Biomarkers in Clinical Studies Flashcards
1) What is the definition of a biomarker?
- A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions.
- Molecular, histologic, radiographic, or physiologic characteristics are types of biomarkers.
2) What is the definition of a clinical endpoint?
A characteristic or variable that reflects how a patient feels, functions or how long a patient survives.
3) What is the definition of a surrogate endpoint?
A biomarker intended to substitute a clinical endpoint. A clinical investigator uses epidemiological, therapeutic, pathophysiological or other scientific evidence to select a surrogate endpoint that is expected to predict clinical benefit, harm, or lack of harm.
4) What is a diagnostic biomarker?
- A biomarker used to identify individuals with the disease or condition of interest or to define a subset of the disease. - Examples:
- Sweat chloride levels in cystic fibrosis (CF)
- Galactomannan in invasive aspergillosis
- Blood sugar or HbA1c in DM
- Blood pressure in hypertension
- Serum creatinine or GFR (glomerular filtration rate) in kidney failure
- Ejection fraction in heart failure
5) What is a monitoring biomarker?
- A biomarker measured serially and used to detect a change in the degree or extent of disease.
- Monitoring biomarkers may also be used to indicate toxicity or assess safety, or to provide evidence of exposure, including exposures to medical products. - Examples:
- HCV-RNA in chronic hepatitis C
- INR or PT in warfarin
- PSA in prostate cancer
- CA-125 in ovarian cancer
- BNP or NT-proBNP in pediatric pulmonary hypertension
6) What is a pharmacodynamic (response) biomarker?
- A biomarker used to show that a biological response has occurred in an individual who has received an intervention or exposure.
- Examples:
- Circulating CD20-positive B lymphocytes in SLE treated with B lymphocyte stimulator inhibitor
- Blood pressure in HTN treated with anti-hypertensives or sodium restriction
- Cholesterol in hyperlipidemia treated with lipid-lowering agents or dietary changes
- HbA1c in DM treated with anti-hyperglycemic or lifestyle changes
- Sweat chloride in cystic fibrosis treated with anti-hyperglycemic
- INR in patients treated with warfarin
- Viral load in anti-retroviral treatment
7) What is a predictive biomarker?
- A biomarker used to identify individuals who are more likely than similar patients without the biomarker to experience a favourable or unfavorable effect from a specific intervention or exposure.
- Examples:
- EGFR mutations in NSCLC for anti-EGFR drug therapy
- BRCA1/2 mutations in OC for PARP inhibitors (give)
- KCNJ11 mutations in pediatric diabetes for sulfonylurea treatment
- HLA-B*5701 genotype in HIV pre-abacavir treatment for severe skin reactions (don’t give)
- CFTR mutations in CF for ivacaftor
- TPMT genotype in 6-mercaptopurine or azathioprine treatment for severe toxicity
8) What is a prognostic biomarker?
- A biomarker used to identify likelihood of a clinical event, disease recurrence or progression.
- Examples:
- BRCA1/2 mutations in BC patients for the likelihood of a second BC
- Ch17p deletions in CLL for the likelihood of death
- PSA in prostate cancer for the likelihood of cancer progression
- Plasma fibrinogen in COPD for high risk for exacerbation
- CRP levels in adults for the likelihood of coronary artery disease
- Gleason score in prostate cancer for cancer progression
- Total kidney volume in PCKD for high risk renal function decline
- Peak VO2 <15 ml/kg/min, PVR/SVR > 1.0 in pediatric pulmonary hypertension
9) What is a safety biomarker?
- A biomarker used to indicate the presence or extent of toxicity related to an intervention or exposure.
- Examples:
• Hepatic aminotransferases in hepatotoxicity
o Released in the bloodstream during liver damage o ALT/AST measured
o Acetaminophen induced hepatotoxicity
- Serum creatinine in nephrotoxicity
- Urinary kidney biomarkers (Kim-1, Albumin, Total Protein, b2 Microglobulin, Urinary Clusterin, Urinary TFF3, Urinary Cystatin C) in acute drug-induced nephrotoxicity • Corrected QT interval in Torsades de Pointes
10) What is a susceptibility (risk) biomarker?
- A biomarker that indicates the potential for developing a disease or medical condition or sensitivity to an exposure in an individual without clinically apparent disease or medial condition.
- Examples:
- BRCA1/2 mutations in the predisposition for breast cancer
- Factor V leiden in the predisposition for DVT
- APOE gene variations in the predisposition of earlier onset of Alzheimer’s disease
- Infection of HPV subtypes in the likelihood for cervical cancer
11) What is an example of a biomarker with multiple purposes?
1) pre hypertensive ppl with high BP undergoing lifestyle changes experiences a drop in BP (in this case, BP is a monitoring and response biomarker)
2) if the person who undergoes lifestyle changes does not experience a drop in BP, BP becomes a diagnostic biomarker
12) What is the paradigm shift in biomarkers?
In the past: All subjects are randomly assigned to drug and placebo, then responders/non-responders are stratified.
Now: subjects are genotyped to identify levels of certain biomarkers before stratified to drug and placebo group based on whether they are tested positive/negative on certain biomarkers.
13) What are the strategies of biomarker driven trial design?
Take tumor samples from patients, do tumor genomic analysis. Identify predictive/prognostic/pharmacogenomic biomarkers and design trial based on these results.
One type of clinical trial design in the umbrella trial design. This involves testing all patients with the same disease for certain biomarkers. Stratify patients based on biomarkers, then assign a specific intervention to each group.
Another type is the basket design, where patients with different diseases but have the same biomarker are assigned the same intervention. Essentially, this allows for design of more customized treatment for each patient.
