Learn Connect Succeed JCAHPO Regional Meetings 2017
STANDARDIZING MEASUREMENTS FOR CLINICAL RESEARCH AND OUTCOMES STUDIES AMY JOST, BS, COMT, CCRC, OSC FINANCIAL DISCLOSURE I have no financial interests COURSE OBJECTIVES Identify research staff training basic necessities List common testing measurements for collecting data for ophthalmic research and outcomes studies Determine frequency of calibration of testing equipment and appropriate documentation Maximize consistency in exam procedures STAFF TRAINING AND DELEGATION FOR CLINICAL RESEARCH CURRICULUM VITAE ICH GOOD CLINICAL PRACTICES Name, Practice Name(s), Address of current research Brief account of education, qualifications, and previous experience Includes research and ophthalmology experience Specifies ophthalmic exam component competencies Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. 1
PROTOCOL-SPECIFIC TRAINING TRAINING AND DELEGATION Identifies specific exams and timelines for investigators and study staff Evaluate the feasibility of the study, or notify Sponsor Ensures collection of crucial information Institutional Review Board (IRB) approval All investigators and research staff must be trained and have delegated duties documented INFORMED CONSENT COMMON OPHTHALMIC TESTING MEASUREMENTS FOR CLINICAL RESEARCH Informed Consent must be obtained before performing any studyspecific tests or evaluations. MEDICAL HISTORY AND DEMOGRAPHIC DATA CONCOMITANT MEDICATIONS Clinically significant diseases, including chronic and ongoing conditions (e.g., trauma, cancer, cardiovascular, and ophthalmic history); cancer history Tobacco use Surgeries Reproductive status Demographic data will include age, sex at birth, and self-reported race/ethnicity List all medications used by the patient within a specific amount of time before and during study Prescription drugs Over-the-counter drugs Herbal or homeopathic remedies, nutritional supplements 2
MANIFEST REFRACTION BEST CORRECTED VISUAL ACUITY (BCVA) Precede other procedures or any examination requiring contact with the eye Slit lamp examination Administration of topical anesthetic agents or other eye drops Intraocular pressure measurement EARLY TREATMENT DIABETIC RETINOPATHY STUDY (ETDRS) ETDRS = logmar Chart Progression of letter size is in 0.1 logmar intervals logmar 1.0 (20/200) to logmar -0.3 (20/10) 5 letters on each line ETDRS CHART FACTS Chart is comprised only of letters - no numbers Should attempt to read each letter line-by-line, moving left to right, beginning with line 1 at the top of the chart. Read slowly (about one letter per second) to achieve the best identification of each letter Should not proceed to the next letter until giving a definite response to the preceding letter ETDRS TESTING DISTANCE Distance of 4 m, 2 m, or 1 m Depends on Protocol and Chart used Adjustments: +0.25 D is used to correct for optical infinity at 4 m +0.50 D is used to correct for optical infinity at 2 m +0.75 D is used to correct for optical infinity at 1 m ETDRS ILLUMINATION ETDRS ILLUMINATION- LIGHTING REQUIREMENTS The visual acuity chart should be retro-illuminated ( back-lit ) Illumination checked at regular intervals to be consistent with ETDRS guidelines Some brands require 96-hours of burn-in time for new bulbs Photometer: An instrument used for making measurements of light in the visible range. Example: Gossen Starlite Photometer Measuring chart luminance (cd/m 2 ) Measuring room lighting from the patient s eye to the chart (lux) 3
ETDRS ILLUMINATION- CHART ETDRS ILLUMINATION- ROOM LIGHTING Lighting requirements of the ETDRS chart ~160 cd/m 2 Overhead lights OFF Measuring illuminance (lux): From the subject s spectacle plane facing the ETDRS chart lux range should be 3 8 lux (~ 5) STEPS FOR LOGMAR SCORING: LOGMAR SCORING Letters Read Correctly Each letter identified correctly will be circled on the Distance Visual Acuity Worksheet Letters NOT Read Correctly Letters read incorrectly are indicated by marking out that letter with a slash Letters not attempted are not marked on the form Or Letters read incorrectly or not read at all are not marked on the form LogMAR 0 1 2 3 4 5 Line 1.0 1.00 1.02 1.04 1.06 1.08 1.10 0.9 0.90 0.92 0.94 0.96 0.98 1.00 0.8 0.80 0.82 0.84 0.86 0.88 0.90 0.7 0.70 0.72 0.74 0.76 0.78 0.80 0.6 0.60 0.62 0.64 0.66 0.68 0.70 0.5 0.50 0.52 0.54 0.56 0.58 0.60 0.4 0.40 0.42 0.44 0.46 0.48 0.50 0.3 0.30 0.32 0.34 0.36 0.38 0.40 0.2 0.20 0.22 0.24 0.26 0.28 0.30 0.1 0.10 0.12 0.14 0.16 0.18 0.20 0.0 0.00 0.02 0.04 0.06 0.08 0.10-0.1-0.10-0.08-0.06-0.04-0.02 0.00-0.2-0.20-0.18-0.16-0.14-0.12-0.10-0.3-0.30-0.28-0.26-0.24-0.22-0.20 1.0 C O H Z V 0.9 S Z N D C 0.8 V K C N R 0.7 K C R H N 0.6 Z K D V C 0.5 H V O R K 0.4 R H S O N 0.3 K S V R H 0.2 H N K C D 0.1 N D V K O 0.0 D H O S Z -0.1 V R N D O -0.2 C Z H K S -0.3 O R Z S K LOGMAR SCORE CALCULATIONS Missed 4 letters, but read down to the -0.20 line ( 4 x 0.02) + ( -0.20 ) = -0.12 (#Ltrs incorrect x (Last line read) (logmar score) value of each Ltr) CHARTS R, 1, AND 2 Refraction on ETDRS Chart R Right Eye BCVA using Chart 1 Chart 1 Left Eye BCVA using Chart 2 Chart 2 4
ETDRS CONSISTENCIES GLARE AND CONTRAST TESTING Specific lighting conditions Exact viewing distance Identified process for testing and documentation Contrast CONTRAST SENSITIVITY GLARE AND CONTRAST TESTING Glare ETDRS CERTIFICATION ENDOTHELIAL CELL COUNTS (ECC) Certification of the facility, equipment and examiners at each investigative site may need to occur prior to any evaluation of study subjects. Specular microscopy to take central and peripheral images Important for anterior chamber device implants (IOLs, MIGS, etc.) Endothelial Cells: Are easily damaged during surgery or with any sort of touch/disturbance Do NOT regenerate Damage is permanent and progressive: cells may continue to drop off well after surgery Damage may lead to edematous opaque corneas, requiring removal of the device and/or cornea transplant 5
ECC IMAGE CAPTURE ECC IMAGE CAPTURE To capture a good image: Get subject comfortable and aligned Encourage the subject to blink for better corneal surface Instruct the subject to be still and open eyes wide Ask the subject to look at the fixation light Be patient as multiple attempts may be necessary, especially in pseudophakic eyes If necessary, use the manual setting if you are trained and able to do so Common sources of variability in ECC image capture are: Variations in cornea location, even with fixation Poor image quality (less than 100 countable cells) Technician error Improper reader analysis Maintaining equipment calibration/alignment ECC CENTRAL READING CENTER Choice and certification of equipment Training and certification of technicians at reading center Reading images and conducting image analysis Site Staff performing ECCs for the study may need to be certified by the reading center QUESTIONNAIRES ABOUT VISUAL FUNCTION National Eye Institute VFQ-25 Visual Functioning Questionnaire 25-Item Version PRO (Patient Reported Outcomes) VF-14 (Visual Function test) THE FUNCTIONAL READING INDEPENDENCE INDEX (FRI INDEX) MEASURING READING SPEED NEAR VISION ILLUMINATION The MNRead acuity cards Radner Reading Cards The cards should be evenly lit, no shadows or glare Luminance of the white background on the cards should be should be between 80 120 cd/m2. 6
VISUAL FIELDS VISUAL FIELDS DEFECTS AND MEAN DEVIATIONS Often performed prior to enrollment as qualification criteria and at selected subsequent visit(s). Visual fields must be determined as automated threshold visual fields (30-2 or 24-2 Humphrey) SITA Standard is often preferred, SITA fast may also be allowed Mean Deviation (Mills GSS criteria were referenced to obtain these choices): Early defect outside of inclusion range = MD of > -2.99 db Early defect within inclusion range = MD of -3.00 db to - 6.00 db Moderate defect = MD of -6.01 to -12.00 db Advanced defect = MD of -12.01 db to -20.0 db Severe defect = MD of -20.01 db Central Defects <0 db within 5⁰ of fixation None 1 in one hemifield only 2 in one hemifield only 1 in both hemifields 2 in one hemifield and 1 in the other hemifield 2 in one hemifield and 2 in the other hemifield VISUAL FIELDS RELIABILITY PACHYMETRY Visual fields must be reliable Fixation losses less than or equal to 33% False positives less than or equal to 33% False negatives less than or equal to 33% Determines central corneal thickness Pachymetry-corrected IOP may be calculated and used for Glaucoma Studies SHAFFER GONIOSCOPY GRADING SYSTEM Grade 4-45º to 35º angle Wide open Grade 3-35º to 20º angle Wide open Grade 2-20º angle Narrow Grade 1-10º angle Extremely narrow Slit - 0º angle Narrowed to slit APPLANATIONTONOMETRY Calibration for tonometers used in this study must be performed on a quarterly or even monthly basis Must be documented in the calibration log in the study regulatory binder NOTE: Date, Serial Number and/or exam lane, practice address on calibration logs, examiner s initials 7
INTRAOCULAR PRESSURE (IOP) DIURNAL IOP MEASUREMENTS Typically conducted using an Goldmann Applanation Tonometer, some studies allow for Perkins Tonometer or Tonopen The same method should be used throughout the study for each subject IOP measured prior to gonioscopy or dilation of the pupil IOP fluctuates throughout the day, highest in the morning IOP Checked at intervals over an eight (8) hour period Example: 8am ± 30 minutes 12pm ± 30 minutes, and 4pm ± 30 minutes MASKED IOP OBSERVERS For Glaucoma studies, common that IOP will be measured by 2 observers Observer 1 (the IOP operator) looks through slit lamp, turns the IOP dial, while readings are masked Observer 2 (the IOP reader, masked to treatment) will record the IOP readings IOP MEASUREMENTS AVERAGE For Glaucoma Studies, IOP is often measured twice, MEAN value is recorded on the case report form If the two readings differ by more than 2 mmhg, in which case a third measurement is taken and the MEDIAN value is recorded DIURNAL CURVE AVERAGES Mean diurnal IOP will be calculated by using the three mean (or median) values from 8am, 12pm, and 4pm measurements. These three values will be used to derive a mean diurnal IOP value. LOCS III GRADING SCALE Used by doctors to evaluate the density of the crystalline lens 8
OPTIC NERVE HEAD IMAGING EQUIPMENT: Performed using HRT, OCT, GDx or other method. MACULA IMAGING Performed using OCT, or other method. Mean foveal thickness of normal eyes measured with and with SD- OCT resulted 147, and 226, SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY IMAGING (SD-OCT) OCT IMAGES EQUIPMENT Manufacturer and Settings of the OCT Equipment will be outlined in the Protocol/MOP PROCEDURES AND CERTIFICATION Central Reading Center Manual Study manual of Operating Procedures (MOPs) and training materials SD-OCT operators, systems, and software may need to be certified prior to any evaluation of candidates Ave Thickness = 236µm Ave Thickness = 414µm FLUORESCEIN ANGIOGRAPHY COLOR FUNDUS PHOTOGRAPHY EQUIPMENT Manufacturer and Settings of the Fluorescein Angiography will be outlined in the Protocol/MOP Digitally based angiograms captured; Film-based angiography is not acceptable PROCEDURES Central reading center MOPs and training materials Photographers, systems, and software will be certified prior to obtaining angiograms of candidates EQUIPMENT Manufacturer and Settings of the Color Fundus Camera will be outlined in the Protocol/MOP PROCEDURE Central reading center study MOPs and training materials The fundus photographer and photography equipment may need to be certified by the reading center before any study images are taken 9
FUNDUS AUTOFLUORESCENCE (FAF) FA VS. FAF EQUIPMENT Manufacturer and Settings of the Fundus Autofluorescence will be outlined in the Protocol/MOP Equipment utilized during this study is described in the Central Reading Center Manual. PROCEDURES AND CERTIFICATION The central reading center will provide the study manual and training materials. FAF operators, systems, and software may need to be certified prior to any evaluation of patients ADMINISTRATION OF INVESTIGATIONAL PRODUCT (IP) Specific instructions for instillation, application, or injection procedures are provided in the MOP CALIBRATION AND DOCUMENTATION FOR CLINICAL RESEARCH CALIBRATION OF CLINICAL EQUIPMENT CALIBRATION OF TONOMETRY UNITS Example #1: Manual Kerotmeters, Goldman Applanation Tonometry, Check calibration often (monthly) Example #2: Temperature Logs, maintain temperature at room/refrigerator/freezer Note equipment brand/manufacturer, model number, and practice address/exam lane Initial (or sign) and date entries Check at 0, 20, & 60mmHg 10
CHECK CALIBRATION OF KERATOMETER 40.50, 42.50, 44.75 Check calibration with silver calibration spheres Call service professional if needed CALIBRATION SCHEDULES AND DOCUMENTATION With Every Subject Daily Calibration Logs Weekly Trained/Delegated Staff Monthly Documented in detail As indicated Identifiable equipment Per instruction Manual DATA COLLECTION AND OUTCOMES STUDIES MAXIMIZING CONSISTENCY IN DATA COLLECTION FOR CLINICAL RESEARCH Tracking trends in clinic and surgery IOL Calculations/Post-op refractive outcomes Separate by type of lens, IOL Formula used Refractions needed at consistent po visits (1 week or 1 month) Retrospective studies Imaging Studies Surgical outcomes SAME EQUIPMENT THROUGHOUT THE STUDY Same evaluator, trained and delegated Same lighting conditions, per protocol Same equipment used, identified for study use Same time of day; especially important for IOP measurements, Medication dosing intervals Same grading scales 11
SAME GRADING SCALES AT ALL SITES, ALL VISITS EXAM GRADING SCALES Cornea - Staining/Erosion Cornea Edema None (0) No fluorescein staining of epithelium, OR less than mild Mild (+1) Slight fluorescein staining confined to a small focus Moderate (+2) Regionally dense fluorescein staining (1 mm or greater in diameter) with underlying structure moderately visible Severe (+3) Marked fluorescein staining or epithelial loss None (0) Transparent and clear or less than mild Mild (+1) Dull glassy appearance Moderate (+2) Dull glassy appearance of epithelium with large number of vacuoles Severe (+3) Epithelial bullae and/or stromal edema, localized or diffuse, with or without stromal striae Anterior Chamber - Cells (per 1x1 mm slit) 0 (<1 cell) 0.5+ (1-5 cells) 1+ (6-15 cells) 2+ (16-25 cells) 3+ (26-50 cells) 4+ (>50 cells) Sometimes quantifiable Sometimes more subjective Anterior Chamber Flare (per 1x1 mm slit) 0 (none) 1+ (faint) 2+ (moderate, iris and lens details clear) 3+ (marked, iris and lens details hazy) 4+ (intense, fibrin or plastic aqueous) EXAM GRADING SCALES EXAM GRADING SCALES Iris Atrophy/Erosion; Peaking; Rubeosis Posterior Capsule Opacification Iris Atrophy/Erosion; Peaking; Rubeosis Posterior Capsule Opacification None (0) Mild (+1) Moderate (+2) Severe (+3) Posterior capsule opacification (PCO) will be evaluated using the following scale: None Minimal (Top left image) Mild (Top right image) Moderate (bottom left image) None (0) Mild (+1) Moderate (+2) Severe (+3) Posterior capsule opacification (PCO) will be evaluated using the following scale: None Minimal (Top left image) Mild (Top right image) Moderate (bottom left image) EXAM GRADING SCALES Retinopathy 1: No retinopathy 2: Microaneurysms (Ma) only 3: Mild to moderate non-proliferative retinopathy, defined as Ma plus retinal hemorrhages and/or exudates (lipid deposits and/or cotton wool spots) 4: Moderately severe to severe non-proliferative retinopathy, defined as at least one of the following: a. Definite venous beading b. Obvious intraretinal microvascular abnormalities c. Hemorrhages/Microaneurysms standard photograph 2A in at least two quadrants 5: Proliferative retinopathy or scars of panretinal (scatter) photocoagulation GRADING SCALE FOR VITREAL HEMORRHAGE None (0) Retina is visible Trace Retina is visible and red blood cells are visible only on slitlamp examination 1 + Retinal detail is visible; some hemorrhage is visible by ophthalmoscopy. 2 + Large retinal vessels are visible, but central retinal detail is not visible by ophthalmoscopy 3 + Red reflex is visible, but no central retinal detail is seen posterior to the equator by ophthalmoscopy 4 + No red reflex by ophthalmoscopy 12
GRADING SCALE FOR VITREOUS CELLS Cells in Retroilluminated Field Description Grade 0 Clear 0 1 20 Few opacities Trace 21 50 Scattered opacities 1 51 100 Moderate opacities 2 101 250 Many opacities 3 > 251 Dense opacities 4 Modified from: Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis. Fundamentals EXAM GRADING SCALES Nerve Abnormalities None Segmental Loss of Neuroretinal Rim (Notching) Disc Hemorrhage Pseudo Pit of the Disc Nerve Fiber Layer Loss Visible Laminar Dots Other (Specify): STANDARDIZING MEASUREMENTS AND DATA COLLECTION WHAT OTHER DATA DO YOU WISH TO COLLECT FROM ME? Source Documents Case Report Forms Data Entry Statistician Has to be consistent data to truly be able to make comparisons, identify trends, and formulate deductions. Amy Jost, BS, COMT, CCRC, OSC Cincinnati Eye Institute Clinical Research Department 1945 CEI Drive Cincinnati, OH 45242 PH. 513-569-3678 ajost@cincinnatieye.com 13