FDA Today | What you Need to Know About Cures 2.0

Yesterday, Reps. Diana DeGette (D-CO) and Fred Upton (R-MI) unveiled the text of their 21st Century Cures Act 2.0 (Cures 2.0) legislation. The bill has been in the works for almost two years, and much of the legislation should be familiar to folks who read the original discussion draft. But there are quite a few changes. Today, we’re going to highlight a few of the new or updated provisions we think are most interesting.

If you’re an AgencyIQ subscriber, you can read our full, section-by-section analysis of the bill here.

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Cures 2.0 legislation formally introduced: A section-by-section explainer

The top line: After a discussion draft circulated in summer 2021, Reps. Upton (R-MI) and DeGette (D-CO) have formally introduced bill text for the second iteration of the 21st Century Cures Act (“Cures 2.0”). AgencyIQ took a look through to outline the provisions relevant for life sciences regulation – and the key points of context that industry should note.

First, some background: Cures 2.0 has been up for discussion since 2019. While the formal bill text largely aligns with the Discussion Draft from the summer, there are some new additions.

• The 21st Century Cures Act of 2016 was a flagship law spearheaded by Reps. Upton (R-MI) and DeGette (D-CO), “designed to help accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently.” For the FDA, this meant sweeping new authorities and policy activities, including provisions directing the FDA to consider the use of real-world evidence (RWE) in regulatory decision-making for medical products, expanded the use of Clinical Outcome Assessments (COAs), defined software as a medical device (SaMD) and set statutory exemptions, and authorized additional funding for the FDA to build out novel scientific and regulatory activities. It further built on the agency’s existing efforts to help expedite product development in specific areas, creating the Regenerative Medicine Advanced Therapy (RMAT) and Breakthrough Device programs.
• In late 2019, lawmakers indicated that they were looking to build upon the original legislation. In November 2019, Reps. DeGette and Upton released a call for comments on their “initial vision” for a new piece of legislation, dubbed Cures 2.0. At the time, the lawmakers stated that they expected Cures 2.0 to focus more on digital health, including both market access pathways and reimbursement policies. “Recognition of digital platforms as sources of medical services combined with reforms to how digital products may be covered and reimbursed for by payers such as Medicare will be critical to realizing [these technologies’] potential.” The call for comments was followed by a “concept paper” in April 2020. [Read AgencyIQ’s analysis of the April 2020 concept paper here.]
• In June 2021, lawmakers released a Discussion Draft, or legislative text intended to be circulated to other lawmakers for their input and consideration. That draft included four titles with a variety of provisions related to the regulation of medical products – including market access, clinical (and non-clinical) research, and regulatory decision-making. In addition to a focus on Covid-19 related policies, the draft focused on the gaps in regulatory procedure for novel products and sought to bolster regulatory use of non-traditional data sources.
• On November 16th, Upton and DeGette announced that they are formally introducing the legislation. The newest version of the bill closely aligns with the Discussion Draft, but there are some key updates. While the draft clocked in at under 130 pages, the new version is over 170 pages.
• Read on for a section-by-section breakdown, but at a high level the new version adds a few policy provisions compared to the Discussion Draft. This includes new sections of the legislation on decentralized trials (Section 310), data standards for e-prescribing (410), access to CMS claims data (411) and re-authorizing the original Cures’ Research Policy Board (503). In addition, several sections that were present in the Discussion Draft have been heavily amended under the new version, including the provisions related to “Long COVID” research (101), increasing the use of RWD (304), CMS/FDA communication about novel therapies (305), post-approval studies for accelerated approval products (309), coverage of innovative technologies (404), and personalized medicine and genetic testing coverage (407 and 408). In addition, the new legislation includes a more robust series of directives for the proposed new research incubator agency, the Advanced Research Projects Agency for Health (ARPA-H) than was offered by the Discussion Draft offered.

Section 310: Incentives for Decentralized Trials

Regulatory Background: Traditionally, clinical trials have been run in centralized trial sites in which patients physically go to a trial site (the central location). This allows for uniform data collection to mitigate the risk of confounding variables – in effect, investigators are trained in the same way and clinical staff will collect data in a uniform fashion, which helps control for any unintended bias in the data. However, there is an increasing interest in decentralized trials, in which data can be captured at locations outside of that central location, such as at a patient’s home (often using digital reporting). The benefits of decentralized approaches are twofold: first, by decoupling clinical trials from traditional sites, researchers can reach a new participant population and increase representativeness in their trial data sets. Second, digital reporting directly from patients allows the capture of outcomes and measures that are directly impactful to patients, improving information on the context of an investigational product.

How it would work: This new section of the legislation, which was not included in the Discussion Draft, would task HHS to convene a meeting with “covered representatives,” including drug sponsors, device manufacturers, clinical research organizations, the tech industry and patient advocate groups, to discuss opportunities for decentralized trials. The Cures 2.0 text would also adopt a formal statutory definition of the term decentralized trial, which would be: “a clinical trial method that includes the use of telemedicine or digital technologies to allow for the remote collection of clinical trial data from subjects, including in the home or office setting.”

Analysis: The use of decentralized clinical trials has become more prominent – and in some cases necessary – during the pandemic. Travel restrictions and clinical trial site closures during the Covid-19 public health emergency all but required many clinical trials to implement decentralized approaches meant to reduce person-to-person interactions between trial participants and staff. These efforts allowed many trials to maintain existing trial enrollees, though it did often require modifications to be made to trial protocols at the urging of both the FDA and European Medicines Agency. [ Read AgencyIQ’s analysis of the FDA’s guidance document on this topic.]

However, regulators have expressed their reservations about these models. At a recent speaking engagement, leadership from the FDA’s Oncology Center of Excellence (OCE) highlighted barriers to widespread adoption of these research models, including telemedicine licensing jurisdiction, provider training about regulatory requirements and remote trial personnel supervision. Overall, regulators questioned whether the data collected under decentralized trial methods during the pandemic will be high quality enough to support regulatory decisions. Notably, OCE is currently engaged in an initiative to better understand decentralized trials, using the experiences from the pandemic research. Further, some researchers have highlighted the need for new, enhanced participant engagement methods to ensure that data are being captured appropriately, and that participants from traditionally underrepresented populations that may be participating in research for the first time through a decentralized trial are being supported in the research process.

While the Cures 2.0 provision is relatively conservative – directing the FDA only to convene a meeting on decentralized trials, not take any other action – it does herald continued interest in this area from a variety of stakeholders.

Section 404: Coverage and payment for Breakthrough Devices under the Medicare Program

Summary: Directs CMS to provide transitional coverage under the Medicare program for medical devices that have been granted a Breakthrough Device Designation (BDD) by the FDA.

How it would work: The FDA grants Breakthrough Device Designations (BDDs) for medical devices intended to treat “life-threatening or irreversibly debilitating” conditions that address unmet needs, are in the best interest of patients, or represent “breakthrough technology.” These are typically granted early in the device’s regulatory process. However, while a sponsor of a Breakthrough device will receive additional support from FDA during the review process, the BDD does not grant the device expedited coverage decisions from CMS.

Under the proposal, BDDs that have received market access by the FDA would be “deemed to be reasonable and necessary” for Medicare coverage. Further, they would automatically qualify for additional payment under the Medicare prospective payment systems, including the New Technology Add-On Payment (NTAP) for the inpatient payment system (excluding the cost criterion for eligibility) and pass-through payment for the outpatient payment system. The “transitional coverage” would begin on the day of a market access decision by the FDA and last for up to four years. HHS would be further required to provide coding (either a unique temporary code or permanent code or codes) for the product within three months of market access and develop a full coverage proposal within two years of market access.

Notably, the text of the legislation has been updated since the Discussion Draft. The new version adds language to explicitly note that HHS may stop (i.e., suspend or terminate) coverage of a device “based on clinical evidence” that it offers no benefit or may cause (or does cause) “serious harm.”

Analysis: The provision in the bill includes policies previously introduced in the House as the Ensuring Patient Access to Critical Breakthrough Products Act, which has been sponsored and introduced by Rep. Suzel DelBene (D-WA) since at least 2016. [ Read AgencyIQ’s analysis of the 2020 version of that bill here.]

The provisions in this bill are similar to the previous administrations Medicare Coverage of Innovative Technologies (MCIT) pathway, which was finalized in early January 2021 but has been recently repealed by the Biden administration. Notably, in an email notification of the rule’s withdrawal, CMS stated that it “intends to explore coverage process improvements that will enhance access to innovative and beneficial medical devices in a way that will better suit the health care needs of people with Medicare.”

Although the section-by-section of the Cures 2.0 Act states that the provision would be intended to “codify the current Medicare Coverage of Innovative Technologies (MCIT) pathway at CMS,” the legislative proposal actually differs from that policy. First, the bill would allow “flexibility” for CMS to cover medical devices for which no benefit category under the Medicare program currently exists, which was a key limitation of the MCIT pathway. Second, the final MCIT rule allowed for “transitional coverage” to begin not on the day of market access, but any time within two years of the FDA’s decision. [Read AgencyIQ’s analysis of the MCIT rule here]

Also notably, at least part of this bill is already current policy. Under the 2021 Medicare Inpatient Prospective Payment System (IPPS), medical devices with a BDD have a streamlined pathway to receive an NTAP, which is an additional payment for novel technologies provided in the inpatient setting. However, those devices still need to go through the process of applying for an NTAP, and must still meet the cost criterion (i.e., the newness and clinical improvement criterion on which NTAP is traditionally considered are considered met if a device has a BDD).

However, the future of the inclusion of this provision is unclear. While the medical device industry has strongly supported both the Ensuring Patient Access to Critical Breakthrough Products Act and the MCIT, the bill has had limited success in previous sessions of Congress and other federal stakeholders have raised concerns about the policy. For example, the Medicare Payment Advisory Commission (MedPAC) penned a letter to CMS about the MCIT proposal in 2020, arguing that the MCIT pathway proposal would effectively delegate authority to determine Medicare program coverage to the FDA, which it states is inappropriate given the specific considerations for Medicare beneficiaries (i.e., individuals 65+) and the differences in the statutory mandates for Medicare coverage and BDDs. Notably, CMS made several of the same arguments in its regulatory actions to withdraw the MCIT.

Section 304: Increasing use of Real-World Evidence

Regulatory Background: Real world evidence (RWE) is clinical evidence on a product’s safety or efficacy that is generated from analysis of data that is captured outside of a clinical trial (called real-world data, or RWD). This includes data from electronic health records (EHRs), billing and claims data, data from clinical registries and new and emerging data sources like wearables and biosensors. Currently, the FDA’s approach to the use of RWE in regulatory decision making is limited for drug products. In general, the agency is concerned about the relevancy and validity of RWD sources (i.e., does the data relate to the question being asked, and was the data captured in a validated and consistent way), as well as RWE methodologies, which may be biased.

How it would work: HHS (likely through the FDA) would be tasked with issuing new guidance about the use of RWE in post-market (i.e., post-approval or licensing) evaluations of drugs that went through an expedited review process, specifically including products with a Breakthrough Therapy designation, a Fast Track review or “product considered for accelerated approval.” In addition, the new version of the legislation updates the text to specifically include medical devices that have received a breakthrough device designation (BDD).

The guidance would include recommendations on ensuring adequate representation among the population, acceptable endpoints and outcome measures for RWD sources, data quality and transparency expectations and how the studies should be designed. In addition, HHS would be directed to evaluate the FDA’s RWE framework and “identify consistent, clear approaches” for use in the whole Department to harmonize RWD, not only for market access decisions but also “in regulating, purchasing, and supporting the purchase of health care products and services.”

Finally, the bill would establish an RWE Task Force, which would include leadership from HHS’ core science and health care regulatory agencies and other stakeholders (CMS, FDA, NIH and “additional Federal officials” and “private sector representatives” selected by HHS, specifically including patient groups), would make recommendations on how to engage patients in RWD development, and “participate in postapproval clinical trials for the collection of real world evidence.”

Analysis: The FDA’s programs outlined in the bill are intended to expedite market access for products that fill a significant unmet need or represent a significant clinical benefit over available therapies. However, the expedited development and review processes can leave some outstanding questions about the long-term safety and efficacy of these products, leading to increased post-market evidence generation expectations for sponsors.

Recently, federal officials have been raising some concerns about the conduct of these studies to confirm benefit, especially for products approved under the Accelerated Approval pathway. Under the proposal in Cures 2.0, sponsors would be able to leverage RWD sources, such as clinical registries, to help support post-market commitments. While the use of RWD can reduce the burden on a sponsor to independently stand up a research program, the FDA is currently hesitant to allow RWE to be used for these study commitments for drug products (although the process is well-established for medical devices, and the agency encourages device sponsors to use RWD sources for post-market commitments whenever possible).

This provision as outlined could reduce duplicative research efforts for some of these products. For example, a product that has been granted Accelerated Approval and is subject to follow-up study requirements by FDA may also be subject to a Coverage with Evidence Development (CED) policy from CMS, and having HHS harmonize how RWE will be considered at all levels within the Department could streamline these processes. Further, having HHS establish Department-wide standards for RWE not only in market access decisions but also payment and purchasing could clarify to sponsors how federal payers will consider products that are granted market access based on RWE, potentially smoothing the process to coverage and reimbursement and help researchers feel more confident in investing in RWE-based research programs.

Finally, the utility of the current mandate for the RWE Task Force seems limited at this time. Although there are several outstanding questions related to RWD that could benefit from a cross-agency task force, such as unified data standards and how to address data gaps (e.g., clinical laboratory data, socioeconomic status data), the bill currently tasks the Task Force with developing recommendations to engage patients in RWD development. However, according to a recent FDA meeting on PGHD , patients are already overwhelmingly willing to engage in RWD development when they can, including those who are underrepresented in traditional clinical trials.

The Cures 2.0 text comes after a busy few months in RWE policy for the life sciences industry. Under PDUFA VII commitments, the FDA has agreed to begin conducting RWE-based submission pilot reviews by the end of 2022. Further, the agency issued new guidance on its expectations for the use of specific RWD sources in drug applications, and additional guidance on the operational expectations for submitting these data. However, those interested in RWE policy can also see new lessons emerging from the use of RWE in device submissions, which is a more advanced field than in drug products. Overall, while RWD has been used to support label expansions and meet post-market commitments, developers have struggled to use RWE in new submissions. For example, a Pre-Market Approval (PMA) application for a new device supported by an RWE analysis (that was actually run by FDA, not the sponsor) was recently shot down in an advisory committee meeting, while another device submission sought to leverage claims data from Medicare, but both the advisory committee and FDA raised concerns about coding and data lag in claims data. While the policy in Cures 2.0 could serve as an impetus for the FDA to invest in RWE for expedited access products, the operational realities of defining regulatory-grade RWD are likely to remain a challenge.

This is just a preview of our analysis. Subscribers can also read our full analysis of this legislation, including a section-by-section breakdown, by clicking here.

What we're watching and reading

• …this news that Pfizer has filed an Emergency Use Authorization application for its Covid-19 antiviral pill.
• …this news that some states are circumventing FDA and CDC guidelines on booster shots. A few high-level thoughts: Will the FDA take action to enforce its Emergency Use Authorizations? Will companies take action? Would the CDC take action to enforce its contracts with providers which require adherence to EUAs and guidelines?
• …this analysis of the Build Back Better drug pricing negotiation language, which comes to the conclusion that the current language might actually undercut the ability for generic and biosimilar drugmakers to bring new products to market.
• …this news that the FDA has authorized the marketing of a new “virtual reality system” intended for use to help reduce chronic lower back pain in adults. The device works by helping to facilitate relaxation through deep breathing exercises.
• …this news that efforts to pass the Cures 2.0 legislation are likely to take a backseat to other legislative priorities for months. One key question: Could the legislation ultimately be combined with the FDA user fee reauthorization effort?
• …this news that the SEC is investigating Cassava Sciences over the potential manipulation of research results. The investigation follows a series of petitions submitted this year to the FDA raising concerns.
• …this news that U.S. overdose deaths topped 100,000 last year – the most ever, and a 30% jump over the prior year, likely due to the effects of the pandemic and increased availability of fentanyl.
• …this recap of remarks made by Grail Sipes, the Deputy Center Director for Regulatory Policy at FDA’s Center for Drug Evaluation and Research (CDER), at a hemp and CBD conference. The key details: “Clear answers to many important questions are still lacking, such as what adverse reactions may be associated with CBD from hemp-derived products and what risks are associated with the long-term use of these products.”
• …this new Natural Disaster Contingency Planning guide published by Rx360. While it’s high-level, it’s still a helpful resource for thinking about how to plan for, assess and response to supply chain risks.
• …this news that the International Warehouse Logistics Association is meeting with the Office of Information and Regulatory Affairs (OIRA) about FDA’s pending rule on national standards for the licensure of wholesale drug distributors and third-party logistics providers.
• …this hiring notice for a Senior Advisor to the Deputy Commissioner for Policy, Legislation, and International Affairs.
• …this analysis of what a new FDA Commissioner might mean for the power of the FDA’s Oncology Center of Excellence, such as the authority to actually approve products.
• …this news that new warnings are being attached to some NSAID drugs about their risks for pregnant or breastfeeding persons.
• …FDA’s rejection of a petition from King & Spalding to market a new strength of a generic drug.
• …this upcoming workshop on biases and fairness in AI-enabled health software.

Analysis available exclusively to AgencyIQ subscribers:

Cures 2.0 legislation formally introduced: A section-by-section explainer

After a discussion draft circulated in summer 2021, Reps. Upton (R-MI) and DeGette (D-CO) have formally introduced bill text for the second iteration of the 21st Century Cures Act (“Cures 2.0”). AgencyIQ took a look through to outline the provisions relevant for life sciences regulation – and the key points of context that industry should note.

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