An early focus of the U.S. Food and Drug Administration (FDA) under the new leadership of FDA Commissioner Scott Gottlieb, MD, has been regenerative medicines, which “hold significant promise for transformative and potentially curative treatments for some of humanity’s most troubling and intractable maladies.” One of the areas of regenerative medicine that can be particularly difficult to regulate is treatments with human cells, tissues, and cellular and tissue-based products (HCT/Ps), because these treatments tend to be fairly individualized and there is a fine line of demarcation between medical practice and processes regulated by FDA.

This fine line is likely why the provider community has been concerned, since even the proposed rules for HCT/Ps were published, about ensuring that the activities that are part of their day-to-day medical practice do not trigger FDA regulation. In a recent development on this front, on November 16, 2017, FDA issued a final guidance document clarifying one of the exceptions to the HCT/P regulations: Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception: Guidance for Industry (the “Guidance”).

This article will discuss this recently finalized guidance and how it clarifies the parameters of the Same Surgical Procedure Exception (the “Exception”). Gaining a better understanding of the Exception may allow hospitals and medical practices to determine how they might ensure that they operate within the Exception or take affirmative steps to determine the scope of their regulatory requirements under Part 1271 or under other FDA regulations. First, I will provide a brief summary of the regulatory framework within which the Exception operates, to give context around the implications of not meeting the requirements of the Exception. Then, I will introduce the reader to the elements of the Exception itself, followed by an in-depth analysis of each of the elements.

Framework for the HCT/P Regulations

FDA has taken a “risk-based tiered approach” to the regulation of HCT/Ps. The regulations specific to HCT/Ps (21 C.F.R. Part 1271) were promulgated under FDA’s authority in Section 361 (Control of Communicable Diseases) of the Public Health Service Act (PHSA), even though FDA could choose to regulate HCT/Ps under the Federal Food, Drug, and Cosmetic Act (FDCA) and/or Section 351 (Regulation of Biological Products) of the PHSA. Part 1271 effectively divides HCT/Ps into three groups: (1) those that are not subject to regulation by FDA; (2) those that are subject to the limited regulatory requirements of Part 1271; and (3) those that are fully regulated as a drug, medical device, and/or biological under the FDCA or Section 351 of the PHSA.

A subset of HCT/Ps are not subject to FDA regulation because they qualify for one of the exceptions under 21 C.F.R. § 1271.15. Among those exceptions is 21 C.F.R. § 1271.15(b), commonly referred to as the Same Surgical Procedure Exception, which is discussed further below.

If an HCT/P is not fully excepted from FDA regulation under 21 C.F.R. § 1271.15, it may only be subject to the limited requirements of Part 1271 if it meets the criteria of 21 C.F.R. §1271.10(a), including “minimal manipulation” and “homologous use,” which are the subject of another recent guidance document. The primary regulatory requirements under Part 1271 are establishment registration with the FDA, listing the HCT/Ps for the establishment, and following the Current Good Tissue Practices.

For HCT/Ps that do not qualify for one of the exceptions in 21 C.F.R. § 1271.15 and do not meet the criteria of 21 C.F.R. §1271.10(a), Part 1271 specifically states that these HCT/Ps are subject to the full requirements of the FDCA and/or Section 351 of PHSA. This can include premarket approval requirements and following Current Good Manufacturing Practices.

The Same Surgical Procedure Exception

Under 21 C.F.R. § 1271.15(b), a facility is not required to comply with the requirements of 21 C.F.R. Part 1271 if the facility “removes HCT/P’s from an individual and implants such HCT/P’s into the same individual during the same surgical procedure.” Thus, to qualify for the Exception, the treatment must meet the following elements:

The material must be an HCT/P;
The HCT/P must be reimplanted into the same person from whom it was removed (i.e., autologous use);
The reimplanted HCT/P must be the same HCT/P (i.e., “such” HCT/P); and
The HCT/P must be removed and reimplanted during the same surgical procedure.

Reimplanting an HCT/P

As the name suggests, HCT/Ps are defined as articles that contain or consist of “human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” The regulatory definition includes the following examples: “bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue.” A number of articles that might otherwise meet the scientific definition of an HCT/P are specifically excluded from the regulatory definition (e.g., blood and blood products).

Because Part 1271 and the Same Surgical Procedure Exception are limited to HCT/Ps, if a material does not meet the definition of an HCT/P, then it cannot qualify for the Exception, and, therefore, other regulations might apply to that material.

Reimplanting in the same person (i.e., autologous use)

One of the more simple requirements of the Exception is that the HCT/P must be limited to what the Guidance summarizes as autologous use (i.e., the HCT/P that is implanted into a person must have originally come from that person). The HCT/P may not come from another person, and cells/tissues that come from a non-human animal are not considered HCT/Ps.

Reimplanting “such HCT/Ps”

The regulatory text of the Same Surgical Procedure Exception states that “such HCT/Ps” must be reimplanted into the same individual, and the Guidance explains that HCT/Ps are “such” HCT/Ps when they stay in their “original form.” However, the Guidance does allow HCT/Ps within the Exception to undergo the following types of further processing: “rinsing, cleansing, sizing, and shaping.” FDA does not explain why these specific processes are allowed, but generally indicates that HCT/Ps that have undergone these processes still meet the general goal of the Exception, which is to ensure that the reimplantation of the HCT/P does not create “additional risks of contamination and communicable disease transmission beyond that typically associated with surgery.”

FDA also does not provide a definition of these four processing activities, and only provides examples for sizing and shaping (i.e., “dilatation to size a vascular graft in coronary artery bypass graft surgery, cutting parathyroid tissue into pieces appropriately sized for reimplantation, and meshing of skin grafts to facilitate shaping and sizing to cover cutaneous burn wounds”). Without the assistance of a definition, facilities should consider only performing those processing activities explicitly permitted in the Guidance, or risk disqualifying an HCT/P from the Exception. For example, “centrifugation or filtration solely to remove debris (e.g., lipids, blood, bone particles)” would qualify as rinsing or cleansing, but centrifuging or filtering for the purpose of “cell isolation, cell expansion, cell activation, or enzymatic digestion” would be beyond the four allowed processes.

Although not listed among the four allowed processes, temporary storage is another action that appears to be permitted because it is not considered “processing” and the Guidance indicates it is allowed. The term “storage” is explicitly excluded from the regulatory definition of “processing.” Thus, when the Guidance states that the only types of further processing that are allowed are the four listed above, this does not necessarily mean FDA is trying prevent storage, because storage is not further processing. Additionally, temporary storage is mentioned a number of times in the Guidance.

The Guidance also indicates that certain types of preserving might be allowed for the purpose of temporary storage while still remaining within the Exception, but only for specific HCT/Ps. A footnote states that “temporary storage of a cranial bone flap or portion of parathyroid tissue may include steps to preserve those HCT/Ps in an appropriate condition for reimplantation, such as disinfecting or cryopreserving.” This allowance for preservation steps should be read narrowly because this is the only mention of allowing preserving activities, and this statement was specifically for bone flaps and parathyroid tissue, which, as will be discussed later, hold a special status in this Guidance. Additionally, “preservation for storage” is considered “processing,” according to the regulatory definition, and the only types of further processing allowed are the four specified processes (i.e., rinsing, cleansing, sizing, and shaping). Except for this narrow allowance, the Guidance should generally be read as only allowing those preservation activities that could be considered one of the four specified processes.

Reimplanting during the “same surgical procedure”

Generally, to qualify for the Exception, reimplanting the HCT/P must occur during the “same surgical procedure” as when the HCT/P was removed. FDA views the “same surgical procedure” as meaning “a single operation performed at the same establishment,” with examples including “autologous skin grafting and coronary artery bypass surgery involving autologous vein or artery grafting.” However, the Guidance suggests that FDA may consider certain sets of multiple operations to be within the same surgical procedure, as well as sometimes allowing removal and reimplantation to occur at different establishments.

After explaining that the “same surgical procedure” means a “single operation,” FDA states that, under “limited circumstances,” procedures that include multiple operations a “number of days apart” can be considered the “same surgical procedure.” The Guidance provides specific examples of procedures that could be eligible: (1) “Craniotomy or craniectomy with subsequent implantation of the bone flap to reverse the cranial defect;” (2) “Parathyroidectomy with subsequent implantation of a portion of the tissue to preserve parathyroid function;” and (3) “Adipose tissue [that] is recovered by tumescent liposuction” and is “cleansed . . ., temporarily stored, and injected during a predetermined, limited number of subsequent operations.” This last procedure regarding adipose tissue (i.e., “[c]onnective tissue in which adipocytes or fat cells predominate”) was not included in the section of the Guidance where FDA was providing examples of multiple operations that would be considered the same surgical procedure, but, rather, was provided in response to a question related to the parameters of the “such HCT/P” definition. However, with FDA’s statement allowing the adipose tissue to be injected during “subsequent operations,” FDA is explicitly allowing more than a single operation and implicitly allowing those operations to take place over a number of days.

Unfortunately, FDA provides neither an explanation for why these three procedures would qualify for the “same surgical procedure” nor any criteria for the “limited circumstances” under which it would consider a multi-operation procedure to qualify. Without this additional information, it is hard to determine whether a procedure that would require multiple operations, other than the three above, would be considered the “same surgical procedure.” Given the relatively different procedures, are there correlate attributes between the three that would apply to other procedures? Were these procedures selected based on FDA’s general risk-based approach of limiting risk to be no greater than what is typically associated with surgery? Were they selected because of their ubiquity in the medical field and/or because of a general understanding that these procedures must be performed over multiple operations for the safety and efficacy to the patient? The regulatory history for the HCT/P regulations supports the idea that the three described procedures are not the only multi-operation procedures allowed. As part of responding to comments in the final rule, FDA agreed with the following interpretation of the Same Surgical Procedure Exception, assuming the lack of any other activities that would be included in the definition of “manufacture”: “hospitals retaining autologous tissue, not used in a scheduled surgical procedure, to be used in a subsequent application on the same patient, are exempt from registration and listing because the two applications are essentially a single continuous procedure.”

While the Guidance states that the Exception requires that the “same surgical procedure” must be “performed at the same establishment,” the Guidance also indicates that FDA will allow removal and reimplantation to occur at different facilities, but, again, under “limited circumstances.” The reason for the general rule is that moving the HCT/P to another establishment raises the risks “beyond those typically associated with surgery.” However, acknowledging that “medical necessity” may require such transportation of HCT/Ps, FDA indicates that it “does not intend to object” in such cases, provided (1) the procedure is a “craniotomy, craniectomy, or parathyroidectomy” and (2) “precautions will be taken to protect the HCT/P from contamination and cross-contamination.” The wording and structure of the paragraph indicate that such procedures (i.e., removal at one establishment and reimplantation at another) would not fall within the Same Surgical Procedure Exception, but that FDA is employing enforcement discretion in not expecting such establishments to meet their regulatory obligations (e.g., establishment registration and listing).

Impact for Health Care Providers

Because FDA has taken a risk-based approach to regulating the use of HCT/Ps, treatment with these materials can be subject to a number of different sets of regulatory frameworks. The distinguishing criteria between those frameworks are complex, and the implications to a hospital or a medical practice of how its HCT/Ps are regulated can be significant, given that the FDA requirements could range from no requirements to requiring the facility to seek premarket approval before reimplantation.

When performing a fat grafting procedure, when will centrifugation be considered rinsing/cleaning versus additional processing that will disqualify the establishment from the Exception? In anticipation of performing a stem cell transplant, what preservation steps can be employed during storage while the patient is receiving chemotherapy? These are just a couple of examples of the types of questions to consider when determining where your facility falls on the spectrum of FDA’s regulation of HCT/P treatments.

For HCT/Ps, qualifying for one of the exceptions under 21 C.F.R. § 1271.15 presents the least amount of regulation. As discussed above and detailed in the Guidance, the following are the core criteria for the Same Surgical Procedure Exception: (1) removed from and reimplanted into the same person; (2) subject to no further processing other than “rinsing, cleansing, sizing, and shaping”; and (3) removed and reimplanted within a single operation at one facility. Facilities would be prudent to inventory the types of procedures being conducted on the premises to prevent inadvertently or unknowingly becoming subject to this complicated area of FDA regulations.

Justin M. Mann is an associate at Alston & Bird LLP with the Health Care Group and a member of the Food, Drug & Device/FDA Team. His practice includes regulatory counseling, guidance on FDA compliance and enforcement matters, and transactional support related to FDA regulations. He can be reached at 202.239.3115 or by email at [email protected].

February 21, 2018/by NCBARBLOG