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Orthopaedic Device Forum
Present:
Approval of May 6-7,2002 Summation Report Members reviewed and approved the summation report from the May, 2002 meeting of the Orthopaedic Device Forum. New members and guests were introduced to the Forum. Disclosure statements were updated. | ||||||
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Presentation by Dr. Phil Noguchi
Dr. Noguchi, the Acting Director of the Office of Cellular, Tissue and Gene Therapies, in the Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA), presented an overview of biological regulations from 1798 to the present. 2002 marks the 100th anniversary of the 1902 Biologics Control Act, which gave the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) the authority to regulate biological products and ensure their safety for the American public. Gene Therapy Dr. Noguchi cited the extraordinary efforts of industry, academia and CBER in finding solutions to the recent gene therapy trial problems. Nonetheless, in 2002 a three-year old patient most likely developed cancer from a modified retrovirus. This patient was undergoing treatment in a French clinical trial for severe combined immunodeficiency.
Cell-Based Therapies Cell-based therapies pose different problems than drugs or devices due to the potential presence of adventitious agents in the original specimen, and the possible lack of adequate methods for testing or removal. Aseptic processing must occur at every stage of manufacturing or the possibility exists that the product may not be effectively sterilized prior to implantation.
Combination Products Combination products may be a derivation of a drug, biologic, or device developed together into one product. Companies have found these products to have long development times and have not easily recouped investigatory expenses. Notably, two tissue-engineering companies declared bankruptcy in 2002. Interested parties will need to develop better adverse reporting systems and track long-term consequences of these products.
Standards A past Chairman of the F-04 Medical/Surgical division of the American Society for the Testing and Materials (ASTM) expressed frustration at the lack of participation from the CBER division in the development of biological standards. The Tissue Engineered Medical Products (TEMPS) division of ASTM has been developing standards for several years. Forum members stated that most companies are in active development of combination products and that CBER will be involved in the regulatory review of these products. Members suggested much more interactive involvement between the scientific community and CBER.
Dr. Noguchi acknowledged ASTM’s efforts in developing standards; however CBER is not mandated to utilize standards in their review process, as is CDRH. CBER has standards for safety, purity, and potency.
Tissue The FDA anticipates that the Donor Suitability and Good Tissue Practice regulations will be finalized and published in January 2004. The Validation of Procedures for Processing of Human Tissues Intended for Transplantation final rule has presented a significant challenge to industry to prove that their processing technologies accurately confirm that tissues are free from disease causing organisms.
Senator Susan Collins (R-ME) introduced the Human Tissue Transplant Safety Act of 2002 into the Senate on May 17, 2002. The bill would amend the Public Heath Service Act and authorize the Commissioner of the FDA to conduct oversight of any entity engaged in the recovery, screening, testing, processing, storage, or distribution of human tissue or human tissue-based products.
AAOS will work with CBER and other interested organizations to develop a biological safety coalition that will help implement changes in tissue processing. Additionally, the coalition will advocate for funding to support research for tissue processing. Centers for Medicare & Medicaid Services (CMS) The CMS announced that they will evaluate the scientific evidence to determine the indications for which arthroscopic lavage and/or debridement for the treatment of the osteoarthritic knee is reasonable and necessary following the publication of the Moseley article in the New England Journal of Medicine, Volume 347, No. 2, 2002. Expected completion date of review is January 8, 2003. CMS may refer this issue to a federal advisory panel upon completion of their review. The link to the inquiry is: http://www.cms.gov/coverage/8b3%2Duuu1.asp
AAOS is concerned that this inquiry has set a new precedent for existing reimbursement codes. Furthermore, the New England Journal of Medicine is a publication that is not specific to orthopaedic issues. A Forum member questioned how CMS investigates procedures that don’t work. Hip Replacement Guidance The Orthopaedic Surgical Manufacturers Association (OSMA) originated a draft of the clinical trial design for hip replacement systems document. Forum subcommittee members met via teleconference prior to the October meeting to discuss the draft document.
The purpose of the document is to propose a standardized method for designing clinical trials intended to measure the safety and efficacy of hip replacement systems. A standardized method of study design provides a least burdensome approach to the design, review, and acceptance of study protocols for both sponsors and the FDA.
Complication Rate Forum members agreed that the complication rate needed to be defined and appropriate references provided to justify the benchmark. Some surgeons contend that 2-7 % is an acceptable complication rate. A list will be compiled of standard complications for hip surgery and included in the trial systems draft. Members noted that a complication rate might not be known if the product is new. Additionally, minimally invasive surgeries might present with different sets of complications.
Success Forum members remarked that patient success and study success might not necessarily coincide. The complication rate will be benchmarked and trial data will be compared to the benchmarked figures.
Scoring Mechanisms The Harris Hip Score (HHS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) are included in the draft document as further benchmarks, in addition to the complication rate. However, Forum members had varying opinions on the two scoring mechanisms.
The HHS is widely quoted in orthopaedic literature, however some members believe it is too biased towards pain measurement. Members stated that clinical studies would have to begin using other measurement tools and publish the studies thereby providing alternatives to currently used tools. A Forum member advocated the use of the Merle D'Aubigne-Postel scoring mechanism. The WOMAC is preferable to the SF-36 or SF-12 but is copyrighted in the U.S. A royalty payment is expected for each patient completing the scoring mechanism.
Radiological evaluation Members suggested adding radiostereometric analysis (RSA) as a measurement tool, given that fixation and wear are the two critical indicators of problems with joint replacement devices. Members suggested that while foreign clinical studies have documented polyethylene wear with RSA, it is a technology that has limited utilization in this country at present. It was agreed that the same patients should be followed in the post-approval study and that clinical study success must be definitive.
Timeframe The CDRH has recently reviewed applicable literature on hip studies and found little documentation of data for the period between twelve and twenty-four months of clinical studies. Investigational Device Exemption trial data was also reviewed. While the data remains confidential, FDA contends that some complications are apparent in the 12-24 month timeframe.
Orthopaedic surgeons argue that the two-year timeline was established as a standard for orthopaedic publications and is not applicable to the establishment of efficacy of the device. Efficacy for some orthopaedic devices might not be apparent after ten years. CDRH noted that if there are justifications for a shorter timeframe than two years, those justifications should be provided in the document.
The American Association of Hip and Knee Surgeons (AAHKS) will review the clinical trial design for hip replacement systems document after the Forum subcommittee has refined it. Global Harmonization Task Force (GHTF) In 1997, the Food and Drug Administration Modernization Act (FDAMA) mandated that the Secretary of Health and Human Services (HHS) should investigate efforts, participate in meetings, and develop a plan to reduce the burden of regulation and harmonize regulatory requirements.
The Global Harmonization Task Force (GHTF) is a voluntary international consortium. Since 1992, the GHTF attempts to reduce regulatory differences between countries, encourages performance measures, and suggests methods to reduce the regulatory differences between countries. The five founding member countries are the European Union, Canada, United States, Australia, and Japan. GHTF has 4 study groups:
Study Group1 (SG1) has been charged with comparing operational medical device regulatory systems around the world and from that comparison, isolating the elements/ principles that are suitable for harmonization and those that may present obstacles to uniform regulations. In addition, the group is also responsible for developing a standardized format for pre-market submissions and harmonized product labeling requirements. (Source: www.ghtf.org) Study Group 1 (premarket) has finalized three key documents:
GHTF has originated approximately one-hundred documents to date and posts them on their website. They encourage transparency and consensus among member countries. At present, member countries are developing a pilot document to create a standard format for the approval/clearance for medical devices.
Future Discussion Topics
CDRH Fellows Program The Center for Devices and Radiological Health is establishing partnerships with academic institutions and professional societies to involve experts to work for CDRH on a limited appointment. Opportunities include internships, sabbaticals, fellowships, co-operative programs and part-time experts. FDA Spinal Seminar The CDRH sponsored a review session for staff on September 27, 2002. Spinal Implants: Beyond Pedicle Screws consisted of the following presentations:
The spinal session generated positive responses; a joint replacement session will be scheduled for 2003. Combination Products Advamed sent a letter to the FDA Chief Counsel, Daniel Troy, objecting to the FDA’s proposal to change the jurisdictional classification, assignment, and premarket review of certain products that consist of living human cells in combination with a device matrix to the Center of Biologics, Evaluation and Research (CBER). The letter was sent in response to a Part 15 hearing held on June 24, 2002. Advamed contends that the interpretation of the primary mode of action may have changed and that changes in interpretation will profoundly affect the industry. Therefore, FDA must proceed with notice and comment rulemaking prior to any jurisdictional changes for wound healing products. Standards The National Institute of Standards and Technology (NIST) and the American Society for Testing and Materials (ASTM) will likely partner to present a workshop on implant cleanliness. Both groups are anticipating the development of test methods as a result of this workshop.
ASTM is hosting two symposia in Miami, FL on November 4-6, 2002: tissue engineering and cross-linked and thermally treated ultra-high molecular weight polyethylene (UHMWPE) for joint replacements will be addressed in during the fall meeting. CDRH has developed a web site with tissue engineering information: http://www.fda.gov/CDRH/Tisseng/temps.html
The International Standards Organization (ISO) Technical Committee (TC) 150 hosted a meeting in Alexandria, Virginia in September 2002. Some European members were displeased about ASTM’s newly implemented international standards strategy. TC 150 leaders have been invited to ASTM meetings and will be encouraged to participate in the development of ASTM international standards. ASTM standards development provides greater transparency during the process than some other organizations.
In general, standard bodies intend to have minimal duplication in the development of standards, both nationally and internationally. Harmonization with international regulatory efforts will be imperative. In the past, ISO has reformatted ASTM standards, thereby eliminating potential revenue for ASTM. With emphasis on patient safety in the U.S., standards are increasingly necessary and are designed specifically to provide greater measures of safety for the patient population. FDA Update The Federal Food, Drug, and Cosmetic Act as amended by the Medical Device User Fee and Modernization Act of 2002 (MDUFMA) (Public Law 107-250), authorizes FDA to collect user fees for certain medical device applications. Fees are effective for applications submitted on October 1, 2002, and will remain in effect through September 30, 2007.
In March 2002, the CDRH Office of Compliance sent letters to manufacturers of demineralized bone (DMB) products stating that DMB products with additive ingredients other than those intended for storage, preservation or sterilization are regulated products. Therefore, those products will be regulated in the CDRH rather than the CBER. Companies may want to reference the CDRH calcium salts guidance document for their 501(k) applications.
The Tissue Engineered Medical Products (TEMPS) division of ASTM wrote a guidance document on the osteoinductivity of demineralized bone products. The guidance however, did not specify the review processes. Several AAOS surgeons have advocated a rating scale, similar to the sun protection factor (SPF) scale, to rate osteoinductivity levels. One member noted that bone banks would not be able to afford the use of assays. Biomedical Engineering Committee The AAOS Biomedical Engineering Committee is rewriting The Use of Laser Advisory statement. Members are actively working on standards issues with ASTM. Biological Implants Committee The AAOS Biological Implants Committee will meet in Rosemont in November 2002. They are currently revising the Use of Animals in Research Position statement. Members will participate as faculty in the 2003 AAOS meeting with an instructional course lecture on bone graft substitutes and an allograft safety symposium and scientific exhibit. Additionally, the Tissue Banking Project Team is providing recommendations to the Board of Directors for future allograft safety initiatives. National Joint Registry The AAOS Joint Registry Team will update the Board of Directors at their December 2002 meeting. The Pilot Project team has determined a minimum data set requirement and is exploring mutual interests with governmental agencies. The Governance team will propose several registry models and is investigating independent review board (IRB), consent and disclosure issues. OSMA OSMA is compiling a reclassification petition for mobile bearing knees. Some of the American data is short term, however the petition will also include references to the review of over 70 articles and a meta-analysis of 31 publications. The European data is mature, for instance, European countries have substantial 20-year data on mobile bearing knees. OSMA is hopeful that the petition will be completed before 2003.
Mobile bearing rate usage is approximately 10% in the U.S. whereas usage in Germany is approximately 75%. FDA questioned if a special controls document was to be included with the reclassification petition.
Additionally, three member companies in OSMA met to discuss the possibility of exploring joint meetings with FDA on their antibiotic bone cement 510(k) applications. One company has submitted their application and will meet with FDA experts from the CDRH and the Center for Drug, Evaluation and Research (CDER). Board of Directors Report
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