The 21st Century Cures Act, a $6.3 billion bill signed into law by U.S. President Barack Obama in December 2016, significantly amends the Federal Food, Drug and Cosmetic Act, the Public Health Service Act, and other federal laws. At a time when drug access and pricing have taken center stage across political, pharmaceutical industry, and consumer arenas, the passage of the Act—which increases appropriations and legislative muscle to advance drug development—was a watershed moment. An overwhelming number of congressional members have expressed their support for the Act.

The Act mandates appropriation of funds and resources, aimed at accelerating drugs from discovery to the public, but it does not specify enforcement of the timing and usage of such funds. The Act also describes measures expediting the drug approval process and grants the U.S. Food and Drug Administration (FDA) authority to implement these strategies. These approaches include: renewing the priority review voucher program for pediatric rare cancers, which was set to expire in 2016; creating a new priority review voucher program for medical threat countermeasures; and specifying a so-called breakthrough designation status with expedited review for those medical devices addressing an unmet medical need. Together, these programs are vital because they shift the focus from drug development for chronic and preventable conditions to advances that address urgent, life-threatening diseases, and conditions that cause imminent harm to public health.

Despite its attractive elements, the Act is a myopic and misplaced attempt at allocating the appropriate resources to improve the health care system. Its statutory provisions are primed to further industry interests and benefit drug development at the expense—and to the detriment—of the public’s health. Amidst a groundswell of challenges to pricing and affordability, and growing concerns about unsustainability of current pricing trends, passage of the Act will only further shift the balance of power to pharmaceutical manufacturers. The Act also raises grave ethical considerations because it prevents actionable policy to ensure a greater number of uninsured or underinsured individuals have the ability and the means to access life-saving therapies.

The notable and pervasive provisions of the Act that are most likely to affect public health may be grouped into two categories: 1) measures intended to expedite drug development and market approval, and 2) mandates allowing for new sets of criteria, or surrogate parameters, for clinical effectiveness. These legislative measures are of critical relevance for patients with life-threatening disease and who are, consequently, at the mercy of skyrocketing market-driven price points that often seem arbitrary.

Drug Approval: Is faster better?

To begin, consider how the Act expedites the drug approval process. In describing drug development tools (H.R. 34, Section 3011), the FDA is mandated to establish a qualification process that may include a biomarker, outcome measures, and any other material that can aid the agency in reviewing and expediting the review process. This approach is a drastic shift from the traditional model of evidence-based approval grounded in empirical data from clinical studies. Traditionally, the FDA has placed the evidentiary bar high, with the underlying rationale of prioritizing safety and efficacy, requiring sponsors of new drugs to demonstrate therapeutic equipoise in seeking institutional review board (IRB) approval for human clinical trials. The process of balancing risks and benefits is designed to ensure that studies employ a control arm, which may be a placebo, the standard of care, or no intervention at all. The burden to demonstrate superior efficacy or, at the very least, non-inferiority is placed on the drug sponsor. As a result, the majority of new drug approvals rely on the rigors of prospective, randomized, and double-blind Phase 3 studies [1] to assess efficacy and safety of drugs.

The shift to permitting surrogate markers in the interest of expedited review could trigger sponsors to develop outcome parameters of sub-clinical standards, with little to no statistical bearing on clinical efficacy. Validating non-clinical factors, as part of the approval criteria, casts doubt on the clinical evidence and establishes a dangerous precedent that may flood an already crowded, undifferentiated drug market place, without providing clinical benefit to consumers.

A second set of amendments similarly devalues the prominence of statistically significant outcomes measures by instead placing value on patient data and post-marketing claims analyses.  In particular, these provisions of the Act grant authority to consider data that

“(1) are collected by any persons (including patients, family members and caregivers of patients, patient advocacy organizations, disease research foundations, researchers, and drug manufacturers; and (2) are intended to provide information about patient’s experiences with a disease or condition […] including the impact […] on patients’ lives [and] patient preferences with respect to treatment of such disease or condition” (H.R. 34, Section 3001). 

Measures relating to patient experience represent individual experiences that may not be generalizable, or applicable, to the larger population, let alone patients with unique genotypic profiles or disease characteristics. The Act’s approach presupposes that the effects and applications of a drug on one patient can be extrapolated for others. Yet, recent advances in solid and blood tumor biology (e.g., non-small-cell lung cancer, multiple myeloma) have demonstrated that tumors are heterogeneous in nature and that different patients have different tumor features. Using the Act’s criteria in regulatory decision-making, therefore, risks—and may even ensure—an overreliance on subjective data, by allowing manufacturers to replace objective clinical research with other, less reliable forms of data, in order to accelerate pre-market approval for new drugs. Removing the burden of statistically significant clinical outcomes measures from drug sponsors effectively undermines the significance of safety and efficacy signals that can only be ascertained through rigorous clinical trials. A provision of the Act attempts to address this issue by mandating that the FDA publish how the new types of data permitted under the Act are used, but this requirement would not take effect until 2021, years after the new provisions would have been used to gain approval for new drugs.

“Real-World Evidence” at What Cost?

A third provision of the Act affects drug trial design by placing heavy dependence on data that are not derived from clinical trials, termed real-world evidence (RWE). The law specifically defines RWE as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.” RWE and the data from which it is derived, relies on information ascertained from clinical charts, insurance claims, and hospital records. In addition to the ethical hazards of releasing and distributing patient information—albeit de-identified—dependence on RWE for drug approval purposes also enables managed care organizations (MCOs) and other payer entities to use economic data to leverage policy for formulary inclusion/exclusion and drug coverage. Should RWE make its way into FDA-approved product labeling, payer decision makers would be armed with financial policies restricting members from accessing life-saving therapies. Likewise, creation of pathways that require step-edits and other cost-management measures are poised to place greater pressure on clinicians to prescribe sub-optimal therapeutic options that fail to meet the clinical needs of their patients. This amendment, then, on balance stands to benefit pharmaceutical companies who are incentivized to sacrifice the scientific rigor associated with clinical studies for now permissibly less reliable data. Also benefiting from this Act are health care payers who will have access to financial metrics through RWE and may use such data in aggressive cost-containing coverage policies.

Empowering the Already Powerful

Heavy reliance on outcomes information poses a real threat to patient access. Previously, section 114 of the United States Food and Drug Administration Modernization Act of 1997 (FDAMA 114) specifically regulated dissemination of health economic information by pharmaceutical companies to payers that decide which drugs are covered under their policy. Historically, the FDA has not provided detailed guidance on FDAMA 114. The amended provision in the Act now grants the pharmaceutical industry greater flexibility in engaging MCOs and their decision makers with information that frames the value of therapies through the lens of economic and cost-saving factors, rather than centrally on efficacy-based rationales. Pharmaeconomics certainly plays a fundamental role in evaluating cost effectiveness, as seen in frameworks developed the Institute for Clinical and Economic Review (ICER). These should not, however, downplay or disregard the clinical effectiveness of a drug and the therapeutic relevance for patients. 

The Act further prioritizes the interests of payers over those of patients by making poor, if any, attempts to alleviate the financial burden on patients by amending provisions for expanded access to investigational drugs. While it is a laudable effort to mandate that manufacturers play their part in providing greater access to investigational drugs to a greater number of individuals in need, the Act does not achieve it. Specifically, the statutory language requires manufacturers to make public their policies for expanded access to investigational drugs, but it is not “a guarantee of access to any specific investigational drug by any individual patient” (Section 3032). Equally concerning, the lack of agency authority to mandate allocation of funding to those who face financial hardship only further propels an industry agenda to escalate development of drugs at prices that place greater economic strain on the health care system.

"Amidst a groundswell of challenges to pricing and affordability, and growing concerns about unsustainability of current pricing trends, passage of the Act will only further shift the balance of power to pharmaceutical manufacturers."

Together, these amendments paint a bleak future for individual access to life-saving therapies, as manufacturers would be incentivized to develop and leverage market dynamics to price their product at a premium. Consider the headline-making decision by Turing Pharmaceuticals in 2015 to increase the price of the antimicrobial agent Daraprim by 500 percent. This move alone should have served as a cautionary tale for lawmakers.

Critics of this projection are quick to argue that the free-market will allow others to compete with more attractive prices. But free-market equilibrium is unlikely to occur. Even the recent availability of biosimilar products has failed to trigger drastic pricing adjustments for the original products.

However well-intentioned, the 21st Century Cures Act exposes a series of ethical fissures and limitations for drug access. In an effort to incentivize drug development and expedite market entry, lawmakers turned a blind eye to pressing public health concerns, namely access to medications, drug safety and efficacy. Greater appropriation of funds to the NIH may help support research and clinical development, but this funding would be of little use if the fruits of scientific progress are unsafe or are financially inaccessible. The Act falls short of empowering the FDA to protect the public, while granting greater latitude to the pharmaceutical industry, which is already financially empowered and now stands to benefit even more.

Jeffrey Gruenglas, MA, MBE ’17 can be reached at BioethicsJournal (at) hms.harvard.edu.

 

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