Present:

Presentations by Joanne R. Less, PhD and Robert M. Campbell, Jr., MD

Joanne R. Less, PhD, the Associate Director for Clinical Research and Government Affairs in the Center for Devices and Radiological Health at the Food and Drug Administration (FDA) presented a discussion entitled “Premarket Considerations for Pediatric Medical Devices.” Dr. Less covered pediatric device development and availability issues, including the impact of the Medical Device User Fee and Modernization Act of 2002 (MDUFMA). MDUFMA was the first time the law has addressed pediatric device issues, and included specific provisions requiring:

1. Pediatric expertise on advisory panels where appropriate;
2. Institute of Medicine (IOM) study of the adequacy postmarket surveillance to provide safeguards regarding the use of devices in pediatric populations;
3. FDA report to Congress concerning IOM’s findings and any recommendations for changes;
4. FDA guidances on the types of information necessary to reasonably assure the safety and effectiveness of devices used in pediatric populations and protection of children who participate in clinical trials of devices.

The IOM study, Safe Medical Devices for Children, was published July 18, 2005. The FDA published guidance documents on pediatric expertise for advisory panels (June 3, 2003) and the premarket assessment of pediatric medical devices (May 14, 2004), which resulted in the definition of a pediatric population. In October 2004, the FDA presented Congress with a report entitled “Barriers to the Availability of Medical Devices Intended for the Treatment or Diagnosis of Diseases and Conditions that Affect Children,” concluding that it was too early for policy, regulatory, or legislative changes. The report provided three recommendations to address the barriers:

1. Enhance communication between clinicians and device manufacturers;
2. Use the children’s hospital network to aid in identification of pediatric clinical study sites;
3. Enhance the use of the FDA's Office of Pediatric Therapeutics and Pediatric Advisory Committee

Stakeholder meetings held in 2004 and 2005 identified a host of special needs and considerations that present challenges to developing and marketing pediatric medical devices. Factors that restrict the use of adult devices in children include:

• Disease/condition may be limited to children
• Size of device
• Growth of patient
• Hormonal influences
• Activity level of patient
• Maturity level of patient

Pediatric data can ensure that the device is properly designed, demonstrate safety and efficacy, provide accurate risk and adverse event assessments, and supply age-appropriate instructions for use. Because of the unique circumstances and ethical considerations involved with doing research in the pediatric population, pediatric clinical data is sought only where no reasonable alternatives can provide equivalent information. These occasions include times when bench/animal data are not sufficient/relevant, adult data are not available, relevant or sufficient (e.g., different risks, adverse events), when there is a need to verify design modifications, and/or a need to develop treatment regimen for pediatrics.

Many of the barriers to development of pediatric devices can be placed into one of three categories: economic, clinical, and regulatory. Economic barriers include a lack of exclusivity for devices similar to that which is available to drugs and the restriction of profit-making on Humanitarian Device Exemption (HDE) products. These measures seriously limit a manufacturer’s ability to recoup research and development costs for new products. A Humanitarian Use Device (HUD) is a device that is intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect or is manifested in fewer than 4,000 individuals in the United States per year.

The primary clinical barriers to the development of pediatric devices include the belief that pediatric trials are unethical, difficult requirements for informed consent and institutional review boards, increased loss to follow-up, and concerns about exposure to additional testing. The limited population for testing these products is further constrained by ethical unease and the stringent requirements of research.

Finally, regulatory requirements not clear and frequent size changes require increased regulatory activity, which subsequently increases the time necessary to navigate the pathway. It is clear, however, that more device-specific guidance documents are needed.

The following are a sample of proposed solutions to these barriers:

• Encourage pediatric discussions at pre-submission meetings
• Clarify marketing requirements, especially related to clinical data
• Develop more guidance for pediatric devices
• Expedited review of pediatric 510(k)
• Modify HDE statute, removing the profit-making limit and increasing number per year
• Add a custom pediatric provision to the law

In order to learn more about unmet needs, a targeted survey of several medical specialties will inquire about specific information that will help the FDA facilitate pediatric device development in the current environment. The survey will also provide feedback regarding what kind of changes to MDUFMA can be made that would be appropriate and meaningful. CDRH has a pediatric working group with representatives from each office and representatives from each review division in CDRH. The work group seeks to increase consistency and predictability, coordinate pediatric-related activity across CDRH, and keep the commissioner's office aware ongoing activities.

During the discussion period a question arose about how the majority of pediatric products were submitted. Dr. Less indicated that approximately 4,000 submissions were 510(k), 50 as Premarket Applications, 6 as HDEs, and 200-300 under Investigational Device Exemptions (IDE). She particularly noted that many of these products are used on pediatric patients. However, they may not be not labeled specifically for use in the pediatric population, such as dressings.

The group talked about the risks involved in the off-label use of HDEs. Surgeons should be aware of device status, the requirements for IRB approval, and whether the device will be billed to Medicare. The practicality of seeking IRB approval and the time necessary to follow such a path prior to treating a patient was discussed. It was noted that compassionate use requests generally had a shorter timeline than seeking IRB approval for an off-label use. Since the final HDE rule was passed in 1997 approximately 50 devices have been approved for use under this provision.

Robert M. Campbell, Jr., MD gave a presentation entitled “Titanium Rib Prosthesis 1987-2005: A Joint Orthopaedic-Pediatric Device,” chronicling his experiences developing the Vertical Expanding Pediatric Titanium Rib (VEPTR), a device used in lethal forms of pediatric scoliosis, and the challenges faced in getting it to market. Dr. Campbell’s 18-year quest began in 1987 with one child with rib absence, chest-wall deformity and an immediate need for a device. An improvised device was produced to stabilize the scoliosis. As a result of receiving the device, the child was off the ventilator in 2 days and began growing. Since the implant was not going to grow with the child, the improvised device was not a long-term solution. Shortly thereafter development began on a long-term rib implant. While much was learned from past successes, there more valuable lessons to be gathered from those that have failed. Key questions that needed to be answered:

• What is the path to success?
• Who would manufacture the device?
• What about patents and FDA?

The timeline of VEPTR development started first with a sketch on a napkin that yielded a device 18 months later. Once word got out, the referral flood gates opened and the project began in 1989. The report of the first two patients was presented at the Pediatric Orthopaedic Society of North America in 1990 and Orthopaedic Research and Education Foundation (OREF) funding was sought and denied. Institutional Review Board approval was sought for each child as a custom device although the device was not different for each patient. A study protocol was drafted in 1990 and a feasibility study was approved by the FDA in 1991. In 1992 research funding was received from the National Organization of Rare Disorders. This was followed by the FDA Office of Orphan Product Development, with financial support for a sole site study from 1994-1997 and a multi-center study from 1997-1999. On August 24, 2004, the VEPTR device received FDA approval under the Humanitarian Device Exemption.

Dr. Campbell discussed possible solutions to the some of the difficulties that he faced and that other innovators still struggle with. Teaching forums, sponsored mentorship, study groups, subspecialty surveys, and a voluntary registry are a few examples of activities that could make a positive impact on the development of devices for underserved populations.

In February 2005, the AAOS surveyed members of the Pediatric Orthopaedic Society of North America (POSNA) and the Scoliosis Research Society to assess the unmet need for pediatric orthopaedic devices.

Approximately 33.3% of respondents indicated they had used adult-sized devices in children and 1 in 3 had used devices "off-label" to treat pediatric patients. Most felt that manufacturers were trying to meet the needs of this patient population. When asked to select from a list of 12 devices that needed to be developed for pediatric patients, nearly 50 % of the respondents identified 7 of the 12 devices, with an emphasis on devices that reduce the need for subsequent surgeries or limit the number of procedures required to treat the patient. Examples include bioabsorbable screws/plates and smarter hardware that fit children.

More data are needed about unmet device needs, subspecialty surveys, mentoring resources for innovators, transparent regulatory pathways, and affordable approval mechanisms that provide proof of efficacy and safety. The larger question remains; how many new pediatric devices will we have in 5 years and who will implant them?

The group discussed the length of time this particular product took to progress from concept to production. A surgeon inquired whether, based on the concept that POSNA exists and that there is a group interested in this subspecialty area, is there any options for innovators to collaborate rather than compete? Dialogue is needed between surgeons, the FDA, medical specialty societies to kindle these types of collaborations.

Forum Priorities

In July 2005, the Forum identified combination products and research and education as their top two priorities. New workgroups were formed to address these areas. Comments were solicited on the priorities list and a member stated that custom devices/short-run devices need to be addressed. It was noted that custom devices were more prevalent 30 years ago and the current environment hampers initial development efforts, thereby affecting the availability of these products. The group discussed the FDA definition of custom products, following up on discussions from the previous evening.

General comments on the priority list included an observation by an OSMA representative that 510(k)s have improved, and noted their appreciation. An industry member asked about the source of questions that come out close to 90-day cut-off. An FDA liaison stated that most of those questions stem from a need for more information about the product before a determination can be made.

Chantilly Revisited Workgroup Conference Call

The workgroup is focused on continuing progress on regulatory issues and clearly defining the role of the Forum in this work. To that end, a call was convened in October 2005 and the group discussed issues for further development including:

• FDA staff education;
• Concerns related to guidance document development;
• Function of the FDA Science Board;
• Impact of vacancies within the FDA on the day-to-day functioning of the centers.
An FDA staff member explained that the FDA Science Board functions as an agency self-check. The board looks across centers to assess staff education and internal expertise.

Combination Products Workgroup Conference Call

The group discussed the mode of action for determining how a combination product is assigned to a center within the FDA for review. Training on this topic or a biologics license application (BLA) would be helpful to the scientific and industry communities. Members also suggested a chart of relevant information that is generally requested by reviewers that could be used as an educational or reference tool. Since there are different evaluation pathways within the FDA, companies with combination products face unique challenges navigating the regulatory pathways. The time spent seeking approval makes coverage/payment for these products even more crucial.

There is a role for the AAOS and the scientific orthopaedic community to define clinical endpoints for different diseases/treatments and to develop measurements for the success of a treatment. Follow-up beyond 2 years is deemed necessary. A member of the standards community indicated this is an active item with ASTM tissue engineered medical products group. The goal of the Forum workgroup is to define how to approach these issues and it was recommended that the group focus on one product as an example.

Educational Seminars

The budget for FY 2006 educational programs is due to be released early December 2005. One application for FY 2006 has been submitted from the Forum and the draft of a second application is ready. Feedback from faculty and participants at previous seminars has been positive. FDA personnel commented that the informal interaction was well received and the information presented was very helpful. Suggested topics for future programs include pediatric orthopaedic issues, combination products, and post-traumatic non-union.

Center for Biologics Evaluation and Research (CBER) Update

Representatives from CBER were invited to speak to the Forum to help educate the members about the center’s structure, function, and priorities. The presentations covered a review of biologics from the Office of Cellular, Tissue, and Gene Therapies; FDA regulation of human tissue allografts; and reporting adverse events related to orthopaedic tissues.

The review of biologics spoke to the regulations governing these products, which include both device and drug regulations. The presentation outlined the critical path for the development of biotherapeutic agents, underscoring the importance of early, extensive communication between the review team and the sponsor prior to the submission of an investigational new drug application (IND) or investigational device exemption (IDE). Key phases in the review process include identification of specific toxicity, investigational submission – the point at which many failures occur, and the new drug application (NDA)/biologic license application (BLA) review process. To date, only one BLA product has been approved. It was noted that priority reviews for biologics are generally completed in 6 months and standard reviews in 10 months.

An overview of the history, scope, and implementation of the rules governing human tissue allografts was given, with emphasis on donor testing and screening, good tissue practice requirements, and the Tissue Safety Team within CBER. Human tissue allografts regulations set forth requirements for donor screening and testing, written procedures, records, inspection, and enforcement of the regulations. The goal of these regulations is to prevent the transmission of communicable disease via human tissue, which does not require pre-market review or approval. Implementation of the requirements includes the establishment of manufacturer registration and product listing, donor eligibility rules, and current good tissue practices. The Tissue Safety Team within CBER was created to provide a coordinated approach between the center’s offices when they are investigating reported adverse reactions related to tissue transplantation. Follow up of these reports may include inspections, recalls, physician notification, and other regulatory actions. Additional information about human tissue regulation may be found at www.fda.gov/cber/tiss.htm.

The final presentation explained adverse event reporting for orthopaedic tissues. Prior to May 25, 2005, adverse event reporting related to tissue was voluntary. Once the FDA’s “Current Good Tissue Practices” went into effect manufacturers were required to report to FDA certain adverse reactions involving a communicable disease. The Joint Commission on the Accreditation of Healthcare Organizations’ (JCAHO) Tissue Issuance and Storage Standards were published July 1, 2005 and encompass organizations that store or issue tissue. Provisions of the JCAHO standards include procedures to investigate recipient adverse events and prompt reporting to the source facility cases of post-transplant infections or adverse events.

Medicare Coverage Advisory Committee Meeting

A national coverage determination was opened on artificial lumbar disc replacement. The Centers for Medicare and Medicaid Services (CMS) requests that members comment on the document posted on the web site. A vertebroplasty/kyphoplasty guidance document is forthcoming and members should monitor the CMS web site and the Federal Register for opportunities to submit comments.

A question was raised concerning how the members of the coverage advisory committee were selected. A CMS liaison explained that there is a pool of 100 MCAC voting members to pull from, each member having a term of 2 years. Nominations for that poll are accepted annually, usually in early June. The committee’s meetings are scheduled on an as needed basis, address only coverage issues, are open to the public, and are always held in Baltimore, MD. Regardless of the outcome of committee’s vote, CMS considers all comments from these meetings. An observation from a member of the research community was that the recent meeting was not beneficial to orthopaedics, with scientific panel members expecting the studies presented to adhere to the drug trial model. The member also felt that the orthopaedic panel was not familiar with orthopaedic surgery and that the therapies that were reviewed were approved 25+ years ago when studies were conducted differently. An orthopaedic surgeon echoed this sentiment and noted that input from experts prior to questions being drafted would be helpful to the process. An industry representative noted that the inclusion and exclusion criteria seemed to systematically eliminate 90% of literature on the products involved.

A CMS representative stated that technology assessments (TA) have to be done by an outside group to prevent bias. CMS staff cannot push specific issues, even if education is necessary. The CMS liaison also noted that CMS staff is prohibited from discussing what the panel questions are unless it is done within a public forum. The panels have methodologist members because the evidence burden has changed over the years. A surgeon asked if topics for TA could be recommended. A CMS representative confirmed that this is an option, particularly if the technology is currently covered or particularly controversial. The representative said many factors influence the technologies selected for these assessments, from coverage decisions to presentations at scientific meetings and internal discussions. No coverage determinations are pending on either item from September 2005 MCAC meeting.

The discussion presents a challenge to orthopaedics, to determine if there is a larger need for guidelines to inform these types of decisions (reimbursement).

National Institute of Biomedical Imaging and Bioengineering (NIBIB)

An NIBIB representative presented an overview of the institute, including current grant areas and future research directions. NIBIB was created by legislation in December 2000 and awarded its first research grants in 2002. The institute’s mission is to “improve human health by leading the development and accelerating the application of biomedical technologies.” With a projected budget of $297 million for FY 2005, NIBIB funds research through various grant mechanisms in areas that include biomaterials, medical devices and implant science, and tissue engineering. Tissue preservation and the development of novel biomaterials for use as tissue scaffolds that mimic the extracellular matrix are examples of currently funded tissue engineering research areas. The development of enabling technologies for tissue engineering and engineered 3D human tissue model systems were cited as two examples of potential future tissue engineering research directions.

A New Investigator Policy, seeking to improve the success of new investigators applying for R01 awards, is among the several research funding opportunities that exist within NIBIB. There are R01, R21, and Small Business Innovation Research/Small Business Technology Transfer (SBIR/STTR) awards available under the trans-NIH Bioengineering Consortium (BECON). The NIBIB Quantum Projects is soon to be introduced with the objective of producing a profound (quantum level) improvement in healthcare by addressing a major human health problem. These projects are to be collaborative, inter-disciplinary, multi-organizational, and able to be completed in 7-10 years.

The presentation also highlighted the transition from paper to electronic application submission at NIH. All mechanisms for grant application will be electronic by May 2007 under the transition plan. Institutions must register at http://grants.gov/GetStarted at least 4 weeks before their application is due. The transition plan and additional information about electronic submission is available at http://era.nih.gov/ElectronicReceipt/.

A member of the orthopaedic research community commented that the structure of NIBIB is cross-cutting, which creates an environment conducive to Forum interaction. The NIBIB representative noted that they work extensively with other institutes and hand the research over to those institutes when it moves into the clinical phase. The AAOS Research Committee and staff from the Washington office have met with several institute directors with an eye to increasing involvement with other institutes. Specifically, the group is working on establishing an orthopaedic presence on the NIBIB Advisory Council.

Center for Devices and Radiological Health (CDRH) Update

CDRH staff provided an update on staffing, panel meetings, reclassifications, guidance documents and performance within the Division of General, Restorative, and Neurological Devices (DGRND).

From July through November 2005, several CDRH staff members are on detail throughout the center. Additionally, there is one new staff person. However, six individuals have left CDRH. As a result, the Orthopaedics and Restorative Device Branches are down 5 staff members for 2005.

The Orthopaedic and Rehabilitation Devices Panel met on September 8-9, 2005 to review the Birmingham Hip Resurfacing premarket approval (PMA) application from Smith and Nephew and to discuss general spinal topics associated with the use of spinal devices indicated for patients with mild to moderate back pain. At the time of this meeting the hip resurfacing PMA was still under review. The panel determined that the use of the spinal devices in question should be evaluated on a case-by-case basis.

Reclassification petitions currently under review include intervertebral body fusion device, mobile bearing knees, and metal-on-metal hip joint prosthesis. The artificial disc guidance and hip joint clinical guidance are being prepared to undergo good guidance practice review. Other guidance documents in development are femoral stem, cemented knee, and a cross-center cartilage document.

Standards Update

A new grant is underway examining cadaveric material versus revision material. The goal of the study is a long-term assessment of devices that are working and working as intended. Investigators intend to seek input from the AAOS to identify patient populations.

American Society for Testing and Materials (ASTM)

The F04 Committee Week was held in Dallas, TX and featured a wear symposium with 100 attendees. New workshop areas include metallurgical fatigue, nanotechnology, combination TEMPs, cell signaling, poly, and bone cement. Suggestions for additional topics should be sent to the ASTM representative. The F04 Committee will meet in Toronto, Canada, May 16-19, 2006 and Atlanta, GA, November 14-17, 2006. The meeting format has been scaled back to 2 days with a workshop or symposium.

The cleanliness document is now available in the Journal of ASTM International (JAI), and electronically at: http://www.astm.org.

International Organization for Standards (ISO)

TC-150 and TC-106 focused on harmonization between the US and the world. ASTMi is being viewed as a significant competitor to ISO voting in Europe. The European Union (EU) position is expected to get stronger over time and the American standards community needs to find a way to participate and normalize. Each EU member country gets one vote. One point of view exists that the US should get 50 votes, one for each state. The dominance of some EU countries is being felt and presentations before the Koreans reaffirmed the sentiment that US participation should only be counted as 1 vote. There is a significant opportunity for tissue engineering in the future and the EU will be developing tissue standards in opposition to existing standards.

American products should be considered equivalent to international products and continuing negotiations between ISO and ASTMi are working toward ASTMi standards being referenced as normative standards. The initiative advanced as far as the ISO president but not beyond the board. However, the decision was based on a 1 vote difference and it is possible that this will shift in favor of ASTMi in the future.

Orthopaedic Surgical Manufacturers Association (OSMA)

The mobile bearing knee down classification guidance document is being drafted. The metal-on-metal total hip revised down classification petition was sent to the FDA in August 2005 and a new guidance document is being drafted. OSMA’s taskforce on FDA guidance documents is considering the priority lists and will develop comments.

OSMA members discussed a down classification petition for the ceramic hip, commenting that this may be appropriate. Further dialogue was tabled until January relative to concerns about how petitions move through the system and potential delays. OSMA will take a position on gainsharing and will send letter to Congressional representatives as a group instead of individual companies. A number of OSMA members are actively assisting in identifying the victims of Hurricane Katrina.

AAOS Board of Directors

Senior management and leadership are working to define the role of liaisons to external organizations, including panels and advisory committees, and how to identify and nominate members to fill these vacancies. The team is reviewing options for approval of these government liaisons by various advisory committees and the Board of Directors. It was noted that this is a work in progress and very dependent upon the restructuring of the volunteer composition of the Academy.

Biomedical Engineering Committee

The committee is continuing its work on the follow-up of new technologies presented at AAOS Annual Meetings. A 5- year follow-up report, coordination with the Central Program Committee, and tracking of technologies are included in the proposal the will be addressed at the Central Program Committee’s June 2006 meeting. The committee will present a scientific exhibit at the AAOS Annual Meeting in March entitled “Orthopaedic Innovation: Bench, Bedside, and Bank.” The exhibit aims to explain, in simple terms, the pathways that are taken to develop ideas into innovative orthopaedic devices or products.

Biological Implants Committee

An article on Humanitarian Device Exemptions and physician directed usage of devices recently appeared in the AAOS Bulletin. The committee will present two scientific exhibits at the AAOS Annual Meeting. The purpose of “Xenotransplantation: Challenges and Choices in Orthopaedic Surgery” is to educate orthopaedic surgeons on the growing interest in xenotransplantation procedures for the treatment of a wide variety of musculoskeletal problems. Current materials on the market, as well as newly proposed products will be presented and controversies surrounding musculoskeletal xenotransplantation will be discussed. Both the potential risks and possible benefits of xenotransplants will be explored through the review of basic science and clinical research studies. Co-sponsored by the AAOS Patient Safety Committee, the “Safety of Musculoskeletal Allograft Tissue” exhibit seeks to provide an understanding of tissue bank musculoskeletal practices, the historical record of disease transmission, governmental regulatory oversight, as well as standards and accreditation. This information will help the orthopaedic surgeon to ask key questions to his tissue supplier and provides the surgeon accurate responses for informed patient consent.

The committee is considering a proposal to develop a position statement on alternatives to the use of the term "off-label." Many orthopaedic surgeons find the term to be pejorative and not reflective of the true nature of physician-directed usage of various therapies.

American Joint Replacement Registry Project

The contract with Eclipsys Corporation was dissolved in August 2005. The Oversight Board will meet in early 2006 to develop strategies for moving forward with the project.

New Topics

Replacement Parts for Discontinued Devices

This emerging problem was brought to the attention of a surgeon member by an orthopaedic subspecialty society. Within the arthroplasty arena some parts, primarily polyethylene, are wearing out while stems remain well seated. As a result of successful products and good surgical care, discontinued devices, aging of replacement parts (shelf life of approximately 5 years), and limited availability all impact patients who encounter this problem. To provide these parts, manufacturers must do a special run/custom device, which may result in a premium price for the part. A workgroup has been formed to examine the various issues surrounding replacement parts. Further research is planned to define the scope of the problem and the group will report their findings at future meetings.