PTO Eyes Prioritized Patents to Combat Covid-19

The FDA and other agencies at the U.S. Dept. of Health and Human Services have taken a number of measures to push back against the COVID-19 pandemic, but an agency at the Dept. of Commerce is also getting into the fight. The Patent and Trademark Office recently unveiled a prioritized patent examination pilot that will put COVID-fighting applications to the front of the queue, with a special emphasis on small and micro entities.

The May 8 PTO statement indicates that the agency will waive the fees ordinarily associated with priority patent applications, but also that these applications will be processed within six months, assuming the applicant responds to PTO queries promptly. PTO director Andrei Iancu said small businesses and independent inventors “are often the difference makers when it comes to cutting-edge technology,” but “are also in most need of assistance” as the pandemic wears on.

In the accompanying Federal Register notice, PTO said the scope of the program is limited to products that are subject to an FDA premarket review process, such as emergency use authorizations, premarket approvals and new drug applications. Biologics license applications are also within the scope of the program, but continuing original patent applications are apparently excluded. Filings must include no more than four independent claims and no more than 30 total claims. Multiple dependent claims are also out of consideration, and applicants that file for an extension for time to file a reply will lose their place in this expedited program.

FDA Resets Serology Test Policy for Pandemic

The FDA has maintained a steady pace of policy changes in connection with the COVID-19 pandemic, including a May 4 policy that calls on makers of some serological tests to file for an EUA for their tests. The change followed congressional criticism that many of these tests did not work as advertised, but also followed an extended period during which a large number of tests came to market and thus there was a less pressing need for a relaxed policy.

In an accompanying statement, the FDA said the original testing policy under the emergency use authorization program was borne of a need to provide sufficient regulatory flexibility to bring surveillance testing to the medical front lines. A number of serology tests have arrived with claims of FDA approval or authorization despite lacking such a regulatory acknowledgment, but other tests were shown to perform poorly despite otherwise avoiding the agency’s ire.

Consequently, commercial test developers have 10 days to file for authorization under the EUA program after notifying the agency of the results of test validation, or 10 days after the date of publication of the May 4 policy. High-complexity labs that develop their own tests must still forward validation data to the agency, although they are not required to seek authorization via the EUA program. The FDA recommends they do seek inclusion in the EUA listing, however.

The testing policy was updated again May 9 with the news that the first antigen test for the SARS-CoV-2 virus had gained a place in the EUA policy, and the FDA said more such tests will soon be thus authorized. The anticipation regarding antigen testing is that it will rapidly increase the total volume of tests made to the American public, a critical piece in the effort to bring the pandemic under control. However, the agency advised that antigen testing is even more prone to false negatives than molecular testing for viral RNA, and a negative result for an antigen test may have to be checked by a molecular test – usually a polymerase chain reaction (PCR) test – prior to any clinical decision-making.

Still, the FDA noted that antigen tests are less expensive to deploy than PCR tests and usually provide more rapid turn-around. Antigen tests may boost overall testing capacity by millions per day, but the FDA noted that these are intended as diagnostic tests even as the agency noted that they may also aid in the effort to “identify infection rates closer to real time.”

ONC, CMS Delay Compliance Dates for EHR Interoperability

The COVID-19 pandemic has incurred a number of regulatory casualties in recent weeks, and the final rules for electronic health records (EHRs) promulgated earlier this year are two of the latest among those. Not all aspects of these rules were on the same original compliance deadline, however, and vendors will have to delve into the details of these respective delays to keep them straight.

The Office of the National Coordinator and the Centers for Medicare & Medicaid Services posted a joint statement about the delayed implementation date. ONC director Don Rucker said his agency will offer three months of enforcement discretion to EHR vendors “at the end of … certain compliance dates,” a concession to the pandemic. In contrast, CMS administrator Seema Verma stated that hospitals will generally have an additional six months to implement the related requirements.

The ONC announcement was accompanied by a tabular presentation of revised compliance deadlines, many of which simply add three months onto the original six-month deadline. The roll-out of application programming interface (API) functionality was originally subject to a 24-month compliance date, but now enjoys 27 months of regulatory relief. Many other requirements, such as the information blocking requirement, were initially on a six-month delay from the date of the final rule, but this requirement will not be in force until the end of the year at the earliest. The ONC rule appears in the Federal Register with a date stamp of May 1 and an effective date of June 30.

The CMS stated that the requirements for the patient access API are now in force as of Jan. 1, 2021, the same date as the provider directory API. The CMS requirement for information blocking enjoys a less crisply defined compliance date of “late 2020,” while payer-to-payer data exchange functions must be up and running by Jan. 1, 2022.

FDA Posts AE Reporting Policy

Among the pandemic-related considerations undertaken by the FDA is a policy document spelling out the agency’s expectations regarding adverse event (AE) reporting. The terms of the policy apply to medical products and dietary supplements, and deals with the prospect that COVID-driven absenteeism might hamper a company’s AE reporting program.

The policy, which updates a 2012 guidance addressing influenza outbreaks, allows companies to focus their AE reporting efforts on products related to the COVID-19 pandemic. Affected companies are expected to develop a continuity of operations plan (COOP), which should spell out AE reporting and updates for any events that are stored during the pandemic. Companies should document the start and ending dates of their nations’ emergency declarations as well as the impact of absenteeism on AE reporting.

The FDA says it “does not plan to object” if a company is unable to file AE reports on time due to absenteeism caused by they pandemic, but the affect entities have to file those reports within six months of restoration of normal order of a company’s operations. Companies that can report at least some AEs in a timely fashion must do so, and firms that can file all required reports are expected to make timely reports. If the agency expresses concern about reports in connection with specific products or a particular set of circumstances, the FDA will offer no leniency on the standard reporting requirements, the guidance states.

FDA Reacts to Coronavirus as Stimulus Bill Passes

The FDA is scrambling to meet the demands imposed by the COVID-19 outbreak, including a series of guidances dealing with a variety of issues. However, the predicament has also prompted two pieces of legislation, one an economic stimulus package and the other a bill that would tie the FDA’s hands where regulation of lab-developed tests is concerned.

After considerable wrangling, the U.S. Senate and the House of Representatives sent the Coronavirus Aid, Relief, and Economic Security Act (CARES Act, or H.R. 748) to the Oval Office, which President Trump signed into law March 27. This was the latest – but perhaps not the last – of legislative packages to offset the damage done by the SARS-CoV-2 virus.

The FDA has ramped up a series of guidance documents to deal with the pandemic. One of the earliest policy documents was a Feb. 29 guidance by the FDA’s device center, which the agency updated March 16 to give the states more leeway to ramp up testing. The pandemic was widely seen as potentially crimping ongoing clinical trials, leading the FDA to post a guidance to deal with such concerns. In a March 18 statement, the agency acknowledged that protocol deviations may be unavoidable, and that study protocols may thus have to be amended. One of the related changes the FDA will allow is the use of telemedicine for some patient follow-up appointments.

Another piece of the regulatory puzzle for coronavirus in the U.S. is the FDA’s enforcement policy for ventilators and other respiratory devices. This policy guidance spells out the conditions under which product labels and device functionality of ventilators and other respiratory devices would not be subject to the usual enforcement standards. The emphasis here, the agency said, is to allow manufacturers to add production lines to existing sites and to allow manufacturing at alternate sites. Among the 13 product codes listed within the scope of the document are those for oxygen conservers and anesthesia gas machines.

The agency’s device center has routinely updated a coronavirus FAQ for diagnostic testing, including updates on swabbing procedures and sites that would be acceptable for testing. In a March 23 statement, the FDA made note of a concern that the SARS-CoV-2 virus could be passed along during fecal microbiota transplantation procedures. There is also some concern that cancer patients may be at greater risk of contracting COVID-19 due to compromise of their immune systems.

The FDA also took action on respirator masks in a March 27 statement to the CDC, which authorizes the use of all disposable filtering facepiece respirators that have been approved by the National Institute for Occupational Safety and Health. The scope of this policy includes NIOSH-approved respirators that have passed product expiry, assuming these items are not damaged and have been stored in the appropriate conditions. Two days earlier, the FDA dropped an enforcement policy document for the use of face and respirator masks, which includes some conditions for reprocessing of these items.

Bill Would Ban FDA Regulation of LDTs

Sen. Rand Paul (R-Ky.) has drafted a bill that would disallow FDA regulation of lab-developed tests, at least in part a reaction to the agency’s laggardly response to the SARS-CoV-2 virus. Paul said in a March 18 statement that S. 3512 would remove “unnecessary government barriers that have drastically slowed the response to the COVID-19 outbreak. The Verified Innovative Testing in American Laboratories (VITAL) Act of 2020 would affirm that the Public Health Service Act “governs all aspects” of lab-developed testing procedures, according to the associated fact sheet.

The bill states that “all aspects of a laboratory-developed testing procedures shall be regulated” under Section 353 of the Public Health Service Act, and that “no aspects of laboratory-developed testing procedures shall be regulated under the Federal Food, Drug, and Cosmetic Act.” This would apply during public health emergencies as well as during periods of normal activity.

Paul’s bill comes shortly after two members of the House of Representatives resurrected the Verifying Accurate, Leading-edge IVCT Development (VALID) Act, which has been modified from previous iterations to address the COVID-19 outbreak. Reps. Diana DeGette (D-Colo.) and Larry Bucshon (R-Ind.) said their legislation would create a new product category for diagnostic and lab tests, but they also point to the need to allow labs to respond quickly to public health crises. The bill would allow developers to electronically file their tests for FDA review.

There is a companion bill for the VALID Act in the Senate, but there is also some question as to whether either of these bills will pick up any traction this year, given the impact of the coronavirus on congressional schedules. It might be noted that discussions regarding the fiscal 2021 budget have been displaced by the COVID-19 outbreak at least for the time being, and that the upcoming election is likely to bring a halt to routine legislative activity by the end of August.

Coronavirus Prompting Reaction in Washington

The newest mutation to the coronavirus has had a massive impact in China and has prompted a reaction from the World Health Organization (WHO). The impact on makers of devices and diagnostics has been minimal so far, but the signs are that this could change quickly if the virus continues to proliferate.

The 2019-nCoV virus has prompted two press briefings by a U.S. federal government task force led by HHS Secretary Alex Azar, developments that followed a Jan. 31 declaration of emergency by WHO. Much of the concern about the virus is that it can be transmitted even from those who are asymptomatic, but the test for the virus developed by the U.S. Centers for Disease Control and Prevention has proven less than fully reliable.

Robert Redfield, director of the CDC, said in a Jan. 31 press briefing that the CDC test will return both positive and negative results on a patient who has been confirmed to carry the pathogen. The U.S. government response has been questioned, given that influenza is still proving more lethal, but Anthony Fauci of the National Institute of Allergy and Infectious Diseases said influenzas predictably fade as winter gives way to spring, whereas the trajectory of the new coronavirus is unknown.

The FDA recently issued an emergency use authorization for the CDC test, a reverse-transcriptase polymerase chain reaction test to be used with swabs from the upper and lower respiratory tracts. The CDC posted a press release two days later in which the agency said the test will initially be shipped to roughly 200 domestic sites and another 200 sites located in other nations. The test provides results within four hours, CDC said.

The Department of Health and Human Services posted a Feb. 6 announcement stating that HHS is taking submissions for diagnostics that would receive federal funding under the Biomedical Advanced Research and Development Authority (BARDA) program. This program requires that the test in question would have to be available on a platform already cleared by the FDA, and that the test would be ready for live use within 12 weeks of receipt of the award.

Congress Prods FDA for Assurances

Capitol Hill has demonstrated some concern about the impact of the coronavirus outbreak on the availability of medical products from China. Two members of the Senate, Florida Republican Marco Rubio and Connecticut Democrat Chris Murphy said in a Feb. 6 statement that they have a series of questions they would like answered by Feb. 18. Among the questions is whether the FDA has the resources to determine whether the impact of the coronavirus in China will affect the availability of drugs and devices for U.S. patients.

Murphy and Rubio noted that China is the source of the majority of active pharmaceutical ingredients used to produce drugs in the U.S., and that 10% of devices used in the U.S. are also imported from China. FDA commissioner Stephen Hahn said in the Feb. 7 press briefing that there was no evidence of any slowdown in the supply chain of the various products in question at that point in time, but he noted that the situation “is fluid” and that this could change in short order.

Perhaps as disturbing as any other recent event associated with the coronavirus is the discovery that more than four in 10 coronavirus patients in a hospital in China had contracted the virus while at the hospital. The majority of the patients presumed to have contracted the virus at the hospital site were employees of the hospital, although this single-site study might not reflect the broader experience in China. Nonetheless, the authors say that as many as 10 health care workers had presumably been infected by a single patient.

Paclitaxel Focus of Device Controversy

The technology behind percutaneous treatment for the coronary arteries has advanced much more rapidly than for the peripheral vasculature, but the use of paclitaxel, a chemotherapeutic agent, as a go-to antiproliferative for any part of the anatomy could be near an end. The FDA published a letter to physicians in January stating that a medical journal article suggested that paclitaxel-bearing drug-eluting stents (DESs) and drug-coated balloons (DCBs) for the peripheral arteries had demonstrated an unexpectedly high long-term mortality rate compared to bare-metal stents and non-coated balloons. However, the conclusions drawn in that medical journal are the subject of a dispute that may determine whether paclitaxel has any future at all in the circulatory system.

The article in the Journal of the American Heart Association describes a meta-analysis covering more than two dozen randomized, controlled trials for both DES and DCB devices, all coated with paclitaxel. The authors stated that all-cause death at both two and five years for paclitaxel devices was significantly higher than for their non-eluting counterparts when used in the arteries of the lower extremities, but that more study is warranted, in part because only two of those studies ran for a full five years. The authors hypothesize that the crystalline form of paclitaxel, which has a longer half-life than other formulations, may be the culprit.

Medtronic, the Dublin-based manufacturer of the In.Pact Admiral DCB, took issue with the JAHA authors in an article in the Journal of the American College of Cardiology, stating that there is no statistically significant difference in mortality between DCBs and plain angioplasty balloons at five years. As is the case with the JAHA analysis, there are a number of moving parts in the Medtronic summary, including that the data are drawn from patients in a variety of nations that exhibit different patterns of post-procedural care, not to mention differences in the use of dual anti-platelet therapy (DAPT). The company argued that much of the difference in mortality outcomes could hinge on the more aggressive use of DAPT in patients treated with bare-metal stents and plain angioplasty balloons.

Whether any of this clinical data will translate into regulatory action is impossible to forecast, but the FDA advised that it still sees the benefit of these devices as outweighing the risks. If Medtronic’s view – that the mortality rates at five years out, at least in statistical terms – wins the day, device makers might be on the hook for nothing more than a somewhat greater post-market surveillance liability. Makers of DCBs might already be on that track, as the Centers for Medicare & Medicaid Services (CMS) declared it will pay what clinicians and device makers see as a sub-optimal rate for these devices, unless and until CMS sees some compelling data that the difference in cost between DCBs and plain balloons is justified by outcomes.

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:

8.16 - guidance flowchart

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.