Harvard professors question aspects of 21st Century Cures Act

08-Jun-2015 - Last updated on 09-Jun-2015 at 13:08 GMT

The 21st Century Cures Act may actually offer the FDA too much discretion to approve drugs without conventional clinical trials, and in some cases “on the basis of less rigorous data,” two medicine professors from Harvard write in an editorial in the New England Journal of Medicine.

The bill, which passed the House Energy and Commerce committee unanimously and has yet to see any real political opposition, would boost the NIH’s budget by about $10bn over five years and would be a boon to CROs with a host of new clinical trial provisions.

However, Harvard professors Jerry Avorn and Aaron Kesselheim note that the bill may be trying to fix something that isn’t broken and that it “could lead” to drug and device approvals that are less safe or effective than current criteria would permit.

“An underlying premise of the bill is the need to accelerate approval for new products, but this process is already quite efficient,” the professors write, noting that the six to ten month time-periods for FDA approval are a sign of “an impressive turnaround for such complex assessments.” In addition, the authors say that one-third of new drugs are already approved on the basis of a single pivotal trial, while more than two-thirds of new drugs are approved on the basis of studies lasting six months or less.

Nonetheless, this House bill calls on the FDA “to consider nontraditional study designs and methods of data analysis to further speed approvals.” The authors note that adaptive trial designs and the use of Bayesian methods “hold promise in some kinds of evaluations, particularly in oncology.

“However, more problematic proposals include encouraging the use of ‘shorter or smaller clinical trials’ for devices and the request that the FDA develop criteria for relying on ‘evidence from clinical experience,’ including ‘observational studies, registries, and therapeutic use’ instead of randomized, controlled trials for approving new uses for existing drugs,” the authors say, adding that there’s “considerable evidence that these approaches are not as rigorous or valid as randomized trials in assessing efficacy.”

The bill would also encourage the FDA to rely more on biomarkers and other surrogate measures rather than actual clinical end points in assessing the efficacy of both drugs and devices.

The FDA already uses surrogate end points in about half of new drug approvals, the authors note and while “a drug's effect on a biomarker can make approval quicker and less costly, especially if the comparator is placebo, it may not always predict the drug's capacity to improve patient outcomes.”

The authors offer the example from 2013 when patients began receiving a new drug for tuberculosis approved on the basis of a randomized trial relying on a surrogate measure of bacterial counts in the sputum — even though patients given the drug in that trial had a death rate four times that in the comparison group, mostly from tuberculosis.

The authors also take issue with the way the bill would tinker with the informed consent process. The only time informed consent isn’t used is when it’s impossible to obtain or contrary to a patient's best interests, but a clause in the proposed law adds a new exception: studies in which “the proposed clinical testing poses no more than minimal risk” — which the authors call “a major departure from current human subject protections” as it is not clear “who gets to determine whether a given trial of a new drug poses ‘minimal risk.’”

In conclusion, the authors question what kind of an impact the bill may end up actually having on patients and physicians, noting that it “could actually bring back some of the problems we thought we had left behind in the 20th century.”