FDA Indication Extrapolations—Allowing Flexibility While Providing Greater Clarity

On June 7, 2021, the US Food and Drug Administration (FDA) granted accelerated approval to aducanumab for the treatment of Alzheimer disease, of any disease severity, despite the pivotal clinical trials that supported its approval having tested the drug only in patients with mild disease.¹ After substantial outcry, the agency amended the drug label, clarifying its indication for use only for patients with mild cognitive impairment or mild dementia stage of disease and noting that safety and efficacy had not been established for patients with earlier or later stages of disease.² Nevertheless, the initially overbroad indication approval by the FDA raised a question: How often does the FDA extrapolate findings from pivotal clinical trials of treatments for use in a broader population of patients?

Feldman and colleagues³ address this timely question by examining the frequency of extrapolation of pivotal trial evidence from the studied population to those included within the final FDA-approved drug label, defining extrapolation as the FDA approving an indication for use in a broader population than was studied in the pivotal trials by disease severity, disease subtype, or concomitant medication use. In their cross-sectional analysis of 113 new drugs and biologic medicines approved by the FDA between 2015 and 2017, the investigators found that, for 20% of the drugs (n = 22), there was extrapolation of the approved indication beyond the pivotal trial population.

Most commonly, extrapolation was related to disease severity, with the FDA approving the use of a new drug or biologic agent for patients with either greater or lesser disease severity than those enrolled in the pivotal clinical trials.³ For example, the FDA approved sacubitril with valsartan for the treatment of any patient with chronic heart failure with reduced ejection fraction, although the pivotal trials that supported approval tested the drug predominantly in patients with less severe heart failure; approximately three-quarters of trial participants had class I or II heart failure, and less than 1% had class IV heart failure.

Differences between FDA-approved indicated populations and the studied pivotal trial populations may be clinically appropriate, particularly when the FDA narrows the indication approval based on subgroup analyses from the pivotal trials. Alternatively, broadening the indication may make sense when clinical evidence suggests that certain pivotal trial findings can be applied to populations excluded from the trials. However, as with aducanumab and sacubitril with valsartan, the FDA has extrapolated approved indications for use without clear clinical rationale. Such action 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.⁴

Patients and payers are then 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. For instance, our research group’s recent study⁵ illustrated the outcome associated with the broad FDA indication approval for sacubitril with valsartan, as it accounted for a large part of the estimated 280% increase in out-of-pocket payments between 2009 and 2019 for Medicare beneficiaries receiving recommended treatment for heart failure with reduced ejection fraction.

These findings also highlight the importance of pivotal trial inclusion and exclusion criteria for informing discussions of drug safety and efficacy in clinical practice. In the case of aducanumab, Anderson et al⁶ found that more than 92% of Medicare beneficiaries with Alzheimer disease and related disorders and 85% with mild cognitive impairment would have been excluded from the pivotal trials that supported the drug’s FDA approval based on pivotal trial exclusion criteria. Moreover, although Feldman and colleagues³ addressed extrapolation of approvals with respect to disease severity, disease subtype, and concomitant medication use, they acknowledge that they did not examine the implications of underrepresentation of minority populations in pivotal trials, as reported by Downing et al.⁷ Again, FDA approval of aducanumab was illustrative, enrolling only 19 participants (0.6%) who identified as being of Black race, of whom only 6 were randomized to receive the FDA-approved treatment dose despite Alzheimer disease incidence rates being twice as high in older Black patients compared with older White patients.⁸

To limit clinical uncertainty resulting from extrapolation of pivotal trial evidence, the FDA could simply ensure that the approved indications match those of populations tested within pivotal clinical trials. However, the FDA should have some flexibility to avoid limiting patient access to potentially promising drugs where there is evidence that extrapolation may be reasonable. For example, FDA approval of rolapitant for the prevention of delayed nausea and vomiting associated with emetogenic chemotherapy, tested only in patients with highly emetogenic chemotherapy, could be considered for use in other populations because it is a second-generation medication with predecessors approved for moderately and highly emetogenic therapy.⁹ With additional input from practicing clinicians and patients, the FDA could develop guidance regarding when such extrapolation may be appropriate.

To better prevent label extrapolation, the FDA could offer input on trial inclusion and exclusion criteria before pivotal trial enrollment to ensure that trial populations better reflect the patients most likely to use the approved treatments. In addition, when the FDA approves a drug with an extrapolated indication for use, the agency could include language on the drug label explicitly stating that the approved indication had been extrapolated from the pivotal trial population as well as the type of extrapolation and justification for doing so. Such language should include the caution that there could be serious consequences for patients if the safety or efficacy of the drug differs between patient populations approved for use and those included and excluded from pivotal trials. This clarity may aid clinical decision-making in determining whether specific patients should be prescribed the drug if they are not represented among the pivotal trial participants, as well as inform payer decisions.

In addition, when the FDA extrapolates pivotal trial findings to a broader population for use, the agency should condition such approvals with postmarketing studies, requiring the sponsor to confirm clinical efficacy and safety within those populations that were not tested in pivotal trials. Failure to complete or initiate these mandated studies in a timely manner would result in the FDA withdrawing the broader indication approval, similar to the accelerated approval pathway.¹⁰ Payers could also mitigate potential consequences of extrapolation by either limiting coverage of these drug to tested populations or only in settings where further data on clinical efficacy and safety are collected.

Flexibility of the FDA in broadening or narrowing the indication approval from pivotal trial populations may occasionally be clinically warranted. Nonetheless, the rationale must be made clear to both patients and clinicians and be scientifically justified. When such extrapolations are not clinically warranted, 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.

Published: April 19, 2022. doi:10.1001/jamanetworkopen.2022.7961

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Ramachandran R et al. JAMA Network Open.

Corresponding Author: Joseph S. Ross, MD, MHS, Section of General Internal Medicine, Yale University School of Medicine, PO Box 208093, New Haven, CT 06520 (joseph.ross@yale.edu).

Conflict of Interest Disclosures: Dr Ramachandran reported that she sits on the boards of the American Medical Student Association Foundation and Universities Allied for Essential Medicines North America (unpaid). She also leads the Doctors for America Food and Drug Administration Task Force (unpaid), which is supported by Arnold Ventures. Dr Ross reported receiving grants from Food and Drug Administration, Johnson and Johnson, Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality, the National Institutes of Health National Heart, Lung, and Blood Institute, and the Laura and John Arnold Foundation outside the submitted work. Dr Ross is an expert witness at the request of Relator's attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc.

Disclaimer: The views expressed in this commentary are those of the authors and do not necessarily reflect those of the US Department of Veteran Affairs or the US government.