The summer of 2016 saw a flood of new medical device-related guidance documents coming out of FDA’s Center for Devices and Radiological Health (CDRH). Some of these draft guidance documents, such as those addressing device modifications and the 510(k) process, have been long-awaited and are broad in scope, applying to all or a wide swath of the medical device market. However, other recent Agency guidance has been narrowly focused on issues related to the operationalization of so-called precision medicine goals (i.e., “giving the right treatment, to the right patient, at the right time”).

As discussed further below, FDA has released its first draft guidelines for next-generation sequencing technologies as well as draft guidance addressing the application of such cutting-edge genomics technology within clinical settings. For example, one of these important policy documents relates to the codevelopment of therapeutic products with DNA screening tests that enable providers to predict whether the products will be effective in a particular individual. All medical device stakeholders should be keeping abreast of FDA’s policies and expectations that are expressed via guidance.

The recent high level of regulatory activity by CDRH and other FDA centers and offices was expected to occur, as typically does in the final year of a White House Administration. But this year these newly announced policies are even more critical to the growth and development of the medical device industry, as the United States sits on the cusp of a medical revolution that will integrate connected/mobile health technologies, genomics and personalized medicine, and highly effective biological therapies.

Guidance on Device Modification and Software Modification 510(k) Policy

In August, FDA released two new draft guidances intended to help device manufacturers determine when a modification to a cleared, marketed device triggers the obligation to file a new 510(k) premarket notification. The first draft guidance, entitled Deciding When to Submit a 510(k) for a Change to an Existing Device (“2016 Device Change Guidance”), is a revision to FDA’s 1997 final guidance of the same name (“1997 Final Guidance”). The other guidance is a so-called spinoff guidance, entitled Deciding When to Submit a 510(k) for a Software Change to an Existing Device (“2016 Software Device Change Guidance”), which is specific to software modifications. It is important to note that although the 1997 Final Guidance continues to represent the Agency’s official current policy on device modifications, in our experience, revised policy elements expressed in draft guidances are often used by FDA even before finalization. Thus, even these draft guidance documents should be reviewed and considered today.

The new draft guidances focus on helping manufacturers through the decision-making process and to make reasonable decisions about when a modification significantly alters a device’s risk profile or its indications for use. To that end, FDA has retained the flowchart or logic tree model that it has used in the past, and it has honed the questions to be more descriptive and applicable to real-world device changes.

The 2016 Device Change Guidance emphasizes the Agency’s intent to distinguish between significant new changes and changes that have only superficial impact on the marketed device. FDA accomplishes this by using three approaches:

1. Questions acknowledging that risk-profile changes stemming from a device modification may already be mitigated.
2. General risk-based analysis categories with relevant guidelines.
3. A separate appendix with a range of examples relevant to each flowchart question.

FDA also released separate draft guidance specific to 510(k) modification decisions when the device involved is undergoing software changes. Although certain sections of the 2016 Software Device Change Guidance closely mirror the 2016 Device Change Guidance, such as the guiding principles and general focus on possible new risks or hazards related to changes, the software guidance focuses on version control, coding issues, and other software-specific design considerations. This two-document approach is allowing FDA to treat modifications involving coding and software-hardware interaction issues separately from hardware-specific issues.

The 2016 Software Device Change Guidance includes a flowchart that calls out the most significant changes that would clearly trigger the new 510(k) requirement (e.g., changes to cybersecurity, software specifications, risks, and clinical functionality), but it also includes an overall, risk-based strategy for catching more general or cumulative changes that could affect the device’s risk profile or indication. Appendix A of the draft guidance includes multiple examples specific for each flowchart question.

Another helpful element included in the 2016 Software Device Change Guidance is the “Common Software Change Types” section, which describes different types of modifications, such as to software “infrastructure” and the “core algorithm,” and provides general advice about whether such types of modifications typically will or will not require new 510(k)s (for example, “cosmetic changes” that only alter the appearance of the device likely would not require a new 510(k)).

Guidance concerning manufacturer responsibilities with respect to medical device software modifications has been one of the critical missing links in FDA guidance for several years now. The Agency has attempted to take a balanced approach in the two newly issued draft guidances, but all manufacturers that produce medical devices with a software component should consider both guidances and determine whether the flowcharts guide reporting decisions to a reasonable conclusion based on the proposed modification. Comments on each of these draft guidances can be filed electronically via Regulations.gov until November 7, 2016.

Initial Guidance for Next-Generation Sequencing Devices

Building on last year’s public workshops related to Next-Generation Sequencing (NGS) and expanding its efforts to advance the Obama Administration’s Precision Medicine Initiative, this year FDA released three draft guidance documents on different aspects of NGS-based diagnostic tests. NGS is a term used to describe new technologies that allow rapid sequencing of large segments of an individual’s DNA or even entire genomes. The Agency’s stated goal is “to create a flexible and adaptive regulatory approach to the oversight of NGS-based tests,” given the rapid and innovative advancements being made in the technologies.

The first draft guidance, entitled Use of Public Human Genetic Variant Databases to Support Clinical Validity for NGS-Based In Vitro Diagnostics, describes an approach to allow test developers to rely on clinical evidence from FDA-recognized public genome databases to support claims for their tests and to provide assurance of accurate clinical interpretation of genomic test results, potentially offering a streamlined path to approval.

If a genetic variant database meets the quality requirements set forth in FDA’s draft document, the Agency states that the database administrators could then request (voluntarily, of course) recognition from FDA that the assertions contained within it be considered “valid scientific evidence” to support a future NGS-test premarketing review submission. The developer of an NGS-based test would then incorporate the recognized database’s assertions about specific genetic variants and the data supporting those assertions in its submission. FDA’s proposed Recognition Process for Genetic Variant Databases would, most critically, include a review of the policies, procedures, and other documentation from the database; such information would be expected to be made public by the database administrator after receiving FDA recognition as part of the transparency commitment.

The second document, entitled Use of Standards in FDA Regulatory Oversight of NGS-Based In Vitro Diagnostics Used for Diagnosing Certain Germline Diseases, provides recommendations to developers of NGS-based tests regarding the design, development, and validation of such tests for germline diseases only. Germline diseases are genetic diseases or other conditions that are inherited or de novo mutations in egg or sperm cells (i.e., not mutations that arise from DNA damage after birth through exposure to environmental contaminants or as a result of other factors.) Accordingly, therefore, this foray by FDA into providing regulatory advice to NGS stakeholders is narrowly limited to a subset of the massive potential for the application of NGS-based technologies.

The key takeaways from this FDA proposed policy are:

• An NGS-based test for germline disease may be appropriate for classification as a Class II device, through the de novo classification process, because “there is a reasonable probability that the risks associated with [such tests] (e.g., those related to the consequences of a false positive or negative result provide to a patient) may be sufficiently mitigated by a combination of general and special controls, and that the safety and effectiveness of this type of test may be reasonably assured by such controls.” This discussion is practically an invitation by the Agency for someone, anyone, to submit a de novo classification request for NGS-based tests with this specific intended use.
• Once classification is established, even if as a Class II device, it is possible that FDA may exempt the NGS-based test for germline disease from premarket notification requirements of section 510(k) of the FD&C Act. Importantly, FDA would not alter any “limitations of exemption,” meaning that, according to prior guidance and regulation, the 510(k) exemption would be exceeded if there is a different intended use or technology. Exemption from the premarket notification requirements may be established based on conformance with FDA-recognized standards for analytical validity, although the guidance notes “FDA has not yet determined how conformity with standards…should be demonstrated and plans to discuss this in future guidance documents.”
• The remainder of the guidance delves into detailed recommendations for design, development, and validation of NGS-based tests for germline diseases. It first characterizes NGS-based tests for germline diseases so a test developer will be able to determine if their test is, in fact, captured by the guidance. If so, then specifics for indications for use, accuracy and performance, and test validation are described in detail.
• Content and format of Test Reports for the end users (health care professionals or consumers) are summarized, with requirements for such reports to include information about test limitations and information about any unknown variants.

This second guidance importantly notes that while FDA is willing to recognize scientific standards, “FDA is unaware of any existing, comprehensive standard for analytical validation applicable to NGS-based tests for germline diseases that it believes could be used to help provide reasonable assurance of the safety and effectiveness of these tests.” Perhaps the title will be reconsidered before finalization of the guidance.

These two more broadly applicable NGS draft guidances remain open for public comment (via Regulations.gov) until October 6, 2016.

Finally, before those two documents were released, FDA also issued a third draft guidance related to a narrow application of NGS, entitled Infectious Disease Next Generation Sequencing Based Diagnostic Devices: Microbial Identification and Detection of Antimicrobial Resistance and Virulence Markers. The formal comment period on that proposed policy has closed, and public comments are available for review now in the electronic docket.

Guidance on Codevelopment of Therapeutic Products and Screening Tests

FDA also recently released draft guidance on the codevelopment of therapeutic products (such as drugs and biologics) and companion tests that are used to determine if the therapeutic products will be safe and effective.

The codevelopment of therapeutic products and companion tests, known as in vitro companion diagnostic devices (“IVD companion diagnostics”), is not a new advance. In 1998, FDA approved both the cancer drug Herceptin along with an IVD companion diagnostic called HercepTest. HercepTest measures the expression of human epidural growth factor receptor 2 (HER-2) in breast cancer tissue. Some breast cancer cells have too many copies of the HER-2 gene, which can lead to an overproduction of proteins that cause cell growth. Herceptin works by attaching itself to the HER-2 receptor, thereby reducing the overproduction of these proteins. However, only 25 to 30% of those with breast cancer overexpress the HER-2 gene. As an IVD companion diagnostic, HercepTest allows physicians to determine whether their patients overexpress the HER-2 gene and thus may benefit from Herceptin.

The discovery of “biomarkers” like HER-2 have increased tremendously, and, as FDA notes in the new draft guidance, the codevelopment of IVD companion diagnostics and therapeutic products is critical to the advancement of precision medicine. To facilitate these advances, the Agency’s draft guidance provides developers with principles that can help them effectively codevelop the products while satisfying FDA’s regulatory requirements. The draft guidance specifically focuses on the following four topics:

• general principles to guide codevelopment to support obtaining contemporaneous marketing authorization for a therapeutic product and its corresponding IVD companion diagnostic;
• certain regulatory requirements that sponsors should be aware of as they develop such products;
• considerations for planning and executing a therapeutic product clinical trial that also includes the investigation of an IVD companion diagnostic; and
• administrative issues in the submission process for the therapeutic product and IVD companion diagnostic.

The codevelopment of these products presents unique challenges given that therapeutic products and IVDs companion diagnostics are typically developed on different schedules, are subject to different regulatory requirements, and have different points of interaction with the appropriate review review centers at FDA. Cooperation–both among the codevelopers and between the codevelopers and the FDA–is a crucial part of the navigating the codevelopment process. (This new guidance supplements a more general guidance document on In Vitro Companion Diagnostic Devices that was finalized in August 2014.) Electronic comments may be submitted on this proposed policy document before the October 13, 2016.

Other Recently Released Device-Related Guidance That May Be of Interest

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