The Timing and Characteristics of Supplemental Indications for Medicines

ABSTRACT

Objectives: We investigated the timing of supplemental indications and characteristics of those approved after 9 years (small molecules) or 13 years (biologics) post initial approval across all therapeutic areas.

Study Design: Using FDA databases, we identified small molecule drugs (n = 97) initially approved between 2004 and 2015 and biologics between 2004 and 2011 (n = 21), allowing for at least 9 and 13 years of follow-up, respectively.

Methods: We reviewed drug labels as of 2024 to identify supplemental indications. We characterized supplemental indications approved at least 9 or 13 years post approval in several ways: by FDA expedited review pathway, whether they had orphan designation, whether they were approved for pediatric or geriatric populations, and their therapeutic class. We calculated the mean time between consecutive indications for small molecules and biologics.

Results: Overall, 24.0% of small molecule supplemental indications were approved at least 9 years post approval, and 10.0% of biologic supplemental indications were approved at least 13 years post approval. Of the supplemental indications approved (whether for small molecules or biologics) at least 9 or 13 years after initial approval, 56.9% received at least 1 FDA expedited review, 39.2% had orphan status, 49.0% were approved for pediatric use, and 62.7% were approved for older adults. The mean time between consecutive indications was longer for small molecules than for biologics (4.0 vs 3.3 years).

Conclusions: Additional drug indications approved after 9 years for small molecules and 13 years for large molecules are not uncommon. Many of these later-approved indications receive expedited or orphan designation and target populations with high unmet medical needs.

Am J Manag Care. 2026;32(7):In Press

Takeaway Points

Additional drug indications approved after 9 years for small molecules and 13 years for large molecules are not uncommon.

• Roughly one-fifth of supplemental indications were approved many years after a drug’s initial market entry.
• Many of the later-approved indications received expedited or orphan designation and targeted populations with high unmet medical needs.
• The Inflation Reduction Act Drug Price Negotiation Program could have a greater impact on therapeutic innovation for small molecules, as their supplemental indications were developed over longer timelines and were more likely to be approved after the Maximum Fair Price effective time compared with biologics.

The Inflation Reduction Act (IRA) Drug Price Negotiation Program (DPNP) aims to reduce prices for selected medicines to improve access and affordability, but raises concerns that it could reduce incentives to pursue supplemental indications, particularly as drugs approach the Maximum Fair Price (MFP) effective date: 9 years for small molecules and 13 years for biologics.¹ We investigated the timing and characteristics of supplemental indications approved at least 9 (small molecules) or at least 13 years (biologics) post initial approval across all therapeutic areas, building on prior research focused on orphan, high-spend, and oncology drugs.^2-4

METHODS

Using FDA databases,^5,6 we identified small molecule drugs approved between 2004 and 2015 (n = 97) and biologics approved between 2004 and 2011 (n = 21), allowing for at least 9 and at least 13 years of follow-up, respectively (eAppendix Text and eAppendix Table [eAppendix available at ajmc.com]).

We reviewed 2024 labels to identify supplemental indications—new FDA-approved indications post initial approval—and characterized those approved at least 9 years (small molecules) or at least 13 years (biologics) post approval by expedited review, orphan designation, pediatric or geriatric populations, and therapeutic class (eAppendix Text). We calculated the mean time between consecutive indications and compared it to that for more recently approved small molecules (2016-2023) and biologics (2012-2023). Sensitivity analyses examined earlier time points (small molecules, 7 years; biologics, 11 years) corresponding to when MFP negotiations started.

RESULTS

Among 253 supplemental indications, 44 (24.0%) of 183 small molecule indications were approved at least 9 years post approval and 7 (10.0%) of 70 biologic indications were approved at least 13 years post approval (Figure). Of these 51 supplemental indications (Table), 56.9% had at least 1 expedited review designation (59.1% for small molecules vs 42.9% for biologics), 39.2% had orphan status (36.4% vs 57.1%), 49.0% were for pediatric use (50.0% vs 42.9%), and 62.7% were for older adults (61.4% vs 71.4%). Common therapeutic areas for small molecules were oncology (34.1%), infectious disease (15.9%), and circulatory disease (9.1%), and for biologics, oncology (28.6%), musculoskeletal disease (28.6%), and circulatory disease (14.3%). Findings were broadly consistent for the 7- or 11-year thresholds, representing 90 (32.8%) of 274 indications (eAppendix Figure).

The mean time between consecutive indications was longer for small molecules than for biologics (4.0 vs 3.3 years). These mean times were also longer than their corresponding values among more recent approvals (2.0 vs 1.5 years).

DISCUSSION

Under the DPNP, all indications of the same active moiety/ingredient are treated as 1 qualified single-source drug, effectively shortening the market exclusivity for later-approved indications. Roughly one-fifth to one-third of supplemental indications were approved many years after initial entry. These later-approved indications frequently received expedited or orphan designations and were often for use in populations with unmet need. Limiting the development of such indications may have adverse consequences for population health, particularly among Medicare beneficiaries.

Our study suggests that DPNP timelines could disproportionately affect small molecules, whose supplemental indications emerge over longer timelines and are more likely to be approved after the MFP effective time. We also observed signs of more and accelerated development of supplemental indications among drugs approved in the last decade (ie, shorter time between consecutively approved indications), suggesting that the DPNP could affect newer innovative therapies that may still be under clinical investigation for additional uses even more.

Our study limitations include not accounting for off-label use preceding supplemental approvals, clinical outcomes, and manufacturers’ responses to mitigate the IRA disincentives, such as prioritizing high-value, early–life cycle innovation. The potential influence of the DPNP and other IRA provisions on drug innovation remains unclear.

Future research should identify high-value supplemental indications, examine recently approved drugs and supplemental indications, and monitor manufacturers’ responses to the provisions of the IRA.

Acknowledgments

The authors thank Mr Daniel Enright for his support in data collection for this study.

Author Affiliations: Center for the Evaluation of Value and Risk in Health, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center (YZ, CHB, PJN, JDC, PJL, ML), Boston, MA; Eli Lilly and Company (HT, JNT), Indianapolis, IN.

Source of Funding: This study was funded by Eli Lilly and Company.

Author Disclosures: Dr Zhu holds stock options in Eli Lilly and Company. Dr Tian is employed by and holds stock in Eli Lilly and Company. Dr Tran is employed by Eli Lilly and Company. Dr Neumann is affiliated with the Center for the Evaluation of Value and Risk in Health, which is funded by multiple parties including Eli Lilly and Company. Dr Lin reports consulting income from Biogen and Halozyme outside the submitted work and grants received from Argenx, Arnold Ventures, Eli Lilly and Company, and No Patient Left Behind to Tufts Medical Center. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (YZ, CHB, HT, PJN, JDC, PJL, ML); acquisition of data (YZ, CHB, PJN); analysis and interpretation of data (YZ, HT, JNT, PJN, JDC, PJL); drafting of the manuscript (YZ, PJN, JDC, PJL); critical revision of the manuscript for important intellectual content (YZ, HT, JDC, PJL, ML); statistical analysis (YZ); obtaining funding (JNT, PJL, ML); administrative, technical, or logistic support (YZ, CHB, JNT, ML); and supervision (YZ, ML).

Address Correspondence to: Meng Li, PhD, Center for the Evaluation of Value and Risk in Health, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, 800 Washington St, Box #63, Boston, MA 02111. Email: meng.li@tuftsmedicine.org.

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