from local laboratory to standardisation and beyond applying a common grading system
DESCRIPTION
Presentation at PhUSE 2007TRANSCRIPT
PhUSELisbon, Portugal – 8-10 October 2007
From Local Laboratory toStandardisation and beyond:Applying a commonggrading system
Data Management Stream (DM01)
Angelo TinazziData Management and Programming UnitSENDO Tech S.r.l. – Milan (ITALY)co-authors
Irene Corradino, Enrica Paschetto, Sonia Colombini
Early Drug Development Early Drug Development In OncologyIn Oncology
2Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
SENDO (Southern Europe New Drug Organisation )
� Non profit Academic Research Organisation (ARO)� Early Drug Development in Oncology� Coordinating a Network of oncology-hospitals
� 5 phase I (2 in Italy, 3 in Switzerland)� ~ 30 phase II (Italy, Switzerland, Spain)� Pre-clinical Laboratory (PK, PD)� Head Quarter based in Milan
� Clinical Development� Clinical Operations� Data-Management� Biostatistics� Medical Writing
3Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
IOSI, Bellinzona,Cristiana Sessa
HQ-ActivitiesClinical development
Clinical OperationData Center RegulatoryMonitoring
Logistic
INT, Milano Luca Gianni
and also .... CHUV Lausanne, KSSG S Gallen, Istituto Mario Negri Milano
Core activitiesTrial design
Selected Screening & MoAClinical trials
PharmacokineticsPharmacodynamics
SENDO (Southern Europe New Drug Organisation) - Partner s
4Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Previous Discuss at PhUSE about Lab Data Management
Szilagyi B, Binder C.Complex Laboratory Data Management, Strategiesand Tools for a Way out of the Maze. PhUSE 2005; DM05
5Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Laboratory Data
� Use of Laboratory Tests in Clinical Trials� For safety� Activity� Categories
� Pharmacodynamic� Pharmacokynetic� Microbiology� Immunology� Cytology� Pharmacogenomic
� They are also used to make immediate clinicaldecision for patient’s care and to define the drugprofile….focus on� Haematology� Chemistry� Urinalysis
6Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Laboratory Data Characteristics
� Qualitative vs Quantitative vs Semi-Quantitative� Quantitative
� Most chemistry/hematology� They are expressed in a specific unit� They refere to a range (minimum-maximum)
� Semi-Quantitative (i.e. trace)� Qualitative (i.e. +/-)
� Clinical Interpretation� Not clinically significant
� Clinically Significant (Adverse Event)
7Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Laboratory Data Characteristics
� Focus on hematology data� White Blood Count (WBC)
� Hemoglobin� Neutrophils� Monocytes� Basophils� Eosinophils� Band� Lymphocytes
� Platelets� Red Blood Cells� Hematocrit� Hemoglobin� Coagulation tests (i.e. PTT, PT)
8Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Laboratory Data Characteristics
� Focus on chemistry data� Electrolytes
� Sodium
� Potassium
� Chloride� Bicarbonate
� Carbon Dioxide
They maintain body fluid and blood pressureessential for the function of most body systems
9Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Laboratory Data Characteristics
� Focus on chemistry data� Enzymes
� Aspartate Aminotransferase (AST/SGOT)� Alanine Aminotransferase (ALT/SGPT)
� Gamma Glutamyl Transferase (γGT)
� Alkaline Phosphatase� Troponin I
� Creatine Phosphokinase (CPK)
� Lactate Dehydrogenase (LDH)
They help diagnose liver and heart diseases
10Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Laboratory Data Characteristics
� Focus on urinalysis data� Protein
� Cells� Hormone
They tests the health of organ and body process
11Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Laboratory Data Characteristics
� Normal RangesNormal ranges, or reference ranges, are used to determine if a person’s value is “normal”. The ‘normal range’ for a givenconstituent of clinical interest is considered to be the concentrations of the constituent which are found in the body fluid or excretions of a group of clinically normal persons.� by gender� by age� fasting / non-fasting� analysis method / kit used by laboratory may change over
time, and so the normal ranges
12Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Local Laboratory vs Central Laboratories
� Central LabsLab samples are analysed (and taken) in the same lab center
� Standard methods (and machine calibration)� Unique normal ranges for each sample� Electronic data transfer (no data-transcription errors)
� Local LabsLab samples are analysed (and taken) in different lab centers
� Sample can be taken anywhere / anytime� Multiple normal ranges, so different methods applied� No transport issue, but data need to re-keyed
13Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Local laboratory data-management
14Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Laboratory CRF – Option 1
Normal Ranges and UnitCollected directly onto patient CRF
15Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Laboratory CRF – Option 2
100 0 350 0120 0
120 109/L (100-350)
16Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
The SENDO Experience with 4 Trials
97Overall in SENDO Repository
1.4 (1-3)1114 (2-33)384 (ph II)
2.8 (1-5)3124 (2-61)203 (ph I)
2.7 (1-6)3327 (2-79)322 (ph I)
3.0 (1-7)4437 (2-90)341 (ph I)
Average Nr. of Local Labs Used by each patient (min-max)
Nr. of Different Local Labs Used
Nr. of samples collected (average nr by Patient, min-max)
Nr. of Patients
Study Nr
High heterogeneity inunit reported (the exampleis for Platelets count only)
17Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Quality Control
� Missing data (unit, range, interpretation)� Hand writing legibility� Unit and value incosistencies
� Normal Range Validity� Outliers detection
18Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Statistical Analysis Process
� Main Analysis� Univariate (mean, std, min, max, etc)� Shift Tables / Change From Baseline (absolute, %, log)� Correlations� Time to Event (i.e. Time to lowest observation, or time to nadir)� Worst toxic effect observed
Data must be ‘manipulated’ so that results obtainedfrom different labs can be summed, weighted and compared
19Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Statistical Analysis Process
�StandardisationEnsures that all laboratory values are expressed in the same unit (Système International d’Unités - SI)
It consists in the adoption of a standard unit by applyingconversion factors
Potassium �13.7 mg/dL SI unit is mmol/L 3.5 mmol/L
Multiply 0.2558
20Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
�NormalisationThe application of a normalisation method to ensurehomogenization of results obtained from different locallabs
Statistical Analysis Process
xx
ssxs LU
LULxLs
−−
−+= )(Reference/Standard Range
Local Labs RangeObserved Value
The standard reference can be taken from the literature or from a sample of normal ranges by taking the 10°and the 90°percentiles
Assume an observed value of 10 measured in the lab with normal range 5-25, ifour standard range has been determined to be 10-35…..
25.16525
1035)510(10 =
−−−+=s The normalised value
5-2912-3510-4515-4012-30
5101212152930354045
The statistical basis of Laboratory Normalization. Kar vanen J. DIA, Vol. 37, pp. 101-107; 2004
21Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Applying a common grading system: the CTCAE
Ocular / VisualPain Pulmonary / Upper RespiratoryRenal / GenitourinarySecondary MalignancySexual / Reproductive FunctionSurgery / Intra-Operative InjurySyndromesVascular
Gastrointestinal Growth and DevelopmentHemorrhage / BleedingHepatobiliary / PancreasInfectionLymphaticMetabolic / LaboratoryMusculoskeletal / Soft TissueNeurology
Allergy / ImmunologyAuditor / EarBlood / Bone MarrowCardiac ArrhythmiaCoagulationConstitutional SymptomsDeathDermatology / SkinEndocrine
CTCAE Event Categories
� NCI Common Terminology Criteria for AdverseEvents – CTCAE (v3.0)� A standard in oncology for classifying Adverse Events
Severity� A Grading system ranging from ‘0’ (no toxic effect) to ‘4’
(severe toxic effect), with the addition of ‘5’ (death)� An event has unique representation� Events are organised in categories� Link with MedDRA Term
22Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Applying a common grading system: the CTCAE
Qualitative Definition (Arthritis)� a grade 1 is defined as “Mild pain with inflammation, erythem a, or
joint swelling, but not interfering with function”� a grade 4 , is defined as “Disabling”
Quantitative Definition (Diarrhea)� a grade 1 , is defined as “Increase of <4 stools per day over baseline;
mild increase in ostomy output compared to baseline”� a grade 4, is defined….
Quantitative Definition based on Lab Data Results (Pla telets Count)
<25,000/mm3<25.0 x 10^9 /L
<50,000 – 25,000/mm3<50.0 – 25.0 x 10^9 /L
<75,000 – 50,000/mm3<75.0 – 50.0 x 10^9 /L
<LLN – 75,000/mm3<LLN – 75.0 x 10 ^9 /L
Grade 4Grade 3Grade 2Grade 1
23Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Example of Platelets Count from Local Lab to CTCAE Calculation
<25,000/mm3<25.0 x 10^9 /L
<50,000 – 25,000/mm3<50.0 – 25.0 x 10^9 /L
<75,000 – 50,000/mm3<75.0 – 50.0 x 10^9 /L
<LLN – 75,000/mm3<LLN – 75.0 x 10 ^9 /L
Grade 4Grade 3Grade 2Grade 1CTCAE Platelets Definition
24Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Quality Control – Additional tips in identifying Invalid Values
� For each parameter, sort the converted SI value in ascending order
� Review the lowest and highest values whenare different from the expected/normal valuesby a factor of 10,100,1000
� Look for jumps in values� Look for values that are substantially above or
below typical normal ranges values� Review grade 3-4 CTCAE
25Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Conclusions – 1
� In many studies, laboratory data represent 50-80% of the data to be collected
� Central laboratory are not always applicable, however electronical data-transfer from mainindividual laboratory used may help
� Tools (i.e. SAS macro routines), are required tomanage and control the various steps of LocalLaboratory Data collection and analysis
� Specialist in laboratory data-management
26Tinazzi A Corradino I Paschetto E Colombini S: From Local Laboratory to Standardisation and beyond: Applying a common grading system PhUSE 2007, DM01 (Lisbon, Portugal – 8-10 October 2007)
Conclusions – 2
� Estabilish a central data-repository of local labs� How small are the differences / abnormalities
that need to be defined?� Choice between a more or less sophisticated
method of harmonization of laboratory results (e.g. Normalization vs SI Standardization)
� CDISC LAB Team