Five years of EMA-approved systemic cancer therapies for solid tumours—a comparison of two thresholds for meaningful clinical benefit

Grössmann, N.; Paggio, Joseph C Del; Wolf, Sarah; Sullivan, Richard; Booth, Christopher M.; Rosian, Katharina; Emprechtinger, Robert; Wild, Claudia

doi:10.1016/j.ejca.2017.05.029

Cited by 38 publications

(36 citation statements)

References 22 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, whereas the academic trials included a range of nondrug interventions, with more than half (58%) in the curative setting, the industry-sponsored trials were weighted heavily (79%) toward drug trials in the noncurative setting. This preponderance of trials in noncurative settings is supported in other studies [8,18,19].…”

Section: Clinical Benefitssupporting

confidence: 69%

“…The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a tool used to assess the clinical benefit of novel cancer therapies [10] and has been reported to correlate with clinically relevant survival gains [11]. Using both the ESMO-MCBS and a modified version adapted for Health Technology Assessment (HTA) [12], an analysis of 5 years (2011-2016) of EMA cancer drug approvals showed that 89 and 79% of therapies did not meet the MCBS or modified threshold respectively [13]. A USA analysis, using the ESMO-MCBS threshold, showed that over the period of 2006-2016, only 43.8% of randomized controlled trials supporting FDA approvals for new cancer drugs met the MCB threshold [14].…”

Section: Clinical Benefitsmentioning

confidence: 99%

See 1 more Smart Citation

Biased by design? Clinical trials and patient benefit in oncology

2019

View full text Add to dashboard Cite

trial design • drug development • drug registration • patient benefit • risks of bias Pivotal clinical trials: biased? A recent study by Naci et al. examined the design characteristics, risks of bias and reporting adequacies of pivotal randomized controlled trials of cancer drugs approved by the EMA in the period 2014-2016 [1]. During this period, 32 new cancer drugs were approved by the EMA on the basis of 54 pivotal trials-of these, 41 (76%) were randomized controlled trials and 13 (24%) were non-randomized or single arm trials. The study reported that 49% of trials were judged to be at high risk of bias based on aspects of their design, conduct or analysis. Furthermore, only 10 (26%) randomized controlled trials measured overall survival as a primary end point, with the majority of trials evaluating surrogate metrics such as progression free survival or response rates. Furthermore, there were also discrepancies between scientific publications and regulatory documentation, thereby raising concerns of reporting inadequacies and risks of bias in both sources of information. These findings raise serious questions regarding clinical trial design and the drug registration process, particularly with regards to patient benefits. The problem is not restricted to Europe alone; previous studies have also raised concerns with US FDA approvals. For example, a study that assessed all FDA approvals of novel drugs, across all areas of medicine in the period 2005-2012, reported wide disparities in pivotal trial characteristics across different therapeutic areas [2]. While overall 219 of 448 (48.9%) pivotal trials included a surrogate end point, for cancer it was 46 of 55 (83.6%). Pivotal trials in cancer were also less likely to be randomized, double-blinded or to not include a placebo or active comparator. Another notable finding was that most cancer approvals were on the basis of a single pivotal trial, whereas for other therapeutic areas, approvals were based on two to four pivotal trials. A different study examining FDA cancer drug approvals based on response rate showed that many cancer drugs are approved based on low or modest response rates, typically tested in single-arm studies [3]. It could be argued that the surrogate end points used in such pivotal trials are acceptable as they correlate to overall survival and/or quality of life in the long term [4]. However, the data to support such an argument is lacking [5]. A recent systematic review of the association between surrogate end points and overall survival in oncology showed that the vast majority (82%) are low or moderate in strength [6]. A study of FDA approvals of cancer drugs during 2008-2012, a period in which 67% of approvals were made on the basis of a surrogate end point, assessed whether subsequent data emerged to show an increase in overall survival [7]. With a median follow-up of 4.4 years, the study reported that of 36 drugs approved with surrogate end points, only five subsequently reported improved overall survival in a randomized controlled trial, 18...

show abstract

Section: Clinical Benefitssupporting

confidence: 69%

Section: Clinical Benefitsmentioning

confidence: 99%

Biased by design? Clinical trials and patient benefit in oncology

2019

View full text Add to dashboard Cite

show abstract

“…Se usan cuando los desenlaces críticos e importantes son raros o se presentan a largo plazo (5,39). Otras razones para usar estos desenlaces son: 1) las terapias que reciben los pacientes antes y después de los estudios, lo que dificulta evaluar el efecto clínico de la intervención; 2) la posible alteración de la SG al cruzar los pacientes a nuevas terapias luego de las investigaciones, cuando se encuentra una adecuada eficacia de estas (21); 3) la historia natural de algunos Ca muestra una SG larga, explicada por efecto del diagnóstico y el tratamiento tempranos, lo que obligaría a realizar investigaciones de larga duración con muestras grandes, lo que dificulta su realización (39) y; 4) el uso de desenlaces sustitutos, acorta la duración de las investigaciones y el tiempo de aprobación de los medicamentos (7,14).…”

Section: ¿Por Qué Se Usan Los Desenlaces Sub-ro-gados En Los Estudiosunclassified

“…Los tratamientos anti-Ca tienen un alto costo, situación que viola los principios éticos, justicia y equidad; al promover terapias con pocos beneficios clínicos, se pueden negar recursos que permitan implementar en forma temprana estrategias diagnósticas y de intervención para las neoplasias malignas (7,13,14).…”

Section: ¿Existe Lucro Por La Aprobación De Medi-camentos Anti-cáncer?unclassified

“…La mayoría de los tratamientos anti-Ca tienen precios altos, muchos de ellos ofrecen poca mejoría en la disminución de la mortalidad o en la percepción de CVRS y en general pueden producir problemas serios de seguridad (13,14). Entre 1975Entre -1979, la mediana del costo mensual para los nuevos medicamentos fue de 120 dólares, mientras para 2010-2014 alcanzó los diez mil dólares, representando un crecimiento exponencial del precio.…”

Section: Introductionunclassified

See 1 more Smart Citation

Investigación de la eficacia y criterios de aprobación de los tratamientos con medicamentos para pacientes con cáncer: una revisión

Arango-Vélez

Arroyave-Hoyos

Tobón

et al. 2018

iatreia

View full text Add to dashboard Cite

Los diversos trastornos malignos de los tejidos humanos afectan a una gran proporción de personas de Colombia y el mundo, lo que ha llevado al incremento de los tratamientos farmacológicos para estas enfermedades, sin que se tenga claro el real beneficio para los pacientes que los reciben. Además, se tienen dudas sobre la calidad de la evidencia en la que se basan las instituciones que avalan los tratamientos anti-cáncer con medicamentos, como son la Food and Drug Administration (FDA) y la European Medicines Agency (EMA). Este trabajo tuvo como objetivo conocer cómo se realizan los estudios de eficacia y la forma en que se aprueban los tratamientos con medicamentos que se ofrecen a las personas con cáncer; se realizó una revisión narrativa, que se basó en la formulación de preguntas que guiaron el desarrollo de los temas que se incluyeron en ella. Se hizo la búsqueda de la información en Pubmed de una forma estructurada, no sistemática. Se incluyeron artículos publicados en inglés y español, sin restricción por fecha de publicación.

show abstract

Clinical Value of Molecular Targets and FDA-Approved Genome-Targeted Cancer Therapies

Tibau,

Hwang,

Molto

et al. 2024

JAMA Oncol

View full text Add to dashboard Cite

ImportanceThe number of new genome-targeted cancer drugs has increased, offering the possibility of personalized therapy, often at a very high cost.ObjectiveTo assess the validity of molecular targets and therapeutic benefits of US Food and Drug Administration–approved genome-targeted cancer drugs based on the outcomes of their corresponding pivotal clinical trials.Design and SettingsIn this cohort study, all genome-targeted cancer drugs that were FDA-approved between January 1, 2015, and December 31, 2022, were analyzed. From FDA drug labels and trial reports, key characteristics of pivotal trials were extracted, including the outcomes assessed.Main Outcomes and MeasuresThe strength of evidence supporting molecular targetability was assessed using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Clinical benefit for their approved indications was evaluated using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS). Substantial clinical benefit was defined as a grade of A or B for curative intent and 4 or 5 for noncurative intent. Molecular targets qualifying for ESCAT category level I-A and I-B associated with substantial clinical benefit by ESMO-MCBS were rated as high-benefit genomic-based cancer treatments.ResultsA total of 50 molecular-targeted drugs covering 84 indications were analyzed. Forty-five indications (54%) were approved based on phase 1 or phase 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials, and 48 (57%) were approved on the basis of subgroup analyses. By each indication, 46 of 84 primary end points (55%) were overall response rate (median [IQR] overall response rate, 57% [40%-69%]; median [IQR] duration of response, 11.1 [9.2-19.8] months). Among the 84 pivotal trials supporting these 84 indications, 38 trials (45%) had I-A ESCAT targetability, and 32 (38%) had I-B targetability. Overall, 24 of 84 trials (29%) demonstrated substantial clinical benefit via ESMO-MCBS. Combining these ratings, 24 of 84 indications (29%) were associated with high-benefit genomic-based cancer treatments.Conclusions and RelevanceThe results of this cohort study demonstrate that among recently approved molecular-targeted cancer therapies, fewer than one-third demonstrated substantial patient benefits at approval. Benefit frameworks such as ESMO-MCBS and ESCAT can help physicians, patients, and payers identify therapies with the greatest clinical potential.

show abstract

Five years of EMA-approved systemic cancer therapies for solid tumours—a comparison of two thresholds for meaningful clinical benefit

Cited by 38 publications

References 22 publications

Biased by design? Clinical trials and patient benefit in oncology

Biased by design? Clinical trials and patient benefit in oncology

Investigación de la eficacia y criterios de aprobación de los tratamientos con medicamentos para pacientes con cáncer: una revisión

Clinical Value of Molecular Targets and FDA-Approved Genome-Targeted Cancer Therapies

Contact Info

Product

Resources

About