1. FDA Regulation of Combination Products Barbara D. Boyan, Ph.D. American Academy of Orthopaedic Surgeons Professor and Deputy Director for Research for the Georgia Tech/Emory Center for the Engineering of Living Tissues November 25, 2002

2. AAOS has a commitment to quality care and patient safety initiatives. AAOS has a commitment to quality care and patient safety initiatives. AAOS suggestions for the regulation of combination products. AAOS suggestions for the regulation of combination products.

3. Decrease regulatory burden Combination products provide unique challenges to FDA- under current scheme it will be difficult to get products to market. Combination products provide unique challenges to FDA- under current scheme it will be difficult to get products to market. Large start up capital Large start up capital Tissue-engineered products have a smaller potential market (except cartilage subs.) Tissue-engineered products have a smaller potential market (except cartilage subs.) 2 TE companies filed for bankruptcy- regulatory problems 2 TE companies filed for bankruptcy- regulatory problems Coordinate with CMS Coordinate with CMS

4. Team Approach Both in-house and 3 rd party reviews Both in-house and 3 rd party reviews Multidisciplinary Coordination Multidisciplinary Coordination  Materials Scientist  Biologist  Clinician  Engineer Odd number of reviewers Odd number of reviewers Sponsor should have the opportunity to provide additional information with the FDA Homework packet Sponsor should have the opportunity to provide additional information with the FDA Homework packet

5. Focus more on safety than effectiveness Effectiveness could take 10-20 years in orthopaedic products. Single and consistent regulatory pathway over time. For mode of action in bone products-

6. Osteogenesis Cellular elements, either from the host or from the TE product, which survive transplantation and synthesize new bone at recipient site. Cellular elements, either from the host or from the TE product, which survive transplantation and synthesize new bone at recipient site.

7. Osteoinduction New bone realized through the active recruitment of host mesenchymal stem cells from the surrounding tissue, which differentiate into bone-forming osteoblasts or form bone by endochondral ossification. Facilitated by presence of growth factors, principally BMPs.

8. Osteoconduction The facilitation of blood-vessel incursion and new-bone formation into a defined trellis structure The facilitation of blood-vessel incursion and new-bone formation into a defined trellis structure

9. Use foresight in preparing for global harmonization CBER should work with the TEMPS subcommittees of ASTM on tissue standards CBER should work with the TEMPS subcommittees of ASTM on tissue standards Several standards have already been finalized Several standards have already been finalized Encourage global harmonization efforts Encourage global harmonization efforts

10. Create Advisory Panel Consider the establishment of an FDA Advisory Panel with biological and device expertise. Consider the establishment of an FDA Advisory Panel with biological and device expertise. FDA biologist and engineer reviewers should work side-by-side during the review process. FDA biologist and engineer reviewers should work side-by-side during the review process. The review should consider method of use as well as primary mode of action. The review should consider method of use as well as primary mode of action. TEMPs are not the same as drugs or biologics. TEMPs are not the same as drugs or biologics.

11. Adverse Event Reporting Patient Safety movement Patient Safety movement AAOS supports legislation introduced into the 106 th & 107 th Congress that will encourage a nonpunitive approach for reporting that ensures appropriate confidentiality & peer review protections AAOS supports legislation introduced into the 106 th & 107 th Congress that will encourage a nonpunitive approach for reporting that ensures appropriate confidentiality & peer review protections AAOS encourages the finalization of the Donor Suitability & Good Tissue Practice regulations AAOS encourages the finalization of the Donor Suitability & Good Tissue Practice regulations

12. Adverse Event Reporting (continued) AAOS suggests that FDA work with experienced clinicians to define the term “adverse event” for procedures. AAOS suggests that FDA work with experienced clinicians to define the term “adverse event” for procedures. FDA’s interpretations of adverse events are too broad. FDA’s interpretations of adverse events are too broad. For combination products, users will not readily understand the regulatory class- coordinate reporting within FDA. For combination products, users will not readily understand the regulatory class- coordinate reporting within FDA. FDA mechanism is not interactive. FDA mechanism is not interactive.

13. General Principles Consistency Consistency Predictability Predictability FDA Accountability FDA Accountability Don’t change rules midstream- very difficult for companies to have the regulatory status changed. Don’t change rules midstream- very difficult for companies to have the regulatory status changed. One application One application

14. AAOS looks forward to working with the FDA on bringing new products to market and ensuring patient safety.

15. AAOS appreciates the opportunity to participate in this open public meeting. Thank You