Study: Extrapolation of drug indications from study populations by FDA is ‘common’

Regulatory NewsRegulatory News | 19 April 2022 |  By 

Extrapolation of indications in new drug approvals by the US Food and Drug Administration (FDA) to populations not originally studied in pivotal clinical trials is a common occurrence, according to a recent investigation published in JAMA Network Open.
Between 2015 and 2017, FDA extrapolated indications for 21 drugs a total of 23 times, Daniel Feldman, of the 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 colleagues said. Though the practice was known, it was unclear up to this point how often FDA used it, the authors noted.
“Extrapolation of a drug’s indications beyond information available from the pivotal trials on which approval was based is often necessary in the approval of new medications because preapproval trials cannot possibly cover all patient subpopulations, age categories, and comorbidities,” Feldman and colleagues wrote. “However, extrapolation of clinically limited data to generate broad official indications can sometimes extend past the bounds of what is plausible given the characteristics of patients studied in preapproval trials, potentially influencing the drug’s effectiveness and safety when used in routine practice.”
The authors compared the differences between patients enrolled in pivotal trials and the FDA indications for those drugs in 105 drugs that met inclusion criteria and were approved between 2015 and 2017. The investigators examined the basis for extrapolation, how often it happened, the category of disease and whether patients were using concomitant medication.
A total of 23 extrapolations occurred in 21 of 105 novel FDA drug approvals (20%) between 2015 and 2017, with 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 in 14 drugs, disease subtype in 6 drugs, and concomitant medication use in 3 drugs.
“Although such extrapolation may be justified at the time of regulatory approval, our findings also point to the importance of follow-up research to confirm the expected outcomes. It may be beneficial to incorporate formal post-approval surveillance, using both prospective trials and well-conducted observational studies, into the rollout of novel therapies for which such extrapolation has occurred to ensure better ascertainment of real-world effectiveness and safety,” the investigators wrote. “When such clinical extrapolation is necessary at the time of approval, its details should be made clear in the labeled indications for physicians and patients. Until that time, it would be useful for physicians to recognize that the FDA-approved indication alone may be insufficient information on which to decide whether a given medication will benefit a patient who may differ meaningfully from those studied in the clinical trials on which approval was based.”
In an invited commentary, Reshma Ramachandran, MD, MPP; and Joseph S. Ross, MD, MHS, of the Yale University School of Medicine, said the investigation was timely given the FDA’s recent approval of aducanumab as an Alzheimer’s disease treatment for patients with mild cognitive impairment, a situation where FDA used extrapolation without evidence of clinical benefit (RELATED: FDA approves aducanumab for use in Alzheimer’s disease, Regulatory Focus 07 June 2021).
Another example of FDA using extrapolation is when the agency approved sacubitril with valsartan for chronic heart failure with reduced ejection fraction, but the pivotal clinical trial enrolled patients with less severe heart failure. The authors of the commentary said that while extrapolation is clinically appropriate in certain scenarios, when it occurs without clear clinical rationale, it can “lead to confusion, as occurred when professional cardiovascular societies initially recommended use of sacubitril with valsartan only for patients with class II and III heart failure, despite the broader FDA approval.”
These decisions then affect stakeholders downstream, such as patients and payers, who are "faced with whether to pay for or reimburse the cost of drugs with broadened indications for use, or only for patients who are similar to those tested in the pivotal trials," they said.
A certain degree of flexibility is needed for FDA to expand the indication of approved drugs, Ramachandran and Ross noted, but “the rationale must be made clear to both patients and clinicians and be scientifically justified.”
“When such extrapolations are not clinically warranted,” they said, “the FDA should use additional safeguards to ensure alignment between the indication approvals and pivotal trial populations to reduce clinical uncertainty and ensure patients are prescribed treatments that are safe and effective.”



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