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Introduction
The United States Food and Drug Administration (FDA) authorizes the use of already-approved drugs for new clinical indications through Supplemental New Drug Applications (sNDAs).Reference Wang and Kesselheim1 Supplemental indication approvals may extend the authorized use of a drug far beyond the initially-approved indication, and supplemental indication approvals have implications for inclusion in clinical practice guidelines, insurance coverage decisions, and other organizational standards that influence clinical practice.Reference Berndt, Cockburn and Grépin2 Despite being quite common, regulatory decision-making for supplemental indications is less well-understood than that for new drugs. Both processes share some common features, like the requirement for demonstrated efficacy and safety of proposed use. Unlike new drugs, however, already-approved drugs can be prescribed off-label by clinicians for any indication at any time, even without formal regulatory review, and even if a supplemental indication is submitted but not approved. Given the immediate actionability of information discussed for supplemental indications, the importance of transparency in this domain of regulatory decision-making may be heightened compared to new drug approvals.
Clinicians and researchers have traditionally relied on FDA’s New Drug Application (NDA) review documents to understand the basis on which new drugs were approved. However, while federal law requires that FDA publicly release these review documents for NDAs, no such requirement exists for the release of review documents for sNDAs.3 One avenue through which the FDA does release information regarding pending sNDAs is through its advisory committees, groups of external experts who are convened by the agency to discuss questions pertaining to proposed actions, particularly those viewed as scientifically or politically contentious.Reference Moffitt4 Though recent studies have found variations in the degree to which FDA is responsive to their advice, advisory committee voting aligns with final FDA decisions in most cases.Reference Smith5 Advisory committees can thus serve as a vehicle to increase transparency of FDA decision-making to health care providers, patients, and other stakeholders, a role highlighted during the COVID-19 pandemic when committee deliberations over new vaccines were widely publicized.Reference Gupta6
Because of the role of supplemental indications in expanding the market for and clinical use of new drugs, there is value to better understanding regulatory decision-making for new indications and how the process may differ from that of new drugs. We conducted a qualitative study of all new sNDAs and sBLAs for supplemental indications reviewed by FDA advisory committees from 2008–2022, performing a thematic analysis of reasons cited for approval or non-approval. We focus on a subset of supplemental indications not eventually approved by the FDA, products that may nonetheless be prescribed for those uses without FDA labeling (“off-label”). Advisory committee analyses and deliberations regarding these indications are particularly salient as they may represent the most complete source of public information regarding benefits and harms to inform their use.
Study Data and Methods
Data
We obtained information on sNDAs and sBLAs discussed by advisory committees from January 2008 through December 2022 using the FDA Advisory Committee website.7 We reviewed all advisory committee meeting materials and included sNDAs and sBLAs if they discussed and voted on the approval of a supplemental indication. We excluded sNDAs and sBLAs submitted for the conversion of accelerated approvals to full approvals and for label changes such as new dosing or clinical study information. Using the Drugs@FDA database,8 we searched for the included supplemental indications by application number and indication name, including in our final sample only those supplemental indications that were not eventually approved.
Analysis
We characterized sNDAs and sBLAs using documents from the approval package and advisory committee minutes and transcripts, including year and name of advisory committee. We characterized sNDAs and sBLAs by drug type (small molecule or biologic) and indication type, which was defined as one of four categories: new claim (new disease area), modified claim (same disease area but different claim from existing approval), expanded population (same disease area and claim but different age or disease subgroup from existing approval), or over-the-counter (OTC) switch (same disease area and claim but switching from prescription to over-the-counter status). We also characterized sNDAs and sBLAs by regulatory features including prior history of approved supplemental indications, identified using the Drugs@FDA database; and use of orphan drug designation, identified using the Orphan Drug Designations Database.9
We used information within advisory committee transcripts to identify themes that arose during committees’ evaluations of supplemental indications that were not subsequently approved by FDA. These transcripts contain discussion between committee members and justification for their responses to voting questions. We identified a single voting question or two voting questions most representative of voting for approval, prioritizing questions in this hierarchy: (1) vote for the overall approval of a supplemental indication, (2) separate votes for efficacy and safety of the supplemental indication, used only if an overall approval vote was not available. Two investigators (ADZ, NC) abstracted relevant passages of advisory committee transcripts containing committee rationales for voting on these specific voting questions.
We performed thematic analysis to identify the range of themes arising in committees’ evaluations of supplemental indications that were not subsequently approved by FDA. Using the inductive approach of the constant comparative method,Reference Glaser10 three investigators (ADZ, JLS, JSR) independently reviewed and preliminarily coded committee members’ rationales for voting, continuously comparing each new observation to others coded in a theme. More than one theme could be identified for each vote. Through a negotiated consensus process involving these investigators, we then iteratively adjusted and recoded preliminary themes, combining themes when they shared essential properties, until we reached theoretical saturation, generating a single set of integrated themes and identifying a set of quotations to illustrate each theme.
Study Results
Supplemental Indication Characteristics
From 2008 through 2022, FDA advisory committees discussed a total of 84 sNDAs and sBLAs involving supplemental indications of approved drugs. Fifty-two (62%) were eventually approved, with 47 (56%) approved within 1 year of the advisory committee date. Thirty-two (38%) remained unapproved as of August 1, 2023, of which 27 (84%) had been viewed unfavorably by the advisory committee and 5 (16%) had been viewed favorably by the advisory committee but nonetheless not approved by the FDA. Use of advisory committees varied over the period, with a peak of 19 sNDAs and sBLAs discussed by advisory committees in 2009, and a low of 1 sNDA discussed by advisory committees in 2021 (Figure 1).
Outcomes of supplemental indications reviewed by a Food and Drug Administration (FDA) advisory committee, 2008-2022.
The most common type of supplemental indication was a new efficacy claim (n=54, 64%). (Table 1). The most common therapeutic area represented was oncology (n=16, 19%). A subset of supplemental indications involved orphan designations (n=9, 11%). A majority of supplemental indications discussed were for drugs that already had prior supplemental indications (n=44, 52%).
Characteristics of supplemental indications reviewed by Food and Drug Administration (FDA) advisory committees, 2008-2022
1 One supplemental indication was discussed at two separate advisory committee meetings and is counted twice.
2 Before 2015, the role of the Antimicrobial Drugs Advisory Committee was taken by two separate advisory committees, the Anti-Infective Drugs Advisory Committee and the Antiviral Drugs Advisory Committee. All three committees are included in this tally.
Voting Rationales: Efficacy and Safety Concerns
Consistent with FDA’s statutory charge, advisory committee members cited efficacy and safety as a rationale for approval or non-approval in every meeting involving a new supplemental indication that was not subsequently approved by FDA (Table 2). More specifically, concerns fell in two major categories: those in which committee members expressed reservations about the validity or magnitude of net benefit demonstrated by the presented data, and those in which they deemed the data insufficient or inconsistent enough to support a favorable decision.
Themes and sub-themes illustrating efficacy and safety concerns by FDA advisory committees voting on supplemental indications that were not subsequently approved, 2008-2022
Concerns About Magnitude of Net Benefit
Concerns about efficacy or safety that did not meet the threshold for approval dominated the discussion when committee members were asked to justify their vote. These concerns were often raised in relation to the magnitude of efficacy demonstrated for the drug, as for one proposed combination chemotherapy: “I didn’t see a role for the combination in terms of the limited clinical benefit.” In other cases, committee members identified safety signals as their predominant reason for voting against approval: “I just couldn’t justify voting yes for a drug that may cause higher-grade prostate cancers.”
Subthemes in the failure to demonstrate benefit also included concerns particular to sNDAs compared to their initial approvals. These included a failure for trials to reach the endpoint targeted by the sNDA, rather than an already-approved endpoint: “I believe that the drug does show signs of symptomatic effect in this … but the higher bar is whether it does anything for disease modification.” Another subtheme was a mismatch in the choice of population in which the sponsor tested the drug: “I do see a potential role for this drug … but I cannot use the currently available data to judge whether this drug is ready to be used in that population because that’s not specifically what they studied.”
Finally, a recurring subtheme salient to sNDAs seeking pediatric indications after an initial approval for an adult indication was the validity of extrapolation of efficacy from adult to pediatric populations, especially when this formed the basis of the sNDA for a pediatric indication for use. In many of these cases, committee members suggested trying to “craft a population” in which the drug could be appropriately used, especially if the perception of need for the drug was great.
Concerns About Insufficient or Inconsistent Data
More often, advisory committee members agreed that some degree of efficacy was demonstrated by the drug sponsors but challenged whether the supporting data was sufficient to meet the threshold of “substantial evidence of effectiveness and safety” required for approval. This was most evident in cases where only one trial was conducted or met this threshold: “The lack of two studies was compelling.” This was also often invoked in cases where the new indication sought to substantially expand the population of patients exposed to the drug compared to the initial indication, or where the expected exposure would be over a much longer period of time compared to the initial indication, in which cases committee members considered supporting trials’ enrollment or duration of follow-up to support their claims: “I still have a great deal of difficulty with a four-year study; how can I extrapolate that to a lifetime use of a drug.”
The interpretation of the threshold of evidence needed to meet approval was sometimes influenced by the availability of other drugs for treatment of the same indication. In these cases, committee members often highlighted specific areas of weakness in trial design that weakened the case for approval, such as the use of placebo rather than active controls: “a well-conducted non-inferiority trial in the population against one of the others [drugs of the class] would go a long way towards establishing that [evidence for approval].” Other trial design issues highlighted by committee members raising concern for the reliability of data supporting supplemental indications included representativeness of the trial population; choice of endpoint; choice of analytic method; and handling of missing data.
Voting Rationales: Contextual Considerations
Among those cases where advisory committee members disputed the appropriate benefit-harm threshold against which to hold the new indication that was not subsequently approved by FDA, contextual considerations were often invoked to justify decision-making (Table 3). We define contextual considerations here to represent considerations of the clinical and social context outside of the direct evidence of efficacy and safety presented by the FDA and/or drug sponsor in the advisory committee meeting. These comprise two concerns unique to supplemental indications: concerns relayed from prior experience with the drug, and concerns about the future use of the drug, as well as two concerns shared with new drug approvals: concerns about unmet need and demand and concerns about long-term impacts of approval on research and development. Multiple concerns were invoked at meetings, and it was also common for committee members at the same meeting to offer differing votes while citing the same class of concerns.
Themes and sub-themes illustrating contextual considerations by FDA advisory committees voting on supplemental indications that were not subsequently approved, 2008-2022
Concerns From Prior Experience
One key factor that differs between regulatory decision-making for supplemental indications and for new drug approvals is the availability of existing market experience of the product. In many cases, committee members used their own clinical experience with a new supplemental indication to support approval, as with one proposed drug dosing for diabetic macular edema: “I already use the 0.5 milligram dosing, so I think it would be appropriate.” In some cases, however, experience with the product raised concerns for expanding the indications for which it is approved, particularly with respect to safety. As for one antipsychotic drug seeking a new indication, committee members noted that “the long-term risks of dyskinesias and metabolic side effects are fairly well documented, and I don’t think they’re acceptable for this use.”
Further, committee members may invoke existing market availability and off-label use as a justification not to approve the new indication of the drug: “I guess always in the back of my mind is that these drugs are available, and physicians use them in special circumstances.” While continued off-label availability could be used as a justification for failing to approve the supplemental indication, some committee members noted that failure to approve the indication nevertheless can limit access due to policies imposed by payers: “It is now labeled, but if you have someone with severe disease who is under the age of two, you have to get a written decree from God, which is hard to get these days.”
Concerns About Future Use
While concerns about parameters for future use are salient for approvals of both new drugs and supplemental indications of already-approved drugs, supplemental indications involve unique considerations because they involve products already available to clinicians and patients even if the supplemental indication is not approved. Concerns about the risk-benefit threshold for supplemental indication approval were particularly salient in cases where the new proposed indication changed the population of patients potentially exposed to the drug, and numerous committee members expressed concerns about potential for further “indication creep.” These were heightened in cases where indication expansion was expected to be practice-changing, as with one drug submitted for secondary prevention of cardiovascular events: “What we’re really saying … is that patients with ACS should be treated with three drugs, not two … We really want to have very compelling evidence … we could expose hundreds of thousands of Americans to a three-drug regimen with increased risk of bleeding.” However, committee members sometimes took into consideration the expected role of third parties in guiding appropriate use after approval: “The FDA’s role is to decide if a study is positive or not, and it’s other bodies that decide what’s clinically significant, relevant, and applicable.”
Committee members also cited existing FDA regulatory oversight pathways to justify approval, such as risk evaluation and mitigation strategies (REMS), postmarketing requirements (PMRs), or mandatory follow-up advisory committee meetings. Other regulatory strategies were also presented, such as the FDA’s ability to issue “Dear Healthcare Professional” letters and communicate with professional societies. Despite this, discussions suggested that negative prior experiences with the implementation of such programs could be a liability for new indications. For one opioid drug proposing a new indication to treat non-cancer patients, committee members were hesitant to support approval without evidence the existing risk management plan was efficacious, with one member stating that “it would have been nice today to see a registration system update rather than a registration system preliminary plan.”
Concerns About Unmet Need and Demand
Concerns about disease and indication characteristics were factors in decisions to vote for or against approval in borderline cases of new supplemental indication approval. Orphan diseases or diseases for which there was perceived unmet need sometimes led committee members to state that they were adopting more lenient stances on issues with efficacy and safety: “I think it should be approved but I must admit I have lowered the bar since this is an orphan application.” However, not all other committee members were thus convinced, stating, “Just because it is an orphan drug doesn’t mean that the bar should be set low.”
Concerns About Long-Term Development Impacts
Concerns about long-term development impacts were rare but influenced some committee members’ assessments of the risk and benefits of approval of a new indication. These were most often described in terms of concerns about the failure to approve a drug putting a halt to future development, or as one committee member put it, “fears … that a no vote would throw a chilling effect on this field.” However, this concern was not universal. One committee member noted that approval could disincentivize the development of truly innovative drugs: “I am concerned that if we lower the bar for standards of efficacy and approvability that other medications will come forth and say, well, this is a small population; they have a fatal disease; you should approve us.”
Discussion
We reviewed all FDA advisory committees reviewing new sNDAs and sBLAs from 2008–2022 and found variability in the frequency with which advisory committees were called to discuss new supplemental indications for already-approved drugs. We found that advisory committee discussion of supplemental indications not subsequently approved by FDA commonly involved efficacy and safety concerns, in addition to contextual considerations including concerns based on prior use of the product, particularly around safety, and about future use of the product, including off-label use. These often modulated the interpretation of the threshold for efficacy and safety required for approval.
These findings represent the first systematic evaluation of the use of FDA advisory committees for the review of supplemental indication approval applications specifically. We found that advisory committee discussions for supplemental indication approvals for already-approved drugs involved unique considerations compared to new drug approvals. Among supplemental indications that were not subsequently approved by the FDA, efficacy and safety concerns were dominant considerations in advisory committee voting, paralleling previous findings for new drug approvals.Reference Ross, Dzara and Downing11 However, the contexts in which concerns were evoked reflected differences between these two types of approvals. For instance, because supplemental indications involve a drug that has already been approved, safety concerns reflected a narrower subset of concerns related to safety in a new age group or safety in a new disease area for which the benefit-harm ratio was not yet established. Committee members were also able to invoke direct prior experience with a drug to inform their understanding of efficacy and safety of the supplemental indication.
Contextual concerns, including prior experience, future use, unmet need, and influence on future development, were also commonly expressed as secondary considerations for voting on supplemental indications. Some of these contextual concerns are also unique to supplemental indication approvals, particularly those incorporating prior experience and concerns about future use of the product with or without supplemental indication approval, given market availability of the product. While these concerns were not typically used as committee members’ sole justification of their vote, they played a key modulating role in interpreting efficacy and safety data in the context of approval. The incorporation of such concerns can be seen as a means of exercising regulatory flexibility in determining the appropriate threshold for evidence of efficacy or safety necessary for approval.Reference Janiaud12 While we are unable to quantify with this enriched sample the degree to which such primary and secondary considerations occur in supplemental indications at large, these differences warrant further investigation to understand how supplemental indications are evaluated relative to new approvals.
These concerns highlight the importance of the public transparency function of advisory committees for supplemental indications, which is particularly salient in cases where the products being deliberated are already on the market. We identified numerous examples in which committee members raised concerns about the efficacy and safety of supplemental indications that drug sponsors nonetheless deemed promising enough to submit for regulatory approval. These include the submission of a direct oral anticoagulant drug as part of first-line triple therapy for secondary prevention of acute coronary syndrome, and submission of a 5-alpha reductase inhibitor for the prevention of prostate cancer, both of which were deemed to have expected harms unacceptable relative to expected benefits. It is unclear whether these concerns would have become publicly known under existing pathways of knowledge distribution, or whether risks would have had the potential to reach wide audiences through off-label use. Prior studies have highlighted the limitations of journal publications as a complete source of information about new medical products, given the prevalence of selective publication and publication bias.Reference Turner13 In these cases, advisory committees can offer a public venue for the presentation of data and deliberation of new uses and safety concerns that may not otherwise be legible.
One means by which advisory committees can promote the clarity of their opinions is through voting, which serves a crucial communication role in providing direct feedback to the agency on discrete questions, and accordingly, has already been the subject of agency reforms.Reference Broniatowski and Magee14 Several benefits of advisory committee voting to communication have been suggested in previous literature.Reference Urfalino, Costa and Elster15 First, through voting on a discrete question, committee members are unambiguously rendering and conveying their judgment on the same, specific issue — in contrast to an open forum, in which the terms or context of a proposed action may change over the course of the discussion, leaving ambiguity as to committee members’ stances and corresponding recommendations to FDA. Second, by casting votes, the committee expresses its collective judgment on that issue in an easily synthesizable way — namely, the final vote count. Third, by disaggregating voting and discussion, the overall judgment of committee members is less likely to be misinterpreted in relation to their reasons for voting as they did — for instance, it may be informative if a committee member deems an orphan drug designation an important contextual factor in their decision-making but nonetheless ultimately votes against approval.16 Such structural benefits of voting suggest that recent proposals to eliminate voting in advisory committees would likely have negative effects to advisory committees’ function by reducing the quality of information exchange, particularly so in the specific and unique context of the evaluation of sNDAs by these groups.
Finally, the role of advisory committees in making public evidence and data about supplemental indications highlights one further difference between the supplemental indication and new drug approval processes. Unlike new drugs, supplemental indications do not currently carry a requirement for the proactive release of review materials, such as a summary of the pivotal trials to support approval.17 Nor is there a standard for the release of complete response letters, which express the basis for FDA non-approval, despite the benefit of increasing transparency of efficacy and safety concerns for supplemental indications that may be used off-label. Given that the approval of supplemental indications has become a means of expanding the eligible population for new drugs, setting the standard for the timely and proactive release of such materials would help the FDA fulfill its public health role in informing the public to improve medical decision-making.
This study has several limitations. First, although we were able to obtain information on supplemental indications through publicly available advisory committee meeting records, these may not be representative of all sNDAs and sBLAs for new indications evaluated by the FDA. Nor are we able to determine how many supplemental indications are evaluated by advisory committees as a function of indications submitted, as this information is not made public. However, our study is intended to describe the range of themes in the evaluation of such contentious supplemental indications, for which advisory committee meetings may be particularly well-suited as they are thematically enriched. Second, the limited information available in the advisory committee context regarding unapproved sNDAs limited our ability to analyze how voting justifications are associated with certain features of drug review. Special designations such as Accelerated Approval and Breakthrough Therapy were not systematically available for products not yet approved. Finally, although prior studies have shown high concordance between advisory committee recommendations and subsequent FDA decision-making,18 advisory committees’ judgment may not fully reflect FDA decision-making. Because there were only five advisory committee meetings for unapproved sNDAs that were discordant with the FDA in this study, we could not reliably draw conclusions on additional factors that predict discordance in this context beyond those previously described. Further, because the FDA does not systematically release either the approval packages associated with new supplemental indications, which include data and the agency’s rationale for approval, or complete response letters, which express the basis for non-approval, we were unable to confirm whether the themes discussed in advisory committees were representative of those discussed by the FDA in making regulatory decisions.
Conclusion
FDA’s use of advisory committees for the evaluation of supplemental indications demonstrates variability over time. As with new drugs, supplemental indications are primarily evaluated along the dimensions of efficacy and safety for approval, but these evaluations are modulated by contextual concerns including prior experience, future use, unmet need, and long-term impacts on development. Greater transparency at the FDA regarding new supplemental indications and their evaluation by advisory committees would promote public health by enhancing public knowledge and thereby informing clinical decision-making.
Disclosure statement
Dr. Zhang currently receives research support from the Health Resources and Services Administration (HRSA) of the US Department of Health and Human Services (HHS) as part of an award totaling $550,341 with 158% financed with non-governmental sources (T32HP42013). The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by HRSA, HHS or the US Government. Dr. Ramachandran currently receives research support through Yale University from Arnold Ventures for the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT); the Stavros Niarchos Foundation through Yale Law School for a project entitled Re-envisioning Publicly Funded Biomedical Research and Development; and the US Food and Drug Administration for a project entitled Best Practices for Adequately Representing Women, Older Adults and Patients Identifying as Racial and Ethnic Minorities in Oncology Research: A Positive Deviance Approach; consultant fees for the ReAct-Action on Antibiotic Resistance Strategic Policy Program at Johns Hopkins Bloomberg School of Public Health in 2022, which was funded by the Swedish International Development and Cooperation Agency, all outside the submitted work. Dr. Ross currently receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), and from Arnold Ventures; formerly received research support from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST) and from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644); and in addition, Dr. Ross was 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. that was settled September 2022. Dr. Schwartz currently receives research support through Yale University from Arnold Ventures for the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT) and from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) (R01AI170137).
Funding
This manuscript was supported by Arnold Ventures through the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT).
