Part 1: The Premarket Approval Process
Note: This is Part 1 of a Guide to FDA Approval and Testing Processes for Implantable Devices Made from PEEK Polymer and Summarizes Requirements for Premarket Approval (PMA). A summary of the FDA’s 510k Clearance process for implantable devices is available as Part 2, elsewhere on this site. Both guides are intended as a general summaries only. Medical Device Manufacturers (MDM) must follow the FDA processes and steps required for each specific device in detail.
Implantable medical devices are tightly regulated by the FDA. They must pass through an advanced testing and approval process that often takes more than a year to complete. For MDM attempting to introduce implantable devices to the market, knowledge of the FDA’s approval and clearance processes and to which classes of devices they apply can prevent costly delays. Moreover, specifically with devices made from PEEK polymer, working with an experienced PEEK resin supplier and a medical grade polymer conversion specialist can help make the work required more efficient and effective.
Implantable Devices Require Either Premarket Approval (PMA) or 510k Clearance, Including PEEK Devices
Implantable devices are typically considered Class II or III devices by the FDA. Unlike Class I devices, Class II and III medical devices are responsible for supporting or sustaining essential life functions. They may also pose a higher risk of injury or illness should they fail.
Given the risks involved, the FDA requires Class II and III devices including those made from implantable PEEK polymers to be cleared through a 510k process or meet the requirements for pre-market approval (PMA) before they can be brought to market.
What Must Be Included in a PMA?
PMAs are comprehensive and should include at the minimum the following:
- The name of the applicant and their address
- A table of contents
- An abstract that summarizes the data included in the application. It must include indications for use and under what conditions the device will be used.
- A description of the device, including the scientific concepts underpinning its function, as well as any standout physical or chemical properties.
- A marketing history of the device, if any. This should include the countries where the device has been marketed, as well as any adverse reports on its safety or efficacy.
- A summary of the included technical information; specifically non-clinical and clinical studies and their results.
- A detailed description of the device, with pictures, information about each functional element, and the device’s operating principles and properties. Information about manufacturing, processing, packing and storage methods should also be included.
- A bibliography of all published reports associated with the device’s safety and efficacy.
- At least one sample of the final device and its components. This sample should pass through the same manufacturing, packaging, and labeling processes as the final product.
- A copy of all device labeling, which may include instructions for placement and use, as well as any marketing literature.
Before a PMA is approved, the FDA’s regulatory board reviews the application in detail including all data. As a PMA may often exceed 100 hundred pages, reviews can be lengthy.
What Testing Methods Does the FDA Require for Implantable PEEK?
During its review of the PMA’s study data, the FDA committee verifies several factors including the device’s shelf life, wear characteristics, stress tolerance, effectiveness, and biocompatibility. Biocompatibility is largely determined during the non-clinical phase of trials, where animal and laboratory tests are the preferred method.
In biocompatibility testing, the material from which the device is made is what generally affects the results. To facilitate this step, PEEK suppliers or device OEMs often contract with independent labs to test implantable PEEK grades for biocompatibility in advance.
What Biocompatibility Testing Procedures Are Required for Implantable PEEK Devices?
The FDA requires a broader spectrum of tests for implantable devices than it would for a Class I device. Specifically, these implantable devices require an array of biocompatibility testing procedures which can include a combination of the following:
- Cytotoxicity testing determines the general toxicity of the device material. During cytotoxicity testing, device extracts are suspended in a solution that’s delivered to several mouse fibroblast-derived cell cultures. Researchers note any cell death or abnormalities.
- Sensitization testing demonstrates how tissues might react to the presence of the device or polymer. Material extracts are placed in the tissue of live animal subjects. Any edema or redness is noted, as this indicates immune system activity at the challenge site.
- Irritation (intracutaneous reactivity) testing involves placing device extracts in animal subjects that are then observed for a few days for any signs of irritation. Irritation presents a bit like sensitization, in that it causes redness and swelling. However, it results from physical damage that the device causes to the cells, while sensitization results from the body’s immune response to the device.
- Acute, subchronic and chronic systemic toxicity testing reveals whether a material can cause toxicity as it migrates to other tissues. Systemic toxicity testing delivers material samples to the animal subject via multiple pathways, including dermal, oral, inhalation and intravenous routes.
During acute systemic toxicity testing, researchers look for any signs of toxicity that emerge within 24 hours of sample delivery.In subchronic toxicity testing, the subjects are monitored for weeks or months, depending on how long the device is expected to be implanted in a human subject.Chronic toxicity testing requires monitoring for most of the test subject’s lifespan. This test is designed to identify sublethal clinical features of toxicity, such as reduced growth, tissue repair, and reproduction.
- Material-mediated pyrogenicity testing involves looking for any pyrogenic response caused by the device material. A pyrogenic response produces fever and cold-like symptoms, suggesting an immune response and the presence of inflammatory cytokines.
- Genotoxicity and carcinogenicity testing determines the presence of genotoxic materials that can damage genetic material inside cells. As this damage can result in cancer formation, carcinogenicity testing is typically done alongside genotoxicity testing.
During testing, researchers consider whether the sample material is affecting chromosomes and genetic expression. There are several genotoxicity testing methods, but the Ames mutagenicity test is the most common.
During the Ames test, Salmonella bacteria is combined with a sample extract and placed in cell media plates. One of these plates contains zero histidine, which is necessary for Salmonella growth and reproduction. If the histidine-free plate demonstrates Salmonella reproduction, then researchers can conclude that the material sample is capable of producing genetic mutations, and possible tumors, in exposed tissues.
- Implantation testing involves surgically placing the material in animal subjects. Implantation sites are designed to mimic placement in human patients, so local pathological effects can be observed with the relevant tissues. Following the test’s conclusion, cell samples from the subject are histologically analyzed for any abnormalities, signs of toxicity or damage.
How Can an Implantable PEEK Conversion Specialist Help Expedite Device Approvals?
While the FDA may reject an application for administrative reasons (incorrect address, for example), its focus is on the study data. If this data is not present in its entirety, it will result in extended and extremely costly delays.
Working with a company that specializes in converting implantable PEEK polymer into extruded shapes for machining, machined prototypes and injection molded components can help avoid delays. In addition to their expertise in polymer processes, these companies also serve as data storehouses for the polymers they transform for medical device customers. This includes biocompatibility data and information on the polymer’s stiffness, impact resistance and other physical properties important to the device’s functionality.
A capable PEEK polymer conversion specialist will have this information readily available for customers. It can help device manufacturers proceed through both 510k clearances and premarket approval (PMA) with minimal setbacks.