FDA to Resume Domestic Device Inspections

The FDA was forced to announce in March 2020 that it would suspend inspections of drug and medical device manufacturing sites because of the COVID-19 pandemic, but the agency has partially reversed that decision in a July 10 statement. FDA commissioner Stephen Hahn said the pause that had been applied to inspections did not prevent the agency from conducting mission-critical inspections, although routine surveillance inspections had been shuttered for four months.

The FDA has been tracking state and local conditions with the aid of a rating system designed to establish which locations are reasonably safe for a site inspection. This COVID-19 advisory rating system makes use of real-time data to provide a qualitative assessment of the number of cases in an area. These data are shared with the agency’s partners on the state level who handle some inspectional activities, presumably including inspections of mammography facilities.

The rating system is broken down into three levels of risk on a county-by-county basis, starting with the category of counties where inspections will only take place when those inspections are deemed mission-critical. The second tier of inspections takes into account whether the agency can send field investigators who have not identified themselves as vulnerable to poor outcomes for infection with the SARS-CoV-2 virus. The last tier is for counties that are open to a resumption of normal activities. The agency’s objective is to resume surveillance inspections the week of July 20, although the FDA said that conditions on the ground would continue to drive the level of inspectional activity.

FDA Posts Two Draft Updates

Regulatory science has not completely stagnated in the COVID-19 pandemic, a fact of life demonstrated by two draft guidances the FDA published for updates to existing guidances. One of these is a July 13 update for 510(k) submissions for devices that provide atherectomy for the peripheral vasculature, comments for which are due Sept. 11.

The scope of the draft is limited to intraluminal artery strippers that fall under the MCW product code, which includes four technologies, including rotational atherectomy devices. Sponsors can use ISO 10993 to test for biocompatibility, and ISO 14971 for risk evaluation and management. Devices that are packaged with a pre-installed internal battery will have to fulfill several performance testing recommendations, including shelf life, and the sponsor will have to determine the impact of sterilization on the battery when the battery will be left in the device during sterilization procedures.

The FDA states that it has no intention of imposing changes to the existing guidance that are not specified in this latest draft. Interestingly, the existing final guidance was issued in February 2020, less than two years after the previous draft had been published.

The second updates draft published in the month of July is the July 14 draft for clinical and non-clinical investigations into devices for treatment of benign prostatic hyperplasia (BPH), which will also limit updates to the existing to the contents of the draft. This draft will update the recommendations for devices that are covered by four product codes (KNS, PEW, PZP and NOY), and includes updates to recommended approaches to animal studies.

Among the draft recommendations is that animal studies should include both gross and histological examinations of the treated area by a pathologist who is blinded to the treatment. The draft states that animal studies of thermotherapy devices should include evaluations of how well the device limits the volume of affected tissue by checking parameters such as blood flow and tissue heterogeneity. There are also recommendations for animal studies of stents used for BPH.

Also included in the updates draft for BPH devices are recommendations for pilot and pivotal studies, including a recommendation that the sponsor make use of a randomized, controlled study design for the pivotal study. While the standard of care for the population under investigation might be the most appropriate control treatment, the FDA said the risk-benefit ratio of the investigational device should be comparable to that of the control treatment. The comment period for this draft closes Sept. 14.

September a Guidance Drop Month for FDA

September was an unusually busy month for the FDA’s device center, which released more than 20 draft and final guidances in the final 30 days of fiscal 2019. Several of these documents are related to the de novo device program, but the agency also updated its approach to the humanitarian device program as required by recent legislation.

Humanitarian Use Guidance Updated
The final guidance for the FDA’s humanitarian device exemption (HDE) program explains how the agency determines whether the sponsor has demonstrated a probable benefit, although the final encodes the new limit for humanitarian use devices of 8,000 per year as seen in the 21st Century Cures Act. Another change due to statutory mandates, in this case the Food and Drug Administration Reauthorization Act of 2017, is that the sponsor need not rely on a local institutional board, a change intended to offer some efficiencies in the conduct of multi-site clinical investigations.

The HDE guidance is applicable to devices reviewed by both the Center for Devices and Radiological Health and the Center for Biologics Evaluation and Research. HDE applications will be reviewed within 75 days under this policy, a much quicker turn-around than is available to PMA devices at 180 days. Device makers are now allowed to make a profit on these devices unless the volume sold exceeds the annual distribution number limit of 8,000, and manufacturers are required to file an annual report on profitability only if the price charged for the device exceeds $250.

De Novo Program Rates Three Guidances
The agency also released three guidances pertaining to the de novo premarket program, including the final guidance spelling out the actions both device makers and the agency can take in relation to these applications. Also topical for the agency’s purposes is how those actions might affect review goals under the current user fee program.

The FDA said the clock will stop on a de novo application should the agency have questions that cannot be answered in a reasonable amount of time, although the guidance does not provide any metrics for “reasonable.” The hold goes into effect when the FDA issues the request, and the guidance states that a request for additional information stops the review clock and “marks the end of an FDA review cycle.” The clock will resume once the agency is in receipt of a complete response from the sponsor.

De novo submissions are now subject to user fees, and the target turn-around time for de novo petitions is 150 days, although the percentage of applications that must meet that deadline varies by year. For fiscal 2018, the target ratio of applications that met the 150-day target was 50%, but that goes up to 70% in the final fiscal year of this user fee schedule, which is FY 2022. The review staff assigned to that application will be available to discuss any problems with the sponsor if it is still outstanding at 180 days, at which point the reviewers will discuss next steps, including the deadlines for completion of those next steps.

The final guidance for acceptance review of de novo applications employs the same refuse-to-accept (RTA) principles that govern RTA policies for 510(k) and PMA applications. One important difference for the de novo version is that the sponsor has to document that there is no cleared predicate on the market, assuming the device in question is not a class III device. The FDA staff is tasked with determining whether any 510(k) or PMA applications are in process for devices with the same technology and same indication for use.

There are a number of considerations for de novo applications that are combination products, including whether the drug component for a drug-device combination product is the subject of a patent. The guidance includes a checklist which the sponsor is advised to complete prior to filing the application with the FDA. The checklist starts with four questions regarding whether the device in question is a combination product, highlighting the agency’s interest in resolution of any combination product questions before the de novo reaches the FDA.

Innovation on Tap at FDA, HHS

Few major U.S. federal government initiatives move as quickly as hoped, but those initiatives are nonetheless crucial for stakeholders in the life sciences intent on bringing innovative products to the clinical setting. The Department of Health and Human Services recently unveiled a program that could bring new drugs and devices to the market more rapidly than has been the case up to now, while the FDA provided an update on its digital health plan that reinforced the notion that the plan will indeed take time to put into place, even as the agency makes changes with the intent of streamlining the plan.

HHS Eyes Faster Medical Product Access

The Department of Health and Human Services said in a recent announcement that it will hold a two-day meeting June 20-21 to obtain stakeholder feedback on how to decrease the time needed for drugs and devices to make their way into clinical use. This is one of the programmatic areas under the ReImagine HHS initiative, and among the topics to be discussed is whether the department should play a role in connecting medical product developers with private payers and Medicaid managed care plans.

HHS said this portion of the proceedings is in response to complaints from both developers and payers that the process of communication between the two sides is inefficient. The FDA’s device center already has an office to facilitate communications with private payers during the device development process, so this move on the part of HHS would presumably scale up the CDRH version and expand it to include pharmaceuticals and biotech therapeutics. Another subject for discussion is “knowledge sharing,” which again is intended to bolster the rate of transmission of medical product innovation to the marketplace, in this case by giving the public more access to both confidential and already publicly available HHS information.

Device makers have complained over the years that public health programs have stifled access to therapies and diagnostics that could represent a meaningful improvement over the current state of the art, and among the initiatives already underway to fix those problems are some changes to the Medicare local coverage determination process. The Centers for Medicare & Medicaid Services also proposed in the draft inpatient prospective payment system for fiscal 2020 to provide coverage to any products that are accepted into the FDA breakthrough devices program. The breakthrough devices coverage concept seen in the 2020 inpatient draft reflects an industry proposal designed to aid small device makers in developing the evidence needed to meet the reasonable and necessary standard for Medicare coverage. The combination of these developments suggests that HHS Secretary Alex Azar has determined that healthcare innovation is hindered by the size of government and the complexity of its regulatory instruments, and that patients are suffering as a consequence.

Precert Test Plan May

The FDA is inching along with its precertification program for software as a medical device, announcing recently that it will accept applications for the precert test plan that will unfold over the balance of the current year and possibly into next year. However, the agency said it will accept applications for the precert program that run dual tracks with either the 510(k) or the de novo program, the former of which was not an explicit part of the precert concept until recently.

The FDA had previously appended the de novo petition process to the precert program in a move some argued was prompted by a desire to avoid accusations that the precert concept was entirely extralegal. The addition of the 510(k) pathway seems to offer no additional benefit in that regard, however, although it would bring on some test cases that reflect the majority of class II device applications, those that are based on a predicate rather than those that represent a technological novelty.

The announcement reiterates that companies involved in the testing phase will not actually obtain precertification merely by virtue of participation in the test phase, although applicants need not subject themselves to the full gamut of precertification evaluation modules. However, the FDA said that participants in the test phase may be limited to companies that have a track record in developing software products, seemingly leaving software start-ups out in the cold. Also of note is that this test plan may run beyond 2019, a sign that regulatory innovation is no less a feat than innovation in medical technology.

BIO, PhRMA Not Opposed to AKS Proposal

Makers of drugs and biotech therapeutics might have been expected to resist the Trump administration’s proposal regarding the anti-kickback statute, but that proves not to be the case. Two leading trade associations have voiced their support for the proposal, although they each indicated they would take a closer look at the proposal before lending it their full-throated support.

It has been argued on more than one occasion that rebates paid to pharmaceutical benefits managers are rebates rather than kickbacks, a point made by at least one observer. There have been instances in which drug makers paid fines to deal with allegations they used rebates to gain exclusive listings in PBM formularies, but that is not the usual run of business where these rebates to PBMs are concerned.

The latest proposal by the Department of Health and Human Services includes a removal of the safe harbor for rebates paid to several entities, including PBMs, although PBM service fees would enjoy a safe harbor along with rebates provided directly to beneficiaries enrolled in federal government health programs. HHS Secretary Alex Azar said in a statement the proposal is “a major departure from a broken status quo that serves special interests,” and which “moves toward a new system that puts American patients first.” The proposal would further provide more transparency about such transactions, and Azar seemed to taunt Congress on this point, stating that members of both parties who have sought to lower prescription drug costs “have criticized this opaque system for years, and they could pass our proposal into law immediately.”

Despite the seeming promise of disruption of the existing system, both the Biotechnology Innovation Organization and the Pharmaceutical Research and Manufacturers of America issued statements that were generally supportive of the proposal. BIO President/CEO Jim Greenwood said in a Jan. 31 statement that the association “strongly supports the goal” of the proposal, but advised that BIO is taking a close look at the proposal. Greenwood said the current system creates some perverse incentives that feed the drug pricing problem, urging HHS to adopt a system that provides affordable access.

PhRMA emphasized a need to ensure that the $150 billion in annual rebates and discounts are used to lower costs for patients at the pharmacy. PhRMA President/CEO Steve Ubl stated that the existing approach favors products with high list prices, but he also pointed to the pressing problem of price hikes associated with drug products used for diabetes, which has been a significant flashpoint in recent months. Despite the supportive tone, Ubl said PhRMA would also take a close look at the proposal before offering specific comments.

FDA Rewrites Title of Abbreviated 510(k) Draft

The FDA’s device center managed to wrap up a 2018 draft guidance dealing with abbreviated 510(k) applications, but ended up renaming the document in the process. The net effect is seemingly to put another nail in the substantial equivalence coffin, which some might argue has been a policy priority for the Center for Devices and Radiological Health dating back to 2011.

The 2018 draft guidance bore a title that explicitly mentioned the abbreviated 510(k) program and suggested that a determination of substantial equivalence would be more easily obtained by demonstrating conformance with performance criteria. The final guidance is dubbed the Safety and Performance-Based Pathway, which advises that third party reviewers can be invoked for these devices, which was not acknowledged in the draft.

One of the more notable differences between the draft and the final is that the latter suggests that the performance criteria requirements for Declarations of Conformity might be more explicitly product-specific than perhaps was understood upon the emergence of the draft. The final guidance says a DoC ought to suffice to support a finding of substantial equivalence “unless noted otherwise in the relevant Safety and Performance Based Pathway guidance.” While there is a seemingly related provision in the draft – which states that the FDA may “establish performance criteria through guidance and/or special controls” – the revision appearing in the final seems to lend more teeth to the notion that at least some procodes will be the subjects of product-specific performance criteria.

Precisely when the agency might promulgate such guidance is not explained, but the implications of this and other recent policy changes at CDRH include that the historical understanding of the role of substantial equivalence is no longer in vogue at the Office of Device Evaluation. Only time will tell whether reviewers at ODE can resist the urge to use performance criteria as a means of imposing more regulatory hurdles for class II devices

FDA’s Statement on Its Modernization of Its 510(k) Program

Jordan Lipp, Esq. |Attorney, Managing Member | Childs McCune

On November 26, 2018, the FDA released a statement on its views on the modernization of its 510(k) process. Historically, the 510(k) process is the FDA’s clearance of a medical device to be sold in the United States, if the FDA finds the device is substantially equivalent to a previously approved (or grandfathered in) device.

In the FDA’s recent statement, FDA Commissioner Scott Gottlieb, M.D. and Director of the Center for Devices and Radiological Health Jeff Shuren, M.D., explained that “[t]he most impactful way that we can promote innovation and improved safety in the 510(k) program is to drive innovators toward reliance on more modern predicate devices…” As such, they explained that they “believe that newer devices should be compared to the benefits and risks of more modern technology; that is why we’re looking at ways to promote the use of more recent predicates.” So, the FDA is considering putting on its website which cleared devices are based upon predicate devices that are more than 10 years old, and it is seeking public feedback on this plan.

The FDA is also planning in early 2019 to finalize guidance establishing an alternative 510(k) process, called the “Safety and Performance Based Pathway,” which will permit manufacturers of certain devices “to rely on objective safety and performance criteria to demonstrate substantial equivalence” based upon a contemporary baseline. The goal, as described by the FDA, is for the FDA and manufacturers to look to the future as opposed to looking to the past as the baseline for safety and efficacy.

The FDA’s statement also discussed the recent increase in the size of the 510(k) submissions, the increase in review time of these submissions while a simultaneous decrease in the time until clearance, and its actions in “up-classifying” certain devices from Class II to Class III (i.e., taking an existing device out of the 510(k) process and requiring the more vigorous Class III premarket approval.) For those in the industry, the six-page long statement, linked here, is worth reviewing.

FDA’s Device Export Draft Draws Jeers

The FDA posted a draft guidance in August dealing with certificates for export of medical devices, a move prompted by the Food and Drug Administration Reauthorization Act, but the response from industry and regulatory attorneys was anything but favorable. Among the complaints about the draft is that it collides with how the FDA typically handles a device maker’s proposed corrections, but others said the draft does not comply with the statute.

The draft deals with how device makers can revive a request for a certificate for export after a difficult inspection, and one of the responders, Stacey Backlund of BTG International in Philadelphia, pointed out that denials of certificate for export are not in the class of significant regulatory decisions. Consequently, these are not subject to the 30-day time limits for filing and review of petitions, but Backlund was hardly the only regulatory consultant to make the point.

Allyson Mullen of Hyman, Phelps and McNamara made the same point about 30-day turnarounds in her comments to the docket, but Mullen also said that the agency’s response to a proposed set of corrections after an inspection is often dead silence, which leaves the device maker in a nearly insoluble predicament. The Advanced Medical Technology Association was no fan of the draft, either, arguing that the FDA went beyond the language in FDARA in that the draft required that the agency accept a proposed set of corrections as adequate. AdvaMed’s Steve Silverman said such an expectation is implausible if only because corrective actions tend to morph over time.

Silverman went on to note that the draft excludes certificates for devices that are manufactured outside the U.S., which he said clashes with the statute as amended by FDARA. Silverman said the statute directs the FDA to handle certificates for export for devices that are manufactured in any establishment in any location, so long as that establishment is registered with the FDA. It is not clear when the agency expects to finalize this guidance, however.

FDA; Clinical Data not so ‘Quik’

The FDA has rolled out a pilot program for the Quality in 510(k) review program, which is known as the Quik 510(k) program, an alternative to the standard 510(k). The agency said this program – which entails a 60-day decision – is not suitable for combination product applications, but also that regulatory filings that require clinical data might not be good candidates for a Quik 510(k), either.

This pilot will not subject applicants to the refuse-to-accept review used on traditional 510(k)s, but sponsors are expected to respond promptly to any requests from the agency for additional information for the application in question. Any applications deemed ineligible by the Office of Device Evaluation will be handled under the normal 90-day review time frame, but this pilot is limited to a relatively small number of well-understood devices that appear under 40 product codes. In vitro diagnostics are not part of the pilot, and sponsors must use the electronic filing mechanisms in order to qualify.

Third Parties Still an Issue in MDLs

For those in the life sciences, multi-district litigation has proven to be a complex and unruly process, but one of the more prominent issues is that of third-party funding for litigation. This is nothing new, as third-party litigation funding was the subject of concern at least as far back as 2014, but this and several other issues are of concern to attorneys who defend drug and device manufacturers.

Lawyers for Civil Justice was one of several organizations that urged the Advisory Committee on Civil Rules to require disclosure of third-party funding in 2014, but Alex Dahl of the Strategic Policy Council said on a recent webinar that the presence of third parties in multi-district litigation is still not routinely disclosed to defendants. There are a number of other issues that plague the MDL system as well, such as a lack of vetting of individual cases, and by some accounts, between 30 and 50 percent of the individual claims in MDLs are nothing more than junk claims.

The question of third parties was on tap at both the November 2017 and April 2018 meetings of the Civil Rules Advisory Committee, which included an extensive discussion of this and other issues. The committee formed a subcommittee to examine the third party problem, but it is not clear where the subcommittee might land on this and several other issues with MDLs, including the problem of prospectively identifying which complaints in an MDL are without merit. Still, there is at least one district court, the Northern District of California, which has a standing order mandating disclosure of third parties, seemingly setting a precedent for the subcommittee to act.

New Guidance from FDA: When to Submit a 510(k) for a Change to a Cleared Medical Device

Courtney A. Stevens, Esq. |Senior Attorney, Medmarc Loss Control

FDA’s newest guidance for medical device manufacturers, Deciding When to Submit a 510(k) for a Change to an Existing Device, issued August 8, addresses a question manufacturers commonly face,—when a 510(k) is necessary for a change to an already cleared device. Manufacturers’ failures to submit 510(k)s are frequently cited in warning letters as rendering a device adulterated. As such, it’s an issue medical device companies can’t be too careful in scrutinizing. Thankfully, this guidance does provide such much-needed clarity on exactly when a 510(k) is necessary, and when processing the change in accordance with Quality System (QS) requirements (e.g., documentation of changes and approvals in the master record, verification and revalidation, etc.) is sufficient.

The confusion over whether a 510(k) is necessary is largely due to the subjective, relative language in the regulations, requiring device-makers to submit a 510(k) when a change “could significantly affect the safety or effectiveness of the device.” (21 CFR 807.81 (a)(3)). The Agency tried to clarify its interpretation of that language in its first guidance document on this issue, published in 1997, but clearly, as evidenced by the frequency with which the manufacturers’ determination of “significant” changes differed from the Agency’s, greater clarity was needed still. (Once finalized, this draft guidance will supersede the 1997 Guidance on the subject.)

This guidance document improves upon its predecessor by providing a number of exacting flow chart-decision trees to guide manufacturers through the determination of a 510(k)s’ necessity with regard to different types of changes.

It begins by setting out the guidance principles to be first considered in determining the propriety of a 510(k), which I briefly summarize here:

• Modifications made with intent to significantly affect safety or effectiveness of a device. This is the same language as is found in the regulations, and its meaning is fleshed out in the remainder of the document.
• Could “significantly affect” evaluation and the role of testing. In order to determine significance of the effect, manufacturers must conduct risk-based assessments.
• Unintended consequences of changes. One component deemed to make up a “significant effect” is if the change would result in unintended consequences or effects. The draft guidance provides sterilization as an example which may affect device materials, thereby affecting performance of the device.
• Use of risk management. Here, the draft refers to ISO 147981: Medical devices – Application of risk management to medical devices, and instructs manufacturers to utilize an assessment combining the probability of occurrence of harm and the severity of that harm in determining “significant effect.”
• Evaluating simultaneous changes. Even though changes may occur simultaneously, each change should be assessed individually and in combination.
• Appropriate comparative device and cumulative effect of changes. In making the determination of a 510(k)’s propriety, manufacturers need to consider (1) how different a change makes the device from its initial or most recent iteration as described in their most recently cleared 510(k); and (2) the cumulative effect of all changes since the last 510(k) cleared for this device. That is, though previous changes did not require a 510(k) when made in isolation, does the cumulative effect of this change with those previously made nor warrant a 510(k), even if it, by itself, would not?
• Documentation required. Even if a manufacturer determines a 510(k) is appropriate for a particular change, this does not alleviate them from compliance with all existing QS requirements, including all documentation, verification, and validation duties.
• 510(k) submission for modified devices. When a 510(k) is submitted for a device with multiple modifications since its last cleared 510(k), the 510(k) should describe not only the most recent change that warranted the 510(k), but also all previous modifications even though they did not merit the submission of 510(k)s in and of themselves.
• Substantial equivalence determination. Manufacturers need understand that submission of a 510(k) for a change pursuant to everything outlined in the regulation and this guidance document does not assure that a substantial equivalence determination will be provided.

 

With these considerations in mind, manufacturers may proceed to the different parts of the guidance instructing them on decision-making for different kinds of changes—labeling, control mechanisms, operating principles, etc. In each of these, manufactures will find the aforementioned decision trees to guide them through submission criteria.

An example of the flow charts included in this draft guidance:

In addition to charts guiding decision making, the guidance also provides examples of documenting changes and written regulatory change assessments.

This should go a long way in facilitating manufacturers’ understanding of when 510(k)s for changes are necessary, and reduce the number of warning letters for companies’ failure to submit them, accordingly.

Regulatory Roundup: FDA Reports and Guidances in August

Courtney A. Stevens, Esq. | Senior Attorney, Medmarc Loss Control

Recommendations for a National Medical Device Evaluation System

On August 20, the FDA released, for public comment, a report from the Medical Device Registry Task Force and the Medical Devices Epidemiology Network. The report described the inadequacies in the existing framework for medical device evaluation, what a more effective system would look like, what devices would be particularly ripe for evaluation via such a system, and how the system could be implemented. The full report can be found here.

FDA Issued Several New Drug and Device Guidances

The Agency issued several new guidance documents in August, including the following.