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SummaryBackgroundThe extent to which patients with cancer are willing to accept uncertainty about the clinical benefit of new cancer drugs in exchange for faster access is not known. This study aims to examine preferences for access versus certainty, and to understand factors that influence these preferences. MethodsA US nationally representative sample of older adults were recruited via Cint, an online platform for survey research, to take part in an online discrete choice experiment. To be eligible, respondents had to self-report some experience with cancer—ie, they themselves, a close friend or a family member, previously or currently diagnosed with cancer. In the experiment, respondents chose between two cancer drugs, considering five attributes: functional status, life expectancy, certainty of the survival benefit of a new drug, effect of the drug on a surrogate endpoint, and delay in US Food and Drug Administration (FDA) approval time. The first primary outcome was the relative importance of certainty of survival benefit and wait time to respondents. The second primary outcome was willingness to wait for greater certainty of survival benefit, including subgroup analysis by cancer experience, age, education status, race or ethnicity and income. Secondary outcomes were changes in sensitivity to certainty and wait time, depending on the drug's effect on a surrogate endpoint, respondents' functional status, and life expectancy. The study plan was registered with ClinicalTrials.gov, NCT05936632. FindingsBetween July 7 and July 20, 2023, 998 eligible respondents completed the survey. 870 respondents (461 [53%] male, 406 [47%] female, and three [<1%] other) were included in the final analysis. Respondents showed strong preferences for high certainty of survival benefit (coefficient 2·61, 95% CI 2·23 to 2·99), and strong preferences against a 1-year delay in FDA approval time (coefficient –1·04, 95% CI –1·31 to –0·77). Given very low certainty a drug would provide survival benefit (no evidence linking a surrogate endpoint to overall survival), respondents were willing to wait up to 21·68 months (95% CI 17·61 to 25·74) for high certainty (strong evidence) of survival benefit. A drug's effect on a surrogate endpoint had no significant impact on drug choices (coefficient 0·02, 95% CI –0·21 to 0·25). Older respondents (aged ≥55 years), non-White, lower-income (<$40 000 per year) individuals, and those with the lowest life expectancy, were most sensitive to wait time. InterpretationMany cancer drugs approved through the FDA's accelerated approval pathway do not offer any survival benefit to patients. In this study, individuals expressed strong preferences for certainty that a cancer drug would offer survival benefit. Some individuals also expressed a higher willingness to wait for greater certainty than would be necessary to assess the survival benefit (over progression-free survival benefit) of most cancer drugs used in the metastatic setting. FundingThe London School of Economics and Political Science Phelan United States Centre.

The lancet oncology, 2024-12, Vol.25 (12), p.1635-1643

Preferences for speed of access versus certainty of the survival benefit of new cancer drugs: a discrete choice experiment

SummaryBackgroundNew cancer drugs can be approved by the US Food and Drug Administration (FDA) on the basis of surrogate endpoints while data on overall survival are still incomplete or immature, with too few deaths for meaningful analysis. We aimed to evaluate whether clinical trials with immature survival data generated evidence of overall survival benefit during the period after marketing authorisation, and where that evidence was reported. MethodsIn this retrospective analysis, we searched Drugs@FDA to identify cancer drug indications approved between Jan 1, 2001, and Dec 31, 2018, on the basis of immature survival data. We systematically collected publicly available data on postapproval overall survival results in labelling (Drugs@FDA), journal publications (MEDLINE via PubMed), and clinical trial registries ( ClinicalTrials.gov). The primary outcome was availability of statistically significant overall survival benefits during the period after marketing authorisation (until March 31, 2023). Additionally, we evaluated the availability and timing of overall survival findings in labelling, journal publications, and ClinicalTrials.gov records. FindingsDuring the study period, the FDA granted marketing authorisation to 223 cancer drug indications, 95 of which had overall survival as an endpoint. 39 (41%) of these 95 indications had immature survival data. After a minimum of 4·3 years of follow-up during the period after marketing authorisation (and median 8·2 years [IQR 5·3–12·0] since FDA approval), additional survival data from the pivotal trials became available in either revised labelling or publications, or both, for 38 (97%) of 39 indications. Additional data on overall survival showed a statistically significant benefit in 12 (32%) of 38 indications, whereas mature data yielded statistically non-significant overall survival findings for 24 (63%) indications. Statistically significant evidence of overall survival benefit was reported in either labelling or publications a median of 1·5 years (IQR 0·8–2·3) after initial approval. The median time to availability of statistically non-significant overall survival results was 3·3 years (2·2–4·5). The availability of overall survival results on ClinicalTrials.gov varied considerably. InterpretationFewer than a third of indications approved with immature survival data showed a statistically significant overall survival benefit after approval. Notable inconsistencies in timing and availability of information after approval across different sources emphasise the need for better reporting standards. FundingNone.

The lancet oncology, 2024-06, Vol.25 (6), p.760-769

Overall survival benefits of cancer drugs initially approved by the US Food and Drug Administration on the basis of immature survival data: a retrospective analysis

SummaryBackgroundThe trade-off between comparative effectiveness and reproductive morbidity of different treatment methods for cervical intraepithelial neoplasia (CIN) remains unclear. We aimed to determine the risks of treatment failure and preterm birth associated with various treatment techniques. MethodsIn this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials database for randomised and non-randomised studies reporting on oncological or reproductive outcomes after CIN treatments from database inception until March 9, 2022, without language restrictions. We included studies of women with CIN, glandular intraepithelial neoplasia, or stage IA1 cervical cancer treated with excision (cold knife conisation [CKC], laser conisation, and large loop excision of the transformation zone [LLETZ]) or ablation (radical diathermy, laser ablation, cold coagulation, and cryotherapy). We excluded women treated with hysterectomy. The primary outcomes were any treatment failure (defined as any abnormal histology or cytology) and preterm birth (<37 weeks of gestation). The network for preterm birth also included women with untreated CIN (untreated colposcopy group). The main reference group was LLETZ for treatment failure and the untreated colposcopy group for preterm birth. For randomised controlled trials, we extracted group-level summary data, and for observational studies, we extracted relative treatment effect estimates adjusted for potential confounders, when available, and we did random-effects network meta-analyses to obtain odds ratios (ORs) with 95% CIs. We assessed within-study and across-study risk of bias using Cochrane tools. This systematic review is registered with PROSPERO, CRD42018115495 and CRD42018115508. Findings7880 potential citations were identified for the outcome of treatment failure and 4107 for the outcome of preterm birth. After screening and removal of duplicates, the network for treatment failure included 19 240 participants across 71 studies (25 randomised) and the network for preterm birth included 68 817 participants across 29 studies (two randomised). Compared with LLETZ, risk of treatment failure was reduced for other excisional methods (laser conisation: OR 0·59 [95% CI 0·44–0·79] and CKC: 0·63 [0·50–0·81]) and increased for laser ablation (1·69 [1·27–2·24]) and cryotherapy (1·84 [1·33–2·56]). No differences were found for the comparison of cold coagulation versus LLETZ (1·09 [0·68–1·74]) but direct data were based on two small studies only. Compared with the untreated colposcopy group, risk of preterm birth was increased for all excisional techniques (CKC: 2·27 [1·70–3·02]; laser conisation: 1·77 [1·29–2·43]; and LLETZ: 1·37 [1·16–1·62]), whereas no differences were found for ablative methods (laser ablation: 1·05 [0·78–1·41]; cryotherapy: 1·01 [0·35–2·92]; and cold coagulation: 0·67 [0·02–29·15]). The evidence was based mostly on observational studies with their inherent risks of bias, and the credibility of many comparisons was low. InterpretationMore radical excisional techniques reduce the risk of treatment failure but increase the risk of subsequent preterm birth. Although there is uncertainty, ablative treatments probably do not increase risk of preterm birth, but are associated with higher failure rates than excisional techniques. Although we found LLETZ to have balanced effectiveness and reproductive morbidity, treatment choice should rely on a woman's age, size and location of lesion, and future family planning. FundingNational Institute for Health and Care Research: Research for Patient Benefit.

The lancet oncology, 2022-08, Vol.23 (8), p.1097-1108

Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: a systematic review and network meta-analysis

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Preferences for speed of access versus certainty of the survival benefit of new cancer drugs: a discrete choice experiment

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Overall survival benefits of cancer drugs initially approved by the US Food and Drug Administration on the basis of immature survival data: a retrospective analysis

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Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: a systematic review and network meta-analysis

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