Background

A predetermined change control plan (PCCP) is documentation describing what modifications will be made to a device after its initial premarket authorization without requiring a new marketing submission to FDA, and how these modifications will be assessed. Modifications to medical devices that could affect the safety or effectiveness of the device require premarket authorization from FDA. In order to support the iterative development of devices, in 2019, FDA introduced the term “PCCP” in a discussion paper on premarket review of PCCPs for AI- or machine learning-enabled device software functions (ML-DSF). By submitting a PCCP, a sponsor may obtain pre-approval for intended modifications (and their method of implementation) to an ML-DSF without necessitating additional marketing submissions for each modification delineated and implemented in accordance with the PCCP.

In March 2023, FDA issued guidance on how a PCCP could be included in a premarket submission for a device that is [or includes] an ML-DSF. This past week, FDA issued broader draft guidance that addresses marketing submissions for PCCPs for all device types, not just AI/ML-enabled devices. As summarized below, the new guidance:

• provides five “guiding principles” for FDA’s PCCP policy;
• spells out how to determine whether a modification may be appropriate for inclusion in a PCCP, based on whether the underlying device application is a 510(k) / De Novo, or a PMA application or supplement;
• advises on what information to include in a PCCP; and,
• describes FDA’s other proposed PCCP policies, including how to utilize an authorized PCCP to implement modifications, and version control and maintenance of a PCCP.

The draft guidance also includes ten illustrative examples of modifications that generally may be or are not appropriate for inclusion in a PCCP for specific devices.

Five guiding principles

FDA frequently references in the draft guidance how the agency’s advice on PCCPs is underpinned by five guiding principles:

1. Reasonable assurance of safety and effectiveness and substantial equivalence of devices with PCCPs. FDA writes that “the totality of the information included in a PCCP should enable FDA to assess the reasonable assurance of safety and effectiveness or substantial equivalence of the device.” Moreover, the device, including all modifications proposed in the PCCP, must meet the regulatory standard required of that type of application (i.e., if a 510(k) notice, the device modified per the PCCP must still be substantially equivalent to the cited predicate).

2. PCCPs may be a least burdensome option to support device modifications. FDA is promoting PCCPs as a way to implement device modifications without the need for additional marketing submissions for each modification.

3. PCCPs are part of a device’s marketing authorization. The marketing authorization granted will include the specific version of the PCCP that was reviewed by FDA.

4. PCCPs are specific. FDA stresses that a PCCP should include only a few, specific modifications that can be verified and validated, and that do not cover an excessively broad scope.

5. PCCPs harmonize with existing FDA Device Modifications guidances. When a device does not have a PCCP, or when the modification is not consistent with the PCCP, Device Modifications guidances exist to help manufacturers ascertain whether a new marketing submission is required prior to implementing a modification.

Modifications for 510(k)s and De Novos vs. PMA applications and supplements

The new draft guidance focuses on recommendations for how manufacturers should determine whether a modification may be appropriate for inclusion in a PCCP. Consistent with the agency’s overarching approach in evaluating products, FDA adopts a risk-based framework in its analysis of this question. Specifically, the agency states that modifications that could introduce new risks are generally not appropriate for inclusion in a PCCP “because the risks of implementing the modification are likely not adequately mitigated by the existing risk management framework of the device and the manufacturer’s quality system.” In contrast, modifications that significantly modify existing risks may be appropriate for inclusion in a PCCP if the existing risk framework and quality system are adequate to monitor and mitigate the risk. Thus, certain changes to processes (sterilization, packaging), materials/components, software, or labeling may be deemed appropriate for a PCCP, while others (such as changing from prescription to over-the-counter use, or changing/removing contraindications) would generally require a new 510(k) or De Novo submission.

Following the same framework for devices subject to PMA requirements, FDA’s guidance says that modifications that are minor changes or manufacturing changes generally may be appropriate for inclusion in a PCCP “when the risks of implementing the modification are adequately mitigated by the existing risk management framework of the device and the manufacturer’s quality system.” This could include, for example, minor changes in device design or user interface, minor changes to software related to device compatibility or interoperability, or minor changes in software consistent with the intended use to improve device performance. By comparison, significantly changes to components, materials, design, specifications, software, or labeling would not be considered appropriate for a PCCP.

To harmonize with FDA’s policies for device modifications, the agency provides several flowcharts for use in determining whether a modification may be appropriate for inclusion in a PCCP. FDA cautions that these diagrams should be utilized in conjunction with the text of this guidance and other agency documents, as the analysis can be complex.

Components of a PCCP

In FDA’s 2023 guidance on how a PCCP could be included in a premarket submission for a device that is [or includes] an ML-DSF, FDA recommended that a PCCP include a) a detailed description of the specific, planned device modifications; b) the associated methodology to develop, validate, and implement those modifications in a manner that ensures the continued safety and effectiveness of the device across relevant patient populations, referred to as the “Modification Protocol”; and c) an Impact Assessment to evaluate the benefits and risks of the planned modifications and associated risk mitigations. We described these recommended PCCP components at the time online here.

FDA’s new draft guidance maintains these three components of a PCCP. The agency further emphasizes that a PCCP “should clearly delineate which parts of the Modification Protocol are applicable to each modification within the Description of Modifications,” noting that this could be facilitated via a traceability table (of which it provides an example).

Utilizing an authorized PCCP to implement device modifications

The draft guidance emphasizes that a PCCP should be evaluated within the existing risk management framework of the device and must be implemented in accordance with the manufacturer’s quality system. FDA warns that “deviations from the authorized PCCP could significantly affect the safety or effectiveness of the device,” and that significant modifications made to a device that are not specified in, or implemented in accordance with, the authorized PCCP will “likely require a new marketing submission.” FDA notes that when a manufacturer implements device modifications through an authorized PCCP, they should update the labeling for the device as specified in the PCCP.

FDA also advises that the PCCP must be described in the publicly available summaries accompanying authorization of a device (i.e., 510(k) or De Novo Summaries, PMA Summaries of Safety and Effectiveness and approval orders), in sufficient detail to provide transparency regarding the assessment of reasonable assurance of safety and effectiveness or substantial equivalence for the device.

LDT applicability

In May of this year, FDA finalized its historic — and notoriously controversial — rule to explicitly assert the agency’s authority to regulate laboratory developed tests (LDTs), including in vitro diagnostic (IVD) products. We summarized online here FDA’s Final Rule, which became effective on July 5, 2024, and how the changes it describes will be phased in over the course of four years.

FDA’s new draft guidance on PCCPs may be of special import to the clinical laboratory industry as a source of flexibility for modifying and updating LDTs. Indeed, four of the ten examples that FDA provides in the new draft guidance to illustrate types of modifications that likely would and would not be appropriate for inclusion in a PCCP relate to IVD devices.

For example, the first example in the guidance pertains to an over-the-counter microarray-based IVD cancer predisposition risk assessment system, for which FDA advises that addition of new single nucleotide variant may be appropriate for inclusion in a PCCP; however, addition of a new gene would generally not be appropriate. The draft guidance also mentions that, while changes requiring clinical data validation are generally not appropriate for inclusion in a PCCP for most devices, certain such changes may be appropriate for inclusion in a PCCP for an IVD, “such as method comparison data for IVDs.”

Next steps

The new draft guidance states that FDA “highly encourages” early engagement with the agency for a proposed PCCP, especially for combination products and class III devices. The primary avenue for obtaining FDA feedback on PCCPs prior to filing marketing submissions is the Q-Submission program.

FDA has invited comments on the draft guidance through November 20, 2024. The agency is also expected to soon publish the final version of its March 2023 guidance on how a PCCP could be included in a premarket submission for a device that is [or includes] an ML-DSF; we will provide a separate analysis of that final guidance when it is released.

If you may wish to submit a comment, or have any questions on PCCPs, AI/ML-enabled medical device regulations, IVDs, or FDA product marketing applications more generally, feel free to contact either of the authors of this alert or the Hogan Lovells attorney with whom you regularly work.