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RECENT TRENDS & INNOVATIONS IN
CLINICAL TRIALS: EXAMPLES OF
RESPIRATORY DRUG DEVELOPMENT
Robert Lins, MD, PhD
Project Director Respiratory Diseases
SGS Clinical Research
2 SGS BIOPHARMA DAY – OCTOBER 25, 2016
AGENDA
Introduction
Increase performance
Improve design
More precision medicine
More patient centric approach
Take home messages
3 SGS BIOPHARMA DAY – OCTOBER 25, 2016
AGENDA
Introduction
Increase performance
Improve design
More precision medicine
More atient centric approach
Take home messages
4 SGS BIOPHARMA DAY – OCTOBER 25, 2016
NEW CLINICAL RESPIRATORY TRIALS
STARTED IN 2014 (N=439) AND 2015 (N=406)
Clintrials.gov October 20, 2016
0 20 40 60 80
100 120 140 160
2014 2015
2014-2015 diff dis
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10
15
Respir
…
Infe
cti…
Oncolo
…
Card
io…
Gastr
o…
5 SGS BIOPHARMA DAY – OCTOBER 25, 2016
AGENDA
Introduction
Increase performance
Improve design
More precision medicine
More patient centric approach
Take home messages
OUTCOMES IN CHRONIC LUNG
DISEASES
7 SGS BIOPHARMA DAY – OCTOBER 25, 2016
CLINICAL TRIALS IN COPD 1/2 FDA DRAFT GUIDANCE MAY 2016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)
8 SGS BIOPHARMA DAY – OCTOBER 25, 2016
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
POTENTIAL SOLUTIONS FOR
INCREASED PERFORMANCE
10 SGS BIOPHARMA DAY – OCTOBER 25, 2016
REPRODUCIBILITY OF ADEQUATE SAMPLES (N=130)
Total group Healthy volunteers Asthma patients
77% 81% 72%
NS NS
Lins RL. ERS congress London 2016
11 SGS BIOPHARMA DAY – OCTOBER 25, 2016
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
12 SGS BIOPHARMA DAY – OCTOBER 25, 2016
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
13 SGS BIOPHARMA DAY – OCTOBER 25, 2016
PRE- AND POSTTHERAPY CT, PET, AND
PET/CT FUSION IMAGES
Amin R Radiology 2012;264:868–875
14 SGS BIOPHARMA DAY – OCTOBER 25, 2016
AGENDA
Introduction
Increase performance
Improve design
More precision medicine
More patient centric approach
Take home messages
ADAPTIVE TRIALS
16 SGS BIOPHARMA DAY – OCTOBER 25, 2016
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
17 SGS BIOPHARMA DAY – OCTOBER 25, 2016
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
18 SGS BIOPHARMA DAY – OCTOBER 25, 2016
INHANCE TRIAL: DOSE SELECTION AT
INTERIM ANALYSIS TIME POINT
Donohue JF. Am J Respir Crit Care Med 2010;182:155-162
DECREASE VARIABILITY
20 SGS BIOPHARMA DAY – OCTOBER 25, 2016
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
21 SGS BIOPHARMA DAY – OCTOBER 25, 2016
AGENDA
Introduction
Increase performance
Improve design
More precision medicine
More patient centric approach
Take home messages
22 SGS BIOPHARMA DAY – OCTOBER 25, 2016
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
ROLE OF BIOMARKERS
24 SGS BIOPHARMA DAY – OCTOBER 25, 2016
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
25 SGS BIOPHARMA DAY – OCTOBER 25, 2016
SEVERE EXACERBATIONS IN PATIENTS WITH
BASELINE BLOOD EOSINOPHIL COUNTS <
THAN 300 EOSINOPHILS PER ΜL
Wenzel S. Lancet 2016;388(10039):31–44
26 SGS BIOPHARMA DAY – OCTOBER 25, 2016
HYPOTHETICAL RCT IN IDIOPATHIC
PULMONARY FIBROSIS
Kass DJ. Eur Respir Monogr 2013; 62: 179–187
IMAGING
28 SGS BIOPHARMA DAY – OCTOBER 25, 2016
EXTRA FINE BDP/F IN COPD
De Backer J. et al. J Aerosol Med and Pulm Drug Del 2015; 28(2): 88-99
29 SGS BIOPHARMA DAY – OCTOBER 25, 2016
AGENDA
Introduction
Increase performance
Improve design
More precision medicine
More patient centric approach
Take home messages
30 SGS BIOPHARMA DAY – OCTOBER 25, 2016
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
31 SGS BIOPHARMA DAY – OCTOBER 25, 2016
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
32 SGS BIOPHARMA DAY – OCTOBER 25, 2016
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
09/06 /16 11:44Innovat ive Respirat ory Solut ions - ERT Clinical
Page 2 of 5ht tps:/ /www.er t .com/respiratory/respiratory- innovat ive- solut ions/
better performance (including smart control for loop
selection/ deselection and enforced patient rest time)
The only diagnostic platform with biometric user
identi! cation to comply with 21 CFR Part 11 and maintain
quality
Unique Multi-protocol option that allows one device to
support multiple studies
Automatic, secure data transfers optimizes centralized
overread and device software updates, ensuring latest
protocol amendments are in use
L EA RN M ORE
AM3® and AM3® GSM – Home Monitoring made easy
AM3® is an integrated, easy-to-use home spirometer and eDiary for clinical trials that
delivers for your study and patients:
Measures and saves all relevant expiratory " ow volume
parameters such as PEF and FEV1
Records symptoms, events and medication, including
severity and dose – a complete electronic diary for
patient home monitoring
Stores all data in non-volatile memory
Makes data collection painless with web upload and
GSM global text messaging transmission options, all
transmitted securely to ERT’s EXPERT® Central private
cloud platform
O#ers EXACT-PRO, ACQ, and BCSS questionnaires for
Patient Reported Outcomes / Clinical Outcome
Assessments (COAs)
Clinical Research
Healthcare
SOLUTIONS ∠ BLOG RESOURCES ∠ ABOUT ∠ CONTACT LOGIN
33 SGS BIOPHARMA DAY – OCTOBER 25, 2016
AGENDA
Introduction
Increase performance
Improve design
Precision medicine
Patient centric approach
Take home messages
34 SGS BIOPHARMA DAY – OCTOBER 25, 2016
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
THANK YOU FOR YOUR ATTENTION
36 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 : [email protected]
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
37 SGS BIOPHARMA DAY – OCTOBER 25, 2016
QUESTIONS ?
38 SGS BIOPHARMA DAY – OCTOBER 25, 2016