Predictors of withdrawal of anticancer drug indications granted accelerated approval: a retrospective cohort study
Notice bibliographique
Résumé
Background: The accelerated approval pathway allows the FDA to approve drugs for serious conditions based on promising surrogate measures, with confirmatory studies required later. If subsequent testing shows an unfavorable benefit-risk profile, the indication may be withdrawn. This study aimed to identify factors associated with the withdrawal of drug indications following accelerated approval. Methods: In this retrospective cohort study, we identified FDA-approved drugs for solid and hematologic cancers from 1992 to 2022 and extracted factors present at the time of accelerated approval, including pivotal trial characteristics, outcomes, and confirmatory study initiation timing from drug labels and published reports. Clinical benefit was assessed using the European Society of Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS), with high benefit as A-B/4-5 and low as C/≤2. Multivariable logistic regression identified factors associated with drug indication withdrawal. Findings: Among 167 accelerated approval indications for 113 anticancer drugs, by August 2024, 102 (61%) had been converted to regular approval, 31 (19%) were withdrawn, and the remaining 34 (20%) were ongoing accelerated approvals. Of the 133 indications that were either converted or withdrawn, 52 (39%) were approvals for hematologic cancer drugs, and 41 (31%) supported genome-targeted drug approvals. Among 83 eligible indications, 46 (55%) were granted Breakthrough Therapy designation. In the 133 pivotal trials, 112 (84%) used response rate as the primary endpoint, and 66% (86/130) offered low clinical benefit on the ESMO-MCBS. In multivariable analysis, Breakthrough Therapy designations (OR 0.26; 95% CI, 0.10-0.75; p = 0.01) and indications for genome-targeted therapies (OR 0.26; 95% CI, 0.08-0.80; p = 0.02) were associated with lower withdrawal rates. Higher withdrawal rates were associated with low ESMO-MCBS scores (OR, 4.63; 95% CI, 1.50-14.33; p = 0.008). Interpretation: Accelerated approvals based on early data suggesting limited clinical benefit tend to have higher withdrawal rates, whereas therapies with Breakthrough Therapy designation and genome-targeted mechanisms are more likely to validate clinical benefits and achieve regular approval. Patients and healthcare providers should consider these factors when evaluating whether to use therapies granted accelerated approval. Funding: Alfonso Martín Escudero Foundation (to AT) and Arnold Ventures, the Commonwealth Fund, and Kaiser Permanente Institute for Health Policy Research (to ASK).
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».