Guidance - Greenleaf Health

Implementing MoCRA: FDA Releases New Draft Guidances on Insanitary Conditions for Tattoo Ink and Cosmetic Product Registration and Listing

This article was originally published in the Food and Drug Law Institute’s Update magazine, Winter 2023, and is shared with permission.

Since enactment of the Federal Food, Drug, and Cosmetic Act (FDCA) in 1938, the evolution and technological innovation of cosmetic products in the U.S. market have presented the Food and Drug Administration (FDA) with unique regulatory challenges. These challenges, along with commercial globalization and limited resources and enforcement authorities, created a need for a broader and more modern cosmetics regulatory framework.

To meet this need, in December 2022, Congress enacted and President Biden signed into law the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) as part of the Consolidated Appropriations Act, 2023.^[1]This marked the first major update to FDA’s cosmetics oversight since 1938. MoCRA reforms reflected the challenges of regulating a modern cosmetics industry with increasingly diverse products, including a shift towards greater safety and quality for cosmetics, bringing cosmetics regulation more in line with FDA regulation of other types of regulated products. For example, MoCRA provides FDA with new authorities related to adverse event reporting, good manufacturing practices (GMPs), facility registration and product listing, labeling, recordkeeping, and mandatory recall authority. To implement these requirements, new FDA guidance and regulations for the cosmetics industry are forthcoming.

In that vein, FDA recently released two draft guidances to implement MoCRA, both of which are discussed in this Article.^[2]

I. Key Takeaways from FDA’s New Tattoo Ink Draft Guidance

In June 2023, FDA announced the availability of Draft Guidance for Industry: Insanitary Conditions in the Preparation, Packing, and Holding of Tattoo Inks and the Risk of Microbial Contamination (“Tattoo Ink Draft Guidance”).^[3] When finalized, the guidance will represent FDA’s current thinking on “insanitary conditions of tattoo ink preparation, packaging, or holding that may render the inks injurious to health because of microbial contamination.”^[4]

FDA regulates tattoo inks as cosmetics under the FDCA. The FDCA defines “cosmetic” by reference to a product’s intended use(s). The term “cosmetic” means “articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance . . . .”^[5] Tattoo inks are cosmetics because they are articles intended to be introduced into or otherwise applied to the human body for beautifying, promoting attractiveness, or altering the appearance.^[6]

The FDCA prohibits the introduction of an adulterated cosmetic into interstate commerce.^[7]Under the FDCA, a cosmetic is deemed to be adulterated if it “has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health.”^[8]FDA issued the Tattoo Ink Draft Guidance to assist tattoo ink manufacturers and distributors in identifying situations in which a tattoo ink may become contaminated and potentially injurious to health, thus resulting in the adulteration of the tattoo ink.

While the draft guidance is intended for tattoo ink manufacturers and distributors, the cosmetic industry at large can benefit from reviewing the draft guidance. Key takeaways in the draft guidance for the larger cosmetic industry are discussed in more detail below.

FDA Is Preparing to Implement New Regulatory Requirements Applicable to Cosmetics Established by MoCRA

Issuing the Tattoo Ink Draft Guidance is among the first actions that FDA has taken to implement its new regulatory authorities under MoCRA. Indeed, FDA stated in the Tattoo Ink Draft Guidance that it “intend[s] to conduct rulemaking to establish good manufacturing practice regulations as part of the implementation of [MoCRA], which requires FDA to establish good manufacturing practice regulations that, to the extent practicable and appropriate, are consistent with national and international standards.”^[9] FDA also held a public meeting in June 2023 to receive input from stakeholders on topics related to cosmetic GMPs.^[10]In addition, FDA recently issued Draft Guidance for Industry: Registration and Listing of Cosmetic Product Facilities and Products (“Cosmetic Registration & Listing Draft Guidance”), which “provides recommendations and instructions to assist persons submitting cosmetic product facility registrations and product listings to FDA.”^[11]

As FDA’s recent guidance documents and its commitment to conduct rulemaking indicate, the agency has begun transitioning the cosmetic industry from a period of voluntary compliance, with regulatory controls designed to ensure the safety and quality of cosmetic products, to an era of mandatory compliance under the framework established by MoCRA.

FDA Is Still Attempting to Clearly Distinguish Between the Definitions of “Cosmetic,” “Drug,” and “Device”

Historically, FDA has struggled to draw a clear line between cosmetic and drug/device claims. This effort remains evident in the Tattoo Ink Draft Guidance.

The FDCA defines “cosmetic,” “drug,” and “device” by reference to the product’s intended use(s).^[12]

As previously stated, “[t]he term ‘cosmetic’ means (1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance . . . .”^[13]
“The term ‘drug’ means . . . articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man . . . ; and . . . articles (other than food) intended to affect the structure or any function of the body of man . . . .”^[14]
“The term ‘device’ . . . means an instrument, . . . implement, . . . or other similar or related article . . . intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man . . . , or . . . intended to affect the structure or any function of the body of man . . . .”^[15]

Because the regulatory requirements for cosmetics vary considerably from those for drugs and devices, accurately distinguishing between claims that reflect the intended use of a “cosmetic” versus a “drug” or “device” is critical.^[16] For example, cosmetics and cosmetic ingredients—with the exception of color additives—do not require FDA review or approval prior to marketing. In contrast, cosmetics marketed with drug or device claims are considered to be drugs or devices and may require approval or clearance prior to commercialization. However, the line between a “beautifying” (cosmetic) claim and a “therapeutic” or “structure/function” (drug or device) claim can often be ambiguous, given that many beautifying products affect the body to some extent.

To clarify this distinction, FDA has previously suggested that “products that are represented to have only ‘physical’ effects on the skin are cosmetics, while those for which a ‘physiological’ effect is asserted are drugs.”^[17] FDA has interpreted “physical” effects as “mechanical” changes that “cover” the skin (e.g., makeup) or affect “the outermost layers of the skin” (e.g., by softening or moisturizing).^[18] FDA has interpreted “physiological” effects as those which cause biochemical or deep-tissue changes, or which “influence the functioning of cells.”^[19]

In the Tattoo Ink Draft Guidance, however, FDA did not follow this approach. The Tattoo Ink Draft Guidance treats tattoo inks as a cosmetic, despite FDA historically treating such products as drugs and devices due to their deep insertion in the skin below the epidermis (affecting more than the outermost layers). Moreover, the Tattoo Ink Draft Guidance also contradicted FDA’s relatively recent application of this approach as set forth in Guidance for Industry and FDA Staff: Regulatory Considerations for Microneedling Products (“Microneedling Guidance”).^[20]Table 1 below compares the differing approaches in the Tattoo Ink Draft Guidance and Microneedling Guidance.

Table 1.

Tattoo Ink Draft Guidance

Microneedling Guidance

· “Tattoo inks bypass the body’s primary physical barrier against pathogens, because they are inserted below the epidermis.”^[21]
· “Tattooing involves puncturing the epidermis about 100 times per second with needles and depositing ink 1.5 to 2 millimeters below the surface of the skin, deep into the dermis . . . .”^[22]

“FDA considers claims or statements that indicate penetration or some effect beyond the stratum corneum into living layers of skin by such products to be evidence of a firm’s intent to affect the structure or function of the body. The stratum corneum is a dead layer of skin that is naturally shed through the desquamation process. Therefore, claims or statements regarding the removal of the stratum corneum are not considered an intent to affect the structure or function of the body. In contrast, explicitly or implicitly claiming or stating that a microneedling product penetrates living layers of skin (e.g., epidermis and dermis) would be considered an intent to affect the structure or function of the body.”^[23]

Thus, the approach in the Tattoo Ink Draft Guidance is inconsistent with FDA’s approach in the Microneedling Guidance because the tattoo inks are injected well below the stratum corneum. According to the Microneedling Guidance, penetration beyond the stratum corneum would cause a product to be a drug or device.

II. Key Takeaways from Registration & Listing Draft Guidance

As discussed above, under MoCRA, certain owners and operators of facilities engaged in the manufacturing or processing of a cosmetic product for distribution in the United States must now register their facilities (FDCA § 607(a)) and list their products (FDCA § 607(c)) (“Section 607 Requirements”). To help facilitate implementation of these requirements, FDA recently issued Draft Guidance for Industry: Registration and Listing of Cosmetic Product Facilities and Products (“Cosmetic Registration & Listing Draft Guidance”).^[24]

The Cosmetic Registration & Listing Draft Guidance outlines elements of the Section 607 Requirements, including descriptions of who must register and list their products, what information must be submitted as part of registration and listing, and when registration and listing submissions must be made. The Cosmetic Registration & Listing Draft Guidance also provides information about how submissions can be made, whether combination drug/cosmetic products are subject to Section 607 Requirements, and the extent to which registration and listing information may be publicly disclosed. The comment period for initial feedback on the Registration & Listing Draft Guidance closed on September 7, 2023, but cosmetics industry stakeholders should remain engaged and look for future opportunities to provide input.^[25]

Registration & Listing Elements Look Familiar; They Are Not Dissimilar from the Now-Discontinued Voluntary Cosmetic Registration Program (VCRP)

As part of its development of the new registration and listing system, FDA ended the former Voluntary Cosmetics Registration Program (VCRP) earlier this year.^[26] The Cosmetic Registration & Listing Draft Guidance notes that information in the VCRP will not be transferred into the new system, and previous submissions will not satisfy the new Section 607 Requirements.^[27]

The VCRP was a voluntary program implemented via regulations found at 21 C.F.R. Parts 710 and 720. The new Cosmetic Registration & Listing Draft Guidance provides more detail than parts 710 and 720, but those who are familiar with the VCRP will notice similarities to the new, mandatory program and should not have trouble meeting the required registration and listing requirements.

Who Must Register and List

The Registration & Listing Draft Guidance adopts statutory definitions of terms relevant to Section 607 Requirements^[28](i.e., “cosmetic product,”^[29] definitions for “facility,”^[30]“responsible person,”^[31]and “small businesses”^[32]), but also sets forth new definitions^[33] for several terms/phrases not defined by the statute (i.e., “contract manufacturer,” “manufacturing or processing of a cosmetic product,” and “DUNS number”).

Generally, every person that owns or operates a facility engaged in the manufacturing or processing of a cosmetic product must register with FDA, pursuant to Section 607(a)(1). The Cosmetic Registration & Listing Draft Guidance defines cosmetic manufacturing or processing as “engaging in one or more steps in the making of any cosmetic product by chemical, physical, biological, or other procedures, including manipulation, sampling, testing, or control procedures applied to the product.”^[34]An entity that “solely performs” (re)labeling, (re)packaging, holding, and/or distributing of cosmetics,^[35] is excluded from the statutory definition of facility, and from the registration requirements restated in the draft guidance. “Packaging” and “repackaging” do not, however, include filling a product container, and thus, product filling would necessitate facility registration.^[36] Additionally, beauty shops, salons, and retailers are excluded from the statutory definition of facility, and do not need to register with FDA unless they also manufacture or process a cosmetic product.^[37]

With respect to a contract manufacturer’s obligation to register their facility, the Cosmetic Registration & Listing Draft Guidance notes (consistent with the statute) that only a single registration is required per facility, even for those that manufacture cosmetic products for more than one responsible person and/or those that manufacture cosmetic products of their own.^[38] Alternatively, a responsible person whose products are manufactured or processed at a contract manufacturing facility may also submit the facility registration on behalf of that facility, alleviating the contract manufacturer’s need to register their own facility. In other words, either the contract manufacturer or the responsible person (i.e., the entity whose name appears on the product label) must register a single manufacturing facility, but not both.^[39]

For product listing, the responsible person must submit the required information, pursuant to Section 607(c)(1). As defined in Section 604(4), the responsible person is the manufacturer, packer, or distributor whose name is on the label of the product.^[40]Additionally, certain small businesses, as defined in Section 612(b), are not required to register facilities and list cosmetic products.^[41]However, four exceptions to this exemption may apply, depending on the nature of the cosmetic product.^[42]

What Information Must Be Submitted

The first step in a facility’s registration submission process involves obtaining a facility registration number (i.e., the FDA Establishment Identifier (FEI)).^[43]Facility owners or operators can request a new FEI number, or determine whether a facility has an existing FEI number through the “FEI Search Portal”^[44]available on FDA’s website. Once they obtain an FEI number, facility owners must provide FDA with the following data as part of a registration submission, pursuant to Section 607(b)(2) and as outlined in the Cosmetic Registration & Listing Draft Guidance:^[45]

Name of the owner and/or operator of the facility;
Facility’s name, physical address, email, telephone number (for foreign facilities, the contact information for the U.S. agent);
FEI number;
All brand names of cosmetic products manufactured or processed at the facility;
Applicable cosmetic category;^[46] and
Type of submission being made (i.e., initial registration, content update (annual), or abbreviated renewal).

The Cosmetic Registration & Listing Draft Guidance also restates language from the statute as to the data that must be included in a product listing submission, including:^[47]

All relevant FEI numbers (i.e., facilities where the responsible person’s cosmetic products are manufactured or processed);
Name and contact information of the responsible person;
Name of the cosmetic product as it appears on the label;
Applicable cosmetic category;
List of ingredients in the cosmetic product (including fragrances, flavors, or colors);
Product listing number (if any) assigned by FDA; and
Type of submission being made (i.e., initial, content update, or abbreviated renewal).

Although Section 607 requires that the “applicable cosmetic category” be included in both registration and listing submissions, the statute does not describe more precisely what those categories are. In the Cosmetic Registration & Listing Draft Guidance, FDA has developed an initial list of various cosmetic product categories, included in Appendix A.^[48] The appendix includes many recognizable categories of cosmetic products, such as lotions, sprays, oils, and serums, but also contains other less standard products, such as “nail extenders.”^[49]

Significantly, the system for categorizing types of cosmetic products laid out in Appendix A is similar to the system that FDA’s Center for Devices and Radiological Health (CDRH) now uses for organizing various device types—medical device classification product codes.^[50]FDA likely will use these cosmetic categories for some of the same purposes for which it uses device product codes. CDRH has explained that it uses product codes “to obtain quality and reliable data, and perform analyses that are often reported to Congress, the Government Accountability Office (GAO), the general public, the media, and industry.”^[51] Device product codes also have several other important uses, including tracking medical device adverse event reports, imports and exports, and recalls.^[52] Therefore, aside from purposes related to registration and listing, FDA could use cosmetic product categories for many of the same reasons, including tracking adverse event reporting, imports/exports, and recalls. Given the many possible uses for these cosmetic product categories, industry feedback on them will be essential to ensuring that the organizational system for cosmetics is appropriate and effective. FDA seems to recognize the importance of this feedback and specifically requested comments on these product categories.^[53]

Through the Cosmetic Registration & Listing Draft Guidance, FDA also requests various optional data be submitted as part of registration and listing submissions, beyond what is required under Section 607 Requirements.^[54]These items include the parent company name, the facility Data Universal Numbering System (DUNS) Number, Unique Ingredient Identifiers (UNIIs), and any additional contact information relevant to the specific submission, among others.^[55]

When Must Registration and Listing Submissions Occur

The statutory deadline for fulfilling Section 607 Requirements is December 29, 2023; this applies to owners and operators of facilities engaged in the manufacturing or processing of cosmetic products prior to December 29, 2022,^[56]and to responsible persons engaged in the marketing of cosmetic products prior to December 29, 2022.^[57] However, in November 2023, FDA announced in Guidance for Industry: Compliance Policy for Cosmetic Product Facility Registration and Cosmetic Product Listing (“Cosmetic Registration & Listing Compliance Policy”) that it would delay enforcement of Section 607 Requirements for six months, or until July 1, 2024.^[58]This delayed enforcement also applies to owners and operators of facilities engaged in manufacturing or processing of cosmetic products after December 29, 2022, as well as for responsible persons engaged in the marketing of cosmetic products after December 29, 2022; they too now have until July 1, 2024 to meet registration and listing requirements.^[59]

The Cosmetic Registration & Listing Draft Guidance also describes timing requirements, consistent with those in Section 607, for submitting amended facility registration information (i.e., within 60 days of a change), as well as updated listing information (i.e., annually).^[60]Distinct from the statute, the draft guidance recommends that submissions involving updated information include changes resulting in a registration cancellation or a discontinued product.^[61]For purposes of renewals, the draft guidance again adheres to the statutory language and calls for facilities to renew their registration with FDA on a biennial basis (i.e., every two years), even if registration information remains unchanged since their most recent past submission (FDA intends to provide an abbreviated renewal registration submission option for unchanged renewals).^[62]

The Draft Guidance Continues to Emphasize That the Cosmetic Registration & Listing Requirements Do Not Apply to Cosmetic Products That Are Also Drugs

The Cosmetic Registration & Listing Draft Guidance notes that Section 607 Requirements do not apply to cosmetic products that are also drugs, nor do they apply to the facilities that manufacture such products (unless the facility also manufactures or processes a product that is solely a cosmetic).^[63] This is partly consistent with Section 613 of the FDCA, which states that “a cosmetic product or facility that is also subject to the requirements of subchapter V shall be exempt from” Section 607 Requirements.^[64]

Interestingly, subchapter V in the statute sets forth regulatory requirements applicable to both drugs and devices, indicating that “a cosmetic product or facility that is also subject to the requirements” applicable to drugs or devices “shall be exempt from” Section 607. However, the Cosmetic Registration & Listing Draft Guidance only mentions drugs, stating that certain requirements do not apply to cosmetic products that are also drugs.^[65]That being said, this may be an area where clarity is needed as to FDA’s expectations with respect to registration and listing exemptions for cosmetics that are also devices.

In addition, the same electronic submission process used to register an establishment and list a drug will be available for cosmetic facility registration and product listing. The consistency between these processes is intended to streamline the submission of registration and listing information for cosmetics facilities and products for entities that also submit drug establishment and listing information.^[66]

FDA is developing an electronic portal for submitting cosmetic facility registration and product listing information, called Cosmetics Direct.^[67] Additionally, pursuant to the Structured Product Labeling (SPL) Implementation Guide with Validation Procedures, cosmetics facility registrations and product listings are now included within the SPL framework, and Cosmetics Direct will be an FDA-provided SPL authoring tool.^[68]The Cosmetic Registration & Listing Draft Guidance notes that a paper form (i.e., Forms FDA 5066 and 5067)^[69] will also be accepted as an alternative submission method; however, FDA is “strongly” encouraging electronic submissions for more efficient data management.^[70]Both submission tools (i.e., use of the electronic portal and the paper form) will be accessible on FDA’s webpage once developed.^[71]

Limited Disclosure of Cosmetic Registration & Listing Information

The Cosmetic Registration & Listing Draft Guidance notes that FDA will only publicly disclose cosmetic product facility registration and listing information to the extent permitted by law.^[72] Pursuant to Section 607(d), product listing numbers will not be made available for public disclosure.^[73] Additionally, pursuant to Section 607(e), brand names from facility registration submissions or facility registration numbers from product listing submissions will not be made available in response to requests made under the Freedom of Information Act, 5 U.S.C. § 552.^[74]

Conclusion

Both the Tattoo Ink Draft Guidance and the Cosmetic Registration & Listing Draft Guidance are important for members of the cosmetics industry. The draft guidances indicate that FDA is on its way to implementing MoCRA. Therefore, cosmetics industry stakeholders should take full advantage of the comment process for the draft guidances, as well as future public meetings and commenting opportunities, to ensure their valuable input is considered during FDA’s implementation efforts.

In addition, although the modern regulatory framework for cosmetic products is in its infancy, the Cosmetic Registration & Listing Draft Guidance demonstrates how the new cosmetic regulatory framework draws from existing regulatory concepts and requirements (like facility registration and product listing) that exist for drugs and devices. Thus, in addition to paying attention to what already exists for cosmetics (e.g., the VCRP), the cosmetics industry could also benefit from close review of regulatory frameworks for drugs and devices for more clues as to how FDA may implement MoCRA.

Finally, the Tattoo Ink Draft Guidance shows how MoCRA has not fixed all problems with respect to regulation of cosmetic products. The jurisdictional ambiguity related to distinguishing a drug or device from a cosmetic has been a long-standing issue for FDA, and the Tattoo Ink Draft Guidance further demonstrates that clearly distinguishing between cosmetics and drugs/devices remains challenging.

[1] See Consolidated Appropriations Act, 2023, Pub. L. No. 117-328, §§ 3501–3508 (2022).

[2] This Article was finalized in November 2023 and does not include FDA policy updates or announcements that have occurred since then.

[3] Draft Guidance for Industry: Insanitary Conditions in the Preparation, Packing, and Holding of Tattoo Inks and the Risk of Microbial Contamination (June 2023), https://www.fda.gov/media/169265/download [hereinafter Tattoo Ink Draft Guidance]; 88 Fed. Reg. 38,516–18 (June 13, 2023).

[4] 88 Fed. Reg. at 38,516.

[5] FDCA § 201(i), 21 U.S.C. § 321(i) (emphasis added).

[6] See Tattoo Ink Draft Guidance, supra note 3, at 3.

[7] FDCA § 301(a), 21 U.S.C. § 331(a).

[8] FDCA § 601(c), 21 U.S.C. § 361(c).

[9] Tattoo Ink Draft Guidance, supra note 3, at 7.

[10] Public Meeting: Good Manufacturing Practices for Cosmetic Products, June 1, 2023, https://www.fda.gov/cosmetics/cosmetics-news-events/public-meeting-good-manufacturing-practices-cosmetic-products-06012023; see also Docket No. FDA-2023-N-1466.

[11] Draft Guidance for Industry: Registration and Listing of Cosmetic Product Facilities and Products at 3 (Aug. 2023), https://www.fda.gov/media/170732/download.

[12] “Intended use” may be inferred from a manufacturer’s promotional claims. Specifically, “FDA may consider, among other things, any written or oral claims or statements in any label, labeling, advertising, and/or promotion of a . . . product by or on behalf of a firm in determining whether a . . . product is intended to cure, mitigate, treat or prevent disease or affect the structure or function of the body.” Guidance for Industry and FDA Staff: Regulatory Considerations for Microneedling Products at 7 (Nov. 10, 2020), https://www.fda.gov/media/107708/download [hereinafter Microneedling Guidance].

[13] FDCA § 201(i), 21 U.S.C. § 321(i) (emphasis added).

[14] FDCA § 201(g)(1), 21 U.S.C. § 321(g)(1) (emphasis added).

[15] FDCA § 201(h)(1), 21 U.S.C. § 321(h)(1) (emphasis added).

[16] See also Compliance Program Guidance Manual § 7329.001, “Cosmetics Program; Import and Domestic,” https://www.fda.gov/media/78441/download.

[17] E.g., FDA, Cosmetic Labeling Guide (Oct. 1991) (“one may say that a cosmetic is a product intended to exert a physical, and not a physiological, effect on the human body”).

[18] Letter from Cosmetics Manufacturers to John M. Taylor, Associate Commissioner for Regulatory Affairs at 3–4 (Sept. 11, 1987) (describing FDA’s interpretation of the distinction).

[19] Id.

[20] Microneedling Guidance, supra note 12, at 7–8.

[21] Tattoo Ink Draft Guidance, supra note 3, at 5.

[22] Id. at 4.

[23] Microneedling Guidance, supra note 12, at 7.

[24] Draft Guidance for Industry: Registration and Listing of Cosmetic Product Facilities and Products (Aug. 2023), https://www.fda.gov/media/170732/download [hereinafter Cosmetic Registration & Listing Draft Guidance].

[25] 88 Fed. Reg. 53,490–92 (Aug. 8, 2023), https://www.federalregister.gov/documents/2023/08/08/2023-16771/registration-and-listing-of-cosmetic-product-facilities-and-products-draft-guidance-for-industry. Although the comment period has closed, an interested party can submit comments at any time. See 21 C.F.R. § 10.115(g)(5). To ensure that FDA considers comments on a draft guidance before it begins work on the final version, it is best practice to submit comments before the comment period closes.

[26] Constituent Update: FDA Has Stopped Accepting Submissions to the Voluntary Cosmetic Registration Program (Mar. 27, 2023), https://www.fda.gov/food/cfsan-constituent-updates/fda-has-stopped-accepting-submissions-voluntary-cosmetic-registration-program-vcrp.

[27] See Cosmetic Registration & Listing Draft Guidance, supra note 24, at 4.

[28] See id. at 4–6.

[29] FDCA § 604(2), 21 U.S.C. § 364(2); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 5.

[30] FDCA § 604(3), 21 U.S.C. § 364(3); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 5.

[31] FDCA § 604(4), 21 U.S.C. § 364(4); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 6.

[32] FDCA § 612(b), 21 U.S.C. § 364h(b); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 6.

[33] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 4–6.

[34] Id. at 6.

[35] FDCA § 604(3)(B)(viii), 21 U.S.C. § 364(3)(B)(viii); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 5.

[36] FDCA § 604(3)(C), 21 U.S.C. § 364(3)(C); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 6.

[37] FDCA § 604(3)(B), 21 U.S.C. § 364(3)(B); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 6.

[38] FDCA § 607(a)(3), 21 U.S.C. § 364c(a)(3); Cosmetic Registration & Product Listing Draft Guidance, supra note 24, at 7.

[39] Id.

[40] See also Cosmetic Registration & Listing Draft Guidance, supra note 24, at 6.

[41] Id.

[42] FDCA § 612(b), 21 U.S.C. § 364h(b); see also Cosmetic Registration & Listing Draft Guidance, supra note 24, at 6.

[43] See Cosmetic Registration & Listing Draft Guidance, supra note 24, at 8, fn 3.

[44] FEI Search Portal, https://www.accessdata.fda.gov/scripts/feiportal/index.cfm?action=portal.login.

[45] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 8.

[46] See id. at 12–15.

[47] FDCA § 607(c)(4)(A), 21 U.S.C. § 364c(c)(4)(A); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 8–9.

[48] Id.

[49] Id.

[50] See Guidance for Industry and FDA Staff: Medical Device Classification Codes (Apr. 11, 2013), https://www.fda.gov/media/82781/download [hereinafter Medical Device Classification Codes Guidance]; see also FDA Product Code Classification Database, https://www.fda.gov/medical-devices/classify-your-medical-device/product-code-classification-database.

[51] Medical Device Classification Codes Guidance, supra note 50.

[52] Id.

[53] See Cosmetic Registration & Listing Draft Guidance, supra note 24, at 12, fn 6.

[54] See id. at 8–9.

[55] The Data Universal Numbering System (DUNS) number is a unique, site-specific identification number assigned to a facility’s physical location. The UNIIs are generated based on scientific identity characteristics in accordance with ISO 11238 and can be searched through FDA’s UNIIs search service, Global Substance Registration System (GSRS). See FDA’s GSRS, https://precision.fda.gov/uniisearch.

[56] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 10; see also FDCA § 607(a)(1)(A), 21 U.S.C. § 364c(a)(1)(A).

[57] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 11; see also FDCA § 607(c)(2)(B), 21 U.S.C. § 364c(c)(2)(B).

[58] Guidance for Industry: Compliance Policy for Cosmetic Product Facility Registration and Cosmetic Product Listing (Nov. 2023), https://www.fda.gov/media/173606/download; 88 Fed. Reg. 77,323–24 (Nov. 9, 2023).

[59] Cosmetic Registration & Listing Compliance Policy, supra note 24, at 4.

[60] See Cosmetic Registration & Listing Draft Guidance, supra note 24, at 10–11; see also FDCA § 607(a)(4) & (c)(5), 21 U.S.C. § 364c(a)(4) & (c)(5).

[61] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 10–11.

[62] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 10; see also FDCA § 607(a)(2), 21 U.S.C. § 364c(a)(2).

[63] See Cosmetic Registration & Listing Draft Guidance, supra note 24, at 11; see also FDCA § 613, 21 U.S.C. § 364i.

[64] FDCA § 613, 21 U.S.C. § 364; see also 21 U.S.C. §§ 351–360fff-8.

[65] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 11.

[66] Id.

[67] In September 2023, FDA requested comments on its newly developed draft electronic submission portal (Cosmetics Direct) along with paper forms (Forms FDA 5066 and 5067). See 88 Fed. Reg. 63,960–63 (Sept. 18, 2023), https://www.federalregister.gov/documents/2023/09/18/2023-20139/agency-information-collection-activities-submission-for-office-of-management-and-budget-review; see also Draft Cosmetics Direct: Electronic Submissions Portal Screenshots for Commenting (Sept. 2023), https://www.fda.gov/media/171557/download?attachment.

[68] See Structured Product Labeling (SPL) Implementation Guide with Validation Procedures (Oct. 2023), https://www.fda.gov/media/84201/download?attachment; see also Cosmetics Constituent Update: FDA Issues Update on Cosmetic Product Facility Registration and Cosmetic Product Listing (Nov. 2023), https://www.fda.gov/cosmetics/cosmetics-news-events/fda-issues-update-cosmetic-product-facility-registration-and-cosmetic-product-listing?utm_medium=email&utm_source=govdelivery.

[69] See 88 Fed. Reg. 63,961.

[70] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 4.

[71] Id. at 10.

[72] See id. at 9.

[73] Id.; see also FDCA § 607(d), 21 U.S.C. § 364c(d).

[74] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 9; see also FDCA § 607(e), 21 U.S.C. § 364c(e).

Regulation of Digital Health Technologies After Unwinding of Pandemic Guidances

This article was originally published in Med Device Online.

As a result of COVID-19 pandemic lockdowns and limited in-person healthcare opportunities, FDA (and other regulatory authorities) loosened restrictions on the oversight of digital health technologies (DHTs), and even began to encourage their use in certain settings. The expiration of the public health emergency (PHE) and the related unwinding of certain pandemic guidances that created a more permissible environment for DHTs have significant implications for the DHT landscape.

This article covers three guidances particularly salient to DHTs that may sunset this fall, but which are still critical to understand, as the principles enshrined in at least two of the guidance documents are likely to live on. More specifically, based on recent FDA draft guidances, communications from senior FDA leaders, and other sources, the agency appears to continue to recognize the value of DHTs, particularly in clinical trials and in home-based patient monitoring and healthcare management settings. Industry should take advantage of this opportunity to engage with the FDA as it develops the longer-term framework for regulation of DHTs.

Pandemic Health Emergency’s Expiration and Unwinding of Pandemic Guidances Relevant for DHTs

The COVID-19 PHE declaration and the related authorities it granted expired on May 11, 2023, and as a result, some guidances that FDA issued pursuant to those authorities sunset on that date or will sunset soon.¹ FDA sorted the 72 COVID-19 related guidances that were in effect prior to the PHE expiry into four broad buckets:²

22 guidances that are no longer in effect as of the PHE declaration expiry on May 11, 2023 (“May Terminated Guidances”)
22 guidances that will continue in effect for 180 days after the PHE declaration expiry and then will no longer be in effect as of Nov. 7, 2023 (“November Terminated Guidances”)³
24 guidances that will continue in effect for 180 days after PHE expiry (until Nov. 7, 2023), during which time the agency plans to further revise these guidances and there may be a future sunset date or potentially these will remain in effect indefinitely (“Indefinitely Extended Guidances”)
Four COVID-19 related guidances whose duration is not tied to the COVID-19 PHE and thus will remain in effect.

Several guidances related to digital health technologies are affected by the end of the PHE and fall into the November Terminated or Indefinitely Extended guidance category, which could have critical implications for DHT manufacturers.

Guidance on Mental Health DHTs

There is one guidance with implications for digital health technologies that falls into the second category of guidances terminating on Nov. 7, 2023, namely, CDRH’s Enforcement Policy for Digital Health Devices for Treating Psychiatric Disorders During the COVID-19 PHE (FDA-2020-D-1138).⁴

In brief, the guidance signaled that, for the duration of the PHE, the agency would not object to, or enforce against, the distribution and use of computerized behavioral therapy devices and other digital health therapeutic devices, with some caveats, for psychiatric disorders or for low-risk general wellness and digital health products for some mental health or psychiatric conditions.⁵ These psychiatric disorders included, but were not limited to, obsessive compulsive disorder, generalized anxiety disorder, insomnia disorder, major depressive disorder, substance use disorder, post-traumatic stress disorder, autism, and attention deficit hyperactivity disorder.⁶ The guidance also noted that the psychiatric condition could have been a condition existing prior to the pandemic or may have onset during the public health emergency.⁷ The guidance was issued with the explicit two-fold goals of (i) expanding the availability of DHTs for psychiatric disorders at a time when access to mental healthcare would otherwise have been limited and when mental health disorders were skyrocketing due to the COVID-19 pandemic and lockdowns and (ii) limiting patient and provider contact to minimize the spread of infection but still ensure patients received healthcare.⁸

This guidance will remain in effect until Nov. 7, 2023, unless superseded by a revised final guidance before that date. DHT companies, depending on the technology and stated policy caveats, may need to take action to remove their devices from the market or take steps to comply, such as submitting a marketing application. There are also important implications for patients and providers. Will patients who have come to rely on DHTs for access to mental health care be able to continue using existing options or seek out new treatments? Will they be able to switch seamlessly back to in-person provider-based care or forgo it if their access to DHTs is limited? These are open questions, but ones the agency will consider.

Clinical Trial-Related Guidances

In addition, two guidances particularly salient for the digital health industry fall into the bucket that will be revised before Nov. 7, 2023, to either sunset at a later date or continue indefinitely. One is CDER’s Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency (FDA-2020-D-1106-0002).⁹ FDA’s goal in issuing this guidance was to provide general considerations and recommendations to help sponsors in ensuring the safety of clinical trial participants, maintaining compliance with GCP, and minimizing risks to trial integrity and interruptions for the duration of the COVID-19 PHE.¹⁰ The guidance included a lengthy question-and-answer section describing specific scenarios and how FDA would expect sponsors to handle them.¹¹ For example, the guidance discussed when it would be appropriate to conduct remote clinical visits for trial participants; when to remotely monitor clinical sites to ensure both trial participants’ safety but also data integrity; or when and how to ship the studied product to a local healthcare provider to minimize trial participants’ travel and face-to-face contact with others.¹²

In fact, as we anticipated, the FDA released a final version of this guidance at the end of September, with a slightly different title to encompass a broader array of emergency circumstances: Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions to Due to Disasters and Public Health Emergencies.¹³ The final guidance is similar to the COVID version, and recommends approaches that sponsors of clinical trials of medical products can consider when there is a major disruption to clinical trial operations during a disaster or public health emergency.

The other guidance is CDRH’s Enforcement Policy for Non-Invasive Remote Monitoring Devices Used to Support Patient Monitoring during the Coronavirus Disease Public Health Emergency (Revised) (FDA-2020-D-1138).¹⁴ This guidance was issued with the express hope of expanding the availability and capability of remote patient monitoring devices.¹⁵ Specifically, with the guidance, FDA signaled its enforcement policy would apply to an enumerated list of legally marketed non-invasive remote monitoring devices that measured or detected common physiological parameters and that are used to support patient monitoring during the PHE.¹⁶ Examples of covered devices would be a non-invasive blood pressure measurement system and a cardiac monitor, among others.¹⁷Further, modified use of these covered devices would improve access to important patient physiological data “without the need for in-clinic visits and facilitate patient management by healthcare providers while reducing the need for in-office or in-hospital services” during the PHE, decreasing COVID-19 infection/contraction risks for patients and providers alike.¹⁸

Just recently, on October 19, the FDA revised the above as updated final guidance on its enforcement policy for remote patient monitoring devices. The new final guidance includes several revisions, or updates, compared against earlier versions. For example, the FDA removed the oximeter and clinical electronic thermometer device types that were listed in table enumerating legally marketed non-invasive remote monitoring devices. The FDA stressed that manufacturers of non-invasive remote monitoring devices the table must submit a premarket notification and receive clearance prior to marketing these devices in the U.S., to the extent the devices are not 510(k)-exempt, as well as comply with post-marketing requirements. The FDA also expressed its intention to allow limited modifications to the indications, functionality, or hardware or software of certain non-invasive remote monitoring devices used to support patient monitoring without prior submission of a premarket notification in certain examples. The examples provided were moving a subject device from the hospital or healthcare setting to the home or making a hardware or software change to improve remote monitoring of patients. Notably, this updated final guidance has no sunset or expiration date.

The Regulatory Landscape for DHTs in a Post-Pandemic World: Forward-Looking Possibilities

Although the expiry of the PHE means the future of the guidances discussed above is uncertain, lessons learned from the pandemic, and general themes embodied in the guidance documents described above, are consistent with FDA’s current vision for the DHT regulatory landscape. DHT developers and manufacturers should pay close attention to how FDA handles these guidances in November.

As such, we suggest that FDA may be inclined to extend these guidances indefinitely, or at least continue to implement the principles included within those guidances if they do sunset. This is particularly likely for the guidance on conduct of clinical trials and the enforcement policy for digital health devices for treating psychiatric disorders. One motivation for extending these guidances indefinitely is that they seem to fit with the agency’s general regulatory stance on increasing the availability, use, and reliance on DHTs in general, but particularly in clinical trial settings and for patients in home healthcare monitoring/home-based healthcare models.

For example, the draft guidance on the conduct of clinical trials complements and is consistent with the March 2023 Framework for Digital Health,¹⁹ several other post-pandemic recent draft guidances, as well as statements from FDA senior leadership associated with the issuance of draft guidances, and other policy/strategy documents that the agency has released, among others.

More specifically, on June 6, 2023, FDA issued draft guidance from the International Council for Harmonisation on Good Clinical Practices (GCP) E6(R3) and opened the docket for public comment, with comments due by September 6^.20 This FDA draft guidance (embodying the ICH guideline) aims to maintain a flexible GCP framework that ensures the safety of clinical trial participants and data, while also advancing new principles that modernize clinical trials and support more efficient approaches to trial design and conduct.²¹

One way the FDA guidance envisages modernizing clinical trials is encouraging the use of DHTs, particularly fit-for-purpose innovative DHTs.²² The draft guidance states: “[f]or example, innovative digital health technologies, such as wearables and sensors, may expand the possible approaches to trial conduct.”²³Additionally, the draft guidance stresses the fit-for-purpose nature of DHTs, stating that “the use of technology in the conduct of clinical trials should be adapted to fit the participant characteristics and the particular trial design. This guideline is intended to be media neutral to enable the use of different technologies for the purposes of documentation.”²⁴

Equally important to the agency’s emphasis on using DHTs to modernize and decentralize clinical trials, the agency also has stressed the importance of DHTs for patient monitoring/home-based monitoring and care. It is theoretically possible – or maybe even pragmatic – for the agency to extend, revise, or potentially finalize guidance similar to the enforcement policy for digital health devices for treating psychiatric disorders.

Earlier this year, CDRH’s director, Jeff Shuren, gave an interview to Focus, a trade press publication. The interview, published June 16, focused on how the head of CDRH believes that “moving medical technologies from the clinical setting into the home may reduce costs and improve patient care; however, he cautioned that any medical technology used at home must prove that it is fit-for-purpose.”²⁵ Specifically, one of his quoted statements described how the pandemic moved the agency to create “flexible policies to facilitate modifications to devices to have digital remote capabilities to help move care to the home or in some cases even the development of technologies without prior FDA review to be able to facilitate care in the home, some of the adjunctive behavioral therapies, for example.”²⁶

His specific reference to the enforcement policy for digital health devices for treating psychiatric disorders²⁷ guidance demonstrates its significance and that the guidance’s themes are part of, or at least consistent with, the center director’s vision for moving medical technologies into the home and the value of DHTs in doing so. After Director Shuren’s comments, FDA published a list of questions for public comment on what, and how, the agency can do to foster and incentivize the development of at-home DHTs and what factors should be considered when those technologies come to market.²⁸ In particular, the questions include the following:

“How can the FDA support the development of medical technologies, including digital health technologies and diagnostics, for use in non-clinical care settings, such as at home?
What factors should be considered to effectively institute patient care that includes home-based care?
What are ways that digital health technologies can (a) foster the conduct of clinical trials remotely and (b) support local or home-based healthcare models?
How can the FDA facilitate individuals accessing medical technologies in remote locations when they are unable or unwilling to access care in clinical settings?
What processes and medical procedures, including diagnostics, do you believe would be ideal for transitioning from a hospital and/or healthcare setting to non-clinical care settings, for example, home use or school/work use?
- What medical technologies could be ideal to transition to use in non-clinical settings? What aspects of those technologies could potentially benefit from modifications to optimize use in non-clinical settings?
What design attributes and user needs would facilitate the use of medical technologies, including diagnostic and therapeutic devices, for use in a non-clinical setting, for example home use?
For digital health technologies, what design attributes could better facilitate their use by diverse patient populations outside of a clinical setting? What other factors are important to consider which may improve use and acceptance of different digital health technologies by diverse patient populations (for example, older adults, non-English speakers, lower literacy)?
What potential methods and strategies for evidence generation and data analysis could facilitate the regulatory review of medical technologies intended to be used in non-clinical settings, for example home use or school/work use?”²⁹

CDRH’s request for public comment on increasing patient access to at-home use medical technologies, including DHTs, is consistent with CDRH’s broader effort to expand access to home use technologies, including as described, for example, in CDRH’s 2022-2025 Strategic Priority Document focused on advancing health equity.³⁰ Indeed, moving medical technologies including DHTs out of the clinic or traditional healthcare settings into patients’ lives better meets patients where they are.

Conclusion

Expiration of the PHE and the unwinding of COVID-19 related guidances have major implications for FDA-regulated industry and products writ large but also specifically for DHTs. Some guidance documents relevant for DHTs will be in effect until at least November 7 and may be revised to continue indefinitely. However, even if these guidances are not revised or extended indefinitely, it appears FDA has taken “a lessons learned” approach from the pandemic use of DHTs in clinical trials and in at-home patient monitoring/healthcare to inform their vision for the future of the DHT regulatory landscape. As FDA aims to encourage the evolving innovation and technological progress, regulated industry, including DHT developers and manufacturers, should proactively seek opportunities to engage with FDA on DHTs and their use in clinical trials and in patient monitoring/home-based models of care. These technologies hold great promise for modernizing the conduct of clinical trials and for providing patient care.

References/Notes

Fact Sheet, COVID-19 Public Health Emergency Transition Roadmap, https://www.hhs.gov/about/news/2023/02/09/fact-sheet-covid-19-public-health-emergency-transition-roadmap.html. Note that there were 80 COVID-19 related guidances published; however, eight had already been withdrawn because they no longer reflected the agency’s current thinking.
Guidance Documents Related to COVID-19, 88 Fed. Reg. 15417 (Mar. 13, 2023), https://www.federalregister.gov/documents/2023/03/13/2023-05094/guidance-documents-related-to-coronavirus-disease-2019-covid-19.
Note that guidances listed that are subject to the device enforcement policy transition guidance will continue in effect for 180 days after expiration of the PHE declaration unless a different intended duration for the guidance is set forth in the final device transition guidance or the guidance is otherwise superseded by a revised final guidance before that date.
https://www.fda.gov/media/136939/download.
https://www.fda.gov/media/136939/download.
https://www.fda.gov/media/136939/download.
https://www.fda.gov/media/136939/download.
https://www.fda.gov/media/136939/download.
Guidance available here, https://www.fda.gov/media/136238/download.
See id.
See id.
See id.
https://www.fda.gov/media/172258/download
Guidance available here, https://www.fda.gov/media/136290/download.
See id.
See id.
See id.
Id. at 5.
https://www.clinicaltechleader.com/doc/an-overview-of-fda-efforts-to-encourage-dht-use-in-drug-biological-product-development-0001
FDA Draft Guidance on E6(R3) Good Clinical Practice, available here, https://www.fda.gov/media/169090/download. See the FDA Docket, available here, https://www.regulations.gov/docket/FDA-2023-D-1955?utm_source=dailyem,sfmc&utm_medium=email,email&utm_campaign=,Medtech%20Insight%20
Daily%20(Tues%20-%20Fri). Note that the draft guidance tracks with ICH’s recently updated E6(R3) draft guideline, and that guideline was drafted to describe how to deal with technological innovations for clinical trials, among other goals.
FDA Draft Guidance on E6(R3) Good Clinical Practice, available here, https://www.fda.gov/media/169090/download.
Id. at 2.
Id.
Id.
https://www.raps.org/news-and-articles/news-articles/2023/6/shuren-at-home-technologies-must-be-fit-for-purpos?mkt_tok=MjU5LVdMVS04MDkAAAGMZTsbK1r5IMpvnhjfyNGby2h0mjBZwP2wpJ45zqW5JOeu
MFOFTh5GcCY90W3c3KbDVNCWeVLW1JsQ_8a2evANoJRN2mkYXZibZ0bzIuna.
https://www.raps.org/news-and-articles/news-articles/2023/6/shuren-at-home-technologies-must-be-fit-for-purpos?mkt_tok=MjU5LVdMVS04MDkAAAGMZTsbK1r5IMpvnhjfyNGby2h0mjBZwP2wpJ45zqW5JOeu
MFOFTh5GcCY90W3c3KbDVNCWeVLW1JsQ_8a2evANoJRN2mkYXZibZ0bzIuna.
https://www.fda.gov/media/136939/download.
https://www.fda.gov/about-fda/cdrh-strategic-priorities-and-updates/cdrh-seeks-public-comment-increasing-patient-access-home-use-medical-technologies.
https://www.fda.gov/about-fda/cdrh-strategic-priorities-and-updates/cdrh-seeks-public-comment-increasing-patient-access-home-use-medical-technologies.
See https://www.fda.gov/about-fda/cdrh-strategic-priorities-and-updates/cdrh-seeks-public-comment-increasing-patient-access-home-use-medical-technologies. See also CDRH Strategic Priorities, available at https://www.fda.gov/media/155888/download.

FDA Releases Draft Guidance on Decentralized Clinical Trials

This article was originally published as a guest column in Clinical Leader.

In early May, two weeks prior to the expiration of the COVID-19 Public Health Emergency declaration, FDA released the draft guidance Decentralized Clinical Trials for Drugs, Biological Products, and Devices.¹ The timing of this draft guidance is notable as the document builds upon many of the recommendations FDA provided in the March 2020 guidance Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency² (which we covered back in 2020 for Clinical Leader here) which were intended to help sponsors continue their trials throughout the COVID-19 crisis. During the public health emergency, with many trial participants and personnel in isolation, per local COVID-19 control policies, FDA detailed several approaches sponsors could take to maintain continuity of their clinical trials, such as the use of electronic informed consent, use of digital health technologies to conduct assessments, use of local healthcare providers to administer trial procedures, and the direct shipment of investigational products to trial participants, among other measures. Thus, the May 2023 guidance on decentralized trials marks a continuation of FDA’s thinking on the decentralization of clinical trials.

The draft guidance fulfills Section 3606(a) of the Food and Drug Omnibus Reform Act (FDORA)³ requiring the agency to issue guidance on decentralized clinical trials (DCTs) by Dec. 29, 2023. Authored by all three medical product review centers, as well as the Oncology Center of Excellence, the draft guidance recommends a risk-based approach to the conduct and oversight of decentralized clinical trials.

The draft guidance identifies DCTS as trials wherein some or all trial-related activities occur outside of traditional clinical trial sites. More specifically, DCTs incorporate the use of local healthcare facilities, local healthcare providers (HCPs), and local clinical laboratory facilities; visits to trial participants’ homes; and direct distribution of the investigational product to the trial participant. Trials where some activities are conducted at the traditional trial site while other activities, such as follow-up assessments, are conducted remotely are termed “hybrid” clinical trials by the agency.

As noted, FDA recommends a risk-based approach when considering a decentralized trial design – noting that investigational products that are “simple to administer or use, have well-characterized safety profiles, and do not require complex medical assessments”⁴ are the most appropriate and well suited for evaluation in DCTs. The FDA cautions sponsors to be mindful of potential differences in data accuracy and consistency between DCT and conventional trials conducted at a physical site. While these variances may not impact the validity of trial results that seek to establish superiority of one treatment over another, they could impact the accuracy of results in a trial that aims to establish non-inferiority. For example, the effectiveness of a drug tested in a DCT may not be identical to the effectiveness of the same drug tested in a traditional trial that employs an active control, as evaluations performed by local healthcare providers in DCTs may be less precise and more variable than those conducted by dedicated trial personnel at site-based trials.

Beyond defining DCTs and identifying the appropriate situations for their use, the draft guidance provides key recommendations on the innovative approaches sponsors can use to decentralize trials and move trials outside of traditional sites. The draft guidance also includes some important considerations on safety and data security that are likely to arise in remote contexts.

Remote Trial Visits

The draft guidance affirms that telehealth visits can be used instead of in-person trial site visits, especially if no in-person interaction is needed. This was an innovation that FDA introduced in the March 2020 Conduct of Clinical Trials guidance, although it should be noted that the need for alternatives to in-person site visits to facilitate enrollment and conduct of clinical trials was recognized by FDA well before the pandemic. For example, a 2015 Federal Register notice sought comment and recommendations on innovative mechanisms to increase clinical trial enrollment, such as the use of telehealth visits.⁵

In addition to telehealth visits, the draft guidance also provides sponsors with the option to use local HCPs, who are not officially trial personnel. Importantly, the services local HCPs provide should not differ from the services they are qualified to perform in clinical practice. In addition, the activities local HCPs may provide should not require unique or detailed knowledge of the trial protocol or the investigational product.

Should telehealth technologies or local HCPs be used to facilitate decentralized trials, the trial protocol should detail how adverse events will be remotely identified, evaluated, and managed. Additionally, in the interest of trial efficiency and patient experience, sponsors are responsible for training trial personnel on the technology used to conduct a telehealth visit.

Digital Health Technologies

Although digital health technologies (DHTs) are among most common tools used in DCTs, the draft guidance does not focus extensively on this topic as it is well covered in the December 2021 draft guidance Digital Health Technologies for Remote Data Acquisition in Clinical Investigations⁶ [Editor’s note: Covered by Clinical Leader here.] However, the draft guidance does note that sponsors may permit trial participants to use their own DHTs in trials, as long as the sponsor also provides the same DHTs to other participants, so they are not excluded.

Direct Shipment of Investigational Products

The draft guidance confirms that the direct distribution of the investigational product (IP) to trial participants at their homes or other remote location is acceptable. However, should this method distribution be used, sponsors should describe in the protocol how the physical integrity and stability of the IP will be maintained during shipment. Similarly, the protocol should describe how investigators will track and document the receipt of IP by trial participants, as well as how participants should dispose of unused IPs and how this should be documented. IPs that are considered good candidates for direct shipment include those with long shelf lives and good stability profiles.

The draft guidance also notes that sponsors may also use a central distribution service to ship IP directly to trial participants. The investigator, however, must still control the release of the IP by the distributor, as well as monitor receipt and use by trial participants, as specified in the protocol.

Administration of the Investigational Product

As discussed above, sponsors should consider the nature of the IP when determining whether to administer it outside of traditional trial sites. FDA advises that IPs that involve complex administration procedures, have a high-risk safety profile, or are in early stages of development may require in-person supervision by the investigator at a trial site. Similarly, investigators should also consider the safety profile (e.g., risk of hypersensitivity, abuse potential) in determining the type of local care that participants may need to have access to if an adverse event occurs.

Informed Consent and Institutional Review Board Oversight

While discussed extensively in the March 2020 Conduct of Clinical Trials guidance, the DCT draft guidance also addresses the use of remote informed consent, albeit briefly. Specifically, the draft guidance confirms that investigators may obtain electronic informed consent remotely provided that all regulations under 21 CFR Part 50 are met. FDA also recommends that investigators have a central Institutional Review Board (IRB) to facilitate the review of the protocol and the informed consent documents.

Roles and Responsibilities

FDA notes that sponsors’ responsibilities are the same in DCTs as they are in traditional site-based trials. Due to the potential of multiple sources of data collection, sponsors should ensure their data management plan specifies data origin, data flow, and the methods used for data collection and includes a list of vendors involved in data collection, handling, and management. The draft guidance also recommends sponsors detail all operational aspects of a DCT in a trial protocol, while case report forms should identify when and where data is collected.

FDA recognizes that DCTs add complexity to the investigator’s role in overseeing trial conduct, as some decentralized features necessitate additional training and careful coordination of remote activities. FDA reiterates that local HCPs may perform trial-related procedures at a participant’s home or other local healthcare facility. However, local HCPs need not and should not be listed as sub-investigators on Form FDA 1572. The draft guidance also states that some trial protocols may permit the use of clinical laboratory facilities close to the trial participant, although designated clinical laboratory facilities are preferred to minimize variability.

Safety Monitoring

As with site-based trials, safety monitoring plans should describe how participants are expected to respond to and report adverse events, specifically noting where to seek local medical care if needed. In addition, the draft guidance also notes that trial participants should be able to contact trial personnel to report adverse events and arrange for telehealth visits if necessary. Lastly, the safety monitoring report should also describe the information collected by a digital health tool – detailing how the information will be used and monitored and how personnel or participants should respond to electronic alerts.

Software Considerations

The FDA notes that software can be used for multiple purposes in a DCT, including managing electronic informed consent, capturing and storing reports, managing electronic case forms, scheduling trial visits, and tracking IPs shipped directly to participants. Software programs used to produce and process trial records are subject to 21CFR Part 11 and must ensure data reliability, security, privacy, and confidentiality. Real-time video interactions, however, such as telehealth visits, are considered by FDA as live exchanges of information between trial personnel and trial participants and thus are not considered electronic records and subject to 21 CFR Part 11.

The FDA is accepting public comments on the draft guidance until August 1, 2023. All written comments should be identified with the docket number FDA-2022-D-2870.

References

FDA, Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance, May 2023, https://www.fda.gov/media/167696/download.
FDA, Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency, Guidance, March 2021, https://www.fda.gov/media/136238/download.
H.R. 2617; Food and Drug Omnibus Reform Act (FDORA), https://www.congress.gov/117/bills/hr2617/BILLS-117hr2617enr.pdf.
Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance, Lines 63 – 65.
80 FR 66543, October 29, 2015, https://www.federalregister.gov/documents/2015/10/29/2015-27581/using-technologies-and-innovative-methods-to-conduct-food-and-drug-administration-regulated-clinical.
FDA, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, Draft Guidance, December 2021, https://www.fda.gov/media/155022/download.

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