Proceedings from the Workshop on Science-Based Assessment: Accelerating Product Development of Combination Medical Devices (2004)

Richard D. Coutts

University of California at San Diego

Cartilage is an important living tissue that is distinctive in many ways: it contains only one cell type; has no blood flow, innervation, or lymphatic system; and has a low metabolic activity. The tissue is extremely slippery and has a unique structural and biochemical composition. For all of these reasons, this tissue is considered immune privileged, making it an ideal candidate for a living tissue replacement therapy.

As in all tissues, structure defines function, and the arcade-like structure of the collagen in the cartilage, along with its high molecular weight aggrecan proteoglycan, are ideal for binding and structuring water in the tissue. Although the cartilage bears a direct load during use, it maintains a high water content, which protects the chondral area beneath. The cellular component of the tissue originates from mesenchymal stem cells and regulates assembly and turnover of the matrix. The cells are nourished strictly by diffusion of nutrients and signals through the tissue and maintain a state of anaerobic metabolism. As the cartilage ages, the ability of the cells to produce matrix is decreased.

Clinically, problems stem from both focal and generalized damage. Focal defects are frequently due to traumatic injury; if left untreated, over 80 percent of patients with focal traumatic defects will develop arthritis an average of 20 years after the injury. Generalized damage due to osteoarthritis is the biggest clinical manifestation of articular cartilage damage, with virtually 100 percent of patients over the age of 50 showing some degree of erosion.

Although a variety of treatments are currently used, none are considered ideal or 100 percent successful. One repair technique involves the creation of small defects in the underlying bone through abrasion or microfracture methods. These defects result in bleeding, which recruits cells to the area and thus creates a fibrous cartilage. Other transplant methods include: mosaicplasty, where plugs are taken from a non-load-bearing edge to fill in the defect; allograft transplant tissues, which take advantage of the relative immune-privileged status of the cartilage; and chondrocyte transplantation, recently introduced by Genzyme.

Efforts to create a true tissue-engineered cartilage face a host of complex questions. What precise requirements must be met, both by the completed living construct and the individual cells, scaffold materials, and growth factor signals? What animal model is appropriate or predictive of human cartilage use conditions and disease states? What is the appropriate clinical trial design and how long should patients be followed? Finally, the complex environment in which the construct must survive must be examined and considered. In addition, issues regarding concurrent pathologies, extent, severity and duration of lesions, patient age, prior treatments, and range of motion must all be taken into consideration when designing a tissue-engineered cartilage.

Clinically, noninvasive measures of construct function are ideal and a number of such methods are currently available. Pain and function assessment tools have been well established and help generate important data to assess quality of life. Magnetic resonance imaging with metabolic labels has improved the imaging of the joint interface. Finally, while a second-look arthroscopy procedure is considered the definitive way to examine the repaired site, such a second surgical procedure incurs both costs and additional discomfort to the patient. The information gained from this procedure, however—including direct visualization of the tissue and a needle biopsy for histological examination of cell density and distribution, collagen patterns, and proteoglycans—is definitive confirmation of a successful reconstruction. Perhaps a balance can be achieved between the ethical considerations and the scientific merit of such follow-up procedures by utilizing a subset population in a study design.

Today, there are no easy or certain answers that a doctor can give a patient when presented with chondral defects of various etiologies and duration. Each situation requires a unique solution that depends on many factors, including the patient’s willingness to tolerate new or repeated procedures; expected outcomes; reimbursement; and short- versus long-term success rates. Only through careful study designs (both preclinical and clinical), treatment selection, and detailed patient follow-up will it be possible to clearly differentiate treatment modalities, learn from successes and failures, and continue to advance the treatment of cartilage disease and repair.

James W. Burns

Genzyme

As a pioneer in the treatment of cartilage defect disease using autologous cell-based therapies, Genzyme worked closely with its clinical and regulatory partners to bring a novel treatment modality to market. The Carticel^® product comprises an autologous, cultured, chondrocyte suspension that is harvested from a peripheral donor site and expanded in Genzyme’s current good manufacturing practices (cGMP) cell processing center. Once the expanded culture is returned to the clinician for implantation, the cells are localized within the defect with a periosteal cover from the patient’s femur. This technique, pioneered by Dr. Lars Peterson in Sweden in a rabbit model of acute chondral defect, was first used clinically in 1987. In 1994, Dr. Peterson published a paper on the excellent early results of his first series in 23 patients. When Genzyme became involved in the process, however, it quickly became obvious that there were clinical, regulatory, and operational hurdles that had to be overcome by a corporate entity involved in such therapies.

The rather surprising, excellent early results obtained by Dr. Peterson enabled rapid approval by the U.S. Food and Drug Administration’s Center for Biologics Evaluation and Research (CBER). Carticel^® therefore received biologics license approval in August 1997. Behind this seemingly rapid process was a large dedicated effort in the design, development, and validation of all aspects of the autologous cell harvesting and processing facility required to demonstrate compliance with cGMP guidelines. Genzyme worked closely with CBER personnel and others in the field to support the development of new regulatory guidelines for the manipulation of living autologous cells ex vivo for intended structural repair or reconstruction. This effort contributed to the MAS cell guidelines published in May 1996. Considerable effort was also expended in the design and execution of clinical studies, the maintenance of a Carticel^® Cartilage Repair Registry, and ongoing postapproval clinical studies.

Some of the greatest challenges encountered were in the preclinical and clinical areas where Genzyme sought improved healing and reduced rehabilitation time for patients, simplification of the surgical procedure with reduced morbidity using minimally invasive techniques, and development of test systems that provide meaningful data to make rapid decisions regarding next-generation product development. For a business, increased product utility, reduced time to market, and increased product adoption are impor-

tant measures of success. Challenges that had to be overcome included ambiguities in preclinical models, the ethics and logistics of conducting controlled surgical trials, the lack of global harmonization, and difficulties in obtaining reimbursement after regulatory approval. Accelerating the development of important, novel therapies such as Carticel^® and its next-generation products will require that these and other issues be addressed.

Anthony Ratcliffe

Synthasome, Inc.

The growth of cartilage equivalents in vitro by tissue engineering has now been achieved and can be reproduced using a cell-scaffold approach, with growth being done either statically or in bioreactors that can impose perfusion and/or mechanical strain. These constructs have been successfully used in vivo for the repair of articular defects in small animals. In large animals, however, simple cartilage constructs have not been shown to be effective, with the problem of fixation into a defect site being a particular issue. The use of more complex scaffolds that provide a bone-attaching and integration site appears to have overcome this problem, and constructs have now been successfully used in the repair of relatively large defects in the knees of large animals. However, some technical challenges remain: the provision of a cell source that provides enough cells with appropriate phenotype has yet to be identified; the mechanical properties of constructs are inferior to those of native cartilage; and lateral integration with surrounding host articular cartilage has yet to be achieved. The importance of these factors is unknown.

Several significant issues remain that hinder a company’s ability to efficiently move this type of product through technical and regulatory hurdles. The community must still agree on assessments of the constructs, animal models of repair, and appropriate preclinical and clinical outcome measures. This process would benefit immensely from the establishment of standards and guidance documents such as those generated by the American Society for Testing and Materials with input from academia, industry, and the U.S. Food and Drug Administration. Standards and guidance documents should be designed to be an efficient use of resources and should avoid unnecessary time-points or assessments. The uncertain regulatory pathway, the studies required to meet these regulatory needs, and the lack of international agreement on how to regulate these products are difficulties that can be substantial.

Finally, a successful business must be created in an uncertain environment where the realistic size of the market, reimbursement of the product, and time to market acceptance and profitability are significant issues. In the area of cartilage repair, the size of the market for focal defects will most likely be modest. It would therefore be wise to design the product with potential for expanded use in other applications, such as the treatment of arthritis.

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