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BIOMARKERS
Dr. Priyanka Kumawat
Dr. Adesh D. Mishra
Flow of presentation
• Definition
• Classification and types
• Surrogate end points
• Characteristics of ideal biomarker
•...
Introduction
• Biomarker: A characteristic that is objectively
measured and evaluated as an indicator of
• Normal biologic...
Valid biomarker
• “A biomarker that is measured in an analytical test
system with well established performance characteris...
Classification of biomarkers
Natural history of a disease
Eg. symptoms of disease
Natural history of a disease
Eg. symptom...
Types of biomarkers
Based on
disease state
Based on
disease state
Based on
biomolecule
Based on
biomolecule
DNA marker,
ge...
Molecular profiling approaches for identifying novel biomarkers. Epert
opinion.drug saf(2004),3(2): 137-157
Pharmacodynami...
How they all related
Surrogate Endpoint
• Definition: Is a laboratory measurements or physical sign
used in therapeutic trials as a substitute ...
• Death from heart disease--- clinical endpoint
cholesterol-- surrogate marker
• Surrogate endpoints are a subset of bioma...
Biomarkers as Surrogate Endpoints -
Possible Relationships
Type of Relationship Value of the
Biomarker
Example
A. Unreliab...
C. Intervention affects
the endpoint and
marker independently
Biomarker has some
value as a SEP (but
explains the
treatmen...
Characteristics of an ideal biomarker
• Have great sensitivity, specificity, accuracy , high
predictive value
• Safe and e...
• Staging
• Grading
• Selection of
initial therapy
• Monitor
recurrent
diseases
• Staging
• Grading
• Selection of
initial...
• Risk assessment- actual or potential presence of
specific risk characteristics. Eg: Cardiovascular risk
assessment- Lipo...
• Classification, grading and staging-
– Classification of the tissue of origin is first step
towards predicting survival ...
Prognosis and treatment selection-
•Necessary for the selection of neoadjuvant or adjuvant
chemotherapy. Potential to info...
Role of
biomarkers in
drug
development
Current issues in drug development
• Conventional approaches courting failure more than it
has success..
• Attrition rate ...
06/08/17
Biomarkers in clinical research and drug
development
• Biomarkers- may offer information about the
– Mechanism of action o...
Biomarker for efficacy and safety of
drug
• Drug- rosuvastatin
• End point- cardiovascular morbidity & mortaity
• Populati...
Biomarker for mechanism of drug
• Mechanistic biomarkers/ target biomarkers
• These biomarkers can be used to drive critic...
• Mechanistic biomarker- aldosterone(retain sodium and
water)
• Drugs-5-HT4 receptor agonists (cisapride, mosapride)
• Dis...
Biomarker discovery and evaluation
Biomarker Identification technologies
High throughput technologies
1.Genomics
1. Genome sequencing
2. Genome variation
3. ...
Classes of biomarkers in
CliniCal trials
Safety biomarkers
1. Liver safety tests
2. Renal safety tests
3. Hematology safe...
safety
biomarke
Markers of liver toxicity
Cholestatic injury Cytotoxic injury Altered hepatic
function
Alkaline Phosphatase
[AP, ALP]
Aspa...
Markers for KIDNEY TOXICITY
Serum Indicators Urine Indicators
Blood Urea Nitrogen
(BUN)
Physical characteristics Chemical ...
• Bone marrow:- Primary target
• Effect:- changes in peripheral blood components.
• Complete blood count :-
i. Total hemog...
Bone safety biomarkers
• Living connective tissue
• Constantly under process of remodeling
• Includes bone resorption and ...
Basic metabolic safety biomarkers
a) Blood glucose
b) Triglycerides (TG)
c) Total cholesterol
d) Low density lipoprotein ...
effiCaCy
biomarkers
effiCaCy biomarkers
• Purpose differs fundamentally from safety
monitoring
• Used to demonstrate a change in all, or at
le...
06/08/17
Prognostic
biomarkers.
Predictive biomarkers
• Stratify patient populations into responders and non-responders
• Predict whether or not a drug wi...
• 76 genetic and genomic biomarkers (CYP2D6,CYP2C19):-
on FDA labels of 70 approved drugs – oncology, psychiatry,
antivira...
Predictive biomarkers
• Human genome project :- understanding of human
genetics and the associated biology
• Patients with...
PERSONALIZED MEDICINE AND COMPANION
DIAGNOSTICS (CDX)
• Recent advances in cancer research :- focused on drug
candidates w...
• This approach mandates co-development of an IVD with
a drug- a companion diagnostic (CDx).
• Co-development can occur du...
Prognostic biomarkers
• Predict the risk or outcome of a disease in patient population
without the involvement of therapy....
1) Preoperative CA125 to predict metastatic disease in patients with uterine
carcinoma (Gupta et al, 2011)
2) CRP as a ris...
Pharmacodynamic biomarkers
• Demonstrate that a drug hits its target and impacts its
biochemical pathway.
• To demonstrate...
• The contribution of biomarkers to the goals of phase I
oncology trials was analyzed
1. Supported the proposed mechanism ...
• These biomarkers were determined in
1. Serum (36.8% of total)
2. Tumor tissue (25.6%)
3. Peripheral blood mononuclear ce...
06/08/17
LIMITATIONS
….
PRE ANALYTICAL ERRORS
Sample processing, storage, and shipping-
related
- Inadequate coagulation time for serum separation.
- Lag time between s...
Post-analytical
1. Improper documentation of test results, wrong
manual transcription, or questionable interface
between a...
Conclusion
•Patients expect approved drugs that work, are safe and
are “right” for them.
•Biomarkers can help drug develop...
• Biomarker enabled R&D is maturing into a new
discipline that is addressing these goals with more
precision.
• However, t...
“BIOMArkerS hAve cerTAINLy
IMpAcTed ON Our INTerNAL
decISION MAkINg ON wheTher
TO MOve fOrwArd TO The NexT
phASe Of cLINIc...
References
• www.wikipedia
• Biomarkers:An indispensible addition to the drug development
toolkit. EXAMINING THE POTENTIAL...
guIdANce fOr INduSTry
• Regarding context, structure and format of regulatory
submissions for qualification of genomic bio...
Objectives
• To create a harmonized recommended structure for
biomarker qualification applications that will foster
consis...
Scope
• Submissions for clinical and nonclinical genomic biomarkers
related to development of drug
• Including translation...
STrucTure Of BIOMArker
QuALIfIcATION SuBMISSIONS
• Section 1: Regional Administrative Information
• Section 2: Summaries
•...
SecTION 1: regIONAL
AdMINISTrATIve
INfOrMATION
• Documents specific to each region, for
example application forms
• And/or...
SecTION 2: SuMMArIeS
• To discuss and interpret the strengths and limitations of the
submitted data.
• Supported by the se...
 Introduction
• Concise.
• Description of the disease and/or experimental setting
• Definition of the biomarker
• Rationa...
cONTexT Of uSe
(1) The general area,
(2) The specific biomarker use,
(3) The critical parameters
1.General area
Nonclinica...
2.SpecIfIc BIOMArker uSe(S)
• Patient/clinical trial subject
selection
o Inclusion/exclusion criteria
o Trial enrichment o...
3. crITIcAL pArAMeTerS Of
cONTexT Of uSe
• Drug or biotechnology product-specific use/drug class-specific use/use
not link...
Nonclinical Safety
“Messenger RNA levels of kidney injury molecule 1 (Kim-1) and
clusterin (Clu) can be included as genomi...
Clinical Pharmacology/Drug Metabolism
CYP2C9 genetic polymorphism produces poor metabolizer (PM) and extensive
metabolizer...
Summary of Methodology and Results:-
1)Methods and results across studies
2)Review
3)Critical assessment
4)Appraisal of ov...
2. Data Summaries (Analytical, Nonclinical, Clinical)
Detailed factual summarization of information :-
- Methods and rele...
Section 3: Quality :-
Drug quality and manufacturing data - NDA, BLA, or MAA.
Sections 4 (Nonclinical) and (Clinical) :-
1...
Conclusion
1)An assessment of expected benefits for the application of the
biomarker
2)Address issues-
Encountered during...
The evolving role of biomarkers. IBM Global Business Services
Biomarker Identificatoin & detection
The uses of biomarkers in drug development.
1) “Nonsurrogate Biomarkers" will be used to decrease the threats
of medicatio...
Role of Biomarkers in Drug Development
 “Any biomolecule that recognizes something that is irregular in
illness and has c...
Derivation
DISCOVERY/EVALUATI
ON OF BIOMARKERS
Phase I
Specimen/ sample-
•From well
characterised cohorts,
tissue banks or from a
trial with active follow
ups
Phase II
Phase III
• Evaluates the sensitivity and specificity of the test for the
detection of diseases that have yet to be detect...
Phase IV
• Evaluation of sensitivity and specificity of
the test on a prospective cohort
• A positive test triggers a defi...
Phase V
Biomarker Evaluation
Framework
Process should consist of the following three steps:
1.Analytical validation – Biomarker te...
Kidney toxicity
LIVER TOXICITY
• Localization of damage:
Centrilobular (zone 3)
• Most hepatotoxicants (CCl4, APAP)
• Less oxygen + high P...
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Biomarkers final ppt

  1. 1. BIOMARKERS Dr. Priyanka Kumawat Dr. Adesh D. Mishra
  2. 2. Flow of presentation • Definition • Classification and types • Surrogate end points • Characteristics of ideal biomarker • Uses of biomarkers • Role of biomarkers in drug development • Classes of biomarkers in clinical trials – Safety biomarkers- organ toxicity – Efficacy biomarkers- predictive, prognostic, PD biomarkers • Personalized medicine and biomarker • Advantages and disadvantages • Challenges
  3. 3. Introduction • Biomarker: A characteristic that is objectively measured and evaluated as an indicator of • Normal biological processes • Pathogenic processes • Pharmacologic responses to a therapeutic intervention or other health care intervention National Institutes of Health 2001 biological measures of a biological state.biological measures of a biological state.
  4. 4. Valid biomarker • “A biomarker that is measured in an analytical test system with well established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the physiologic, toxicologic, pharmacologic or clinical significance of the test result.” FDA Pharmacogenomics guidance
  5. 5. Classification of biomarkers Natural history of a disease Eg. symptoms of disease Natural history of a disease Eg. symptoms of disease Intervention/Drug activity markers Eg.radioactive isotope(rubidium chloride ) to evaluate perfusion of heart muscle. Eg. Blood glucose lowering after antidiabetic drugs Intervention/Drug activity markers Eg.radioactive isotope(rubidium chloride ) to evaluate perfusion of heart muscle. Eg. Blood glucose lowering after antidiabetic drugs Surrogate markers Eg. "Death from heart disease" is the endpoint of interest, but "cholesterol" is the surrogate marker Surrogate markers Eg. "Death from heart disease" is the endpoint of interest, but "cholesterol" is the surrogate marker
  6. 6. Types of biomarkers Based on disease state Based on disease state Based on biomolecule Based on biomolecule DNA marker, gene DNA marker, gene RNA markerRNA marker Protein marker- enzyme Protein marker- enzyme Carbohydrate marker Carbohydrate marker In silico markerIn silico marker Pathological marker – cell, hormones etc. Pathological marker – cell, hormones etc. Imaging markerImaging marker Based on other criteria Based on other criteria Prognostic marker Prognostic marker Diagnosis marker Diagnosis marker Detection marker Detection marker Prediction marker Prediction marker
  7. 7. Molecular profiling approaches for identifying novel biomarkers. Epert opinion.drug saf(2004),3(2): 137-157 Pharmacodynamic biomarker Biomarker which reflects the pharmacologic response
  8. 8. How they all related
  9. 9. Surrogate Endpoint • Definition: Is a laboratory measurements or physical sign used in therapeutic trials as a substitute for a clinical endpoint and is a direct measure of how a patient feels, functions or survives. • Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinical endpoint. • Eg. Statins reduces cholesterol, without showing directly that statins prevents death (elevated cholesterol levels increase heart disease)
  10. 10. • Death from heart disease--- clinical endpoint cholesterol-- surrogate marker • Surrogate endpoints are a subset of biomarkers • A biological marker ---> surrogate endpoint, if predict clinical benefit or harm based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence
  11. 11. Biomarkers as Surrogate Endpoints - Possible Relationships Type of Relationship Value of the Biomarker Example A. Unreliable interaction between biomarker and the treatment intervention Biomarker of no value as a surrogate endpoint Prostrate-specific antigen is a useful biomarker for prostrate cancer detection but unreliable as an indicator of treatment response. B. The full effect of the intervention is observed through the biomarker assessment Biomarker is an ideal surrogate endpoint None known at present
  12. 12. C. Intervention affects the endpoint and marker independently Biomarker has some value as a SEP (but explains the treatment effect partly) Most established SEPs (HIV antivirals-- CD4 Count as biomarker, with mortality as end point, development of OI ) D. Intervention has favorable effect on marker but has no or unfavorable effect on disease or well-state Biomarker is of little practical use as a SEP PVCs as a biomarker of fatal arrhythmias following MI (CAST trials)
  13. 13. Characteristics of an ideal biomarker • Have great sensitivity, specificity, accuracy , high predictive value • Safe and easy to measure • Cost efficient to follow up • Modifiable with treatment • Consistent across gender and ethnic groups MANOJ KUMAR, SHIV K SARIN.Biomarkers of diseases in medicine. Current trends in sciences.platinum jublee issue
  14. 14. • Staging • Grading • Selection of initial therapy • Monitor recurrent diseases • Staging • Grading • Selection of initial therapy • Monitor recurrent diseases • Drug development • Drug development
  15. 15. • Risk assessment- actual or potential presence of specific risk characteristics. Eg: Cardiovascular risk assessment- Lipoprotein-associated phospholipase A2, vitamin B6, IL-6, C-reactive protein • Screening- discriminates the healthy from the asymptomatic disease state. Eg: mammography for breast cancer, pap smear for cervical carcinoma
  16. 16. • Classification, grading and staging- – Classification of the tissue of origin is first step towards predicting survival and choosing therapy eg: high-throughput RNA, protein and tissue microarray technologies – Each anatomical site has its own histological grading system eg: screening mammograms, computerized tomography (CT) scans and standard X-ray films – Staging- clinical+ pathological eg: X-ray, CT, MRI, PET, endoscopic examination, biopsy, and surgical exploration, F-FDG, C-acetate, and dual-tracer PET/CT for staging of HCC (metastasis )
  17. 17. Prognosis and treatment selection- •Necessary for the selection of neoadjuvant or adjuvant chemotherapy. Potential to inform treatment decisions and to bring personalized medicine into clinical practice. • Eg: CD20 positivity for treatment of lymphomas with rituximab • HER2/NEU positivity for treatment of breast cancer with trastuzumab • BCR-ABL translocation for treatment of chronic myelogenous leukaemia (CML) with imatinib MANOJ KUMAR, SHIV K SARIN.Biomarkers of diseases in medicine. Current trends in sciences.platinum jublee issue
  18. 18. Role of biomarkers in drug development
  19. 19. Current issues in drug development • Conventional approaches courting failure more than it has success.. • Attrition rate for drugs in clinical development is high. • Requiring a huge amount of money, time, and patients. • Very few drugs are making it out of the clinical research pipeline.. • Many drugs are withdrawn from market due to serious toxicities and sufferings after their approval
  20. 20. 06/08/17
  21. 21. Biomarkers in clinical research and drug development • Biomarkers- may offer information about the – Mechanism of action of the drug – Efficacy – Safety/toxicity – Metabolic profile. • Dose selection (PK/PD modeling) • Evaluation of dose response • Personalized medicine approach • Identifying earlier those candidates that are likely to fail, they reduce drug development costs, giving life to the concept of ‘fail early, fail cheap’.
  22. 22. Biomarker for efficacy and safety of drug • Drug- rosuvastatin • End point- cardiovascular morbidity & mortaity • Population- Apparently healthy with low LDL and high CRP • Biomarker- CRP (released by inflammed atherosclerotic plaque) • Result- drug effectively improves the prognosis of individuals with high CRP levels. • Conclusion- CRP offers a new way of measuring the efficacy of statins. Many studies showed that statin t/t improves survival in people with coronary artery disease & now CRP is being proposed as a surrogate marker for efficacy Many studies showed that statin t/t improves survival in people with coronary artery disease & now CRP is being proposed as a surrogate marker for efficacy
  23. 23. Biomarker for mechanism of drug • Mechanistic biomarkers/ target biomarkers • These biomarkers can be used to drive critical ‘go/no go’ decision in drug development • To measure pharmacological effect of a drug – Whether the drug interacts with its receptor (enzyme, protein) – Whether it is distributed to the site where it needs to act – Whether there is some form of downstream pharmacology – The dose ranges in which the drug is pharmacologically active.
  24. 24. • Mechanistic biomarker- aldosterone(retain sodium and water) • Drugs-5-HT4 receptor agonists (cisapride, mosapride) • Disease- GERD • Aldosterone secretion is a side effect of these drugs • So aldosterone biomarker can assess whether novel 5- HT4 agonists in development have a pharmacological effect • Aldosterone can also be used to assess at what doses the 5-HT4 agonists have an effect. Drug distribution or receptor occupancy can be evaluated by imaging techniques Drug distribution or receptor occupancy can be evaluated by imaging techniques Biomarkers:An indispensible addition to the drug development toolkit. EXAMINING THE POTENTIAL OF BIOMARKERS. ©2010 Thomson Reuters.
  25. 25. Biomarker discovery and evaluation
  26. 26. Biomarker Identification technologies High throughput technologies 1.Genomics 1. Genome sequencing 2. Genome variation 3. Genome annotation 2.Transcriptomics 1. Microarrays 2. Gene expression data 3.Proteomics 1. Y2H method 2. Mass spectrometry 3. Protein chips 4.Metabolomics 1. NMR 2. Mass spectrometry 5. Other technologies- 1. Fluorescent indicators 2. Lab-on-chip 3. Nuclear magnetic resonance 4. Mass spectrometry/liquid chromatography 5. Nanobiotechnology 5. Imaging
  27. 27. Classes of biomarkers in CliniCal trials Safety biomarkers 1. Liver safety tests 2. Renal safety tests 3. Hematology safety biomarkers 4. Bone safety biomarkers 5. Basic metabolic safety biomarkers 6. Other specific safety biomarkers Efficacy biomarkers • Surrogate biomarkers • Predictive biomarkers 1. In personalized medicine 2. Personalized medicine and companion diagnostics (CDx) • Prognostic biomarkers • Pharmacodynamic (PD) biomarkers
  28. 28. safety biomarke
  29. 29. Markers of liver toxicity Cholestatic injury Cytotoxic injury Altered hepatic function Alkaline Phosphatase [AP, ALP] Aspartate aminotransferase [AST] Creatine phosphokinase [CPK] 5’ Nucleotidase‐ [5-NT] Lactate Dehydrogenase [LDH] Choline Esterase [ChE] (acetylcholine esterase and butyrylcholine esterase)γ - Glutamyl Transpeptidase [GGT] Alanine aminotransferase [ALT] Total Serum Bile Acids Ornithine carbamyl transferase [OCT] Decreased dye clearance •Sulfobromophthalein •Indocyanine greenPlasma Bilirubin Alanine aminotransferase [SDH]
  30. 30. Markers for KIDNEY TOXICITY Serum Indicators Urine Indicators Blood Urea Nitrogen (BUN) Physical characteristics Chemical Characteristics Blood Creatinine Color/turbidity (RBC’s, bilirubin) Urinary protein – tubular (low MW) or glomerular (high MW) Volume Urinary glucose – no elevation of blood glucose but glucosuria (tubular) Osmolality Urinary brush border enzymes (ALP, AST, GGT)
  31. 31. • Bone marrow:- Primary target • Effect:- changes in peripheral blood components. • Complete blood count :- i. Total hemoglobin ii. Hematocrit iii. Red cell count iv. Mean red cell volume, v. Mean cell hemoglobin vi. Red cell distribution width% vii.Mean cell hemoglobin concentration viii.Total white cell count ix. Differential white cell count (Neutrophils, lymphocytes, basophils, x. esinophils, and monocytes), and platelets – (Craig, 2004). Hematology safety biomarkers
  32. 32. Bone safety biomarkers • Living connective tissue • Constantly under process of remodeling • Includes bone resorption and formation. • Bone biomarkers in clinical trials:- Serum calcium and inorganic phosphates
  33. 33. Basic metabolic safety biomarkers a) Blood glucose b) Triglycerides (TG) c) Total cholesterol d) Low density lipoprotein cholesterol (LDLc) e) High density lipoprotein cholesterol (HDL-c). – are commonly used within the safety biomarker panel but can be used as efficacy biomarkers too. Other specific safety biomarkers a) Serum immunoglobulin levels, C-reactive protein (CRP), fibrinogen b) Thyroid stimulating hormone (TSH), thyroxine, testosterone, insulin c) Lactate dehydrogenase (LDH), Creatine kinase (CK) and its isoenzymes, cardiac troponin (cTn), and methemoglobin (Craig, 2004;Reagan, 2010 and Subramaniam et al, 2010)
  34. 34. effiCaCy biomarkers
  35. 35. effiCaCy biomarkers • Purpose differs fundamentally from safety monitoring • Used to demonstrate a change in all, or at least a good proportion of treated subjects • The more positive the biomarker, the higher the efficacy of a drug.
  36. 36. 06/08/17 Prognostic biomarkers.
  37. 37. Predictive biomarkers • Stratify patient populations into responders and non-responders • Predict whether or not a drug will have the intended effect • Or forecast the extent to which a drug can be effective and/or toxic in different patient populations. • Mahgoub et al, 1977 and Tucker et al, 1977:- The discovery of Cytochrome P450-2D6 (CYP2D6) polymorphism in 1977 opened the door for research on the impact of such metabolizing enzyme’s genetic variability on the efficacy and toxicity of drugs.
  38. 38. • 76 genetic and genomic biomarkers (CYP2D6,CYP2C19):- on FDA labels of 70 approved drugs – oncology, psychiatry, antiviral and cardiovascular drugs • Drug label information on genomic biomarkers :- 1) Describe drug exposure and clinical response variability 2) Risk for adverse events 3) Genotype specific dosing 4) Mechanisms of drug action 5) Polymorphic drug target and disposition genes 6) Precautions- interactions, contraindications, patient counseling, nutritional management (FDA, 2011b)
  39. 39. Predictive biomarkers • Human genome project :- understanding of human genetics and the associated biology • Patients with different genetic makeup manifest diseases differently and respond to medication differently – in terms of both efficacy and safety. • “Right population , right drugs, right time, right dose, right price” • Potential for mitigating the problem of universalizing therapy into a single, all-encompassing solution. PersonaliZ eD meDiCine
  40. 40. PERSONALIZED MEDICINE AND COMPANION DIAGNOSTICS (CDX) • Recent advances in cancer research :- focused on drug candidates with specific molecular targets including mutated genes in cancer cells. • In-vitro diagnostic test (IVD) - To achieve the greatest benefit from such types of therapeutic agents • IVD can be an existing test for a biomarker :- FDA as “known valid;” Eg. LDL-c, HbA1c, and CYP2C19. • Biomarker appears to have predictive value but not yet replicated or widely accepted:- classified by the FDA as“probable valid,” Eg. EGFR and KRAS mutations.
  41. 41. • This approach mandates co-development of an IVD with a drug- a companion diagnostic (CDx). • Co-development can occur during any stage of drug development • Ideally - integrated early in the drug’s development program so that trial data will support both drug and test approval. • Clinical qualification :- prospective, retrospective path remains a possibility. • Biomarker assay should be analytically validated before testing clinical samples.
  42. 42. Prognostic biomarkers • Predict the risk or outcome of a disease in patient population without the involvement of therapy. Eg. a population that tested positive for a given prognostic biomarker can survive longer or live better than another that tested negative. • In addition to its predictive power, prognostic biomarkers may help enrich a clinical trial by choosing people more likely to respond to treatment • Prostatic specific antigen to predict survival in prostatic cancer patients – (D’Amico et al, 2004 and Kelloff et al, 2004)
  43. 43. 1) Preoperative CA125 to predict metastatic disease in patients with uterine carcinoma (Gupta et al, 2011) 2) CRP as a risk factor in cardiovascular events (Ridker et al, 2008 and Abd et al, 2011) 3) CRP to predict reduced overall and disease-free survival breast cancer ( Allin et al, 2011) 4) Serum LDH to predict overall survival in metastatic brain tumors (Eigentler et al, 2011). 5) The number of circulating tumor cells (CTC) was shown to predict overall and progression-free survival in patients with metastatic breast and ovarian cancers (FDA, 2005 and Poveda et al, 2011) 6) To predict the effect of treatment earlier than imaging (Nakamura et al, 2010). 7) HER2-positive CTC was suggested as a prognostic value in metastatic breast cancer (Hayashi et al, 2011).
  44. 44. Pharmacodynamic biomarkers • Demonstrate that a drug hits its target and impacts its biochemical pathway. • To demonstrate proof of the drug’s mechanism of action (POM), i.e. markers of pharmacological response. • Proof of concept (i.e., Does hitting the drug target result in the desired biologic effect?). • In correlation with pharmacokinetic (PK) measurements, help to determine- effective dose and dose schedule. • Constitutes the majority in early phases of drug discovery (preclinical, phase I, and, probably, phase II).
  45. 45. • The contribution of biomarkers to the goals of phase I oncology trials was analyzed 1. Supported the proposed mechanism of action in 39% of the trials 2. Contributed to dose selection for subsequent phase II studies in 13% 3. Contributed to the selection of dosing schedule for phase II studies in 8% 4. Potentially useful for selecting a patient population in subsequent studies in 19% of the trials.
  46. 46. • These biomarkers were determined in 1. Serum (36.8% of total) 2. Tumor tissue (25.6%) 3. Peripheral blood mononuclear cells (22.7%) 4. Normal solid tissue (3.7%) 5. Cerebrospinal fluid (0.2%) 6. In addition to 10.9% by special in-vivo imaging.  The non-imaging biomarkers included • Proteins • Cytokines • Enzyme activity in serum, CSF, or tissue lysates, proteins by immunohistochemistry (IHC), and DNA and RNA gene expression (Goulart et al, 2007).
  47. 47. 06/08/17
  48. 48. LIMITATIONS ….
  49. 49. PRE ANALYTICAL ERRORS
  50. 50. Sample processing, storage, and shipping- related - Inadequate coagulation time for serum separation. - Lag time between sampling and analysis. - Wrong centrifugation temperature, speed, or time. - Storage temperature or wrong freezer, e.g. automatic freeze-thaw. - Necrotic tissue/fluid or wrong tissue collected via fine needle biopsy. - Inappropriate acquisition and handling of fresh frozen tissue for RNA, proteins, or phosphoproteins analyses. - Inappropriate fixation and embedding of tissue biopsies into paraffin blocks. - Wrong thickness of tissue sections for histopathology, IHC, FISH, etc. - Unsuitable shipping conditions.
  51. 51. Post-analytical 1. Improper documentation of test results, wrong manual transcription, or questionable interface between analyzing instrument and database. 2. Incorrect patient identification information entered at time of test. Patients’ results May be mixed with one another. 3. Failure to recognize and act on abnormal results, e.g. repetition of samples with unexpected results or panic values
  52. 52. Conclusion •Patients expect approved drugs that work, are safe and are “right” for them. •Biomarkers can help drug development focus more on defined subgroups of patients, thereby potentially increasing treatment efficacy and safety. •Helps to make a decision to move to the next phase •Offer strong supporting evidence and in the future will be the key data in certain programs. •Offer an objective, biological indicator, rather than just seeing whether the patients feel better
  53. 53. • Biomarker enabled R&D is maturing into a new discipline that is addressing these goals with more precision. • However, the science is outpacing widespread acceptance. • The path toward acceptance by regulators and the medical community is through discovery and consistent validation of genomic, proteomic, in vitro and imaging biomarkers. • Further collaborative efforts and powerful technology approaches can increase public confidence.
  54. 54. “BIOMArkerS hAve cerTAINLy IMpAcTed ON Our INTerNAL decISION MAkINg ON wheTher TO MOve fOrwArd TO The NexT phASe Of cLINIcAL deveLOpMeNT” • James Weatherall, astraZeneca
  55. 55. References • www.wikipedia • Biomarkers:An indispensible addition to the drug development toolkit. EXAMINING THE POTENTIAL OF BIOMARKERS. ©2010 Thomson Reuters. • MANOJ KUMAR, SHIV K SARIN.Biomarkers of diseases in medicine. Current trends in sciences.platinum jublee issue • John C. Waterton.What imaging biomarkers are and how they are used. John Waterton ISMRM Honolulu April 2008 • Dr Jens Hoefkens.towards unbiased biomarker discovery.Drug Discovery World Spring 2010
  56. 56. guIdANce fOr INduSTry • Regarding context, structure and format of regulatory submissions for qualification of genomic biomarkers • A biomarker qualification application might be submitted to regulatory authorities if the biomarker directly or indirectly helps in regulatory decision-making
  57. 57. Objectives • To create a harmonized recommended structure for biomarker qualification applications that will foster consistency of applications across regions and facilitate discussions with and among regulatory authorities • Appropriate when biomarker data are submitted as part of a new drug application (NDA), a biologics license application (BLA), a market authorization application (MAA), or other post-approval regulatory procedures, or upon request by the regulatory authorities.
  58. 58. Scope • Submissions for clinical and nonclinical genomic biomarkers related to development of drug • Including translational medicine aproaches,pharmacokinetics, pharmacodynamics, and efficacy and safety aspects • Applicable to a variety of biomarker categories (e.g., genomics, proteomics, imaging) and other qualification contexts associated with drug development • A qualification submission for a combination of biomarkers (e.g., genomic together with nongenomic biomarkers) is also possible.
  59. 59. STrucTure Of BIOMArker QuALIfIcATION SuBMISSIONS • Section 1: Regional Administrative Information • Section 2: Summaries • Section 3: Quality Reports • Section 4: Nonclinical Reports • Section 5: Clinical Reports • Analytical assay development reports • Analytical assay validation reports • Nonclinical study reports (in vitro) • Nonclinical study reports (in vivo, specify species) • Analytical assay development reports • Analytical assay validation reports • Clinical pharmacology study reports • Clinical efficacy and/or safety study reports
  60. 60. SecTION 1: regIONAL AdMINISTrATIve INfOrMATION • Documents specific to each region, for example application forms • And/or cover letter. The content and format of this section can be specified by the relevant regulatory authorities.
  61. 61. SecTION 2: SuMMArIeS • To discuss and interpret the strengths and limitations of the submitted data. • Supported by the separate technical, preclinical and clinical data summaries 1.Biomarker Qualification Overview  Introduction  Context of use  Summary of methodology and results  Conclusion 2.Data summaries
  62. 62.  Introduction • Concise. • Description of the disease and/or experimental setting • Definition of the biomarker • Rationale for the biomarker’s use in drug or biotechnology product development, from discovery through post-approval. key characteristics:- • Strengths and limitations • Whether it is a single or composite biomarker composite biomarker:- component markers and selection process • Objective and design of the studies supporting its use:- prospective versus retrospective study design, study comparators and sample size
  63. 63. cONTexT Of uSe (1) The general area, (2) The specific biomarker use, (3) The critical parameters 1.General area Nonclinical/Clinical • Pharmacology • Toxicology • Efficacy • Safety • Disease
  64. 64. 2.SpecIfIc BIOMArker uSe(S) • Patient/clinical trial subject selection o Inclusion/exclusion criteria o Trial enrichment or stratification • Assessment of disease state and/or prognosis • Assessment of mechanism of action o Mechanism of pharmacological mode of action o Mechanism of therapeutic effect o Mechanism of toxicity/adverse reaction •Dose optimization o No observed effect level (NOEL) in animal models o No observed adverse effect level (NOAEL) in animal models o Algorithm-based dose determination (quantitative algorithmic dosing) o Determination of likely dose range Drug response monitoring o Monitoring drug safety o Monitoring drug efficacy • Efficacy maximization o Indicating/predicting drug efficacy • Toxicity/adverse reactions minimization o Indicating/predicting toxicity/adverse reactions o Detecting/monitoring onset/reversibility of toxicity/adverse reactions
  65. 65. 3. crITIcAL pArAMeTerS Of cONTexT Of uSe • Drug or biotechnology product-specific use/drug class-specific use/use not linked to specific drug or biotechnology products or drug classes • Disease diagnosis and phenotypes, prognosis, or stage • Sample collection • Assay specifications • Tissue or physiological/pathological process • Species • Demographics, including ancestry and/or geographic origin • Environmental factors
  66. 66. Nonclinical Safety “Messenger RNA levels of kidney injury molecule 1 (Kim-1) and clusterin (Clu) can be included as genomic biomarkers of drug or biotechnology-induced acute renal tubular toxicity in rat toxicology studies.” • General Area: nonclinical safety and toxicology • Specific Biomarker Use: assessment of mechanism of toxicity and dose optimization (NOAEL) in animal models • Critical Parameters of Context of Use: o Drug or biotechnology product-specific use: no o Assay specifications: mRNA o Tissue or physiological/pathological process addressed: kidney o Species: Rattus norvegicus
  67. 67. Clinical Pharmacology/Drug Metabolism CYP2C9 genetic polymorphism produces poor metabolizer (PM) and extensive metabolizer phenotypes and differences in Drug A exposure • General Area: Clinical Pharmacology/Drug Metabolism and Safety • Specific Biomarker Use: patient/clinical trial subject selection (inclusion/exclusion criteria, trial enrichment or stratification), dose optimization in individual patients and predicting adverse reactions/risk minimization • Critical Parameters of Context of Use: o Drug or biotechnology product-specific use: Drug A o Assay specifications: Genotyping o Species: Homo sapiens o Demographics including ancestry and/or geography: population-specific allele frequency
  68. 68. Summary of Methodology and Results:- 1)Methods and results across studies 2)Review 3)Critical assessment 4)Appraisal of overall results 5)Discussion 6)Interpretation of the findings with regard to the proposed context
  69. 69. 2. Data Summaries (Analytical, Nonclinical, Clinical) Detailed factual summarization of information :- - Methods and relevant aspects of study design -Technical and biological replication - Statistical analysis,hypothesis statements, endpoints, and justification for sample size. Describe the rationale for the selection of the population sample studied in the biomarker qualification and discuss constraints derived from this selection Contain criteria for determining sample suitability Describe the analytical performance characteristics of the assay Describe the results supporting the nonclinical/clinical use of the biomarker
  70. 70. Section 3: Quality :- Drug quality and manufacturing data - NDA, BLA, or MAA. Sections 4 (Nonclinical) and (Clinical) :- 1)Full study reports for biomarker qualification 2)Raw data made available to the regulatory authorities upon request. 3)Information on compliance with Good Clinical Practices (GCP) can be included in these sections. 4)Format of the data will depend on the characteristics of the biomarker measured (e.g., for genomic biomarkers, SNPs, and/or CNV) and the methodology used (e.g., for genomic biomarkers, microarray and/or Polymerase Chain Reaction).
  71. 71. Conclusion 1)An assessment of expected benefits for the application of the biomarker 2)Address issues- Encountered during the biomarker qualification studies, explaining how they have been evaluated and resolved; Identify unresolved issues 3) Explain why they should not be considered barriers to Qualification for the proposed context of use and/or describe plans to resolve them, if applicable.
  72. 72. The evolving role of biomarkers. IBM Global Business Services
  73. 73. Biomarker Identificatoin & detection
  74. 74. The uses of biomarkers in drug development. 1) “Nonsurrogate Biomarkers" will be used to decrease the threats of medication growth. 2) Any given biomarker is usually useful for only one of four kinds of threat reduction: that associated with  An unsuitable dosing regimen;  Signing up of nonresponsive topics into medical trials;  An lack of ability to identify an effectiveness indication easily and effectively in serious disorders;  Late identification of prospective adverse reactions or poision.
  75. 75. Role of Biomarkers in Drug Development  “Any biomolecule that recognizes something that is irregular in illness and has confirmed value in a well-controlled medical research that provides a doctor with workable details eventually used at the factor of analysis or therapy.”  Improving specifications for more and better illness diagnostics and therapeutics, along with new technology and increasing regulating specifications, have stimulated the development of biomarker programs in medication development and development,  Associates of instrumentation organizations, medication organizations and research organizations report difficulties of throughput, uniqueness, approval and interpretation as important factors to making biomarkers more effective predictors of medication action.
  76. 76. Derivation
  77. 77. DISCOVERY/EVALUATI ON OF BIOMARKERS
  78. 78. Phase I Specimen/ sample- •From well characterised cohorts, tissue banks or from a trial with active follow ups
  79. 79. Phase II
  80. 80. Phase III • Evaluates the sensitivity and specificity of the test for the detection of diseases that have yet to be detected clinically. • Specimen- study subjects before the onset of clinical symptoms (with active follow up to ascertain disease occurrence) • Time consuming & expensive • This is when most biomarker validation studies ends and biomarkers are ready to use
  81. 81. Phase IV • Evaluation of sensitivity and specificity of the test on a prospective cohort • A positive test triggers a definitive diagnostic procedure- often invasive (major difference from phase III) • More expensive
  82. 82. Phase V
  83. 83. Biomarker Evaluation Framework Process should consist of the following three steps: 1.Analytical validation – Biomarker tests need to be reliable, reproducible across multiple laboratories and clinical settings, and maintain adequate sensitivity and specificity before data based on them can be used in subsequent evaluation steps. 2.Qualification – Qualification requires: (1) evaluation of the nature and strength of evidence regarding whether a biomarker is associated with the disease, and (2) assembly of available evidence demonstrating that interventions targeting the biomarker impact the clinical endpoints of interest. 3.Utilization – Decisions to use biomarkers 3. depend on the specific use proposed in addition to the strength of the available evidence. Strong evidence and a compelling context are needed for the use of a biomarker as a surrogate endpoint. Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease. Institute of medicine MAY 2010
  84. 84. Kidney toxicity
  85. 85. LIVER TOXICITY • Localization of damage: Centrilobular (zone 3) • Most hepatotoxicants (CCl4, APAP) • Less oxygen + high P450 conc. Periportal (zone 1) • Phosphorus, aflatoxin, allyl alcohol • High oxygen + highest dose at site Midzonal (zone 2) – • Beryllium • Massive necrosis - iproniazid, MAOI Liver Lobule 100

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