Table 1.
Overview of major published studies addressing contemporary clinical oncology trials and regulatory drug approvals.
| Overall survival: clinical trials leading to regulatory drug approvals with a limited OS benefit | ||
| YOP | Timespan study | Results |
| 2014 | 2002–2014 | Solid cancer drug approvals by FDA: 71 approvals with median OS of 2.1 months [16] |
| 2016 | 2003–2013 | 62 new drugs approved by both FDA and EMA: 23 (43%) with OS improvement ≥3 months, 6 (11%) <3 months, 8 (15%) unknowns, with no evidence of OS increment in remaining approvals. Mean OS gain of all approvals 3.43 (SD 0.63) months relative to treatment available in 2003 [17] |
| 2017 | 2009–2013 | EMA approved 48 cancer drugs for 68 indications: at the time of market approval, median OS benefit was 2.7 months (range 1.0–5.8) in 24/68 (35%) of indications [14] |
| 2020 | 2000–2016 | First time FDA approval of novel cancer drugs for any type of cancer; 92 novel drugs for 100 indications based on 127 trials: median OS 2.40 months (IQR 1.25–3.89) [15] |
| 2021 | 2011–2020 | pCODR-approved drugs: 78/104 submissions received positive recommendation; median OS gain in approved drugs 3.7 (IQR 2.7–6.5) months as opposed to median OS increase of 1.9 (IQR 1.4–4.5) months in rejected submissions [18] |
| 2021 | 2010–2020 | 298 RCTs of systemic treatment in breast, colorectal and NSCLC published in high-impact journals: 86 (29%) had OS as the primary endpoint; in trials with a positive outcome, median OS increase 3.5 (IQR 2.5–6.6) months [19] |
| Medical society value-based scales: drugs tested in oncology RCTs are assessed as meaningful in less than half of cases in most studies | ||
| YOP | Timespan study | Results |
| 2014 | 2002–2014 | Solid cancer drug approvals by FDA: 30/71 (42%) would have met ASCO-CRC threshold for a clinically meaningful benefit to patients (2.5 months and ≥25–30% OS increase), 9/71 (13%) uncertain benefit [16] |
| 2017 | 2011–2015 | All RCTs on breast, pancreas, lung and colorectal cancer: 277 RCTs; 138 (50%) favour experimental group with 43/138 (31%) meeting ESMO-MCB benefit threshold (score 4 or 5 in a palliative setting, score A or B in curative setting) [31] |
| 2017 | 2011–2015 | All RCTs on breast, pancreas, lung and colorectal cancer with significant difference favouring experimental group: 277 RCTs; median ASCO-VF score 25 (range 2–77; score ≥45 considered substantial benefit) and 38% met the ESMO-MCB benefit threshold [30] |
| 2017 | 2009–2013 | EMA approved 48 cancer drugs for 68 indications: 23 associated with OS benefit; 11/23 (48%) were scored as meaningful with the ESMO-MCB scale [14] |
| 2017 | 2000–2015 | All new biologics and molecular entities that were FDA approved; 37/51 (72%) new drugs evaluated: 13/37 (35%) drugs showed meaningful benefit by ESMO-MCB with median ASCO-VF 37 (IQR 20–52) [32] |
| 2017 | 2006–2016 | FDA-approved 63 drugs for 118 indications; 46 (43.8%) met the ESMO-MCB threshold of clinical benefit [33] |
| 2017 | 2011–2016 | EMA approved 38 solid cancer drugs based on 70 studies; 11 and 21% met approval thresholds of adapted and original ESMO-MCB, respectively [34] |
| 2020 | 2009–2017/19a | New drugs for solid cancers approved by both FDA and EMA; 47 drugs for solid cancers; ESMO-MCB 13/47 (28%) met the benefit threshold and 15/36 (42%) met substantial benefit threshold of the ASCO-VF (not applicable to 11 indications) [38]. |
| 2020 | 2012–2017 | 106 trials led to FDA approvals of 52 drugs for 96 indications: thresholds of clinical benefit were met in 43% of ASCO-VF, 34% of ESMO-MCB, 73% of ASCO-CRC (OS >2.5 months and PFS > 3 months) and 69% of NCCN Evidence Blocks (score 4 and 5 and combined 16 or higher for efficacy, safety, quality and consistency of evidence, affordability) [35] |
| 2021 | 2011–2020 | pCODR-approved drugs: 78/104 submissions received positive recommendation; 61% of accepted submissions considered of benefit based on ESMO-MCBS as to 19.2% in rejected submissions [18] |
| 2021 | 2006–2019 | FDA approved 55 oncology drug indications scorable with ASCO-VF with subsequent publications relevant for reassessing ASCO-VF scoring: at FDA approval 40.0% substantial benefit (score ≥45), 49.1% low (score ≤40) and 10.9% intermediate. At 3 years post approval based on 9 follow-up publications, despite changes in individual scores, 40.0% remained substantial, 50.9% low (score ≤40) and 9.1% intermediate [37] |
| 2021 | 2006–2017 | 214 FDA and 170 EMA approvals with 40 and 58% of indications including QOL assessment in trials; using ASCO-VF and ESMO-MCB scales, QOL bonus criteria were detected in 13 and 17% of FDA and 21 and 24% of EMA approvals [36] |
| Quality of life: studies show PROs are often not studied and that adherence to CONSORT-PRO guidelines in oncology drug research is not optimal | ||
| YOP | Timespan study | Results |
| 2015 | 2007–2011 | 325 phase 3 RCTs reviewed only 48% of trials reporting PROs. PRO reporting with mean PRO RQS 5 on an 11-point scale [22] |
| 2015 | 2004–2013 | RCTs including PRO endpoint identified in 557 RCTs; <50% reported at least 4/6 CONSORT-PRO items [25] |
| 2016 | 2003–2013 | 62 new drugs approved by FDA and EMA: 17 (32%) demonstrated improvement in QOL based on empirical evidence [17] |
| 2017 | 2009–2013 | EMA approved 48 cancer drugs for 68 indications: 9/68 (13.2%) associated with an increase in QOL [14] |
| 2019 | 2014–2017 | Of 160 published RCTs based on NIHR registered protocols with PROs included in endpoints, 61 (38.1%) did not include PROs in any publication. The remaining trials scored a mean of 3 (SD 3) of 14 CONSORT-PRO checklist items in published PRO findings [26] |
| 2019 | 2004–2019 | 649 RCTs with PRO reporting, 72 (11.1%) of trials analysed included patients ≥70 years; only 24 (33.3%) had high-quality PRO reporting according to ISQOLR-PRO standards [23] |
| 2020 | 2014–2019 | 71 RCTs reporting on PROs in haematological malignancies were identified with the quality of reporting in RCTs employing CONSORT-PRO extension being higher than trials not citing this extension [24] |
| 2020 | 2011–2018 | FDA approved 42 immunotherapy indications with PROs published in 21/44 (47.7%) of the trials. The mean score of a 24-point PRO Endpoint Analysis Score was 12.71 (range 5–27, SD 3.71) [27] |
| Surrogate endpoints: oncology trials use of surrogate endpoints. | ||
| YOP | Timespan study | Results |
| 2011 | 1992–2010 | FDA approved 35 oncology drugs for 47 indications via accelerated approval pathway: all studies based on surrogate endpoints. Conversion to regular approval in 26/47 (55.3%) indications; 16/26 still based on a surrogate endpoint [44] |
| 2014 | 2005–2012 | FDA approved 188 novel agents for 206 indications based on 448 trials; 55/448 are cancer trials of which 83.6% measured a surrogate endpoint [40] |
| 2015 | 2009–2013 | 51 FDA approved oncology for 63 indications; 70% of approvals based on a surrogate endpoint [41] |
| 2015 | 2008–2012 | FDA approved 36/54 drugs based on a surrogate endpoint [47] |
| 2017 | 2009–2013 | EMA approved 48 cancer drugs for 68 indications: surrogate endpoint in 53 of 72 RCT’s (73%) [14] |
| 2018 | 1992–2017 | FDA granted AA for 64 drugs for 93 indications; all based on surrogate endpoints [42] |
| 2019 | 2014–2016 | EMA approved 32 new drugs based on 54 trials; 39/41 were published RCT’s with 29/39 (74%) evaluating surrogate endpoints as a primary outcome measure [46] |
| 2019 | 2006–2018 | FDA approved 59 drugs for 85 indications based on RR [39] |
| 2019 | 1992–2017 | AA was granted for 93 cancer drug indications based on surrogate endpoints; confirmatory trials in 19 (20%) measured the same surrogate endpoint, 20 (21%) a different surrogate endpoint, 19 (20%) reported OS improvement with the remaining trials not reported at the time of publication [43] |
| 2021 | 2011–2020 | pCODR approved drugs: 78/104 submissions received positive recommendation; 67.9% surrogate endpoints in approved indications, as opposed to 76.9% in rejected submissions [18] |
| 2021 | 2016–2020 | 49 drug approvals by FDA based on 52 trials for haematological malignancies: 84% report surrogate endpoints [45] |
| 2021 | 2010–2020 | 298 RCTs of systemic treatment in breast, colorectal and NSCLC published in high impact journals compared to RCTs from 1995–2004 and 2005–2009: PFS as an endpoint: 0 (1995–2004), 18 (2005–2009) and 42% (2010–2020) [19] |
| Non-randomised and single-arm studies: drug approvals are increasingly based on single RCTs or non-randomised single-arm studies. | ||
| YOP | Timespan study | Results |
| 2011 | 1992–2010 | FDA approved 35 oncology drugs for 47 indications via accelerated approval pathway: 28/47 (59.6%) were based on non-RCTs. Conversions to regular approval occurred in 26/47 (55.3%) indications; 24/26 (92%) based on RCTs [44] |
| 2014 | 2005–2012 | FDA approved 188 novel agents for 206 indications based on 448 trials; 55/448 are cancer trials; 52.7% not randomised [40] |
| 2016 | 1999–2014 | 76 pharmaceuticals (44/795 EMA, 60/774 FDA) approved without RCT; 34 haematological, 15 oncological indications [56] |
| 2017 | 2009–2013 | EMA approved 48 cancer drugs for 68 indications: 8 (12%) single-arm study [14] |
| 2018 | 1992–2017 | FDA granted AA for 64 drugs for 93 indications; 67 of 93 (72%) indications were based on single-arm trials [42] |
| 2019 | 2006–2018 | FDA approved 59 drugs for 85 indications based on RR: only 9% were RCTs [39] |
| 2020 | 2000–2016 | First time FDA approval of novel cancer drugs for any type of cancer; 92 novel drugs for 100 indications based on 127 trials: 95 (74.8%) nonrandomized [15] |
| 2020 | 2011–2018 | FDA approved 42 immunotherapy approvals; 21/44 (477%) were single-arm trials [27] |
| 2020 | 2014–2019 | 187 trials led to 176 approvals by FDA for 75 anticancer drugs; 64 (34%) were single-arm trials [57] |
| 2021 | 2016–2020 | 49 drug approvals by FDA based on 52 trials for haematological malignancies: 40% non-phase 3 trials [45] |
| 2021 | 2011–2020 | pCODR approved drugs: 78/104 submissions received positive recommendation; 92.3% phase 3 RCT in approved indications, as opposed to 57.7% in rejected submissions [18] |
YOP year of publication, OS overall survival, FDA Food and Drug Administration, EMA European Medicines Agency, SD standard deviation, IQR interquartile range, pCODR pan-Canadian Oncology Drug Review, RCT randomised controlled trial, NSCLC non-small cell lung cancer, ASCO-CRC American Society of Clinical Oncology Cancer Research Committee, ESMO-MCB European Society of Medical Oncology-Magnitude of Clinical Benefit scale, ASCO-VF American Society of Clinical Oncology Value Framework, NCCN National Comprehensive Cancer Network, PRO patient-reported outcome, CONSORT consolidated standards of reporting trials, RQS reporting quality score, NIHR National Institute for Health Research, ISQOLR International Society of Life Research, RR response rate, PFS progression-free survival, AA accelerated approval.
PubMed was searched for all reviews and systematic reviews investigating oncology drugs, approvals, value scales, PRO assessment with publication dates 2000 until the present including search terms such as ‘drugs, approvals, cancer, value, PRO’, and per the study, the ‘similar articles’ link was also assessed. Studies regarding a specific disease indication were not included. Studies were selected according to relevance to the topic of this review.
a2009–2017 for FDA and 2009–2019 for EMA approvals.