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J Am Acad Orthop Surg, Vol 16, No suppl_1, July 2008, S123-S128.
© 2008 the American Academy of Orthopaedic Surgeons
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Orthopaedic Joint Devices: The FDA’s Short Answers to Your Questions

Jonette R. Foy, PhD and Barbara D. Buch, MD

Dr. Foy is Chief, Orthopaedic Joint Devices Branch, Division of General, Restorative and Neurological Devices, Center for Devices and Radiological Health, US Food and Drug Administration, Rockville, MD. Dr. Buch is a Deputy Director of the Division of General, Restorative and Neurological Devices, Center for Devices and Radiological Health, US Food and Drug Administration.

None of the following authors or a member of their immediate families has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Foy and Dr. Buch.

No official support or endorsement of this article by the US Food and Drug Administration (FDA) is intended or should be inferred. The views presented in this article do not necessarily reflect those of the FDA. The findings and conclusions in this article should not be construed to represent any FDA determination, guidance, or policy.


   Abstract
Top
 Abstract
Organizational Structure
 Overview of the Regulatory...
 Frequently Asked Questions
 Conclusion
 Tables
 References
 
This article briefly describes the US Food and Drug Administration regulatory process for medical devices, focusing on orthopaedic joint device examples. The mission of the Center for Devices and Radiological Health is to promote and protect the health of the public by ensuring that the medical devices that reach US consumers are safe and effective for their intended function. A question and answer section is included as a reference guide for the orthopaedic community to broadly address some common issues related to orthopaedic device constructs, such as hybridization of joint systems, labeling claims, modifications to ultra-high–molecular-weight polyethylene sought by manufacturers to minimize wear and osteolysis, combination products, and the responsibilities of an orthopaedic surgeon. The FDA relies on accurate scientific evidence and regulatory science to determine the safety and effectiveness of orthopaedic joint devices. 


   Organizational Structure
Top
 Abstract
 Organizational Structure
Overview of the Regulatory...
 Frequently Asked Questions
 Conclusion
 Tables
 References
 
The US Food and Drug Administration (FDA) is one of the major regulatory bodies assigned with safeguarding the health of the nation. The Center for Devices and Radiological Health (CDRH) within FDA1 is responsible for pre- and postmarket regulation of medical devices. The Division of General, Restorative and Neurological Devices (DGRND), under CDRH’s Office of Device Evaluation, reviews most devices used for the treatment and diagnosis of orthopaedic musculoskeletal diseases. The Orthopaedic Joint Devices Branch within DGRND is responsible for evaluating premarket applications related to joint arthroplasty, orthopaedic trauma, and musculoskeletal repair devices and making a regulatory determination before a company markets products.


   Overview of the Regulatory Process
Top
 Abstract
 Organizational Structure
 Overview of the Regulatory...
Frequently Asked Questions
 Conclusion
 Tables
 References
 
The Medical Device Amendments of 1976 to the Federal Food, Drug, and Cosmetic Act of 1938 established three classes of medical devices depending on the regulatory controls needed to provide reasonable assurance of their safety and effectiveness.2,3 These classes are based on the risk to the patient and how the risks are mitigated. Device classification depends on the intended use and indications for use of the device. The pathways to market for devices parallel the scientific evidence and scrutiny each application requires to determine the safety and effectiveness of the device based on its classification. Class I includes devices with the lowest risk and class III includes those devices with the greatest risk. Table 1 lists some examples of orthopaedic joint devices, with their classifications and regulatory submission types.


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  		Table 1  Examples of Classifications* and the Types of Premarket Applications Required for Common Orthopaedic Joint Devices
 
Exempt Devices
For a class I or II exempt device, a manufacturer is generally not required to submit a marketing application before commercialization,4 but both types are subject to "general controls" to provide reasonable assurance of safety and effectiveness.

Class II Devices
Class II devices require Premarket Notification (510[k]) clearance before marketing.5 In general, class II devices are compared with legally marketed devices and with devices in use before 1976 with a previous clinical history and "cleared" as substantially equivalent through the 510(k) process to legally marketed devices, also called "predicates" (in use previously).

For class II devices, general controls are not sufficient to address the potential risks to health, additional "special controls," which are evaluations specific to the device, are required.3 Table 2 provides examples of general versus special controls. Currently available guidance documents6 and FDA-recognized standards/guides applicable for orthopaedic joint devices,7 which can serve as special controls, are summarized in Table 3, which is available online at http://www.jaaos.org/cgi/content/full/16/Suppl_1/S123/DC1.


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  		Table 2  Examples of General and Special Controls for Devices*
 

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  		Table 3 Currently Available Guidance Documents and FDA-recognized Standards/Guides Applicable for Orthopaedic Joint Devices
 
If a 510(k) for a class II device provides data characterizing the device as comparable to a predicate and shows that it has the same intended use and technological characteristics, or if it has different technological characteristics demonstrated to be as safe and effective as those of the predicate, then the device can be cleared for marketing. When specific indications are different enough from legally marketed predicate devices, the FDA may request clinical data to support equivalence or determine that the device is not substantially equivalent and request a premarket approval application.

Class III Devices
In general, class III devices usually require clinical data to demonstrate reasonable assurance of safety and effectiveness, and are "approved" through the Premarket Approval (PMA) process.8 These devices tend to be higher risk and/or raise new types of safety and effectiveness questions. Data in a PMA application must demonstrate a "reasonable assurance" of safety and effectiveness,9 and the data provided must stand alone; thus, it cannot be leveraged from another regulatory submission unless legally authorized by the owner of the data. Alternative bearings to ultra-high–molecular-weight polyethylene (UHMWPE), such as metal-on-metal and ceramic-on-ceramic couplings for total hip replacement, are class III devices. Novel technologies, including devices that were found not to be substantially equivalent through the 510(k) process, fall into the category of class III because there are no appropriate predicate comparisons available.

From a regulatory perspective, the terms "cleared" and "approved" have different regulatory implications.10


   Frequently Asked Questions
Top
 Abstract
 Organizational Structure
 Overview of the Regulatory...
 Frequently Asked Questions
Conclusion
 Tables
 References
 
1. What is "off-label" use? As an orthopaedic surgeon, what should I be concerned about if using a product off label?

Off-label use is the use of a medical device for treatments beyond what has actually been explicitly cleared/approved in the product labeling (eg, indications). Accurate and informative product labeling allows physicians to make an informed judgment regarding the risks and benefits of a product for their patients and lets patients make an informed treatment decision. Although off-label use by a physician in routine practice of medicine is not regulated by the FDA, routine off-label use of products can eliminate a manufacturer’s incentive to study or seek FDA clearance/approval for the off-label indication. Physicians should be aware that off-label uses are not subject to a rigorous premarket review process to identify adverse events or establish performance, therefore, the safety and effectiveness of devices when used off label is unknown. Further, the physician takes on the responsibility of determining the device’s suitability for the intended off-label use, with the physician and/or institution assuming liability for any unintended and/or negative consequences. Additionally, manufacturers may not advertise/promote their products for off-label use.

2. As a clinician, I want to use a combination of cleared/approved components from different companies for total joint arthroplasty. Are there any special concerns I should be aware of?

The FDA considers the combination of commercially available, individual off-the-shelf components, used together, as "hybrid" systems. As noted in the manufacturers’ labeling, a product is only compatible with that company’s own complementary products. A frequently misunderstood concept by the professional community is whether physicians can combine components from different manufacturers or systems to form a patient-matched implant system. Although this decision is considered common in the practice of medicine, the FDA highly discourages such hybridization because of the risks to patient safety and performance of the resulting assembly.

To illustrate the FDA’s concerns, assume that Company X has a highly congruent total knee arthroplasty system, System X, which has been cleared by the FDA. If one were to combine the System X femoral component with any standard tibial bearing component, not only would the inherent constraint provided by the system be lower, but also the contact stresses on the tibial bearing component resulting from this combination may lead to failure of the system due to increased wear or component fatigue. Consequently, it is important to realize that when a company submits a marketing application to the FDA for a device component (eg, a femoral component), the review considers the safety and performance of that device when used as a system only with its compatible components.

3. How can I determine if a product is FDA-cleared/approved?

Information about cleared11 and approved12 devices is available in FDA databases. These databases are publicly searchable.

4. What is a "claim," and what information does the FDA request to support claims within marketing applications for orthopaedic joint devices?

Claims in labeling are statements that assert a finding as fact. Claims may be based on limited experience (eg, animal study) and draw general conclusions about a device’s performance characteristics.

Depending on the claim being sought in a marketing application, the FDA may request nonclinical and/or clinical testing results to support the claim. For example, multiple manufacturers have submitted applications in which a "wear" claim has been requested. The type of information typically submitted for such a claim has included clearly identified trade names/models and sizes (including insert thickness) of the subject and control articulating counterfaces; and a description of the type of simulator (eg, manufacturer, model) used for testing, including the test duration (number of cycles); the lubricant used; and the amount of volumetric (or gravimetric) wear particulates produced. As the manufacturing and sterilization processes have been shown to influence in vitro wear characteristics, testing is typically completed on finished, sterilized devices/components.

Often, statements to further define limitations with a claim are included. Including this information helps surgeons assess whether the claim has significant merits to affect their choice of device for a particular patient. For example, if a claim is based on the results of in vitro testing, it may be appropriate to state that the basis of the claim is in vitro testing, with clarification to further indicate that results may not be predictive of in vivo performance. Claims are not usually appropriate for inclusion within the indications statement for a device. When claims are not supported with appropriate data, they are considered to be exculpatory and should not be included within any labeling (eg, marketing materials) for the product, whether a 510(k) or PMA.

5. How can I be assured that some of the "newer" polyethylenes in an implant system are durable and will perform as well as conventional UHMWPE?

Although manufacturers subject conventional UHMWPE to a battery of standard tests,13 modifications to UHMWPE, such as subjecting it to extreme irradiation (eg, highly cross-linked), packaging in inert environments, or the introduction of additives (eg, {alpha}-tocopherol), may influence its integrity, stability, and long-term performance. Consequently, additional chemical, physical, and/or mechanical engineering tests are typically performed to understand the impact of these modifications on its integrity and long-term performance. Potential changes in the properties of the UHMWPE can be more clearly understood with identification of all the processing parameters and a complete assessment of the influence of cross-linking and residual free radicals on the mechanical performance.

These types of modifications to UHMWPE are reviewed through the same regulatory application process (510[k] or PMA) as that deemed appropriate for the original articulating components. If claims are being sought, appropriate supportive information should be provided.

6. There is a novel material for an articular bearing that I am interested in using to replace the joint. What needs to be provided to the FDA to get this material marketed?

CDRH does not clear/approve materials or new surgical procedures but rather clears/approves devices based on their intended use(s). If the material of interest is novel and has not been used before in weight-bearing orthopaedic joint applications, in addition to the full battery of nonclinical characterization tests necessary to support the mechanical performance, durability, and biocompatibility of the finished product, then the FDA would normally request clinical performance data.

If the material is designed to be degradable, the test environment will be an extremely important aspect of the experimental setup and interpretation of the results. As with all devices that may contain degradable materials, it is important to understand the degradation profile (both in vitro and in vivo) to ensure that the timelines for supportive studies (eg, animal and/or clinical) are appropriate. The specific test parameters to consider will depend on the device construct and the specific intended use because the periods of healing and short-term performance differ. Often, devices composed of novel materials are regulated through the PMA process due to the additional risk, lack of safety information, and lack of an appropriate predicate on which to base the effectiveness or safety.

7. What is a combination product?

A combination product is defined in Title 21, Code of Federal Regulations (CFR), Section 3.2(e).14 Although there are four specific definitions for a combination product, one of the most common examples is a product that combines two or more regulated components (ie, drug and device, biologic and device) that are physically, chemically, or otherwise combined or mixed and produced as a single entity. The Office of Combination Products assists in making jurisdictional determinations regarding which FDA center will have primary jurisdiction of the combination product15,16 (Table 4).


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  		Table 4 Examples of Jurisdictional Determinations Previously Made for Orthopaedic Products16
 
8. What is the orthopaedic surgeon’s role in public health?

The orthopaedic surgeon plays a critical role in providing and participating in adequate training for new technologies before use by the clinical community and understanding the need for high-quality clinical trials, with sufficient appreciation of the regulatory process, to ensure that clinical trials are appropriately designed to fulfill both regulatory and scientific advancement. Further, orthopaedic surgeons should know which products are FDA-cleared/approved and commit to participating in postmarket surveillance studies when requested. The FDA urges health-care professionals to know how to report serious and unexpected adverse reactions associated with products to the FDA MedWatch reporting program or the manufacturer of the device (Table 5).


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  		Table 5  Available Procedures for Reporting Adverse Event Information to the FDA
 
Orthopaedic surgeons can also serve as members of the Orthopaedic and Rehabilitation Devices Panel or as FDA Consultants (Special Government Employees)17 to review significant or novel devices/topics.


   Conclusion
Top
 Abstract
 Organizational Structure
 Overview of the Regulatory...
 Frequently Asked Questions
 Conclusion
Tables
 References
 
CDRH promotes and protects the health of the public by ensuring that the medical devices that reach our country’s citizens, whether directly or through surgeons’ utilization, are safe and effective in performing their intended function. The FDA relies on accurate scientific evidence and regulatory science to determine the safety and effectiveness of devices for human use.


   Acknowledgments
 
The authors would like to thank Ms. Ashley Boam, Ms. Elizabeth Frank, Mr. Robert Gatling, Dr. Ronald Jean, Mr. Bill MacFarland, and Mr. Mark Melkerson for review of this manuscript.


   Tables
Top
 Abstract
 Organizational Structure
 Overview of the Regulatory...
 Frequently Asked Questions
 Conclusion
 Tables
References
 


   References
Top
 Abstract
 Organizational Structure
 Overview of the Regulatory...
 Frequently Asked Questions
 Conclusion
 Tables
 References
 

  1. FDA Organization Charts. Available at: http://www.fda.gov/oc/orgcharts/orgchart.html. Accessed April 8, 2008.
  2. 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act. Available at http://www.fda.gov/opacom/laws/fdcact/fdcact5a2.htm. Accessed April 14, 2008.
  3. FDA Device Classes. Available at: http://www.fda.gov/cdrh/devadvice/3132.html. Accessed April 8, 2008.
  4. Medical Device Exemptions 501(k) and Good Manufacturing Practice (GMP) Requirements. Available at: http://www.accessdata.fda.gov/script s/cdrh/cfdocs/cfpcd/315.cfm. Accessed April 8, 2008.
  5. Premarket Notification 501(k). Available at: http://www.fda.gov/cdrh/dev advice/314.html. Accessed April 8, 2008.
  6. Search Guidance Database. Available at: http://www.accessdata.fda.gov/sc ripts/cdrh/cfdocs/cfGGP/Search.cfm. Accessed April 8, 2008.
  7. Standards Program. Available at: http://www.fda.gov/cdrh/stdsprog.html. Accessed April 8, 2008.
  8. Device Advice. Available at: http://www.fda.gov/cdrh/devadvice/pma/. Accessed April 8, 2008.
  9. Title 21 CFR 860.7: Determination of safety and effectiveness. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm. Accessed April 8, 2008.
  10. Buch B: FDA device approval: Things you didn’t learn in medical school and residency. Am J Orthop 2007; 36:407-412. [Medline]
  11. Search 510(k) Database: Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm. Accessed April 8, 2008.
  12. Search Premarket (PMA) Approval Database: Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm. Accessed April 8, 2008.
  13. ASTM F648-07: Standard Specification for Ultra-High-Molecular-Weight Polyethylene Powder and Fabricated Form for Surgical Implants. West Conshohocken, PA: American Society for Testing and Materials, 2007.
  14. Medical Device User Fee and Modernization Act (MDUFMA) of 2002. Available at: www.fda.gov/cdrh/mdufma. Accessed April 8, 2008.
  15. Office of Combination Products. Available at: http://www.fda.gov/oc/combination/. Accessed April 8, 2008.
  16. Jurisdictional Determinations. Available at: http://www.fda.gov/oc/combination/determinations.html. Accessed April 8, 2008.
  17. CDRH Advisory Committees. Available at: http://www.fda.gov/cdrh/panel/ . Accessed April 8, 2008.




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Right arrow Articles by Foy, J. R.
Right arrow Articles by Buch, B. D.

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