US Spending on High-Revenue Rare Disease Drugs in 2022

ABSTRACT

Objectives: To estimate the use and spending for high-revenue rare disease drugs in 2022 in the US.

Study Design: Cross-sectional study.

Methods: Among the 100 prescription drugs with the highest 2022 US net sales revenue, we selected drugs exclusively approved to treat rare diseases as designated under the Orphan Drug Act. We estimated commercial, Medicare, and Medicaid spending using manufacturer-reported net sales and public Medicare and Medicaid spending data. We also estimated the number of individuals using each drug based on Medicare spending per beneficiary data.

Results: Nineteen of the 100 highest-revenue prescription drugs in 2022 were exclusively approved to treat Orphan Drug Act–designated conditions; 9 had a single indication, and 10 had multiple indications. Median annual net sales for the 19 drugs were $1.97 billion (range, $988 million-$8.36 billion). Total spending on these 19 drugs was $45.1 billion, which represented approximately 7.5% of the $603 billion in prescription drug spending in 2022. The median estimated number of individuals using each drug was 17,152 (range, 3735-71,171). Of the total spending, $23.6 billion (52.3%) was spent for individuals with Medicare, $3.5 billion (7.8%) for those with Medicaid, and $18.0 billion (39.9%) for those with commercial insurance.

Conclusions: Approximately 1 in 5 of the highest-revenue prescription drugs in the US in 2022 was approved to treat only rare conditions; these drugs were used by a small number of patients but accounted for a sizeable share of spending. Rare disease drugs should be included in federal and state policies aimed at improving the affordability of prescription drugs for patients and the health care system.

Am J Manag Care. 2025;31(11):In Press

Takeaway Points

• In this cross-sectional study, 19 of the 100 prescription drugs with the highest annual net sales in 2022 were solely approved to treat rare diseases.
• These drugs were used by a median of 17,152 patients, but they accounted for approximately 7.5% of US pharmaceutical spending in 2022.
• Excluding rare disease drugs from state and federal programs to lower prescription drug prices results in high costs to the health care system.

Congress passed the Orphan Drug Act of 1983 to incentivize pharmaceutical companies to invest in treatments for rare conditions.¹ The law provides tax credits to partially offset clinical trial costs for developing drugs to treat rare diseases and 7 years of exclusivity protection from FDA approval of generic competitors. To qualify for these incentives, drug makers were initially required to attest that there was “no reasonable expectation” that a drug could generate a profit, but the designation was subsequently amended to include all drugs treating conditions that affected fewer than 200,000 Americans.² During the past several decades, the number of FDA-approved drugs with Orphan Drug Act designations has increased substantially, accounting for 41% of drugs approved by the FDA from 2008 to 2018.³

The increase in drugs approved to treat rare conditions has been heralded as a success,⁴ but in recent years, the necessity of Orphan Drug Act incentives has been questioned due to the high prices and substantial revenues associated with treatments for many rare diseases.^2,5,6 Average launch prices for new drugs with Orphan Drug Act designations are 7 times higher than prices for nonorphan drugs.⁷ Several gene therapies approved to treat rare conditions, including spinal muscular atrophy, have been priced at well over $1 million.⁸ In the first 5 years after approval, drugs with Orphan Drug Act designations generate similar sales to drugs treating more common conditions.⁹

Nonetheless, several state and federal policies to address rising prescription drug costs exempt treatments with Orphan Drug Act designations, with policy makers and advocates arguing that such exemptions are necessary to protect the innovation of these treatments.^10-12 Several state legislatures have enacted prescription drug affordability boards, some of which have the authority to set statewide upper payment limits.^13,14 These state policies seek to promote savings for various populations, including state consumers, public plan enrollees, and Medicaid enrollees.¹⁵ The Oregon Prescription Drug Affordability Board is prohibited from considering drugs with orphan designations, and Colorado and other state legislatures have also considered similar exclusions for their states’ boards.^10,16,17 In addition, the Inflation Reduction Act of 2022 granted Medicare the authority to negotiate prices for certain drugs, but drugs approved to treat a single orphan-designated condition were excluded, preventing Medicare from negotiating lower prices for drugs that cost the government billions each year.^18,19 The One Big Beautiful Bill Act of 2025 expanded this exemption to include drugs that treat multiple orphan-designated conditions and delayed negotiation for drugs first approved for rare diseases and subsequently approved for nonorphan conditions.^20,21

To understand how exempting rare disease drugs from programs intended to lower drug prices for patients might affect state and federal prescription drug budgets, we measured public and private US spending on high-revenue drugs targeting rare diseases in 2022.

METHODS

In this cross-sectional study, we identified the 100 prescription drugs with the highest annual net US sales in 2022 from SSR Health, which collects sales data from public financial filings by pharmaceutical companies.²² In these financial filings, manufacturers report quarterly net sales (ie, total sales revenue after all discounts and rebates). These data are frequently cited in research estimating US drug sales.^23-26 For these 100 drugs, we used the FDA’s Orphan Drug Designations and Approvals database and drug labeling information from the Drugs@FDA database to identify products that were approved by the FDA to exclusively treat Orphan Drug Act–designated conditions as of December 31, 2022.¹⁸ We categorized drugs as “sole-orphan” if they were approved for a single orphan-designated indication and “multi-orphan” if they were approved to treat multiple Orphan Drug Act–designated indications.¹⁸ We excluded drugs with indications for rare and common conditions because most of the spending on these drugs is for their use to treat common conditions.²⁷ When manufacturers combined products to report net sales, we categorized them as single products. For example, the subcutaneous form of rituximab (Rituxan Hycela) was only approved to treat rare conditions, but we excluded this version because sales were combined with the intravenous form of rituximab (Rituxan) that had indications for rare and common conditions.^28,29

Public and Private Spending

To identify public spending on these drugs, we used Spending by Drug data sets from 2022 for Medicare Part D, Medicare Part B, and Medicaid published by CMS. Spending reported for Medicare Part D does not include confidential rebates from manufacturers, but such rebates tend to be very low or nonexistent for rare disease drugs that lack within-class competition. For example, a Congressional Budget Office report estimated that Medicare Part D rebates averaged 11% for a sample of 64 high-priced drugs and 12% for a sample of 68 top-selling specialty drugs.³⁰ We accounted for mandatory coverage gap discounts owed by drug companies, which averaged 6.3% of Part D spending in 2022.³¹ We assumed out-of-pocket spending of 5%, which is the coinsurance patients pay once they reach the catastrophic phase of spending, which commonly occurs for patients using expensive drugs to treat rare conditions.³²

For clinician-administered drugs, Medicare Part B spending is based on manufacturer-reported average sales prices to private payers after discounts and rebates. Reported Part B spending does not include spending on clinician-administered drugs for patients enrolled in Medicare Advantage plans. We therefore extrapolated Part B spending on these drugs to the entire Medicare program because 48% of Medicare beneficiaries were enrolled in Medicare Advantage plans in 2022.³³

Reported Medicaid spending does not account for statutory rebates that manufacturers must offer through the Medicaid Drug Rebate Program; for most branded drugs, these rebates are at least 23.1% of the drug’s price.³⁴ Medicaid rebates can be higher if drug manufacturers raise prices faster than inflation or offer larger discounts to private purchasers (ie, “best price” discounts); however, neither practice is common for rare disease medications. Based on available data from SSR Health for 16 of the 19 rare disease drugs in this study, the difference between list and net prices ranged from 10% to 32% (median, 20%) in 2022.^22,30 Rebates make up only part of this difference, so we assumed that these drugs would not have best price discounts exceeding the statutory minimum 23.1% Medicaid rebate for branded drugs.³⁵

To estimate commercial spending, we subtracted estimated net Medicare and Medicaid spending from manufacturer-reported net US sales. We did not account for other public sources of spending, such as the Veterans Health Administration, which make up less than 5% of prescription drug spending in the US.³⁶

Number of Users

We estimated the number of individuals using each drug via Medicare Part B and Part D data from CMS; this included the number of beneficiaries who used each drug and the mean spending per beneficiary. To estimate the number of non-Medicare users, we divided estimated net Medicaid and commercial spending by the mean Medicare spending per beneficiary. We accounted for the 23.1% Medicaid rebate for branded drugs^22,30,34,35; for commercial spending, we assumed that spending would be offset by 5% due to manufacturer-sponsored coupons and patient assistance programs that cover some patients’ out-of-pocket portion.³⁷ Patient out-of-pocket costs amount to 14% of US prescription drug spending, and we assumed that the share of costs borne by patients would be lower for high-cost rare disease drugs and that not all of these out-of-pocket costs would be offset by patient assistance programs.³⁶

Statistical Analysis

We performed descriptive analytics on the drug cohort and spending estimates. We assessed for a correlation between the number of users and spending by calculating Pearson correlation coefficient.

For context, we compared spending on the high-revenue drugs with orphan designations to total US spending on the top 100 highest-revenue drugs (from SSR Health),²² estimated US spending on all prescription drugs,³⁸ and approximated national health care spending in 2022.³⁹ Analyses were performed in Excel (Microsoft). This study was not submitted for institutional review board review because it does not constitute research on human participants.

RESULTS

Nineteen of the 100 prescription drugs with the highest annual net sales in 2022 were exclusively approved to treat diseases with orphan designations (Table).²² These drugs included 9 with a single indication and 10 with multiple indications. The most common clinical conditions treated by these drugs were in the fields of oncology (9; 47.4%), pulmonary medicine (3; 15.8%), and hematology (2; 10.5%). Five (26.3%) were biologic products, and 14 (73.7%) were small-molecule drugs. Of the 81 other products, 24 had approved indications for both Orphan Drug Act–designated and nonorphan conditions, and the remaining 57 had no Orphan Drug Act–designated approvals (eAppendix [available at ajmc.com]).

Median net sales for the 19 drugs in 2022 were $1.97 billion (range, $988 million-$8.36 billion). The drugs with the highest net sales were lenalidomide (Revlimid; $8.36 billion), elexacaftor/tezacaftor/ivacaftor and ivacaftor (Trikafta; $4.91 billion), and daratumumab (Darzalex; $4.21 billion) (Figure 1).²²

Public and Private Spending

Spending for the 19 drugs in 2022 totaled $45.1 billion, of which $23.6 billion (52.3%) was spent for patients with Medicare, $3.5 billion (7.8%) for those with Medicaid, and $18.0 billion (40.0%) for those with commercial insurance. The distribution of spending varied based on the patient population treated by each drug. Drugs with the highest proportion of Medicare spending were daratumumab ($3.70 billion of $4.21 billion; 87.9%), ibrutinib (Imbruvica; $2.53 billion of $3.43 billion; 73.8%), tafamidis (Vyndaqel/Vyndamax; $0.85 billion of $1.25 billion; 68.0%), and venetoclax (Venclexta; $0.68 billion of $1.01 billion; 67.3%). By contrast, the proportion of spending on commercially insured patients was highest for tolvaptan (Jynarque; $861 million of $988 million; 87.1%), sodium oxybate (Xyrem; $791 million of $1.02 billion; 77.5%), and elexacaftor/tezacaftor/ivacaftor and ivacaftor ($3.26 billion of $4.91 billion; 66.4%). The proportion of spending on Medicaid patients was highest for emicizumab-kxwh (Hemlibra; $610 million of $2.42 billion; 25.2%), elexacaftor/tezacaftor/ivacaftor and ivacaftor ($1.07 billion of $4.91 billion; 21.8%), and selexipag (Uptravi; $166 million of $1.10 billion; 15.1%).

Number of Patients

The median number of patients using each of these 19 drugs in 2022 was 17,152 (range, 3735-71,171). Except for lenalidomide (71,171 users), each drug was used by fewer than 31,000 individuals each year. As with spending, the distribution of Medicare, Medicaid, and commercial users varied by drug (Figure 2). There was a moderate correlation (r = 0.48) between the number of users and spending on these drugs after excluding the outlier lenalidomide (Figure 3).

Spending in Context

In 2022, the $45.1 billion spent on these 19 Orphan Drug Act–designated drugs represented 16.4% of the $275 billion spending on the 100 highest-revenue drugs,²² 7.5% of the $603 billion estimated spending on all prescription drugs,³⁷ and 1.0% of the $4.5 trillion in total national health expenditures (Figure 4^22,38,39).³⁹

DISCUSSION

In this cross-sectional study, we found that nearly 1 in 5 prescription drugs with the highest US net sales in 2022 was approved to treat only rare diseases and that most of these drugs were used by fewer than 31,000 patients in the US. Despite such limited use, high-revenue drugs with Orphan Drug Act designations accounted for $45.1 billion in health care spending in 2022, or 7.5% of prescription drug spending that year in the US.³⁸

Our study findings align with others demonstrating that drugs designated as treating rare diseases under the Orphan Drug Act can generate substantial revenue for pharmaceutical companies.^9,18 Companies have been able to offset smaller populations of patients by charging much higher prices.⁷ Although our study focused on drugs exclusively approved to treat rare diseases, many blockbuster Orphan Drug Act–designated drugs have supplemental approvals to treat common conditions.²⁷

Approximately half of the high-revenue Orphan Drug Act–designated drugs in our study treated cancers, which may be partly explained by the advent of targeted molecular therapies that have allowed narrower populations of patients with cancer to qualify for designations. For example, osimertinib (Tagrisso) treats lung cancer, one of the most common cancer types affecting hundreds of thousands of people in the US each year⁴⁰; however, osimertinib is only approved to treat a subpopulation of patients with EGFR-mutated lung cancer, which allowed the drug to be granted an Orphan Drug Act designation. In addition to treating cancers, these high-revenue rare disease drugs treat a range of other life-threatening and life-altering conditions, including hematologic conditions, pulmonary arterial hypertension, and cystic fibrosis. In some cases, patients with these conditions had limited treatment options prior to the approval of these drugs.

Some patients and advocates have argued for excluding Orphan Drug Act–designated drugs from state and federal programs aimed at addressing excessive US drug prices, voicing concern that companies will cease to invest in rare disease drugs if they are included in such programs.^11,12 Data from multiple studies now show, however, that rare disease drugs can achieve substantial revenues despite treating small patient populations.^7,9 The fact that Orphan Drug Act–designated drugs now account for nearly 1 in 5 of the highest-revenue drugs in the US calls into question whether such carve-outs are necessary, particularly for rare disease drugs that have been commercially successful.²

Yet, exemptions to Orphan Drug Act–designated drugs have become common in state and federal policies addressing the high cost of prescription drugs.^10,11 The Inflation Reduction Act allows Medicare to negotiate prices for high-revenue drugs but excludes those that treat only rare conditions.¹⁹ Some state legislatures have also restricted new prescription drug affordability boards from studying or enacting payment limits for drugs with Orphan Drug Act designations.^10,17 Our results suggest that excluding these drugs from these policies is a missed opportunity to help patients struggling with high prescription drug costs because these drugs account for a sizeable share of US pharmaceutical spending. Such policies aim to lower prescription drug spending for consumers,¹⁵ and these high-revenue drugs likely increase premiums for all insured patients, even if manufacturers enact assistance programs to limit the out-of-pocket costs for patients who use these drugs.

Limitations

We focused on the 100 drugs with the highest revenue in the US, so the results may not be generalizable to lower-revenue drugs. However, a small cohort of prescription drugs comprises the majority of US pharmaceutical spending⁴¹; the 100 drugs in our study accounted for nearly half of prescription drug spending in the US. Although net sales were reported by manufacturers, the breakdown among Medicare, Medicaid, and commercial spending was limited by lack of transparency about confidential rebates from manufacturers to health plans, manufacturer patient assistance programs, and the 340B Drug Pricing Program. We believe that the 340B Drug Pricing Program causes a small underestimation of spending in our study based on an estimate that the program affected 9.6% of Medicare Part D claims in 2020.⁴² Although our user estimates were based on average prices per patient in Medicare, prices for specific patients may differ by indication or patient age or weight, and these could vary among the commercial, Medicaid, and Medicare populations. In addition, although other sources of prescription drug spending comprise less than 5% of total prescription drug spending, they may account for more or less than 5% for these specific high-revenue Orphan Drug Act–designated therapies.³⁶ Lastly, spending estimates for Medicare Advantage extrapolated from Medicare Part B might be overestimated because Medicare Advantage plans frequently use prior authorization and other strategies to limit use of expensive medications.⁴³

CONCLUSION

This cross-sectional study found that nearly 1 in 5 of the drugs with the highest net sales in the US exclusively treat rare diseases. Despite these drugs being used to treat very few patients, they accounted for more than 7% of US prescription drug spending in 2022.³⁸ The high spending on drugs with Orphan Drug Act designations affects all consumers through higher insurance premiums and stretching limited financial resources, particularly in the case of public insurance programs. Excluding these drugs from federal and state policies to address high drug prices substantially limits potential savings for patients and the health care system.

Author Affiliations: Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital (HM, ASK, BNR), Boston, MA; Harvard Medical School (ASK, BNR), Boston, MA.

Source of Funding: This work was supported by grants from Arnold Ventures, the Commonwealth Fund, and Kaiser Permanente Institute for Health Policy.

Author Disclosures: Dr Kesselheim reports serving as an expert witness for the Federal Trade Commission in a case against pharmacy benefit managers related to insulin, in a case on behalf of a payer against Johnson & Johnson related to availability of biosimilar Stelara, and in a case on behalf of a class of patients against Gilead related to its tenofovir-containing products. Drs Kesselheim and Rome report research grants to their institution from the National Academy of State Health Policy and from Colorado, Washington, and Oregon related to prescription drug affordability boards. Ms Mooney reports 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 (HM, ASK, BNR); acquisition of data (HM, BNR); analysis and interpretation of data (HM, ASK, BNR); drafting of the manuscript (HM, BNR); critical revision of the manuscript for important intellectual content (HM, ASK, BNR); statistical analysis (HM); obtaining funding (ASK); and supervision (ASK, BNR).

Address Correspondence to: Benjamin N. Rome, MD, MPH, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, 1620 Tremont St, Ste 3030, Boston, MA 02120. Email: brome@bwh.harvard.edu.

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