The Operational Reality in Inflammation:The Operational Reality in Inflammation: Challenges in IMID clinical trials – and best practice

Joan Meyer, PhD

practice

Executive DirectorOperational Strategy & Planning

IMIDs: What’s Covered?

Immune mediated inflammatory diseases:• prevalence 2000 – 3000 per hundred thousand of the population • 80+ chronic autoimmune diseases targeting virtually any part of the body• 80+ chronic autoimmune diseases targeting virtually any part of the body,

including:

Respiratory SystemRespiratory System Connective Tissues Skin Gastrointestinal SystemGastrointestinal System

Others:Vascular System (vasculitides: Wegener’s, Giant Cell Arteritis, Churg-Strauss, Polyarteritis)Endocrine System (Type 1 diabetes, Addison’s disease, Thyroid disease)Nervous System (Demyelinating diseases Myasthenia gravis)

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Nervous System (Demyelinating diseases, Myasthenia gravis)Eyes (Uveitis)

IMID Paradigm

• Chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation

• RA, IBD, MS, psoriasis, many others• Affects 2-5% of population, incidence increasing

• May result from immune responses against self antigens• May result from immune responses against self antigens(autoimmunity) or microbial antigens (Crohn’s disease?)

• Involve immune cells (T&B lymphocytes and granulocytes), ( y p y g y ),cytokines and antibodies

• May be systemic or organ-specific

A New Approach

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Impact of Diseases – Unmet Need

Debilitating, variable, organ-specific or multi-system presentationsUnderlying immune driven pathology which can present with overlapping features

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features

Plenty of Unmet Need – Also OperationallyPitfalls common to Inflammation studies abound, e.g.• Placebo response

– Inherent in studies with subjective endpointsU di t bilit f h i itti / l i di tt– Unpredictability of chronic remitting/relapsing disease pattern

– Eligibility creep• Patient Reported Outcomes (PROs)

– Missing datag– Questionnaire fatigue– “Car park completion” (diaries)

• Study drug complianceStudy drug plus standard of care– Study drug plus standard of care

– Injectables• Inter- and intra-rater variability• Patient retention (long-term studies)( g )

Plenty of room for improvement in clinical trial conduct

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Plenty of room for improvement in clinical trial conduct

Inflammation Study Similarities• Standard of Care, e.g.

– azathioprine, methotrexate, corticosteroids, biologicals• Patient Reported OutcomesPatient Reported Outcomes

– Questionnaires– Diaries

• Requirement for Rater training• Requirement for Rater training• Similar lab tests, e.g. interleukins, interferons, CRP, TNFα• Patients generally already known to sites

P i li i ll d• Patient compliance is generally good• All supported by good network of advocacy groups

Lessons learned, best practices can be applied across diseases

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Physician Assessed Study Endpoints• Typical endpoints:

–American College of Rheumatology 20 (ACR20) - RA

C h ’ Di A ti it I d (CDAI) i l d ti t di d t–Crohn’s Disease Activity Index (CDAI) – includes patient diary data

–Mayo Score – Ulcerative Colitis

–Psoriasis Area and Severity Index (PASI)

–SLE Responder Index (SRI)

–FEV1 – Asthma & COPD

Study specific training• Study-specific training–Investigator Meeting workshops

–Reduce inter- and intra-rater variability

Focus on up-front and ongoing site training

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Centralized Assessment of Endpoints

• X-rays/MRI (RA)– Structural damageg

• Photographic images (Psoriasis)g p g ( )– Lesion changes

• Spirometry (Asthma & COPD)– PFT changes

Extensive experience organizing central assessments pays off

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Patient Reported Outcomes (PROs)• Typically used in all target indications, e.g.:

– Asthma Control Questionnaire (ACQ-5)– Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL)– Psoriasis Disability Index (PDI)

• More frequently being used for label claims– Requires robustness of data

• ePRO– Translation– Validation

P ti t Di i• Patient Diaries– Paper vs eDiary

Early planning is essential

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Placebo Response

• Inherent in studies with subjective severity assessments• Rate as demand for patients against a limited supply

SFR d t bi i b li h t i ti• SFR due to bias in baseline characterization

Crucial to carefully and proactively review trial design

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Challenges for Patients• Study duration, e.g.

– RA radiographic studies– Ulcerative colitis remission studies

• PROs– Questionnaire fatigue– Daily diaries

• Self-administered injections – biologics• Self-administered injections – biologics• Biopsies (ulcerative colitis, Crohn’s disease, psoriasis)• Stool samples (ulcerative colitis, Crohn’s disease)• Clinic visitsC c s ts

– Incapacitating diseases• Multiple drugs

– New treatments are often add-on therapy

Be cognizant of the need to ease the patient burden –integrate operational approaches into trial

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g p pp

Patient Recruitment• Patients are generally already known to site

– Opportunity for initial recruitment bolus• Sites can target “compliant” patients• Good opportunity to target high performing sites…

Indication # Sites in XcellerateTM

A th >1 100Asthma >1,100

COPD >1,400

Crohn’s Disease >520

Psoriasis >400

Rheumatoid Arthritis >3,000

Lupus (SLE) >260Lupus (SLE) >260

Ulcerative Colitis >260

Crucial to identify most appropriate sites e g XcellerateTM

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Crucial to identify most appropriate sites – e.g. XcellerateTM

Case Study• Challenge

– Client’s Rheumatoid Arthritis study running behind schedule for recruitment; highly competitive enrollment environmentOwn investigator database exhausted; 60 additional sites required– Own investigator database exhausted; 60 additional sites required for activation

• Solution– Covance identified 239 high performing sites through Xcellerate –g p g g

16 countries across Europe, Asia Pac and the Americas– Sites contacted; CDA exchange; Feasibility process activated with

153 sitesOnly 15% of sites declined study– Only 15% of sites declined study

– Feasibility exercise performed between 27 Sep and 2 Nov 2011• Result

– Achieved 53% positive response rate; 68 sites recommendedAchieved 53% positive response rate; 68 sites recommended– Enabled trial to proceed: all PSVs completed by December 2011

XcellerateTM helped client recover in a rescue situation where all a en es open to the client has been e ha sted

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avenues open to the client has been exhausted

Competitive Environment

INDICATION

NUMBER OF STUDIES*

PLANNED OPEN TO ENROLMENT

Asthma 42 66

COPD 27 48

Crohn’s Disease 24 43

Psoriasis 24 28

RA 37 81RA 37 81

SLE 11 30

Ulcerative Colitis 30 27

Vital to have a deep view into site/patient competition –and plan accordingly

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*Industry-sponsored clinical trials, Phase II-III, April 2012Note: biosimilar studies will further crowd the market

Biologics - Geographic Considerations• Biologics more accessible in developed countries

– Need for biologic experienced patients leads to Western geographic bias, e.g. rituxan studies

Bi l i ï i i fi d i i k• Biologic naïve patients easier to find in emerging marketsRheumatoid Arthritis - Recruitment by Region

Median and Interquartile Ranges

3

1.5

2

2.5

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0.5

1

Rec

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ALL AP

CEEU EU

LAM NA

RoW

Region

Must identify and handle the impact of drug type to geography, # it & ti li

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# sites & timelines

Operational Considerations in Summary

• Operationally approaching IMIDs as one, interconnected

areas makes practical sense – and makes it possible toareas makes practical sense and makes it possible to

leverage experience across diseases

• Trial design and site training crucial to lower placebo

response

• Investigator knowledgebase is significant in most IMIDs

• A solid basis of IMID study experience is neededA solid basis of IMID study experience is needed

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