Avicenna: A Strategy for In Silico Clinical TrialsAdriano Henney

Executive Director VPH Institute

Increasing ageing population Prevalence of chronic debilitating diseases in over 65sCurrent therapies limited success

Increasing unmet medical needTendency for medicines to benefit smaller proportion of patient population

increasing emphasis on “Personalised Medicine”

Ability to deliver effective novel medicines to market declining

costs escalatingincreasing burden on healthcare budgets

“A Perfect Storm” in 21st Century Healthcare

2

Equates to growth from 3.5% to 8.5% GDP over

the same period

3

PricewaterhouseCoopers Reporthttp://www.pwc. com/gx/en/pharma-life-sciences/pharma-2020/pharma-2020- vision-

path.jhtml.

“

”

•We believe that, if the industry is to become more innovative and cut its R&D costs, four features will be vital: • A comprehensive understanding of how

the human body works at the molecular level

• A much better grasp of the pathophysiology of disease

• Greater use of new technologies to “virtualise” the research process and accelerate clinical development

• Greater collaboration between the industry, academia, the regulators, governments and healthcare providers.

What is Avicenna?

Ab Al al- usayn ibn Abd All h ibn Al-Hasan ū ʿ ī Ḥ ʿ āibn Ali ibn S nī ā

The Canon of Medicine 1025 AD In Silico Clinical Trials: How Computer

Simulation Will Transform The Biomedical Industry

An international research and development roadmap for an industry-driven initiative

EC funded Cooperation and Support Action

In silico clinical trials• The use of patient-specific computer modelling

and simulation applied in the research and development of new biomedical products, as well as in their evaluation and assessment

• Both clinical and pre-clinical. • From physiology-based pharmacokinetics to

collections of patient-specific dynamic models• Quantitative data, including medical imaging

and sensing• Dynamic system view

Not a “single hit” phenomenon

Arise from maladaptations

that reflect an alteration in the

state of a system

Driven by the reorganisation of

regulatory networks ->

defective system response

Correction requires

identification of key control

points focusing on

normalising system response

Complex Multifactorial Diseases

6

Complex Network Analytics

7

StatisticsBioinformatics

‘Omics Data

Signatures, Profiles, Associations, InferenceSignatures, Profiles,

Associations, Inference

Static ViewStatic View

Modelling & Simulation

8

Courtesy Prof Peter Sorger, Harvard Med Sch

New

Sim

ulat

ion

Refine ModelVerify Simulation

Verify Simulation

“Validated”ModelModel

“Validated”ModelModel

Dynamic not Static

Dynamic not Static

Community of Practice

Avicenna: major objectives

Roadmap Industrial Alliance

Mapping the territory: a new ISCT industry

Merging two existing sectors: • Clinical trial industry (provides design, execution and interpretation of clinical trials)

+• Virtual Prototype industry (provide in silico design and assessment for industrial sectors – aero-space, nuclear…)

Objectives

• Stakeholder engagement• Map processes -> CT• Identify points of CM&S application• Collect data from widest possible sources• Acquire opinions on key themes• Identify key areas & topics for action -> roadmap• Achieved using AO process- Schellingpoint LLP

Opinion Surveys

Producers

Spenders

Providers

Consumers Research

Regulators

CSA Structure

AO process -> collects/ analyses information to input and review/process output

Alignment Cycles gather and process the

four categories of opinion that drive our actions and inaction

Alignment Cycles gather and process the

four categories of opinion that drive our actions and inaction

2014-05-27 20:44Foundation Document

Sida 1 av 2https:/ /aot.schellingpoint.com/foundation_documents/1872/edit

F o u n d a t i o n D o c u m e n tF D T h e C u r r e n t S t a t e o f I n S i l i c o C l i n i c a l T r i a l s

T h e e n d o r s e d o p i n i o n s d e s c r i b i n g t h e c u r r e n t s t a t e , t r e n d s , a s s e t s a n d g u i d i n g p r i n c i p l e s a n d v a l u e s g u i d i n g t h e a d v a n c e m e n t o f I n S i l i c o C l i n i c a l T r i a l s

B e n e f i t - C T , B e n e f i t - P h a r m a , B e n e f i t s , B e n e f i t s - D e v i c eM a n y d e v i c e C T s t u d i e s i n v o l v e a l o w n u m b e r o f p a t i e n t s , l e a d i n g t o l o w q u a l i t y w i t h o u t a b r o a d b e n e f i t t o t h e d e v i c e i n d u s t r y .T h e a p p l i c a t i o n o f I S C T i s m i n i m a l w i t h i n t h e p h a r m a i n d u s t r y .T h e r e a r e e x a m p l e s o f s u c c e s s f u l I S C T .T h e r e i s e v i d e n c e o f u s e . C o n f u s i o n m a y a r i s e f r o m t h e u s e o f I S C T a n d a n . . . t h a t t h i s o n l y a p p l i e s t o c l i n i c a l t r i a l s a l o n e n o t d i s c o v e r y a n d p r e c l i n i c a lT h e r e i s g r e a t i n t e r e s t i n I S C T i n p h a r m a .

D e v i c e s , D i s e a s e s , W h e r e , W h e r e - D e v i c e sA n e c d o t a l e v i d e n c e s u p p o r t i n g t h e s e s t a t e m e n t s e x i s t s .D e v i c e C T f a i l u r e s o c c u r m o s t i n t h e l a s t 1 0 % o f t h e p i p e l i n e w h e r e 9 0 % o f t h e a c t i v i t y n e e d e d t o g e t t h e d e v i c e o u t t o m a r k e t t a k e s p l a c e .I S C T w i l l h e l p u s u n d e r s t a n d h o s t - d e v i c e r e s p o n s e u p t o 8 0 % .S o m e s i m p l e t a r g e t s w i l l a p p e a r i n b o t h t h e d e v i c e a n d t h e m e d i c i n e s a r e n aT h e r e a r e I S C T u s e d i n P K P D , p e d i a t r i c s , a n d f o r m u l t i - t r i a l s i n e l d e r l y , t h a t s h o w m o d e l - s p e c i f i c a s p e c t s o f t h e t r i a l .T h e r e w i l l b e g r e a t e r o p e n n e s s t o I S C T m e t h o d s i n a r e a s w i t h h i g h r e s e a r c h a c t i v i t y .

C a p a b i l i t i e sI S C T w i l l n e v e r r e p l a c e e n t i r e l y c l i n i c a l t r i a l s , b u t o n l y r e d u c e a n d r e f i n e t h e m .

D a t a , M o d e l i n g , M o d e l i n g - M e t h o d sA p o o r e x a m p l e o f u s i n g I S C T i s w h e r e g r o u p s a r e f o c u s e d o n s p e c i f i c a r e a s b u t d o n o t i n c l u d e t h a t i n t h e C T w o r k f l o w .A n e x c e l l e n t e x a m p l e o f I S C T i s w h a t i s b e i n g d o n e i n t h e v i r t u a l p h y s i o m e , b u t . . . i s s t i l l a l o t t o d o b e f o r e i t g e t s c l o s e t o w h a t ’ s g o i n g o n i n t h e b o d y .A t t e m p t s a r e b e i n g m a d e t o r e p l a c e s o m e o r g a n f u n c t i o n s i n s i l i c o u s i n g b i o m i m e t i c s .C o m b i n a t o r i a l c h e m i s t r y h a s e n h a n c e d d i s c o v e r y .C o m p u t e r b a s e d m o d e l s a r e b e i n g u s e d t o s t u d y t h e i n f l u e n c e o f p h a r m a c o g e n o m i c s .F o r I S C T t o u l t i m a t e l y w o r k , w e w i l l n e e d t o c r e a t e t h e S y s t e m s D y n a m i c s m o d e l o f t h e h u m a n b o d y .G o o d e x a m p l e s o f t h e p o t e n t i a l o f I S C T h a v e b e e n p r o t o t y p e d b y E n t e l o s , b u t n o t s u c c e s s f u l l y i m p l e m e n t e d .L a c k o f c l a r i t y r e g a r d i n g d a t a m g m t a n d i t s a p p l i c a t i o n i n t h e c l i n i c a l c o n t e x tM i c r o f l u i d i c s a n d n a n o t e c h n o l o g y a r e h u g e l y d i s r u p t i v e a n d w i l l r e s u l t i n c o n s e q u e n c e s f o r e x i s t i n g C T b u s i n e s s e s .M o d e l i n g a n d s i m u l a t i o n i s b e i n g u s e d b o t h i n a c a d e m i a a n d i n i n d u s t r y . C o n f u s i o n a r r i s e s o v e r t h e e m p h a s i s t h a t I S C T i m p l i e s o n c l i n i c a l t r i a l u s e .M o d e l i n g a n i m a l t o h u m a n - t h e r e h a v e b e e n w h o l e c o m p a n i e s e s t a b l i s h e d t o d o t h i s - b u t w i t h n o m a t e r i a l r e s u l t s .P h a r m a c o l o g y m o d e l s d o e x i s t f o r u n d e r s t a n d i n g c h e m i c a l i n t e r a c t i o n m o d e l i n g .P r o b l e m s t h a t h a v e b e e n e n c o u n t e r e d i n m a p p i n g r e a l i t y w i t h m o d e l l i n g o u t c o m e s i n p r o c e s s d e s i g n c a n b e u s e f u l t o d e v e l o p i n g I S C T .Q u a n t i t a t i v e s y s t e m s p h a r m a c o l o g y i s a n a r e a t h a t h a s e n j o y e d s o m e a d o p t i o n .

T h e r e a r e f e w e x a m p l e s o f m o d e l s t h a t c a n p r e d i c t d r u g a b s o r p t i o n , d i s t r i b u t i o n , m e t a b o l i s m , e x c r e t i o n a n d t o x i c o l o g y ( A D M E T ) .W e c a n b e g i n t o a d v a n c e I S C T w i t h t h e s c i e n c e a n d m o d e l i n g c a p a b i l i t i e s w e h a v e n o w - m o d e l i n g c a p a b i l i t i e s a r e n o t w h a t i s h o l d i n g u p p r o g r e s s .W e h a v e n o t y e t e x p l o i t e d t h e m o d e l s a n d s i m u l a t i o n s t h a t a l r e a d y e x i s t .W i t h m o r e a n d m o r e E H R i n c o u n t r i e s , t h e i n n o v a t i o n w i l l b e c o m e a c c e s s i n g h e a l t h o u t c o m e s d a t a .

U s e r s , V a l i d a t i o nO v e r - s o p h i s t i c a t i o n o f m o d e l s i s n o t t h e r e a s o n t o d a y ' s I S C T m e t h o d s s u f f e r l o w a d o p t i o n .T h e v a l i d a t i o n o f m o d e l s i s f a r f r o m s u f f i c i e n t n o w .

C o l l a b o r a t i o n , K n o w l e d g e T r a n s f e r , O t h e r C o m m u n i t i e sA c u l t u r e o f t r u s t a n d o p e n n e s s i s r e q u i r e d t o m a k e I S C T s u c c e s s f u l .I S C T i s h u g e l y m u l t i d i s c i p l i n a r y a n d c a n n o t b e d e l i v e r e d b y s m a l l g r o u p s w o r k i n g i n a l a b .M o d e l i n g a n d s i m u l a t i o n a p p r o a c h e s a r e c l e a r l y b e i n g u s e d w i t h i n b i o m e d i c a l . . . L a c k o f c o n v i n c i n g e v i d e n c e e x i s t s r e g a r d i n g w h e r e i t c a n b e o p t i m a l l y u s e d n o w .

C u l t u r e , F i n a n c e sP h a r m a c a n n o t a f f o r d t h e i n c r e a s i n g c o s t o f f a i l u r e a n d m u s t a d v a n c e I S C T .R e s i s t a n c e t o I S C T w i l l e x i s t f r o m b a s i c R & D t o r e g u l a t o r s u n t i l w e c a n s h o w t h a t i t h a s a r e m o t e c h a n c e o f s u c c e e d i n g .

a b o u t c o n t a c t u s a n d e r s s i g n o u t h o m e

m e a s u r e m a x i m i z e a d m i n Avicenna

The Alignment Cycle translated ‘We each think’

into -We are here

-We should go there-This is how to get there

The Alignment Cycle translated ‘We each think’

into -We are here

-We should go there-This is how to get there

Class Analysis• Alignment within a

class (balls)• Alignment between

classes (lines)• Green= excellent,

Yellow= good• Line thickness= level

of alignment• Table- detail of

alignment levels across categories

• Industry statistics show standard alignment index is in the order of 44-83•Avicenna is very high by comparison•Indicates strong basis for future collaboration

• Industry statistics show standard alignment index is in the order of 44-83•Avicenna is very high by comparison•Indicates strong basis for future collaboration

Summary of AO delivery

• What we have– A refined and comprehensive view of the

stakeholder landscape– A better understanding of what constitutes “ISCT”-

beyond Clinical Trials– Key, detailed data on topics and areas of focus

• How we are applying it– The foundation content to build the detailed

Roadmap– Building a time-phased action plan for implementing

the Roadmap

Biomedical Industry

clinical trialsindustry

clinical trialsindustry

Virtual Prototypeindustry

Virtual Prototypeindustry

IT industry

CAE tools

CRO

Regulatory

Engineering firms

Researchhospitals

“Engaged Discussants”Community of Practice

Roadmap Industrial Alliance

Informs

Alliance Objectives

• Prototype & build confidence in application of CM&S

• To lobby the EC to fund ISCT in H2020• Develop a mid/long term vision for

ISCT

Alliance Activities ➨• Develop and disseminate “Good Modelling Practices” for the

use, verification, validation, and accreditation of ISCT

• Promote events that foster interdisciplinarity and related training

• Promote, sustain, and disseminate data and model sharing

• Develop educational content and provide targeted training

• Maintain an observatory of all ISCT success stories

• Secure funding for ISCT research and technological development

• Drive necessary standardisation and interoperability efforts

Alliance is focused on PoP

Alliance: Lobbying & Influencing

• A European Trade Association for in silico medicine

• Market focused• A platform for industries and research

institutions to discuss bottlenecks to progress on in silico medicine

• The go-to Association for all things in silico in European Politics.

General Benefits for Members

• Targeted at all those with a vested interest in the in silico market eg: Pharma, Medtech, Cosmetics, Software industries, Research institutions

• Ability to set the policy and advocacy agenda of the Association in year 2

• Access to Rohde Public Policy expertise/VPH PAWG analysis of all Regulatory and policy issues affecting specific market interests

• Potential opportunity to create new funding streams for in silico research: Public Private Partnership

Public Private Partnership• EC conversation -> invitation to

consider more ambitious alternative to Alliance concept

• Work with industry to scope a plan and make a proposal

• Industry-driven, EC, Academics • Implications- financial (huge),

governance, oversight, legal and ethical, management

• Potential to move from demonstrating evidence of utility to full implementation and ultimately routine practice

Written interest from …

PPP: PoP -> Adoption

Current Status

• Outreach to industry ongoing• Likely that key MEP will be honorary President

of the Alliance• First gathering of emerging Alliance partners in

Barcelona in June• Exploratory discussions with EMA held• Active discussions with EFPIA- link to IMI2 and

SGGs• Contact with EC ongoing to ensure feasible

timeline for PPP submission

“The Virtual Physiological Human (VPH) will revolutionise the way health knowledge is

produced, stored and managed as well as the way in which healthcare is currently delivered”

- European Commission

AVICENNAEVENT 5

Hosted by AQuASAgency for Health Quality and Assessment of Catalonia

4th and 5th June 2015, Barcelona, Spain

In Silico Clinical Trials: the future is now

Thank you

Adriano Henney