The 21st Century Cures Act (“Cures Act”) relies on the concept of real-world evidence (“RWE”) to improve the Food and Drug Administration (“FDA”) approval process. This has amplified interest and furthered momentum in applying RWE more broadly, beyond FDA regulation. In this article, we discuss the understandable appeal of RWE's pragmatic application and its many potential benefits. But we also caution that claims about RWE's wide-ranging, ameliorative impact on the health care system are likely overstated.

The real world of RWE is messy and uncertain. Successfully incorporating RWE into regular health care system decision-making, beyond the FDA, faces considerable obstacles and limitations. We review the reasons to be wary about RWE as a game-changer. These concerns including data reliability, insufficient incentives for stakeholders to generate and engage with high-quality RWE, and lack of comprehensive regulatory oversight. In addition, the push for RWE may impact the enforcement of the health care fraud and abuse laws, perhaps not in necessarily positive ways. Increased reliance on RWE may have significant implications for off-label fraud enforcement, further conflating the distinction between claims that are false for reimbursement rather than for scientific purposes.

Healthcare database analyses (claims, electronic health records) have been identified by various regulatory initiatives, including the 21st Century Cures Act and Prescription Drug User Fee Act (“PDUFA”), as useful supplements to randomized clinical trials to generate evidence on the effectiveness, harm, and value of medical products in routine care. Specific applications include accelerated drug approval pathways and secondary indications for approved medical products. Such real-world data (“RWD”) analyses reflect how medical products impact health outside a highly controlled research environment. A constant stream of data from the routine operation of modern healthcare systems that can be analyzed in rapid cycles enables incremental evidence development for regulatory decision-making.

Key evidentiary needs by regulators include 1) monitoring of medication performance in routine care, including the effectiveness, safety and value; 2) identifying new patient strata in which a drug may have added value or unacceptable harms; and 3) monitoring targeted utilization. Four broad requirements have been proposed to enable successful regulatory decision-making based on healthcare database analyses (collectively, “MVET”): Meaningful evidence that provides relevant and context-informed evidence sufficient for interpretation, drawing conclusions, and making decisions; valid evidence that meets scientific and technical quality standards to allow causal interpretations; expedited evidence that provides incremental evidence that is synchronized with the decision-making process; and transparent evidence that is audible, reproducible, robust, and ultimately trusted by decision-makers.

Evidence generation systems that satisfy MVET requirements to a high degree will contribute to effective regulatory decision-making. Rapid-cycle analytics of healthcare databases is maturing at a time when regulatory overhaul increasingly demands such evidence. Governance, regulations, and data quality are catching up as the utility of this resource is demonstrated in multiple contexts.

The 21st Century Cures Act encourages the Food and Drug Administration to consider “real-world evidence” in its regulation of the safety and efficacy of drugs and devices. Many have interpreted this mandate to focus on non-randomized observational research. However, we suggest that regulatory science must also move from rarefied academic hospitals to community-based settings, where the vast majority of patients in fact receive care in the fragmented U.S. healthcare system. This move is especially important if innovations are to reach, and be validated in, more diverse populations. A solution can be found in the 183 Practiced-Based Research Networks (“PBRN”), i.e., groups of primary care clinicians and practices in all 50 states working to improve clinical care and translate research findings into practice. This symposium contribution seeks to (1) describe some of the common shortcomings of clinical trials, (2) explore the opportunities and challenges posed by use of real-world evidence as a basis for drug and device regulation, (3) briefly describe the history and evolution of PBRNs, and (4) articulate the challenges and opportunities for using PBRNs to fulfill the 21st Century Cures Act mandate for real-world evidence.

Regenerative medicine (“RM”) is a 21st century technology whose regulation has badly needed a 21st century cure. It is not clear that the 21st Century Cures Act (“Cures Act”) is that cure, but it has not been a poison. For some months prior to the passage of the Cures Act it seemed that it might be a catalyst for really endangering the field by allowing a flood of untested therapies to continue to enter the market. That, fortunately, did not happen. Thus far, the Cures Act has been a useful tonic; its effect on RM has been largely symbolic. But it has allowed the Food and Drug Administration (“FDA”) to redirect resources, and it demanded the quick adoption of guidance. That has allowed the Agency to finalize a regulatory framework that has been sorely needed. The evidentiary flexibility within the Cures Act is extremely important for the development of technologies that do not fit easily into the traditional approval rubric.

Perpetual debate regarding the delicate balance between access and innovation and the protection of the public health and safety dominate discussions of the United States Food and Drug Administration (“FDA”). Established chiefly as a command and control federal administrative agency, iterative changes in legislation have shaped the FDA's activity in drug, biologic, and medical device regulation over the course of the last one hundred plus years. The most recent fundamental reframing of the agency's authority and directive presented itself in the 21st Century Cures Act, reflecting an important role for patient perspectives in the regulatory process. This Article explores recent developments in patient-focused product development efforts at the FDA and offers modest insights on the increasing role of patients, and patient advocacy groups, in agency decision-making. The Article terms this era “21st century citizen pharma.”

The U.S. federal government awards a priority review voucher (“PRV”) to a pharmaceutical manufacturer after the Food and Drug Administration (“FDA”) approves a product for one of a list of voucher-eligible indications. The voucher, which can be transferred or sold, allows the company to accelerate the review timeline of another product for any indication. The PRV program was proposed in 2006 as an incentive for research and development for neglected diseases, such as dengue and leishmaniasis.

Neglected tropical diseases (“NTDs”) predominantly affect the world’s poorest populations and are associated with significant morbidity and mortality. Despite their global public health importance, neglected diseases were estimated to account for less than 1% of pharmaceutical research and development expenditures. The voucher program was intended to address this gap between investment and disease burden: “[t]he major obstacle to stimulating the R&D of new medicines for neglected diseases is lowincome nations' inability to pay for such medicines.” The voucher would provide an additional financial incentive to fund clinical development of these products without requiring additional appropriations from Congress.

Certificates of Confidentiality (“Certificates”) are a federal legal tool designed to protect sensitive, identifiable research data from compelled disclosure. Congress first authorized their use in 1970 to facilitate research on illegal drug use. The scope of their use was later expanded to cover mental health research and then again to apply broadly to identifiable, sensitive research data, regardless of topic. Certificates can be critical to enabling conduct of essential research on sensitive topics, such as effective interventions to curb the opioid epidemic or reduce HIV transmission among minority youth. Nevertheless, there have been criticisms about Certificates and their use on several grounds. For example, researchers and institutional review boards (“IRBs”) may lack sufficient knowledge about them and, therefore, may not consider using them in studies for which they would be appropriate. In contrast to other protections, such as Department of Justice Privacy Certificates, Certificate protections were not automatically extended to these studies, but instead required an application. In addition, the concept of identifiable data had not kept up with technological changes that may allow for reidentification of data previously considered unidentifiable. Although a researcher who obtained a Certificate could use it to resist a legal demand for identifiable data, little was known about the actual effectiveness of the protection provided.

The 21st Century Cures Act substantially revises the Certificates authorizing statute, and many of the changes are directly responsive to the criticisms that have been raised. Significantly, the Secretary of the Department of Health and Human Services (“HHS”) must issue Certificate protection to federally funded research involving identifiable, sensitive research data, and the National Institutes of Health (“NIH”) will automatically include such protections to research it funds. Non-federally funded researchers can continue to apply for Certificate protection. The definition of identifiable has been expanded to include data “for which there is at least a very small risk” of identification. Certificates will now not only protect against compelled disclosure, but also render protected data inadmissible in legal proceedings without participant consent. In addition, voluntary disclosure is no longer authorized, but there is now a broad exception for disclosure as required by federal, state, and local laws. In this paper, based on our previous research on Certificates, we critically evaluate the 21st Century Cures Act's Certificates revisions and their positive and negative impact on the dual goals of facilitating important, sensitive research while maximally protecting individual research participants.

Signed into law in 2016, the landmark 21st Century Cures Act is as complex as it is divisive. For some stakeholders, including patient groups and representatives of regulated industries, the Act represented a major leap forward in pharmaceutical innovation, human subjects protections, and numerous other provisions. For other observers, this legislation was characterized as a major rollback in important regulations, which would leave patients worse off and the payers holding the bag. The one element of the Act that was relatively uncontroversial covered a number of provisions related to addressing the opioid crisis.

This was by design. Provisions related to this issue were not part of the original legislation and were added to win over additional members of Congress who needed to be brought along to support the legislation. Many of the statute's provisions were intertwined with the Comprehensive Addiction Recovery Act (“CARA”) passed previously, but that legislation was stripped of much of its funding for opioid crisis response.

By the time this article is published, our collective memory of the school shooting in Parkland, Florida could have faded or, even worse, been superseded by another mass shooting. Although details are still sparse, the perpetrator appears to be a 19-year-old man with a well-documented history of behavior disturbing enough to invoke referrals to mental health treatment, but not so disturbing as to warrant either commitment or even arrest. Unfortunately, the picture presented is one most familiar in the public imagination of how people with mental illness interact with the criminal justice system. In actuality, the violence of the perpetrator's crime makes him very untypical of the vast majority of people with mental illness who are no more likely to be violent than any other member of the general public.

This Article will first describe the current situation in which people with mental illness have become part of the growing mass incarceration problem in the United States.

Drug development prior to 1800 was based almost completely on observational trial and error. The earliest known exception was a controlled drug trial conducted by James Lind in 1747 on an English ship to show the effectiveness of citrus fruit in the treatment of scurvy. Clinical tests, but not concurrent comparative trials, were conducted by Charles Maitland in 1722 in London to show the effectiveness of variolation in preventing smallpox, and a controlled drug trial was conducted by Edward Jenner in London in 1796 to show the effectiveness of material taken from cowpox sores of young milkmaids (later called smallpox vaccine) in preventing smallpox. In 1775, William Withering learned from an elderly woman herbalist in Shropshire, England about her use of the Foxglove plant (whose active ingredient Withering later determined to be digitalis) in treating heart disease, and in 1785 published the results of his treatment of 158 patients with the drug, but he did not conduct a controlled study.

Mental health is currently one of the most expensive health care issues. The cost of treating mental illness’s effects not only impacts the health care industry as a whole, but also imposes indirect costs on businesses through absenteeism, lower productivity, and reduced earnings. Mental illness, and the effects of mental illness, costs the U.S. economy several billion dollars in losses every year, with predictions suggesting that these costs will only continue to rise in the next two decades. Between 2006 and 2009 alone the costs of mental health care rose from approximately $57 billion to more than $150 billion. These numbers will likely be exacerbated due to the mental health problems that are continuing to rise within the United States as teenagers and adolescents are experiencing mental illness at escalating rates. Despite the rapid growth of mental illness, mental health coverage has not been expanding to meet the increasing demand for treatment. It is estimated that about 28% of the U.S. population has a diagnosable mental illness, even though only 8% actually seek treatment.