Post-approval indications and clinical trials for cardiovascular drugs: some implications of the US Inflation Reduction Act

Abstract

Objective

To describe the historical baseline landscape of cardiovascular drug post-approval activity, including the number and timing of post-approval clinical trials and approved indications. The US Inflation Reduction Act of 2022 (IRA) Drug Price Negotiation Program (DPNP) and its Maximum Fair Prices (MFPs) will affect incentives for investment in post-approval activity such as clinical trials for new indications. While three of the first ten drugs selected for the DPNP and MFP-setting are cardiovascular or antithrombotic drugs, limited attention has been paid to potential cardiovascular drug impacts, and to post-approval innovation.

Methods

For the 65 drugs originally approved by the FDA from 1995 through 2021 for a cardiovascular or antithrombotic indication (60 small molecules and 5 biologics), we develop a novel dataset of industry-sponsored, post-approval clinical trials and FDA-approved label changes for new indications. We analyze their number and timing relative to DPNP drug selection and MFP implementation dates, by drug approval-year cohort.

Results

We find 49% of indications were awarded and 76% of industry-funded clinical trials were completed post-approval, reaching 98% of trials for drugs in the earliest 1995–99 cohort. For the 60 small molecules, 76% of post-approval trials ended five years or more after original drug approval, 65% ended seven or more years after original drug approval (i.e. after potential DPNP selection), and 53% nine or more years after original drug approval (i.e. after potential MFP implementation).

Conclusions

Post-approval FDA indication approvals and clinical trial starts and primary completion dates often occurred after or near new DPNP selection and MFP implementation dates. This has economic consequences for future investment incentives. Post-approval trials for small molecules, longer-duration trials, and larger-enrollment trials, and post-approval indications focused on limited patient populations and older patients could face particular economic challenges.

Keywords:

• Prescription drugs
• indications
• clinical trials
• Inflation Reduction Act
• innovation

JEL classification codes:

• I11
• I10

Transparency

Declaration of financial/other relationships

HG has been a consultant to several government agencies and business organizations and has served as an expert witness in pharmaceutical patent-related litigation on behalf of both plaintiffs and defendants. GL is an employee of Analysis Group, Inc., a consulting company that has provided services to brand-name and generic biopharmaceutical manufacturers and government agencies. The analysis presented was designed and executed entirely by the authors, and therefore, they are responsible for any errors or misstatements.

Author contributions

HG and GL contributed to the conception and design of the study, the analysis and interpretation of the data, the drafting and revising of the manuscript, and gave final approval of the manuscript to be published. All authors agree to be accountable for the aspects of the work as described above.

Acknowledgements

The authors thank Jacob Klimek and Dody Eid of Analysis Group, Inc. for valuable data preparation assistance.

Reviewer disclosures

Peer reviewers on this manuscript have received an honorarium from JME for their review work but have no other relevant financial relationships to disclose.

Notes

i Social Security Act, §1192.

ii Specifically, the price ceiling for a given drug is the lower of either the Part D average net price or Part B average sales price, as relevant, or a percentage of the average non-federal average manufacturer price (“non-FAMP”, the price paid to manufacturers by wholesalers and distributors in the commercial market after wholesaler discounts and chargebacks), that is 75%, 65%, or 40%, depending on whether the drug is a small molecule 9 to 12 years after US approval (75%), a small molecule or biologic 12 to 16 years after approval (65%), or a small molecule or biologic more than 16 years since approval (40%).

iii The only exception being a transitional temporary price floor for small biotech drugs in 2029 and 2030, following expiration of the small biotech exclusion in place for 2026 through 2028. SSA, §1194(d).

iv Social Security Act, §1194.

v Manufacturers who reject CMS’s MFP “final offer” must either be subject to an excise tax that would increase from 186% and reach 1,900% of total US revenues from all purchasers for the drug after nine months, withdraw all drugs from coverage by Medicare and Medicaid (not just the DPNP MFP drug), or, according to recent CMS Guidance, transfer their interest in the drug to another entity. Congressional Research Service, Tax Provisions in the Inflation Reduction Act of 2022 (HR5376). [cited 2024 Feb 1] Available from: https://crsreports.congress.gov/product/pdf/R/R47202. As a result of the magnitude of these impacts, the Congressional Budget Office (CBO) assumed that no manufacturer would opt to reject the MFP and withdraw from the DPNP. Congressional Budget Office. How CBO Estimated the Budgetary Impact of Key Prescription Drug Provisions in the 2022 Reconciliation Act, February 2023. [cited 2024 Feb 1] Available from: https://www.cbo.gov/system/files/2023-02/58850-IRA-Drug-Provs.pdf). Similarly, the Joint Committee on Taxation assumed no revenues would be generated by such an excise tax provision, as no manufacturer would elect to be subject to it. Congressional Budget Office. Re: Effects of Drug Price Negotiation Stemming From Title 1 of H.R. 3, the Lower Drug Costs Now Act of 2019, on Spending and Revenues Related to Part D of Medicare, October 11, 2019. [cited 2024 Feb 1] Available from: https://www.cbo.gov/system/files/2019-10/hr3ltr.pdf.

vi As confirmed by Citeline’s Pharmaprojects database. (Citeline, Inc., New York City).

vii As defined in the Citeline Pharmaprojects database. (Citeline, Inc., New York City).

viii 21 U.S.C. 355a.

ix 42 CFR Part 11.

Additional information

Funding

Funding was provided for this research by Bristol Myers Squibb.