Medical Device & Diagnostic Industry Magazine
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An MD&DI June 1998 Column

FDA MODERNIZATION ACT

Implementation of the FDA Modernization Act of 1997

New FDA guidance documents provide insights into how device manufacturers will benefit from the new statute.

Jonathan S. Kahan and Howard M. Holstein

This past February 19, FDA released 12 guidances on the CDRH home page of its Web site relating to implementation of the FDA Modernization Act of 1997. Prior to that release, the agency had issued on February 6 a Level 1 guidance document titled "FDA Modernization Act of 1997—Guidance for the Device Industry on Implementation of Highest Priority Provisions." In addition, on January 30, the agency issued the guidance document "Determination of Intended Use for 510(k) Devices—Guidance for Industry and CDRH." This article, the third in this series on the Modernization Act, is based primarily on an evaluation of these guidances. (Part I of the series ran on pages 105–127 of the March issue and Part II ran on pages 77–86 of the April edition.) FDA will, of course, be issuing numerous implementation regulations and additional guidelines that will also provide insights into how it will carry out the intentions of Congress. These new directives may be the subject of an additional article at a future date.

EARLY COLLABORATION MEETINGS

Section 201 of the Modernization Act allows sponsors of clinical studies of any Class III device to submit an investigational plan (including a clinical protocol) for early FDA review. Similarly, section 205 provides that FDA must, upon request, meet with any sponsor of a premarket approval (PMA) application to determine the type of valid scientific evidence necessary to support approval. The February 19 guidance document "Early Collaboration Meetings under the FDA Modernization Act, Guidance for Industry and CDRH Staff" describes these two types of early collaboration meetings and the procedures industry should follow to benefit from them.

The first type of meeting, designated an "agreement meeting," is open to any person planning to investigate the safety and efficacy of a Class III product or an implant. The guidance notes that the purpose of the meeting is to reach agreement on the investigational plan, including the clinical protocol, and further explains that any agreement reached in the meeting is to be put in writing by FDA staff, shared with the sponsor, and made part of the administrative record. Considered binding on FDA as well as on the sponsor, such an agreement can be changed only with the written consent of the sponsor or "when there is a substantial scientific issue essential to determining the safety and effectiveness of the device."

The second type of meeting is described in the guidance as a determination, or pre-PMA meeting, and is designed to focus on the broad outline of the clinical trial design. Based on the discussion at this meeting, the agency will determine whether clinical studies with concurrent randomized controls, concurrent nonrandomized controls, or historical controls (or other types of evidence) will be needed to demonstrate that the device is safe and effective for its intended use. FDA's determination is to be written and shared with the applicant within 30 days following the meeting. This determination is then binding unless adherence to the determination "would be contrary to the public health."

FDA expects that these meetings will take place early in the development of a product. The guidance document provides details on what a sponsor should submit to the agency when requesting an early collaboration meeting. Briefly, this submission must include: (1) a detailed description of the device; (2) a detailed description of the proposed conditions of use; (3) a proposed plan for determining whether there is a reasonable assurance of the device's effectiveness; (4) information regarding the expected performance of the device, if available; and (5) (for an agreement meeting) a detailed clinical protocol. This information should be in a document approximately 10 to 20 pages long, including only those appendices necessary for clarity. FDA will schedule a meeting within 30 days of receiving a request accompanied by the required information. These meetings may be face-to-face, by videoconference, or by telephone. Within two weeks of a meeting, a draft memorandum of the agency's determination or agreement will be circulated for review among the FDA participants and then signed by the division director (upon concurrence of the director or deputy director of CDRH's Office of Device Evaluation [ODE]). The results then will be placed in the administrative file and conveyed to the applicant within 30 days.

The intent of the Modernization Act's provisions for early collaboration was to give device sponsors greater certainty about the appropriate clinical trial design and the scientific evidence necessary for achieving FDA approval. The meetings described in this guidance should help accomplish that task. FDA believes that one meeting may often be able to accomplish the objectives of both section 201 and section 205; it recognizes, however, that some sponsors will request and benefit from separate agreement and determination meetings.

One of the key issues concerning implementation of the early collaboration provisions relates to whether the determinations or agreements are actually going to be binding. In each case, FDA has the opportunity to change its mind. With respect to the scientific evidence necessary to support premarket approval, the agency can change its determination if adhering to it would be contrary to the public health. Similarly, an agreement on an investigational plan can be abrogated if a substantial scientific issue arises that is essential to determining the safety or efficacy of the device. Because the statute does not define what might be essential to determining safety or efficacy, FDA has a great deal of discretion in making decisions to abrogate an agreement or determination.

In addition, the guidance states that the binding nature of both agreements and determinations is predicated on the manufacturer not significantly changing the underlying parameters (e.g., the device's intended use and indications, product design, investigational plan, or clinical study protocol). If these parameters are changed, then the basis for the agreement or determination will have been abrogated by the sponsor, and the agreement or determination will have no more influence on FDA's later decision making than any other general agency advice. This caveat is disconcerting because it seeks to give the agency even greater leeway in setting aside agreements and determinations than it already has. However, Congress will undoubtedly be watching FDA's actions to ensure that if the agency does decide to change or abrogate an agreement or determination, it has good reasons for doing so. Both Congress and industry expect FDA to adhere to its agreements and determinations except in the most unusual of cases.

DAY-100 MEETINGS

Under section 209 of the Modernization Act, FDA must, upon the written request of the applicant, meet with a sponsor within 100 days of receipt of a PMA application to discuss the review status of the submission. Prior to this meeting, the agency must inform the applicant in writing of any identified deficiencies and indicate what data are required to resolve them. FDA is also obligated to notify the applicant promptly if additional deficiencies are identified after the meeting or if any additional information is required to complete agency review. This section also reflects the desire of Congress for early collaboration and increased interaction between FDA and the device industry.

To implement these provisions, FDA issued a guidance document on February 19 titled "Guidance on PMA Interactive Procedures for Day-100 Meetings and Subsequent Deficiencies—for Use by CDRH and Industry." Under this guidance, a day-100 meeting request should be submitted no later than 70 days after FDA receipt and filing of the PMA application or 70 days from submission of an amendment that was required before FDA would file the application. The guidance explains that this lead period is needed to allow the agency enough time to schedule the meeting. The applicant is requested to specify the type of meeting desired, whether it should be face-to-face, a telephone conference, or a videoconference. At the time of a PMA filing, a contact person on the FDA review team will be appointed as the PMA project manager. That person will be responsible for the day-100 meeting and for any status reports following it.

The FDA guidance indicates that approximately 90 days from the PMA application filing date, the agency will provide the applicant with a written description of any deficiencies in its application and of the information required to correct them. Minor deficiencies may also be described at that point. This deficiency letter will be faxed to the applicant to "facilitate a meaningful dialogue" whether a day-100 meeting is requested or not.

The guidance also indicates that the following activities may occur during a day-100 meeting:

1. A general discussion of identified issues and discussion of remedial actions,

2. A discussion of an action plan with estimated dates of completion,

3. A discussion of FDA estimated timetables for completion,

4. Identification of the need for panel involvement, [and]

5. A discussion of possible premarket versus postmarket requirements.

Draft minutes of the meeting will be distributed to all attendees, and the review team leader will also provide the final minutes to the attendees and others at FDA. In the guidance, FDA also commits itself to continue to communicate promptly with the applicant on the status of the review. This communication will occur at least every four weeks.

The procedures outlined in this guidance should help overcome some of the past inadequacies of the PMA review process. Industry has complained for years that FDA's requirements have been a moving target and that the review process has been drawn out and not sufficiently interactive. Along with the other provisions for early collaboration, the deficiency letters and day-100 meetings should help alleviate those concerns.

THIRTY-DAY NOTICES AND PMA SUPPLEMENTS

In addition to its provision for pre-PMA meetings, section 205 of the Modernization Act includes provisions to reduce the necessity of submitting PMA supplements for certain "minor" modifications to previously approved Class III devices and to speed up the review and approval of such supplements. Under the act, minor manufacturing and process changes can be made 30 days after providing notice to FDA. The February 19 guidance document titled "30-Day Notices and 135-Day PMA Supplements for Manufacturing Method or Process Changes, Guidance for Industry and CDRH" implements those provisions.

In this guidance, FDA seeks to clarify which changes to a manufacturing method or process require the submission of a PMA supplement. By way of background, the agency explains that changes being adopted to reduce manufacturing and/or labor cost, reduce manufacturing time, reduce waste, or compensate for a change in suppliers of raw material or components may qualify for a 30-day notice. Examples the guidance gives of actions that would probably qualify include changes in or from:

1. Purchasing controls,

2. The sterilization type or process parameters within the same facility,

3. A manual process to an automated process,

4. A "joining" process where the toxicological and biocompatibility properties of a new adhesive are well known and not considered to be a potential problem,

5. A "joining" process where different solvent or energy sources are used to join the parts,

6. Cleaning methods used to remove manufacturing materials,

7. Manufacturing materials,

8. Cleaning specifications,

9. Vendors of a material where specifications of the material are unchanged . . . ,

10. A quality control test used to determine a specific attribute of an incoming component or raw material, the in-process device, or the finished device,

11. The type of process used (e.g., machining a part to injection molding the part), [and]

12. The environmental conditions in the manufacturing, storage or distribution facilities.

The guidance also states that certain manufacturing changes would probably not qualify for a 30-day notice, including those being made to accommodate a change in the manufacturing or sterilization site; the device design or performance specifications; the material specifications when the toxicological and biocompatibility properties of the material, when used in similar applications, are not well known; and the device's operating software. PMA sponsors making such changes should notify FDA in a standard, or 180-day, PMA supplement.

If a 30-day notice is submitted and FDA finds that it is not adequate, the sponsor will be informed that a PMA supplement is necessary. Under the Modernization Act, FDA has 135 days to review such a requested supplement; however, the elapsed time during the 30-day window is considered part of the 135 days. FDA provides great detail in the guidance document about what it expects to see in 30-day notices and 135-day PMA supplements.

If a change qualifies for a 30-day notice, the change may be made by the applicant 30 days after FDA receives the notice unless the agency informs the PMA holder within that time that the 30-day notice is not adequate and it describes the additional information or action required (Figure 1). The guidance also explains that review of 30-day notices and 135-day PMA supplements will be performed jointly by the CDRH Office of Compliance (OC) and ODE. OC will be the lead office in reviewing the submission, maintaining the administrative record, and constructing any written correspondence. This is a change from previous practice where ODE generally had the lead responsibility on PMA supplements and consulted with OC. Both ODE and OC will designate contact persons who, within five days of the filing of a 30-day notice, will confer and determine whether the change qualifies for this notification process.

Figure 1. Flowchart detailing the possibilities following submission of a 30-day notice to FDA by a premarket approval holder.

Will this new process help reduce the burdens of filing and reviewing PMA supplements? Some personnel at FDA are concerned that the agency could be flooded with 30-day notices for changes for which manufacturers have not been filing supplements. However, other staffers estimate that the new policy will eliminate 40 to 50 supplements per year or about 10% of the approximately 400 PMA supplements filed in fiscal years 1996 and 1997. For its part, industry would like the qualifying examples listed in the guidance to be expanded so that even more types of changes could be implemented under the 30-day notice process. Indeed, many feel that FDA should consider a similar process for minor design changes in Class III devices that have been validated using the process mandated by the quality system regulation.

DETERMINATION OF INTENDED USE FOR 510(k) DEVICES

Under section 513(i) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), FDA may find a new device substantially equivalent (SE) to a legally marketed one only after determining that the new device has the same intended use and is as safe and effective as the predicate device. Section 205 of the Modernization Act directs FDA to confine such a substantial equivalence review to the conditions of use identified on the device's proposed labeling. This provision was designed to prohibit the agency from requesting data on "implied intended uses." In its January 30 guidance on this issue, "Determination of Intended Use for 510(k) Devices—Guidance for Industry and CDRH," FDA explains that while the section 205 provision is a different statutory requirement than that in the FD&C Act, "it is not different from the manner in which 510(k)s have been traditionally reviewed."

In the guidance, FDA defines labeling as "all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article," and notes that proposed labels, labeling, and advertising sufficient to describe the device, its intended use, and the directions for use must be submitted for review during a substantial equivalence evaluation. Based on all of this information, FDA will itself determine the intended use of the device.

Although FDA is statutorily directed to limit its 510(k) review to a device's labeled use, in some cases the director of ODE has the authority to require specific labeling caveats, which could include information about an off-label or implied use. The guidance document sets forth the procedures that could lead to such a requirement. If, while reviewing a 510(k) notice, ODE staff determine that there is a reasonable likelihood that the device will be used in a manner other than that described in the proposed labeling and that such off-label use could cause harm, the review of the submission will then proceed in the following way: All deficiencies with regard to the submission except those regarding the off-label use will be discussed with the applicant and resolved in accordance with established procedures. Once that has occurred, or if no deficiencies are found, the concern about the off-label use will be brought to the attention of the chief of the premarket notification section of the Program Operations Staff (POS), who will be responsible for coordinating a resolution of the off-label use issue with the ODE director. Upon receipt of a referral from POS regarding an off-label use issue, the ODE director will evaluate the information and determine whether the two statutory criteria for going forward with a labeling caveat are met. Specifically, the director must decide whether there is a reasonable likelihood that the device will be used for the off-label use and whether such use could cause harm. If the director believes these criteria are met, the 510(k) applicant will be provided an opportunity to modify the device design to address the off-label use or to request a written determination from the director. If the modified design adequately satisfies the agency's concern, a routine substantial equivalence determination can be rendered. If the firm fails to modify the device or decides to request a written determination, the ODE director will, within 10 days, issue an SE Letter with Limitations specifying the restrictions regarding the off-label use to be included in the product labeling. A draft of such a limitations letter is provided as part of the guidance.

FDA's guidance on the 510(k) review provision appears to properly implement congressional intent. However, whether the agency has fully accepted the legislative restraints on its authority will only become clear as the steps outlined in the guidance are applied on a case-by-case basis.

DISPUTE RESOLUTION

Section 404 of the Modernization Act provides that when a scientific dispute arises between FDA and a regulated company and no specific provision of the FD&C Act or a regulation provides a right of review, the company may request a review by an appropriate scientific advisory panel. On February 19, FDA issued a guidance document on this provision titled "Medical Device Appeals and Complaints." In an unusual foreword to the document, CDRH director D. Bruce Burlington indicated that the center will appoint an ombudsman to help resolve difficult regulatory and scientific disputes. This CDRH ombudsman will be in addition to FDA's existing agencywide Office of Chief Mediator and Ombudsman.

The body of the "Medical Device Appeals and Complaints" guidance, however, is essentially an overview of FDA's already existing dispute resolution processes and does not introduce any new procedures. Its primary role is to describe, for the first time in one document, the numerous dispute resolution provisions of FDA's regulations, ranging from appeals to supervisors as authorized by 21 CFR 10.75 to the filing of citizen petitions under 21 CFR 10.30. Other dispute resolution mechanisms discussed include petitions for administrative reconsideration, the invocation of investigational device exemption (IDE) review committees, and provisions relating to formal evidentiary hearings and public hearings before boards of inquiry.

The guidance includes a chart of the primary FDA dispute resolution processes and the advantages and disadvantages of invoking each type, along with specific examples of use. A further guidance on the creation and use of scientific review panels is expected.

EXEMPTIONS FROM PREMARKET NOTIFICATION

Under section 206 of the Modernization Act, FDA was directed to publish in the Federal Register within 60 days of the act's signing a list of the types of Class II devices that do not require premarket clearance. The agency carried out its obligation and exempted 62 types of Class II devices on January 21, 1998 (63 FR:3142). In addition, FDA was given authority to exempt additional Class II devices from premarket notification following publication of this list, either on its own initiative or upon petition by an interested party. Before granting such additional exemptions, however, the agency must publish a notice in the Federal Register of its intent or of the petitioner's request. The Federal Register notice will provide a 30-day period for public comment; then, within 120 days of publication of the notice, FDA will publish its final determination in the Federal Register. If the agency receives a petition requesting an exemption from premarket notification for a Class II device and does not respond within 180 days of receipt of the petition, the exemption will be deemed effective.

On February 19, FDA issued the guidance document "Procedures for Class II Device Exemptions from Premarket Notification, Guidance for Industry and CDRH Staff" to explain the criteria it will use to determine future exemptions. Specifically, the guidance states that the agency will consider the following criteria in determining whether to exempt a type of Class II device:

1. The device does not have significant history of false or misleading claims or of risks associated with inherent characteristics of the device, such as device design or materials . . . ;

2. Characteristics of the device necessary for its safe and effective performance are well established;

3. Changes in the device that could affect safety and effectiveness will either: (a) be readily detectable by users by visual examination or other means such as routine testing, before causing harm, e.g., testing of clinical laboratory reagent with positive and negative controls; or (b) not materially increase the risk of injury, incorrect diagnosis, or ineffective treatment; and

4. Any changes to the device would not be likely to result in a change in the device's classification.

The guidance also describes the procedures that manufacturers should follow to request an exemption.

An attachment to the guidance specifically states that any granted exemption would apply only to those new devices that have the same existing or reasonably foreseeable characteristics as commercially distributed devices within that generic type, and to those new in vitro diagnostics (IVDs) for which a missed diagnosis caused by using the device would not be associated with high morbidity or mortality. FDA wants to make sure that industry does not interpret the scope of any exemption too broadly. Accordingly, the guidance states that a device would not be considered exempt if it:

1. Has an intended use that is different from the intended use of a legally marketed device in that generic type; for example the device is intended for a different medical purpose, or the device is intended for lay use instead of use by health care professionals; or

2. Operates using a different fundamental scientific technology than that used by a legally marketed device in that type; or

3. Is a specific kind of in vitro device such as those intended for diagnosis, monitoring, or screening of neoplastic diseases or, for example, IVDs that present a risk upon misdiagnosis.

For years the medical device industry has been urging FDA to exempt more Class I and Class II devices from premarket notification requirements. With the assistance of Congress in the Modernization Act, almost all Class I devices and a growing number of Class II devices are now exempt from such requirements. It is hoped that FDA will continue this trend and implement the provisions of section 206 as Congress intended.

MEDICAL DEVICE TRACKING

The Safe Medical Devices Act of 1990 (SMDA) provided FDA with mandatory and discretionary authority to require device tracking. Although the bulk of the SMDA device tracking regulation remains unchanged, section 211 of the Modernization Act revised FDA's authority by removing the provision for mandatory tracking of devices meeting statutory criteria and by requiring the agency to issue an order informing manufacturers when they must adopt tracking. The February 19 FDA guidance on these new provisions, "Guidance on Medical Device Tracking," states that tracking may be required for a Class II or Class III device, "the failure of which would be reasonably likely to have serious adverse health consequences; or which is intended to be implanted in the human body for more than one year; or which is a life sustaining or life supporting device used outside a device user facility."

The guidance notes that FDA has sent letters to each manufacturer currently marketing and distributing devices that must be tracked. These letters are intended to serve as the requisite order from FDA under section 211. Subsequently, the agency will issue similar orders to sponsors of newly submitted 510(k)s or PMA applications if their devices meet the tracking criteria cited above.

In addition, the guidance states that FDA, via a Federal Register notice (63 FR:10638), has requested comments on what factors it should consider in determining whether a particular device should be tracked, and lists 13 specific devices for which the agency is considering abrogating the tracking requirements. Those devices include vascular graft prostheses; interarticular disk prostheses; annuloplasty rings; tracheal prostheses; arterial stents used in coronary or peripheral arteries; inflatable penile implants; inflatable silicone breast prostheses; silicone gel–filled breast, testicular, and chin prostheses; silicone gel–filled angel chik reflux valves; and infusion pumps designed and labeled for use exclusively for fluids with low potential risks.

To assist manufacturers that must continue to track their devices, the guidance explains what a tracking program must accomplish, what information must be kept for both single- and multiple-use devices, what the requirements are for manufacturer audits and FDA inspections, and what to do if a company goes out of business. General information about their respective tracking responsibilities is also provided for distributors and user facilities.

As with other provisions of the Modernization Act, in section 211 Congress sent FDA a message to follow the least tortuous regulatory pathway. As its first step in implementing that charge, FDA is proposing to reduce the number of devices subject to tracking. Presumably, over time, the list of devices requiring tracking will continue to be evaluated and will not grow significantly.

POSTMARKET SURVEILLANCE

The Modernization Act significantly modified the statutory requirements for postmarket surveillance initially enacted in section 522 of SMDA. Specifically, section 212 of the new act deleted the provision for required postmarket surveillance and limited the discretionary postmarket surveillance authority granted to FDA. Now, the agency may order postmarket surveillance only for those Class II or Class III devices whose failure would be reasonably likely to have serious health consequences, or which are intended to be implanted in the human body for more than one year or are life-sustaining or life-supporting and are used outside a device user facility. FDA has issued three guidance documents on its postmarket surveillance procedures.

FDA's Transition Plan. Under SMDA, FDA established 18 categories of devices that required postmarket surveillance, and, using its discretionary authority, also ordered a number of other devices to be studied. As outlined in its guidance on the transition to its new authority, "SMDA to FDAMA: Guidance on FDA's Transition Plan for Existing Postmarket Surveillance Protocols," FDA first undertook a review of each device category subject to postmarket study requirements. The agency considered the state of the technology, the premarket regulatory pathway, the exposed patient population, the public health issues that postmarket surveillance would address, and the question of whether other potential postmarket strategies (e.g., special controls or registries) might provide sufficient information on those issues. The agency also is soliciting comments regarding whether certain existing postmarket surveillance orders should continue in effect.

The guidance identified several device categories for which FDA is considering rescinding postmarket surveillance orders. These devices include annuloplasty rings; automatic implantable cardioverter defibrillators that have not been marketed since January 1, 1996; coronary vascular stents with postapproval study requirements for a duration of five years or more; implantable pulse generators; vascular grafts; ventricular bypass (assist) devices; plasma-sprayed porous-coated hips that do not have mechanical properties equivalent to sintered or diffusion-bonded porous-coated hips; and injectable collagen. FDA will publish its final list after consideration of the solicited comments. Thus, companies that make products currently subject to postmarket studies should submit comments if they believe their devices should be included on the list of rescindments.

Determining Postmarket Surveillance Strategies. On February 19, FDA issued a corollary to the guidance discussed above. Titled "Guidance on Procedures to Determine Application of Postmarket Surveillance Strategies," this document describes FDA's procedures for invoking postmarket surveillance under section 522 of the FD&C Act. The guidance notes that the director of the Office of Surveillance and Biometrics (OSB) will establish internal committees to consider and evaluate device-specific issues and available postmarket mechanisms and make recommendations for appropriate action regarding postmarket surveillance strategies.

As described in the guidance, anyone in CDRH can recommend a device for consideration by the postmarket strategies committee. Concurrence of the division director is required, however, before the Postmarket Surveillance Studies Branch (PSSB) will determine whether the device should be presented to the OSB committee for formal consideration. Before making its recommendation, PSSB will consider the statutory criteria for postmarket surveillance, review the rationale proposed, and evaluate the applicability of postmarket surveillance to address the issues of concern. The OSB director, after committee consideration and consultation with others at FDA—including, as appropriate, OC and ODE staff—will decide whether to require postmarket surveillance. If the director determines that such surveillance is appropriate, he or she will issue an order containing the rationale and CDRH's recommendation as to the type of data collection needed to address identified concerns. Meetings then will be held with the affected manufacturer or manufacturers to discuss specific surveillance objectives, appropriate surveillance and analytical methodologies, and reporting time frames.

While this process may seem somewhat cumbersome, it does allow a full exploration of all applicable postmarket surveillance questions and alternatives before study requirements are imposed.

Review of Postmarket Surveillance Submissions. A third guidance related to postmarket surveillance, "Guidance on Procedures for Review of Postmarket Surveillance Submissions," describes how FDA will review postmarket surveillance submissions from affected manufacturers. Within 10 days of receiving a surveillance plan, PSSB will designate a lead reviewer, determine whether there is a need to consult with others in the agency, and, if so, distribute the plan to the reviewers. The CDRH division that has the expertise most relevant to the postmarket surveillance issue under consideration will designate a technical lead for the review. The PSSB lead in conjunction with the technical lead will have primary responsibility for reviewing the submission and providing a response, including a listing of any noted deficiencies, to the sponsor. OSB must make the final decision to approve or disapprove a plan within 60 days of receipt of the submission.

Once a plan is approved, the PSSB lead and the technical lead will maintain responsibility for determining whether or not the sponsor is conducting the surveillance in accordance with the plan and for evaluating the resulting data. The surveillance will be considered complete when the questions or issues that justified ordering surveillance have been addressed. However, if new issues or questions develop from the results of the study, FDA may require additional actions, including extending the study or changing the device or its labeling. The guidance concludes by noting that if a manufacturer has not conducted its postmarket surveillance in accordance with the approved plan, OSB and OC will develop an appropriate enforcement strategy.

RECOGNITION AND USE OF CONSENSUS STANDARDS

Section 204 of the Modernization Act specifies that FDA may recognize and use all or part of a medical device standard developed by a nationally or internationally recognized standards development organization. Such recognition may allow a manufacturer seeking FDA approval to submit a "declaration of conformity," certifying that its device conforms to a specific standard in place of certain test data.

The February 19 FDA guidance on this issue, "Guidance on the Recognition and Use of Consensus Standards," describes how the agency will recognize standards and how those standards can be used by industry. The guidance also contains an initial, but extensive, list of standards that FDA currently recognizes and on which manufacturers may rely as part of FDA's review of IDEs, humanitarian device exemptions, product development protocols, PMA applications, and 510(k)s. In most cases, a declaration of conformity will eliminate the need to provide actual test data for those aspects of the device covered by the standard. However, there may be safety or effectiveness issues that are not addressed by the conformity declaration and that will require the submission of additional information. FDA's list of recognized standards will be maintained on the CDRH Web site and will be updated at least annually.

In discussing procedures for the use of consensus standards, the guidance notes that conformance is voluntary and that manufacturers may choose to declare conformance with a standard or to address the issues covered by it in another manner. If a manufacturer elects to rely on one or more recognized standards, it must include a declaration of conformity in its submission to FDA and maintain records documenting conformance for two years or the expected design life of the device, whichever is longer. These records need not be provided to FDA in the original submission, but if they are not, FDA may request their submission or ask to examine them during GMP inspections.

Ordinarily, manufacturers will not be required to include in a premarket submission data relating to those aspects of safety and effectiveness covered by the cited standard. However, where a recognized standard describes a test method but does not specify any performance limits, the test results normally should be submitted to FDA. Testing to support a declaration of conformity may be conducted by the manufacturer or by a third party. FDA specifically states in the guidance that falsifying a declaration is a violation of law and results in the device being considered adulterated.

The guidance also describes the required contents of a conformity declaration. When applicable, the declaration should:

• Identify the applicable standard.

• Specify that all requirements were met except for those that may be inapplicable or from which there are deviations.

• Identify ways in which the standard may have been adapted for application to the device under review.

• Identify any requirements that are not applicable to the device.

• Specify any deviation(s) from the standard that are necessary to meet U.S. conventions.

• Specify what differences exist, if any, between the tested device and the device to be marketed and justify the use of test results where there are differences.

• Provide the name and address of any third-party testing organization used by the manufacturer.

FDA has the authority to request additional information or data from a sponsor when it receives a declaration of conformity. However, such instances are expected to be "rare," according to the guidance. To help ensure that they are, the agency requires that reviewers consult with their immediate supervisor and with the division director or the director of ODE before a request is made. In addition, if a reviewer believes that a declaration of conformity is inadequate to satisfy safety and effectiveness concerns, the reasons for this inadequacy must be explained.

Section 204 offers manufacturers a number of opportunities to simplify submissions and follow the least burdensome route to the market. This movement toward reliance on recognized standards is also reflected in FDA's new 510(k) paradigm, issued on March 20, which allows reliance on recognized standards in order to avoid sometimes burdensome 510(k) data requirements. Whether industry will actually be able to use conformity declarations in place of data requirements, rather than in addition to such requirements, remains to be seen. Nevertheless, the trend toward FDA recognition of consensus standards makes it important for companies to closely monitor and, whenever possible, participate in standards development activities. Industry input will help ensure that standards are appropriate for regulatory purposes and will allow manufacturers to use them to their greatest advantage.

AUTOMATIC CLASS III DESIGNATION

Section 207 of the Modernization Act establishes a de novo, or risk-based, classification mechanism that applies to "lower-risk devices" that formerly would have been placed into Class III only because they were found to be not substantially equivalent (NSE) to a predicate device during review of a 510(k). Under the new provision, within 30 days of receiving an NSE determination the 510(k) applicant may request that FDA consider a de novo classification to either Class I or Class II. Within 60 days of receiving such a request, FDA must notify the submitter in writing of its device classification decision. If the device remains in Class III, it may not be marketed until a PMA application or a product development protocol has been submitted and approved. If the device is reclassified, it may be marketed immediately and it then serves as a predicate for subsequent submissions. Within 30 days of a reclassification, FDA must publish a notice in the Federal Register announcing the classification and the controls necessary to provide a reasonable assurance of safety and effectiveness.

According to FDA's guidance, "New Section 513(f)(2)—Evaluation of Automatic Class III Designation, Guidance for Industry and CDRH Staff," once an NSE determination has been made, the request for evaluation of the Class III designation must describe the device and provide detailed information about it, such as that contained in a 510(k) or reclassification petition. Any available data from human experience with the device should be included, in addition to bench or animal test results. The request also should compare the potential benefits of the device when used as intended with the anticipated risks, and should discuss the proposed general or special controls that are necessary to provide a reasonable assurance of safety and effectiveness. Finally, the request may suggest a classification.

The guidance also sets forth the procedures CDRH will follow. For devices that appear to satisfy the low-risk criteria, NSE letters will state that the device may be an appropriate candidate for de novo classification. If, however, FDA determines that the device is not a likely candidate for review, the NSE letter will say so. When the agency believes that advisory panel input would be helpful in the classification decision, its review staff will make arrangements for convening such a panel as early as possible within the 60-day time frame allotted for review. Upon receipt of a de novo reclassification request, FDA will conduct an initial administrative review to determine whether all required elements for de novo review are present. If they are not, FDA will notify the applicant by telephone and identify the information needed to allow a substantive review to begin. The 60-day clock begins at the time a complete request is received.

Section 207 provides FDA with an excellent opportunity to remove devices from Class III in an expeditious fashion. Unfortunately, the guidance on this section does not specify what types of devices will be considered as "lower risk." It is also unfortunate that the procedure requires submission of a 510(k) and an NSE determination before de novo classification can be requested. This may be appropriate in some circumstances, but there are devices that clearly lack adequate predicates but are nevertheless low risk. For these devices, the 510(k) submission process will add to the time required for the review process. On the other hand, by front-loading much of the de novo review into the 510(k) process, FDA is able to more easily meet the 60-day statutory limit for making the de novo reclassification decision.

DISSEMINATION OF INFORMATION ON OFF-LABEL USES

FDA has not yet issued a guidance document regarding how it will regulate the dissemination of information on off-label uses of devices, which is permitted, to some extent, under section 401 of the Modernization Act. Nevertheless, we thought it appropriate to address briefly the implications of this important provision.

The compromise reached by Congress in passing this provision so limited the distribution of off-label information that it may be that very few medical device manufacturers will be able to take advantage of this new promotional path. FDA apparently has formed an internal working group that is debating how rigidly to interpret the statutory limits. At this time, the device industry will just have to await some actual examples of companies submitting off-label information to FDA for review to judge whether this provision will have any discernible benefit.

CONCLUSION

FDA is to be congratulated for its promptness in meeting the initial implementation requirements of the Modernization Act. The abundance of guidance documents discussed in this article will help industry understand and better utilize many of the act's provisions. However, much work remains to be done—and many implementation documents are still under development (e.g., those covering general versus specific intended uses, IDE modifications, and use of PMA data after six years). What these documents will contain and, most important, how FDA applies the act's provisions during the initial implementation period will help determine how successful the legislation will be in ensuring the timely and appropriate regulation of medical technology.

Jonathan S. Kahan and Howard M. Holstein are partners in the law firm of Hogan & Hartson (Washington, DC). Jonathan Kahan is also a contributing editor and an editorial advisory board member for MD&DI.

Illustration by Warren Gebert