Home > Advisory Services

Challenges of Regulating Cannabis

Greenleaf Regulatory Landscape Series

The Agriculture Improvement Act of 20181 (the 2018 Farm Bill) removed hemp from the definition of marijuana under the Controlled Substances Act2 (CSA). The 2018 Farm Bill defined hemp as cannabis (Cannabis sativa L.), and its derivatives, containing no more than 0.3%, on a dry-weight basis, of the psychoactive compound delta-9-tetrahydrocannabinol (THC). Hemp derivatives include cannabidiol (CBD), as well as a range of other cannabinoids. While the 2018 Farm Bill changed the legal status of hemp for purposes of cultivation, it did not change the Food and Drug Administration’s (FDA) authority, under the Federal Food, Drug, and Cosmetic Act (the FD&C Act) and Section 351 of the Public Health Service Act, over FDA-regulated products (i.e., drugs, devices, dietary supplements, food, cosmetics, and veterinary products) that contain hemp derivatives.3 The FD&C Act still considers a cannabis product (hemp-derived or otherwise) to be a drug when it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, or is an article (other than food) intended to affect the structure or function of the body. Therefore, since a new drug must be approved by the FDA for its intended use, with the exceptions of investigational new drugs (INDs) and cosmetic products, most products containing CBD and other cannabinoids that are on the market today are in violation of the FD&C Act.

Exploding CBD Market

Since 2018, the national CBD market has exploded in size, diversity, and value – it is currently estimated to be worth close to $6 billion, with projections continuing upward over the next several years (see Figure 1).4

This market explosion has meant that consumers today have access to a wide variety of product types, including tinctures, dabs, capsules, topicals, vape oils/cartridges, combustibles, edibles, and pet products, along with an increasingly diverse set of alternative cannabinoids and substances (e.g., CBN, CBG, delta-8 THC, THC-0 acetate, etc.). Additionally, these products are being used to treat a growing number of self reported conditions, such as pain, anxiety, insomnia, stress, inflammation, and more.5

Statutory Preclusion of CBD in Foods and Dietary Supplements

Despite the prominence and continued growth of the CBD industry, the FDA has maintained that statutory barriers prevent the marketing of CBD in dietary supplements and conventional food.6 The FD&C Act §201(ff)(3)(B) (known as the “Exclusion Clause”) and §301(II) (the food prohibition) exclude CBD from inclusion in dietary supplements and food, respectively. This is because CBD is the active ingredient in an FDA-approved drug, called Epidiolex, which, through the drug’s development and approval process, subjected CBD to substantial clinical investigations prior to the market availability of CBD-containing dietary supplements and food.7 The FDA has the authority to issue enforcement discretion and carve out CBD from these statutory preclusions through notice-and-comment. However, due to toxicity concerns observed in the Epidiolex clinical trials, and with the ubiquity of CBD on the market today, the agency is reticent to green light these products until their ingredients can be shown to meet safety standards required for new dietary ingredients (NDI) and food additives per the FD&C Act.

This position was made clear in July 2021, when the FDA rejected NDI notices submitted by two CBD companies, namely Charlotte’s Web and Irwin Naturals, for their full-spectrum hemp extract ingredients.8 In their NDI notices, the companies argued that full-spectrum hemp extract is not the highly purified CBD isolate that was investigated in the Epidiolex clinical trials, and therefore, is not a pharmaceutical ingredient that would otherwise be excluded from the definition of dietary supplements. The FDA disagreed, but also indicated that even if CBD was not excluded from the dietary supplement market, per §201(ff)(3)(B), safety evidence provided by the companies did not substantiate an NDI approval. Specifically, the agency took issue with the companies’ reliance on deficient categories of evidence, deficient and/or vague evidence of the ingredient’s history of use, unreliable studies, and studies that did not adequately address reported toxicity endpoints of the ingredient (e.g., hepatoxicity and reproductive toxicity).9 In order for companies to receive an NDI approval for CBD, the FDA would need to see clinical data on particular use scenarios, such as chronic use of exaggerated doses of CBD, in order to alleviate the toxicity concerns it has with broad, cumulative use of CBD products already available to consumers.

Meeting Research Needs

The FDA, for its part, has acknowledged a lack of understanding about everyday CBD use that could better inform the toxicological impact of such products.10 Since the market took off in 2018, the agency has engaged in a sweeping data gathering initiative to fill its knowledge gaps and inform a potential regulatory framework for cannabis-derived products (CDPs).11 This work has involved conducting analytical sampling studies, gathering information on the market landscape and CDP usage, initiating FDA-led toxicological studies, monitoring adverse event reports collected through local and national portals, reviewing scientific literature, working with established external research partners, and performing post-market studies as part of ongoing drug development.12

Additionally, in late 2021, the FDA issued the Cannabis-Derived Products Data Acceleration Plan (DAP) to outline areas of research focus and remaining research needs.13 Overall, the goal of the DAP is to identify safety vulnerabilities, both current and emerging, across the CDP market. In addition to housing ongoing toxicological clinical research (assessing endpoints such as male reproductive toxicity, neurotoxicity, pharmacokinetics, transdermal exposure, etc.) and leveraging novel data sources and advanced data analytics, the FDA will look to forge internal and external government data-generating partnerships to further inform policy development in this space.14

Narrow Enforcement Activity Places Industry in a Conundrum

While it has refrained, for now, from establishing a broader regulatory framework, the FDA has persistently taken targeted enforcement action against CDPs that pose the greatest risk to public health.15 These activities have primarily involved issuing warning letters, in addition to posting consumer updates on its website. Products that have been the subject of such enforcement activities include those marketed to treat or cure serious diseases (e.g., Alzheimer’s, cancer, and COVID-19), those marketed to vulnerable populations (e.g., minors, elders, and pregnant/lactating people), and those with concerning routes of administration (e.g., nasal, ophthalmic, and inhalation).16 The agency has also called out firms marketing CDPs for food producing animals and food for humans and pets (with an emphasis on food products marketed to minors).17 Additionally, the FDA has raised quality and legal concerns related to the synthesis of delta-8 THC.18

This ‘de facto’ enforcement discretion policy, one that only targets what the agency perceives as the biggest threats to the public, has meant that essentially all CBD products on the market today are able to remain there uncontested, despite their violative legal status. In fact, even the firms that have received administrative actions have not removed their products from the market. This has created somewhat of a conundrum for both industry and the agency, where responsible CDP manufacturers feel disincentivized to engage in lengthy and expensive clinical research in order to clear NDI safety hurdles for their high-demand products, while the agency has refused to take a harder line on market participants as a whole until such clinical data is made available. In the meantime, however, the FDA has not subsided in emphasizing that GMP compliance and the presence of mature quality systems at any FDA-regulated manufacturing facility, especially those disseminating CDPs, are critical.

Changing Tides: 2023 & Beyond

Since 2019, an intra-agency work group (now titled the Cannabis Products Council (CPC)) has explored potential pathways for lawfully marketing CBD products and sought to develop FDA’s broader cannabis policy and enforcement strategy. In January 2023, FDA Principal Deputy Commissioner Janet Woodcock, as chair of the CPC, announced the agency’s determination that existing pathways for approval are inappropriate for CBD, given safety concerns, along with its intent to work with Congress to create a new pathway.19 Within this statement, Woodcock explained that “a new regulatory pathway for CBD is needed that balances individuals’ desire for access to CBD products with the regulatory oversight needed to manage risks.” Legislation providing for such a pathway could include the establishment of a dedicated Center for Cannabis, not unlike the undertakings of the Family Smoking Prevention and Tobacco Control Act in 2009. Following this announcement, the FDA will coordinate with members of Congress to draft legislation while continuing to monitor the marketplace and take enforcement actions where appropriate.

Separate from the FDA’s CBD regulatory policy, recent events have furthered the potential for a new era of federal marijuana policy more broadly. In October 2022, President Biden called for the initiation of administrative processes to review how marijuana (currently a Schedule 1 controlled substance) is scheduled under federal law, while simultaneously granting mass pardons for federal convictions of marijuana possession.20 Then, in November 2022, President Biden signed the bipartisan Medical Marijuana and Cannabidiol Research Expansion Act to advance scientific research into cannabis by easing federal restrictions.21

Federal marijuana descheduling and/or broader policy reform would open doors for consumer products that contain non-hemp-derived THC or that do not meet the 0.3% THC threshold, implicating other regulatory considerations beyond the FDA. Per the 2018 Farm Bill, the FDA only contemplates what to do with products containing hemp-derived THC below 0.3% limits that are meant for non-recreational use purposes (i.e., products that make disease claims or structure/function claims). However, for products that contain non-hemp-derived THC and/or that exceed the 0.3% THCl limit, different rules will apply. For example, high-THC products that are intended to achieve a psychoactive effect will likely be treated in a similar fashion as alcohol and/or tobacco, which means very strict federal limits on toxicity will apply. These products (i.e., those with >.0.3% THC) will likely fall outside of the FDA’s jurisdiction and could be regulated by multiple other federal agencies (as is done for alcoholic beverages). With these changing tides, it’s also worth noting that federal regulatory reform has the potential to upend already well-established state frameworks for regulating everything from CDPs to medical marijuana to adult use/recreational marijuana. Existing state standards for CDP testing, labeling, dosing, and the like could also serve as models for future federal policies.

Conclusion

As the FDA works with Congress to develop a cross-agency strategy for federal cannabis regulation, they will also continue to monitor the market for bad actors and products that pose risks to humans and animals alike. This is especially the case due to recent negative public health research citing significant uptick in pediatric edible cannabis exposure and acute toxicity cases reported from 2017 through 2021,22 as well as the growing market for cannabinoids with psychoactive effects (e.g., delta-8 THC and THC-0 acetate). Since the passage of the 2018 Farm Bill, the FDA has sought to better understand the toxicological impact of CDP use by the public at large, while proposed congressional legislation, state and local legalizations, and other federal research and policy development efforts have all begun to imagine what an end to federal prohibition will look like from a regulatory standpoint. Unending policy questions remain before a regulatory framework is up and running – to name a few, upper THC toxicity limits and dosing, testing requirements and quality standards, packaging and labeling requirements, and tools for measuring impairment all still need to be worked out. However, as cannabis markets continue to point towards a strong future, regulators, and the FDA in particular, will be preparing to meet the evolution of these products head on in order to protect and promote public health.

1. PL 115-334 (December 2018), available at https://www.congress.gov/115/plaws/publ334/PLAW-115publ334.pdf.

2. 21 U.S.C. §801 et seq.

3. See Statement from FDA Commissioner Scott Gottlieb, M.D., on passage of the 2018 Farm Bill and the agency’s regulation of products containing cannabis and cannabis-derived compounds, (December 2018), available at https://www.fda.gov/newsevents/press-announcements/statement-fda-commissioner-scott-gottlieb-md-signing-agriculture-improvement-act-and-agencys

4. See Council for Federal Cannabis Regulation webinar, Janet Woodcock, M.D., Patrick Cournoyer, Ph.D., “Understanding FDA’s Approach to Cannabis Science, Policy, and Regulation” (October 2022).

5. Id.

6. See FDA Regulatory Resource, “FDA Regulation of Dietary Supplement & Conventional Food Products Containing Cannabis and Cannabis-Derived Compounds,” (updated January 2021), available at https://www.fda.gov/media/131878/download.

7. See FDA Webpage, “FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD),” (updated January 2021) (Question 9), available at https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd#dietarysupplements.

8. Letter from Cara Welch, Ph.D., Acting Director, Office of Dietary Supplement Programs, CFSAN, to Tim Orr, Charlotte’s Web, Inc. (July 2021), available at FDA, 75-Day Premarket Notification for New Dietary Ingredients 2021, Docket No. FDA-2021-S-0023-0053, https://www.regulations.gov/document/FDA-2021-S-0023-0053; Letter from Cara Welch, Ph.D., Acting Director, Office of Dietary Supplement Programs, CFSAN, to Irwin Naturals (July 2021), available at FDA, NDI 1199 – Full-Spectrum Hemp Extract (FSHE) from Irwin Naturals, Docket No. FDA-2021-S-0023-0050, https://www.regulations.gov/document/FDA-2021-S-0023-0050.

9. Id.

10. See FDA Voices, Stephen Hahn, M.D., FDA Commissioner, and Amy Abernathy M.D., Ph.D., FDA Principal Deputy Commissioner, “Better Data for a Better Understanding of the Use and Safety Profile of Cannabidiol (CBD) Products,” (January 2021), available at https://www.fda.gov/news-events/fda-voices/better-data-better-understanding-use-and-safety-profile-cannabidiol-cbd-products.

11. See supra, n.4

12. Id.

13. FDA News & Events, “Cannabis-Derived Products Data Acceleration Plan,” (October 2021), available at https://www.fda.gov/newsevents/public-health-focus/cannabis-derived-products-data-acceleration-plan.

14. Id.

15. See FDA Webpage, “FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD) – FDA Communications,” available at https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derivedproducts-including-cannabidiol-cbd#fdacomm.

16. See supra, n.4

17. FDA Constituent Update, “FDA Warns Companies for Illegally Selling Food and Beverage Products that Contain CBD,” (November 2022), available at https://www.fda.gov/food/cfsan-constituent-updates/fda-warns-companies-illegally-selling-food-and-beverageproducts-contain-cbd.

18. FDA News Release, “FDA Issues Warning Letters to Companies Illegally Selling CBD and Delta-8 THC Products,” (May 2022), available at https://www.fda.gov/news-events/press-announcements/fda-issues-warning-letters-companies-illegally-selling-cbd-anddelta-8-thc-products.

19. FDA Statement, “FDA Concludes that Existing Regulatory Frameworks for Foods and Supplements are Not Appropriate for Cannabidiol, Will work with Congress on a New Way Forward,” (January 2023), available at https://www.fda.gov/news-events/pressannouncements/fda-concludes-existing-regulatory-frameworks-foods-and-supplements-are-not-appropriate-cannabidiols.

20. White House Briefing Room, “Statement from President Biden on Marijuana Reform,” (October 2022), available at https://www.whitehouse.gov/briefing-room/statements-releases/2022/10/06/statement-from-president-biden-on-marijuana-reform/.

21. See Marijuana Moment, “Biden Will Sign Bipartisan Marijuana Research Bill Passed by Congress This Week, White House Says,” (November 2022), available at https://www.marijuanamoment.net/biden-will-sign-bipartisan-marijuana-research-bill-passed-bycongress-this-week-white-house-says/.

22. AAP, “Pediatric Edible Cannabis Exposures and Acute Toxicity: 2017-2021,” (January 2023), available at https://publications.aap.org/pediatrics/article/doi/10.1542/peds.2022-057761/190427/Pediatric-Edible-Cannabis-Exposures-and-Acute?autologincheck=redirected; See also, WaPo, Elizabeth Chang, “Steep increase of kids accidentally eating cannabis edibles, data shows,” (January 2023), available at https://www.washingtonpost.com/parenting/2023/01/03/edibles-kids-increasing/.

Digital Health: A Key Priority in MDUFA V and PDUFA VII Commitments

Greenleaf Regulatory Landscape Series

Considering the increasing interest in and use of digital health technologies in clinical care and research, it should come as no surprise that several performance goals related to digital health technologies are included in the Food and Drug Administration’s (FDA) user fee legislation1 for the medical device and prescription drug programs for fiscal years 2023 through 2027. Indeed, researchers have found that between 2000 and 2018, the use of digital health tools in clinical trials grew at a compound annual growth rate of 34%.2

The Medical Device User Fee Amendments (most recently reauthorized as MDUFA IV) and Prescription Drug User Fee Act (most recently reauthorized as PDUFA VI) sunset every five years, unless reauthorized by Congress. This year both User Fee Amendments were reauthorized by Congress on September 29, 2022, one day before MDUFA IV and PDUFA VI’s sunset date. As part of the reauthorization process, the FDA negotiates user fee commitment letters with regulated industry. These commitment letters set forth the performance goals agreed to by the FDA for the next five fiscal years in exchange for outlined user fees to be paid by industry. This landscape describes in detail the digital health commitments included in the user fee commitment letters accompanying the legislation to reauthorize the device and prescription drug user fee programs, MDUFA V3 and PDUFA VII4.

MDUFA V Digital Health Commitments

Several of the FDA’s MDUFA V commitments related to digital health build on agency efforts already in progress. The FDA agreed to “continue to build its digital health expertise and continue working to streamline and align FDA review processes with software lifecycles for digital health products.” More specifically, the FDA agreed to continue to:

  • Develop expertise to support the review of premarket submissions that include digitial health technologies like artificial intelligence (AI), virtual reality, and wearables;
  • Expand staff understanding of digital health topics and work to ensure the consistent review of digital health-related submissions through training and agency infrastructure;
  • Participate in international harmonization efforts related to digital health; and
  • Engage with stakeholders through roundtables, informal meetings, and teleconferences to explore regulatory approaches to digital health technologies.

In addition, the FDA committed to finalizing one guidance document and issuing a new draft guidance. The FDA agreed to finalize the draft guidance titled, “Draft Guidance for Industry and FDA Staff: Content of Premarket Submissions for Device Functions” by August 20235 and also to publish a draft guidance document “describing a process to evaluate a predetermined change control plan for digital health devices.”

PDUFA VII Digital Health Commitments

As opposed to the FDA’s broader MDUFA V commitments to continue to build digital health expertise and align FDA review processes, the goals related to digital health in the PDUFA letter are focused more narrowly on developing a regulatory framework to help advance the use of digital health technologies (DHTs) in clinical trials. Highlighting the need for a more robust regulatory framework for DHTs, the FDA states in the commitment letter, “FDA recognizes the potential for DHTs to provide scientific and practical advantages in supporting the assessment of patients by generating information outside of the traditional clinic visit.6 Thus, to encourage the adoption of DHTs in clinical trials to support drug registration, label expansion, and safety monitoring, the FDA has committed to the following goals.

Develop a Regulatory Framework

Similar to the Real-World Evidence (RWE) Framework that the FDA published in December 2018 to outline its proposed regulatory approach to RWE, the FDA has agreed to issue a regulatory framework for digital health technologies by end of the Q2 2023. The document will identify objectives for workshops and demonstration projects, describe methodologies for evaluating DHTs as endpoints, and discuss standardized processes for managing and submitting continuous or extensive datasets.

Establish a DHT Committee

To promote regulatory consistency across the Centers and oversee the development and implementation of the DHT regulatory framework, the FDA has committed to establishing a DHT committee with representatives from both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). The committee will also be responsible for engaging external stakeholders and gathering intelligence on the current challenges related to DHTs.

Convene Workshop Series on DHTs

By the end of Q2 2023, the FDA will convene a series of five public workshops to gather input from external stakeholders on key issues related to the use of DHTs in regulatory decision-making. As noted in the letter, meetings will likely focus on:

  • Using DHTs to increase trial diversity;
  • Approaches to DHT validation;
  • DHT data processing and analysis techniques; and
  • Regulatory acceptance of safety monitoring tools using AI and machine learning.

Launch DHT Demonstration Projects

The FDA will launch a series of demonstration projects designed to inform regulatory policy developments related to DHTs. Projects will likely be designed to further examine validation methods, investigate different approaches to addressing missing data, and inform the use of multi-channel inputs.

Issue Guidance

The FDA has committed to issuing a wide swath of guidances to further develop the DHT regulatory paradigm. By Q1 2023, the FDA will issue draft, revised, or final guidance documents on the following topics:

  • Use of DHTs in traditional and decentralized trials;
  • Validation of measurement by DHTs;
  • Developing novel endpoints and measuring existing endpoints with DHTs;
  • Using patients’ own DHTs, such as cellular phones or smart watches;
  • DHT usability considerations for patients;
  • Detection of safety signals during continuous data acquisition; and
  • Data security and confidentiality.

In addition to the abovementioned topics, the FDA has also committed to issuing guidance on regulatory considerations for Prescription Drug Use-Related Software by the end of 2023 and on any other specific topics identified through stakeholder engagement by 2024.

Expand Organizational and Technological Capacity

To accommodate the anticipated wave of regulatory submissions incorporating DHT-derived data, the FDA will have to enhance both its organizational and technological capacities. To develop the technical expertise needed, the FDA will invest in training on digital technologies and on relevant statistical methodologies. The FDA has also committed to establishing a consistent approach to the review of DHT- related submissions across all three Centers. To upgrade the Agency’s technological systems, in FY 2023, the FDA will establish a secure cloud technology to enhance its infrastructure and internal analytics environment to process the large volume of DHT-generated data. The Agency will also work on recommending and implementing data standards to make DHT-derived data more analyzable.

1. See https://www.congress.gov/117/bills/hr6833/BILLS-117hr6833eas.pdf.

2. Mara, C., et al. “Quantifying the Use of Connected Digital Products in Clinical Research,” npj Digital Medicine, 3 (50), 2020, https://www.nature.com/articles/s41746-020-0259-x#Abs1.

3. FDA, “PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2023 through 2027,” https://www.fda.gov/media/151712/download.

4. FDA, “MDUFA Performance Goals and Procedures, Fiscal Years 2023 through 2027,” https://www.fda.gov/media/158308/download.

5. See https://www.fda.gov/media/153781/download.

6. FDA, “PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2023 Through 2027,” August 2021, https://www.fda.gov/media/151712/download.

The Drug Supply Chain Security Act (DSCSA): Current Implementation Update

Greenleaf Regulatory Landscape Series

In the seventh year of implementation of the Drug Supply Chain Security Act (DSCSA), trading partners involved in manufacturing, repackaging, distributing, and dispensing pharmaceuticals in the U.S. (industry) continue to grapple with its requirements. The goal of the DSCSA, which was enacted in November 2013 under Title II of the Drug Quality and Security Act,1 is to produce a system that enhances national pharmaceutical supply chain security by implementing a fully interoperable and electronic system for securing and tracing products by November 2023.2 Trading partner authorization, product tracing, verification, and product identification (including serialization) are four key components needed to achieve this goal.3

Since enactment of the DSCSA, two phases of implementation have been imposed. In the first phase, traceability requirements at the lot level were implemented beginning in 2015. In the second phase, interoperability requirements allowing for product tracing at the package level are scheduled to become effective in November 2023. Once in place, the interoperability requirements will involve: the exchange of transaction data by authorized trading partners; the ability of trading partners to verify products at the package level; and the maintenance of product tracing processes such that transaction data going back to the manufacturer can be provided upon request.4

The interoperability requirements, as opposed to the traceability requirements, are not clearly defined by the DSCSA, and yet, are particularly complex due to their electronic interconnectedness across the various industry sectors.5 As such, industry stakeholders have reported slow uptake of requirement testing and implementation thus far, which has been fueled by a lack of consistency, clarity, and awareness among trading partners, as well as added burdens related to the pandemic.6 Specifically, important testing of data systems by some manufacturers has not occurred at rates needed to ensure requirements are in place by 2023. Needed collaboration with trading partners, greater system governance, consistent DSCSA legal interpretation, and missing standards are all additional challenges weighing down implementation efforts.

Figure 1

FDA Efforts to Support Industry Readiness

To help enhance industry’s overall readiness ahead of 2023, the Food and Drug Administration (FDA or Agency) released four guidance documents in June 2021 aimed at providing clarity and understanding around various DSCSA requirements.7 These guidance documents are summarized in Figure 2 below. The Agency also hosted multiple webinars in 2021 outlining key DSCSA requirements and explaining its new guidance documents and how they fit into the overall 2023 implementation scheme.8

Figure 2 9

Additionally, in February 2022, the FDA issued a proposed rule setting forth licensing standards for wholesale distributors and third-party logistics providers (3PLs), as mandated by the DSCSA.10 A national licensing system for distributors and 3PLs falls under the law’s key requirement that trading partners involved in the exchange of prescription drugs must be authorized such that they are appropriately registered or licensed to receive or transfer products.11 Establishment of national licensing standards eliminates an existing patchwork of state standards and is meant to provide industry-wide uniformity to better ensure all trading partners along supply chains are appropriately qualified to distribute prescription drugs. Diverging from its initial position issued in a 2014 draft guidance, the FDA’s proposed rule preempts state licensing laws that establish stricter standards, meaning that states can only continue licensing distributors and 3PLs if they match federal requirements.12 Once the rule is finalized, wholesale distributors will have two years, and 3PLs will have one year, before requirements take effect. Stakeholders have until June 2022 to comment on the proposed rule.13

Remaining Implementation Challenges: A Need for Further Clarity and Alignment

Despite new guidance and key implementation updates provided by the Agency, industry has continued to call for stronger alignment and the provision of more information around interoperability requirements. At a November 2021 public meeting,14 industry stakeholders called for the finalization of draft guidance on standards for secure, interoperable exchanges of product data and the endorsement of the global GS-1 standard for creating and sharing transaction data, or Electronic Product Code Information Services (EPCIS).15 The FDA has given assurance that finalized guidance is forthcoming.16 The Federal Food, Drug, and Cosmetic Act, as amended by the DSCSA, mandates17 that the FDA recommend data exchange standards that comply with those of widely recognized international organizations in order to facilitate the adoption of secure, interoperable, electronic data exchange along pharmaceutical distribution supply chains.18 Draft guidance released in November 2014 recommended the use of EPCIS, but also mentioned other methods and standards that could be used as well.19 The lack of a finalized standard recommendation has made many in industry reticent to begin implementing and testing data exchange systems, which are essential for ensuring systems are ready to go live in November 2023

Additionally, in Fall 2021, a number of industry stakeholders submitted comments expressing concern for perceived inconsistencies between the track and trace system put forth in new draft guidance and the plain language of the DSCSA, as well as a lack of other important information about requirements for 2023 compliance.20 The new draft guidance, “Enhanced Drug Distribution Security at the Package Level Under the DSCSA,” sets out the Agency’s decision as to whether data security system structures should be centralized or distributed, backing a distributed/semi-distributed model based on the idea that this approach allows trading partners to maintain control over their own data.21 Industry and other stakeholders disagree, however, as to whether this is the right approach for achieving interoperability. An August 2021 report from the International Coalition of Medicines Regulatory Authorities (ICMRA) promoted a centralized model as the “most efficient and simple” design for storing and reporting traceability data from multiple entities (although, the report also noted that “it is perfectly possible […] to design a system with distributed databases where each originator stores their own data”).22 In comments submitted to the new draft guidance docket, the Healthcare Distribution Alliance (HDA) stated that it did not believe a distributed or semi-distributed model is feasible, noting that what currently exists is “an ecosystem … of thousands of privately owned and maintained systems that are all different” (emphasis added).23

Other comments submitted to the docket reiterated HDA’s concerns with the new draft guidance, and also addressed concerns related to the sharing of proprietary information between trading partners and government authorities/other trading partners.24 In calling for the withdrawal of the draft guidance, and noting discussed challenges and concerns, HDA and other stakeholders expressed uncertainty as to industry’s ability to meet implementation requirements of the proposed electronic system in time for the 2023 deadline.25 Despite this looming deadline, the FDA has maintained that its planned electronic, interoperable track and trace system will go live in November 2023.26

Conclusion

The FDA has stressed that a system for enhancing drug distribution security will need to be robust, yet flexible.27 The Agency has also said it will leverage a range of coordinated mechanisms, such as: standardized data; standardized data exchanges; data analyses; investigations of suspect and illegitimate products; and other compliance guidance documents and enforcement tools.28 The complexity involved in achieving full implementation of the DSCSA is apparent and has been exacerbated in recent years by the COVID-19 pandemic. Thus, greater industry understanding about requirements through additional guidance and communication from the FDA will be an important part of breaking down remaining challenges to full DSCSA implementation in 2023.

  1. H.R. 3204, Sec. 201, “Drug Supply Chain Security,” (November 2013), available at https://www.govinfo.gov/content/pkg/PLAW-113publ54/pdf/PLAW-113publ54.pdf. See also, FDA Webpage, “Drug Supply Chain Security Act (DSCSA)”, available at https://www.fda.gov/drugs/drug-supply-chain-integrity/drug-supply-chain-security-act-dscsa.
  2. CDER SBIA Virtual Compliance Conference, Connie Jung, RhP, PhD, “Enhancing Drug Distribution Security under DSCSA” (January 2021), available at https://www.fda.gov/drugs/news-events-human-drugs/cder-compliance-conference-01142021-01142021.
  3. Id.
  4. Partnership for DSCSA Governance, “DSCSA 2023 Requirements,” available at https://dscsagovernance.org/.
  5. Id.
  6. RAPS Focus, “Panelists: Sluggish pace of DSCSA testing is worrisome” (May 2021), available at https://www.raps.org/news-and-articles/news-articles/2021/5/supply-chain-members-concerned-over-sluggish-testi?utm_source=MagnetMail&utm_medium=Email%20&utm_campaign=RF%20Today%20%7C%204%20May%202021.
  7. FDA In Brief, “FDA provides new guidance to further enhance the security of prescription drugs in the U.S. supply chain” (June 2021), available at https://www.fda.gov/news-events/press-announcements/fda-brief-fda-provides-new-guidance-further-enhance-security-prescription-drugs-us-supply-chain?utm_medium=email&utm_source=govdelivery.
  8. See, CDER SBIA Virtual Compliance Conference, Connie Jung, RhP, PhD, “Enhancing Drug Distribution Security under DSCSA” (January 2021), available at https://www.fda.gov/drugs/news-events-human-drugs/cder-compliance-conference-01142021-01142021; and CDER SBIA Webinar, Connie Jung, RhP, PhD, “Enhanced Drug Distribution Security in 2023 Under the DSCSA,” (October 2021), available at https://www.fda.gov/drugs/news-events-human-drugs/enhanced-drug-distribution-security-2023-under-dscsa-10052021-10052021.
  9. See, FDA Draft Guidance, “Enhanced Drug Distribution Security at the Package Level Under the Drug Supply Chain Security Act,” (June 2021), available at https://www.fda.gov/media/149704/download; FDA Final Guidance, “Drug Supply Chain Security Act Implementation: Identification of Suspect Product and Notification” (June 2021), available at https://www.fda.gov/media/88790/download; FDA Revised Draft Guidance, “Definitions of Suspect Product and Illegitimate Product for Verification Obligations Under the DSCSA” (June 2021), available at https://www.fda.gov/media/111468/download; and FDA Final Guidance, “Product Identifiers Under the DSCSA Questions and Answers” (June 2021), available at https://www.fda.gov/media/116304/download.
  10. FDA Announcement, “FDA announces proposed rule: National Standards for the Licensure of Wholesale Drug Distributors and Third-Party Logistics Providers” (February 2022), available at https://www.fda.gov/drugs/drug-supply-chain-security-act-dscsa/fda-announces-proposed-rule-national-standards-licensure-wholesale-drug-distributors-and-third-party?utm_medium=email&utm_source=govdelivery.
  11. See, supra n.8.
  12. Docket, FDA-2020-N-1663, available at https://www.regulations.gov/docket/FDA-2020-N-1663/document.
  13. Id.
  14. FDA Event, “Public Meeting on Enhanced Drug Distribution Security at the Package Level Under the DSCSA,” (November 2021), available at https://www.fda.gov/drugs/news-events-human-drugs/public-meeting-enhanced-drug-distribution-security-package-level-under-drug-supply-chain-security#event-materials.
  15. RAPS Focus, “FDA urged to endorse EPCIS to spur manufacturers’ uptake of DSCSA” (November 2021), available at https://www.raps.org/news-and-articles/news-articles/2021/11/fda-urged-to-endorse-epcis-to-spur-manufacturers-u.
  16. FDA Draft Guidance, “Enhanced Drug Distribution Security at the Package Level Under the Drug Supply Chain Security Act,” (June 2021), available at https://www.fda.gov/media/149704/download at p.6.
  17. FD&C Act, Sect. 582(h)(4)(A).
  18. See, supra n.16.
  19. Id.
  20. Docket, FDA-2020-D-2024, available at https://www.regulations.gov/document/FDA-2020-D-2024-0005/comment. See also, RAPS Focus, “Industry calls for withdrawal of FDA electronic tracing guidance” (September 2021), available at https://www.raps.org/news-and-articles/news-articles/2021/9/industry-calls-for-withdrawal-of-fda-electronic-tr.
  21. FDA Draft Guidance, “Enhanced Drug Distribution Security at the Package Level Under the Drug Supply Chain Security Act,” (June 2021), available at https://www.fda.gov/media/149704/download.
  22. ICMRA Report, “Recommendations on common technical denominators for traceability systems for medicines to allow for interoperability” (August 2021), available at https://www.icmra.info/drupal/sites/default/files/2021-08/recommendations_on_common_technical_denominators_for_T&T_systems_to_allow_for_interoperability_final.pdf.
  23. See, supra n.20.
  24. Id.
  25. Id.
  26. RAPS Focus, “FDA official: Agency will not extend 2023 DSCSA interoperability deadline” (August 2021), available at https://www.raps.org/news-and-articles/news-articles/2021/8/fda-stands-firm-on-november-2023-interoperability.
  27. See, supra n.2.
  28. Id.

Update on Ongoing User Fee Negotiations

Greenleaf Regulatory Landscape Series

The Food and Drug Administration (FDA or the Agency) user fee programs help to provide funding for the Agency to achieve its mission of protecting the public health and providing safe and effective medical products to patients in the United States.1 The user fee programs provide the FDA with financial support to meet specified performance goals and commitments related to medical product submissions. These specific performance goals and commitments are negotiated and agreed upon between the FDA and industry in the years leading up to the reauthorizations and must be sent to Congress for review and approval.

All medical product user fees are renegotiated every five years. As the Prescription Drug User Fee Amendments (PDUFA VI), the Biosimilar User Fee Amendments (BsUFA II), and the Medical Device User Fee Amendments (MDUFA IV) are also set to expire on September 30, 2022, it is expected that all three user fee program extensions will be part of the same legislative package.2,3 The next set of authorizations for these programs will cover Fiscal Years 2023 to 2027.

Below is a summary of the current status of the PDUFA, BsUFA, and MDUFA negotiations as well as a description of the key commitments being discussed between the FDA and industry.

PDUFA

PDUFA VII will build upon the progress of past programs by providing the FDA with the resources and tools it needs to keep pace with advances in drug development. Considering recent scientific breakthroughs in cell and gene therapy and the bolus of investigational new drug (IND) applications for advanced biological therapies received by the Agency, PDUFA VII seeks to provide the Center for Biologics Evaluation and Research (CBER) with the funding and authority to hire additional staff to meet this demand. With negotiations being held virtually against the backdrop of the COVID-19 pandemic, PDUFA VII also aims to formalize some of the lessons learned from the pandemic, including guidance and workshops on the use of alternative tools to assess manufacturing facilities and additional resources to support the broader use of digital health tools (DHTs). The commitment letter,4 which was made public in late August 2021, includes the following commitments: 

Strengthen Scientific Dialogue. Recognizing the need for further dialogue between the Agency and sponsors, the FDA will formalize the INTERACT meeting framework as well as establish a similar meeting type for the Center for Drug Evaluation and Research (CDER). Both industry and the FDA also discussed the possibility of sharing metrics related to all PDUFA meeting types and associated interactions.

Promote Innovation. To shorten review timelines for certain approved therapies and support efficacy endpoint development for rare diseases, PDUFA VII will establish the Split Real Time Application Review (STAR), modeled after CDER’s Real Time Oncology Review (RTOR).5

Support Advanced Biological Therapies. As noted, CBER will likely be provided dedicated resources to ensure the timely review of all applications for innovative biological therapies. Negotiations also focused on including the patient voice in gene therapy development programs as well as the potential for a workshop on how sponsors could leverage prior knowledge to accelerate gene therapy development. The FDA and industry also discussed a proposal on potential guidance dedicated to clarifying evidentiary standards for the RMAT program.6

Modernize Evidence Generation and Drug Development Tools. To advance the use of real-world evidence (RWE), both industry and the Agency discussed the establishment of a pilot program to develop new methods for using real-world data (RWD) in regulatory decision-making, including in the review of applications.7 Both industry and the FDA expressed an interest in continuing the Model Informed Drug Development (MIDD) paired meeting program. Issuance of guidance related to Complex Innovative Designs (CID) is also included in the commitment letter.8

Advance IT Infrastructure. PDUFA VII will also modernize data and information technology (IT) capacity and capabilities, including the adoption of cloud-based technologies as described in the FDA’s Technology Modernization Action Plan as well as technology convergence across the review centers more broadly.9 Both industry and the FDA also discussed potential programs and initiatives that could inform the evaluation of DHT-generated data.10

Next Steps

The initial draft of the PDUFA commitment letter has been published and is currently open to comment.11 The letter will also be reviewed and discussed at a public meeting on September 28, 2021.

PDUFA VII Negotiation Process

BsUFA

With negotiations recently completed on the heels of the PDUFA VII negotiations, BSUFA III will likely include several commitments that were agreed to in PDUFA VII, such as the development of guidance on alternative tools to assess manufacturing facilities, the dedication of resources to modernize the FDA’s data and information technology capabilities, and resources to enhance hiring and retention. Additional focus areas from the BSUFA III negotiations are outlined below:

Greater Collaboration Between Sponsors and the FDA. To improve collaboration between the Agency and sponsors, the commitment letter will likely include a new Biosimilar Biological Product Development (BPD) meeting type in which the Agency can provide focused targeted feedback. Modifications to the timelines and processes for Type 4 meetings are also likely.12

Regulatory Science Program. To facilitate more efficient biosimilar and interchangeable product development, as well as enhance regulatory decision-making, both the FDA and industry appeared to have agreed to funding a BsUFA Regulatory Science Program, modeled on the successful GDUFA Regulatory Science Program.13

Expedited Application Review. During negotiations, industry and the FDA discussed best practices for application review and opportunities for implementing those best practices into FDA documents and procedures.14

Next Steps

The BsUFA commitment letter is currently being reviewed by the Department of Health and Human Services (HHS), the Office of Personnel Management, and the Biden Administration. The BsUFA letter will also be open to public comment and discussed in a public meeting, likely to be held in mid-fall 2021, before being sent to Capitol Hill. 

BsUFA III Negotiation Process

MDUFA

The MDUFA V negotiations have also been shaped by the experience of the FDA, industry, and other stakeholder groups during the COVID-19 pandemic. Both the FDA and industry want to keep elements of the regulatory flexibility that was provided during the pandemic as well as the increased amount of interaction between sponsors and the Agency. Additionally, for MDUFA V, both groups want to carry over many of the commitments and goals that were set during MDUFA IV. This approach aims to help maintain the status quo and ensure stability and continuity for the premarket review program in light of the many adjustments that the Agency had to make to manage the additional workload brought on by the COVID-19 pandemic. This approach will also provide additional time to achieve some of the commitments outlined in MDUFA IV that have not yet been met.15

Several proposals made by each group during the MDUFA V negotiations are still under discussion. These proposals include the following:

Hiring Targets and Vacancies. Throughout the negotiations there has been significant discussion regarding the number of vacancies for full-time equivalent (FTE) staff positions tied to user fees and the salaries for these positions. As part of MDUFA V, industry has proposed that annual specific numerical hiring targets be set in order to increase the formality of these goals, including increased transparency and prioritization by the Agency.16

Review of MDUFA IV One-Time Costs. Industry has proposed a review of funding for one-time costs from MDUFA IV including renewing funding for certain programs but not others. More specifically, industry would like to continue funding for “initiatives for patient engagement, recruitment, retention, and the independent assessment” while not renewing as part of MDUFA V funding “the investment to stand up time reporting” or “the IT investment to support digital health.” Other programs would require further discussion in order to be extended with MDUFA V funding, including “IT enhancements for premarket review work; real-world evidence; standards conformity assessment; and third party review.” In addition, industry has proposed to reinstate 5th year offset fees as the carryover balance has grown to a significant level.17

Device Safety. The FDA has presented a proposal to enhance its capabilities related to postmarket surveillance to allow the Agency “to more accurately and precisely identify the scope of potential concerns, to more efficiently resolve device performance and patient safety issues, and to provide timely and clear communications with patients and healthcare providers.”18 Although industry supports these enhanced capabilities, they noted during the negotiations that MDUFA funding has statutorily been limited to only premarket activities, and this significant change for industry-based funding would require statutory changes.

The Total Product Life Cycle Advisory Program (TAP). The FDA has presented the TAP program as a new model for frequent and rapid FDA interaction with sponsors that would also provide valuable feedback from external stakeholders such as payers and providers. The FDA described the program as including the hiring of new premarket review staff with different levels of expertise as well as inviting external stakeholder groups to participate in the process. The FDA also explained that the program aims to provide a more iterative engagement process with sponsors that could lead to higher quality submissions and fewer review cycles. Industry has voiced serious concern that many elements of the TAP program as currently outlined, such as convening private payers, seem to go beyond the scope of MDUFA and could require statutory changes. Industry is also concerned that this model could lead to more complex reviews and thereby increased program costs. Lastly, industry noted that there are already several FDA premarket programs that provide sponsors with increased engagement with the FDA as well as opportunities to discuss coverage with payers.19

Next Steps

The FDA and industry will continue to meet throughout the coming year to develop an agreed-upon commitment letter to present to Congress. All stakeholder groups are encouraged to participate in the ongoing public negotiations. The most recent FDA-industry meeting was scheduled for May 19, 2021, but meeting minutes have not yet been published.20 Public records also show that several additional stakeholder consultation meetings were scheduled through the end of August.21

MDUFA V Negotiation Process22

1. Food and Drug Administration Website, FDA User Fee Programs, https://www.fda.gov/industry/fda-user-fee-programs.

2. Although not discussed in this memo, the Generic Drug User Fee Act (GDUFA) has the same end date and will likely be a part of the same legislative package as PDUFA, BsUFA, and MDUFA.

3. Derek Gingery, “PDUFA VII Negotiations Completed, Commitment Letter Ratification Ongoing,” Pink Sheet, 22 March 2021, https://pink.pharmaintelligence.informa.com/PS144034/PDUFA-VII-Negotiations-Completed-Commitment-Letter-Ratification-Ongoing.

4. FDA, PDUFA VII Commitment Letter, August 2021, https://www.fda.gov/media/151712/download.

5. PDUFA Reauthorization Meeting Summary, FDA and Industry Pre-Market Subgroup, 27 January 2021, https://www.fda.gov/media/147552/download.

6. PDUFA Reauthorization Meeting Summary, FDA and Industry CBER Breakout Subgroup, 10 November 2021, https://www.fda.gov/media/145588/download. 

7. PDUFA Reauthorization Meeting Summary, FDA and Industry Pre-Market Subgroup, 21 January 2021, https://www.fda.gov/media/147564/download.

8. PDUFA Reauthorization Meeting Summary, FDA and Industry Negotiation Regulatory Decision Tools Subgroup, 1 December 2021, https://www.fda.gov/media/146389/download.

9. PDUFA Reauthorization Meeting Summary, FDA and Industry Digital Health and Informatics, 27 January 2021, https://www.fda.gov/media/146779/download.

10. PDUFA Reauthorization Meeting Summary, FDA and Industry Digital Health and Informatics, 16 December 2021, https://www.fda.gov/media/146775/download.

11. FDA, PDUFA VII Commitment Letter, August 2021, https://www.fda.gov/media/151712/download.

12. BSUFA Reauthorization Meeting Summary, FDA and Industry Steering Committee Meeting, 27 April 2021, https://www.fda.gov/media/149026/download.

13. BSUFA Reauthorization Meeting Summary, FDA and Industry Steering Committee Meeting, 13 April 2021, https://www.fda.gov/media/148185/download.

14. BSUFA Reauthorization Meeting Summary, FDA and Industry Steering Committee Meeting, 20 April 2021, https://www.fda.gov/media/149025/download.

15. Meeting Minutes, FDA–Industry MDUFA V Reauthorization Meeting, 28 April 2021, https://www.fda.gov/media/150625/download.

16. Ibid.

17. Ibid.

18. Ibid.

19. Ibid.

20. Ibid.

21. FDA Webpage, Stakeholder Consultation Meetings – Medical Device User Fee Amendments 2023 (MDUFA V), https://www.fda.gov/industry/medical-device-user-fee-amendments-mdufa/stakeholder-consultation-meetings-medical-device-user-fee-amendments-2023-mdufa-v.

22. FDA Webpage, Medical Device User Fee Amendments 2023 (MDUFA V), https://www.fda.gov/industry/medical-device-user-fee-amendments-mdufa/medical-device-user-fee-amendments-2023-mdufa-v.

Advanced Manufacturing Technologies

Greenleaf Regulatory Landscape Series

For nearly two decades, the Food and Drug Administration (FDA or the Agency) has supported the development of innovative manufacturing technologies that modernize quality management systems and provide greater quality assurance across medical product supply chains. Evidence of the FDA’s commitment to the development and implementation of this technology appeared most recently in January 2021 with the creation of a new collaboration between the FDA and the National Institute of Standards and Technology (NIST), under a Memorandum of Understanding (MOU), aiming to increase U.S. supply chain resilience and advanced domestic manufacturing by adopting innovative technologies, such as continuous manufacturing processes, as well as artificial intelligence and machine learning. The purpose of this effort is to mitigate risks of supply chain disruptions leading to product shortages, a concern that has grown more problematic under an increasingly globalized approach to medical product production.

Since the onset of the coronavirus pandemic (COVID-19) in Spring 2020, similar efforts to support uptake of advanced manufacturing technologies have been met with a greater sense of urgency across other parts of the federal government as well. Consistent with these efforts, actions to on-shore and increase domestic manufacturing capacity and modernize medical product manufacturing have been bolstered by pandemic-related legislation and executive orders alike.

Federal Initiatives Related to Medical Product Supply Chains During COVID-19

Even though acute awareness of the potential benefits of advanced manufacturing resurfaced during the pandemic, the origins of the FDA’s pursuit of modern quality systems through advanced manufacturing began in August 2002 with the launch of its “Pharmaceutical Current Good Manufacturing Practices (cGMPs) for the 21st Century” initiative. This initiative evaluated the Agency’s pharmaceutical regulatory programs and released a final report in September 2004, introducing a new risk-based quality assessment system that would replace the chemistry, manufacturing, and controls (CMC) review process, encouraging implementation of process analytical technologies, and framing innovative technologies as essential components of a modern quality system. Later that same year, the FDA issued final guidance for industry, “Process Analytical Technology (PAT) and a Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance,” establishing a regulatory framework intended to support more innovation and quality modernization in pharmaceutical production.

Part of the Agency’s intention in its initial push for adopting advanced manufacturing technologies stemmed from concerns about quality management deficits associated with conventional batch manufacturing processes. The decades-old batch manufacturing model consists of frequent testing, storage, and shipping across regions, making it time-sensitive and more prone to product contamination. In addition, the batch manufacturing model was linked to reactive and wasteful discarding of final drug products due to quality issues. Instead, the FDA envisioned transitioning to a risk-based, quality management framework involving a more controlled and efficient pharmaceutical production regime.

Benefits of a Continuous Manufacturing System Versus
a Batch Manufacturing System

Pursuant to this vision, the FDA supported implementation of advanced manufacturing technologies, such as continuous manufacturing, by establishing platforms for engagement between the Agency and companies interested in producing products using innovative technologies. These platforms involve CDER’s Emerging Technology Program (ETP), CBER’s Advanced Technology Teams (CATT), and CDRH’s Case for Quality initiative. Additional final guidance on “Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization” continued to support companies seeking to adopt advanced manufacturing technologies. Under this regime, nine drug products manufactured with advanced technologies, one of which uses biomanufacturing processes, have been approved by the FDA – three of these products were approved in 2020 according to CDER’s Office of Pharmaceutical Quality (OPQ) Annual Report.

The National Academies of Sciences, Engineering, and Medicine (NASEM) held a workshop in June 2020 on barriers that hinder pharmaceutical manufacturing innovation, finding that external, regulatory challenges “loom large.” At this workshop, CDER-OPQ Director Mike Kopcha, Ph.D., distilled what he saw as regulatory barriers to the adoption of advanced manufacturing, including the need to fit new technologies into existing regulatory frameworks and the need for global regulatory harmonization. That is, because the current regulatory framework is “based in offline testing of batch processes, regulatory requirements do not currently translate well into new manufacturing technologies that allow for varied batch sizes, inline analytics, and higher-fidelity methods for detecting batch-to-batch variation.”

While the FDA has done much in the way of encouraging industry implementation of innovative and emerging technologies, barriers to achieving more substantial implementation persist. Earlier this year, NASEM released a report highlighting gaps where future guidance and clarity would be helpful in mounting identified regulatory barriers. These include:

  • Consideration of more fluid and targeted guidance that is shorter and published promptly to allow for industry comment.
  • Greater focus on underlying technology, as opposed to individual product approvals.
  • Creation of new mechanisms and pilot programs for incorporation of industry input and collaboration.
  • Expanded scope of the ETP to create greater opportunities for interested companies to engage.

With that said, the FDA is working to finalize its February 2019 draft guidance on “Quality Considerations for Continuous Manufacturing,” in which it has the opportunity to respond to gaps identified by NASEM, as well as others. With Acting Commissioner Janet Woodcock, M.D., at the helm, the FDA’s commitment towards advanced manufacturing technologies is likely to remain a top priority – Dr. Woodcock has long championed the increased adoption of advanced manufacturing technologies throughout her FDA career. Even if a permanent nominee other than Dr. Woodcock were to take her place as FDA Commissioner, advanced manufacturing is still seen as a key element to modern, risk-based quality systems and part of secure and efficient supply chains. Therefore, the FDA’s support of the adoption of advanced manufacturing will continue. Additionally, as previously noted, efforts to strengthen medical product supply chains by focusing on advanced technologies and re-focusing on U.S.-based manufacturing has enjoyed recent bipartisan support, in large part due to lessons learned from the pandemic. Thus, although industry adoption has been slow, advanced manufacturing technologies are expanding in scope and will likely become more of a norm in a post-COVID-19 world.

Resources

  • FDA & NIST MOU, “Accelerating the Adoption of Advanced Manufacturing Technologies to Strengthen Our Public Health Infrastructure” (January 2021)
  • Trump Executive Order, “Buy American for ‘Essential Drugs’ and Medical Supplies” (August 2020)
  • Biden Presidential Campaign, “Rebuild U.S. Supply Chains and Ensure the U.S. Does Not Face Future Shortages of Critical Equipment” (June 2020)
  • Biden Executive Order, “Sustainable Public Health Supply Chain” (January 2021)
  • Biden Executive Order, “America’s Supply Chains,” (February 2021)
  • FDA Initiative, “3D Printing in FDA’s Rapid Response to COVID-19” (November 2020)
  • FDA PREPP Initiative, “FDA’s COVID-19 Pandemic Recovery and Preparedness Plan (PREPP) Initiative: Summary Report” (January 2021)
  • FDA In Brief, “FDA Provides Update on COVID-19 Pandemic Recovery and Preparedness Plan Initiative” (April 2021)
  • FDA Initiative – Final Report, “Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach” (September 2004)
  • FDA Final Guidance, “PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance” (October 2004)
  • FDA Final Guidance, “Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization” (September 2017)
  • FDA Draft Guidance, “Quality Considerations for Continuous Manufacturing” (February 2019)
  • NASEM Workshop – Proceedings in Brief, “Barriers to Innovations in Pharmaceutical Manufacturing” (September 2020)
  • NASEM Report, “Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations” (2021)

COVID-19 Pandemic Accelerates Digitalization of Clinical Trials

Greenleaf Regulatory Landscape Series

Recently the Food and Drug Administration (FDA or the Agency), led primarily by the Center for Devices and Radiological Health (CDRH), has been supporting multiple initiatives to promote the development of digital health technologies and to encourage the use of digital health tools (DHTs) in medical product development. In 2017, for example, the FDA published the Digital Health Innovation Action Plan, in which the FDA committed to hiring digital health experts and provided a timeline for issuing new digital health-focused guidances. This was followed by the launch of the Digital Health Center of Excellence (DHCOE) in August 2020. Sitting within CDRH, the DHCOE is intended to serve as a “one-stop shop” for all digital health-related inquires and will coordinate digital health activities both across the Agency and with other regulators internationally.

Source: FDA Digital Health Center of Excellence Listening Session #1, 19 Oct 2020,
https://www.fda.gov/media/143078/download.

In the face of the COVID-19 pandemic, as the clinical trial enterprise seeks to maintain continuity while ensuring the safety of trial participants, the FDA’s digital health initiatives seem particularly well-timed. Indeed, during the past few months the use of DHTs have been critical in ensuring the continuity of disrupted trials by supporting remote data collection. During the pandemic, DHTs have been used to facilitate enrollment screening, conduct real-time safety monitoring, evaluate dose effects, and conduct endpoint assessments. In a recent survey of 245 clinical trial investigators, participants reported that 57% of patient interactions during ongoing trials were now conducted remotely.1 The same survey found that 77% of investigators expected the use of DHTs for remote patient monitoring to increase, while 54% expected an increase in use of DHTs to conduct electronic clinical outcomes assessments (eCOAs) and electronic patient reported outcome assessments (ePROs).2 This represents a marked increase over past DHT usage in medical product development, with DHTs only being used in 13% of registrational trials for the time period 2000 to 2018, according to recent research.3

A Regulatory Framework for DHTs

Acknowledging this trend, the FDA has requested funding in the PDUFA VII negotiations to support the development of a DHT framework to strengthen review capabilities of DHT- generated data in submissions, build staff capacity in digital health, and develop IT capacities to store and use DHT data.4 The FDA also shared in the summary report on the COVID-19 Pandemic Recovery and Preparedness Plan (PREPP) Initiative5 that that Agency is currently developing a guidance, which will be released this year, on the use of DHTs to capture study- related data directly from patients.

In the short term, the FDA has addressed the use of DHTs in the guidance “Conduct of Clinical Trials During the COVID-19 Public Health Emergency,”6 providing sponsors with recommendations on how to shift from in-person to remote assessments during the pandemic. In the guidance, the FDA provides sponsors with the flexibility to change the method of administration of clinical outcome assessments (COAs), specifically identifying performance outcomes (PerfO) assessments, interview-based clinician-reported outcome (ClinRO) assessments, PRO assessments, and observer-reported outcome (ObsRO) assessments as COAs that can be conducted remotely. In considering this change in administration, the FDA states that the change must be documented, and any additional variables related to the change should be included in the clinical trial data. The Agency also emphasizes the importance of prioritizing trial participant safety and privacy, maintaining data quality and integrity, and ensuring that both trial personnel and participants are appropriately trained on using any new technologies that are introduced.

DHTs in Clinical Trials

The emerging regulatory framework for DHTs in clinical trials is being built upon a regulatory paradigm that is already, in many respects, supportive of the remote collection of data in trials. As early as September 2013, the Agency addressed the use of DHTs to capture trial data in the guidance “Electronic Source Data in Clinical Investigations.”7 In the guidance, the FDA encourages electronic data capture, noting that it eliminates unnecessary duplication of data, reduces the possibility for transcription errors, and promotes real-time access for data review.

Although the FDA has not issued guidance specifically addressing the use of DHTs in clinical trials since 2013, the Agency has signaled an openness to the use of DHTs so long as they are fit for purpose, private and secure, and compliant with 21 CFR part 11.8 In public meetings and through work with the Clinical Trials Transformation Initiative (CTTI), the FDA has discussed how sponsors could best use digital technology to evaluate clinical benefit in trial participants. For example, prior to selecting a DHT, the FDA states that the concept being measured must be clinically meaningful, measuring what patients would like to see improved through treatment.9 Similarly, in selecting a technology, the sponsor should assess the reliability of the DHT through verification in the laboratory and validation in the field. On a practical level, sponsors also need to consider the technical aptitude and willingness to use a DHT among the population they are studying.10 As DHTs generate large volumes of data, sponsors should pre-specify how the data will be analyzed according to the data characteristics (e.g., intensity, frequency, event, etc.).11 Lastly, as previously noted, DHTs and DHT-generated data must be secure and participants’ privacy must be protected.

1. Xue, et al., “Clinical trial recovery from COVID-19 disruption,” Nature Reviews Drug Discovery, 10 Sept 2020, https://www.nature.com/articles/d41573-020-00150-9.

2. Ibid.

3. Mara, et al., “Quantifying the Use of Connected Digital Products in Clinical Research,” npj Digital Medicine 3, 50 (2020), https://www.nature.com/articles/s41746-020-0259-x.

4. U.S. Food and Drug Administration, “Prescription Drug User Fee Act (PDUFA) Reauthorization: FDA and Industry Digital Health and Informatics,” 30 Sept. 2020, https://www.fda.gov/media/143237/download.

5. FDA, “FDA COVID-19 Pandemic Recovery and Preparedness Plan (PREPP) Initiative: Summary Report,” January 2021, https://www.fda.gov/media/145129/download.

6. FDA, Guidance for Industry, “Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency,” March 2020, https://www.fda.gov/media/136238/download.

7. FDA, Guidance for Industry, “Electronic Source Data in Clinical Investigations,” September 2013, https://www.fda.gov/media/85183/download.

8. 21 CFR part 11 establishes the criteria under which electronic records and electronic signatures are considered by the FDA to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures.

9. FDA, Draft Guidance for Industry, “Patient-Focused Drug Development: Methods to Identify What is Important to Patient,” October 2019, https://www.fda.gov/media/131230/download.

10. John Concato, Comments at FDA/CMS Summit, December 7, 2020.

11. Dashielle-Aje, Ebony, et al., ” Digital Health Technology Tools: Use in Clinical Investigations to Evaluate Clinical Benefit in Patients,” DIA Global Forum, June 2019, https://globalforum.diaglobal.org/ issue/june-2019/regulatory-perspective-digital-health-technology-tools/.

FDA Inspectional Activities During COVID-19

Greenleaf Regulatory Landscape Series

On March 10, 2020, following the global emergence of the novel coronavirus (SARS-CoV- 2) and spread of COVID-19 disease, the Commissioner of the Food and Drug Administration (FDA or the Agency) suspended most foreign inspections of facilities that manufacture FDA- regulated products. The following week, domestic surveillance inspections, if not deemed “mission-critical,” were postponed as well. These policies were extended in subsequent months, with prioritized, pre-announced domestic inspections only resuming in July 2020. As the pandemic progressed, these travel restrictions and on-site limitations led to a growing backlog of regulatory inspections. Regulators responded by undertaking various alternative approaches to inspectional work to ensure the continued supply of quality medicines to patients, and to mitigate the creation of drug shortages.

Timeline of On-Site Inspection Policies at FDA During COVID-19

Under Section 704(a)(4) of the Food, Drug, and Cosmetic Act (FDCA), FDA can “in advance of or in lieu of an inspection” request records or information to determine whether inspection of a drug manufacturing facility is needed. Note: Section 704(a)(4) does not apply to other FDA inspection types (e.g., the Bioresearch Monitoring Program (BIMO), good clinical practice (GCP) inspections, medical device manufacturing facility inspections, etc.). Leveraging this authority, FDA began utilizing 704(a)(4) records requests to enable abbreviated on-site inspections so that the risk of exposure to COVID-19 was otherwise reduced. By August 2020, Elizabeth Miller, Assistant Commissioner for Medical Products and Tobacco Operations at FDA, said that 424 records requests to drug manufacturers had been made during the pandemic – 111 in the pre-approval space and 313 in the post-approval, good manufacturing practice (GMP) space. Miller added that another 123 records requests to biologics manufacturers had been made during the same time frame. Additionally, FDA made use of flexibilities established under the Mutual Recognition Agreement (MRA) for products evaluated by the European Union (EU), as well as information from inspections occurring outside the EU provided by the Pharmaceutical Inspection Co-Operation Scheme (PIC/S).

On August 19, 2020, FDA published final guidance, “Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers,” which closely followed previously posted guidance from April 2020 and continued “mission-critical” inspections, which had been on-going throughout the pandemic, as well as prioritized, domestic inspections based on a case-by-case risk analysis. Although the new guidance did not indicate whether FDA would begin to lean into virtual technologies as a supplement to 704(a)(4) records requests and/or on-site inspection requirements, foreign regulators demonstrated interest in implementing virtual approaches to their inspectional activities early on in the pandemic. For example, health authorities in the UK, EU, and Singapore piloted various virtual practices and tools as supplements to standard GMP inspections.

Foreign Health Authorities’ Adoption of Virtual Inspectional Activities

In November 2020, speculation grew as to whether FDA would begin conducting some form of virtual GMP assessments or inspections, similar to its foreign counterparts. Brian Hasselbalch, the Deputy Director of the Office of Policy for Pharmaceutical Quality at the Center for Drug Evaluation and Research (CDER), confirmed that guidance “on remote evaluations using interactive video or other types of interactive tools and techniques” is under development. Hasselbalch said that such a document will describe the role these types of interactions are to play in the Agency’s decision making with respect to pending applications, surveillance activities, and possibly even for-cause inspections. He added that manufacturers with pending applications involving facilities, or plans to submit such applications, should begin to equip themselves with necessary streaming technologies.

Despite indications that FDA is planning to utilize virtual technologies in some form, it is unclear what this will mean for inspection requirements under the FDCA. When implementing a virtual approach to inspectional work, the Agency has to work within its Section 704 authority and ensure this authority reaches across various product areas (e.g., drugs, biologics, and medical devices). Importantly, there is a distinction between a virtual assessment, where the Agency would rely on virtual tools to facilitate a 704(a)(4) records request (e.g., by following up on a records request with live streaming of the facility, etc.), and otherwise allowing an actual virtual inspection, where an inspector would present an FDA Form 482 and could issue an FDA Form 483. The approach taken by FDA will depend on whether it interprets a virtual inspection to count as a statutorily required inspection under Section 704 of the FDCA, although the Agency’s stance on this has not been made clear. Irrespective of FDA’s allowance of virtual inspection, or mere virtual assessments as part of 704(a)(4) records request, it seems inevitable that further incorporation of various virtual tools and technologies is approaching, especially as COVID-19 continues to impact regulatory operations and oversight around the world.

Related Sources

In Vitro Diagnostic EUAs for COVID-19

Greenleaf Regulatory Landscape Series

On February 4th 2020, the Secretary of Health and Human Services (HHS) declared that the threat to public health caused by the coronavirus justified the authorization of emergency use of in vitro diagnostics for the detection and/or diagnosis of COVID-19. This declaration, pursuant to section 564 of the Food Drug & Cosmetic Act (FD&C Act), allowed the Commissioner of the Food and Drug Administration (FDA or Agency) to issue Emergency Use Authorizations (EUAs) for developers of in vitro diagnostic tests aimed to detect and/or diagnosis COVID-19.


Following the declaration, the FDA began to receive a sudden flurry of EUA requests from diagnostic test developers before truly having an opportunity to develop its own guidance and recommendations for laboratories, manufacturers, and FDA staff. The FDA quickly developed guidance that outlined what specific tests required EUA authorization prior to marketing, what tests could use the notification pathway, and what validation and clinical testing was required for an EUA. The Agency focused on the authorization of molecular, antigen and antibody (serology) tests and informed healthcare providers and the public as to the type of information that each test could provide. As more became known about COVID-19 and as tests were in shortage across the United States, the FDA continued to evolve its regulatory framework and recommendations for in vitro diagnostic EUAs including publishing a revised guidance on its “Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency.” Over the course of several months, the FDA published templates for both commercial manufacturers and laboratories for each of the three types of diagnostic tests and updated them with recommendations for the validation of pooled samples and the testing of asymptomatic individuals. The Agency also published templates for tests that use home specimen collection and for non-laboratory use tests.


Throughout the pandemic, the FDA has had to explore options to quickly allow diagnostic tests to reach patients while still ensuring that these tests are safe and effective. To enhance transparency around the FDA’s decision-making and to provide a forum for public questions, the FDA’s Center for Devices and Radiological Health (CDRH) began holding weekly virtual Town Halls for developers of diagnostic tests. These Town Hall meetings have been led by Dr. Timothy Stenzel and Toby Lowe from CDRH’s Office of In Vitro Diagnostics and Radiological Health. Each week, CDRH staff provides developers with an update on any major changes in the FDA’s policies related to diagnostic tests and provide insight on what changes may be coming in the near future. Dr. Stenzel has also expressed the Agency’s willingness to work with developers of novel technologies and to remain flexible in its regulatory approaches. CDRH has already held 30 Town Hall meetings for diagnostic test developers and has committed to holding these events throughout October 2020.

During the Town Hall meetings, Dr. Stenzel shared that the FDA has received more than 2,000 EUA requests from developers and explained the triage process that CDRH has developed in order to respond to these requests with the resources that the Agency has available. Recently, Dr. Stenzel noted that after issuing more than 200 EUAs for diagnostic tests, the FDA is now prioritizing EUA requests for specific types of tests including point-of-care tests, at-home tests, and tests with high-throughput capacity with ability to scale. He explained that the FDA is still taking EUA requests for tests that do not have these specific features but that they will receive lower priority in terms of review. Another major development that was recently announced during a CDRH Town Hall meeting is that CDRH will no longer be reviewing EUAs for Laboratory Developed Tests (LDTs). This comes after the Department of Health and Humans Services (HHS) published a notice in August stating that the FDA would no longer require premarket review of LDTs for COVID-19. Although HHS’s announcement stated that companies could still voluntarily submit EUA requests for LDTs, the Agency has since stated that it will no longer review them. Dr. Stenzel explained that this change was made to help focus the FDA’s resources on the EUAs that have been identified as priority. During last week’s Town Hall meeting, Dr. Stenzel noted that CDRH will soon be updating their FAQ pages to provide further clarity on how this policy will impact current LDT submissions and EUAs that are already authorized.

As of October 23, 2020, there are 283 EUAs that are authorized for COVID-19 diagnostic tests
including 221 molecular, 56 antibody and 6 antigen tests. FDA’s website also provides a complete list of all current EUA authorizations for the following EUA categories:

  • Individual EUAs for Molecular Diagnostic Tests for SARS-CoV-2
  • Umbrella EUA for Molecular Diagnostic Tests for SARS-CoV-2 Developed And Performed By Laboratories Certified Under CLIA To Perform High Complexity Tests
  • Individual EUAs for Antigen Diagnostic Tests for SARS-CoV-2
  • Individual EUAs for Serology Tests for SARS-CoV-2
  • Umbrella EUA for Independently Validated Serology Tests for SARS-CoV-2
  • Individual EUAs for IVDs for Management of COVID-19 Patients

Overall, the FDA has made significant progress in authorizing EUAs for COVID-19 diagnostic tests and has helped to facilitate access to these tests for patients across the United States. FDA’s regulatory policies will continue to be updated as the pandemic changes and as developers begin to transition their EUA authorizations to full premarket clearance or approval.

Related Sources

8 records

Services
Drug & Biological Products
Devices & Combo Products
Quality & Compliance
Cell & Gene Therapy
Advisory Services
Regulatory Policy
Digital Health
Cosmetics
Litigation Support

Greenleaf is a regulatory consulting firm and does not provide legal advice or legal services.

Our Team
Knowledge Center
Resources
About Us

Contact Us

1055 Thomas Jefferson Street, NW, Suite 450
Washington, D.C. 20007
202.609.8996 x5
Email Greenleaf

Let’s Connect

LinkedIn