Date 01.12.2008

Drug regulatory process, the supporting information systems, and the Escher-projectTommi TervonenFaculty of Economics and BusinessUniversity of Groningent.p.tervonen@rug.nl

Date 01.12.2008

What is drug discovery and drug development?

Ambit biosciences, commercial compound DBs (ambitbio.com)

Example drug development costs of Trimeris Inc. (thebody.com)

Date 01.12.2008

>What are Drug Information Systems (DISs)?>What are they being used for?>Who uses them?>What could they be used for?

Discovery

Development Launch

Pre-clinical trials

Clinical trials

Phase I Phase II Phase III

Marketing

Phase IV clinical trials

Drug lifecycle

Date 01.12.2008

> DIS classes Compound DBs Pre/clinical trial DBs Summary of Product Characteristics (SmPC) DBs Adverse Drug Reaction (ADR) DBs CPOEs

Discovery

Development La

un

ch

Pre-clinical trials

Clinical trials

Phase I Phase II Phase III

Pre/clinical trial DBs

Compound DBs

Marketing

Phase IV clinical trials

ADR DBs

SmPC DBs

CPOEs

Tim

e

Date 01.12.2008

DIS Data Organization

Class Name

Type (Structural/Trial/Reg

ulative/Patient) Details

Qu

antitative

(Yes/N

o)

Ag

greg

ated/R

aw

Name

No

n-p

rofit (Y

es/No

)

Compound Cambridge structural database

S Molecule crystal structures Y R CCDC NCompound NCI 3D database S Molecular 3d structures Y R NCI Y

CT clinicaltrials.gov T Only CT settings and objectives N A NIH / FDA YCT Janus T, R Not functional yet Y A, R FDA YCT EudraCT T No public functionality* N A EMEA YCT Cochrane T CT Meta-analyses Y A Cochrane YCT clinicalstudyresults.org T Detailed clinical study results N A PhRMA N

CT / SmPC NCI Drug Dictionary/thesaurus

T, RSmPC and clinical trials for cancer drugs N A NCI Y

SmPC Drug Information Online RSmPC, drug interactions, condition medication, pill labeling N A

Micromedex, Cerner Multum, Wolter Kluwer,

and others N

SmPC RxList RSmPC, drug interactions, condition medication, pill labeling N A RxList, Inc. N

SmPC Lung Association of Saskatchewan lung disease drug repository

RSmPCs for drugs with indication in lung diseases N A

Lung Association of Saskatchewan Y

SmPC Drug Digest RSmPC, drug interactions, pill labeling N     N

SmPC DailyMed R Detailed SmPC N A NLM YSmPC EMEA EPAR R EPAR, incl. detailed SmPC Y A EMEA YADR MedEffect R Superficial ADR N A Health Canada YADR FDA ADR R ADR quarterly reports N A FDA YADR EMEA ADR R No public functionality* N A EMEA Y

CPOE Various R, P SmPC through internal SmPC DB N A Various N

Date 01.12.2008

> The drug regulatory process Aims to make sure, that the drugs entering market are both safe and efficient Is laborious and slow Has relatively poor dissemination of results Doesn’t have transparent decision making Has recently all participating parties (drug industry, academia, and regulatory authorities) concerned about reforming

the process

> The main reason forreforming the regulatoryprocess is to limitthe linear growthof costs,but…

Benefit-risk assessment

Data and evidence

Regulatory Logic

Date 01.12.2008

>The current DISs don’t store regulatory information of sufficient precision; only aggregated information is available

>Systematic, quantitative analysis is not possible without suitable quantitative information. Current Benefit-Risk analysis is qualitative!

Discovery

Development Launch

Pre-clinical trials

Clinical trials

Phase I Phase II Phase III

Pre/clinical trial DBs

Compound DBs

Marketing

Phase IV clinical trials

ADR DBs

SmPC DBs

CPOEs

Tim

e

Date 01.12.2008

>Dose-response curve-fitting with various A-II antagonists

Dose (mg/d)

-12

-10

-8

-6

-4

-2

0

0 100 200 300

Tro

ugh D

BP

(m

m H

g)

Dose (mg/d)

-12

-10

-8

-6

-4

-2

0

0 50 100 150 200

Tro

ugh D

BP

(m

m H

g)

Similar compounds, partially different indications, totally different clinical data!

Date 01.12.2008

Escher-projectWorkpackages 3.1 and 3.2

Date 01.12.2008

>ESCHER Is a TI-Pharma project with an objective to

“demonstrate, that another way is possible” Incorporates 3 universities (+medical centers), 4

PostDocs, 17 PhD students, 4 drug development companies, and x external personnel

WP 3.1: develop a new framework for drug benefit-risk assessment

WP 3.2: build a drug information system that allows quantitative comparisons

>Benefit-risk analysis of WP 3.1 requires data from the DIS of WP 3.2

Date 01.12.2008

>Escher 3.1 How can we measure benefits and risks?- Rank drugs and placebo for the same indication- Multiple criteria

Inherent value judgements- But what about clashing / missing preference

information? Quantitative data available- But data is uncertain!- Should it be used “as is”?

Multi-Criteria Decision Analysis (MCDA)

Date 01.12.2008

> Stochastic Multicriteria Acceptability Analysis (SMAA) Allows MCDA with

imprecise criteria measurements and missing/incomplete preference information

Criteria measurements can be defined through joint probability distributions -> RCT data can be used +- directly

Date 01.12.2008

> SMAA central weights Central weights are “typical” preferences that

favour different alternatives Although drug A might not have “better” benefit-

risk ratio than drug B with all preferences, some preferences usually support A as well

Elevator planning with SMAA

Date 01.12.2008

>Rank acceptability indices describe stability of ranking, and can be used in risk management

b1

b3

b5

b7

b9

BE

N

CA

S

DA

K

TA

N

AG

A

RA

B

OU

J

MA

R

FE

Z0

10

20

30

40

50

60

70

80

Acceptability

Rank

Alternative

Rank acceptability indices

BEN

CAS

DAK

TAN

AGA

RAB

OUJ

MAR

FEZ

Choosing a location for a new cargo airport in Morocco with SMAA

Date 01.12.2008

>Escher 3.2 Supports various other workpackages by

building an information system that allows quantitative analyses

Web-based drug repository (Java, Spring) Agile development Enables various new

research topics

Date 01.12.2008W

hy A

gile

?

Date 01.12.2008

>How to model relevant data (SmPC)?

5.1 Pharmacodynamic propertiesPharmacotherapeutic group: Drugs used in erectile dysfunction. ATC Code: G04B E03…Studies in vitro have shown that sildenafil is selective for PDE5, which is involved in the erectionprocess. Its effect is more potent on PDE5 than on other known phosphodiesterases. There is a 10-foldselectivity over PDE6 which is involved in the phototransduction pathway in the retina. At maximumrecommended doses, there is an 80-fold selectivity over PDE1, and over 700-fold over PDE2, 3, 4, 7,8, 9, 10 and 11. In particular, sildenafil has greater than 4,000-fold selectivity for PDE5 over PDE3,the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility.…

5.1 Pharmacodynamic properties Pharmacotherapeutic group: {group [lowest available level]}, ATC code: {code} [For products approved under “conditional approval”, include the following statement:] <This medicinal product has been authorised under a so-called “conditional approval” scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency (EMEA) will review new information on the product every year and this SPC will be updated as necessary.> [For products approved under “exceptional circumstances”, include the following statement:] <This medicinal product has been authorised under “Exceptional Circumstances”. This means that due to <the rarity of the disease> <for scientific reasons> <for ethical reasons> it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.>

Template Viagra SmPC

Date 01.12.2008

>US Food and Drug Administration (FDA) is working to build a DIS (Janus) incorporating “raw” data

>The European Medicines Agency (EMEA) doesn’t see aggregated data as a problem

>Cause? FDA is multi-disciplinary, EMEA consists of medical doctors

Date 01.12.2008

>Conclusions Drug regulatory process is in need of reform Current drug information systems cannot

support the future needs, because they don’t store the data in an appropriate format

Escher-project tries to show, that a different “way of doing things” is possible

Department of B&IS participates in the project through Bert, Tommi, Vahid, Douwe (starting 1d/w@Jan), and 1 more PhD-student (starting@Apr)

Date 01.12.2008

>Thank you!>Q?>Future publications:

T. Tervonen, V. Oskuee, E.O. de Brock, P.A. de Graef, H.L. Hillege (2008). Current status and future perspectives in Drug Information Systems (manuscript)

T. Tervonen, D. Postmus, H.L. Hillege (2009) Multi-criteria decision analysis in drug benefit-risk analysis. Invited presentation, 23rd European Conference on Operational Research, Bonn, Germany. July 5-8, 2009

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