Characteristics of Clinical Studies Used for US Food and Drug Administration Supplemental Indication Approvals of Drugs and Biologics, 2017 to 2019

Key Points Question What is the strength of evidence supporting supplemental new indication approvals for drugs and biologics and how does it compare with the evidence that supported their original approval? Findings In this cross-sectional study of 107 therapeutics approved for 146 supplemental indications by the US Food and Drug Administration between 2017 and 2019, supplemental approvals for oncology drugs were based on fewer pivotal efficacy trials with less rigorous designs than supplemental approvals for other therapeutic areas. Supplemental approvals were based on fewer pivotal trials than their original indication approvals, but their designs were similar. Meaning These findings suggest that there was little difference in the evidence supporting supplemental and original indication approvals, but the number and design of pivotal trials supporting supplemental indication approvals varied according to therapeutic area.


Introduction
To receive US Food and Drug Administration (FDA) approval for a new small-molecule or biologic drug, sponsors must submit "adequate and well controlled investigations" 1 to demonstrate the drug's efficacy and safety. Although the FDA suggests that sponsors submit at least 2 trials demonstrating efficacy, also known as pivotal efficacy trials, the number and characteristics of pivotal efficacy trials supporting new drug and biologic approvals vary widely. 2,3 For example, approximately one-third of new approvals are based on a single pivotal trial, whereas nearly one-half are based on trials solely focused on surrogate markers of disease, as opposed to clinical outcomes. 2 This flexibility highlights the FDA's ability to adapt its standards to the clinical context and use of the drug or biologic under consideration. 4 Less is known about the clinical trial evidence that supports supplemental indication approvals by the FDA, which are required when sponsors intend to add use of the originally approved drug for new clinical indications or in specific subpopulations to the labeling. Supplemental indication approvals by the FDA for already marketed drugs occur in frequencies similar to those for approvals for novel therapeutics. For instance, in 2014, the FDA approved 40 new supplemental indications compared with 44 new drug approvals. 5 Supplemental new indication approvals are particularly common among oncology therapies, such as the anti-programmed death-1 biologic pembrolizumab (Keytruda), which was originally approved for the treatment of advanced melanoma in 2014 and has since been approved for 19 additional clinical indications. 6 Moreover, it is critical that both new and supplemental indication approvals are based on strong evidence, because certain therapeutics may be prescribed more often for their supplemental indications than for their initially approved indication. 7 Supplemental indication approval by the FDA is also critical for ensuring insurance coverage, especially for more expensive biological therapies and those used for oncology, where effective treatment options may be more limited. 8 There have been few studies characterizing the clinical trial evidence that supported supplemental indication approvals by the FDA. One study 9 broadly examined nearly 300 supplemental indication approvals between 2005 and 2014 and found that approximately one-third used active comparator groups and one-third used clinical outcomes as primary end points. Another study 10

Methods
This study was prepared in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies. This study did not require institutional review board approval or informed consent because it was based on publicly available information and involved no patient records, in accordance with 45 CFR §46.

Sample Construction
One study author (M.D.) identified all new drugs and biologics approved for supplemental indications between January 2017 and December 2019 using the Drugs@FDA database. We limited our sample to sNDAs and sBLAs approved by the FDA for new clinical indications, identified through full-text review of sNDA and sBLA approval letters; corresponding FDA approval letters and printed labels were obtained as they are hyperlinked in the Drugs@FDA database. Duplicate records were removed, and sNDAs and sBLAs for contrast agents, nontherapeutic agents, and generics and biosimilars were excluded. Furthermore, we excluded any sBLAs that were determined to be (original) BLAs and removed from FDA's Orange Book on March 23, 2020, under the Biologics Price Competition and Innovation Act of 2009. Next, for each therapeutic for which an sNDA or sBLA was identified and included in our study, we identified the original indication NDA or BLA approved by the FDA, along with the pivotal trials supporting the FDA's approval for their original indication using previously described methods. 2,3

Supplemental Indication and Regulatory Characteristics
New indication approvals and original indication approvals were characterized by agent type, therapeutic area, and special regulatory status. For each approval, we determined whether the approved therapeutic was a small molecule or biologic from the letter and label. Treatments were characterized as short-term if the therapeutics were expected to be used for less than 1 month, as intermediate if they were expected to be used for 1 month to 2 years, and long-term if they were expected to be used for more than 2 years. Therapeutic area was classified for each approval was based on the World Health Organization Anatomical Therapeutic Classification System. 11 Using publicly available information on the FDA website, we determined whether each indication in our sample was evaluated under a special regulatory program such as Priority Review, 12 Accelerated Approval, 13 Fast Track 14 for (NDAs and BLAs only), or Breakthrough Therapy. 15

Trial Identification
To identify the pivotal clinical trials supporting the sNDAs and sBLAs, we reviewed the drug labels updated by the FDA to correspond to the specific new indication approval, which typically reference the clinical trial using the ClinicalTrials.gov registration number (ie, National Clinical Trials identifier).
Generally, those studies considered pivotal are labeled as such in the Clinical Studies section of the printed label. Furthermore, if not directly stated as pivotal, efficacy for an indication is stated to be based on the evidence from a trial or number of trials. If an approval was based on the results of more than 1 trial, all these trials were included in our study. To identify pivotal trials not directly referenced in the label using a National Clinical Trials number, general study information (eg, number of study participants, primary efficacy end point, masking, and randomization) was cross-referenced with study information from ClinicalTrials.gov to identify the relevant National Clinical Trials number.

Pivotal Trial Characterization
For all pivotal trials supporting NDA, sNDA, BLA, and sBLA approval by the FDA, 1 study author (M.D.) extracted the following information from ClinicalTrials.gov if not available from or previously collected as part of prior research from FDA action packages, including approval letters and review documents: randomization, double-blinding, comparator, study end point, agent type, total number of participants, and number of patients in intervention group. 2,3 For each trial included in our sample, we determined its use of randomization and double-blinding and characterized the comparator group as active, placebo, or none. Next, the primary trial end point was identified and was designated into 1 of 3 categories-clinical outcome, clinical scale, or surrogate marker-by 1 study author (M.D.) and was reviewed by another study author (J.S.R.); any conflicts were resolved by consensus. In brief, surrogate markers (eg, hemoglobin A 1c ) are metrics expected to be associated with patient outcomes, where clinical outcomes (eg, death) measure patient outcomes. Importantly, if at least 1 primary trial end point was categorized as a clinical outcome or clinical scale, the trial would be categorized as such even if another primary trial end point was a surrogate marker. The number of participants, intervention model, and number of patients in the intervention group were also extracted. Trial duration was extracted from study descriptions using methods previously described. 2,3 For time-associated end points, duration was defined as the date of measurement of the primary end point. For event-associated end points, duration was determined as the median follow-up time for participants or the weighted average of the median follow-up time in cases in which it differed between study groups.

Statistical Analysis
We used descriptive statistics to examine differences in trial characteristics and indication characteristics. Frequencies of use of randomization and double-blinding among the trials in our sample were calculated excluding single-group studies. We next used χ 2 and Wilcoxon tests where appropriate to examine differences between supplemental indication approvals for therapeutics in our sample at multiple levels, including agent type, special regulatory pathway, and therapeutic area, all of which were defined before data collection. Analyses were performed using R statistical (68%) were for pharmacologics and 47 (32%) were for biologics; 74 (51%) were approved using at least 1 special regulatory program, including 20 using the Accelerated Approval pathway and 61 designated for Priority Review ( Table 1). Most commonly, the supplemental indication approvals were for the treatment of cancer (78 approvals [53%]) or autoimmune and musculoskeletal (24

Supplemental Indication Approvals, Comparing Product Types
The 99 pharmacologic supplemental indication approvals were supported by 125 pivotal trials, whereas the 47 biologic approvals were supported by 56 trials ( Table 2). The median (IQR) number of trials per approval was 1 (1-1) for pharmacologic approvals and 1 (1-1) for biologic approvals; 18 pharmacologic indications (18.2%) and 5 biologic indications (10.6%) were approved on the basis of at least 2 pivotal trials. Likewise, the trials supporting supplemental indication approvals were broadly similar in design between pharmacologics and biologics. Trials supporting pharmacologic approvals were as likely as trials supporting biologic approvals to be randomized (

Supplemental Indication Approvals Compared With Original Indication Approvals
The 107 therapeutics for which we identified supplemental indication approvals were originally approved by the FDA for 109 clinical indications (Table 1); original indication approvals took place between 1991 and 2018, and 18% (19 of 107 approvals) were approved for a supplemental indication in a different therapeutic area from the original indication approval, the majority of which (11 approvals) were approved for a supplemental indication for use for autoimmune or musculoskeletal disease after an original approval for a different clinical use. The median (IQR) number of trials per approval was 1 (1-2) and 1 (1-1), respectively (  approval of novel therapeutics. In addition, substantial variation has been described with regard to the pivotal efficacy trials supporting the approval of novel oncology therapeutics. 16 The Generating additional drug safety and effectiveness evidence through observational research may offer advantages with respect to time and resources, compared with clinical trials. However, there are outstanding issues to resolve, including data definitions, establishing which data are fit for purpose, and establishing best practices, 23 such as study registration. 24 Furthermore, our recent study 25 found that few of the recently published, highest-impact trials could be feasibly replicated using RWE because much of the data needed for randomized clinical trials are not captured in electronic health records in a structured format, if at all. Although the strengths and limitations of using RWE for the evaluation of supplemental new indication approvals for therapeutics already available for use are better characterized, there is a clear opportunity to complement randomized clinical trials to offer more information on product safety and efficacy.

Limitations
Our study has some limitations. First, we only assessed a recent, 3-year sample of therapeutics approved by the FDA for supplemental new clinical indications and, therefore, could not capture long-term trends in supplemental indication approvals or supplemental indication approvals by other national regulators. Second, our study did not evaluate whether the FDA considered other data regarding use of these therapeutics in other countries, which may have informed the agency's efforts to evaluate supplemental new indication approval safety and efficacy.

Conclusions
In this cross-sectional study, we found that there was little difference in the evidence supporting supplemental and original indication approvals by the FDA, but the number and design of pivotal trials supporting supplemental indication approvals varied according to therapeutic area, with the strength of evidence for cancer indications weaker than that for other indications. Overall, our results highlight the need for ongoing postmarket evaluation of supplemental new indications to ensure our understanding of product benefit and safety, as well as to inform both clinicians' and policy makers' decisions, including ongoing efforts to leverage observational studies and RWE, as opposed to clinical trials, to support FDA regulatory decisions and evaluations.