By Ann Neuer 

October 14, 2015 | In a dazzling display of bipartisanship, the United States (US) House of Representatives passed the 21^st Century Cures Act (“Act”) on July 10, 2015, by a wide margin. The vote was 344 to 77, unleashing praise from both sides of the aisle that this Act will speed needed therapies to market through a more streamlined regulatory approval process while offering substantial savings to the federal budget.

But outside of the Capitol, the Act has evoked both positive and negative reaction. Essentially, the Act seeks to transform the clinical trial ecosystem, by revolutionizing the entire discovery, development, and delivery steps in its quest for faster cures. It addresses trial design, precision medicine, collaborative drug development, and device approval. This is a tall order for a piece of legislation headed to the Senate, where it is expected to be taken up in the fourth quarter of 2015.

Modernizing the Drug Development Pathway

For many years, reports coming out of the Tufts Center for the Study of Drug Development (CSDD), CenterWatch, and other venues have highlighted inefficiencies in the clinical development process, and the need for reform. They have pointed to complex protocols, siloed technologies, archaic management practices, patient enrollment challenges, and regulatory stumbling blocks to explain why it takes so long to bring much-needed new therapies to market. In an era of cloud-based technologies, application program interface (API) capability that integrates various eClinical functions, and risk-based monitoring, it seems that now is the time to use these tools in conjunction with regulatory changes to streamline the drug, biologic, and medical devices development processes.

The 21^st Century Cures Act strives to do just that. The Act was initiated in the House Energy & Commerce Committee under the leadership of Chairman Fred Upton (R-Michigan), and Representative Diana DeGette (D-Colorado) and received a unanimous vote from the Committee—51-0—before heading to the full House in May 2015. While being formulated, the Committee spent 18 months gathering input from a cadre of stakeholders including doctors, health advocates, and policy experts on ways to modernize clinical trials, and include the patient’s voice throughout the trial development process.

The Act seeks to overhaul many of the procedures traditionally associated with how investigational products are reviewed for approval. The new rules aim to bring therapies to market in ways that are less expensive, less time consuming, less resource-intensive, and more predictable. The result would be faster access to therapies for patients who need them.

As soon as the Act passed in the House, supporters and detractors began taking sides. To be sure, there is a lot to like about the legislation, most notably, substantial increases in funding for the National Institutes of Health (NIH). The Act calls for annual increases of 3% per year for three years, and an additional $8.75 billion over five years to create a temporary “Innovation Fund” in support of biomedical research. This funding should boost research for cures and treatments for Alzheimer’s disease, treatments for antibiotic resistance, and support the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. The Innovation Fund would also authorize an additional $550 million to help the Food and Drug Administration (FDA) comply with new review requirements spelled out in the Act.

Kim McCleary, Managing Director at FasterCures, an organization dedicated to accelerating and improving medical research, says, “When the bill passed the House, there was a lot of enthusiasm from many stakeholders, as well as from patients and patient organizations.” Her organization worked closely with the Energy & Commerce Committee to help shape the legislation over a nine month period.

The Act’s proposed changes are significant. These include expediting the approval of drugs designated as breakthrough therapies as early as possible in the clinical development process, regardless of the phase of development; use of evidence from clinical experience to support approvals; and greater use of drug development tools to help FDA approve new therapies more quickly. These tools—biomarkers, surrogate endpoints, a clinical outcome assessment, patient reported outcomes, and other methods—are to be developed through a collaborative process established by the Secretary of Health & Human Services. And, for some antifungal and antibacterial drugs intended to treat life threatening infections, approval could rely on Phase II efficacy data, smaller patient populations, traditional endpoints, alternate endpoints, or a combination, as well as limited data sets. The Secretary could also require other confirmatory evidence.

McCleary says FasterCures supports these changes, including those in which randomized clinical trials, the gold standard, would not necessarily be required. “We need to move things more quickly, and FDA has said that it is comfortable with this version of the bill, and it does not compromise patient safety,” she says.

Similarly, Janet Woodcock, director of the Center for Drug Evaluation and Research at FDA told the Washington Post that in the case of antibiotics, allowing them to be approved based on laboratory and animal tests and small, early clinical trials is critically important given the “societal crisis” of drug-resistant infection. She explained that the Act would encourage development of treatments for seriously ill patients, and that the standards of efficacy remain the same.

Others disagree, strongly. Gregg Gonsalves, co-director of the Yale Global Health Partnership, says that FDA already has the tools it needs to perform expedited reviews and what is being proposed in the Act would lower the standards for approval. “The bill is superfluous and unnecessary. Approvals from FDA are already the fastest in the world, as compared to other regulatory agencies, and the percentage of drug applications receiving approval has reached a new high in 2015,” Gonsalves tells Clinical Informatics News. In fact, this year FDA has approved 25 drugs, an 89% approval rate attributed to FDA working to meet its mandated deadlines, and implementing good communication pathways with sponsors to facilitate faster approval.

FDA began working on expedited drug approval during the AIDS crisis in the 1980s. The FDA and the AIDS community cooperated then to speed access to experimental drugs, developing novel processes to accelerate approvals, such as breakthrough and fast-track designations and conditional release with the stipulation that companies perform more studies.

But now, the 21^st Century Cures Act opens the door for even faster review. Gonsalves cautions that the Act follows a wave of legislation since the 1980s and 90s meant to weaken the safety and efficacy requirements at the Agency. “The bill would make mere clinical experience acceptable for evaluating new drugs, rather than rigorous clinical trials, force the use of biomarkers for a wide variety of conditions on terms largely set by industry, and even let manufacturers make changes in medical devices without FDA review,” he explains. He notes further that only a set of initial studies could be required for approval of much needed new antibiotics, and the critical post-marketing studies that show that new drugs are effective, and even save lives, could be made optional.

Jerry Avorn and Aaron Kesselheim voiced similar sentiments in a thoughtful editorial published in the New England Journal of Medicine. Avorn and Kesselheim took issue with the Act’s requirement that the Secretary of Health & Human Services develop criteria for relying on “evidence from clinical experience,” including “observational studies, registries, and therapeutic use” instead of randomized, controlled trials for approving new uses for existing drugs. While these data can provide important insights about drug use and safety after market, the authors pointed to considerable evidence that these approaches are not as rigorous or valid as randomized trials in assessing efficacy. “These provisions in the legislation would not immediately change FDA approval standards, but they would give the agency greater discretion, backed by congressional support, to approve drugs on the basis of less rigorous data,” the two wrote in their editorial. The authors are also concerned about additional reliance on biomarkers and other surrogate measures instead of actual clinical endpoints in assessing the efficacy of both drugs and devices. Avorn and Kesselheim note that surrogate endpoints are already used in half of new drug approvals; some are accurate predictors of disease risk, and speed approval, but not always.

What Next?

Much like the divergence of opinion over the drug side of the Act, supporters and detractors have lined up on opposing sides for changes that would impact the device industry as well. Supporters are stating that safety standards would remain unchanged, and the Act would simply allow for use of more types of evidence. Detractors, however, claim that in some cases, clinical trials might not even be necessary for approval, instead relying on less rigorous evidence, such as a case series.

“Devices can save lives, and we want patients to have them if they are safe and effective. The problem is that you can’t extrapolate case series information as representative of the diversity of patients who might use a device,” says Sanket Dhruva, M.D. of Yale. In a New York Times editorial he co-authored with Dr. Rita Redberg of University of California, San Francisco, Dhruva noted that the regulatory pathway for device approval is already weak, and the proposed law may shift the burden of evidence to clinical studies that are occur only after the devices have been put on the market, if at all.

Currently, the Senate’s Health, Education, Labor, and Pensions Committee is working on a parallel initiative to the House 21^st Century Cures Act. According to David Nexon, Senior Executive Vice President of AdvaMed, and Senior Health Policy Advisor to the late Senator Edward M. Kennedy, “We expect a discussion draft or some other form of legislative proposal to be released by the Committee as early as this month.”