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Presentation on Allografts
Richard Hurwitz, MD, CEO of LifeNet briefly reviewed the history of tissue banking. Allograft tissue usage continues to increase and remains an important therapeutic alternative for orthopaedic surgeons.
The Centers for Disease Control and Prevention (CDC) led an investigation into allograft tissue processing following the death of a Minnesota man in 2001. More recently, the CDC reported on the case of a 17 year old in Colorado who underwent an elective anterior cruciate ligament repair with a hemi-patellar tendon allograft. The patient was later diagnosed with Streptococcus pyogenes, a group A streptococcus (GAS). Preprocessing cultures from the donor tissue also yielded GAS. The New York Times attributed both cases to Tissue Processor A, or Cryolife, Inc. Allograft associated infections are rarely reported in peer-reviewed medical literature; however, the CDC cites case reports through the Morbidity and Mortality Weekly Report.
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5248a1.htm
Voluntary oversight for the accreditation of tissue banks is accomplished by the American Association of Tissue Banks (AATB) a scientific, not-for-profit, peer group organization founded in 1976 to facilitate the provision of transplantable cells and tissues of uniform high quality in quantities sufficient to meet national needs. The AATB publishes standards and inspects facilities in addition to providing accreditation. The majority of musculoskeletal tissue transplanted in the U.S. is from AATB accredited banks. Donor screening is extensive, requiring physical assessment, time limits on procurement, review of medical records including autopsy (if available), hemodilution calculation, physical assessment, serological testing, absence of sepsis, medical/behavioral risk assessment, and other screening mechanisms.
http://www.aatb.org/
The use of the term “sterile” has provided controversy for allograft processors. The American National Standards Institute, the American Association for Medical Instrumentation, and the International Standards Organization have created a standard for sterility testing. Tissue processors must validate their procedures according to the Food and Drug Administration’s guidance, Validation of Procedures for Processing of Human Tissues Intended for Transplantation:
http://www.fda.gov/cber/gdlns/tissval.htm
Demineralized bone, with the addition of a substance other than a carrier that sterilizes, preserves, or is a storage agent, is currently regulated as a medical device. Manufacturers of demineralized bone products are seeking substantial equivalence determinations to calcium sulfate preparations.
Discussion
Members questioned if the sterilizing dose of radiation, approximately 10 kilogray, is too high a dose for allograft tissue. A research scientist suggested that biological integrity may be compromised with high radiation levels.
Nucleic acid testing (NAT) for cadaveric specimens to determine Human Immunodeficiency Virus (HIV), Hepatitis B virus, (HBV), and Hepatitis C virus (HCV) transmission is being developed and will further minimize the risks of viral disease transmission. Currently, the window period on testing for Hepatitis C is 70 days for allograft tissue.
The American Academy of Orthopaedic Surgeons (AAOS/Academy) encourages the finalization of the last two FDA proposed rules on donor suitability and good tissue practices. Transplantation of human tissue is accomplished approximately one million times per year with an extremely low risk/benefit ratio. The AAOS has prioritized patient safety as one of its most important initiatives. Member Alerts are sent to the entire fellowship on recalls for devices or drugs, and allograft tissue processing problems. The Academy will feature a Bulletin cover article on allograft processing in February 2004. Orthopaedic surgeons are encouraged to call the Medical Director of their tissue bank regarding safety concerns of allograft tissue.
http://www.aaos.org/wordhtml/bulletin/feb04/feature1.htm
Hip Guidance Document
The Forum hip guidance subcommittee solicited input on the hip draft document and incorporated comments from OSMA. The document is designed to serve as a template for performance measurement of devices and could be beneficial for the long-term growth of orthopaedic devices.
The subcommittee requested further clarification on the complications listed in the 277 articles assessed in literature review. Complications need to be categorized as either device related, possibly device related, patient related, or non-device related. However, reviewers noted the lack of information in the literature as to specifically when a complication following a hip replacement had occurred. The FDA requires a time line of all complications; therefore, the data are always requested. Surgeons will schedule a brief meeting at the AAOS Annual Meeting in San Francisco to provide further input on the proper assignment of complications into categories.
Subcommittee members will contact orthopaedic journal editors and explain that it would be very beneficial to the orthopaedic community to have a timeline of complications documented in the medical literature. Surgeons encouraged industry members to proceed with a few case studies from Investigational Device Exemption (IDE)/Premarket approval (PMA) data to determine a timeline of adverse events from the collected data. The subcommittee and OSMA will attempt to send the document to the FDA docket and submit it for the June 2004 Panel meeting.
Chantilly Revisited
The Orthopaedic Research Society representatives acknowledge that the Forum might benefit from input from a tissue engineer. The scientists have contacted their Board of Directors and may nominate a representative from a biologically focused company. The Chantilly Revisited subcommittee will assess progress in medical innovations during the last decade.
Disc Replacement
“The Pre-clinical and Clinical Trial Design for Cervical and Lumbar Disc Replacement Systems” draft guidance document is being circulated electronically to members of that subcommittee. Members attested to real or perceived conflicts of interest. Forum members discussed that other outcomes measures should be considered in addition to the Owestry disability inventory. The subcommittee will review current literature including the December 2003 Spine article “Intermediate Follow-up After Treatment of Degenerative Disc Disease With the Bryan Cervical Disc Prosthesis: Single-Level and Bi-Level” by Goffin, et. al.
Biologics
The Forum Biologics subcommittee held a brief conference call in February 2004. Members reviewed the ASTM bone induction standard and were reminded that all negative votes must be resolved prior to the affirmation of the standard in that organization. Allograft issues have focused on bacterial issues over the past two years; however, some members suggest that it might be appropriate to revisit problems and incidence of viral transmission in allograft tissue. A speaker from the CDC may be identified for a future Forum discussion.
FDA Educational Seminar
The Forum coordinated an educational seminar on January 23, 2004 for FDA staff on joint arthroplasty issues. Orthopaedic surgeons discussed assessing outcomes and understanding the data, the impact of evolving technologies and techniques on device regulation, alternative bearing surfaces, biological concerns, and clinical assessment. The FDA frequently confers with neurosurgeons on emerging issues. Members suggested increasing the amount of time allotted for questions and answers. Future seminars are planned and possible topics include the cleanliness of implants, allograft tissue, bone morphogenetic proteins and demineralized bone matrix.
Cartilage Guidance
The Forum’s previous versions of the “Repair of Hyaline Articular Cartilage” draft guidance document should be divided into clinical and preclinical documents. Forum members will resurrect the document and circulate it for comment.
ASTM International is preparing the “Standard Guide for the Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage” for ballot. The draft standard assesses the testing of preclinical measures for animal articular cartilage remodeling. Forum members acknowledged that some companies are currently having success with cartilage growth and that assessment is desired early in the development of this technology.
Standards
- The American Society for Testing and Materials (ASTM) International is meeting in April 21-23, 2004 in Salt Lake City, Utah. The fall meeting will be held in Washington, DC on November 9-12, 2004. A symposium on titanium, niobium, zirconium, and tantalum for medical surgical applications will be held November 9-10, 2004.
http://www.astm.org
- The United States continues to lead tissue-engineering standards development with the ASTM efforts on standards for terminology, biomaterials and biomolecules, cell and tissue engineered constructs, assessments, and adventitious agents safety. Japanese scientists are interested in collaborating on tissue standards to avoid a duplication of labor.
- AAOS representatives participated in the International Standards for Medical Technologies in Geneva, Switzerland in February 2004, in conjunction with the International Standards Organization.
AAOS BOD Report
- The AAOS reorganized their executive structure to include a Chief Financial Officer, Chief Education Officer, Chief Operations Officer and Medical Director reporting to the Chief Executive Officer.
- The AAOS is currently the third largest publisher of orthopaedic books.
- Doctors for Medical Liability Reform (DMLR) is a coalition of 230,000 medical specialists working to promote the passage of federal legislation to cap non-economic damages awarded in medical liability cases. The AAOS is a founding member of DMLR.
http://www.protectpatientsnow.org/
- The AAOS brought fifteen patients to Capitol Hill to advocate for increased funding for musculoskeletal conditions. Patients and surgeons met with their local U.S. representatives and members of the Committee on Appropriations. Homeland security initiatives are receiving a large percentage of funding dollars allocated to research.
- The CMS quality initiatives are providing incentives to hospitals to utilize specific evidence-based measures. Similar initiatives are expected in the future.
http://www.cms.hhs.gov/quality/
http://www.cms.hhs.gov/media/press/release.asp?Counter=965
Priorities
In 2003, the Forum identified their priority projects as antibiotic bone cement issues, metal/metal hip reclassification, mobile bearing knee reclassification, and educational initiatives. Forum members are encouraged to nominate projects for 2004.
Discussion on Innovative Products
Several Forum members contend that new orthopaedic product development is generally occurring in Europe rather than the United States. Some U.S. manufacturers suggest previously a custom implant provided a solution to bringing new products to market.
Documents such as the disc replacement draft guidance are the types of documents that are beneficial when the FDA reviews PMAs. The FDA encourages the development of guidance documents that identify endpoints on safety and effectiveness of developing technologies.
Currently, development of new technologies is generally done by committee. Previously, a surgeon- entrepreneur initiated new device development. Some Forum members noted that some oncology patients truly require a custom implant.
Members questioned if the pre-clinical studies on some disc replacements were adequate. Pre-clinical testing tends to be less stringent in Europe than in the U.S. Forum members suggested that companies should provide data on how much development is occurring overseas and include relevant financial details. An AAOS surgeon representative suggested that Forum members choose a device as a test case and dissect all the processes and pertinent financial information. It is suggested that members report back to the Forum at the next meeting on their test case technology, such as disc replacements.
Antibiotic Bone Cement
The Academy is seeking information on how antibiotic loaded bone cement (ABLC) is used and in what concentrations. Anecdotal information relates that ABLC is being used in primary joint replacement surgeries.
The AAOS sent a survey to 1060 hip and knee surgeons and the response rate was 31%. Respondents reported a high percentage of premixed ABLC preparations, which is somewhat suspect given that the first product of this type was granted market clearance in May 2003. Companies have FDA-cleared indications of either the second stage in a two-stage revision or the use as a spacer in a two-stage revision.
Forum members wondered how often systemic antibiotics were used concurrently with the local delivery of antibiotics in the cement. The AAOS will attempt to collect more data at the 71st AAOS Annual Meeting at the antibiotic bone cement scientific exhibit.
CDRH Guidance Document Review
Forum subcommittee members are reviewing selected CDRH guidances to determine if there is a consensus on revisions to the guidances. The subcommittee is currently assessing the guidance on Investigational Device Exemptions (IDE) and Premarket approval (PMA) applications for bone growth stimulators. Members suggested that a nine-month time frame for a non-union was too long however, the FDA explained that the untreated patient was serving as the control group. Forum subcommittee members will submit suggested revisions prior to the next meeting.
- Guidance Document for Industry and CDRH staff for the Preparation of Investigational Device Exemptions and Premarket Approval Applications for Bone Growth Stimulator Devices; Draft
http://www.fda.gov/cdrh/ode/bgsguide.pdf
FDA Update
- The Medical Device User Fee Modernization Act of 2002 (MDUFMA) is providing the CDRH with increased funds to update their information services capabilities and provide CDRH with an internal divisional document tracking system.
- PMA applications appear to be adhering to mandated MDUFMA timelines. CDRH allocated a project manager to assess applications that may have deficiencies or may be seeking a future Orthopaedic and Rehabilitative Devices Panel (Panel) review.
- The Panel met on December 11, 2003 in Gaithersburg, MD and unanimously voted to recommend that FDA reclassify the intervertebral body fusion (cage) device into class II. The cage is 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. The device does not include combination products, such as the intervertebral body fusion device using morphogenic proteins and scaffolds. The Panel recommended three special controls to control to reasonably assure the safety and effectiveness of the device: 1) a guidance document, that may include clinical data for designs and materials beyond those currently approved, 2) device tracking (for all implants, not just cages) for a limited period of time, and 3) testing guidelines, including fracture toughness, potential and response to wear particulates, and device retrieval analysis for a limited number of explanted devices.
- The CDRH received the mobile bearing knee reclassification petition from the Orthopaedic Surgical Manufacturers Association (OSMA). The FDA is requesting some additional information on this petition.
- The CDRH is working with a neurosurgeon part-time as part of their Fellowship program. The FDA is still interested in qualified candidates for other opportunities.
http://www.fda.gov/cdrh/mdfp/
OSMA Update
- France and Britain requested an increased classification from the European Commission for hip, shoulder, and knee joints on November 5, 2002. The request does not provide any scientific justification for such an action. Industry unanimously objects to the Franco-British request and has always supported initiatives to increase the safety of medical devices. A vote on this action is scheduled for April 2004. Industry contends that they will be hampered by substantial additional costs that may cause financial hardship for some companies. Dr. David Williams of the University of Liverpool, UK provided an independent report for Eucomed to respond to the Franco-British inquiry.
- OSMA is drafting a petition on the downclassification for spinal cages. A number of orthopaedic companies will share their Premarket approval (PMA) data and summaries on safety and effectiveness (SSE).
- OSMA has a task force to investigate the cleanliness of implants. Endotoxins are an important issue for inspectors.
- The Advanced Medical Technology Association (Advamed) has adopted a new Code of Ethics effective January 1, 2004. The policy was adopted to facilitate ethical interactions with health care practitioners. Modest accommodations and meals will be provided for meetings to be held in locations appropriate to the business being conducted. Forum members contend that the adherence to the policy will fundamentally change continuing medical education.
http://www.advamed.com/
Biological Implants Committee
Allograft issues continue to be of concern to the Academy. The Biological Implants committee provides guidance on these matters. The committee will meet with ASTM officials in March to discuss input to the tissue engineered medical products standards.
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 AAOS Biomedical Engineering committee encourages standards development for computerized assisted surgery. Several orthopaedic companies are currently marketing computerized systems and instruments that will not be compatible with each other.
The International Society for Computerized Assisted Orthopaedic Surgery (CAOS), is a non-profit organization, serves as a forum for the exchange of information of both an investigative and clinical nature which relates to preoperative planning, intraoperative execution and postoperative follow up by means of computer assistance.
The Fourth annual conference of CAOS International will be held on June 16-19, 2004 in Chicago, IL. http://www.caos-international.org/
CMS Update
A New York Times article published on December 31, 2003 “An Operation to Ease Back Pain Bolsters the Bottom Line, Too” examines Medicare payments for spinal fusions. Orthopaedic surgeons are concerned that a newspaper article may provide the impetus for an investigation into payment issues on spinal fusions. The Centers for Medicaid and Medicare Services (CMS) is interested in hearing from the orthopaedic community on the effectiveness and proper patient population for spinal fusions.
The investigation on the national coverage determination on arthroscopy was initiated by a New England Journal of Medicine (NEJM) article by Moseley, et. al. The orthopaedic community objected on several grounds: the NEJM is not an orthopaedic journal; the study was not reproduced; the Outerbridge instrument is unpublished; and Outerbridge is a post-operative classification system.
Registry Update
The AAOS is moving forward with the 18-month pilot project to collect data on total joint replacement procedures. Data collection will begin in April 2004 and involve 10 hospitals and approximately 1,250 patients.
Software and hardware will capture the following data:
- Patient identifiers (patient name, date of birth, Social Security number, gender, age)
- Surgeon identifiers (surgeon name, surgeon code)
- Hospital identifiers (hospital name, hospital code)
- Surgical data (date of surgery, patient diagnosis, surgical procedure, laterality, implants)
- Data entry points will be at primary TJR, revision TJR, and death
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