Clinical Trial Evidence Supporting US Food and Drug Administration Approval of Novel Cancer Therapies Between 2000 and 2016

Abstract

IMPORTANCE Clinical trial evidence used to support drug approval is typically the only information on benefits and harms that patients and clinicians can use for decision-making when novel cancer therapies become available. Various evaluations have raised concern about the uncertainty surrounding these data, and a systematic investigation of the available information on treatment outcomes for cancer drugs approved by the US Food and Drug Administration (FDA) is warranted. OBJECTIVE To describe the clinical trial data available on treatment outcomes at the time of FDA approval of all novel cancer drugs approved for the first time between 2000 and 2016. DESIGN, SETTING, AND PARTICIPANTSThis comparative effectiveness study analyzed randomized clinical trials and single-arm clinical trials of novel drugs approved for the first time to treat any type of cancer. Approval packages were obtained from drugs@FDA, a publicly available database containing information on drug and biologic products approved for human use in the US.Data from January 2000 to December 2016 were included in this study. MAIN OUTCOMES AND MEASURESRegulatory and clinical trial characteristics were described. For randomized clinical trials, summary treatment outcomes for overall survival, progression-free survival, and tumor response across all therapies were calculated, and median absolute survival increases were estimated. Tumor types and regulatory characteristics were assessed separately. RESULTS Between 2000 and 2016, 92 novel cancer drugs were approved by the FDA for 100 indications based on data from 127 clinical trials. The 127 clinical trials included a median of 191 participants (interquartile range [IQR], 106-448 participants). Overall, 65 clinical trials (51.2%) were randomized, and 95 clinical trials (74.8%) were open label. Of 100 indications, 44 indications underwent accelerated approval, 42 indications were for hematological cancers, and 58 indicationswere for solid tumors. Novel drugs had mean hazard ratios of 0.77 (95% CI, 0.73-0.81; I 2 = 46%) for overall survival and 0.52 (95% CI, 0.47-0.57; I 2 = 88%) for progression-free survival. The median tumor response, expressed as relative risk, was 2.37 (95% CI, 2.00-2.80; I 2 = 91%). The median absolute survival benefit was 2.40 months (IQR, 1.25-3.89 months). CONCLUSIONS AND RELEVANCEIn this study, data available at the time of FDA drug approval indicated that novel cancer therapies were associated with substantial tumor responses but with prolonging median overall survival by only 2.40 months. Approval data from 17 years of clinical trials suggested that patients and clinicians typically had limited information available regarding the benefits of novel cancer treatments at market entry.

An urgent call to raise the bar in oncology

“… 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 ...…”

“… 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 controll...…”

An open science pathway for drug marketing authorization—Registered drug approval

“…Too often, trials ask the wrong question: Trials may explore superiority over an inappropriately weak comparator such as placebo when superiority versus an already approved active comparator would be more clinically relevant [ 4 ]. Trials can also be underpowered [ 4 ], focus on surrogate markers, or omit clinically relevant outcomes [ 5 ]. Moreover, the regulator is laissez-faire with respect to trial publication in journal articles, allowing the sponsor to freely choose which findings to include and how to frame them, often diverging starkly from the regulator’s reviews.…”

“…Systematic investigations demonstrate that approvals based on weak and limited evidence are the rule rather than the exception [ 4 , 5 ], although there are notable instances where approval was based on strong evidence, such as the recent case of Coronavirus Disease 2019 (COVID-19) vaccines. As a result, more drugs with little, if any, added benefit are brought to the market in a process increasingly reliant on disputable evidence [ 6 ] and divorced from public interest.…”

National early access programs and clinical trials: What opportunities for early access to therapeutic innovations for patients with malignant melanoma?

“…To speed up access to new anticancer drugs, regulatory agencies launched accelerated approval procedures, such as the accelerated European assessment of Priority Medicines (PRIME) program 6 . Between 2000 and 2016, the FDA approved 92 new anticancer drugs for 100 distinct clinical indications (9% in oncodermatology), and 44% of those drugs underwent an accelerated approval 7 . As mentioned by Christen et al, the French National Agency for Medicines and Health Products Safety (ANSM) is in charge of the so‐called temporary authorization for use (ATU) NEAP, which allows access for patients with cancer who have no therapeutic option to off‐label and as‐yet‐unavailable drugs until further MA is granted.…”