{"id":"trial-modernisation-roadmap","name":"Trial modernisation roadmap: the randomised trial → platforms and adaptive designs → decentralised, pragmatic and always-on","route":"/roadmaps/trial-modernisation-roadmap/","eras":[{"era":"1948-2000","title":"The randomised trial and the cooperative groups","description":"The first randomised controlled trial in medicine (streptomycin, 1948) gave oncology its method, and the US cooperative groups, the EORTC and later national groups in Canada, the UK and Europe ran the trials that made chemotherapy, adjuvant therapy and combined-modality treatment evidence-based. ClinicalTrials.gov (2000) made registration public. The model worked; it also fixed the template of one question, one comparator, years of follow-up and hundreds of millions of dollars.","status":"historic","refs":[{"id":"nci","kind":"institution","name":"National Cancer Institute (NIH)","route":"/institutions/nci/","tldr":"The NCI is the US government's cancer research agency, spending ~$7B a year and running the Cancer Centers Program, TCGA, and Rosenberg's cell therapy lab."},{"id":"swog","kind":"company","name":"SWOG Cancer Research Network","route":"/companies/swog/","tldr":"SWOG is one of the US National Cancer Institute's cooperative groups: thousands of community and academic sites running practice-changing trials, including the 2026 first-line Hodgkin lymphoma result."},{"id":"ecog-acrin","kind":"company","name":"ECOG-ACRIN Cancer Research Group","route":"/companies/ecog-acrin/","tldr":"US cooperative group that pairs a therapy group with an imaging group; its E1910 trial moved blinatumomab into frontline leukaemia treatment."},{"id":"alliance-oncology","kind":"company","name":"Alliance for Clinical Trials in Oncology","route":"/companies/alliance-oncology/","tldr":"US cooperative group formed from CALGB, ACOSOG, and NCCTG; running OptimICE-pCR, which asks whether TNBC patients with a complete response still need a year of immunotherapy."},{"id":"nrg-oncology","kind":"company","name":"NRG Oncology","route":"/companies/nrg-oncology/","tldr":"The US cooperative group formed from the radiation, gynaecologic, and breast trial groups; it co-led OlympiA, the trial that put a PARP inhibitor after surgery for BRCA carriers."},{"id":"cctg","kind":"company","name":"Canadian Cancer Trials Group (CCTG)","route":"/companies/cctg/","tldr":"Canada's national academic trials group, which ran the CHALLENGE exercise trial and co-led the SABR-COMET oligometastasis trial."},{"id":"childrens-oncology-group","kind":"company","name":"Children's Oncology Group (COG)","route":"/companies/childrens-oncology-group/","tldr":"The Children's Oncology Group is the world's largest paediatric cancer trials organisation; most children with cancer in North America are treated on or according to a COG protocol."},{"id":"clinicaltrials-gov","kind":"collection","name":"ClinicalTrials.gov","route":"/collections/clinicaltrials-gov/","tldr":"ClinicalTrials.gov is the master list of clinical trials. Every trial on this site links to its record."}],"trials":[],"papers":[]},{"era":"2005-2018","title":"Platforms, baskets and the mutation as the indication","description":"STAMPEDE, opened in 2005, showed that a multi-arm multi-stage platform can add and drop arms under one protocol and answer several questions for the price of one, establishing docetaxel and abiraterone in prostate cancer along the way. Basket and umbrella trials assigned drugs by mutation across cancers; Pediatric MATCH did it nationally for children. Tissue-agnostic approvals (2017, 2018) followed, and accelerated approval on surrogate endpoints became the norm for oncology, with confirmatory trials that were often late or never done.","status":"historic","refs":[{"id":"stampede","kind":"trial","name":"STAMPEDE","route":"/trials/stampede/","status":"positive","tldr":"STAMPEDE is the longest-running platform trial in oncology, and showed that both docetaxel and abiraterone extend life when started at first diagnosis of metastatic disease."},{"id":"pediatric-match","kind":"trial","name":"NCI-COG Pediatric MATCH (APEC1621)","route":"/trials/pediatric-match/","status":"active","tldr":"Pediatric MATCH was the first nationwide precision-medicine trial for children: every child with a relapsed solid tumour could have their tumour sequenced and, if a matching drug existed, join a trial arm for it. It proved the plumbing works, even though most single drugs given alone did little."},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/","tldr":"A tumour-agnostic approval lets a drug be used for any cancer carrying a specific molecular feature, regardless of where it started."},{"id":"accelerated-approval","kind":"term","name":"Accelerated approval","route":"/terms/accelerated-approval/","tldr":"FDA approval based on early evidence (like tumour shrinkage) on condition that a confirmatory trial follows."},{"id":"surrogate-endpoint","kind":"term","name":"Surrogate endpoint","route":"/terms/surrogate-endpoint/","tldr":"A quicker, easier measurement used as a stand-in for what really matters. Tumour shrinkage or delayed growth stands in for living longer, on the assumption, not always true, that one leads to the other."},{"id":"idea-reg-conditional-approval-sunset","kind":"idea","name":"Conditional approvals that lapse automatically if the confirmatory trial is late","route":"/ideas/idea-reg-conditional-approval-sunset/","tldr":"Drugs given accelerated or conditional approval on surrogate endpoints have often stayed on the market for years after the confirmatory trial stalled or failed. The approval would lapse automatically if the sponsor missed agreed enrolment milestones or the readout date, unless an independent panel granted a documented extension."},{"id":"idea-reg-confirmatory-trial-escrow","kind":"idea","name":"Sponsors deposit the confirmatory trial budget in escrow at accelerated approval","route":"/ideas/idea-reg-confirmatory-trial-escrow/","tldr":"To get an early approval, a company would set aside the money for the follow-up trial up front, so the trial cannot be quietly abandoned."}],"trials":[{"id":"stampede","name":"STAMPEDE","route":"/trials/stampede/","outcomes":[{"endpoint":"Overall survival, abiraterone arm (M1 subgroup)","primary":true,"unit":"%","arms":[{"name":"ADT + abiraterone","note":"6-year OS 60%"},{"name":"ADT alone","note":"6-year OS 45%"}],"hr":0.6,"ci":[0.5,0.71],"source":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00367-1/fulltext"},{"endpoint":"Overall survival, docetaxel arm (M1)","unit":"months","arms":[{"name":"ADT + docetaxel","value":60},{"name":"ADT alone","value":45}],"hr":0.76,"source":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01037-5/fulltext"},{"endpoint":"Overall survival, abiraterone comparison","unit":"deaths","arms":[{"name":"Androgen deprivation with abiraterone and prednisolone","n":960,"value":184},{"name":"Androgen deprivation alone","n":957,"value":262}],"hr":0.63,"ci":[0.52,0.76],"p":"<0.001","source":"https://doi.org/10.1056/NEJMoa1702900"},{"endpoint":"Metastasis-free survival at 6 years, high-risk non-metastatic comparison","unit":"%","arms":[{"name":"Androgen deprivation with 2 years of abiraterone","value":82},{"name":"Androgen deprivation alone","value":69}],"hr":0.53,"ci":[0.44,0.64],"p":"<0.0001","source":"https://doi.org/10.1016/S0140-6736(21)02437-5"},{"endpoint":"Overall survival, prostate radiotherapy comparison","arms":[{"name":"Standard of care with prostate radiotherapy","n":1032},{"name":"Standard of care","n":1029}],"hr":0.92,"ci":[0.8,1.06],"p":"0.266","source":"https://doi.org/10.1016/S0140-6736(18)32486-3"},{"endpoint":"Overall survival (median), metformin comparison","unit":"months","arms":[{"name":"Standard of care with metformin","n":936,"value":67.4},{"name":"Standard of care","n":938,"value":61.8}],"hr":0.91,"ci":[0.8,1.03],"p":"0.15","source":"https://doi.org/10.1016/S1470-2045(25)00231-1"}],"setting":"Multi-arm multi-stage platform in men starting long-term hormone therapy for high-risk locally advanced or metastatic prostate cancer: docetaxel, zoledronic acid, celecoxib, abiraterone, radiotherapy to the prostate, abiraterone with enzalutamide, metformin and transdermal oestradiol added to ADT and compared with ADT alone","enrolled":11992,"enrolledBasis":"registry"},{"id":"pediatric-match","name":"NCI-COG Pediatric MATCH (APEC1621)","route":"/trials/pediatric-match/","outcomes":[{"endpoint":"Actionable alteration detected (first 1,000 tumours)","primary":true,"unit":"%","arms":[{"name":"Screened tumours","n":1000,"value":31.5}],"source":"https://doi.org/10.1200/JCO.21.02838"},{"endpoint":"Enrolled on a treatment arm","unit":"%","arms":[{"name":"Screened patients","n":1000,"value":13.1}],"source":"https://doi.org/10.1200/JCO.21.02838"}],"setting":"Relapsed or refractory solid tumours, non-Hodgkin lymphomas and histiocytic disorders, age 1-21: tumour sequencing then assignment to one of a dozen single-agent targeted-therapy phase 2 arms","enrolled":1377,"enrolledBasis":"registry"}],"papers":[]},{"era":"2016-2024","title":"Decentralised, pragmatic and more inclusive","description":"Real-world evidence gained a regulatory framework; the pandemic forced remote consent, telehealth visits and home delivery of study drugs and the FDA wrote them into guidance (2024); weekly electronic symptom reporting became a trial tool as well as a care tool. ASCO and Friends of Cancer Research rewrote eligibility so that brain metastases, prior cancers, controlled HIV and modest organ dysfunction no longer excluded patients by default, and diversity action plans became a filing requirement. Federated real-world networks and curated clinico-genomic databases made external comparison possible, if not yet trusted.","status":"current","refs":[{"id":"real-world-evidence","kind":"term","name":"Real-world evidence","route":"/terms/real-world-evidence/","tldr":"Data from routine care rather than clinical trials, used to check whether results hold outside the trial population."},{"id":"remote-patient-monitoring","kind":"technology","name":"Electronic patient-reported outcomes and remote monitoring","route":"/technologies/remote-patient-monitoring/","status":"established","tldr":"Apps and sensors that let patients report symptoms between visits, which in trials improved survival and cut emergency visits."},{"id":"telemedicine-teleoncology","kind":"technology","name":"Telemedicine, teleoncology, and telepathology","route":"/technologies/telemedicine-teleoncology/","status":"established","tldr":"Video visits, remote second opinions, and slides reviewed from afar, which let rural and low-resource patients reach specialists."},{"id":"science-37","kind":"company","name":"Science 37 (eMed)","route":"/companies/science-37/","tldr":"Pioneer of the 'metasite' decentralised trial model, acquired by eMed in 2024."},{"id":"medidata","kind":"company","name":"Medidata (Dassault Systèmes)","route":"/companies/medidata/","tldr":"Medidata, owned by Dassault Systèmes, makes Rave, the most used electronic data capture system in clinical trials, plus randomisation and outcome-assessment tools and synthetic control arms built from past trial data. Whether regulators accept synthetic controls for oncology approvals is the open question."},{"id":"trinetx","kind":"company","name":"TriNetX","route":"/companies/trinetx/","tldr":"Federated real-world data network across health systems, used for trial feasibility and observational studies."},{"id":"flatiron-health","kind":"company","name":"Flatiron Health (Roche)","route":"/companies/flatiron-health/","tldr":"Oncology EHR (OncoEMR) and the largest curated real-world oncology database, acquired by Roche for $1.9B in 2018."},{"id":"flatiron-foundation-cgdb","kind":"collection","name":"Flatiron Health and Foundation Medicine Clinico-Genomic Database","route":"/collections/flatiron-foundation-cgdb/","tldr":"Real-world evidence at scale: what happened to patients with a given genomic profile on a given treatment."},{"id":"idea-tr1-justify-every-exclusion","kind":"idea","name":"Default-inclusive eligibility: sponsors must justify every exclusion criterion","route":"/ideas/idea-tr1-justify-every-exclusion/","tldr":"Trials should let people in unless there is a scientific or safety reason to keep them out. Every exclusion rule would need a written reason, reviewed like the rest of the protocol."},{"id":"idea-tr1-remote-consent-tele-screening","kind":"idea","name":"Remote consent and tele-screening so the first trial visit is a video call","route":"/ideas/idea-tr1-remote-consent-tele-screening/","tldr":"Much of trial screening is paperwork, questions and reviewing scans that already exist. Doing this by video and electronic consent before any travel would let patients decide without a wasted trip."},{"id":"idea-tr1-diversity-plans-with-consequences","kind":"idea","name":"Diversity action plans with consequences: unmet targets trigger post-approval requirements","route":"/ideas/idea-tr1-diversity-plans-with-consequences/","tldr":"Companies now have to file a plan for enrolling a representative mix of patients. If the trial misses the plan, the label should say so and the company should be required to fill the gap after approval."},{"id":"idea-tr1-external-control-rulebook","kind":"idea","name":"A public rulebook for when an external or synthetic control arm is acceptable","route":"/ideas/idea-tr1-external-control-rulebook/","tldr":"Sometimes a trial cannot randomise, so the new drug is compared with past patients' records. Clear published rules on when that is allowed, and how it must be done, would replace case-by-case guesswork."}],"trials":[],"papers":[]},{"era":"2022-2026","title":"Better endpoints and evidence-based doses","description":"Molecular residual disease in blood reads out in months rather than years and has now changed treatment in randomised trials: DYNAMIC, CIRCULATE-Japan, SERENA-6 and IMvigor011, the first ctDNA-guided approval. Pre-surgery windows turned pathological response into a fast biomarker engine (NICHE-2, PHERGain, KEYNOTE-522). The FDA's Project Optimus (final guidance August 2024) ended the maximum-tolerated-dose default for new oncology drugs by requiring randomised dose comparison; the harder task of re-optimising approved doses falls to public funders and trials such as PERSEPHONE. Central imaging reads and companion diagnostics are being standardised as trial infrastructure.","status":"current","refs":[{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/","status":"established","tldr":"An ultra-sensitive blood test after surgery that detects leftover cancer months before a scan would."},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/","status":"standard-of-care","tldr":"A blood test that reads fragments of DNA shed by the tumour, so you can genotype or monitor cancer without a needle in the tumour."},{"id":"dynamic","kind":"trial","name":"DYNAMIC","route":"/trials/dynamic/","status":"positive","tldr":"Showed that a blood test can safely halve the number of colon cancer patients given chemotherapy after surgery."},{"id":"circulate-japan","kind":"trial","name":"CIRCULATE-Japan (GALAXY / VEGA / ALTAIR)","route":"/trials/circulate-japan/","status":"active","tldr":"Japan's national programme tests whether a blood test after surgery should decide who gets chemotherapy, and whether treating a positive test early helps."},{"id":"serena-6","kind":"trial","name":"SERENA-6","route":"/trials/serena-6/","status":"positive","tldr":"The first trial to change treatment because of a blood test rather than a scan: switching to camizestrant when an ESR1 mutation appeared in the blood delayed progression by seven months."},{"id":"imvigor011","kind":"trial","name":"IMvigor011","route":"/trials/imvigor011/","status":"positive","tldr":"The first trial to use a blood test for leftover cancer to decide who gets immunotherapy, and it worked."},{"id":"idea-tr2-ctdna-mrd-qualification","kind":"idea","name":"Formally qualify tumour-DNA blood tests as a surrogate endpoint for adjuvant trials","route":"/ideas/idea-tr2-ctdna-mrd-qualification/","tldr":"If a blood test reliably shows whether cancer will come back after surgery, trials could use it instead of waiting years for relapse. Regulators have a process to bless such a test; oncology should use it."},{"id":"niche-2","kind":"trial","name":"NICHE-2","route":"/trials/niche-2/","status":"positive","tldr":"In NICHE-2, four weeks of immunotherapy before surgery wiped out most mismatch-repair-deficient colon cancers, and nobody had relapsed three years later."},{"id":"phergain","kind":"trial","name":"PHERGain","route":"/trials/phergain/","status":"positive","tldr":"Using an early PET scan to spot responders let a third of women be cured of HER2-positive breast cancer without any chemotherapy."},{"id":"keynote-522","kind":"trial","name":"KEYNOTE-522","route":"/trials/keynote-522/","status":"positive","tldr":"The trial that added immunotherapy to pre-surgery chemotherapy for triple-negative breast cancer and, uniquely, improved survival."},{"id":"idea-bio2-neoadjuvant-biomarker-engine","kind":"idea","name":"Use pre-surgery immunotherapy windows as the field's biomarker engine","route":"/ideas/idea-bio2-neoadjuvant-biomarker-engine/","tldr":"Giving immunotherapy for a few weeks before surgery produces a tumour sample that shows exactly what the drug did. That is the fastest way to learn who responds."},{"id":"idea-tr1-window-of-opportunity-default","kind":"idea","name":"A short pre-surgery drug window as the default early test of new agents","route":"/ideas/idea-tr1-window-of-opportunity-default/","tldr":"Between diagnosis and surgery there are usually a few weeks. Giving a new drug in that window and comparing the tumour before and after surgery shows whether it hits its target in real people, quickly and cheaply."},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/","tldr":"Most drug doses were chosen as the highest a person can tolerate, which is often more than they need."},{"id":"idea-reg-global-dose-optimisation-guideline","kind":"idea","name":"Make pre-approval dose optimisation an ICH standard so it is done once worldwide","route":"/ideas/idea-reg-global-dose-optimisation-guideline/","tldr":"The FDA now asks companies to find the right dose of a cancer drug before approval. If every regulator asked the same way, companies would do it once and doses would match worldwide."},{"id":"idea-tr1-randomised-dose-comparison-before-pivotal","kind":"idea","name":"Randomise at least two doses in phase 2 before any pivotal trial","route":"/ideas/idea-tr1-randomised-dose-comparison-before-pivotal/","tldr":"Cancer drugs are usually tested at the highest dose patients can stand, and that dose sticks for life. Comparing two or more doses head-to-head before the big trial would find doses that work as well with fewer side effects."},{"id":"persephone","kind":"trial","name":"PERSEPHONE","route":"/trials/persephone/","status":"positive","tldr":"Six months of trastuzumab was almost as good as twelve, with half the heart toxicity, though twelve remains the global standard."},{"id":"imaging-core-labs","kind":"technology","name":"Imaging core labs and central review","route":"/technologies/imaging-core-labs/","status":"standard-of-care","tldr":"Independent radiologists who re-read every scan in a trial the same way, so response rates mean the same thing across hospitals."},{"id":"companion-diagnostic","kind":"technology","name":"Companion diagnostics","route":"/technologies/companion-diagnostic/","status":"standard-of-care","tldr":"The test that decides whether a specific drug is right for you, approved together with the drug."}],"trials":[{"id":"dynamic","name":"DYNAMIC","route":"/trials/dynamic/","outcomes":[{"endpoint":"Recurrence-free survival at 2 years (non-inferiority)","primary":true,"unit":"%","arms":[{"name":"ctDNA-guided management","n":302,"value":93.5,"note":"Non-inferiority met (margin −8.5 points)"},{"name":"Standard management","n":153,"value":92.4}],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2200075"},{"endpoint":"Patients receiving adjuvant chemotherapy","unit":"%","arms":[{"name":"ctDNA-guided management","value":15},{"name":"Standard management","value":28}],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2200075"}],"setting":"Stage II colon cancer: ctDNA-guided adjuvant chemotherapy vs standard management","enrolled":455,"enrolledBasis":"registry"},{"id":"circulate-japan","name":"CIRCULATE-Japan (GALAXY / VEGA / ALTAIR)","route":"/trials/circulate-japan/","outcomes":[{"endpoint":"GALAXY (observational): recurrence risk by post-operative ctDNA status (4 weeks after surgery)","arms":[{"name":"ctDNA-positive","note":"n = 1,039 resectable stage II-IV CRC; ctDNA positivity was the strongest prognostic factor and identified who benefited from adjuvant chemotherapy (HR 6.59)"},{"name":"ctDNA-negative"}],"hr":10,"p":"<0.0001","source":"https://doi.org/10.1038/s41591-022-02115-4"},{"endpoint":"ALTAIR (randomised phase 3): disease-free survival in post-adjuvant ctDNA-positive patients","primary":true,"unit":"months","arms":[{"name":"Trifluridine/tipiracil","n":122,"value":9.3,"note":"Primary endpoint not met"},{"name":"Placebo","n":121,"value":5.55}],"hr":0.79,"ci":[0.6,1.05],"p":"0.107","source":"https://doi.org/10.1038/s41591-026-04428-0"}],"setting":"Resected stage II-IV colorectal cancer: ctDNA (Signatera) to guide adjuvant chemotherapy de-escalation (VEGA) or escalation with trifluridine/tipiracil (ALTAIR)","enrolledBasis":"registry"},{"id":"serena-6","name":"SERENA-6","route":"/trials/serena-6/","outcomes":[{"endpoint":"Progression-free survival","primary":true,"unit":"months","arms":[{"name":"Switch to camizestrant + CDK4/6","n":157,"value":16},{"name":"Continue AI + CDK4/6","n":158,"value":9.2}],"hr":0.44,"ci":[0.31,0.6],"p":"<0.0001","source":"https://www.onclive.com/view/fda-approves-camizestrant-plus-a-cdk4-6-inhibitor-for-emergent-esr1-mutated-hr-her2-advanced-breast-cancer"}],"setting":"First-line HR+/HER2- advanced breast cancer on AI + CDK4/6 with an ESR1 mutation detected in ctDNA before radiographic progression: switch to camizestrant + CDK4/6 vs continue AI + CDK4/6","enrolled":315,"enrolledBasis":"registry"},{"id":"imvigor011","name":"IMvigor011","route":"/trials/imvigor011/","outcomes":[{"endpoint":"Disease-free survival (ctDNA-positive, randomised)","primary":true,"unit":"months","arms":[{"name":"Atezolizumab","n":167,"value":9.9},{"name":"Placebo","n":83,"value":4.8}],"hr":0.64,"ci":[0.47,0.88],"p":"0.005","source":"https://www.roche.com/media/releases/med-cor-2025-10-20b"},{"endpoint":"Overall survival (ctDNA-positive)","unit":"months","arms":[{"name":"Atezolizumab","value":32.8},{"name":"Placebo","value":21.1}],"hr":0.59,"ci":[0.41,0.86],"p":"0.005","source":"https://www.roche.com/media/releases/med-cor-2025-10-20b"},{"endpoint":"Disease-free survival at 12 months, persistently ctDNA-negative (untreated surveillance)","unit":"%","arms":[{"name":"ctDNA-negative, surveillance only","n":357,"value":95.4,"note":"12-month OS 100% in this group"}],"source":"https://www.roche.com/media/releases/med-cor-2025-10-20b"}],"setting":"Muscle-invasive bladder cancer after cystectomy, ctDNA-positive (Signatera): atezolizumab vs placebo","enrolled":761,"enrolledBasis":"registry"},{"id":"niche-2","name":"NICHE-2","route":"/trials/niche-2/","outcomes":[{"endpoint":"Pathologic complete response","primary":true,"unit":"percent","arms":[{"name":"Neoadjuvant nivolumab + ipilimumab","n":111,"value":68}],"source":"https://www.nejm.org/doi/abs/10.1056/NEJMoa2400634"},{"endpoint":"3-year disease-free survival","unit":"percent","arms":[{"name":"Neoadjuvant nivolumab + ipilimumab","n":111,"value":100}],"source":"https://www.annalsofoncology.org/article/S0923-7534(24)03843-2/fulltext"}],"setting":"Locally advanced (mostly stage III) dMMR colon cancer: 4 weeks of neoadjuvant nivolumab + one dose ipilimumab, then surgery","enrolled":115,"enrolledNote":"ClinicalTrials.gov lists an estimated 353 participants for the amended NICHE protocol, which is still recruiting to further cohorts; the NEJM 2024 NICHE-2 analysis enrolled 115 patients, 111 of them in the efficacy analysis.","enrolledBasis":"registered"},{"id":"phergain","name":"PHERGain","route":"/trials/phergain/","outcomes":[{"endpoint":"3-year invasive disease-free survival (PET-adapted arm)","primary":true,"unit":"%","arms":[{"name":"PET-adapted HP ± chemotherapy","n":285,"value":95.4}],"source":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00054-0/fulltext"}],"setting":"HER2+ early breast cancer: chemotherapy-free trastuzumab + pertuzumab with early 18F-FDG PET response assessment to decide whether chemotherapy is needed","enrolled":377,"enrolledBasis":"registry"},{"id":"keynote-522","name":"KEYNOTE-522","route":"/trials/keynote-522/","outcomes":[{"endpoint":"Pathologic complete response (ypT0/Tis ypN0)","primary":true,"unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","n":401,"value":64.8},{"name":"Placebo + chemotherapy","n":201,"value":51.2}],"p":"0.00055","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1910549"},{"endpoint":"Event-free survival at 5 years","primary":true,"unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","n":784,"value":81.2},{"name":"Placebo + chemotherapy","n":390,"value":72.2}],"hr":0.65,"ci":[0.51,0.83],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2409932"},{"endpoint":"Overall survival at 5 years","unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","value":86.6},{"name":"Placebo + chemotherapy","value":81.7}],"hr":0.66,"ci":[0.5,0.87],"p":"0.002","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2409932"},{"endpoint":"Event-free survival at 7 years","unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","value":78.3},{"name":"Placebo + chemotherapy","value":69.8}],"source":"https://www.lbbc.org/news/pivotal-progress-in-tnbc-asco-2026"},{"endpoint":"Overall survival at 7 years","unit":"%","arms":[{"name":"Pembrolizumab + chemotherapy","value":85.1},{"name":"Placebo + chemotherapy","value":77.2}],"source":"https://www.lbbc.org/news/pivotal-progress-in-tnbc-asco-2026"}],"setting":"Early-stage (II-III) TNBC: pembrolizumab + chemotherapy before surgery, pembrolizumab after","enrolled":1174,"enrolledBasis":"registry"},{"id":"persephone","name":"PERSEPHONE","route":"/trials/persephone/","outcomes":[{"endpoint":"4-year disease-free survival","primary":true,"unit":"%","arms":[{"name":"6 months trastuzumab","n":2043,"value":89.4},{"name":"12 months trastuzumab","n":2045,"value":89.8}],"hr":1.07,"ci":[0.93,1.24],"source":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30650-6/fulltext"}],"setting":"Adjuvant HER2+ early breast cancer: 6 vs 12 months of trastuzumab","enrolled":4088,"enrolledBasis":"registry"}],"papers":[]},{"era":"2025-2029","title":"AI and data in trial operations","description":"Language models that read the record and flag a matching trial at the moment a treatment is chosen, eligibility simulated against real-world data before a protocol is locked, AI-assisted central imaging reads to cut endpoint cost, target-trial emulation in real-world data to decide which randomised trials are worth running, validated real-world progression endpoints so pragmatic trials can use them, and digital twins as virtual controls where randomisation is unethical. Each has a pilot; none has a standard.","status":"emerging","refs":[{"id":"ai-trial-matching","kind":"technology","name":"AI trial matching & clinical decision support","route":"/technologies/ai-trial-matching/","status":"established","tldr":"Software, increasingly LLM-based, that reads a patient's record and finds trials or guideline options they qualify for."},{"id":"trial-library","kind":"company","name":"Trial Library","route":"/companies/trial-library/","tldr":"Trial Library is software that helps everyday cancer clinics spot which patients might qualify for a clinical trial, refer them, and remove practical barriers like transport so more people, especially in under served communities, can join trials."},{"id":"massive-bio","kind":"company","name":"Massive Bio","route":"/companies/massive-bio/","tldr":"Massive Bio uses artificial intelligence to read a cancer patient's medical records and match them to clinical trials they may be eligible for, anywhere in the world, with doctors checking the results."},{"id":"tempus","kind":"company","name":"Tempus AI","route":"/companies/tempus/","tldr":"Genomic testing plus one of the largest multimodal clinical datasets, used for AI models and trial matching."},{"id":"idea-tr1-ehr-point-of-care-trial-alert","kind":"idea","name":"Trial matching inside the electronic record at the moment a treatment is chosen","route":"/ideas/idea-tr1-ehr-point-of-care-trial-alert/","tldr":"When an oncologist opens the order screen to prescribe a new line of treatment, the record would show the trials this patient may fit, with the nearest open site and a one-click referral."},{"id":"idea-tr1-eligibility-impact-statement","kind":"idea","name":"Simulate eligibility against real-world data before every protocol is locked","route":"/ideas/idea-tr1-eligibility-impact-statement/","tldr":"Before a trial is finalised, run its entry rules against records of real patients with that cancer and report what fraction would qualify. If it is under half, explain why."},{"id":"idea-tr1-ai-central-imaging-reads","kind":"idea","name":"AI-assisted central imaging reads to cut endpoint cost and variability","route":"/ideas/idea-tr1-ai-central-imaging-reads/","tldr":"Measuring tumours on scans for trials is slow, expensive and inconsistent between readers. Software that measures lesions and flags changes, checked by a radiologist, could make trial endpoints cheaper and more reliable."},{"id":"idea-tr1-target-trial-emulation-to-prioritise-rcts","kind":"idea","name":"Emulate the trial in real-world data first to decide which trials to run","route":"/ideas/idea-tr1-target-trial-emulation-to-prioritise-rcts/","tldr":"Before spending millions on a randomised trial, analyse existing patient records as if the trial had already happened. If the answer is obvious or the question is unanswerable, skip or redesign the trial."},{"id":"idea-tr1-validate-real-world-progression-endpoints","kind":"idea","name":"Validate real-world progression endpoints so pragmatic trials can use them","route":"/ideas/idea-tr1-validate-real-world-progression-endpoints/","tldr":"Pragmatic trials want to use the progression dates recorded in ordinary clinic notes instead of expensive protocol scans. Checking how well those routine records match formal trial measurements would show when that shortcut is safe."},{"id":"digital-twins-trials","kind":"technology","name":"Digital twins and virtual control arms","route":"/technologies/digital-twins-trials/","status":"emerging","tldr":"Using a model of what would have happened to a patient on standard treatment, so fewer people have to be randomised to it."}],"trials":[],"papers":[]},{"era":"2026-2032","title":"Standing infrastructure: trials that never close","description":"The proposal that would change the economics most is a perpetual platform trial in every major cancer, funded as infrastructure, with one ethics approval and one consent form across countries, arms added as drugs arrive and dropped as answers come in, and response-adaptive allocation that learns as it goes. Variants: a national platform every ctDNA-positive patient can join, a platform that assigns treatment by resistance mechanism, one umbrella for all rare cancers, a RECOVERY-style platform for cheap repurposed drugs, and a DRUP-style protocol for off-label generics. Registry-embedded randomisation answers everyday questions inside routine care.","status":"emerging","refs":[{"id":"idea-tr1-standing-platform-per-cancer","kind":"idea","name":"A standing platform trial for every major cancer, funded as infrastructure","route":"/ideas/idea-tr1-standing-platform-per-cancer/","tldr":"Rather than building a new trial from scratch for every drug, keep one permanent trial open per cancer where new treatments can be slotted in and dropped out, sharing the same patients, control group and infrastructure."},{"id":"idea-tr2-perpetual-platforms","kind":"idea","name":"A perpetual platform trial in every major cancer, funded as infrastructure","route":"/ideas/idea-tr2-perpetual-platforms/","tldr":"Instead of starting a new trial for every drug pair, keep one always-open trial per cancer that new arms can join and leave, sharing the same control group."},{"id":"idea-tr2-platform-single-ethics","kind":"idea","name":"One ethics approval and one consent form for a platform trial across countries","route":"/ideas/idea-tr2-platform-single-ethics/","tldr":"Adding a new arm to an international platform trial currently needs approval in every country again. A single, pre-agreed process would let arms open in weeks."},{"id":"idea-tr2-bandit-allocation","kind":"idea","name":"Let the trial learn: response-adaptive allocation across many combination arms","route":"/ideas/idea-tr2-bandit-allocation/","tldr":"As results come in, the trial sends more new patients to the arms that are working and fewer to those that are not, so more people benefit and bad arms die faster."},{"id":"idea-bio2-national-mrd-platform","kind":"idea","name":"A national platform trial that every ctDNA-positive patient can join","route":"/ideas/idea-bio2-national-mrd-platform/","tldr":"Blood tests can now find leftover cancer months before scans, but most patients who test positive have nothing to enrol in. One standing trial per country would fix that."},{"id":"idea-bio1-resistance-platform-trial","kind":"idea","name":"A standing platform trial that assigns treatment by how the tumour escaped","route":"/ideas/idea-bio1-resistance-platform-trial/","tldr":"Instead of a new trial for each resistance mechanism, one continuous trial could sort patients into arms based on the reason their last treatment failed."},{"id":"idea-bio2-rare-cancer-umbrella-platform","kind":"idea","name":"One standing umbrella trial for all rare cancers in a country","route":"/ideas/idea-bio2-rare-cancer-umbrella-platform/","tldr":"Rare cancers together make up a fifth of all cancers, but no single one supports its own trial, so most patients get off-label therapy with no data capture. One permanent national umbrella trial, with molecular screening for all comers and arms opened by mechanism, would give every rare cancer a route."},{"id":"idea-reg-recovery-style-platform-repurposing","kind":"idea","name":"A RECOVERY-style permanent platform trial of cheap drugs added to cancer care","route":"/ideas/idea-reg-recovery-style-platform-repurposing/","tldr":"The UK's RECOVERY trial answered questions about dexamethasone and other cheap COVID drugs within months by randomising tens of thousands of ordinary hospital patients with a two-page consent and routine-data follow-up. Cancer needs the same permanent platform to test generics such as statins, metformin, aspirin and propranolol added to standard care."},{"id":"idea-reg-generic-targeted-therapy-drup","kind":"idea","name":"A DRUP-style protocol for off-label generic targeted drugs in rare tumours","route":"/ideas/idea-reg-generic-targeted-therapy-drup/","tldr":"Cheap generic versions of targeted cancer drugs like imatinib exist, but patients with rare tumours carrying the matching mutation often cannot get them. A structured programme would treat them and collect the evidence."},{"id":"idea-tr2-neoadjuvant-combo-platform","kind":"idea","name":"Pre-surgery platform trials that test combinations on pathological response in months","route":"/ideas/idea-tr2-neoadjuvant-combo-platform/","tldr":"Give drug combinations before surgery and measure how much tumour remains at resection; that answer arrives in months. A standing neoadjuvant platform with a shared control arm, as I-SPY 2 runs in breast cancer, would test combinations quickly in lung, bladder, melanoma, head and neck and oesophago-gastric cancer."},{"id":"idea-tr1-registry-embedded-randomisation","kind":"idea","name":"Randomise inside the cancer registry: registry-based trials for everyday questions","route":"/ideas/idea-tr1-registry-embedded-randomisation/","tldr":"National cancer registries already collect the outcome data. Adding a randomisation button lets doctors compare two standard treatments across thousands of patients at a fraction of the usual cost."},{"id":"add-aspirin","kind":"trial","name":"Add-Aspirin","route":"/trials/add-aspirin/","status":"active","tldr":"Add-Aspirin is an 11,000-patient trial across four common cancers in the UK, Ireland and India asking whether cheap daily aspirin after curative treatment stops cancer coming back."},{"id":"challenge","kind":"trial","name":"CHALLENGE (CCTG CO.21)","route":"/trials/challenge/","status":"positive","tldr":"The first randomised trial to show that a coached exercise programme after cancer treatment reduces recurrence and death, in colon cancer."}],"trials":[{"id":"challenge","name":"CHALLENGE (CCTG CO.21)","route":"/trials/challenge/","outcomes":[{"endpoint":"Disease-free survival at 5 years","primary":true,"unit":"%","arms":[{"name":"Structured exercise","n":445,"value":80.3},{"name":"Health education","n":444,"value":73.9}],"hr":0.72,"ci":[0.55,0.94],"p":"0.02","source":"https://doi.org/10.1056/NEJMoa2502760"},{"endpoint":"Overall survival at 8 years","unit":"%","arms":[{"name":"Structured exercise","value":90.3},{"name":"Health education","value":83.2}],"hr":0.63,"ci":[0.43,0.94],"source":"https://doi.org/10.1056/NEJMoa2502760"}],"setting":"Resected stage III or high-risk stage II colon cancer after adjuvant chemotherapy: 3-year structured exercise programme vs health-education materials","enrolled":889,"enrolledBasis":"registry"}],"papers":[]},{"era":"2030+","title":"Measuring what matters, including everyone","description":"Trials that report patient-reported side-effects as rigorously as efficacy, win-ratio endpoints that weigh survival, toxicity and quality of life together, tolerability defined as carefully as efficacy, a mandatory over-70s cohort with geriatric assessment in every pivotal trial, a pragmatic trial after approval in the patients the pivotal trial excluded, sponsor-funded sites in Africa, South Asia and Latin America, and participants paid for their time. An independent programme to validate surrogate endpoints setting by setting would tell everyone which shortcuts are safe.","status":"speculative","refs":[{"id":"idea-moon-pro-ctcae-in-every-pivotal-trial","kind":"idea","name":"Patient-reported side-effects (PRO-CTCAE) collected and published in every registrational trial","route":"/ideas/idea-moon-pro-ctcae-in-every-pivotal-trial/","tldr":"Doctors record only part of what patients suffer. Make it compulsory that patients report their own side-effects in every trial used to approve a drug, and that those data are published next to the doctor-graded ones."},{"id":"idea-tr1-win-ratio-net-benefit-endpoint","kind":"idea","name":"Win-ratio endpoints that weigh survival, toxicity and quality of life together","route":"/ideas/idea-tr1-win-ratio-net-benefit-endpoint/","tldr":"Every patient on the new drug is compared with every patient on the old one: who lived longer, and if equal, who had fewer serious side effects, and if still equal, who felt better. The share of 'wins' becomes the result."},{"id":"idea-tr1-tolerability-estimands","kind":"idea","name":"Define tolerability endpoints as rigorously as efficacy endpoints","route":"/ideas/idea-tr1-tolerability-estimands/","tldr":"Trials report side effects as a table of percentages that hides how long they lasted, how bad they felt and whether people stopped treatment. Tolerability should be measured with defined endpoints and a decision rule, like efficacy."},{"id":"idea-tr1-mandatory-older-adult-cohort","kind":"idea","name":"A mandatory over-70s cohort with geriatric assessment in every pivotal trial","route":"/ideas/idea-tr1-mandatory-older-adult-cohort/","tldr":"Most people with cancer are over 65, but trials mostly enrol younger, fitter people. Requiring a group of older patients, assessed for frailty, in every big trial would show whether the drug works and is safe for those most likely to receive it."},{"id":"idea-tr1-post-approval-pragmatic-trial-in-excluded","kind":"idea","name":"After approval, a pragmatic trial in the patients the pivotal trial excluded","route":"/ideas/idea-tr1-post-approval-pragmatic-trial-in-excluded/","tldr":"Drugs are approved on trials of fit, younger patients and then given to everyone. A required follow-on trial in older, sicker and more diverse patients would show whether the benefit holds in real life."},{"id":"idea-tr1-lmic-sites-in-pivotal-trials","kind":"idea","name":"Pivotal trials include sites in Africa, South Asia and Latin America, sponsor-funded","route":"/ideas/idea-tr1-lmic-sites-in-pivotal-trials/","tldr":"Most of the world's cancer patients live in countries that host almost no registrational trials. Including sites there, and paying to build them up, would make results apply globally and speed local access."},{"id":"idea-tr1-pay-participants-for-time","kind":"idea","name":"Pay trial participants for their time, not only their expenses","route":"/ideas/idea-tr1-pay-participants-for-time/","tldr":"Trial visits take hours and cost people wages. Paying a fair hourly rate for time spent beyond normal care would make trials possible for those who cannot afford unpaid days off."},{"id":"idea-tr1-protected-physician-time-for-enrolment","kind":"idea","name":"Pay oncologists for the time it takes to enrol a patient","route":"/ideas/idea-tr1-protected-physician-time-for-enrolment/","tldr":"Discussing and enrolling a patient in a trial takes an oncologist far longer than prescribing the usual treatment, and they are not paid for it. Paying for that time would remove a quiet disincentive."},{"id":"idea-tr1-surrogate-validation-programme","kind":"idea","name":"An independent programme that validates surrogate endpoints, setting by setting","route":"/ideas/idea-tr1-surrogate-validation-programme/","tldr":"Trials often measure a stand-in for survival, such as time until the cancer grows on scans. An independent body would test, for each cancer and treatment type, whether the stand-in actually predicts survival, and publish the answer."},{"id":"global-access-roadmap","kind":"roadmap","name":"Global access and affordability roadmap: essential medicines and generics → biosimilars and frugal trials → reliance, pooling and homegrown innovation","route":"/roadmaps/global-access-roadmap/","tldr":"Seven in ten cancer deaths happen in countries with almost no cancer care, and even rich systems cannot afford every new drug. The roadmap is the set of levers that already work, from generics and biosimilars to trials that cut the dose, and the ones being built: regulators trusting each other's reviews, pooled purchasing, and drugs and cell therapies made where patients live."}],"trials":[],"papers":[]},{"era":"What sets the pace","title":"Enrolment, cost, exclusion and hidden failures","description":"Fewer than one in ten adults with cancer joins a trial, and trials close for lack of patients rather than lack of questions. A phase 3 costs hundreds of millions and takes years. Older, poorer, rural and minority patients are under-represented, so results do not transfer. Real-world data are too weak to fill the gap. Negative results and abandoned programmes are rarely published, so mistakes repeat; a reversal registry and mandatory disclosure of top-line data are the proposed fixes. Regulators still review the same dossier separately in each region.","status":"current","refs":[{"id":"b-trial-enrolment","kind":"bottleneck","name":"Trials enrol too few, too slowly","route":"/bottlenecks/b-trial-enrolment/","tldr":"Fewer than one in ten adults with cancer joins a trial. Trials close for lack of patients, not lack of ideas."},{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/","tldr":"A phase 3 trial takes years and hundreds of millions of dollars, and often answers a question that has already moved on."},{"id":"b-trial-diversity","kind":"bottleneck","name":"Trials do not represent the people who get cancer","route":"/bottlenecks/b-trial-diversity/","tldr":"Older, Black, Hispanic, Asian, rural, poor and multimorbid patients are under-represented, so results may not apply to them."},{"id":"b-real-world-evidence","kind":"bottleneck","name":"Weak real-world evidence and registries","route":"/bottlenecks/b-real-world-evidence/","tldr":"We do not reliably know what happens to patients after approval, so we cannot tell which drugs deliver in practice."},{"id":"b-aging-comorbidity","kind":"bottleneck","name":"Older and multimorbid patients are excluded and undertreated","route":"/bottlenecks/b-aging-comorbidity/","tldr":"Most people with cancer are over 65 but most trial patients are younger and fitter. We guess how to treat the majority."},{"id":"b-negative-results","kind":"bottleneck","name":"Failures are hidden","route":"/bottlenecks/b-negative-results/","tldr":"Negative trials, failed drugs and abandoned programmes are rarely published, so the same mistakes are repeated."},{"id":"idea-tr2-material-failure-disclosure","kind":"idea","name":"Listed companies must disclose top-line data, not just 'did not meet endpoint'","route":"/ideas/idea-tr2-material-failure-disclosure/","tldr":"When a public company announces a trial failure, it should be required to give the actual numbers, as it must for a success."},{"id":"idea-tr2-reversal-registry","kind":"idea","name":"A public registry of cancer treatments that were later shown not to work","route":"/ideas/idea-tr2-reversal-registry/","tldr":"Keep a running, well-documented list of cancer practices and approvals that were reversed by later evidence, so the pattern of mistakes is visible and teachable."},{"id":"b-regulatory-fragmentation","kind":"bottleneck","name":"Regulatory divergence between regions","route":"/bottlenecks/b-regulatory-fragmentation/","tldr":"Regulatory divergence means a drug approved in one country can take years to reach another, or never arrive."},{"id":"project-orbis","kind":"term","name":"Project Orbis","route":"/terms/project-orbis/","tldr":"Project Orbis is a scheme where the FDA and partner regulators (Australia, Canada, UK, Switzerland, Singapore, Brazil, Israel) review a cancer drug at the same time."},{"id":"idea-reg-orbis-work-sharing","kind":"idea","name":"Turn Project Orbis into a work-sharing review with one shared assessment report","route":"/ideas/idea-reg-orbis-work-sharing/","tldr":"Regulators in several countries already look at the same cancer drug dossier at the same time. Let them split the work and write one report instead of six."}],"trials":[],"papers":[]}],"watch":[]}