In releasing guidance entitled, “Balancing Premarket and Postmarket Data Collection for Devices Subject to Premarket Approval – Draft Guidance for Industry and Food and Drug Administration Staff,” FDA attempts to clarify current policy on balancing premarket and postmarket data collection during the Agency’s review of premarket approval applications (PMAs).
Comments and suggestions regarding the draft document are due by July 22, 2014. Submit electronic comments to http://www.regulations.gov/. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions about this document concerning devices regulated by CDRH, contact the Office of the Center Director at 301-796-5900. For questions about this document concerning devices regulated by CBER, contact the Office of Communication, Outreach and Development (OCOD) by calling 1-800-835-4709 or 301-827-1800.
I. Introduction
The draft guidance clarifies the Food and Drug Administration’s (FDA or the Agency) current policy on balancing premarket and postmarket data collection during FDA review of premarket approval (PMA) applications. More specifically, the guidance outlines how FDA considers the role of postmarket information in determining the extent of data that should be collected in the premarket setting to support premarket approval, while still meeting the statutory standard of reasonable assurance of safety and effectiveness.
The right balance of premarket and postmarket data collection facilitates timely patient access to important new technology without undermining patient safety. FDA believes this guidance document will improve patient access to safe and effective medical devices that are important to the public health, by improving the predictability, consistency, transparency, and efficiency of the premarket review process.
FDA’s mission is to protect and promote the public health.Part of CDRH’s mission is to “assure that patients and providers have timely and continued access to safe and effective and high quality medical devices,” and to “facilitate medical device innovation.”(emphasis added).
FDA recognizes that there are risks associated with every medical device on the market. At the time of device approval, certain safety and effectiveness questions may not be fully resolved due to significant obstacles, such as the time and cost involved to address possible rare adverse events or long-term safety issues, and because controlled clinical studies do not fully represent the benefit-risk profile of a device when used in real-world clinical practice.
Getting the right balance between premarket and postmarket data collection—specifically, where appropriate, a greater reliance on postmarket collection—can reduce the extent of premarket data submission and directly impact when patients will have access to high-quality, safe and effective medical devices. But, greater reliance on postmarket data collection could undermine patient safety if the necessary and timely data collection does not occur.
Section 513(a)(3)(C) of the FD&C Act specifically requires FDA to consider the use of postmarket controls in lieu of collecting and reviewing all effectiveness data prior to PMA approval. Specifically, section 513(a)(3)(C) states:
In making a determination of a reasonable assurance of the effectiveness of a device for which [a premarket approval application] has been submitted, the Secretary shall consider whether the extent of data that otherwise would be required for approval of the application with respect to effectiveness can be reduced through reliance on postmarket controls.
As discussed below, FDA has long applied postmarket controls as a way to reduce premarket data collection, where appropriate, while assuring that the statutory standard for approval of reasonable assurance of safety and effectiveness is still met. This guidance provides a resource for industry and FDA staff on how FDA determines when it is appropriate for a sponsor of a PMA to collect some data (clinical or non-clinical) in the postmarket setting, rather than premarket.
FDA believes that applying postmarket controls in order to reduce premarket data collection, when appropriate, improves patient access to safe and effective medical devices that are important to the public health. As discussed in this guidance, there are certain circumstances where FDA may consider it acceptable to collect certain data in the postmarket setting, rather than premarket. FDA applies careful postmarket monitoring to support continued safety and effectiveness of the device.
Postmarket data collection is a factor FDA considers as a part of making benefit-risk determinations. FDA states:
FDA may consider the collection of postmarket data as a way to clarify the magnitude and effect of mitigations or as a way to develop additional information regarding benefits or risks for certain device types or in specific patient populations when making a benefit-risk determination. . . . In addition, pursuant to section 513(a)(3)(C) of the FD&C Act, in certain cases, such as if a device is likely to be denied approval due to uncertainty about its effectiveness, FDA will consider whether postmarket data collection or other conditions might be structured so as to permit approval subject to those conditions.
As part of FDA’s benefit-risk determination, one of the factors that FDA considers is the degree of certainty of the probable benefits and probable risks of a device in the Agency’s review of a PMA application. FDA states that:
There is never 100% certainty when determining reasonable assurance of safety and effectiveness of a device. However, the degree of certainty of the benefits and risks of a device is a factor FDA considers when making benefit-risk determinations.
FDA recognizes that medical device approvals are not made with absolute certainty due to significant obstacles, such as the time and cost involved to address possible rare adverse events or long-term safety and because clinical studies do not fully represent how a device will be used in clinical practice.
When making a determination whether it is appropriate to collect certain data in the postmarket setting, rather than premarket, FDA considers, among other factors, the device’s potential impact on public health. FDA may approve a device with a greater degree of uncertainty regarding the benefits and risks of the device if this uncertainty is sufficiently balanced by other factors, including the probable benefits of the device and the extent of postmarket controls. For example, as discussed in FDA’s Expedited Access for Premarket Approval Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions Draft Guidance,as part of FDA’s proposed Expedited Access PMA program, FDA may accept greater pre-approval uncertainty regarding specific benefits and risks of devices demonstrating the potential to address unmet medical needs, as long as the premarket data still support a reasonable assurance of safety and effectiveness. In addition, the extent to which FDA will accept certain data to be collected in the postmarket setting, rather than premarket, is impacted by the Agency’s current authority to mandate completion of post-approval studies, and to withdraw PMA approval for the marketed device should FDA later determine that there is a lack of a showing of reasonable assurance that the device is safe or effective under the conditions of use prescribed.
As discussed below, during the review of a PMA, FDA may consider it acceptable to collect certain data in the postmarket setting, rather than premarket, under certain circumstances when FDA has uncertainty regarding certain benefits or risks of the device, but the Agency has less uncertainty about the overall benefit-risk profile of the device at the time of premarket approval. In these circumstances, in accordance with existing statutory requirements under the FD&C Act, including section 513(a)(3)(C) of the FD&C Act, its implementing regulations, and consistent with current guidance, FDA intends to appropriately balance the submission of premarket and postmarket data. For example, uncommon or minor risks raised prior to PMA approval may, in appropriate instances, be addressed postmarket; assessing the long term benefit-risk profile of the device may also be deferred to the postmarket phase. In addition, in cases where FDA has robust experience with the device type, typically a more mature technology, there may be less uncertainty about probable risks and benefits of the device, and FDA may leverage such experience to defer some data collection to the postmarket setting.
IV. When Post-Approval Studies May Be Appropriate at the Time of PMA
Approval
FDA may consider it acceptable to collect certain data in the postmarket setting, rather than premarket under certain circumstances when FDA has uncertainty regarding certain benefits or risks of the device, but the Agency has less uncertainty about the overall benefit-risk profile of the device at the time of premarket approval.
Examples:
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Mature technology. A mature technology is a device type that is well understood and the benefits and risks are well-characterized because of a robust history of testing and clinical use. Therefore, FDA may allow for a shift of some premarket data collection to the postmarket setting for a device with a mature technology because the postmarket studies are likely to produce similar results to previously conducted similar studies for the same type of device.
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Confirm mitigation effectiveness for a known risk in a post-approval study. Mitigations may be necessary for known safety risks associated with use of the device. Confirmation of the adequacy of the mitigation may be evaluated post-approval if mitigation of the risk is not fundamental to FDA’s determination at the time of approval that the probable benefits outweigh the probable risks of the device.
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Modify warnings, contraindications, precautions in approved labeling. Post-approval studies may be designed to collect further data on specific adverse events or event types for which there was limited knowledge during premarket review (e.g., small number of adverse events that occur within a subpopulation or uncertainty relating to the probability of minor adverse events), and the review of the postmarket data may result in revision of the warning, contraindications and/or precautions in the labeling.
- Approve for an intended population beyond what was fully evaluated in the pivotal trial, with a confirmatory post-approval study. In some cases, a device may be approved for a patient population that has not been fully evaluated in the premarket clinical studies, if the approval is conditioned on a post-approval confirmatory trial in the indicated patient population and other data support a reasonable assurance of safety and effectiveness for the intended population at the time of approval.
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Example: HPV testing devices have two distinct intended use populations with inherently different risk levels for cervical pre-cancer and cancer. Approval for both populations was based on full analytical data and agreement of clinical samples against a valid comparator, and clinical evidence of safety and effectiveness for the high risk population. A post-approval study assessed the longitudinal risk of cervical cancer in the population with lower risk.
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Assess long-term performance in a post-approval study. Long-term performance of a specific aspect of a device may be difficult to assess in a premarket study as it may be necessary to collect data over a number of years in order to fully establish the performance of the device. Shifting the collection and evaluation of long-term performance of a specific aspect of a device to a post-approval study allows FDA to approve the device based on a reasonable assurance of safety and effectiveness demonstrated in the premarket study, with any uncertainty regarding the long-term performance to be addressed postmarket.
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Example: Long-term chronic performance and mechanical integrity of new pacemaker leads is established through a standard post-approval study design requiring 1000 patients out to 5 years. This postmarket study is in lieu of requiring chronic/long term data prior to premarket approval, which FDA recognizes would be difficult to obtain in a timely fashion. Current premarket clinical trials for this device require data out to one or two years.
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- Assess rare adverse events in a post-approval study. It may be more appropriate to assess rare anticipated adverse events in the postmarket setting when FDA has a low degree of uncertainty regarding the positive benefit-risk balance at the time of premarket approval.
- Confirm bench data with clinical data collected in a post-approval study. It may be possible to approve a new device or a change to an existing device based on bench data with postmarket confirmatory clinical data.
FDA’s Expedited Access for Devices Draft Guidancealso describes circumstances under which FDA may consider it acceptable to collect certain data in the postmarket setting, rather than premarket, while still ensuring that the statutory standard for premarket approval of reasonable assurance of safety and effectiveness is met. As part of the Expedited Access PMA Program described in the Expedited Access for Devices Draft Guidance, in order to facilitate earlier patient access to devices that demonstrate the potential to address an unmet medical need, FDA may accept a higher degree of uncertainty about the benefit-risk profile of the device at the time of approval by collecting certain data in the postmarket setting rather than premarket.
FDA believes it is important to routinely reassess whether data that the Agency receives in a premarket submission for a device type may instead be collected postmarket or if the data are no longer necessary for FDA to determine that there is a reasonable assurance of safety and effectiveness for the device type. Sponsors who believe that the extent of data FDA previously expected in a premarket submission for the device type for which they plan to submit a PMA should be collected postmarket or should no longer be required, should submit a Pre-Submission (“Pre-Sub”),as described in FDA’s draft guidance, “Medical Devices: The Pre-Submission Program and Meetings with FDA Staff“(“Pre-Sub Guidance”).
As discussed above, the extent to which FDA will accept certain data to be collected in the postmarket setting, rather than premarket, is affected by the Agency’s current authority to mandate completion of post-approval studies and to withdraw PMA approval for marketed devices for which FDA later determines that there is a lack of a showing of reasonable assurance that the device is safe or effective under the conditions of use prescribed. Therefore, FDA may impose postmarket requirements at the time of approval of the device, including conditioning the device approval on continuing evaluation and periodic reporting on the safety, effectiveness, and reliability of these devices for their intended uses, in accordance with 21 CFR 814.82(a)(2). These postmarket data will enable the Agency to assess the risks and benefits of these devices with a higher degree of certainty and take action where this information raises concerns regarding the safety or effectiveness of these devices.
FDA may also impose conditions of approval on the labeling of the devices under 21 CFR 814.82(a)(3) if important for the device’s safe and effective use (e.g., in order to ensure that patients and healthcare providers have complete and accurate information regarding the benefits and risks of the device). In addition, if necessary to provide for a reasonable assurance of the safety and effectiveness of these devices, FDA may restrict the device as a condition of approval under 21 CFR 814.82(a)(1).
In circumstances where post-approval data collection is appropriate, FDA intends to require post-approval studies as a condition of approval. These studies may include both clinical and non-clinical testing. The approval order will specify the agreed upon timeframe for the sponsor to complete the post-approval study, conduct analyses and submit the data to FDA.
In appropriate instances, FDA may order the sponsor to conduct postmarket surveillance under section 522 of the FD&C Act in lieu of a post-approval study. Note that the failure or refusal of a manufacturer to comply with section 522 is a prohibited act under section 301(q)(1)(C) of the FD&C Act, 21 U.S.C. 331(q)(1)(C). Further, under section 502(t)(3) of the act, 21 U.S.C. 352(t)(3), a device is misbranded if there is a failure or refusal to comply with any requirement under section 522 of the FD&C Act. Please note that violations of sections 301(q)(1)(C) or 502(t)(3) may lead to enforcement action including seizure, injunction, prosecution, or civil money penalties.
B. Reporting Requirements for Post-Approval Studies
FDA may impose continuing periodic reporting on the safety, effectiveness, and reliability of the device for its intended use under 21 CFR 814.82(a)(2) (e.g., periodic reporting of the status and interim data or analyses of the required postmarket data collection). The reports required to be submitted will be included in the post-approval order.
FDA may impose certain labeling requirements as a condition to PMA approval, under 21 CFR 814.82(a)(3) that are important for the device’s safe and effective use (e.g., information on the risks and benefits of the use of the device). Any labeling requirements will be included in the approval order.
The labeling of a device approved should include a succinct description of the uncertainty about anticipated benefits and risks and the extent of data that supported approval and the required post-approval study(ies).
There are several actions that the sponsor or the FDA may, as appropriate, take in the postmarket setting as a result of the required conditions of approval, depending on whether the sponsor conducts and completes the required post-approval study and submits, in a timely manner, the data from the study to FDA as specified in the approval order, as well as on the study’s results. FDA may take enforcement action if the sponsor has not met the required conditions of approval, including failure to initiate or complete a post-approval study specified in the approval order for the device.
In addition, as provided in the FDA guidance entitled, “Procedures for Handling Post-Approval Studies Imposed by PMA Order,” issued June 15, 2009 (“post-approval guidance”), FDA posts certain information about the post-approval studies for devices on FDA’s website at: Post-Approval Studies.
The actions that the sponsor or FDA may take in the postmarket setting include, but are not limited to, the following:
(1) Submission of a PMA Supplement
The results from the post-approval study may trigger the need for the sponsor to submit a PMA supplement to FDA in accordance with 21 CFR 814.39(a) if the sponsor makes a change affecting the safety or effectiveness of the device. Examples include, but are not limited to, narrowing or expanding the indication for use of the device, labeling changes, and changes in the performance or design specifications.
Labeling Changes
Depending on the results of the post-approval study, the sponsor could revise the device’s labeling, with the approval of FDA, to reflect the population and condition for which a clinical benefit was directly established in the post-approval study(ies), including expanding the indication for use, narrowing the indication for use, or removing or revising language in the labeling regarding the level of uncertainty about the approved indication for use. The sponsor may decide to revise other sections of labeling (e.g., contraindications, warnings, precautions, adverse events and clinical studies), with FDA’s approval, to ensure that, based on the new data, the labeling adequately describes the safety and effectiveness of the device.
Importantly, information learned about a device postmarket can change the information required in device labeling. For example, new information about an adverse event may require labeling changes to device instructions for use or to warnings or precautions to ensure the device complies with section 502(f) of the FD&C Act and 21 CFR Part 801. During its review of post-approval study reports, FDA may discuss changes to the labeling based on the study findings to ensure the device labeling has adequate directions for use.
(2) Safety Communications
In some instances, it may be in the best interest of public health for FDA to issue a safety communication, such as if the post-approval study raises new safety concerns, but FDA believes there is still a reasonable assurance of safety and effectiveness.
(3) Panel Meeting
As described in the post-approval guidance, FDA may seek the advice of panels when considering the progress of, or data from the post-approval study, such as when the results of the study may be difficult to interpret.
(4) Administrative and Enforcement Actions
FDA may take a variety of actions if the Agency concludes that based on the data from the required post-approval study or other source there is a lack of reasonable assurance that the device is safe or effective under the conditions of use, or if the sponsor has not met the required conditions of approval under 21 CFR 814.82, including failure to initiate or complete a post-approval study specified in the approval order. For example, failure to comply with certain post-approval requirements under 21 CFR 814.82(a)(2) may cause the device to be misbranded under section 502(t)(2) of the FD&C Act and constitute a prohibited act under section 301(q)(1)(B) of the FD&C Act, which could result in seizure, injunction, or civil money penalties. Failure to comply with a post-approval requirement under 21 CFR 814.82(a)(3) may cause the device to be misbranded under section 502 of the FD&C Act.
FDA recognizes that circumstances may arise outside of the sponsor’s control that may adversely affect the ability of the sponsor to complete the post-approval study on time. Therefore, although FDA expects sponsors to undertake efforts to complete the study on time, when appropriate, FDA intends to be reasonably flexible about the timeframe for completing a post-approval study and submitting data to the Agency.
In accordance with section 515(e) of the FD&C Act and 21 CFR 814.46, FDA may also withdraw PMA approval of a device if, for example:
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On the basis of the data from the required post-approval study(ies), or other new information with respect to such device, evaluated together with the evidence available to FDA when the PMA application was approved, FDA finds that there is a lack of a showing of reasonable assurance that the device is safe or effective under the conditions of use prescribed, recommended or suggested in the labeling;
- The sponsor fails to meet any post-approval requirement imposed by the PMA approval order, which includes failure to complete a post-approval requirement within the timeframe established in the approval order; or
- On the basis of new information, evaluated together with the evidence available to FDA when the PMA was approved, FDA finds that the labeling, based on a fair evaluation of all material facts, is false or misleading in any particular, and such labeling is not corrected within a reasonable time after receipt of written notice from FDA.
If FDA determines there are grounds for withdrawal, the Agency may ask the sponsor if they would like to voluntarily request withdrawal of approval under 21 CFR 814.37(d). If the sponsor does not voluntarily request the Agency to withdraw approval, FDA will notify the sponsor of FDA’s proposal to withdraw approval in a notice of opportunity for an informal hearing under 21 CFR Part 16.If the sponsor does not request a hearing or if after the part 16 hearing, FDA decides to proceed with the withdrawal, FDA will issue the sponsor an order withdrawing approval of the application. The order will be issued under 21 CFR 814.17, will state each ground for withdrawing approval, and will include a notice of an opportunity for administrative review under section 515(e)(2) of the FD&C Act. FDA will give the public notice of an order withdrawing approval of a PMA, in accordance with 21 CFR 814.46(e).