OnCo
bottlenecksBottleneck

Failures are hidden

Negative trials, failed drugs and abandoned programmes are rarely published, so the same mistakes are repeated.

A large share of completed clinical trials never report results, and negative trials are published later and less often than positive ones. In the first years after the US results-reporting mandate took effect, only about one in eight applicable trials posted results on ClinicalTrials.gov within the required year, and fewer than half of NIH-funded trials were published within thirty months of completion. Commercial programmes that fail in phase 1 or 2 are usually terminated silently, and preclinical negative results are almost never shared, so companies and academic groups repeat the same experiments and the same mistakes. The costs are duplicated trials, patients exposed to hypotheses already refuted, and meta-analyses biased toward benefit. Enforcement of existing law, journals that publish nulls, and registries of terminated programmes and preclinical negatives would fix most of it.

majortrials50 ideas to fix it
How big the problem is
13.4%
Applicable trials reporting results on ClinicalTrials.gov within 12 months of completion, 2008-2013
Fewer than half (46%)
NIH-funded trials published in a peer-reviewed journal within 30 months of completion
Root causes
  • Journals and careers reward positive, novel findings over nulls.
  • Sponsors have commercial reasons to keep failed programmes and their data private.
  • Reporting requirements are weakly enforced; the FDA has issued few penalties under FDAAA 801.
  • Preclinical work has no registration or reporting infrastructure at all.
  • Writing up a failure costs time and money that no one funds.
What is already being tried
  • The FDAAA 801 Final Rule (2017) requires results posting for applicable trials, and the EU Clinical Trials Regulation makes CTIS results public.
  • The AllTrials campaign and the TrialsTracker (EBM DataLab, Oxford) publicly name sponsors and institutions that fail to report.
  • Registered Reports (Center for Open Science) and journals such as PLOS ONE and eLife commit to publishing regardless of result.
  • The Reproducibility Project: Cancer Biology published every replication attempt, positive or negative.
  • ASCO's TAPUR and NCI-MATCH publish negative cohorts as a matter of policy.
What breaking it looks like
More than 90% of completed trials post results within a year, every terminated drug programme has a public record of why it stopped, and preclinical negative results are routinely deposited in a searchable registry.

Ideas to fix it

50top
early clinicalindustrymedium cost
A commons of shelved cancer drugs with their full data, open to new hypotheses

Companies stop developing many drugs that were safe but did not work in the disease they tried. Sharing those drugs and their data lets others test them where they might work.

early clinicalregulatorsmall cost
A formal regulatory route for validating a biomarker on archived trial samples

Completed trials have stored samples. Testing a new biomarker on them with the plan written in advance is nearly as good as a new trial and far cheaper, but regulators have no clear route to accept it.

speculativephilanthropysmall cost
A funder-backed, indexed journal of negative and inconclusive cancer results

Create a proper, indexed journal that publishes failed experiments and trials quickly, with fees paid by funders so that there is no barrier to reporting failure.

speculativepolicymedium cost
A global ledger of negative results and failed compounds with mandatory deposition

Every failed cancer drug, experiment and trial gets recorded in one open ledger, so nobody repeats a failure that has already cost years and millions.

speculativephilanthropysmall cost
A home for the animal and organoid experiments that failed

Failed laboratory experiments are rarely published, so other teams repeat them. A searchable place to deposit them would save years of duplicated work.

speculativedatasmall cost
A machine-readable taxonomy of why cancer drugs fail

Drugs fail for very different reasons: the target was wrong, the drug did not reach it, the side-effects were too bad, or the trial was badly designed. Recording which reason each time would show where the system is broken.

speculativedatasmall cost
A public registry of cancer treatments that were later shown not to work

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.

speculativedatasmall cost
A public registry of stalled academic assets and shelved company compounds

Thousands of promising cancer compounds sit unused in university freezers and company archives. A public catalogue of what exists, what is known and who to ask would let others pick them up.

early clinicaldatasmall cost
A public transparency score for every trial sponsor, used by sites and patients

Rate sponsors on whether they publish their results, share data and register outcomes honestly. Hospitals and patients can then prefer sponsors that behave well.

speculativeresearchsmall cost
A registry for preclinical experiments that did not work

Most lab experiments that fail are never written up, so other labs repeat them. A simple, structured registry with a citable record for each failed experiment would stop the waste.

early clinicaldatamedium cost
A single oncology trial data trust with mandatory deposit within eighteen months

Every cancer trial's anonymised patient-level data would go into one trusted repository within eighteen months of completion, with a single access committee, so researchers can re-analyse, pool and learn from trials that today stay locked up.

speculativeregulatorsmall cost
A standing rulebook for one-patient treatments

Sometimes a treatment must be designed for a single patient. Agreeing in advance what evidence and safety checks are needed would make that fast, fair and learnable.

speculativedatasmall cost
A target de-risking index that counts failures as well as successes

For each drug target, show how many programmes have been tried against it and how many failed, so new teams know what they are up against.

early clinicalregulatorsmall cost
Actually fine sponsors who do not post trial results

US law already requires trial results to be posted within a year and allows fines of over ten thousand dollars a day. Almost no fines have ever been issued. Start issuing them.

speculativedatasmall cost
Alert guidelines and trials when a paper they rely on is retracted

When a study is retracted, everything built on it should get a warning. Today, retracted cancer papers keep being cited and used for years.

speculativedatasmall cost
An annual map of high-burden questions that nobody is funding

Mine grant databases and the literature to find cancer types and questions with heavy burden and zero active projects, then publish the list so funders and scientists can go there.

early clinicaldatasmall cost
Automatically detect when a trial changes its outcomes after the fact

Trials sometimes quietly swap the outcome they promised to measure for one that looks better. Software can compare the registered plan with the published paper and flag the switch.

speculativeregulatorsmall cost
Bayesian shrinkage for subgroup claims to stop false 'works in this group' stories

Trials look at dozens of patient subgroups and some will look good by chance. A statistical method that pulls extreme subgroup results toward the overall result would make these claims more honest.

speculativephilanthropysmall cost
Bounties for documented failed replications of high-impact findings

Pay a reward to any lab that carefully tries to repeat an important cancer finding and documents that it did not work. Today that work is unpaid and unpublished.

early clinicalpolicysmall cost
Deposit trial results as structured data, not just PDFs

Trial results (hazard ratios, confidence intervals, subgroups, toxicities) would be deposited in a computer-readable form so they can be pooled, checked and used by software immediately.

speculativepolicysmall cost
End the abstract-to-paper gap: require full results with any conference presentation

Trial results are often presented at conferences months or years before the full paper appears, leaving doctors to act on slides. Require that the full structured results are published the same day.

speculativephilanthropysmall cost
Funder bonuses for releasing results and data within six months, negatives included

Pay scientists a small bonus, added to their grant, when they post their results and data openly within six months of finishing an experiment, whether the result was positive or not.

speculativeresearchsmall cost
Give negative trials plenary slots at the big cancer conferences

Conferences headline the trials that worked. A dedicated plenary for important trials that failed would make the lessons impossible to miss.

speculativepolicysmall cost
Grant progress reports must list what did not work

Researchers report their successes to funders every year. Make them report their failures too, in a structured, searchable way.

speculativepolicysmall cost
Listed companies must disclose top-line data, not just 'did not meet endpoint'

When a public company announces a trial failure, it should be required to give the actual numbers, as it must for a success.

early clinicalresearchmedium cost
Living systematic reviews of animal and organoid evidence before every new trial

Before testing a drug in people, someone should systematically gather all the animal and laboratory evidence, including the studies that failed. Almost no cancer trial does this.

preclinical evidenceresearchsmall cost
Make in vivo metastasis screens a required step in drug discovery

Drug candidates are tested for shrinking tumours, almost never for stopping spread. A standard spread test would find anti-metastatic drugs we are throwing away.

speculativeregulatorsmall cost
Make post-progression sampling a condition of accelerated approval

Drugs approved on early evidence come with follow-up obligations. One of them should be finding out how tumours escape the new drug.

speculativeresearchmedium cost
Match therapy to the type of scar-forming cell in the tumour

The support cells that build a tumour's scaffolding come in several types: some protect the tumour, others restrain it. Treating all of them the same way explains past failures.

speculativeregulatorsmall cost
No new trial approval until the sponsor has reported its old ones

Ethics committees should check whether a sponsor has published the results of its previous finished trials before approving the next one.

early clinicalphilanthropymedium cost
One definitive ketogenic diet trial in glioblastoma, then stop

Patients with brain tumours are sold ketogenic diets on the strength of mouse data and small feasibility studies. A single adequately powered trial with dietitian support would either prove it or let clinicians say clearly that it does not work.

early clinicalpolicysmall cost
Patient-level data from failed trials becomes open by default after two years

When a trial fails, the company has little commercial reason to keep the detailed data secret. Make sharing it the default rather than something researchers must beg for.

speculativeclinicsmall cost
Pay investigators for finishing and publishing trials, not for enrolling patients

Trial sites are paid per patient recruited, so nobody is paid to finish the study or report the answer. Shift part of the payment to completion and publication within a year.

being tested at scaleregulatorsmall cost
Plain-language trial results returned to every participant within a year

If you join a cancer trial you should be told what it found, in plain words, within twelve months of the results, including if the treatment did not work.

speculativepolicysmall cost
Pre-register animal efficacy studies like clinical trials

Clinical trials must be registered before they start so that failures cannot be hidden. Animal studies used to justify human trials should follow the same rule.

speculativepolicysmall cost
Pre-registration and results reporting for real-world cancer studies

Just as clinical trials must be registered before they start, studies using hospital data should be registered too, so the failed or unwelcome ones cannot quietly disappear.

speculativeresearchsmall cost
Promote academics for trials completed, data shared and findings replicated

Universities and cancer centres would change how they promote scientists, giving credit for finishing trials, sharing data, replicating others' work and publishing failures, not just for papers in famous journals.

speculativeindustrysmall cost
Public post-mortem reports when a cancer drug programme is stopped

When an aeroplane crashes, an independent report explains why so it does not happen again. When a cancer drug programme is abandoned, nothing is written. Change that.

early clinicalregulatorsmall cost
Publish every complete response letter and negative opinion across all regulators

When a regulator rejects a cancer drug, the reasons are usually secret. Publishing them everywhere would stop other countries and companies repeating the same mistakes.

early clinicalclinicmedium cost
Record what happens when doctors use cancer drugs off-label

Cancer drugs are often prescribed outside their approved use based on hope or small studies. Capturing outcomes of these uses would reveal which ones fail so they can be stopped.

early clinicalresearchsmall cost
Registered reports for cancer biology: the plan is peer-reviewed before the result

Journals agree to publish a study based on the quality of the question and plan, before anyone knows the answer. That removes the pressure to make results look positive.

early clinicalindustrymedium cost
Require a randomised phase 2 before any phase 3

Many large trials are launched on the strength of a small study with no comparison group, and most of those large trials fail. Insisting on a smaller randomised comparison first would filter out weak drugs earlier.

speculativepolicysmall cost
Require every oncology candidate to publish how much reaches the brain

Whether a drug gets into the brain is measured early in development but rarely published. Making that number public would show which existing drugs could treat brain disease.

early clinicalresearchmedium cost
Rescue the biological samples from failed trials for biomarker research

Trials that fail still collected thousands of blood and tissue samples. Instead of being destroyed, they should be pooled so scientists can learn who might have benefited.

early clinicalengineeringmedium cost
Robot-placed catheters and live imaging for drug infusion into brain tumours

Pumping drugs slowly through fine tubes into a brain tumour can bypass the barrier, but the fluid often leaks away. Robotic placement and live scans would show where it actually goes.

speculativedatasmall cost
Score every preclinical model by how often it predicted the clinical result

For each type of laboratory model, keep a public record of how often its predictions came true in patients, so that researchers know which models to trust for which question.

speculativephilanthropysmall cost
Small grants that pay scientists to write up abandoned projects

Failed projects are not published because nobody has the time. Paying for a few months of writing would recover years of otherwise lost work.

preclinical evidenceresearchmedium cost
Soften the tissue that new metastases need in order to grow

Cancer cells need stiff, cross-linked tissue scaffolding to settle and grow in a new organ. Blocking the enzymes that build it may stop new colonies taking hold.

speculativeindustrysmall cost
Stop failing trials earlier with pre-registered aggressive futility rules

Many big trials continue for years after the data already show the drug is unlikely to work. Agreeing in advance to stop earlier when the odds look bad would spare patients and free money for better ideas.

being tested at scaleresearchmedium cost
Use pre-surgery immunotherapy windows as the field's biomarker engine

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.

What relieves it today

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Key papers

4top
rctJournal of Clinical Oncology 2024
TROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival

For hormone-receptor-positive metastatic breast cancer that has already had chemotherapy, Dato-DXd controls the disease for longer with fewer severe side effects than chemotherapy, but does not help patients live longer, so it is not a standard option here. The result is a reminder that progression-free survival is a surrogate; regulators and clinicians should wait for survival data before adopting an ADC in a setting where later therapies are effective.

rctNew England Journal of Medicine 2021changed practice
KEYNOTE-564: a year of pembrolizumab after kidney cancer surgery

Patients whose kidney cancer has been removed but who are at high risk of recurrence (large or high-grade tumours, node involvement, or resected metastases) can now be offered a year of pembrolizumab, which increases the chance of being alive and cancer-free several years later. Roughly nine patients need treatment to prevent one recurrence at two years, and some will have permanent side effects, so shared decision-making matters. Why pembrolizumab succeeded where similar drugs failed is not fully understood.

meta analysiseLife 2021
Reproducibility Project: Cancer Biology found that landmark preclinical results mostly shrank or vanished on replication

Many exciting laboratory findings that motivate drug programmes are weaker or less reliable than published, which helps explain the high failure rate of drugs entering clinical trials. It argues for pre-registration, detailed methods, data sharing and independent replication before major translational investment.

rctNew England Journal of Medicine 2005changed practice
Stupp 2005: temozolomide added to radiotherapy for newly diagnosed glioblastoma

Patients with newly diagnosed glioblastoma who are fit and under about 70 receive six weeks of radiotherapy with daily temozolomide followed by six monthly cycles of temozolomide; this is still the backbone of treatment two decades later. Testing MGMT methylation identifies who benefits most and guides decisions in older patients. Median survival with the regimen remains only around 15-20 months, and no drug since has clearly improved on it, which is why glioblastoma is a priority for new approaches.

Connected

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technologies

3

drugs

10

institutions

5

trials

5

ideas

50
A commons of shelved cancer drugs with their full data, open to new hypothesesA formal regulatory route for validating a biomarker on archived trial samplesA funder-backed, indexed journal of negative and inconclusive cancer resultsA global ledger of negative results and failed compounds with mandatory depositionA home for the animal and organoid experiments that failedA machine-readable taxonomy of why cancer drugs failA public registry of cancer treatments that were later shown not to workA public registry of stalled academic assets and shelved company compoundsA public transparency score for every trial sponsor, used by sites and patientsA registry for preclinical experiments that did not workA single oncology trial data trust with mandatory deposit within eighteen monthsA standing rulebook for one-patient treatmentsA target de-risking index that counts failures as well as successesActually fine sponsors who do not post trial resultsAlert guidelines and trials when a paper they rely on is retractedAn annual map of high-burden questions that nobody is fundingAutomatically detect when a trial changes its outcomes after the factBayesian shrinkage for subgroup claims to stop false 'works in this group' storiesBounties for documented failed replications of high-impact findingsDeposit trial results as structured data, not just PDFsEnd the abstract-to-paper gap: require full results with any conference presentationFunder bonuses for releasing results and data within six months, negatives includedGive negative trials plenary slots at the big cancer conferencesGrant progress reports must list what did not workListed companies must disclose top-line data, not just 'did not meet endpoint'Living systematic reviews of animal and organoid evidence before every new trialMake in vivo metastasis screens a required step in drug discoveryMake post-progression sampling a condition of accelerated approvalMatch therapy to the type of scar-forming cell in the tumourNo new trial approval until the sponsor has reported its old onesOne definitive ketogenic diet trial in glioblastoma, then stopPatient-level data from failed trials becomes open by default after two yearsPay investigators for finishing and publishing trials, not for enrolling patientsPlain-language trial results returned to every participant within a yearPre-register animal efficacy studies like clinical trialsPre-registration and results reporting for real-world cancer studiesPromote academics for trials completed, data shared and findings replicatedPublic post-mortem reports when a cancer drug programme is stoppedPublish every complete response letter and negative opinion across all regulatorsRecord what happens when doctors use cancer drugs off-labelRegistered reports for cancer biology: the plan is peer-reviewed before the resultRequire a randomised phase 2 before any phase 3Require every oncology candidate to publish how much reaches the brainRescue the biological samples from failed trials for biomarker researchRobot-placed catheters and live imaging for drug infusion into brain tumoursScore every preclinical model by how often it predicted the clinical resultSmall grants that pay scientists to write up abandoned projectsSoften the tissue that new metastases need in order to growStop failing trials earlier with pre-registered aggressive futility rulesUse pre-surgery immunotherapy windows as the field's biomarker engine

collections

3

key papers

4