Recent Trends & Innovations in Clinical Trials: R&D Respiratory Examples

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


AGENDA

Introduction


Improve design


More atient centric approach

Take home messages


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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15

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AGENDA

Introduction


Improve design



Take home messages

OUTCOMES IN CHRONIC LUNG

DISEASES


CLINICAL TRIALS IN COPD 1/2 FDA DRAFT GUIDANCE MAY 2016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)


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


REPRODUCIBILITY OF ADEQUATE SAMPLES (N=130)

Total group Healthy volunteers Asthma patients

77% 81% 72%

NS NS

Lins RL. ERS congress London 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


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


PRE- AND POSTTHERAPY CT, PET, AND

PET/CT FUSION IMAGES

Amin R Radiology 2012;264:868–875


AGENDA

Introduction


Improve design



Take home messages

ADAPTIVE TRIALS


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


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


INHANCE TRIAL: DOSE SELECTION AT

INTERIM ANALYSIS TIME POINT

Donohue JF. Am J Respir Crit Care Med 2010;182:155-162

DECREASE VARIABILITY


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


AGENDA

Introduction


Improve design



Take home messages


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


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


SEVERE EXACERBATIONS IN PATIENTS WITH

BASELINE BLOOD EOSINOPHIL COUNTS <

THAN 300 EOSINOPHILS PER ΜL

Wenzel S. Lancet 2016;388(10039):31–44


HYPOTHETICAL RCT IN IDIOPATHIC

PULMONARY FIBROSIS

Kass DJ. Eur Respir Monogr 2013; 62: 179–187

IMAGING


EXTRA FINE BDP/F IN COPD

De Backer J. et al. J Aerosol Med and Pulm Drug Del 2015; 28(2): 88-99


AGENDA

Introduction


Improve design



Take home messages


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


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


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


AGENDA

Introduction


Improve design

Precision medicine

Patient centric approach

Take home messages


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


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

https://www.linkedin.com/company/sgs-life-sciences


QUESTIONS ?

Recent Trends & Innovations in Clinical Trials: R&D Respiratory Examples

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Transcript of Recent Trends & Innovations in Clinical Trials: R&D Respiratory Examples