Following a call for comments late last year, Reps. Upton (R-MI) and DeGette (D-CO) released a new “concept paper” on an updated iteration of the landmark 21st Century Cures legislation. While the proposal addresses expected topics like real-world evidence and digital health, it now also seeks to address COVID-19 product development.
By Laura DiAngelo, MPH
The 21st Century Cures of 2016 included sweeping updates for several agencies within HHS, including the FDA. Under the law, the FDA was given new authority to accelerate drug and device development, directed to issue new guidance on the conduct of clinical trials, and instructed to issue guidance on how real-world evidence and data (RWE, RWD) could be used in regulatory decision-making.
RWE and RWD have long been key priorities for the life sciences industry. This data—collected from a variety of non-traditional evidence sources such as electronic health records (EHRs), claims and billing databases, outcomes registries and mobile devices—is generated whenever a patient is exposed to a health care product. However, the FDA has long resisted using this type of evidence as the primary basis for approval for drugs and biologics due to difficulties validating the data. Because this evidence is captured outside of tightly controlled clinical trial settings, the quality of the data can be difficult to ascertain. For example, it can be difficult to control for confounding variables or ensure data was collected according to consistent approaches.
Under the original 21st Cures Act, the FDA was directed to take initial steps to establish how this data could support drug approvals. The agency has worked consistently over the past few years to fulfill these obligations. In 2016 it issued a guidance document on the use of RWE in support of medical device applications. In 2018 it issued a guidance document on best-practices for identifying evidence from electronic health records. And in 2019, it issued guidance that provided specific use-cases for RWE/RWD, such as in support of an application that also has evidence from a clinical trial.
In November of 2019, Reps. Fred Upton (R-MI) and Diana DeGette (D-CO) issued a call for comments meant to provide the foundation for a second version of the 21st Century Cures Act, which they had originally co-sponsored.
The lawmakers have indicated that they received “nearly 500 comments” on the call highlighting new priorities for medical product innovation and regulatory reform, including those from the life sciences industry.
Specifically, the life sciences industry called for new policies to support technological modernization of clinical research, the leveraging of RWE, better regulation of new medical technologies (e.g., mobile health devices, artificial intelligence and machine learning), and better coordination between the FDA and CMS to help speed patient access to approved products.
The New Proposal
On April 27, Reps. Upton and DeGette released a concept paper providing additional details the scope of their legislative intent for the 21st Century Cures Act 2.0 legislation. One recent and notable addition to the legislation are policies intended to respond to the COVID-19 pandemic, indicating increased urgency from the lawmakers.
In this analysis, AgencyIQ identifies the topics that could be most impactful to the life sciences industry from a regulatory perspective and outlines other potential changes.
Real World Evidence and Data
The expanded use of RWE and RWD to support approval decisions has been a top priority for the industry. Although the FDA has taken some initial steps following the implementation of the 2016 21st Century Cures Act, its use is still limited.
In the call for comments on the new iteration, trade association PhRMA noted that a significant barrier to the generation and validation of RWE is the interoperability of clinical and claims data. Ideally, data systems would have a common data architecture, taxonomy and coding to allow them to communicate securely and consistently with each other. In practice, they largely do not, making it difficult to collect and make use of data collected from patient care.
In the new concept paper, the lawmakers state that the bill would require HHS to establish a “consistent and clear regulatory framework for the recognition and utilization of real-world evidence.” This policy would theoretically be intended to set specific standards for data generation that the FDA will consider “usable” and also identify ways that other federal agencies can use RWE.
The validation of RWE to support its inclusion as “substantial evidence” in FDA decisions would likely require alignment between the FDA, CMS, CDC and the Office of the National Coordinator for Health IT (ONC). This would ensure that all sources of data could be shared and are using standard data elements. While placing the authority and coordination responsibility above the FDA could help ensure that all agencies are aligned and reduce the potential for existing data silos to be maintained or even exacerbated, any Department-level guidance would likely be slow to be developed. Under the concept paper, HHS would be required to “outline a framework for the collection of consistent and usable RWD.”
The drive to use RWE in drug development is only likely to grow following the COVID-19 pandemic. The FDA’s Sentinel System is currently running several COVID-19 activities, including a program to track “treatment impact of therapies actively being used in real-world conditions.” Sentinel is also running a program to study the natural history of the disease, which could inform future drug development and regulation decisions. How the FDA will weight that information when considering drug applications, though, remains to be seen.
Breakthrough and Accelerated Therapies
The concept paper also aims to increase the use of RWE for products with Breakthrough Therapy Designation or products granted Accelerated Approval.
Under the proposal, the FDA would be required to issue guidance outlining data quality and transparency requirements for using RWE, but only as a part of post approval commitments. Because products that come through these two pathways typically face an expedited path to market, the need for post-approval commitments is generally higher to flesh out the data on safety and effectiveness used for approval.
Confirmatory studies are required for drugs for which accelerated approval is granted, but not specifically for drugs with a breakthrough designation. Allowing companies to leverage RWE and RWD to fulfill these post-market requirements could reduce the regulatory burden by letting them leverage data that already exists simply by patients using their product, rather than the need to generate new data. Already, some of this data is collected using registries.
The lawmakers are also seeking to increase the number of products that can seek a Breakthrough Therapy Designation or a Regenerative Medicine Advanced Therapy (RMAT) designation, both of which may help accelerate the approval of a viable product. According to the paper, the FDA misconstrued Congress’s intent when it limited eligibility for these designations to products for which a sponsor has submitted an Investigational New Drug (IND) application. Reps. DeGette and Upton call for the FDA to consider designation requests from products without an IND—such as those for which data has been generated in another country.
With the broadened scope of the designations, more products and sponsors will be eligible to apply. However, the policy as outlined wouldn’t change the actual criteria for the granting of a breakthrough or RMAT designation.
The paper also calls for the creation of a parallel-review program for products with Breakthrough Designations. The policy would require the FDA to communicate to CMS that a product has been granted breakthrough status, which could help CMS to establish coverage policies for those products more quickly.
However, the policy may not function as intended, but rather create administrative redundancies and, potentially, waste. According to AgencyIQ analysis, less than half of all drugs that have ever received a Breakthrough designation went on to be approved by the FDA—only 165 out of 375. Because the designation is granted on the basis that a product “may be effective,” based on Phase I clinical trials, the product may not ultimately be approved.
While industry has called for more alignment between FDA approval and market access and coverage policy for innovative products, using the breakthrough designation as an analogue may not be the best proxy for acceleration. The paper does, however, include several additional questions at the end regarding barriers to coverage through the federal health care programs, indicating that the lawmakers may be open to other policy options.
A key focus for the industry in its comments to lawmakers was an emphasis on the regulation of digital health. In particular, stakeholders have raised concerns that the agency’s approach to regulating digital health is piecemeal and decentralized. The agency has previously concurred with these assessments, stating in its FY2021 budget request that existing medical “regulatory pathways under current authority do not promote flexibility for FDA to optimally regulate emerging technologies.”
Under the new proposal, the FDA would be required to “establish regulatory alignment” between its review Centers. It would also be required to issue guidance on how digital endpoints can be used for regulatory review, the use of digital health in conducting trials and developing drugs, and how the FDA will coordinate with foreign regulators to reduce international regulatory redundancies.
The use of digital health in clinical research has recently raised significant questions for both industry and other stakeholders. For example, an April 28 article in the Journal of Law, Medicine & Ethics investigated the use of digital technologies such smartphones, tablets, or other devices in “recruitment, enrollment, data gathering and analysis, and dissemination of research findings.” Overall, researchers found that digital health technologies are loosely regulated at best, potentially endangering patient privacy.
However, the proposal does not specifically mention software as a medical device (SAMD), including artificial intelligence and machine learning—a potential omission.
Under the concept paper, HHS would be required to “implement a national testing, data sharing infrastructure, vaccine, therapeutic, and medical supply readiness strategy to mitigate current and future pandemics.” These policy provisions are intended to plug the holes in interoperability, distribution of health care products, domestic supplies of medical products that have been highlighted by the COVID-19 pandemic.
As AgencyIQ has previously explained, the ability of surveillance systems to share data has been a significant barrier to correct and comprehensive data generation during the outbreak.
The plan also calls for the modernization and expansion of domestic drug manufacturing—specifically through the use of continuous manufacturing. Drug shortages have been a significant concern for lawmakers, and increased domestic production would likely increase the assured supply of drug products in the case of an emergency. However, continuous manufacturing technologies typically increase the price-per-unit of a product relative to batch manufacturing methods, and it’s unclear to what extent industry will adopt such technologies even if provided incentives to do so.
Clinical Trials: Increased participation and new designs
The proposal would require the FDA to update Congress on its progress on the action items identified under its clinical trial diversity report, as required the FDA Safety and Innovation Act (FDASIA).
Additionally, the policy would reduce financial barriers to participation in clinical trials for individuals covered under Medicare and Medicaid. “This policy would ensure that Medicaid covers the routine care costs of clinical trial participation for enrollees with life-threatening conditions,” the paper states. Decreasing financial barriers for certain populations could help increase the number of individuals willing or able to participate in clinical trials to new demographics—and therefore support label expansion.
The lawmakers also propose to authorize funds for the FDA to provide grants “in the area of innovative clinical trial designs,” such as adaptive clinical trials or other novel designs. It would also help fund patient experience data and the incorporation of RWE and RWD, as well as digital health tools. The paper states that RWE/RWD “should be prioritized” for this funding.
The pivot of the 21st CC 2.0 legislation to include COVID-19-related policies could indicate that the legislation will posit itself as the vehicle for life sciences industry pandemic-related reforms. With growing interest in Congress to address the gaps in the health care coverage and innovation regulator frameworks that have been highlighted in response to the virus, this could lend traction to the bill and accelerate its potential passage.
The original 21st Century Cures legislation heralded as a bipartisan achievement, which could prove helpful in Congress.
The significant policies included in the document around RWE and RWD indicate that this is still an area of priority for Congress. However, without mechanisms to require the use of RWE, the new bill will run into the same regulatory issue: The FDA can be given a tool, but only it can decide how and when to make use of it.