The last 50 years have shown a constant decline in approval rates for new therapeutic compounds across all medicine sub-specialties. Also in developing new respiratory drugs, the ever-rising costs and attrition rate makes it mandatory to increase the performance of clinical trials. This presentation will cover recent trends & innovations in clinical trials such as: proof-of-concept studies, adaptive designs through the use of modeling and simulation techniques, the inclusion of targeted patient populations to improve recruitment with consistent data acquisition through the use of dedicated satellite centres, use of innovative PD techniques and biomarkers etc. For more information visit: https://www.sgs.com/exprimo and contact us at: clinicalresearch@sgs.com Follow us on LinkedIn: https://www.linkedin.com/company/sgs

1. RECENT TRENDS & INNOVATIONS IN
CLINICAL TRIALS: EXAMPLES OF
RESPIRATORY DRUG DEVELOPMENT
Robert Lins, MD, PhD
Project Director Respiratory Diseases
SGS Clinical Research

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AGENDA
 Introduction
 Increase performance
 Improve design
 More precision medicine
 More patient centric approach
 Take home messages

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AGENDA
 Introduction
 Increase performance
 Improve design
 More precision medicine
 More atient centric approach
 Take home messages

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NEW CLINICAL RESPIRATORY TRIALS
STARTED IN 2014 (N=439) AND 2015 (N=406)
Clintrials.gov October 20, 2016
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AGENDA
 Introduction
 Increase performance
 Improve design
 More precision medicine
 More patient centric approach
 Take home messages

6. OUTCOMES IN CHRONIC LUNG
DISEASES

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CLINICAL TRIALS IN COPD 1/2
FDA DRAFT GUIDANCE MAY 2016
 Primary efficacy endpoints:
 Improving airflow obstruction: change in FEV1
 Clinically meaningful and relevant symptom relief
 Modifying or preventing exacerbations (Guidance 9/16)
 Altering disease progression: FEV1 decline slope
 Modifying lung structure: imaging
 Secondary efficacy endpoints:
 Various measures of lung function,
 Exercise capacity
 Symptom scores and activity scales
 Health-related quality-of-life instruments
 Biomarkers (FDA guidance 9/16: plasma fibrinogen)

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CLINICAL TRIALS IN COPD 2/2
 Other outcomes
 FeNO (Exhaled nitric oxide fraction)
 EBC (Exhaled Breath Condensate)
 Eosinophils in blood and sputum
 Secondary endpoints: scales, ePRO, biomarkers
 Problems still to overcome
 difficult to validate
 acceptance by authorities

9. POTENTIAL SOLUTIONS FOR
INCREASED PERFORMANCE

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REPRODUCIBILITY OF ADEQUATE SAMPLES
(N=130)
Total group Healthy volunteers Asthma patients
77% 81%
72%
NS NS
Lins RL. ERS congress London 2016

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TESTS OF SMALL AIRWAY FUNCTION
 Uncover benefits not detected by spirometry
 Several tests of small airway function available
 Not yet been incorporated in large clinical trials
 Oscillometry – Forced Oscillation Technique (FOT)
 Non-invasive and independent from performance
 Elastic properties of airways
 Affected by inhomogeinity

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CASE STUDY: MODELING & SIMULATION FOR
MORE EFFICIENT USE OF FEV1
 Background & objective
 FEV1 = biomarker with large within-subject variability
 Analysis failed to detect dose-response relationship
 Study design & methods
 Phase I, SAD, randomized, crossover trial, 34 patients
 Development kinetic-pharmacodynamic (K-PD) model
 Results
 Model appropriately predictive of the data
 Extraction of dose- response information possible
 Conclusions
 Model improves signal-to-noise ratio of efficacy signal
 Characterization of the dose-response relationship
 Selection of doses for subsequent dose- finding study
Wu K. ACOP 2008 – SGS Exprimo

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PRE- AND POSTTHERAPY CT, PET, AND
PET/CT FUSION IMAGES
Amin R Radiology 2012;264:868–875

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AGENDA
 Introduction
 Increase performance
 Improve design
 More precision medicine
 More patient centric approach
 Take home messages

15. ADAPTIVE TRIALS

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ADAPTIVE DESIGNS FOR CLINICAL TRIALS
 Goal
 increase efficiency of randomized clinical trials
 benefiting trial participants and future patients
 reducing costs, enhancing likelihood of true benefit
 Exploratory clinical trials
 finding safe and effective doses
 larger proportion of groups that are performing well
 investigate larger dose range
 Confirmatory trials
 prospectively planned changes to ongoing trial
 four major categories: seamless ph 2–3, sample-size
reestimation, group sequential and population-enrichment
designs

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CASE STUDY ADAPTIVE DESIGN
ONCE-DAILY INDACATEROL VS TIOTROPIUM FOR COPD
 Design: randomised, double-blind, placebo-controlled, trial
with an adaptive seamless design, performed in two stages
 Drug: double-blind indacaterol or placebo via DPI, or open-
label tiotropium 18 mg
 Administration: 2,059 COPD pts in st 1; 1,683 in st 2
 Objective:
 Dose indacaterol > placebo on 24 h FEV1 at week 12
 noninferiority of indacaterol dose to tiotropium at week 12
Result:
• Indacaterol effective once-daily bronchodilator
Challenge
• independent committee using predefined efficacy criteria to
select two indacaterol doses based on 2-week data
Donohue JF. Am J Respir Crit Care Med 2010;182:155-162

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INHANCE TRIAL: DOSE SELECTION AT
INTERIM ANALYSIS TIME POINT
Donohue JF. Am J Respir Crit Care Med 2010;182:155-162

19. DECREASE VARIABILITY

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SATELLITE NETWORK ≈ VIRTUAL MONOCENTRIC
 Use of SGS CPU know-how, expertise, services, procedures
 Dedicated SGS CRC for AZSM projects
 SGS CPU Investigator available
 SGS CPU Study Nurse/Lab techs available
 SGS Pharmacy support
 All trainings will be done in/by CPU staff
 Large public hospital with good access to patients
 Oncology (solid and hematology)
 Respiratory
 Neurology
 Orthopedics
 Organ impairment (hepatic and renal), etc…
 Strong motivation of hospital staff to collaborate with SGS
 Driven by hospital policy for strategic development
AZ St Maarten

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SGS BIOPHARMA DAY – OCTOBER 25, 2016
AGENDA
 Introduction
 Increase performance
 Improve design
 More precision medicine
 More patient centric approach
 Take home messages

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PRECISION MEDICINE
 Increased attention: Precision Medicine Initiative
 Cost of high-throughput genomic sequencing  
 Potential molecular targets for therapy 
 Goal: to select most effective and to avoid ineffective or
harmful drugs for personalized treatments
 Need integrative approach with all stakeholders
 Molecularly targeted agents only if specific biomarker is
known and validated that predicts the effectiveness
 Line between clinical research and clinical care is likely to
be blurred

23. ROLE OF BIOMARKERS

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CASE STUDY TARGETED THERAPY MATTERS TO
PATIENTS
DUPILUMAB IN UNCONTROLLED ASTHMA
 Design: randomised, double-blind, placebo-controlled,
parallel-group, pivotal phase 2b clinical trial with a anti-
interleukin-4 receptor α monoclonal antibody
 Drug: dupilumab as add-on therapy to ICS + LABA
 Administration: 769 uncontrolled persistent asthma pts
 Objective:
 Primary endpoint: change at week 12 in FEV1
 Secondary endpoints: eosinophil groups, exacerbations, FeNO,
Symptom and Quality scores
Result:
• Dupilumab increased lung function and reduced severe exacerbations
Challenge
• Improvement irrespective of baseline eosinophil count
Wenzel S. Lancet 2016;388(10039):31–44

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SEVERE EXACERBATIONS IN PATIENTS WITH
BASELINE BLOOD EOSINOPHIL COUNTS <
THAN 300 EOSINOPHILS PER ΜL
Wenzel S. Lancet 2016;388(10039):31–44

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HYPOTHETICAL RCT IN IDIOPATHIC
PULMONARY FIBROSIS
Kass DJ. Eur Respir Monogr 2013; 62: 179–187

27. IMAGING

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EXTRA FINE BDP/F IN COPD
De Backer J. et al. J Aerosol Med and Pulm Drug Del 2015; 28(2): 88-99

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AGENDA
 Introduction
 Increase performance
 Improve design
 More precision medicine
 More patient centric approach
 Take home messages

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PRAGMATIC TRIALS
 Randomized Clinical Trials performed with relatively small
samples, experienced investigators, highly selected
patients
 Risk overestimating benefits, underestimating harm
 Pragmatic trials showing real-world effectiveness in broad
patient groups required
 Similar to usual care
 Waiver informed consent, cluster randomisation
 Variety of investigator experience, large sample size to
overcome heterogeneity
 Outcomes on major events, important to patients
Drazen JM. N Engl J Med 2016;375:454-63

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CASE STUDY REAL WORLD EFFECTIVENESS
EFFECTIVENESS OF FLUTICASONE FUROATE–VILANTEROL
SALFORD LUNG STUDY
 Design: controlled effectiveness trial comparing once-daily
inhaled study drug to usual care
 Drug: fluticasone furoate100 μg and vilanterol 25 μg
 Administration: 2799 COPD pts, 75 general practices
 Objective:
 Primary outcome: rate moderate or severe exacerbations
 Secondary outcome: primary and secondary care contact
Result:
• Rate of moderate or severe exacerbations 8.4 % lower
• No significant difference in annual contacts
Challenge
• Innovative design, single urban area, one HER
• Challenge automatic transfer of RCT findings to clinical guidelines or everyday
clinical practice. Vestbo J et al. N Engl J Med 2016;375:1253-1260

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INCREASE PATIENT CENTRIC APPROACH
 Collecting Real World Evidence for external validation
 Outcomes relevant to patients, patient engagement
 Big Data (EHR, Reg)– BYOD (Bring Your Own Device)
 ePRO – eCOA
 Integrated approach
 Health status measurement
 Spirometry
 Protocol-specific workflow
 Secure data transfer
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SGS BIOPHARMA DAY – OCTOBER 25, 2016
AGENDA
 Introduction
 Increase performance
 Improve design
 Precision medicine
 Patient centric approach
 Take home messages

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CONCLUSION
 Evolution from classical endpoints with low performance to
more sensitive and patient relevant outcomes
 Evolution from classical RCT with low external validity and
delays to more efficient and adaptive designs
 Evolution from undefined targets to targeted, precision
medicine
 Evolution from researcher centric approach to patient centric
approach

35. THANK YOU FOR YOUR ATTENTION

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SGS BIOPHARMA DAY – OCTOBER 25, 2016
Life Sciences Lins Robert
Project Director Respiratory Diseases
SGS Phone: + 32 15 40 50 82
Agriculture, Food and Life Fax: ++32 15 27 32 50
Life Sciience Clinical Research E-mail : robert.lins@sgs.com
Mechelen
BELGIUM Web : www.sgs.com/lifescience
THANK YOU FOR YOUR ATTENTION
+ 41 22 739 9548
+ 1 866 SGS 5003
+ 65 637 90 111
+ 33 1 53 78 18 79
+ 1 877 677 2667
+ 33 1 41 24 87 87

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QUESTIONS ?

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