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Nonetheless, as introduced, the shown not to benefit patients. the most appropriate patients. If
21st Century Cures Act instructs Similarly, rosiglitazone (Avandia) passed in its current form, the
the FDA to consider nontraditional lowered glycated hemoglobin bill would also provide hospitals
study designs and methods of levels in patients with diabetes with a financial bonus for ad-
data analysis to further speed even as it increased their risk of ministering costly new but un-
approvals. Adaptive trial designs myocardial infarction. In 2013, proven antibiotics, which could
and the use of Bayesian methods patients began to receive a new encourage their more widespread
hold promise in some kinds of drug for tuberculosis approved use. The bill gives the secretary
evaluations, particularly in oncol- on the basis of a randomized of health and human services the
ogy. However, more problematic trial relying on a surrogate mea- authority to expand this nontradi-
proposals include encouraging sure of bacterial counts in the tional approval pathway to other
the use of shorter or smaller sputum even though patients drug categories as well, if the
clinical trials for devices and given the drug in that trial had a public health would benefit from
the request that the FDA develop death rate four times that in the expansion.
criteria for relying on evidence comparison group, mostly from The 21st Century Cures Act
from clinical experience, includ- tuberculosis.4 These provisions in goes still further in altering the
ing observational studies, regis- the legislation would not imme- requirements for approving med-
tries, and therapeutic use instead diately change FDA approval stan- ical devices an area long criti-
of randomized, controlled trials dards, but they would give the cized for lack of rigor as com-
for approving new uses for exist- agency greater discretion, backed pared with drug evaluations,5
ing drugs. Although such data by congressional support, to ap- though regulatory oversight has
can provide important informa- prove drugs on the basis of less improved in recent years. As pro-
tion about drug utilization and rigorous data. posed, the new law would re
safety once a medication is in use, The proposed legislation would define the evidence on which
there is considerable evidence that make immediate changes with high-risk devices can be approved
these approaches are not as rigor- respect to new antibiotics and to include case studies, registries,
ous or valid as randomized trials antifungals by enabling their ap- and articles in the medical litera-
in assessing efficacy. proval without conventional clin- ture, rather than more rigorous
The bill would also encourage ical trials, if needed to treat a clinical trials. Another section
the FDA to rely more on bio- serious or life-threatening infec- would allow device makers to
markers and other surrogate mea- tion in patients with an unmet pay a third-party organization to
sures rather than actual clinical medical need. In place of proof determine whether the manufac-
end points in assessing the effi- that the antimicrobial actually turer can be relied on to assess
cacy of both drugs and devices. decreases morbidity or mortality, the safety and effectiveness of
The FDA already uses surrogate the FDA would be empowered changes it makes to its devices,
end points in about half of new toaccept nontraditional efficacy in place of submitting an appli-
drug approvals.3 Some biomark- measures drawn from small stud- cation to the FDA. Thus certified
ers are accurate predictors of ies as well as preclinical, phar- by the external company, a de-
disease risk and can be useful macologic, or pathophysiologic vice maker would be authorized
measures of the efficacy of a evidence; nonclinical suscepti- to continue to assess its own
new drug (such as low-density bility and pharmacokinetic data, products on an ongoing basis.
lipoprotein cholesterol for statins). data from phase 2 clinical trials; Informed consent by patients
But though a drugs effect on a and such other confirmatory evi- in drug trials has traditionally
biomarker can make approval dence as the secretary [of health been sacrosanct, with exceptions
quicker and less costly, especially and human services] determines made only when consent is im-
if the comparator is placebo, it appropriate to approve the drug. possible to obtain or contrary to
may not always predict the drugs Antimicrobials approved in this a patients best interests. But an-
capacity to improve patient out- manner would carry disclaimers other clause in the proposed law
comes. Bevacizumab (Avastin) de- on their labeling, but there is no adds a new kind of exception:
layed tumor progression in ad- evidence that such a precaution studies in which the proposed
vanced breast cancer but was would restrict prescribing to only clinical testing poses no more
than minimal risk a major Over the past 80 years, this This article was published on June 3, 2015,
at NEJM.org.
departure from current human countrys regulatory approach has
subject protections. It is not clear embraced steadily improving cri- 1. 21st Century Cures Act. May 19, 2015
who gets to determine whether a teria for accurately assessing ther- (http://docs.house.gov/meetings/IF/IF00/
given trial of a new drug poses apeutic efficacy and risk. Patients 20150519/103516/BILLS-1146ih.pdf).
2. Kesselheim AS, Tan YT, Avorn J. The roles
minimal risk. and physicians would not benefit of academia, rare diseases, and repurposing
Embedded in the language of from legislation that instead of in the development of the most transforma-
the 21st Century Cures Act are catapulting us into the future, tive drugs. Health Aff (Millwood) 2015;34:
286-93.
some good ideas that could could actually bring back some of 3. Downing NS, Aminawung JA, Shah ND,
An audio interview streamline the devel- the problems we thought we had Krumholz HM, Ross JS. Clinical trial evi-
with Dr. Avorn is opment and evalua- left behind in the 20th century. dence supporting FDA approval of novel
available at NEJM.org therapeutic agents, 2005-2012. JAMA 2014;
tion of new drugs and 311:368-77.
Disclosure forms provided by the authors
devices; its call for increased NIH are available with the full text of this article 4. Avorn J. Approval of a tuberculosis drug
funding may prove to be its most at NEJM.org. based on a paradoxical surrogate measure.
JAMA 2013;309:1349-50.
useful component. But political 5. Dhruva SS, Bero LA, Redberg RF. Strength
forces have also introduced other From the Program on Regulation, Thera- of study evidence examined by the FDA in
provisions that could lead to the peutics, and Law (PORTAL), Division of premarket approval of cardiovascular devic-
Pharmacoepidemiology and Pharmacoeco- es. JAMA 2009;302:2679-85.
approval of drugs and devices
nomics, Department of Medicine, Brigham
that are less safe or effective than and Womens Hospital and Harvard Medi- DOI: 10.1056/NEJMp1506964
existing criteria would permit. cal School, Boston. Copyright 2015 Massachusetts Medical Society.