Present:

Members reviewed and approved the summation report from the July 2003 meeting of the Orthopaedic Device Forum. Members and guests were introduced to the Forum. All participants disclosed conflicts of interests.

The Center for Devices and Radiological Health (CDRH) investigated problems associated with Sulzer’s InterOp acetabular cups. Many of the prostheses were metal-metal components and originally the histology was assessed for possible metal allergy, as well as infection.

The CDRH suspected that bacterial endotoxin could have been a contributor to the bacteriological response in patients. Bacteria can be divided into either gram negative or gram positive depending on the retention of a stain applied in the laboratory. Gram-negative bacteria do not retain the stain and have a lipopolysaccharide (LPS), or endotoxin component. An endotoxin stimulates macrophages, B-lymphocytes, and an acute inflammatory response, which can simulate the appearance of an infection. Gram-negative bacteria such as E. coli, Pseudomonas, and Salmonella are found extensively near water.

After analysis, some Sulzer InterOp devices were found to have an oily residue left on the acetabular cups after machining. The omission of the nitric acid passivation step was correlated with failure of the device and problems with attachment. 83% of the revision surgeries were from the lots of cups that were not passivated. Eventually, endotoxin was found in the machining sump pumps, and ultimately 2600 cups were revised.

The American Society for Testing and Materials (ASTM) formed a task force under the medical/surgical division (F-04) and held a workshop in May 2003. Since sterilization procedures do not necessarily remove all endotoxin, the prevention of non-sterile environments is essential. The National Institute for Science and Technology (NIST) is also interested in investigating problems with implants and endotoxin.

http://www.nist.gov/public_affairs/guide/interface_of_matls_with_biology.htm
http://polymers.nist.gov/uploads/tesk0103.pdf

Discussion:
Members discussed that sterility and cleanliness are two different issues. In general, orthopaedic implant manufacturers are producing remarkably clean products. The pre-market approval (PMA) application must document the manufacturing process of the device. Devices cleared for marketing under a 510(k) application must follow quality systems regulations and are subject to periodic FDA inspection. Orthopaedic manufacturers are cognizant of the potential implications of a manufacturer deviation in the aftermath of the Sulzer InterOp problem. Current ASTM standards do not address the cleanliness of implants however; implants that transport blood may need to be held to a higher standard.

Autologous Growth Factors (AGF)
Members discussed the article “Efficacy of Autologous Growth Factors in Lumbar Intertransverse Fusions” authored by Bradley K. Weiner, MD and Matthew Walker, MD recently published in Spine. The small retrospective series was the first human study to determine bone formation with AGF in lumbar intertransverse fusions. The use of AGF resulted in inferior rates of fusion compared with autogenous iliac crest alone.

Researchers noted that the AGF contain some white blood cells and that only one human’s biologics are contained in the AGF. Until a broad sample of human AGF is sampled, it may not be prudent to make generalizations based on one small human study, or one human’s biological characterizations.

Hip Guidance
The Forum reviewed the latest draft of the Clinical Design for Hip Replacement Systems. General Counsel at the FDA was consulted for an interpretation of the use of data covered under the 6-year rule. Subsequently, very little of this data was deemed available for use by the public.

The project team used the Journal of Bone and Joint Surgery levels of evidence rating system:

Literature searches were performed and 277 articles were utilized for the guidance document. Authors of the guidance document read through all of the articles. A Clinical Consensus Committee, chosen from among members of the Hip Society was consulted and received a questionnaire. Compliance rate on returned surveys was 100%.

The goal of the hip guidance document is to establish safety and efficacy by comparing new devices with existing devices. The comparison should occur within the context of standardized measures for safety and efficacy, including the complication prevalence, the Harris Hip Score (HHS), revision prevalence, and the radiographic failure prevalence.

The guidance team consulted the clinical committee to achieve consensus on the following:

• Complications attributed to hip replacement systems (HRS) devices themselves
• Minimum acceptable change in the Harris Hip Score (postoperative vs. preoperative)
• Minimum acceptable HHS at final postoperative endpoint
• Radiographic measure and minimal quantities
• Minimum percent difference in clinical success from consensus benchmark composite
• Final postoperative endpoint in terms of time

The outcomes data gathered for the HRS guidance provided the following:

• Complication prevalence= 0
• Harris Hip Score increased 20-30 points (depending on the preoperative score)
• Revision prevalence= 0
• Radiographic failure prevalence= 0
• Endpoint= 2 years
• Study success= 95 percent

Discussion:
Forum members discussed how to define success, i.e. patient success may be different than study success. Also, members discussed that it was difficult to achieve consensus on the definition of failure.

Complication rate was a major area of disagreement. Forum members indicated that it would be prudent to compile a list of complications from the 277 articles used for the guidance document. Complications could be classified as probable, possible, or non-device related. Device applications are often submitted to the FDA without sufficient complication type or rate information and are subsequently determined to be deficient.

Researchers noted the lack of content in the articles and an inability to assess when a complication occurred during a patient’s treatment. Forum members suggested that finding out when complications occurred could have significant national implications. A surgeon stated that complications in the Medicare database generally occur during the first three months after hip replacement surgery. The two- year clinical study time period has become the accepted norm due to journal publication requirements. Nevertheless, if researchers could determine that 90% of complications occurred during the first year after hip replacement surgery, would authorities deem it to be essential for companies to submit two-year clinical data?

Additionally, members suggested that a rate of loss to follow-up of study participants was necessary for the guidance document. Typically, the maximum loss to follow-up used in sample size calculations is 15%. FDA staff noted they typically request intent to treat or sensitivity analyses to address the impact of missing patients or data for cases, independent of the percentage of loss to follow-up. FDA also noted that loss to follow-up of 15% or more make the determination of safety and effectiveness difficult to assess.

The goal of the guidance document is to set objective performance criteria for hip replacement systems. If the guidance document is successful in setting a system for objective performance criteria, a manufacturer may request a panel meeting if their device data does not meet the guidance recommendations.

Next Steps:
OSMA will review the revised guidance at their meeting in January 2004 and review of the guidance may be scheduled for the FDA Orthopaedic and Rehabilitative Devices Panel meeting on March 22-23, 2004.

Artificial Discs
Device companies are looking with anticipation at possible future approvals on disc replacement implants. Two year clinical data is expected by December 2003 on the Charite` III device. The disc replacement market is estimated at 20 million dollars for 2005. The worldwide spine market was projected at 3 billion dollars in 2003.

Forum members discussed emergent issues expected to develop regarding disc replacement devices. Surgeons are unsure if the kinematics of the spine are fully understood. Mechanical loads are different for cervical versus lumbar spine and engineers are challenged to simulate the spine in a laboratory. Additionally, finding the correct center of where a load should be forced does not always simulate human kinematics. Reportedly, companies are not proceeding with facet development however, surgeons anticipate that this could be a future area of interest due to the number of problematic cases with facets. Furthermore, it is unknown how a disc replacement device will affect the adjacent segment.

Surgeons discussed spinal fusion versus disc replacement. Disc replacements will provide more options for spine surgeons but many questions remain unanswered. Infections are not yet cited in the disc replacement medical literature. Forum members agree that non-fusion devices may require a much more complex evaluation than other spinal devices.

Forum members decided to form an ad hoc group to assess disc replacement device issues. Surgeons will contact members of the North American Spine Society, the Cervical Spine Research Society, and the Scoliosis Research Society to draft members to provide advice on preclinical biomechanical studies, preclinical wear studies, characterization of wear debris, clinical indications, clinical performance measures, radiographic performance measures, in addition to other issues. Future symposia could be developed at the AAOS Annual meeting or at an ASTM meeting.

Biologics
Bone morphogenetic protein
Bone morphogenetic proteins (BMP) are being used off label and mixed with allograft bone. Additionally, BMP is being used off label in revision spinal surgery. Surgeons commented that there is little available literature to decide on dosage and mixtures of products.

Change in regulatory status
The FDA changed regulatory responsibility, review and oversight for many biologic therapeutic products from Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER). The following product classes are affected:

• Monoclonal antibodies for in-vivo use;
• Cytokines, growth factors, enzymes, immunomodulators; and thrombolytics;
• Proteins intended for therapeutic use that are extracted from animals or microorganisms, including recombinant versions of these products (except clotting factors)
• Other non-vaccine therapeutic immunotherapies

The review staff from CBER was transferred to CDER. Therefore, continuity should be ensured on the product classes listed above.

• Orthopaedists do not typically use biomolecules systemically. Dental products have incorporated biomolecules in implants previously. Forum members are not aware of significant research ongoing studies in this area at this time.
• Forum members noted that two products to grow cartilage are currently being marketed in Europe.
• The Forum generated cartilage guidance document should be broken into two documents: preclinical and clinical.

Standards- ASTM/ISO
The International Standards Organization met in Turkey in September 2003. A strong U.S. presence led to favorable outcomes. China is attending ISO and has emerged with competitive strategies.

Tissue engineering development continues to be of significant interest in the United States whereas the European community is less unified in their commitment to tissue standards development.

Tissue Engineered Medical Products Standards (TEMPS) home page: http://www.fda.gov/CDRH/Tisseng/temps.html

Metrology and Standards for Cell signaling: Impact on Tissue Engineering National Instituted of Standards and Technology- October 14-15, 2003 http://www.nist.gov/public_affairs/confpage/new031014.htm

ASTM International’s fall meeting will be held in November 2003 in Tampa, Florida. New officers will be elected during the meeting.

Guidance Documents
The Forum subcommittee reviewed the FDA’s Guidance Document on the Preparation of Investigational Device Exemptions and Premarket Approval Applications for Bone Growth Stimulator Devices. The subcommittee agreed that a 9-month time frame was too long for a nonunion study. Subcommittee members will provide references in the medical literature to support a shorter time frame at the next Forum meeting. The FDA stated that allowing for patients to serve as their own control was the reason for the nine-month time frame for non-union indication.

Annually, the FDA sends out a list of guidance documents that are in development or that are suggested for revision.

FDA Educational Seminars
An educational seminar is planned for Jan 23, 2004 on joint arthroplasty issues. The session will be videotaped for future reference and address the following:

• Assessing Joint Arthroplasty Outcome
• The Impact of Evolving Technologies & Techniques on Device Regulation
• Alternative Bearing Surfaces
• Biological Concerns
• Clinical Practicum

Future symposia might address disc prostheses and disc arthroplasty. FDA officials noted that staff college presentations are held every other week for neurology topics. Furthermore, Medical Device User Fee and Modernization Act of 2002 (MDUFMA) funds are allocated to decrease review times and to address the educational needs of the FDA staff. Some experienced staff are retiring or leaving and educational needs are ongoing. Forum members urged that another educational offering could be developed in 2004.

FDA

• The Office of Device Evaluation (ODE) recently created a spine team and a joint replacement team.
• The Orthopaedic and Rehabilitative Devices Panel will be meeting in December 2003 to assess the down-classification of spinal cages. The committee will discuss, make recommendations, and vote on the reclassification of the intervertebral body fusion device (cage) intended for spinal fusion procedures in skeletally mature adults with degenerative disc disease at one or two levels from C2-C7 and L2-S1 using autogenous bone graft. Forum members discussed that many spinal cages are surgically removed and that surgeons are probably not reporting those events to the FDA.
• FDA plans to issue a response to OSMA on the mobile bearing knee petition by the end of 2003, prior to the next OSMA meeting.
• Manufacturers are working on their applications for demineralized bone plus additives. Validation of processing methods has proven to be challenging for some manufacturers.
• The Orthopaedic Devices Branch is seeking to hire two full time mechanical engineers. Experience in clinical areas is desired.
• The FDA is completing paperwork for the CDRH fellowship positions in spine.

OSMA
OSMA is concerned about the effort to up-classify orthopaedic devices in the European Union. The Sulzer InterOp problem is perceived as the impetus for increased regulatory scrutiny. However, the InterOp hip problems resulted from a change in manufacturing processing not a design problem. Dr. David Williams wrote an independent report on the European Commission’s proposed directive to reclassify certain total joint prostheses.

• OSMA created a task force to investigate the down-classification of spinal cages.
• OSMA has not reached consensus on a test method for metal on metal hip prostheses.
• OSMA’s guidance document on demineralized bone matrix will be finalized in 2004. Members of the AAOS Biological Implants committee expressed interest in reviewing the document.

NIAMS
While NIAMS has received substantive budget increases in the past, future increases are not expected to be at the same level. President Bush recommended increases of 2%, though Congress may approve larger increases for NIH. NIAMS is currently considering how to allocate funds for substantive grant applications. Ongoing program announcements have been issued on joint implant wear grants.

NIH Panel Confirms Effectiveness of Total Knee Replacement http://www.nih.gov/news/pr/dec2003/od-10a.htm

NIH Consensus Development Conference on Total Knee Replacement December 8-10, 2003 Draft Statement: http://consensus.nih.gov/cons/117/117cdc_statement2.htm

AHRQ Evidence Report:http://www.ahrq.gov/clinic/epcsums/kneesum.htm

CMS
The Centers for Medicare and Medicaid Services (CMS) representative reported that CMS is currently discussing payment codes for bone morphogenetic proteins and extracorporal shock wave therapy.

American Joint Replacement Registry
The AAOS has reached a contractual agreement with a software company to extract data from hospital systems on total joint replacement procedures. The systems do not allow for an identification of the implant however, bar coding should capture the pertinent information. The pilot project will assess data from approximately thirteen sites and if the pilot is deemed successful, a national joint registry may be considered.

Antibiotic Bone Cement
Surgeons regularly use antibiotic bone cement in total joint arthroplasty and for other applications such as bone void filler during tumor surgery. However, AAOS is not aware of a consensus on the application, the amount of antibiotic, nor the type on antibiotic mixed with the bone cement. Several manufacturers have received market clearance for antibiotic bone cement products since May 2003. The AAOS will survey joint replacement specialists on antibiotic bone cement usage and report to the Forum in February 2004. At a recent AAHKS meeting, 40 % of members reported using antibiotic bone cement on primary hip or knee surgeries. European data suggest that antibiotic resistance is not problematic due to the use of these products.

AAOS Committees
Biological Implants Committee
The Biological Implants committee has officially added a seat on their committee designated for a tissue-banking expert. The committee will meet in the Washington, DC in mid-November to engage in discussions with FDA liaisons.

Three members of the AAOS Biological Implant committee are moderating symposia at the 2004 AAOS Annual Meeting. Symposia include: Commonly used Enhancers of Bone Healing, The Role of Pharmacological Agents in Fracture Healing and Implant Fixation, and Cell Based Therapies in Bone and Cartilage Repair. The committee also plans two scientific exhibits: one on xenotransplantation and a followup to last year’s allograft safety exhibit. The Biological Implants committee will host a retrospective exhibit of Dr. Marshall Urist’s contributions to medicine at the 2004 AAOS meeting in San Francisco, CA.

Biomedical Engineering Committee
The Biomedical Engineering committee continues to meet at the fall ASTM meeting. The committee is investigating computer-assisted surgery and assessing multiple ways to standardize the technologies. The committee will present an instructional course lecture on the mechanism of injury at the 2004 AAOS Annual Meeting in San Francisco, CA.

Future Agenda Items

• New Product Development particularly for small volume products.
• Chantilly Revisited subcommittee- will examine data from the 1995 Chantilly, VA conference vs. new data and assess what percentage of new product development is occurring overseas.