Implementation of the FDA Modernization Act of 1997

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

FDA MODERNIZATION ACT

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

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:

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:

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.