Preparation and Review of Investigational Device Exemption Applications (IDEs) for Total Artificial Discs

Name of Guidance:
Preparation and Review of Investigational Device Exemption Applications (IDEs) for Total Artificial Discs

Status of Guidance:
Final

Name of Organization:
Food and Drug Administration
Center for Devices and Radiological Health

Date of Guidance:
April 2008

Target Audience:
Sponsors submitting IDE applications for artificial disc devices and FDA staff reviewing these applications

Laws and Regulations Referenced:

21 CFR 812.20 Describes when and how a sponsor should file an
Investigational Device Exemption (IDE) application
21 CFR 812.25 Outlines what should be included in a device investigation plan
21 CFR 812.27 Describes what should be included in a report of previous
investigations when submitting an IDE application
21 CFR 812.43 Describes how study investigators and monitors should be selected
21 CFR 860.7 Explains how device classification is determined based on safety and
effectiveness data
21 CFR Part 50 Describes how human subjects must be protected during clinical trials
21 CFR 50.25 Outlines what is involved in obtaining informed consent from subjects
in clinical trials
21 CFR Part 58 Explains what constitutes good laboratory practice for nonclinical
studies

Definitions:

Total artificial disc – An implant that replaces a vertebral disc in the human spine

Spinal system – The complete spinal implant including all parts

Component – An individual part of a spinal implant

Construct – The entire spinal implant system
Device/system – Interchangeable terms referring to the artificial disc

Background:
The artificial disc was first approved in the United States in 2004 to treat certain disorders of the spine.¹ The US Food and Drug Administration (FDA) still considers the artificial disc to be a new technology.^2(p13) Before the FDA will consider approving a new artificial disc, or an existing disc for a new use, the device must be tested in animals and humans. Because artificial discs pose substantial and unique health risks to patients, the FDA must grant permission before human studies are conducted. This permission is called an Investigational Device Exemption (IDE). In this guidance, the FDA issues recommendations specific to applying for an IDE for a total artificial disc device.

Summary:
This guidance provides recommendations to those who wish to apply for permission to test artificial discs in humans. The guidance outlines each section of the IDE application, and explains what type of information should be included.

The IDE application should begin with a detailed description of the artificial disc, including photographs, drawings, and material specifications. Following this description, the authors should include all information already known about the device or similar devices. This section, entitled Report of Prior Investigations, should describe previous results from testing in animals and humans. Animal data should establish that the device poses a minimal risk of toxicity, and provides basic functionality and performance over time. A variety of animals are used to test spinal devices, and the investigators must provide a rational for their choice of animal model.

The IDE should address the issue of wear debris, which is a major area of safety concern. Normal wear may cause the device to break down on a microscopic level, releasing particles of foreign material into the body. Investigators must test the effects of such particulate matter in animals prior to testing the device in humans.

Artificial discs are designed to preserve the motion of the spine, as opposed to traditional spinal fusion, in which motion is eliminated. Mechanical testing of the artificial disc should establish its ability to preserve the 6 primary motions, which are lateral bending (to the left and right), flexion and extension (to the front and back), and axial rotation (twisting left and right). The testing parameters should be presented in detail, any device failures documented, and the results interpreted.

Mechanical testing should be conducted, with results measured after 10 million repetitions of a given motion. The maximum range of motion the device allows should be documented. Such testing is typically performed using cadaver specimens.

Mechanical testing should also verify that the device is not prone to migration (moving out of position), or stress relaxation (in which the more flexible components of the device stretch out and lose elasticity over time). Testing should further establish that the surrounding bones of the spine (vertebrae) grow into the areas in which they come in contact with the device, providing stability (osseointegration) over time. They must also show that any coatings applied to the device do not wear off or break down over time.

Finally, prior investigations should examine the shelf life of the device to determine whether the components degrade with age.

The next section of the IDE application outlines the investigator’s plan to conduct a human study. After outlining the purpose of the study, the application should describe the design of the study in detail. The FDA recommends various criteria for including and excluding potential study participants. Many of these criteria relate specifically to the condition of the patients’ spines. Patients may be excluded because they have complex and interconnected spinal disorders, which would make it difficult to assess the performance of the device to be tested.

The FDA also addresses the fact that very few studies have tested the use of artificial discs at more than one spinal level in the same patient. They recommend that, if multi-level disc replacement is studied, enough patients are included to provide useful data, and that results be analyzed separately for patients with a one- and multi-level treatment.

The guidance describes various spinal problems that should exclude a patient from participating in a study of artificial discs, but allows the investigators to include such subjects if they provide an acceptable rationale.

The FDA recommends that subjects be followed for at least 2 years after surgery. They also recommend asking patients to consent to long-term follow-up that may continue for 5-10 years.

The guidance describes in detail the ways in which the failure or success of the device may be determined. These include x-ray images of device positioning, bone ingrowth, and spinal motion, as well as evaluations of the health of the spinal levels above and below the implant. They also include patient surveys about pain and their ability to perform daily activities.

The guidance lists potential risks that test subjects may face, some related to surgery, and others related specifically to the artificial disc. It recommends the IDE applicant address how the study design minimizes these risks.

In the interest of providing information on the long-term use of artificial discs, the FDA also recommends that any devices that are eventually removed from patients be analyzed.

Finally, the IDE application should include proposed packaging and surgeon instructions for the artificial disc. These instructions should describe not just the implantation of the device, but also the removal of the device or revision of the surgery if required.

Rationale:
This guidance provides important detail that is useful in submitting an artificial disc IDE. Artificial discs pose numerous safety risks and their effectiveness remains controversial. Therefore, it is appropriate that the FDA describe its specific areas of concern about these relatively new devices, and guide applicants in addressing them through appropriate testing, analysis, and documentation.

Resulting Recommendations:

· The investigator’s choice of animal model should be justified by providing a description of its relevance to the expected human use of the artificial disc.

· Wear debris should be evaluated in a small animal model and after 10 million repetitions of a given motion in a cadaver specimen.

· Animals should be studied after 3 and 6 months of device implantation.

· The range of motion allowed by the artificial disc should be documented.

· Artificial discs should be evaluated for their tendency to migrate or slip out of position.

· The durability of any coatings applied to the artificial disc should be tested.

· The shelf life of the artificial disc should be evaluated.

· Clinical trials should involve multiple centers, control groups, and patient randomization to test the safety and effectiveness of artificial discs.

· If artificial discs are to be implanted at more than one level in a single patient, the study should include enough such cases to provide adequate data, and these data should be analyzed separately from single-level cases.

· Patients should be excluded from the study if they have less than 5 mm of disc height between vertebrae, if they have a spinal problem other than the one being studied, if they are taking medications affecting bone metabolism, if they have myelopathy (spinal cord disorder),³ if they have certain degenerative diseases or deformities of the spine, or if they have had certain prior spine surgeries.

· Patients should be followed for at least 2 years after surgery, and preferably for 5-10 years.

· Endpoints for studies should include back, leg, neck, and arm pain, ability of patients to perform daily activities, device stability, amount of spinal motion, bone growth into device, disc height, and overall satisfaction of the patient.

· Successful bone ingrowth should be defined as covering at least 75% of the implant contact surface.

· Studies should examine the relationship between range of motion and pain to determine whether the preservation of motion is associated with reduced pain.

· Levels of the spine above and below the implant should be assessed for their disc height and range of motion.

· Studies should be designed to minimize patient risks, including breakage or slippage of the artificial disc, fracture of bone adjacent to the implant, loss of spinal motion, undue wear of the device, degeneration of adjacent vertebrae and discs, infection, and neurological side effects.

· Devices that are surgically removed should be studied for wear.

· Device packaging should include surgical instructions not only for implanting the artificial disc, but also for removing it or revising the original surgery.

Impact:
Artificial discs have the potential to treat a variety of spinal disorders while preserving motion in the spine. New devices may provide significant improvements on original designs, and their safety and efficacy must be studied in humans before widespread use. Moreover, the long-term effects of artificial disc implantation must be examined. To these ends, this guidance provides useful advice to device manufacturers and investigators who wish to obtain FDA approval to test their artificial discs in humans.

1. Feder BJ. An Alternative to Spinal Fusion. New York Times. December 24, 2004. Accessed May 23, 2011.

2. U.S. Food and Drug Administration. Guidance for Industry and FDA Staff: Preparation and Review of Investigational Device Exemption Applications (IDEs) for Total Artificial Discs. April 11, 2008. Accessed May 19, 2011.

3. Myelopathy. The Free Dictionary. Accessed May 23, 2011.