Device and Biologic Combination Products: Understanding the Evolving Regulation

January 1, 1999

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Device and Biologic Combination Products: Understanding the Evolving Regulation

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI January 1999 Column


FDA is establishing new policies and guidelines to deal with combination device and biologic products. Manufacturers must keep abreast of the latest developments to avoid costly delays.

In recent years, regulating medical combination products has been a recurring challenge for FDA. A combination product—one that incorporates at least two of the regulated component categories of device, drug, or biologic into one product—presents FDA with unique difficulties for regulation and for determining which of its centers should have jurisdiction over the product. FDA's policies in this regard have sometimes been outpaced by the extremely fast-moving technology for combination products, especially in the subset of products that combine a device and a biologic.

The development of combination device and biologic products is a relatively new field, but one that has produced more than its share of controversy within the medical manufacturing community. As is the case with all combination products, the more time FDA spends debating jurisdiction and regulation, the more it costs the manufacturer, since the process for marketing approval cannot even begin until the agency decides which of its centers should have the power to grant that approval.

Used in the treatment of burns, TransCyte from Advanced Tissue Sciences (La Jolla, CA) is a temporary skin substitute derived from human fibroblasts.

Congress first acknowledged the need for specific regulation on combination products in the Safe Medical Devices Act of 1990 (SMDA). But the continual emergence of new, more-complex combination products quickly blurred any distinguishing lines and has complicated product designation and regulation. The issue of products combining a device and a drug, such as an asthma inhaler, has received considerable scrutiny over the past several years. But products combining a device and a biologic, such as organ replacement or assist devices, have received less attention. Recent trends, however, suggest that device and biologic combination products are quickly moving into the spotlight. A 1998 survey conducted by FDA identified hardware and tissue-engineered combination products as a rapidly growing trend in medical device technology.1

Even less than drug and device combinations, device and biologic products—which include, among other things, cellular and tissue implants, infused or encapsulated cells, artificial and replacement organs, heart valves and pumps, and cardiac, neural, and neuromuscular stimulation devices—do not fit neatly into existing regulatory paradigms. For example, as part of the question of regulation, FDA must take into account the possibility of tissue contamination and other hazards involved in using animal-derived tissues. With the science constantly evolving, it becomes difficult for manufacturers to remain informed of changes in regulation. What follows is a general breakdown of FDA's current policies and initiatives regarding combination device and biologic products, as well as a look at the shaping of new regulatory proposals.


The three centers within FDA that regulate combination products are those for Biologics Evaluation and Research (CBER), Devices and Radiological Health (CDRH), and Drug Evaluation and Research (CDER). Determining which of these centers will have jurisdiction over any particular combination product can be an involved process. To address this issue, FDA decided that the determination of regulation for combination products would be based on the primary mode of action of that product.

To illustrate the current procedure, we can look at a product such as the encapsulated dopaminergic cell. This product uses a device component to deliver a drug (dopamine) by means of a cellular mechanism. All three of the categories are included—drug, device, and biologic—so which center would regulate the product? In this case, FDA determined that the primary mode of action for the dopaminergic cells is in fact via a cellular mechanism; thus, CBER was granted primary jurisdiction over the product with consultation from CDRH for the device component.

Although a product's primary mode of action determines which center has jurisdiction, the designated center could very well lack necessary information regarding components of the product that are outside its area of expertise. For example, while CBER could reliably analyze the cellular component of the dopaminergic cells, could it be entrusted to accurately evaluate the drug and device aspects of the product? In response to this issue, SMDA created intercenter agreements among CBER, CDER, and CDRH. The agreements allowed the center with jurisdiction over a combination product to consult with the other centers regarding product components outside its specialty area. In the case of the dopaminergic cells, before making a decision about the product, CBER would consult with CDER about the drug component and with CDRH about the device component. Because the primary mode of action of the product is a cellular mechanism, CBER would retain jurisdiction and would ultimately make all decisions regarding marketing approval, but it would first enlist the expertise of the other two centers.

The centers involved with combination device and biologic products are CBER and CDRH. When CBER has jurisdiction over a combination product, the intercenter agreement enables it to consult with CDRH regarding the safety, effectiveness, and durability of any device components of that product. Likewise, CDRH may consult CBER about the biologic components of combination products under its jurisdiction. Generally, combination products intended for direct therapeutic application will be regulated by CDRH. Products with components that collect, separate, or process blood or blood products, analogous products, or cellular biologics—including cellular and tissue implants, infused cells, and encapsulated cells of tissue—are regulated by CBER.

Interactive wound-care products provide a useful illustration of how FDA currently regulates combination device and biologic products. Noninteractive wound-care products are regulated either by CDRH as devices (standard wound dressings), or, because they incorporate a drug, by CDER. However, the primary mechanism of interactive or biologically active wound dressings is not medicinal, but rather is achieved through a device or biologic component. These products serve as long-term skin substitutes or temporary synthetic skin and are intended to actively promote healing by interacting directly or indirectly with bodily tissues.

Interactive wound dressings can be divided into acellular products that seek to provide an enhanced environment for skin regrowth and cellular products that contain epidermal and/or dermal tissue. Examples of acellular interactive dressings include polymers or synthetic peptides linked with extracellular matrix constituents. Examples of cellular interactive dressings include products that contain allogeneic epithelial cells or fibroblasts cultured on biodegradable polymers and products that contain keratinocytes and fibroblasts that adhere to collagen substrates. These products meet both the definition of a device, since they work by mechanical mechanisms of action (e.g., they provide a macromolecular scaffold for tissue repair through temporary wound converage), and a biologic, since they contain biologic components (cells). In addition, interactive wound-care products that are considered to have a drug mechanism of action, and therefore would not be classified as wound dressings, may contain other biologic acellular components, such as growth factors and enzymatic debriding agents.

Regranex gel, manufactured by OMJ Pharmaceuticals Inc. (Manati, PR), is one such interactive wound-care product that recently obtained marketing approval. The product stimulates the recruitment and proliferation of wound-repair cells, and it is intended for the treatment of diabetic, neuropathic ulcers of the lower extremities. The active component of Regranex is becaplermin, a recombinant, human platelet—derived growth factor. Because the active component is the growth factor, Regranex is regulated as a biologic and was approved under a biologics license application (BLA). It can be considered an acellular wound-care product, with a primarily biologic/druglike mechanism of action, and not a device.

On the other hand, CDRH was granted jurisdiction over Apligraf, a new interactive wound and burn dressing manufactured by Organogenesis (Canton, MA). Apligraf is an artificial skin graft used to treat serious skin ulcers caused by venous insufficiency. It is produced from bovine collagen, human keratinocytes, and fibroblasts derived from human infant foreskins. The dressing provides wound protection and fosters the growth of healthy new skin. Comprising a scaffold of cells on a collagen substrate, the product can be considered a cellular interactive wound dressing. Despite its cellular composition, however, FDA ruled that the device mechanism of the scaffold architecture constituted Apligraf's primary mode of action and determined that CDRH should regulate the product. Similarly, Dermagraft-TC (Advanced Tissue Sciences; La Jolla, CA), a dermal-replacement wound dressing for use in plantar diabetic foot ulcers, is also being reviewed by CDRH but has not yet been approved. This product consists of neonatal dermal fibroblasts cultured in vitro onto a bioabsorbable mesh.


When a combination product has a clearly definable primary mode of action, FDA can assign jurisdiction quickly, and the intercenter agreement system works as it should. Unfortunately, this is not always the case. It is often difficult for FDA to identify and agree on the primary mechanism at work in a new product, which sometimes results in lengthy disputes over jurisdiction and delays in marketing approval.

If a sponsor suspects that a new combination product might cause debate over jurisdiction or the primary mode of action, the issue can often be resolved at the program level before such disputes begin. As soon as sufficient product information exists for the agency to make a regulatory designation, the manufacturer can contact the CDRH jurisdiction and device status expert or the CBER jurisdiction liaison (CBER ombudsman). Often, one or both of these representatives will expedite the decision-making process. If that approach fails, the sponsor can then make a formal request for product designation. The request (original and two copies) should not exceed 15 pages and should be filed prior to the submission of a premarket approval (PMA) application. All relevant sponsor information is required, along with a thorough description of the product, which should include:

  • The product's classification, common name, and proprietary name.

  • An indication of any component of the product that has already received or is not subject to premarket approval or an investigational exemption.

  • The product's chemical, physical, or biological composition.

  • The status of and brief reports on any developmental work, including animal testing.

  • Descriptions of the manufacturing process.

  • The sources of all components.

  • The proposed use or indications of the product and a description of all known modes of action.

  • The sponsor's identification of the primary mode of action and the basis for that determination.

  • The schedule and duration of proposed use, and the dose and route of product administration.

  • A description of any related products and their regulatory status.

  • The sponsor's recommendation as to which center should have primary jurisdiction, with accompanying rationale for this recommendation.

The request for designation is reviewed for completeness within five working days of receipt by FDA. If it is deemed complete, the agency will inform the sponsor that the request has been accepted for filing. Within 60 days of this filing date, the jurisdiction officer must issue a letter of designation. If the sponsor disagrees with the designation, it may submit a written request for reconsideration within 15 days of receipt of the designation letter. Alternatively, the sponsor may also take its request to the FDA ombudsman for final resolution.


Although it adheres to the established regulation and designation procedures in most combination product cases, FDA is beginning to recognize the need for new programs. In an attempt to match its regulatory process with the technological development of combination device and biologic products, FDA has sought new ideas and solutions to address specific needs in this area. One such proposal resulted in the creation of the Tissue Reference Group, an intercenter reviewing committee. The group is composed of six members, three from CDRH and three from CBER. Each member specializes in the issues concerning tissue-engineered components in new products. The group reviews only those products containing tissue-engineered components, and the hope is that there will be a much-faster response time for product designation.

Fetal cells inoculated into this cartridge replicate until they reach adult form and can take over liver functions (Vitagen; La Jolla, CA).

In addition to the Tissue Reference Group, CBER and CDRH personnel are working together to develop specific standards and guidelines for manufacturers to follow when developing human cellular and tissue-based components for combination device and biologic products. A document recently published by FDA, Proposed Approach to Regulation of Cellular and Tissue-Based Products, proposes a regulatory framework covering the broad spectrum of all uses of human tissue in the medical field.2 As it applies to combination device and biologic products, the proposal seeks to provide each center with the same clear, comprehensive set of regulatory guidelines for combination products containing tissue components. The approach applies to cells and tissues that are combined with nontissue components, are manipulated extensively, or are used for purposes other than their normal functions. It would require manufacturers who develop combination device and biologic products to maintain a level of scrutiny and rigor commensurate with the product's level of risk. The proposal is designed to achieve the following goals:

  • Prevent the unwitting use of contaminated tissues containing the potential to transmit infectious diseases such as AIDS and hepatitis. Although this point is directed more toward autologous or allogeneic tissue and does not specifically address the regulatory requirements regarding the tissue components of combination device and biologic products, it is an important factor in tissue regulation.

  • Prevent improper handling or processing that might contaminate or damage tissues. The manufacturer would be required to follow GMPs and have strict processing controls encompassing clinical safety and effectiveness concerns. The marketing application would have to contain a chemistry, manufacturing, and controls (CMC) section, unless it can be determined that safety and effectiveness requirements can be satisfied by the manufacturer meeting product specifications and processing controls.

  • Ensure that clinical safety and effectiveness are demonstrated in the use of all tissues. Manufacturers would have to submit a BLA, 510(k), or PMA and provide clinical safety and effectiveness data. For products operating via reproductive or metabolic pathways, clinical studies would be conducted under an investigational new drug (IND) application. Studies for products intended for local, structural reconstruction or repair would be conducted under an investigational device exemption (IDE).

In addition to these stipulations, all human tissue and cell product manufacturers would be required to register their establishments and list their products with CBER, regardless of whether the products are regulated as devices or biologics. Furthermore, the agency would require that all labeling and promotion be clear, accurate, balanced, and nonmisleading. Overall, the proposed guidelines attempt to standardize tissue regulation and require all manufacturers to adhere to a strict protocol in the development and testing of tissue-based products.


FDA's regulation of combination device and biologic products has often been fragmented and unclear. Current proposals for more-specific, comprehensive regulation of tissue-based products provide evidence that FDA recognizes the growing problem and is working on developing new policies and guidances. Issues pertaining to product safety—for example, viral contamination or contamination that could arise during manipulation of the tissue—are at the forefront of FDA's concerns. Until it establishes comprehensive and accurate processes for designating jurisdiction and determining a product's primary mode of action, the agency will continue to exercise its discretion on a flexible, case-by-case basis regarding the more-complex or problematic products. Manufacturers should make every attempt to keep abreast of the latest developments at FDA and should design product development and clinical testing protocols that are responsive to the evolving regulatory climate.


1. WA Herman, DE Marlowe, and H Rudolph, Future Trends in Medical Device Technology. Results of an Expert Survey (Rockville, MD: Center for Devices and Radiological Health, FDA, 1998).

2. Proposed Approach to Regulation of Cellular and Tissue-Based Products, Docket No. 97N-0068 (Rockville, MD: Center for Biologics Evaluation and Research, FDA, February 28, 1997).

Sharon A. Segal, PhD, is practice director, medical devices, for The Weinberg Group Inc. (Washington, DC).

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