Present:

Members and government liaisons reviewed and approved the summation report from the November 2004 meeting of the Orthopaedic Device Forum (Forum). Participants disclosed potential conflicts of interest.

NIBIB
The National Institute of Biomedical Imaging and Bioengineering was authorized by public law on December 29, 2000. NIBIB's current director is Roderick Pettigrew, MD, PhD, appointed in 2002.

All NIH institutes engage in strategic planning sessions and NIBIB is finalizing their draft strategic plan which is available at: www.nibib1.nih.gov/about/SP/strategicplan.htm

NIBIB's mission is to improve health by leading the development and accelerating the application of biomedical technologies. In support of its mission the Institute will:

• Support research and research training through existing NIH funding mechanisms, and take the lead in exploring novel approaches for funding technology development and interdisciplinary research.
• Form partnerships with NIH institutes and centers to translate fundamental discoveries into research and applications for specific diseases, disorders, or biological processes.
• Coordinate with other government agencies to translate fundamental or crosscutting discoveries and developments in imaging and engineering, and related areas of information science and technology assessment, into biomedical applications.
• Encourage and support the development of relevant standards and guidelines that will enable widespread adaptability for biomedical imaging, bioengineering, and related information science, technology, and computation, by taking a leadership and coordinating role for the NIH.

NIBIB is seeking to institute an intramural program and encourages public-private partnerships, although they are both undeveloped at this time.

The Whitaker Foundation has funded grants for over a decade and is spending all of its assets and closing in June 2006. No new applications for funding are currently being accepted. The biomedical community will experience a profound loss from the research advances provided by grants from the Whitaker Foundation. www.whitaker.org/index.html

The Coulter Foundation is funding 'bench to bedside' research, or translational research. The foundation is also interested in funding early career awards. www.whcf.org/index.htm

The FDA 'Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products' white paper addressed gaps in translational research in the United States. The biomedical community acknowledges the lack of translational research; however, solutions are not readily apparent. www.fda.gov/oc/initiatives/criticalpath/whitepaper.html

Combination Products
The biomedical engineering community had great aspirations for 'tissue engineering,' a phrase originally coined in 1987. In the late 1990's, the term 'regenerative medicine' began to be used and was often used interchangeably with 'tissue engineering.'

Industry data demonstrate that while the number of companies engaged in tissue engineering increased from 2000 to 2002, the number of employees simultaneously shrank from 3300 to 2700. The annual investment also shrank from $610 million in 2000 to $506 million in 2002.

Even though there have been many problems with the business models of several start-up companies, the future of medicine lies in the biological arena. Some problems encountered by companies include the size of the market, regulatory issues, the cost of conducting clinical trials, management strategies, delays in reimbursement, and the lengthy development time. Notwithstanding, device companies invest heavily in biological research and development.

Some key trends in bioengineered tissue manufacturers have emerged since 2000. They include the development of 33 new firms, 26 firms have increased in size; 16 firms have decreased in size; 17 firms have merged, left the field, or gone out of business; 80% of the new firms are working on stem cell development; and 40% of new firms are located outside of the U.S.

Traditional devices alleviate symptoms and reduce pain, but they are not cures. The use of biologics (delivery of genes, proteins, or cells) holds the promise of providing cures for patients.

Combination products (drug/device, drug/biologic, or device/biologic) are expected to become more commonplace in the upcoming years and are regulated by the Food and Drug Administration (FDA) according to their primary mode of action. Tissue engineered products may exhibit both biologic and device qualities, making a determination on the primary mode of action difficult.

MTLF
The Board of Directors of the Medical Technology Leadership Forum (MTLF) is addressing combination product issues. In July 2004, MTLF participants engaged in a series of regional workshops that led to recommendations for the future regulation of combination products. Four groups representing the country regionally offered different solutions for combination product regulations. Dr. Nerem and others represented the South/Atlanta task force which provided some innovative solutions. The Atlanta task force developed a set of key principles to include:

• A timely and predictable regulatory process for combination products;
• Greater reliance on post-market studies and surveillance, and less in the pre-market area;
• Providing the Office of Combination Products with regulatory authority and not simply the coordination and oversight role of the current office;
• The Office of Combination Products should integrate biologic and device expertise, but should also use external clinicians and scientists in the review process. 'Virtual' teams may need to be assembled rapidly;
• Expert panels should play a role in setting clinical trial requirements and expectations, not just reviewing the results.

Discussion
Dr. Nerem advocates that a national initiative is needed for tissue-engineering products with significant funds devoted to research. Additionally, he suggests financial support for early product stage development and a regulatory process that will accelerate in bringing new technologies to patients. Payment for new technologies has traditionally been delayed. Therefore, redesigning the reimbursement system on these products is an option to be assessed.

Forum members acknowledged the potential for harm in the use of tissue engineering products but reiterated that research is needed to answer scientific questions. Forum participants generally agreed that several tissue-engineered products entered the U.S. marketplace before the basic science was understood. A scientist commented that animal studies don't always predict the outcome of human studies. Payment for new technologies continues to be problematic for companies and pay-for-performance programs are further expected to have a quelling effect on the development and payment of new technologies.

Forum Compilation
The Forum reviewed a draft document that compiles the accomplishments of the Forum from 1996-2004. In 1995, the FDA was having problems with collecting investigational device exemption (IDE) data from companies. Also, manufacturers were experiencing regulatory delays in the review of product applications and the downclassification of devices was stalled. Dow Corning declared bankruptcy during this time due to the recall of silicone breast implants and subsequent legal costs.

In May 1995, the orthopaedic community organized a conference in Chantilly, Virginia to discuss regulatory problems. The most senior officials from organizations including the military were invited to the conference, which was deemed of great value and a collaboration was forged to work on solutions for bringing products to the U.S. market more rapidly.

Editing suggestions for the compilation document include:

• Elaborating on the background section of the document to provide more rationale for the inception of the Forum;
• Include the early developments with tissue, including the workshop and the issuance of the interim rule in 1997;
• Include the mission statement;
• Include the project failures;
• Engage in a SWOT (strength, weaknesses, opportunities, threats) analysis.

Forum members segued into a discussion about changes in the orthopaedic industry since 1995 and the benefit of including a biologic focus to move the Forum activities forward. Scientists encouraged more participation from researchers with a biologic focus.

A surgeon commented that the U.S. is the richest country in the world and yet it is not economically feasible to conduct an investigational device exemption clinical trial for every indication on a particular device. Additionally, a scientist questioned how to facilitate reasonable post-marketing studies. Another Forum member suggested determining the minimum threshold for the amount of data that could be collected by a non-IDE study.

One Forum member commented that effectiveness could be shown in two years and suggested conducting 'mini' IDE studies although there would likely be issues of reimbursement. Forum members acknowledged patient resistance to enrollment in studies after a pre-market approval (PMA) product has been granted access to the U.S. market. Generally, patients want access to the product and are unwilling to be randomized or provided with alternative products. Another member stated that how much a product costs may determine how a product is used.

Forum members discussed innovative solutions to working within the contemporary regulatory framework. Investigation into the following possibilities may include: defining the size of the IDE trial to determine effectiveness if a product has a proven safety profile; changing the trial data requirements i.e. the 'Clinical Trial Design for Hip Replacement Systems' document, and confirming a similar effectiveness of bone morphogenetic protein , for instance, in a different part of the spine than previous studied .

A suggestion was made to define endpoints for clinical trials. One scientist noted that some data is not meant to be shared with the FDA and in other cases, good data is gathered from some investigational review board studies (IRB) and is not in support of an IDE.

The Forum's efforts on the cartilage guidance became stalled due to the lack of a measurable endpoint. Five years later, computed topography (CT) scan is available to measure the growth of cartilage.

The Forum identified the disconnect between payment and approval as a continuing threat to medical innovation. Federal health officials at the highest levels must address this issue for any changes in policy to occur.

The Forum also discussed membership issues. In addition to acquiring representation to provide a broadened biological focus, the Forum still wishes to maintain an atmosphere of conviviality. Therefore, the Forum will not alter the current roster markedly. An orthopaedic surgeon suggested that the Forum focus its agenda for the next 1-3 year time frame.

Standards
The acceptance of standards and the development of the tissue engineered medical products (TEMPS) should be acknowledged as an accomplishment of the Forum. The development of tissue-engineering standards is meant to provide a framework for identifying deficiencies in scientific knowledge. The American Society for Testing and Materials (ASTM) is interested in the cleanliness of implants and will publish the proceedings from a workshop held previously.

The fall Medical/Surgical ASTM symposium will be held in Dallas, Texas on Tuesday, November 8- 9, 2005 and addresses the wear of articulating surfaces- understanding joint simulation.

Guidance Document Review
The subcommittee responsible for the review of the Center for Devices and Radiological Health (CDRH) guidance documents explained that the ceramic hip ball guidance did not address wear testing. Discussion followed and other members were added to the subcommittee. Additionally, a suggestion was made to define the term 'ceramic.' If sufficient portions or the guidance document are added, this document may change from a level two guidance to a level one guidance, necessitating a public comment period.

Guidance Document For The Preparation of Premarket Notification For Ceramic Ball Hip Systems: www.fda.gov/cdrh/ode/355.pdf

Educational Session
The next educational session planned with CDRH staff college will be on ortho-biologics. Following that, a half day session on bone related topics is anticipated in 2006.

CBER
Celia M. Witten, PhD, MD, was appointed as the Director of the Office of Cellular, Tissue and Gene Therapies (OCTGT) in the Center for Biologics, Evaluation, and Research at the FDA. The office has three divisions: cellular and gene therapies, human tissue products, and clinical evaluation and pharmacology/toxicology. OCTGT regulates cellular therapies, tumor vaccines, gene therapies, tissue and tissue based products, some combination products, devices for cells/tissue, and anti-idiotype antibodies.

Regulatory pathways for these products include: investigational new drug applications, investigational device exemptions, biological license applications, PMAs, 510ks, new drug application, and banked human tissue rules.

The final human tissue rule 'Current Good Tissue Practice for Human Cell, Tissue, and Cellular and Tissue-Based Product Establishments; Inspection and Enforcement' is in effect on May 25, 2005.

OCTGT has jurisdiction over therapies which pose regulatory challenges due to the rapidly evolving scientific knowledge base. The office intends to foster scientific and regulatory expertise throughout the staff.

OCTGT developed chemistry, manufacturing and controls (CMC) guidances on gene therapy and somatic cell therapies. The document links are located at: www.fda.gov/cber/genetherapy/gtpubs.htm

CBER and CDRH formed a cross-center team to address combination product issues. The team will draft guidance, provide outreach, review policy development, and capitalize on the expertise in both centers without duplicating efforts.

CBER has initiated a regulatory site visit training program to provide CBER staff with the opportunity to visit biologics facilities to observe first-hand the industry's biologic development and manufacturing processes to obtain a better understanding of the biologics industry and its operations. This program is intended to improve CBER's understanding of current practices, regulatory impacts and needs, and improve communication between CBER staff and industry.

Site of the Federal Register notice: www.fda.gov/cber/meetings/sitevisit.pdf

Cartilage Guidance
The cartilage guidance continues to develop and will be shared with CBER staff. This guidance addresses preclinical and clinical issues. Work group participants have struggled with defining endpoints and appropriate animal models.

Off-label Use
Forum members suggested substituting the term 'physician-directed application' for the term 'off-label' use as the latter seems to have negative connotations associated with it. 'Off-label' is not a regulatory term and is commonly used to apply to the use of an indication not specified in the manufacturer's labeling.

Forum members questioned how far physicians could push the boundaries of off-label use and noted that insurance companies generally will not pay for off-label indications. Other members noted that sometimes off-label indications are reimbursed if the efficacy is documented.

Surgeons expressed consternation about how to communicate complications that occur when drugs, biologics, combination products, or devices are used off-label. Manufacturers may receive initial adverse event or product malfunction reports. Physicians may report problems in a journal article. However, there are lengthy lead times for publishing. The current medical liability crisis does not provide an incentive for voluntary reporting on adverse events with the use of medical products, either used according to label specifications or in an off-label manner.

Surgeons noted that many physicians are unfamiliar with the regulations affiliated with humanitarian device exemption (HDE) products. HDE product applications must demonstrate a reasonable assurance of safety but not effectiveness. Physicians must obtain IRB approval prior to using a HDE designated product. An IRB must either approve or disapprove the use of a HDE product for the FDA-authorized indications; off-label uses are prohibited.

Companies may collect data from a HDE product and use the data to support other marketing applications. For instance, one manufacturer's product received an HDE designation for a temporary hip prosthesis with antibiotic bone cement. Subsequently, after data was collected and bone cement was down classified, the product is currently marketed as a 510k device.

Military issues
The Forum held a subcommittee conference call to discuss issues with collecting data in a military conflict situation. Subcommittee members proposed an educational offering to provide guidance on military issues. Some members favored the creation of a new course while others suggested a slight modification to Dr. James N. Weinstein's annual course, 'Orthopaedic Clinical Trials: Design Implementation and Regulation Issues.' An online course was also suggested as a possibility. www4.aaos.org/mastcaldb/cmedetails_campus.cfm?recordnum=1784

Forum members discussed that the National Institutes of Health (NIH) and the Department of Defense are very different entities. NIH grantees must formulate research grants into a hypothesis-driven format whereas the application style for the DoD is different. The Department of Defense (DoD) generally makes decisions very quickly; Forum members were unsure if the DoD would fund basic research.

The AAOS will testify before the Senate Defense Appropriations Subcommittee at its public witness hearing on FY2006 defense health requests. An AAOS proposal would establish a program at the U.S. Army Institute of Surgical Research (ISR) at Ft. Sam Houston, Texas, to fund peer reviewed intramural and extramural orthopaedic trauma research. AAOS has worked closely with top military orthopaedic surgeons at world-class facilities, including the ISR, Brooke Army Medical Center, and Walter Reed Army Medical Center, to identify gaps in musculoskeletal trauma research and to use this information to advocate for an increased federal commitment to research on trauma. Seventy percent of military trauma is orthopaedic-related.

Furthermore, the AAOS and the Orthopaedic Trauma Association (OTA) are developing a symposium, "Extremity War Injuries: Current, State of the Art, and Future Directions," to be held on January 24-27, 2006 in the Washington, DC area.

CMS
There are currently 41 million beneficiaries with $284 billion dollars in expenditures. Typical steps to Medicare reimbursement include regulatory approval by the FDA, benefit category determination by Congress, coverage, and coding and payment determinations by CMS.

Ninety percent of coverage decisions are made at a local level, while ten percent are national coverage decisions. National decisions may now provide coverage for some data collection systems. Core concepts include: the linking of coverage with prospective data collection systems, extending the CMS concept of medical necessity, and retaining evidence-based medicine as a conceptual framework for coverage and payment.

CDRH
The Division of General, Restorative, and Neurological Devices has experienced staffing reassignments with some FDA staffers on detail in other areas of the division and center. Other developments:

• The CDRH is working to reclassify intervertebral body fusion devices and is drafting the special controls guidance document and Federal Register notices.
• OSMA and the FDA are meeting to discuss the reclassification petition on mobile bearing knees.

Development on FDA guidances includes:

• The submission of an artificial disc guidance document drafted by a Forum ad hoc working group;
• FDA New Guidance: Clinical Trials Considerations: Vertebral Augmentation Devices to Treat Spinal Insufficiency Fractures- Guidance for Industry an FDA staff; www.fda.gov/cdrh/ode/guidance/1543.pdf
• FDA New Guidance: Clinical Data Presentations for Orthopedic Device Applications- Guidance for Industry and FDA staff;
  www.fda.gov/cdrh/ode/guidance/1542.pdf
• The Clinical Trial Design for Hip Replacement Systems draft guidance submitted by OSMA and the Forum is currently undergoing good guidance practice review at the FDA.

Harmonization by Doing
Japan-U.S. Harmonization By Doing (HBD) is a joint effort between CDRH, Japan's Ministry of Health, Labour and Welfare (MHLW), Pharmaceutical and Medical Device Administration (PMDA), and the Duke Clinical Research Institute (DCRI), to promote cardiovascular device clinical trials simultaneously in Japan and the U.S. under common protocols. Currently, the HBD efforts are limited to drug-eluting coronary stents.

HBD is intended to promote cardiovascular device clinical trials simultaneously in Japan and the U.S. under common protocols. The key to HBD success is practical, step-wise proof of concept projects. One of the benefits to the Agency is an increased device safety database. The Forum will circulate information on this effort to manufacturers to gauge industry's interest in working on a similar program in orthopaedics.

Biomedical Engineering Committee
The AAOS Biomedical Engineering (BME) committee is drafting a position statement on the importance of clinical participation in medical/surgical standards. The committee is also developing a course on product development to address regulatory issues, financial concerns, and the problems associated with development in the current litigious environment. The committee is seeking avenues to introduce educational forums on new technologies to the fellowship. The BME committee is promoting a literature follow-up on new technologies with the AAOS Program committee for Annual meeting presentations.

NIAMS
NIAMS officials participated in a 5 year planning session. NIAMS and other NIH institutes are assessing the future and current budgets in the aftermath of the past doubling of the NIH budget. NIAMS is still actively searching for an intramural researcher.

The Program Announcement for implant wear is still active: www.niams.nih.gov/rtac/funding/grants/pa/pa_01_141.pdf

The NIH implemented the following public policy:

Beginning May 2, 2005, investigators funded in full or in part by NIH will be asked to submit the final manuscript, upon acceptance for publication, to PubMed Central (PMC). PMC is the NIH digital repository of full-text, peer-reviewed biomedical, behavioral, and clinical research journals. It is a publicly accessible, permanent, and searchable electronic archive available at www.pubmedcentral.nih.gov/. Through this archive of peer-reviewed, NIH-funded research publications, health care providers, educators, and scientists will be more readily able to exchange and search for research publications, and the public will have greater access to health-related publications. An added benefit of using PMC is that articles returned by a search are automatically linked to a variety of research-related resources in other National Library of Medicine databases, such as DNA and protein sequences, protein structures, small molecules (PubChem) and taxonomy. These databases also provide linkages to a broad collection of other biological and health-related resources. Additional information is available at www.nih.gov/about/publicaccess/Finalpublicaccessimplementation031505.htm.

Registry
The AAOS registry pilot project is on hold until a dissolution agreement between the AAOS and the software company is finalized. The pilot sites continue to express a willingness to participate in a AAOS hip and knee replacement registry.

Biological Implants Committee
The committee is engaged in the following activities:

• Drafting a follow-up article to Dr. Tom Einhorn's 2002 piece for the Bulletin on "Cox-2 inhibitors and Bone";
• Submitted comments to the Secretary of Health and Human Services on the HHS draft reports on the state of the science and informed consent issues in xenotransplantation;
• Drafting a Bulletin article on FDA's encouragement of AAOS fellows reporting to the FDA on adverse reactions with implanted tissue products to their source manufacturers;
• Participating in the Centers for Disease Control and Prevention (CDC) planning team for a summer 2005 workshop on tissue and organ safety;
• Formulating methods to disseminate pertinent information to the fellowship on off-label use;
• Developing educational programs for the AAOS 2006 Annual meeting;
• Participating in the May 2005 ASTM tissue engineering subcommittee meetings.

AAOS BOD Report

• The AAOS Washington office hired a senior regulatory advisor to address orthopaedic specialty society issues for the Council of Musculoskeletal Specialty Societies (COMSS).
• Approximately 75 physicians, staff, and patients participated in Research Lobby Day in March 2005. This was the second year that patients visited members of Congress' offices.
• The AAOS Annual Meeting held February 23-27, 2005 in Washington, DC. Attendance was nearly 27,000 with many federal employees able to attend scientific sessions.
• The National Orthopaedic Leadership Conference (NOLC) was held in Washington, DC. Key issues this year are the Medicare physician payment formula update, preserving the role of in-office imaging services, and opposing direct patient access for physical therapy services. Pay-for-performance initiatives continue to progress in importance on Capitol Hill.