13. Herbalife International of America Inc. Comment to draft guidance for industry: Dietary supplements: New dietary ingredient notifications and related issues [FDA-2011-D-0376] (December 2, 2011). https://www.regulations.gov/document?D=FDA-2011-D-0376-0745. Accessed 1 April 2020.
  14. Food and Drug Administration. Draft guidance for industry: New dietary ingredient notifications and related issues. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/draft-guidance-industry-new-dietary-ingredient-notifications-and-related-issues. Posted 4 October 2016. Accessed 31 March 2020.
About the author
Haiuyen Nguyen is senior director, scientific & regulatory affairs at the Council for Responsible Nutrition. She focuses on developing regulatory and scientific comments on dietary supplement‒related topics submitted to federal agencies, including the US Food and Drug Administration and US Department of Health and Human Services. She has more than 10 years of experience in facilitating industry compliance with dietary supplement regulations, including good manufacturing practices, and engaging in federal nutrition policy-making processes. Nguyen has a bachelor of science degree in cellular and molecular biology and genetics from the University of Maryland, College Park. She can be contacted at hnguyen@crnusa.org.
 
Citation Nguyen H. Integration of master files in the NDI notification process facilitates innovation in dietary supplements. Regulatory Focus. June 2020. Regulatory Affairs Professionals Society.

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