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January 05, 2017

New “21st Century Cures” LegislationSpeed and Ease vs Science

Author Affiliations
  • 1Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
JAMA. Published online January 5, 2017. doi:10.1001/jama.2016.20640

The 21st Century Cures Act was signed into law in December 2016. Praised by its advocates as a means of speeding drug development, the act covers several areas, but the provisions related to the US Food and Drug Administration (FDA) will be among the most problematic and potentially important. An earlier version was passed with a wide margin by the House of Representatives in July 2015; it contained sweeping measures to permit manufacturers to submit less rigorous data to the FDA for approval of drugs and devices, and it recommended annual increases to the National Institutes of Health (NIH) budget of approximately 3% per year for 3 years as well as approximately $8.75 billion over 5 years in additional support.1 Further progress on the bill stalled for about a year until it was taken up again in the congressional session after the recent election.

The revised legislation passed quickly through both houses of Congress in November and December 2016. Recommendations for NIH funding increases were maintained at approximately 3% per year for 3 years, but the additional funding directed to the NIH was decreased to approximately $480 million per year over 10 years on average. However, the funding increases were not guaranteed, with each year subject to new budgetary appropriation. Several other potentially useful sections unrelated to drug development were added to the bill, including $1 billion in grants to states to address opioid misuse and provisions to fund and reorganize mental health care delivery; the law also makes minor adjustments to the health information technology infrastructure and Medicare payment systems. Since 2007, new legislation with budgetary implications has been required to contain provisions for funding the programs it proposes. For the 21st Century Cures Act, support is to come from sale of some of the nation’s Strategic Petroleum Reserve as well as reducing the budget allocated to the Prevention and Public Health Fund included in the Affordable Care Act. The Prevention and Public Health Fund supports local, state, and federal community and clinical prevention programs, such as curbing tobacco use and increasing access to preventive services.

Restoring adequate funding to the NIH is probably the most cost-effective way to encourage the development of transformative therapeutics, because the support it provides to academic centers makes possible much of the fundamental research that leads to new drugs.2 The proposed increase in NIH funding, if it occurs, would help address that in inflation-adjusted dollars, between 2003 and 2015 the NIH actually lost 22% of its capacity to fund research because of budget cuts and sequestration.3 The restored NIH support will be particularly important at a time of reduced research spending by the pharmaceutical industry: inflation-adjusted expenditures by industry in this area decreased 0.6% from 2004 to 2012, following an increase of 6.8% from 1994 to 2004.4 The new dollars for the NIH are to be focused on certain areas, such as the Brain Research for Advancing Innovative Neurotechnologies Initiative, that are closely tied to drug development.

Some of the most problematic aspects of the original House of Representatives version of the legislation were omitted in the final version, including the plan for the FDA to approve medical devices on the basis of nonstandard assessments such as registries, clinical experience, and case series. However, the version signed into law retained several provisions designed to reduce the amount and rigor of clinical testing required before new drugs and devices can be approved for use. These changes are based on the foundational misconceptions that the FDA standards for approval are too demanding and thus keep valuable new treatments from the US public and needlessly increase the cost and duration of drug and device development. In this respect, the law is a solution to a problem that mostly does not exist.5

Among the most concerning sections of the new law are components that address the types of data that manufacturers will be able to use to gain FDA approval of new products or additional indications for existing products. One section directs the Secretary of Health and Human Services to qualify “drug development tools” to facilitate new drug approval. These include biomarkers, surrogate measures, other assessments, and “any other method, material or measure that the Secretary determines aids drug development.” Another provision instructs the Secretary to develop pathways to facilitate submission of “patient experience” information in regulatory decision-making. A third requires the Secretary to establish a program to use “real world evidence”—observational data arising from routine clinical use, rather than prospectively collected data from randomized controlled trials—to support the approval of new uses of existing drugs.

In fact, most of these data elements are already used by the FDA, with about half of all new drugs now approved on the basis of biomarkers and other surrogate measures.5 Overreliance on such measures has recently led to approval of treatments for muscular dystrophy, tuberculosis, and metastatic breast cancer. When biomarkers used as the basis for drug approval are not rigorously validated, they may not actually predict patient benefit, can mislead physicians about whether a drug works, and have the potential to expose patients to poorly effective treatments or unanticipated adverse effects.6 These sections of the bill increase the probability that insufficiently tested biomarkers could be “qualified” under orders from the Secretary. Remarkably, scientific merit is not a mandatory component; instead, the act says, “The Secretary shall determine whether to accept a qualification submission based on factors which may include the scientific merit of the qualification submission” [emphasis added]. Use of such biomarkers and surrogate measures is further encouraged in another section of the statute that instructs the FDA to “maximize the use” of these assessment tools in approving genetically targeted therapies for rare diseases, which could undermine the role of more demanding trials that assess actual clinical outcomes. These conditions now include large numbers of patients with malignancies that have specific tumor markers or genotypes. Similarly, patient-reported outcomes, which can provide important insights about symptom relief, are commonly measured in pivotal trials, but the placebo effect renders their use outside double-blind randomized trials potentially misleading.

The FDA is currently developing guidance on the various uses of so-called real-world evidence,7 which is often drawn from health care claims data. In the new law, this evidence is broadly defined to include any data regarding the “usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials,” and its prominent inclusion as a possible determinant of approval will add congressional pressure on FDA reviewers and managers to rely more heavily on these nonstandard assessments rather than on objective clinical outcomes measured in randomized controlled trials.

The bill also creates a new “regenerative advanced therapy” designation, which allows a wide variety of products to undergo expedited development and review, including “cell therapy, therapeutic tissue engineering products, [and] human cell and tissue products.” But transformative products or those addressing unmet medical needs would already have qualified for expedited development and review. What the act adds is a clear congressional mandate to the FDA to use this designation; the Secretary will now be required to report to Congress annually on the agency’s progress in moving these criteria forward.

The new law also allows the FDA to approve new indications for existing drugs based on data summaries alone. At present, the FDA usually examines all data put forward to support drug approval, including supplemental indications. This herculean effort has proven necessary because manufacturers have sometimes been found (often through litigation) to summarize their data in ways that excessively emphasize benefits of their products and minimize risks. Here, too, Congress will require the FDA to report annually how many times the FDA has used this shortcut—an approach that could be more common if funding for the agency’s staff becomes more constrained in the years ahead.

Even though the 21st Century Cures Act does not formally change the basic need for manufacturers to provide evidence of safety and efficacy of their drugs and high-risk medical devices to the FDA, enactment of some of its provisions could harm the drug and device marketplace by encouraging the FDA to emphasize speed over science and rely on less rigorous data for the approval of new products and indications. Ironically, it was the establishment decades ago of FDA standards for demonstration of efficacy and safety that transformed the US pharmaceutical industry from purveyors of uncertain remedies into one of the most successful industries in the world. Lower standards will most benefit companies adept at “gaming the system” to achieve success in shorter, less costly studies using poorly validated biomarkers, at the expense of more scientifically and clinically minded manufacturers that attempt to demonstrate patient outcome benefits in longer, larger, more expensive trials. The rapid approval of a relatively ineffective drug may reduce incentives for manufacturers to develop truly innovative and effective therapies.

Apart from this legislation, the new presidential administration has stated its desire to deregulate as much of the US economy as possible, and initial Cabinet nominees have borne out these intentions. Along the same lines, the 2 candidates apparently being considered for the job of FDA commissioner have advocated for less FDA oversight of many aspects of new drug and device approvals; one even proposed approving drugs if they are not immediately toxic and then letting efficacy be determined in “the marketplace” through ad libitum use by physicians and patients. An antiregulatory ideology of new FDA and Department of Health and Human Services leadership, coupled with the elements of the 21st Century Cures Act that encourage use of less rigorous data to meet standards for approval, are a dangerous combination that could prove risky to patients as well as to the drug development enterprise.

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Article Information

Corresponding Author: Aaron S. Kesselheim, MD, JD, MPH, Brigham and Women’s Hospital, 1620 Tremont St, Ste 3030, Boston, MA 02120 (akesselheim@partners.org).

Published Online: January 5, 2017. doi:10.1001/jama.2016.20640

Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kesselheim reported serving on the FDA Peripheral and Central Nervous System Drugs Advisory Committee and receiving grants from the FDA Office of Generic Drugs and its Division of Health Communication. No other disclosures were reported.

Funding/Support: This work was supported by a grant from the Laura and John Arnold Foundation. Additional support was provided by the Engelberg Foundation. Dr Kesselheim is a Greenwall Faculty Scholar in Bioethics and is supported by the Harvard Program in Therapeutic Science.

Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript and the decision to submit the manuscript for publication.

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