October 2004 Bulletin

‘Combination products present challenges, opportunities

AAOS members bring orthopaedic concerns to roundtable discussion

By the Biological Implant and Biomedical Engineering Committees

Last spring, the Roundtable on Biomedical Engineering Materials and Applications (BEMA), an activity of the National Academies of Science, sponsored a workshop on “Science-Based Assessment: Accelerating Product Development of Combination Medical Devices.” BEMA serves as a forum focused on the successful navigation of the technical, regulatory and manufacturing elements that affect product development.

BEMA roundtable member representatives, including Josh J. Jacobs, MD, chair of the AAOS Council on Research, met with leaders in government, industry and academia to identify and discuss hurdles faced by manufacturers in the development and Food and Drug Administration (FDA)-approval processes of combination products. A combination product is comprised of two or more regulated components—drug/device, biologic/device or drug/biologic—that are physically, chemically, or otherwise combined or mixed and produced as a single entity.

Regulatory oversight

Specific challenges exist for manufacturers of combination products, most notably the FDA regulatory oversight of a device type that did not exist 20 years ago. Medical products have traditionally been regulated under the auspices of one of three distinct FDA medical product centers: Drugs, Devices or Biologics. The manufacturer of a medical product, using FDA definitions, classified the product as one of the three types. Today, applied research into biocompatibility, along with advanced biomedical technology, produces combination medical products previously unimaginable, such as drug-eluting stents, laser-activated drugs, transdermal patches, antibiotic bone cement and bone morphogenetic proteins with spinal cages.

In 2001, to appropriately address the safety and efficacy issues associated with the regulation of combination products, the FDA created the Office of Combination Products (OCP). Although the OCP does not regulate medical products, as do the other three centers, it does serve as a point of definition for the manufacturers of combination products. The OCP identifies the product’s primary mode of action and assigns the product to one of the three traditional centers, based on that primary mode of action, for product approval and subsequent regulation. The FDA is just beginning to develop procedures for evaluating such combination products, which pose new challenges for assessing efficacy and safety.

AAOS participation

Clinical, engineering and scientific experts from all areas gathered at the roundtable to discuss the uncertainties and difficulties of developing new combination products. Dr. Jacobs moderated a session on bone morphogenetic proteins (BMPs) and orthopaedic repair. The discussion centered on the role standards play in facilitating an accelerated path toward regulatory approval and subsequent introduction of new medical products to the market.

Barbara D. Boyan, PhD, a consultant to the AAOS Biological Implants Committee, discussed the importance of test methods in the development of BMPs. Dr. Boyan noted the inherent difficulty in developing standardized test methods, but stated that the development process builds upon previous successes and failures and that accurate measurement of activity is critical to that process. Another speaker similarly noted that the lack of a standardized measurement of osteoinductivity inhibits the development of new products intended to generate bone formation, as well as impairs orthopaedic surgeons’ clinical decision-making in the selection of products.

Richard M. Coutts, MD, a member of the AAOS Biomedical Engineering Committee, participated in the session on cell-matrix cartilage implants. Dr. Coutts noted that clinicians are confronted with a variety of options in the treatment of patients with chondral defects. According to Dr. Coutts, efforts to create tissue-engineered cartilage for reconstruction must tackle complex concerns, including clinical trial design and the in vivo construct environment.

The discussion highlighted specific barriers investigators face in the design of clinical trials: the appropriate experimental control for a tissue-engineered product; the definition of an endpoint from which success or failure is derived; and the difficulty of measuring the repair and integration of chondral tissue. Session participants also considered whether fully reconstructed tissue-engineered cartilage needs to be formed in vitro or if scaffolding with or without cells or growth factors would be adequate to effect repair.

Participation is important

The Roundtable on BEMA brings together relevant parties to discuss research and development, applications, and regulation of biomedical materials and devices. The AAOS is a full member of BEMA. Academy participation in think tank activities is vital to the development of policies that adequately address the concerns of orthopaedists, including patient safety, the FDA medical product approval process, and the development of more innovative and advanced medical products to treat disease and disability.

The AAOS Biomedical Engineering and Biological Implants Committees monitor and analyze developments in the regulatory and standards arenas for their impact on the practice of orthopaedic surgery.

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