From Thalidomide to Ribociclib: Why Approving Without Mature Data Can Repeat History

Introduction
In the global imagination, the United States Food and Drug Administration (FDA) established itself as a benchmark of regulatory rigor in the early 1960s, thanks to its decisive role in the case of thalidomide.

This drug, originally developed in West Germany, was presented as an “exceptional” breakthrough for controlling nausea and vomiting during pregnancy. Its commercialization in several European countries in the late 1950s was received as a safe solution, free from apparent toxicity. However, within a few years, an epidemic of severe congenital malformations emerged — mainly phocomelia (severe shortening of limb length) and amelia (total absence of limbs) — which affected thousands of newborns.

While Europe and other countries authorized thalidomide without detecting the risk, the FDA — thanks to the resistance and meticulousness of reviewer Frances Oldham Kelsey — denied its approval in the U.S. due to insufficient safety data in pregnancy. This decision not only avoided a massive health crisis on U.S. soil but also cemented the agency’s international reputation as a guardian of evidence and regulatory caution.

Today, more than six decades later, thalidomide remains a paradigmatic example of how rigorous evaluation and resistance to commercial pressures can save lives, and of why the benefit–risk balance must be re-evaluated with the same firmness even when preliminary trial results appear promising.

From the Thalidomide Case to the Current Debate on Ribociclib
Just as in the 1960s the FDA avoided the thalidomide tragedy by prioritizing scientific evidence over commercial pressure, today regulators face a different challenge but with common elements: deciding whether a drug with a statistically significant but clinically modest benefit, and with relevant toxicity, should be approved or funded for a broad population.

The NATALEE trial evaluated the adjuvant use of ribociclib (Kisqali) in early HR+/HER2– breast cancer, an indication with a high risk of recurrence. Published in the New England Journal of Medicine in 2023, it reported an absolute improvement of 3.3 points in invasive disease–free survival (iDFS) at three years compared to standard endocrine therapy. However, this gain came alongside a significant increase in severe adverse events — with treatment interruptions close to 20% and grade ≥3 neutropenia in more than 40% of patients — and without maturity in overall survival data.

While in the United States the drug advances in its clinical use, the Haute Autorité de Santé (HAS) of France reviewed the same evidence and concluded that the benefit–risk balance does not justify its incorporation into the national therapeutic strategy. The difference is not in the numbers, but in the interpretation: the FDA has historically been seen as the most rigorous authority, but in this case, Europe adopts the more conservative stance.

NEJM (2023) – NATALEE Interim Analysis

• Data cut / follow-up: Median 34 months (cut: January 11, 2023)

• Population: 5,101 patients, HR+/HER2–, stages II–III (includes high-risk N0)

• Primary outcome (iDFS): 3 years: 90.4% (RIBO) vs 87.1% (control) – HR 0.75 (95% CI: 0.62–0.91, p=0.003)

• Secondary outcome (OS): Not mature

• Safety / Toxicity: ≥G3 AE: 62.5% (≥G3 neutropenia: 44.3%); discontinuation due to AE: 18.9%

• Interpretation: Statistically significant benefit in iDFS, consistent across subgroups; relevant toxicity; OS not yet mature.

HAS (2025) – Regulatory Evaluation

• Data cut / follow-up: Median 33.3 months (later cut)

• Population: Same as NEJM

• Primary outcome (iDFS): Absolute difference ≈ 3.1 points; HR similar to NEJM

• Secondary outcome (OS): OS not mature, no clear trend

• Safety / Toxicity: ≥G3 AE: ~64%; discontinuation due to AE: 21.1%

• Interpretation: Modest absolute benefit, high toxicity; iDFS not validated as an OS surrogate in adjuvant setting; unfavorable risk–benefit balance for funding.

ClinicalTrials.gov – NCT03701334

• Data cut / follow-up: Initial design (2018)

• Population: Same population and criteria as NEJM and HAS

• Primary outcome (iDFS): iDFS as primary, OS and DRFS as secondary

• Secondary outcome (OS): —

• Safety / Toxicity: Continuous safety monitoring planned

• Interpretation: Open-label trial, 3 years ribociclib + AI vs AI alone; total follow-up estimated until December 2025.

Main differences found among the three sources

• Data cut-off timing

  • NEJM: interim analysis with cut-off January 11, 2023.

  • HAS: later cut-off (33.3 months), slightly adjusting percentages and adverse events.

• Magnitude of absolute benefit

  • NEJM: +3.3 points in iDFS at 3 years.

  • HAS: +3.1 points in iDFS at 3 years.

• Interpretation of the primary outcome (iDFS)

  • NEJM: considers the benefit statistically and clinically relevant.

  • HAS: considers that the absolute benefit is modest and that iDFS is not validated as a reliable OS surrogate in this context.

• Severe adverse events (≥G3)

  • NEJM: 62.5% (≥G3 neutropenia: 44.3%), discontinuation due to AE: 18.9%.

  • HAS: ~64%, discontinuation due to AE: 21.1%.

• Regulatory approach

  • NEJM: positive clinical interpretation aimed at adoption.

  • HAS: conservative regulatory interpretation, unfavorable to incorporation into the national strategy.

• ClinicalTrials.gov

  • Reference document of the initial design, without analyzed results, but confirms OS and DRFS as secondary and total follow-up planned until December 2025.

BBIU Opinion
In the 1960s, the FDA gained worldwide prestige by resisting the pressure to approve thalidomide in the United States. Although the drug was presented as an exceptional solution for nausea and vomiting in pregnancy — and was widely used in Europe — it ended up causing an epidemic of phocomelia and amelia in thousands of newborns. The tragedy showed that even drugs with a clear benefit for symptoms can cause irreversible harm when approved without the complete evidence and maturity of data required.

The NATALEE case exposes a similar dilemma, albeit in an oncological context: a drug that offers a statistically robust but clinically modest benefit, accompanied by relevant toxicity and immature overall survival data.

From BBIU’s perspective, the question is not whether ribociclib “works” in terms of iDFS, but whether the benefit obtained justifies mass exposure to toxicity and cost, considering that:

• iDFS, although accepted as an endpoint in some contexts, is not validated as an OS surrogate in early HR+/HER2– breast cancer.

• The absolute magnitude of the benefit (+3.1–3.3 points) means that most patients will not experience a real impact on their prognosis, despite being exposed to a risk of severe neutropenia and other toxicities.

• Treatment interruptions close to 20% show that clinical tolerance is a limiting factor, especially in uncontrolled settings such as real-world practice.

In early-stage breast cancer — a population potentially cured with standard treatment — the threshold of acceptable risk and cost is much higher, and the cost/benefit equation of ribociclib is not supported by the current evidence.

The thalidomide story reminds us that regulatory systems must not yield to the seduction of preliminary results without maturity in critical data. Commercial pressure and scientific enthusiasm are legitimate forces in innovation, but when it comes to adjuvant therapies in a potentially cured population, the threshold of benefit must be higher and the analysis more conservative.

In this sense, the position of the French HAS — although stricter than that of the FDA — is aligned with a principle of prudence that has historically proven its value: approving early is easy; withdrawing late is devastating.