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A 510(k) PRIMER:FDA'S PREMARKET NOTIFICATION PROCESS

Medical Device & Diagnostic Industry Magazine | MDDI Article Index Originally published January, 1996 Arthur C. Kohler

At FDA, a major effort is under way to streamline the process by which medical devices are reviewed. Review protocols have been changed so that deficient submissions are more quickly identified and returned for further information. Guidances and letters to industry have been issued to assist industry by clarifying the agency's policies and procedures. FDA has even reclassified or exempted some devices from the 510(k) process.

While these initiatives promise to reduce review times and speed new devices to market, they also create the potential for misunderstandings and mistakes that could impede the very process that FDA is trying to improve. For example, FDA's initiative to change the status of some 124 devices, proposed on July 28, 1995, could take effect as early as late December 1995. Of the 124 devices, 12 are currently in Class I; the remainder are in Class II, but the rule would place them in Class I and then exempt them from 510(k) requirements. But changes in classification are not all in one direction. The same proposal that would reclassify these devices downward would place three currently Class I devices into Class II.

Therefore, prospective applicants should exercise caution. When deciding whether to submit a 510(k), the first step should be to determine whether the device has been exempted and to look at the individual regulations regarding devices in Title 21 of the Code of Federal Regulations to be sure that there are no pertinent limitations to those exemptions.1 There are, however, certain basics in the development of an application--fundamental processes that are critical to successful and timely review.

WHETHER TO SUBMIT A 510(k)

Most medical devices sold in the United States today are cleared for commercial distribution or marketing by premarket notification. The Federal Food, Drug, and Cosmetic Act (FD&C Act) requires device manufacturers to submit a premarket notification to FDA if they intend to introduce a device into commercial distribution for the first time, or to introduce--or reintroduce--a device that will be significantly changed or modified to the extent that its safety or effectiveness could be affected.2 Such a change or modification could relate to the design, material, chemical composition, energy source, manufacturing process, or intended use of the device.

What to Expect. There are several milestones along the way to obtaining clearance to market a device in the United States under premarket notification. The first, of course, is preparation and delivery of the notification to FDA. If the application is accepted, FDA will respond with an acknowledgment letter. This letter will state the date the notification was received and will assign it a unique document control number (i.e., K followed by 6 digits), which the submitter must reference in all further interactions with FDA regarding the review of that device. It is important to recognize that this acknowledgment letter is not a clearance from FDA for the manufacturer to sell the device, but simply denotes acceptance of the application.

If the device is found to be substantially equivalent, FDA will send the manufacturer a marketing clearance letter which, for the 510(k) process, is called a substantially-equivalent letter. Otherwise, FDA will send a not-substantially-equivalent letter. In this case, the manufacturer has several options, namely, submitting another 510(k) application with additional information supporting the claim of substantial equivalence, petitioning the agency for reconsideration of its decision, or submitting a premarket approval (PMA) application.

Substantial Equivalence. The basic concept behind obtaining 510(k) clearance is that the device being reviewed is very much like others already being sold in the United States. Two important terms enter into arriving at such a conclusion--substantial equivalence and predicate device. The 510(k) notification must show that the device is substantially equivalent to one or more predicate devices legally marketed in the United States.3 A predicate device is often one that was legally marketed on or before passage of the Medical Device Amendments to the FD&C Act on May 28, 1976. However, a number of predicate devices were first marketed after that date. They have been declared by the agency to be substantially equivalent after submission of a 510(k) application.

As defined in the FD&C Act, a finding of substantial equivalence requires either of two major conditions to be met.4 Substantial equivalence is likely to be determined if the device being reviewed is found to have the same intended use and the same technological characteristics as the predicate device. The device can have different technological characteristics. For example, it may be made up of different materials, have a different design, use a different energy source, or even rely on different principles of operation and still be substantially equivalent to a predicate device--but only if it has the same intended use and the submitter can demonstrate that it is as safe and effective as the predicate device. Additionally, the device being reviewed must not raise any different issues regarding safety and effectiveness when compared to the predicate device.

Device Modifications. Significantly modifying a cleared device may require that a new 510(k) submission be made. Unfortunately, there is no hard and fast rule as to when a new submission is needed. Instead, the agency states that a new 510(k) application is required for modifications to an existing legally marketed device if either of two conditions occur: first, if the modifications could significantly affect the safety or effectiveness of the device or, second, if the device is to be marketed for a new or different indication.5

FDA does not currently accept supplements to amend the submission of a previously cleared 510(k) device. This means that new 510(k) notifications must contain all the needed information. Referencing the earlier submission will not work. (An acceptable twist on this approach, however, is to claim substantial equivalence to the old device.) Also, the 510(k) must include supporting data to show that the manufacturer has considered the consequences that the change or new use might have on the safety and effectiveness of
the device.6

The description of the modified device should include differences from the predicate device that could significantly affect safety and effectiveness. Also included should be all data from in vitro, animal, and human clinical testing, if any, as well as engineering, bench, and design verification data, and any other information that supports the new indication or the claim that the modified device is as safe and effective as the predicate device.

PUTTING TOGETHER A 510(k)

Because FDA allows manufacturers to vary their methods of presentation in order to properly put forward their arguments for substantial equivalence, there is no single way to put together a 510(k) notification. However, certain basic elements are found in all 510(k) applications. A proposed model submission is included in an FDA guidance published last summer.7 In addition to the model, the guidance includes discussion of the 510(k) process and good manufacturing practices, labeling changes, technology or performance changes, materials changes, and materials changes to in vitro diagnostic products.

FDA has developed a decision tree that facilitates making the substantial equivalence determination.8 The Office of Device Evaluation (ODE) has issued many device-specific guidance documents regarding testing and other information to be included in 510(k)s.

Format and Information. The format and information required in a 510(k) premarket notification are specified in several sections of the Code of Federal Regulations.9 The submission should contain a report for each major study or test program conducted, such as biocompatibility studies. For sterile devices, test data must include the results of studies performed using finished, packaged, and sterilized devices. Data obtained from tests conducted on a finished device prior to packaging will not be accepted.

Each study report should contain well-organized information in sufficient detail to permit an FDA reviewer to determine what material or device was tested, what tests were performed, how the tests were performed, and what the test results were. Whenever possible, a summary of test results should be presented in table format. All reports and attachments should be identified with the name of the submitting company, the pages should be numbered, and a table of contents should cite the location of major headings and illustrations.

Care must be taken to be as complete and thorough as possible,
because FDA will not file or substantively review an incomplete 510(k) notification. To facilitate FDA review of the data, analysis, and conclusions of the notification, the manufacturer should conduct a conceptual review of the application. This review should check to
be sure that all data are presented logically, that the tests and analyses are scientifically valid and relevant to both the device and its
intended use, and that the summary report of the tests and studies is complete.

A description of the tests conducted and the results obtained is
essential. Reasonable and sufficient details of all test procedures and test results should be submitted to FDA. If a standard scoring system exists, manufacturers should use it for reporting the results of
each test.

Before submitting the notification, the manufacturer should once again review the data and their presentation. Each test report should include a description of the method used to score the data and cite the number of samples and replicates tested. The samples should be clearly described along with the presentation of any control data used to establish the validity of the tests. The manufacturer should identify the laboratory where the testing was conducted as well as the date of the tests. Finally, the analyses, data interpretation, and conclusions need to be summarized.

A 510(k) FRAMEWORK

While there is no set formula for presenting these data, there is a general framework in which to put them. That framework is actually an assemblage of major components that, if all are included and the data presented properly, will help ensure that the application is complete. Submitters can make FDA's task easier by beginning their submission with three copies of a cover letter or, better yet, by using the new cover sheet available from the Center for Devices and Radiological Health (CDRH). Although not required, this cover sheet incorporates a checklist that can help identify the type of submission and whether all pertinent information is included. Other essentials include the following items.

Identification. It is important not to overlook the obvious. Proper identification is crucial. Be sure that the applicant's name and street address are included; do not use a post office box. Telephone and fax numbers should be included for the contact person, and if that person is not the applicant, special note of that fact should be made. Be sure the applicant signs the submission and that the date of the application is noted.

Include a table of contents with page numbers indicating the location of the truth-and-accuracy statement; the 510(k) summary or statement; and any attachments, appendices, or illustrations. Also be sure to include the addresses of manufacturing and sterilizing sites.10

Truth-and-Accuracy Statement. All 510(k) submitters must include a statement certifying that all information in the application is truthful and accurate and that no material fact has been omitted. The statement may be in the cover letter or on a separate page. In either case, the location of this statement should be noted in the table of contents (see Figure 1).

Device Name. The device name, including both the trade or proprietary name and the classification name, must be included.11

Registration Number. If applicable, supply the FDA establishment registration number of the owner or operator submitting the premarket notification.11 Registration is not required in order for a company to submit a 510(k); however, it is a good idea to obtain one. This can be accomplished by filing a Registration Form 2891 with FDA. If this form is already being processed, or if the company intends to register in the future, say so in the notification.

If applicable, include the registration numbers and addresses of each facility used to manufacture the finished devices, including contract sterilizers. The manufacturing process at each facility must be essentially the same and produce the same device as described in the premarket notification submission.

Classification. Include the class of the device, (i.e., Class I, II, or III). If the device has not been classified, say so. If known, include the appropriate classification panel, for example, anesthesiology or orthopedics.12 If the device does not have a classification panel, state how this was determined. For example, the manufacturer may state that the device was not listed in the classification regulations, nor was it listed in the related FDA publication.1,13

In most cases, an accessory to a classified device takes on the same classification as the parent device. Software and other accessories that accept input from multiple devices usually take on the classification of the parent device with the highest risk.

Standards. The submitter should identify any mandatory or voluntary standards met by the device, citing each by paragraph or requirement. Although a device need not meet any particular standard, if substantial equivalence is being claimed to one or more predicate devices that do meet a given standard, then the new device should also meet it. Except for certain radiation-emitting devices, FDA has no mandatory standards and relies heavily on those accepted by the industry and on its own guidance documents with their standard-like requirements.14 The agency is likely to adopt only one or two mandatory standards in the foreseeable future, and these will pertain to such devices as apnea monitors and electrode leads and wires.15

Labeling. Although manufacturers may submit drafts of their device labeling, including the label on the immediate container of the device, the submission should be representative of the final version. The directions for use should include a specific statement regarding a clinically significant use of the device and any related warnings, contraindications, or limitations (e.g., precautions or adverse effects).16 The label for a prescription device must bear the following statement: "CAUTION: Federal law restricts this device to sale by or on the order of a __________," the blank to be filled with "physician" or another practitioner who can legally use or order the use of the device.17 In the process of clearing the 510(k) notification FDA may change or limit the labeling content, for example by limiting its statement of a device's intended uses.

Substantial Equivalence Comparison. Manufacturers should attempt to make comparison of the new device to its predicate as easy as possible for the FDA reviewer. The 510(k) notification should therefore include discussion of the similarities and differences between
the device and its predicate device, and should make use of comparative tables whenever possible. Comparisons might consider such areas as intended use, materials, design, energy used and delivered, anatomical sites, target population, physical safety, compliance with standards, biocompatibility, and performance. Information used to demonstrate the substantial equivalence of the device to its predicate should be provided in a clear and comprehensible format, making use of tables and graphs where these are helpful to clarify the manufacturer's argument.

Manufacturers should also submit pertinent information about the predicate device, including its labeling if available. For ex-
ample, the notification should state whether the predicate is a legally marketed preamendment device or a Class I or Class II postamendment device that has been granted marketing clearance
by FDA following the submission of a 510(k). If known, provide the 510(k) document control number (i.e., K followed by 6 digits) for the predicate device. Such 510(k) numbers are available via
the Electronic Docket at CDRH; see box on page 134 for contact information.

Class III Certification and Summary. Before claiming substantial equivalence to a Class III preamendment device, the manufacturer should determine whether a PMA is required for that generic type of device and, thus, for their product. If no PMA is required, the 510(k) submission must still have a special added certification statement as shown in Figure 2.18,19

Description. The 510(k) notification should include a physical description of the new device, together with an explanation of its intended use, principles of operation, power source, composition, and other information necessary to understand the device. If the notification is for an accessory, it should describe a typical device with which the accessory will be used. All variations of the new device that will be marketed should be listed.

Manufacturers should look at their descriptions from the point of view of the reviewer, in order to spot information that will be necessary to understand the narrative about the device. In many cases a picture is better than a thousand words. Together with the narrative, it is a good idea to include labeled diagrams, photographs or pictures, engineering drawings, schematics, and any other visual aids. When appropriate, identify all parts of the device--internal and external, assembled, unassembled, and interchangeable--and explain the functions of all significant parts. The device description should include the physical dimensions of the device--for example, its length, width, height, diameter, and weight. Identify any parts intended for single use only.

Performance. Performance data are often needed to help demonstrate that the proposed device is as safe
and effective as the predicate device. These data may
include results from engineering, bench, design verification, human factors, animal, or clinical studies.
Tests should be conducted in a manner as similar as
possible to how the device will be used during routine application.

Biocompatibility. Submissions for devices that directly contact the body--for example, gloves and condoms--must include a description of the characteristics of their materials. This description should compare the device to its predicate in sufficient detail to determine biocompatibility, as well as the kind of tests needed to determine biocompatibility. Any material differences between the device to be reviewed and the claimed predicate device must be stated explicitly, but it is just as important to state whether the materials comprising the two devices are identical. Manufacturers need to provide biocompatibility test data for any materials found in the new device that are not present in the predicate device. The data should be in a separate biocompatibility section--a section identified as such, well organized, and complete.

For some devices--such as gloves, condoms, contact lenses, and surgical sutures--the manufacturer should provide an exact identification of all colors in the inks, dyes, markings, radiopaque substances, and other such materials used in the manufacturing process. If the color is listed by FDA, is the same as the predicate's color, and there are no apparent concerns, or if the color was included in the general leaching tests, color typically will not be an issue.

Software. Applications for computerized devices must follow the appropriate CDRH guidance.20 Test data must support all performance and safety claims under routine and limited conditions.

Software marketed to enhance the performance of a device is
regulated as an accessory to that device. If the software is designed to enhance the performance of a group of different devices, it is regulated as an accessory to the device in the group that poses the greatest risk to the patient. Any instructions, prompts, or cautions displayed by the system are considered labeling and must meet the labeling regulations.

Software that performs library functions or is used for teaching is exempt from the premarket notification requirements. Also exempt is software that is not classified and processes manually entered data, if it does not perform any direct function on the patient. However, this software is a medical device and should be properly labeled and meet its claims.

Sterility. Submissions for devices that are labeled sterile must cite their sterilization method as well as the method used to validate the sterilization cycle. The notification does not, however, have to include actual validation data. The device's sterility assurance level (SAL) that the manufacturer intends to meet must be included. Note that an SAL of 10­6 is a common industry standard and that FDA usually will not accept anything below it. When ethylene oxide (EtO) is to be used to sterilize the device, mention must also be made of the maximum levels of residues of EtO, ethylene chlorohydrin, and ethylene glycol on the device. If radiation sterilization is used, the radiation dose must be stated. The submission should also describe the packaging used to maintain device sterility, but need not include data on packaging integrity.

For devices that contact blood or cerebrospinal fluids, the submission should state whether the device is nonpyrogenic and describe the method used to make that determination. If the entire device is not labeled sterile or nonpyrogenic, the labeling must clearly identify the parts that are nonpyrogenic and sterile. The relevant guidances on sterility should be consulted.21,22 Sterilizers intended for use in health-care facilities must meet the appropriate 510(k) requirements in these documents.

Pyrogens. If the device contacts blood or cerebrospinal fluids and will be labeled nonpyrogenic, state the process controls that will be used to control pyrogens. Also, state what method, such as the Limulus amoebocyte lysate (LAL) or USP rabbit test, will be used to determine that each lot is nonpyrogenic.

Sterilization by User. The labeling for devices intended to be sterilized by the user must identify at least one validated method of sterilization. The instructions should be detailed and specific enough for the user to follow and obtain the required SAL. The instructions should also adequately describe any precautions to be followed, such as special cleaning methods required, changes in physical characteristics of the device that may result from reprocessing and resterilization (especially those that may affect the device's safety, effectiveness, or performance), and any limit on the number of times the device can be resterilized and reused without adversely affecting its safety, effectiveness, or performance.

Convenience Kits and Trays. If the device is to be marketed as part of a convenience kit, the FDA guidance regarding kits should be consulted.23 A critical part of that guidance calls for certification by the applicant that the components of the kits have already cleared FDA (see Figure 3). If the sterile kit contains finished sterile examination gloves, the notification must contain data to demonstrate that the gloves meet the appropriate American Society for Testing and Materials (ASTM) standards, or their equivalent, and that they pass FDA's 1000-ml water leak test.24­26 The gloves must also pass the leak test after undergoing accelerated aging according to one of the protocols described by ASTM, or their equivalent.24,25

If the kit contains sutures, the manufacturer should provide evidence that the sterilant does not contact the sutures during the sterilization process. Some kit assemblers package sutures separately, adding them into the main tray only after it has been processed and sterilized. If sutures are included as part of the kit, the manufacturer cannot change their labeling, packaging, or method of sterilization without prior notification, review, and approval by FDA. Similarly, the supplier of the sutures included in the kit cannot be changed without prior notification, review, and approval by FDA.

If the device kit contains items that are subject to
regulation as drugs, a substantially-equivalent determination by CDRH will not apply to the drugs in the kit. For information on applicable FDA requirements for marketing drugs in a kit, contact the Center for Drug Evaluation and Research.

510(k) Summary or Statement. A premarket notification must include either a summary of the 510(k) safety and effectiveness information upon which the substantial-equivalence determination is based or a statement that this information will be made available by the 510(k) applicant to any person within 30 days of a written request.27,28 In order to comply with this requirement, manufacturers should familiarize themselves with FDA's exact definition of the terms summary and statement.29,30

Summaries are released by FDA when requested under the Freedom of Information (FOI) Act; statements are used to arrange for this FOI request to be fulfilled by the 510(k) applicant. The decision whether to include a summary or a statement can be changed any time before the substantial-equivalence determination is reached, but
not after.

510(k) Summaries. If a summary is included, it must be submitted with the 510(k) notification and clearly marked as such in order for FDA to begin its review. There are specific dos and don'ts in putting together a summary. One absolute is that this summary must be complete and correct in order for FDA to complete its review of a 510(k) submission. FDA will accept summaries and amendments until it issues a determination of substantial equivalence.31 If a summary has been submitted, requests for copies of it are legally supposed to be furnished by FDA through the FOI process within 30 days after determining that the device is substantially equivalent to another device.

510(k) Statements. If a 510(k) submitter chooses instead to provide a 510(k) statement to satisfy the above conditions, that statement must be submitted with the notification in order for FDA to begin its review. The statement should be on a separate letterhead page, clearly identified as "510(k) Statement," and signed by the certifier, and it must include specific language beginning with "I certify . . ."32 (see Figure 4). Written requests by any individual for a copy of the 510(k) must be fulfilled by the statement certifier within 30 days of receipt of the request. Only patient identifiers, trade secrets, and confidential commercial information may be purged from the statement. FDA publishes the names of certifiers on the monthly list of premarket
notification submissions for which substantial-equivalence determinations have been made.33 Those submitting 510(k) applications are not permitted to charge requesters for compiling and disseminating these data.

If a 510(k) submitter fails to comply with the commitment made in the 510(k) statement, FDA will provide the public with a purged copy of the 510(k) submission. Noncompliance with the 510(k) statement is a prohibited act; FDA will use its enforcement powers to obtain compliance.

DELIVERING THE APPLICATION

Make two copies of your complete 510(k) submission. Keep one for your records and submit the other to FDA along with the original. Send the submission to the following address by a method, such as registered mail, that provides a return receipt as proof of delivery:

Document Mail Center

Center for Devices and Radiological Health

U.S. Food and Drug Administration

9200 Corporate Blvd. (HFZ 401)

Rockville, MD 20850

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