This article originally appeared in the June 25, 2001 issue of The National Law Journal.

Advances in medical technology have resulted in the introduction of a rapidly increasing number of novel therapeutic products, in both the traditional pharmaceutical/medical device area, as well as more exotic modalities such as cell therapy and autologous tissue transplantation - transplants back to the original donor.

The Food and Drug Administration (FDA) has considerable experience in its traditional role of providing regulatory oversight for the safety and effectiveness of conventional medical products. On the other hand, regulation of novel therapies have presented a serious challenge to the agency. Over the last 10 years, FDA has been slowly formulating a comprehensive approach for oversight of a number of these new therapies, and recently, some of these efforts have come to fruition.

A key example of FDA's new approach was introduced on January 19, 2001, when FDA promulgated a new regulation for the registration and listing of facilities that produce human cells, tissues, and cellular and tissue-based products.1 In conjunction with several other FDA initiatives that are not discussed in this article, this new regulation represents a significant increase in the Agency's oversight of therapies that consist of human cells, tissues, or products derived from cells or tissues that are intended for use in humans, which FDA refers to as HCT/P.2

With a few exceptions, the regulation requires establishments that "manufacture" HCT/Ps register with FDA.3 The requirements are fairly modest, generally amounting to a semi-annual submission to FDA's Center for Biologics Evaluation and Research (CBER) that provides some basic administrative information about the manufacturer and lists the general types of HCT/P that are produced by the manufacturer.

The HCT/P regulation covers a wide variety of products, such as autologous cell therapies, stem cell transplants, reproductive tissues, and tissues intended for transplant - for example, bone, skin and corneas. HCT/P products currently fall under three diverse general regulatory categories: human tissues intended for transplantation; biological drugs or devices subject to FDA drug and device regulations; and products that are not tissues for transplantation, drugs, or devices, but that still meet the definition of HCT/P. These categories are described in more detail below.

The HCT/P registration and listing regulation is a product of FDA's evolving tissue regulation process that started in earnest in the early 1990s. One of the first steps in the process was the publication in 1993 of the interim final rule for testing human tissue donors for certain communicable diseases (e.g. HIV and hepatitis).4 That regulation was intended to fill what was perceived as an immediate need for oversight of tissue testing, which had been previously largely unregulated.

Two 1997 Documents
With the continued growth of promising novel therapeutic products developed from human tissues and cells came additional concerns about potential associated health risks. To evaluate those risks, and to initiate comprehensive steps for their control, in 1997 the FDA developed two documents, "A Proposed Approach to the Regulation of Cellular and Tissue-based Products"5 and "Reinventing the Regulation of Human Tissue." 6 These documents provided the framework for the development of FDA's regulations for HCT/Ps.

To implement the ideas contained in these documents, FDA formulated a Tissue Action Plan (TAP) that contained, among other things, various milestones for HCT/P regulation, and plans for a Tissue Reference Group, made up of personnel from CBER, the Center for Drug Evaluation and Research (CDER), and from FDA's Ombudsman's Office. The ultimate goal of these efforts was to create a comprehensive regulatory scheme for what are now termed HCT/Ps.

The first regulation created under the TAP, the "Human Tissue Intended for Transplantation" regulation, was issued in July of 1997.7 This regulation finalized the 1993 interim final rule. Infectious disease screening for most donors of human tissues intended for transplantation was required. Ancillary to the screening requirements were record-keeping requirements, and procedures for FDA inspection of human tissue facilities. Shortly after this rule was promulgated, FDA proposed a rule for the listing of HCT/Ps, and the registration of establishments that manufacture HCT/Ps.8 It is that regulation that is finalized by the January 19, 2001 regulation.

The new final HCT/P regulation, along with proposed rule for Good Tissue Practices (GTP)9 and donor screening for tissues and cellular based products,10 will form FDA's comprehensive HCT/P regulations, that will ultimately be found at 21 C.F.R. § 1271 Subparts A through E. Once all the parts of the HCT/P rules are in place, FDA will revoke the tissue donor screening regulation found at 21 C.F.R. § 1270, as it will be made unnecessary by the new section 1271.

Regulatory Authority
Like all regulatory agencies, the FDA derives its authority to create regulations from laws enacted by the legislature. For most FDA regulations, that authority is the Federal Food Drug and Cosmetic Act (FFDCA).11 However, the HCT/Ps regulation is promulgated under the authority of the Public Health Service Act (PHS Act).12 Section 361 of the PHS Act permits FDA to make and enforce regulations for the purpose of controlling communicable diseases.

The FDA stated that it has issued the registration and listing regulation in order to obtain baseline information about HCT/P products, and the establishments that manufacture and distribute them. This information will then be used to effectively monitor the safety of these products, and to enforce future regulations once they are enacted. FDA's actual authority for some aspects of the HCT/P regulations (particularly some aspects of the proposed GTP regulations) is unclear; however, challenging FDA on these grounds is often difficult, as Federal courts have traditionally given the Agency considerable deference, especially in regulating health and safety.

The registration final rule applies to all human articles consisting of or containing human cells or tissues that are intended for transplantation, transfusion, infusion13 or other transfer into human recipients. In addition to gathering basic information about the use of these products, the rule will also provide a mechanism through which FDA can improve accountability of the products' manufacturers. Prior to enactment of this regulation, HCT/Ps were regulated under different rules and levels of Agency oversight depending upon the characteristics of the products.

There are three categories of products that are within the scope of the new rule.

  • HCT/Ps that qualified as biological drugs or medical devices - e.g. expanded chondrocytes14 and autologous vaccines - were regulated under the relevant portions of the FFDCA and the attendant regulations (21 C.F.R. Parts 200 and 800 respectively).15 Regulations of these products usually involves very stringent pre-market controls where manufacturers are required to perform clinical and non-clinical studies to demonstrate the safety and efficacy of their products. Additionally, comprehensive manufacturing controls are in place to assure the safety, identity, and purity of approved drugs and devices. The new HCT/P regulations will complement, not supercede, FDA's current process for these products.
  • Human tissues intended for transplantation - e.g., non-vascularized tissues such as bone, skin, corneas, and connective tissue - are regulated under 21 C.F.R. § 1270. The requirements under that regulation are significantly less involved than those for drugs and devices. Generally manufacturers of tissues for transplantation must meet certain testing and record-keeping requirements, as well as allow for FDA inspection. This regulation focuses on product safety, and does not require a demonstration of effectiveness that is necessary for approved drugs or medical devices. This regulation will remain in effect for the time being along with the new listing and registration regulation.
  • The regulation terms products based upon human cells that are not considered drugs or devices (e.g. unprocessed stem cells).16 These products are termed (under the regulation) "HCT/Ps regulated solely under section 361 of the PHS Act," and have been largely unregulated except through voluntary compliance with one of several industry self-regulating bodies (e.g. American Association of Tissue Banks). The new registration and listing regulation represents a significant expansion of FDA authority and oversight.

Nevertheless, they are still subject to less stringent requirements than either tissues for transplant, or drugs and devices. For this reason, many manufacturers have attempted to characterize their products in a way that permits them to fall in this category. Previously, FDA guidance and regulations provided criteria for "HCT/Ps regulated solely under section 361 of the PHS Act.

The new listing and registration regulation narrows and clarifies the requirements for these minimally regulated products:. They must be: subject to "less than minimal manipulation"17; for homologous use only (i.e. identical in structure to the tissues they will replace; and they must not be combined with any drug or device component (except for certain sterilization, preservation or storage agents). In addition, they either do not have a systemic effect, and do not rely upon the metabolic activity of the living cell for its function or they are for autologous use; for fertility purposes; or are for use between first or second degree blood relatives.

If a cellular based HCT/P does not meet all of these criteria, it will be deemed a biological drug or medical device, and likely subject to FDA pre-market review requirements. FDA has historically interpreted these requirements very narrowly, in particular "minimal manipulation." Accordingly, manufacturers have attempted to fit products within this exception. With the advent of the new listing and registration regulation, FDA will narrow application of this exception to some degree. Additionally when the other proposed regulations under the TAP are ultimately finalized, the scope of FDA regulatory activity will become more extensive, and enforcement efforts by the agency's field personnel will narrow the exception even further.

Listing and Registration
There are two basic requirements under the final rule, establishment registration and product listing.

Registration will be required for all persons or establishments that manufacture HCT/P products, including those regulated as biological drugs or devices. The regulation requires that the establishment be registered within five days of beginning operations (or within 30 days of the regulation's effective date, as discussed below), and that this registration be updated annually. The registration must also be updated within five days if there is any change in establishment ownership or location.

Listing requires providing basic information about all HCT/Ps that are recovered, processed, stored, labeled, packaged, distributed, or tested (including donor screening) at the establishment. The list is fairly non-specific, with FDA only requiring separate listings for each product type in general, and not specific sizes, strengths, or packages. The listing must be updated at least every 6 months, if any material changes are made to the HCT/P listing. If no changes are made, only the annual establishment registration is required.

There are several exceptions to the registration and listing requirements:

  • Establishments that use HCT/Ps for solely nonclinical scientific or educational purposes.
  • Establishments that remove and re-implants HCT/Ps into the same individual, during the course of the same surgical procedure. FDA has also interpreted this exception to include establishments that retain tissues to be used in later procedures for the same patient, so long as those establishments are not engaged in any further processing of those cells.
  • Carriers or shippers of HCT/Ps.
  • Establishments that only receive HCT/Ps for implantation into patients (i.e. hospitals that receive the already processed cells).
  • Establishments that recover, and immediately transfer reproductive cells to a sexually intimate partner of the cell or tissue donor. This exception does not apply to any establishment that stores or banks reproductive cells or tissues.
  • Individuals (not establishments) that recover HCT/Ps from donors under contract with a registered establishment.

Because the new regulation imposes certain requirements on heretofore unregulated products (i.e. products that are neither tissues intended for transplantation nor products subject to drug or device requirements) FDA has instituted a staggered implementation of the regulation. All establishments with tissue HCT/Ps that are currently regulated under 21 C.F.R. § 1271 (e.g., bone, skin, corneas, and fascia) are currently required to register with FDA (as of May 1, 2001). All other HCT/P establishments, including those with products regulated as biological drugs or devices, and those currently unregulated will not be required to register or list until January 21, 2003.

The FDA's listing and registration regulation represents a step by the Agency in an area that has historically had only sporadic regulation. The new listing and registration regulation is only the beginning of involvement in this area by FDA, as it inevitably expands its activities as it exerts jurisdiction over an area. As regulation and policy become better defined, field personnel tend to interpret their jurisdictional mandate more broadly and aggressively.

Additionally, the FDA's new activities bring it in contact with companies that have had little previous contact with the Agency. These factors will necessitate increased vigilance on the part of companies that operate in the HCT/P and related fields to avoid violations of rapidly expanding rules and requirements. Preparation is the key to successfully navigating the regulatory mosaic that is being constructed.

1 66 Fed. Reg. 5447 (Jan. 19, 2001); 21 C.F.R. § 1271 Subparts A and B.

2 Under the new regulations "Human cells, tissues, or cellular or tissue-based products (HCT/P)" are defined as any article containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. A number of examples are provided, including: bone, ligament, skin, dura mater, heart valves, cornea, hematopoietic stem cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen and other reproductive tissues. Specifically excluded are whole vascularized organs, blood and blood components, xenotransplantation products, minimally manipulated bone marrow for homologous use, and extracts from human cells or tissues. 21 C.F.R. § 1271.3(d).

3 "Manufacture" is defined broadly in the regulation, to include all steps in the recovery, processing, storage, labeling, packaging, or distribution of any HCT/P. 21 C.F.R. § 1271.3(e). The Agency has acknowledged that the common meaning of the term "manufacture" is not an exact fit for its intended definition.

4 58 Fed. Reg. 65514 (Dec. 14, 1993).

5 "A Proposed Approach to the Regulation of Cellular and Tissue-based Products," The Food and Drug Administration, February 28, 1997 (Docket Number 97N-0068).

6 "Reinventing the Regulation of Human Tissue," The Food and Drug Administration and the Vice President's National Performance Review, February 1997.

7 62 Fed. Reg. 40444 (July 29, 1997); 21 C.F.R. § 1270.

8 63 Fed. Reg. 26744 (May 14, 1998).

9 66 Fed.Reg. 1508 (Jan. 8, 2001). These proposed regulations provide a framework for the control of processing of tissue based products that is similar to the cGMP requirements for drugs, and the quality system regulations for medical devices.

10064 Fed. Reg. 52696 (Sept. 30, 1999) (Unlike the tissue donor screening requirements from 21 C.F.R. § 1270, this rule will apply to both tissues and cells).

11 21 U.S.C. §7sect; 301 et seq.

12 42 U.S.C. §§ 201 et. Seq.

13 Transfusion is the transfer of fluid from one person to another, either directly or indirectly. Infusion is the transfer into the body of a nonbodily fluid, such as a biological drug or saline solution.

14 Expanded chondrocytes are cartilege cells from the knee that ae removed from the body, multiplied outside the body and reimplanted.

15 21 C.F.R. parts 200 and 800, respectively. Note, however, that not all biological drugs or devices are subject to the HCT/P regulation.

17 The traditional test for these products was whether they were more than minimally manipulated.

17 "Minimal manipulation" as used in the determination of whether HCT/Ps are "HCT/Ps regulated solely under section 361 of the PHS Act" means that any processing does not alter the relevant characteristics of the tissue for its intended use. Examples of minimal manipulation include: density gradient separation, selective removal of certain cells, centrifugation, grinding, lyophilization, freezing, and certain sterilization steps. Specifically excluded are any cellular expansion techniques. 21 C.F.R. § 1271.3(f)

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