most agents provide marginal benefit
patient selection for trials need to minimize risk and maximize potential benefit
bio markers can assist efficient medical product development
Fate of Most Candidate Biomarkers
- found in academic laboratory
- Clinical series published
- Further small series published
- uptake in academic centers in clinical care
- assays commercialized as laboratory service
- Small quantity developed into laboratory tests
- Few integrated into clinical care
- Evidence base for use can be slim/controversial
- Not adopted for use because of absence of needed evidence
Biomarker Development: Challenges
Potential biomarker discovery outpaces validation studies.
- have rarely led to clinical use —> validating cancer biomarkers can be hard.
- Multidisciplinary collaboration between clinicians, laboratory scientists, pathologists, imagers, and statisticians and industry over a period of years.
- Different cultures/goals/priorities.
- Buy-in from collaborators is essential.
Barriers to successful inclusion of biomarker studies
- add-on studies that aren’t necessary for achieving the (primary) objectives of the clinical trial
- its hard for clinical trials to succeed
- Biomarker studies tend to use assays that are not well established
- unrealistic to learn to do an assay while studying a novel treatment
- too many variables
Considerations for Biomarkers
- Biomarkers
Why these biomarkers?
What is the question/purpose?
Determining potential “value-added”
Rationale and supporting data
Laboratory experimentation relevance to subject at hand
Clinical evaluation prevalence and significance in normal and cancer patients
- Assay
Why this technology?
Analytical/Laboratory Validation (based on performance)
How well are you measuring the measurand?
Is it fit for proposed purpose (example on the proposed samples/patients?)
Clinical Validation
Does the test have clinical utility?
Does it have added value over standard tests?
- Specimen
Will the Samples Be Adequate?
Can the question still be answered?
- Trial Design
Phase 1 Considerations
Biomarkers that assist in dose/schedule selection
Small patient numbers and heterogeneity and limited likelihood of clinical benefit limit the types of questions that can be addressed
Small patient numbers require MORE robust assays to yield interpretable results
Phase 2/3 considerations
Biomarkers focus on predicting benefit
Identifying patients more/less likely to benefit Identifying evidence of anti-tumour activity
Randomized designs (experiment versus control) are best
Determine prognostic versus predictive Assess and refine assay/biomarker
Identifying predictive markers is most useful if the agent has evidence of activity
- Trial Execution
- Trial Outcome
- predictable Impact
Biomarkers in Clinical Research: Efficiencies
Phase I – proof of target inhibition after reaching biologically active dose/concentration
Phase II – predictive marker assessment after identifying promising level of activity; studies should be larger and randomized
Phase III – prospective testing of biomarker and treatment
Phase IV – prospective testing of biomarker and treatment
Biomarkers in Clinical Trials
Effective inclusion of biomarker studies in oncology clinical trials requires:
- Clear and compelling hypothesis
- Strong rationale based on experimentation and investigation
- Well defined assay Laboratory validation
- Fit for use on clinical study
- Well defined collection, storage, analysis Well designed and executed clinical trial