Retrospective Study Suggests Large Proportion of EU-Approved Oncology Drugs Offer Minimal or No Added Benefit

Data from a retrospective cohort study showed that a substantial number of oncology drugs approved by the European Medicines Agency (EMA) between 1995 and 2020 offer minimal or no added benefit, particularly for agents with expedited approval. Moreover, although there appears to be an alignment between added benefit and revenues, drugs with lower levels of added benefit were still able to recover their estimated research and development (R&D) expenses within a relatively short period. Findings were published in The BMJ.¹

Researchers identified 131 oncology drugs that covered 166 indications, which were approved between the 25-year period. These drugs were evaluated for their added benefit by at least 1 organization, translating to 458 added benefit ratings. Added benefit was defined as a health technology’s therapeutic value vs at least 1 alternative treatment—typically the standard of care within the given indication.

Among those ratings, 13% (n = 59) of drugs were deemed as having major added benefit, 23% (n = 107) demonstrated substantial benefit, 23% (n = 103) had a minor benefit, and 41% (n = 189) were classified as having negative or nonquantifiable benefit. Drugs that were approved under conditional marketing authorizations or authorizations under exceptional circumstances were associated with higher rates of negative or nonquantifiable added benefit compared with standard marketing authorizations (relative risk, 1.53; 95% CI, 1.23-1.89).

Findings showed that the median time to offset median R&D costs was 3 years; however, the median time to offset median R&D costs was 4 years for drugs approved under conditional marketing authorizations. Notably, 91% (n = 50 of 55) evaluable drugs recovered R&D costs within 8 years. Treatments with higher benefit were generally associated with higher revenues.

“Policy makers should evaluate whether current regulatory and reimbursement incentives effectively promote development of the most effective drugs for patients with the greatest needs,” lead study author Francine Brinkhuis, MSc, and colleagues, wrote. Brinkhuis is a PhD candidate in the Division of Pharmacoepidemiology and Clinical Pharmacology of the Utrecht Institute for Pharmaceutical Sciences at Utrecht University in the Netherlands.

Investigators identified drugs approved in the European Union between 1995 and 2020, excluding veterinary drugs, non-oncology drugs, generics, biosimilars, refused drugs, diagnostics, and duplicates. Added benefit ratings were pulled from reports from organizations such as health technology agencies in Europe and the United States, medical oncology societies, and a drug bulletin. The ratings were then recategorized to major, substantial, minor, or negative/nonquantifiable benefit.

Publicly available financial reports from pharmaceutical companies were compared with published estimates of R&D expenses. The median R&D cost was estimated to be $684 million (£535 million; €602 million; range, $166 million-$2.06 billion), adjusted to 2020 values.

To account for drugs without revenue data, investigators conducted a sensitivity analysis. Utilizing a conservative approach, investigators assumed that these missing agents did not offset the estimated R&D expenses during the follow-up period of the study, thus decreasing the proportion of drugs that offset R&D expenses.

Researchers analyzed the association between added benefit and revenue for the overall cohort and for subgroups, based on EMA approval pathway.

Among the 156 oncology drugs identified for the study, financial data were available for 109, which comprised the revenue cohort. Of those, 43 were evaluated by at least one organization, had 3 years or more of revenue data, and were linked with a single indication at the end of the follow-up period.

Additional data from a linear regression analysis showed that drugs with major or substantial added benefit generated a median cumulative revenue at 3 years after market entry that was $502 million and $506 million higher compared with drugs without added benefit, respectively.

A subgroup analysis demonstrated that in added benefit ratings for drugs approved through standard authorization (n = 341), 36% (n = 124) were negative or unquantifiable. That rate was higher for drugs approved through conditional marketing authorizations (57%; n = 56/98) and authorizations under exceptional circumstances (47%; n = 9/19). Drugs approved through conditional marketing authorization alone (risk ratio, 1.57; 95% CI, 1.26-1.96) and in combination with authorizations under exceptional circumstances (risk ratio, 1.53; 95% CI, 1.23-1.89) were more likely to receive a negative or nonquantifiable added benefit rating vs drugs approved through the standard pathway.

“There is often a great need for new drugs,” study co-author Lourens T. Bloem, PharmD, MSc, of Utrecht University, stated in a news release.2 “This is especially true in oncology, where the medical need is often high. Expedited approval may be a way to have patients benefit from a new drug, but we question whether added benefit can eventually be proven, once additional data are available. Therefore, it is essential to continue to monitor the actual added benefit of these types of drugs and assess the costs involved.”

Additionally, evaluable drugs approved with conditional marketing authorization (n = 17) had a 5-year median cumulative revenue of $1.196 billion compared with $2.301 billion for standard approvals (n = 58). However, this difference did not reach statistical significance (P = .07).¹

The minimum R&D costs of $166 million were exceeded within 2 years for standard and conditional marketing approvals; the maximum R&D costs of $2.06 billion were exceeded at 5 and 8 years, respectively. After 8 years, 90% (n = 37/41) of standard approvals and 89% (n = 8/9) conditional approvals offset the median R&D costs.

Study authors wrote that accelerated pathways are intended to expedite the availability of promising drugs; however, these conditional approvals can be associated with a lack of comprehensive evidence, creating a misalignment between regulatory and reimbursement policies. Although drugs with high added benefit were associated with higher revenue, creating an incentive for developers to pursue high-value drugs, the ability of lower-benefit drugs to recover R&D costs hampers that incentive.

“It is crucial for policy makers to assess whether the current regulatory and reimbursement incentives are properly structured to promote and facilitate the development of the most effective drugs for patients with the greatest needs,” study authors concluded.

References

1. Brinkhuis F, Goettsch WG, Mantel-Teeuwisse AK, Bloem LT. Added benefit and revenues of oncology drugs approved by the European Medicines Agency between 1995 and 2020: retrospective cohort study. BMJ. 2024;384(e077391). doi:10.1136/ bmj-2023-077391
2. Many new oncology drugs approved in the EU lack proof of added benefit. News release. Utrecht University. Published February 28, 2024. Accessed February 28, 2024.https://www.uu.nl/en/news/many-new-oncology-drugs-approved-in-the-eu-lack-proof-of-added-benefit