The US House of Representatives has approved the 21st Century Cures Act, a bill that increases funding to the National Institutes of Health and the US Food and Drug Administration as well as provides for reforms in the drug development and approval process. The bill has drawn both praise and criticism from lawmakers and stakeholders. So what are the key measures of the bill, and where does it go from here? DCAT Value Chain Insights takes an inside look.

The House’s passage of the 21st Century Cures Act, a bipartisan measure, is the first step in a legislative journey, in which companion legislation in the US Senate still has to be considered. The House bill, however, has been praised by some for providing additional funding for the NIH and the FDA, notably $8.75 billion for the NIH and $550 million for the FDA over the next five years. The bill also includes measures that would encourage the use of patient-centered medical product development, further development and qualification of biomarkers, and using real-world evidence in the regulatory review process. DCAT Value Chain Insights examines the implications for drug innovation, development, and commercialization.

Funding for the NIH and the FDA
A key measure of the bill is the creation of temporary, fully offset innovation fund for the National Institutes of Health (NIH) and the US Food and Drug Administration (FDA) for research and researchers (including young scientists) to facilitate biomedical research, Unlike most mandatory spending, or entitlements, this funding is set forth for a specific and limited period of time and sunsets after five years at $1.75 billion per year to the NIH ($8.75 billion for the five-period) and $110 million annually to the FDA ($550 million for five years). This mechanism is intended to stabilize funding for biomedical research and development.

Another important measure of the bill is that it exempts pharmaceutical industry users fees from Congressional sequestration, a move that is supported by the Pharmaceutical Research and Manufacturers of America (PhRMA). Specifically, the bill permanently exempts from sequestration FDA user fees for medical devices, prescription drugs, generics drugs, biosimilars, animal drugs, and generic animal drugs. This provision is intended to create certainty regarding access to FDA user fees and related funding for drug and device review and other agency functions. “PhRMA strongly supports the inclusion of language in H.R. 6 [the 21st Century Cures Act] that exempts future Food and Drug Administration (FDA) user fees from sequestration, which is critical to ensure the FDA is able to fulfill its public health mission by fostering timely patient access to safe and effective new medicines and advancing regulatory science,” said PhRMA President and Chief Executive Officer John J. Castellani, in a statement.

Industry support
PhRMA and the Biotechnology Industry Organization (BIO) also issued their support for other measures of the bill that accelerate and reform the drug development and review process. “PhRMA applauds the House of Representatives for the overwhelming passage of the 21st Century Cures Act and looks forward to continuing our work with the Senate to ensure biomedical advances continue and are available to the patients who need them to live longer, healthier lives,” said PhRMA's Castellani, in a statement issued on July 10, 2015 following the passage of the House bill. BIO President and CEO Jim Greenwood also issued support. “This bill represents forward-looking public policies that sustain scientific discovery and promote biomedical advancement,” he said in a statement. “The future of medicine will harness 21st century scientific tools, advancements in molecular biology, and novel bioinformatics to develop and improve upon therapies that can prevent, diagnose, and treat all stages of disease. This landmark legislation would lay the groundwork for transforming patient care by encouraging innovative approaches to drug discovery, development, and delivery.”

Key provisions of the bill
Patient-focused drug development. So what are key measures of the bill? The bill sets forth measures to develop and use patient- experience data in a structured risk-benefit framework as part of the FDA's regulatory review process. Specifically, the bill requires that the FDA, in the context of the new drug review process, to implement a structured framework to facilitate the incorporation of patient experiences in the consideration of a drug's benefits and risks. The bill also puts forth measures to codify a structured framework at the FDA for the submission, review, and qualification of biomarkers, and other drug-development tools.

Encouraging drug innovation. The bill also emphasizes tools to accelerate review of important drug breakthroughs. It creates provisions to enable the sponsor of a drug that the FDA determines may be eligible for accelerated approval to request voluntarily that the FDA agree to an accelerated approval development plan. The bill also requires the FDA to issue and periodically update guidance defining the term “precision drug or biological product” and authorizes the agency, in the case of a drug or biological product for treating a serious or life-threatening disease or condition designated as a drug for a rare disease or condition, to rely upon data or information previously submitted by the sponsor for a different drug or biological product that incorporates or uses the same or similar underlying approach. This bill also reaffirms that the FDA should continue to expedite the approval of drugs designated as breakthrough therapies as early as possible in the clinical development process, provided that the application for a drug meets the required evidentiary standards of safety and effectiveness.

The bill further builds on existing mechanisms to encourage new drug development in certain areas. The bill builds off the progress Congress made with the passage of the Generating Antibiotic Incentives Now Act as a part of the Food and Drug Safety and Innovation Act in 2012 by facilitating the development of new antibacterial or antifungal drugs through a new FDA approval pathway and creating economic incentives for new drug development. The bill also incentivizes the repurposing of major market drugs for rare diseases by providing a one-time, six-month extension of certain exclusivity periods and patent protection for an already-approved drug if the drug's sponsor obtains approval of a new indication for the drug for a rare disease or condition. The bill also reauthorizes the rare pediatric disease priority review voucher program through December 31, 2018. In addition, the bill broadens the definition of a rare pediatric disease to ensure that pediatric oncology drugs and treatments for sickle-cell disease are eligible for designation. Further, the bill requires that the US Government Accountability Office complete a report evaluating the effectiveness of the program for encouraging drug development for rare pediatric diseases. The bill also requires the FDA to issue a final guidance document describing the role of all agency centers when reviewing a combination product.

Manufacturing. The bill contains several measures to encourage innovation in drug manufacturing. The bill allows the FDA to award grants to higher education and non-profit organizations to study and recommend improvements to the process of continuous manufacturing (and other similar innovative monitoring and control techniques) of drugs and biologics. The bill also allows US pharmaceutical companies to re-export controlled substances similar to foreign pharmaceutical manufacturers in order to provide for a more level-playing field regarding controlled substances exports.

Clinical trial design. With respect to clinical trial design, the bill requires that the FDA hold a public meeting and issue guidance documents that would assist sponsors in incorporating adaptive designs and Bayesian statistical modeling into their proposed clinical protocols and applications for new drugs and biological products. The bill also requires the FDA to establish a program to evaluate the potential use of evidence from clinical experience to help support the approval of a new indication for a previously approved drug and to help support or satisfy post-approval study requirements. In parallel, the bill requires that the FDA identify and execute pilot demonstrations to extend existing use of the Sentinel System to, among other things, support these efforts. The bill further requires the FDA to establish a program authorizing the holder of an approved application to submit a summary of clinical data intended to support the approval or licensure of the drug for a new indication for the treatment of cancer or other types of indications.

Stakeholder feedback
The bill was supported by more than 700 groups, and the legislative process, the FDA issued support for more collaborative measures in the drug review and approval process. In testimony before the Subcommittee on Health of the House Energy and Commerce Committee earlier this year, FDA's Center for Drug Evaluation and Research Director Janet Woodcock supported measures that involving the FDA's review process. “We believe there are opportunities to accelerate medical product development by (1) supporting patient-centered medical product development,” she said. “We are pleased that you have included provisions to help us incorporate patients’ voices into FDA’s decision-making regarding the benefits and risks of new products; (2) encouraging development and qualification of biomarkers; (3) utilizing real-world evidence in the review process; (4) reducing barriers to use of central Institutional Review Boards (IRBs) for device trials; and (5) strengthening FDA’s ability to hire and retain highly qualified experts.”

Others, however, are critical of the legislation and assert that the FDA's review process is timely and among the most efficient among regulatory agencies in the world and that further reform is not required. In an article in The New England Journal of Medicine, Jerry Avorn, professor of medicine at Harvard Medical School and chief of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital, makes that assertion, stating that certain “proposed changes could lead to less salutary outcomes for patients and the health care system.” He said that the drug-approval process is already efficient, pointing to certain data: one-third of new third of new drugs are currently approved on the basis of a single pivotal trial; the median size for all pivotal trials is 760 patients; more than two thirds of new drugs are approved on the basis of studies lasting six months or less; and that once FDA starts its review, it approves new drugs as quickly as any regulatory agency in the world, within six to 10 months.

Additional measures
This bill also sets forth several requirements of the NIH, including requiring the NIH to issue a strategic plan. It also increases accountability at the NIH, including with respect to the award of grants. It directs the NIH to compile research and implement recommendations on how to streamline the grant process for researchers and reduce administrative burdens. The bill also provides the National Center for Advancing Translational Science (NCATS) at the NIH with more flexibility on the use of other transaction authority so it can operate like the Defense Advanced Research Projects Agency (DARPA). The bill also requires the NIH to establish a national pediatric research network composed of research institutions that would operate as a consortium in order to pool resources and coordinate activities related to pediatric rare diseases or birth defects. The bill also sets forth provisions for more collaboration between the NIH, the FDA, the European Union, and industry for establishing a global pediatric clinical study network. The bill also would require the NIH to standardize certain patient inclusion and exclusion information across all trials housed in ClinicalTrials.gov, the federal government's portal for clinical trial information.

The bill also engages other federal organizations. The bill requires that the Centers for Disease Control and Prevention set up a surveillance system for neurological diseases, such as Parkinson's disease and multiple sclerosis. The bill also establishes a public-private partnership to establish or enhance and support an information technology system, including staffing, to collect, maintain, analyze, and interpret data on the natural history of diseases, with a particular focus on rare diseases. The bill also calls for establishing a public-private partnership in the United States to accelerate the discovery, development, and delivery of innovative cures, treatments, and preventive measures for patients.