FDA Today | Explaining the Senate’s Pandemic Proposal

Last year AgencyIQ predicted that 2022 would likely be the busiest, most consequential year in decades – or maybe ever – for FDA-related legislation. We anticipate user fee reauthorization, the 21st Century Cures Act 2.0, the VALID Act, dietary supplement legislation, drug pricing legislation, and pandemic response legislation to all play a role.

Today, we want to dig into some new pandemic response legislation unveiled by the Senate HELP Committee earlier this week known as the PREVENT Pandemics Act. I have a preview of our full analysis of the FDA-specific provisions for you below.

Questions? Comments? Here’s how to reach me. - ( [email protected] / @AlecGaffney / LinkedIn)

Regulatory Explainer: What the Senate’s proposed pandemic response legislation, the PREVENT Pandemic Act, means for the FDA and life sciences companies

The top line: Earlier this week the Senate Health, Education, Labor and Pensions (HELP) Committee released the text of new draft legislation that seeks to enact statutory and regulatory reforms to better prepare the U.S. for future pandemics, as well as the current pandemic. AgencyIQ has analyzed portions of the legislation that are most relevant to the Food and Drug Administration.

Section 501 – Advancing qualified infectious disease product innovation

• Background: This section seeks to build upon the Generating Antibiotic Incentives Now (GAIN) Act which passed as part of the FDA Safety and Innovation Act of 2012. The original law provides special incentives for companies that successfully developed antibiotics or antifungal products. Specifically, pharmaceutical (not biological products) would be eligible to receive an additional five years of marketed exclusivity in addition to any other marketing exclusivity for which they were eligible (I.e., 3 years for a new indication, 5 years for a novel product).
• How it would work: Section 501 would amend the existing GAIN Act provisions by making biological products eligible for part (though not all) of this incentive as well (“a biological product that acts directly on bacteria or fungi or on substances produced by such bacteria or fungi” and one that “is intended to treat a serious or life-threatening infection”). Product would be eligible, for example, if they treat a bacteria or fungi resistant to treatment, including “novel or emerging infectious pathogens.” The FDA would also be able to maintain a list of “qualifying pathogens.” Biological products would also be eligible for priority review. However, they would not be eligible for the additional five years of marketing exclusivity. 21 U.S.C. 355f(c) would be amended to explicitly prohibit biologics from obtaining the additional exclusivity period, limiting biologics to the same 12 years of exclusivity they now enjoy.
• Analysis: This section is effectively identical to legislation introduced several weeks ago, known as the GAIN TOOLS Act, which is sponsored by Sens. Bob Casey (D-PA), Bill Cassidy (R-LA) and Chris Murphy (D-CT). The effort could be useful to helping promote efficient review of some antibiotics that might not ordinarily be eligible for priority review, for example. However, because the relative benefits of the GAIN Act wouldn't extend to the biologics (i.e., any additional exclusivity), it likely won't result in any major new incentives for most companies.
• Note: A previous version of our analysis incorrectly determined that this provision would have granted 5 years of marketing exclusivity to biologics under this section. We regret the error.?

Section 502: Modernizing clinical trials

• Background: The pandemic has led to major transformations in the way that clinical trials take place, pushing a greater percentage of them out of “centralized” clinical trial sites and into patients’ own homes. These trials are known as decentralized trials, and they often rely on sensor-based technologies known as Digital Health Technologies (DHTs) to collect data from participating patients. In addition, the pandemic has also highlighted the importance of expediting clinical trials, including the utility of using trials that are innovative in their designs. Some of these trial types include expansion cohorts, are designed to be “seamless” (i.e., there aren’t distinct Phases of development), are run in parallel (“concurrent”), or have “adaptive” designs (i.e., they prospectively anticipate change).
• How it would work:?This section calls for the FDA to release three specific guidance documents meant to explain the regulator’s preferences as they relate to these novel clinical research approaches. The first guidance document would relate to “clarifying the use of digital health technologies in clinical trials” — a topic that the FDA just released a guidance document on in December 2021 . While the legislation calls for a few points of clarification that aren’t included in the FDA’s draft, such as best practices for communication and early engagement between sponsors and the FDA on data collection methods, it would not be difficult for the FDA to incorporate that feedback into a final version. The FDA is also asked to release a guidance document on “advancing decentralized clinical trials,” which the FDA has had on its planned guidance agenda since 2021. Finally, FDA is asked to release guidance on “seamless and concurrent clinical trials.” While the FDA has published similar guidance on adaptive clinical trials, maintains a pilot program on complex innovative trial designs, and has also published case studies on complex innovative trial designs, it does not yet have published guidance on this exact topic.
• Analysis:?Much of this section calls for the FDA to work on topics that it has already expressed are among its priorities – or in at least one case, has already published. For example, the section also states that the FDA may work with foreign regulators “pursuant to memoranda of understanding or other arrangements governing the exchange of information to facilitate international harmonization of the regulation and use of decentralized clinical trials, digital technology in clinical trials, and seamless, concurrent and other adaptive or innovative clinical trial designs.” The FDA already has the authority to do this and regularly does, especially through the auspices of the International Council for Harmonization (ICH), which typically creates harmonized guidelines. The ICH is currently working to update its E6 guideline to accommodate novel trial designs, including platform trials and decentralized trials.

Section 503: Accelerating countermeasure development and review

• Summary:?This section says that the FDA may, at the request of a sponsor during an emergency (public health, domestic, military or material threat), expedite the development and review of countermeasures for approval, licensure, clearance or authorization.
• How it would work:?FDA would be tasked with potentially taking actions “to ensure that the design of the clinical trials is as efficient as practicable, when scientifically appropriate, such as by minimizing the number of patients exposed to a potentially less efficacious treatment.” FDA would also be tasked with expediting the issuance of guidance documents on the topic of countermeasure development. FDA would of course also be tasked with making use of its expediting authorities, including Fast Track, Priority Review, Rolling Review and more.
• Analysis:?This section doesn’t call for the FDA to do much beyond that which it has already done during the pandemic. It has already greatly expedited the development of therapies, both through the use of Emergency Use Authorization authorities and the use of its Coronavirus Treatment Acceleration Program (CTAP ). In addition, the language here is vague – it says that the FDA “may” do so. The FDA may instead wish for more authority in this area, including requiring that sponsors work together on clinical studies in the hopes of generating higher-quality data through the use of “Master Protocols.” The FDA’s Janet Woodcock has previously written that only a small percentage of trials during the pandemic have resulted in actionable evidence about medical countermeasure efficacy and safety.

Section 504: Third-party test evaluation during emergencies

• Background:?During the pandemic, the FDA’s Center for Devices and Radiological Health (CDRH) has struggled to keep up with the high volume of Emergency Use Authorization (EUA) requests. While the diagnostics office (the Office of In Vitro Diagnostics, or OHT7) supplanted its own review staff by “surging” staffing from other parts of CDRH, the significant interest in Covid-19 test development continues to be a major strain on the Office’s capacity. In addition, the agency has been “declining” to review certain EUA applications – namely, those that the agency has determined would not make a meaningful dent in the public need for tests and diagnostics (e.g., those with limited manufacturing capacity, tests that are complex and/or resource-heavy to run) in the interest of maintaining staff capacity to review tests of perceived higher priority. However, during the pandemic HHS did at one point outsource the review of some diagnostics to a consulting company, NDA Partners. [ Read more about this event and what happened here.] However, this outsourcing was only done on a very limited basis.
• How it would work:?This section calls for the creation of a “Third Party Evaluation” process to be used for in vitro diagnostic (IVD) tests during an emergency situation. This would permit the FDA (or HHS), “as appropriate,” to “consult with persons with respect to such evaluations and recommendations or enter into cooperate agreements or contracts” with the same. The criteria for evaluation would be the same for the third party as they are for the FDA (and specifically, the criteria for emergency use authorization). A third-party evaluator would then need to make written recommendations to the FDA, which would then presumably be subject to the FDA’s own (more rapid) review. (This section is light on details regarding process).
• Analysis:?As with so many provisions in this broader legislation, there’s nothing in current law stopping the FDA from doing this already. As noted above, FDA and HHS have already done this.?And there is another FDA program, the 510(k) Third Party Review Program, which permits companies to work directly with accredited third-party reviewers who act as a sort of pre-review to expedite work by the FDA. However, that program has seen its fair share of troubles , including a case of fraud which resulted in a reviewer being kicked out of the program. Since this program for EUAs would only be active in an emergency, FDA’s ability to provide oversight could be more limited unless it had contracts preemptively in place with trusted companies with accredited staff.

Section 505: Facilitating the use of real-world evidence

• Background:?The pandemic has resulted in hundreds of products marketed through the Emergency Use Authorization pathway. However, the standard of authorization for a medical product is lower for an EUA than it is for a traditional approval. Specifically, the standard is that it “may be effective” rather than a higher standard for most products of “substantial evidence” of effectiveness. Because of this, the FDA has recently begun to think about how companies can demonstrate the effectiveness of their products in support of an eventual full (i.e., non-emergency) market access decision, such as a Premarket Approval, De Novo or 510(k) clearance.
• How it would work:?This section calls for the FDA to issue or revise existing guidance on “considerations for the use of real-world data and real-world evidence to support regulatory decision-making.” Specifically, the FDA would need to address the use of RWD to support the approval of a drug, device or biologic initially granted an Emergency Use Authorization.
• Analysis:?The FDA has not yet released guidance on this topic, and the subject matter is likely to be of interest to companies and regulatory officials alike. While existing FDA guidance has by no means prohibited the use of real-world data to support regulatory submissions to the FDA, it hasn’t yet been discussed explicitly (e.g., in the FDA’s most recent guidance discussing the transition process for medical devices granted an EUA during the pandemic). The greatest difficulty facing companies is likely to be the quality and completeness of the real-world data. There have been widespread “data breaks” and breakdowns in data collection efforts, resulting in companies sometimes having little insight into the real-world performance of their products (for example, an OTC test for which results are not reported back to the company). FDA’s approach to accepting real-world data and evidence is therefore likely to rely heavily on case-by-case determinations about the quality and completeness of data, as well as the timeframe in which it was collected (since some older tests may not be as effective at detecting newer variants).

Section 507: Increasing EUA decision transparency

• Background:?The FDA has issued far more EUAs during the Covid-19 pandemic than any other time in its history – combined. As a result of both the volume of EUAs granted and their importance in confronting the current pandemic, there have been increasing calls for greater regulatory transparency regarding their publication. Some of these calls have already been answered by the FDA. For example, in November 2020 it pledged to release much of the data used as the basis to authorize vaccines and therapeutics on an emergency basis, as it does for products granted full approval.
• How it would work:?This section would modify the current EUA statute (21 U.S.C. 360bbb-3 ) to include some new requirements. First, Section (h) on “Publication [of] Confidential Information” would be updated to include that the FDA “shall promptly publish” all notices about authorizations, terminations or revocations of an authorization on the FDA’s website. Previously, it was only required to do so in the Federal Register (which it will still need to do). In addition, the FDA would be permitted to publish the names and details about applications, requests or submissions for an EUA, “even if such summary may reveal the existence” of a development program. Previously, it was only permitted to do so for products granted an authorization.
• Analysis:?The change to permit the public to know about development programs in a public health emergency is a significant departure for both the FDA and Congress, which have historically not divulged the names of companies developing products not yet approved for use by the FDA. The stated reason for this is that such information is commercially confidential and subject to trade secret laws. The increased transparency could be helpful for companies to determine the status of development in a particular area. However, much of this information is already made public through press releases, SEC filing documents or even ClinicalTrials.gov announcements. Even so, a central repository of such information could be extremely useful – depending on the level of detail in the disclosures. For example, knowing what endpoints other companies are using in their development programs would be exceptionally helpful. However, it's still unclear what details the FDA might be willing or able to disclose.

Section 508: Improving FDA guidance and communication

• Background:?During the pandemic, the FDA has released dozens of guidance documents and guidance revisions. While some of these were undoubtedly helpful to companies, the FDA’s overall guidance practices have certainly not been perfect. Some guidance documents were published too late to be especially helpful or effective (e.g., its guidance on Master Protocols for Covid-19 was only published in May 2021 – more than a year after the start of the pandemic.?Many critical updates to guidance documents were buried in lengthy PDFs, making it difficult to determine what had changed and their importance. In one case, the FDA had to sneak out the publication of a guidance document as part of an advisory committee meeting. For diagnostics manufacturers, guidance documents have largely been replaced in favor of weekly or bi-weekly audio briefings (“Diagnostic Town Halls”) for which text transcripts were frequently only made available weeks later.
• How it would work:?The section calls for HHS to develop and publish a report “identifying best practices for the efficient prioritization, development, issuance and use of guidance documents.” This report would explore these factors across different FDA centers, as well as at other “applicable agencies.” The FDA would then receive a plan for the implementation of these best practices, including with respect to streamlining development and review of guidance documents, streamlining processes for regulatory submissions to the FDA (including revisions to guidances), implementing “innovative guidance development processes and practices,” and transitioning guidance issued during the pandemic. Another report would also explore best practices for communicating with external stakeholders “other than through guidance documents.” For this report, HHS will be tasked with exploring the use of submission templates, webinars, FAQ documents and more. HHS is asked to consult with a wide range of stakeholders on this topic. The report would be published within one year.
• Analysis: Analyzing guidance documents is something we specialize in here at AgencyIQ, and this is a topic about which we know much. There are massive opportunities for improvement with the FDA’s guidance document publication processes, even beyond the pandemic and beyond the FDA. Ultimately, our advice would be that the FDA needs to adopt Regulatory Design Thinking.?The design of a guidance document should anticipate the needs and challenges of a specific audience. In our minds, that means the FDA should be considering publishing track-changes versions of guidance documents, including notes about why?they made specific changes, indicating time stamps for when something was first published and last changed, augmenting guidance documents with recommended reading or webinars, having a central database of all pending or open comment periods, and more. There are significant opportunities to make improvements in this area.

This is just a preview of our full analysis. We analyze another 10+ sections in our full analysis, which is available to AgencyIQ’s subscribers. Interested in obtaining access? Send me an email or submit a demo request.

What we're watching and reading

• …this announcement that the FDA has extended its comment period for its draft guidance document, Assessing the Credibility of Computational Modeling and Simulation in Medical Device Submissions. AgencyIQ subscribers can read our analysis of this guidance here.
• …this news that Biogen now aims to enroll 18% of study participants in its upcoming confirmatory trial for its Alzheimer’s drug Aduhelm from Black and Latino populations.
• …this newly revised FDA Manual of Policies and Procedures on the agency’s approach to issuing information requests and/or discipline review letters for generic drugs. The FDA issued a new final guidance document on that topic yesterday, which we’ve already analyzed.
• …this new CDRH report on its Accreditation Scheme for Conformity Assessment (ASCA) pilot program. The ASCA pilot is intended to allow certain third-parties to conduct certain testing on medical products to support their review by the FDA. Under the program, testing laboratories that are certified by FDA-recognized accreditation bodies can evaluate medical devices for conformity with FDA-recognized standards in support of Declarations of Conformity (DoC) for premarket notification submissions.
• …this recall notice for Philips Respironics’ Trilogy EVO Ventilators – the second in the last year for the same reason (“A Philips supplier incorrectly used polyester-based polyurethane (PE-PUR) sound abatement foam, a non-conforming material, in the muffler assembly of the affected Trilogy Evo ventilators.”) The foam “may break down and potentially enter the device’s air pathway.
• …this report that Senator Rand Paul (R-KY) is pushing a theory that the FDA’s decision earlier this week to restrict the use of two monoclonal antibodies is a plot against “deplorables.” Said Paul: “"These are the people who think we're a bunch of rubes in fly-over country, and they have utter disdain for us. These are the people who would actually limit our access to treatment for Covid. They are, right now, as we speak, limiting monoclonal antibodies being sent to Florida. Too many deplorables, too many Republicans, too many conservatives are getting sick, and so their way to punish us is by not sending treatments and I think it's abominable."
• …this news that Moderna is, like Pfizer, beginning to dose patients in a clinical trial of its omicron-specific Covid-19 vaccine booster.
• …this news that the FDA will find itself back in court this week, with a twist: Pfizer is proposing that it provide assistance to the FDA to help meet a FOIA document disclosure request.
• …this report that some lawmakers are pressing the FDA to broaden the EUA for convalescent plasma.
• …this new approval for a new bispecific biologic for the treatment of adult patients with unresectable or metastatic uveal melanoma.
• …this contract notice indicating that the FDA is spending $1.9 million to upgrade the audio/visual systems in its White Oak Conference Center Building 2.
• …this announcement that the Council for Responsible Nutrition is again calling on the FDA to address the regulatory status of NAC, a dietary ingredient that has been embroiled in controversy after the FDA reversed decades of precedence and declared that it no longer met the legal definition of a dietary supplement since it had earlier been used in a clinical trial.
• …this rare hiring notice for one of the FDA’s top jobs: The Director of the Center for Tobacco Products.