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

Robert S. Schwartz

Minneapolis Heart Institute

Stents stimulate restenosis, which consists of myofibroblasts and an extra-cellular matrix. The major determinants of restenosis are thrombus (platelets/ fibrin), inflammation, proliferation, and migration/seeding. Polymer carriers are one of the leading anti-restenosis technologies. Their advantages include mechanical integrity/handling; precision dose control with uniform drug distribution, uniform release, the ability to modify release, and the ability to prevent overdosing; and versatility of use with other drugs and platforms. Future developments in drug-eluting stent technology will include new coatings and novel polymer processing; a number of companies are developing these technologies.

Several major drug trials have been undertaken on rapamycin and paclitaxel. Rapamycin is a natural antibiotic found on Easter Island that was developed and marketed for the prevention of renal transplant rejection. This drug acts as a selective proliferation inhibitor with the mechanism of action being a novel cell-cycle inhibitor. Paclitaxel is extracted from the Pacific yew tree, which is found in the northwestern United States and Canada. Drug trials on rapamycin and paclitaxel provide evidence that drug-eluting stents will allow treatment of more serious lesions and of patients with greater disease complexity. Complex lesions may require different treatment strategies and/or adjunctive devices.

Hospital economics, however, may influence the adoption and utilization rate of this technology. Patient allergic reactions to the drugs are also a problem that will have to be dealt with. In addition, the handling of stents must be improved; studies indicate that inflammation is significantly reduced if stents are rinsed after manufacture as well as after handling by surgeons.

H. Semih Oktay

CardioMed Device Consultants, LLC

Combination products, such as drug-eluting stents, consist of two or more regulated products, e.g., drugs or biologics and devices. The new Office of Combination Products at the U.S. Food and Drug Administration (FDA) is responsible for determining which FDA center should review each specific combination product based on the product’s primary mechanism of action. In general, the Center for Drug Evaluation and Research is the lead unit for approval of a device that primarily delivers a drug and is distributed containing the drug, while the Center for Devices and Radiological Health (CDRH) is the lead unit for approval of a device that primarily delivers a drug and is distributed without the drug, as well as for a device that incorporates a drug but that primarily serves a device function.

In the case of the drug-eluting stent, there are many complex relationships. The stent interacts with the carrier and tissue; the drug interacts with the carrier and tissue; and the tissue interacts with the stent, drug, and carrier. All of the device components and relationships must be evaluated, including the bare stent, the bare stent plus carrier, the drug, and the bare stent plus carrier plus drug. Preclinical testing requirements are risk-based. Requirements may depend on the intended use, e.g., there may be different requirements for the treatment of long lesions (overlapped stents) than for the treatment of in-stent restenosis (stent within a stent).

In addition to the CDRH guidance for bare-stent testing, standardized testing methods are being developed by the American Society for Testing and Materials subcommittee F04.30.06, the interventional cardiology task group. Physical testing includes testing for specification conformance and for clinically desirable stent characteristics, such as radial strength, uniformity, dimensional verification, and kink and crush resistance.

Preclinical safety information required for drug-eluting stents includes toxicological studies. The vascular wall, regional (myocardium) conditions, systemic conditions, and the correlation between in vivo and in vitro pharmacokinetic studies must all be evaluated. Additional preclinical tests are required on coating durability, sterilization of the finished device, and uniformity of drug distribution. Chemical tests performed on the drug and carrier determine chemical composition, check for impurities and stability, and assess manufacturing processes.

There are many variables and interdisciplinary issues to be considered in the assessment of combination products such as drug-eluting stents.

Challenges include the difficulty of obtaining adequate information on in vivo loading conditions; the development of testing equipment; the development of theoretical models; and interpretation of analyses. The development of performance standards may lead to faster regulatory approvals, faster new design development, marketing advantages, and liability protection.

Ronald A. Sahatjian

Boston Scientific Corporation

Boston Scientific Corporation (BSC) developed the TAXUS drug-eluting stent system during the decade from 1992 to 2002. A focused effort on local drug-delivery technologies was initiated in 1992 and various technologies were investigated, including catheter delivery systems, heparin-coated stents, balloon catheters, and polymer carriers. In developing a polymer-based approach, it was necessary to identify the drug; identify the appropriate polymer carrier; evaluate a maximum dose (loading capacity); identify the maximum tolerable doses; and determine a safe and potentially therapeutic range for the artery. The polymer carrier used by BSC has the necessary mechanical properties (integrity and elasticity) and excellent vascular compatibility.

The TAXUS system is a polymer-based system utilizing paclitaxel release to provide a wide therapeutic and safety window. Clinical trials for the TAXUS system were begun in 2000. Paclitaxel acts on several mechanisms implicated in restenosis, with the mechanism of inhibition being dose and cell dependent. Combined with the appropriate release, paclitaxel continues to demonstrate safety and efficacy in both preclinical and clinical trials. Increases of four times in the total loaded dose of the moderate release formulation demonstrate similar biological responses across doses. In an overlap system, the response to the moderate release formulation remains well within biologically compatible dosing.