Acne Core Outcomes Research Network NIAMS 1U01 AR Diane Thiboutot, Alison Layton, Jerry Tan Anne Eady, Marc Frey, Kathryn Gilliland, Mary Margaret Chren

Developing Standardized Outcome Measures for Acne Clinical Trials: Rationale  Many different grading scales are used in clinical trials for acne  This doesn’t allow for comparison of data across drug trials  Having a standard set of outcome measures (grading scales, QoL) will allow these comparisons to be made without having to do costly head-to-head studies

ACORN Project Aims  Develop an online training module for acne lesion counting including a standardized way to present trial data  Standardized Instrument for Lesion Counting in Acne (SILCA)  Develop a comprehensive acne quality of life instrument  Comprehensive Acne Quality of Life (CompAQ)  Develop and evaluate standardized scale (s) for global assessment of acne  Evaluate novel technologies to assess acne

ACORN working groups  Team Harrogate (UK)  Alison Layton, MD  Anne Eady, PhD  Martin Bland, PhD (statistician consultant)  Team Penn State (USA)  Me  Kathy Gilliland  John Quiring, PhD (statistician consultant)  Andrea Zaenglein, MD  Esther Delll, MS (librarian)  Team Windsor (Canada)  Jerry Tan  Marc Frey, PhD candidate  UCSF  Meg Chren, MD  Other US and international members

Concept of core sets of outcomes & measures Core set – universally agreed and adopted All outcomes – what is being measured O O M M All instruments – ways of measuring different outcomes

Core outcome measure sets in practice  Minimum set of outcomes that should be measured and reported in all late phase clinical trials  Whenever a core outcome is included in a trial, it should be measured by all investigators using the same standardised method or validated instrument  The core set of outcome measures will not include more than one way of measuring the same thing  If other outcomes are included in an acne RCT, they too should ultimately be measured in a standardised way (e.g. sebum secretion)  Not an immediate goal of ACORN but part of the ACORN concept of a toolbox of validated measures

The HOME roadmap  Key features  Global stakeholder representation and involvement  Consensus-derived  Evidence-based  Universally applicable 1.Identification of essential domains (what will be measured) – essentially outcomes of interest 2.Identification (via systematic reviews) or development de novo of validated instruments to measure the core domains

Summary of HOME roadmap Define scope Identify & involve stakeholders Identify core set of outcome domains Develop core set of validated measurement methods Disseminate materials Monitor adoption YEAR onwards ACORN toolbox

ACORN’s scope & stakeholders SCOPE  Acne vulgaris but not acne scarring  Clinical studies including RCTs and, where appropriate, routine clinical care  Universal (global) adoption STAKEHOLDERS  People with acne  Patients (1ary and 2ary care)  Patients (private practitioners, aestheticians)  Those who self-treat  Regulatory agencies in each region  Industry (pharma, cosmetic companies, device manufacturers)  Acne researchers

Main stages of the HOME roadmap I IDENTIFY CORE DOMAINS (WHAT TO MEASURE) Symptoms and signs Impacts Changes expected in each  Assess the relative importance of each  Derive minimum set of outcome domains Using consensus-based methods Involving all types of stakeholder Internationally representative MIXED METHODS APPROACH: systematic reviews, surveys/questionnaires, Delphi exercises, consultation with experts

Report from Harrogate site Activities to date

Progress to date  Development of SILCA ( S tandardisation of L esion C ounting in A cne) aims:-  Web-based teaching and evaluation modules  Training videos available via YouTube  Hard copy manual  Processes to underpin the development of SILCA  A systematic review of acne RCTs  Patient reported outcomes questio n  Professional survey  Methods of data analysis

Why focus on lesion counts?  Most widely used outcome measure in acne RCTs  Can justify inclusion in core outcome measure set on basis of universal adoption  Have additional patient data from Acne PSP to support this decision  Can fast-track through roadmap  Conduct, analysis and reporting not standardised  Zarchi & Jemec (Curr Derm Rep 2012;1:131-6) found lesion counts had been reported in 25 different ways in a snapshot of 18 trials published in  Quality of studies using manual lesion counts highly variable  Conducting a systematic review to demonstrate this  Automated methods under development but none yet sufficiently developed for universal adoption  Standardisation is still relevant

Review of RCTs - Take-home messages  Lesion counting is almost universally used as an outcome measure  Methods used to analyse and report counts are not standardised  Validates designation of lesion counting as a core outcome measure and development of SILCA to harmonise methods  Patient endorsement would be a ‘nice to have’

Outcomes question: Acne Priority Setting Partnership  Embedded the following question in the online survey to identify acne treatment uncertainties:  “Please tell us in your own words how you decide if your treatment has been effective.”  Obtained 710 usable responses  84.6% female  47% aged  1 in 5 non-white  1 in 4 lived outside the UK

Symptom or impact-related outcomes Number of respondents

Conduct of counts: aspects where there is consensus  Position of the patient  Types of patient to exclude from efficacy RCTs  Use of a facial template showing areas to count  Counting PA, PU, OC and CC separately – but not often reported this way and requires more training  How to identify nodules  Exclusion of macules from IL count Developing standardized assessments for acne clinical trials - and your input is greatly appreciated.

Conduct of counts – aspects requiring standardisation  Lighting  Preparation of the subject  Whether and when to use a magnifying lens  Whether to stretch the skin  Whether to include macrocomedones in lesion counts  What to do about lesions on the nose  Recording of counts Analysis of initial results from online survey of clinical investigators Developing standardized assessments for acne clinical trials - your input is greatly appreciated.

Methods of data analysis and presentation  Consulting with expert statisticians underway  Preliminary findings are:  Always report median and mean ± SD  Include absolute and % change from baseline  Report results of ITT and PP analyses  Use LOCF for missing values if N≤50 per arm and multiple imputation if N>50  ANCOVA is the method of choice for significance testing - apply appropriate test for skewness before using  If counts are positively skewed, use rank based method

Report from Windsor site Activities to date

Delphi process online small sample survey technique PATIENTS  In what ways has acne affected you and your life? DERMATOLOGISTS  In what ways has acne affected your patients and their lives? Purpose: 1. compare treatment expectations between patients and experts 2. assist patients in determining treatment options that meet their personal needs. 3. inform future measures that target the quality of life aspects related to acne.

COMPAQ Comprehensive acne quality of life instrument  QoL impact of acne at face and torso  Representation:  Age  Gender  Phototype

Report from Penn site Activities to date

Progress to date: A group effort!  Systematic review of acne impacts (100 articles extracted)  Early draft of the SILCA module prepared  Photo selection in progress  Video segments to be filmed June 2015  Statistical consultations in progress  Evaluation of acne lesion counting computer algorithm  6/34 subjects enrolled  Challenges with higher phototype skin

Next Steps: Expanding the network and building international consensus  Would like to engage your participation in our activities  Delphi processes and surveys  Assistance with systematic reviews  Contribution of content to our website  Participation in working groups/meetings Interested? Sign up at

ACORN meeting at the World Congress of Dermatology Vancouver  SAVE THE DATE: Monday June 8, 2015, –  Location:  Vancouver International Film Center, World Congress of Dermatology, Vancouver, BC  To register, please visit: 

Acknowledgements: ACORN partners Valeant Pharmaceutical North America LLC generously provided data