Posted on April 19, 2022 | By
According to a recent survey published in Open JAMA Network.
Between 2015 and 2017, the FDA extrapolated the indications of a total of 21 drugs 23 times, Daniel Feldman, Program on Regulation, Therapeutics, and Law, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School in Boston, and his colleagues said. Although the practice is known, it was not clear until now how often the FDA uses it, the authors noted.
“Extrapolation of a drug’s indications beyond the information available from the pivotal trials on which the approval was based is often necessary in the approval of new drugs because pre-approval trials cannot cover all patient subpopulations, age categories, and comorbidities,” Feldman and colleagues wrote. “However, the extrapolation of clinically limited data to generate broad official indications can sometimes exceed the limits of what is plausible given the characteristics of the patients studied in pre-approval trials, potentially influencing efficacy and safety. of the drug when used in routine practice.”
The authors compared differences between patients enrolled in pivotal trials and FDA indications for these drugs in 105 drugs that met inclusion criteria and were approved between 2015 and 2017. Investigators reviewed the basis of extrapolation, frequency with which it occurred, disease category and whether patients were taking concomitant medications.
A total of 23 extrapolations occurred in 21 of 105 FDA new drug approvals (20%) between 2015 and 2017, with the FDA using extrapolation 12 times in 2015 (29%), 3 times in 2016 (15 %) and 6 times in 2017 (14%). The most common reason for extrapolation was disease severity for 14 drugs, disease subtype for 6 drugs, and concurrent drug use for 3 drugs.
“While such extrapolation may be warranted at the time of regulatory approval, our results also underscore the importance of follow-up research to confirm expected results. It may be beneficial to incorporate formal post-approval monitoring, using both prospective trials and well-conducted observational studies, in the deployment of new therapies for which such extrapolation has occurred to ensure better determination of real-world efficacy and safety,” the researchers said. wrote. “Where such clinical extrapolation is required at the time of approval, its details should be clearly stated in the labeled indications for physicians and patients. Until then, it would be helpful for physicians to acknowledge that the indication approved by the FDA alone may constitute insufficient information to decide whether a given drug will benefit a patient which may differ significantly from those studied in the clinical trials on which the approval was based.”
In a guest comment, Reshma Ramachandran, MD, MPP; and Joseph S. Ross, MD, MHS, of Yale University School of Medicine, said the survey was timely given the recent FDA approval of aducanumab as a treatment for Alzheimer’s disease for patients with mild cognitive impairment, a situation where the FDA used extrapolation without evidence. of clinical benefit (RELATED: FDA approves use of aducanumab in Alzheimer’s disease, Regulatory guidance June 07, 2021).
Another example of FDA extrapolation is when the agency approved sacubitril with valsartan for chronic heart failure with reduced ejection fraction, but the pivotal clinical trial enrolled heart failure patients. less severe cardiac. The comment’s authors said that while extrapolation is clinically appropriate in some scenarios, when it occurs without a clear clinical rationale, it can “lead to confusion, as happened when professional cardiovascular societies initially recommended the use of sacubitril with valsartan only for patients with Class II. and Heart Failure III, despite broader FDA approval.
These decisions then affect downstream stakeholders, such as patients and payers, who are “faced with the question of whether to pay or reimburse the cost of drugs with expanded indications for use, or only for patients similar to those tested in the pivotal trials”. they said.
Some degree of flexibility is needed for the FDA to expand the indication of approved drugs, Ramachandran and Ross noted, but “the rationale must be clear to patients and clinicians and be scientifically substantiated.”
“When such extrapolations are not clinically warranted,” they said, “FDA should use additional safeguards to ensure alignment between indication approvals and pivotal trial populations to reduce clinical uncertainty. and to ensure that patients are prescribed safe and effective treatments.”
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