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Date 01.12.2008

Drug regulatory process, the
supporting information
systems, and the Escher
-
project

Tommi Tervonen

Faculty of Economics and Business

University of Groningen

t.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
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
Time
Date 01.12.2008

DIS

Data

Organization

Class

Name

Type
(Structural/Trial/Reg
ulative/Patient)

Details

Quanti
tative
(Yes/N
o)

Aggregat
ed/Raw

Name

Non
-
profit
(Yes/No)

Compound

Cambridge structural
database

S

Molecule crystal structures

Y

R

CCDC

N

Compound

NCI 3D database

S

Molecular 3d structures

Y

R

NCI

Y

CT

clinicaltrials.gov

T

Only CT settings and objectives

N

A

NIH / FDA

Y

CT

Janus

T, R

Not functional yet

Y

A, R

FDA

Y

CT

EudraCT

T

No public functionality*

N

A

EMEA

Y

CT

Cochrane

T

CT Meta
-
analyses

Y

A

Cochrane

Y

CT

clinicalstudyresults.org

T

Detailed clinical study results

N

A

PhRMA

N

CT / SmPC

NCI Drug
Dictionary/thesaurus

T, R

SmPC and clinical trials for cancer
drugs

N

A

NCI

Y

SmPC

Drug Information Online

R

SmPC, drug interactions, condition
medication, pill labeling

N

A

Micromedex,
Cerner Multum,
Wolter Kluwer,
and others

N

SmPC

RxList

R

SmPC, drug interactions, condition
medication, pill labeling

N

A

RxList, Inc.

N

SmPC

Lung Association of
Saskatchewan lung
disease drug repository

R

SmPCs for drugs with indication in
lung diseases

N

A

Lung Association
of Saskatchewan

Y

SmPC

Drug Digest

R

SmPC, drug interactions, pill
labeling

N





N

SmPC

DailyMed

R

Detailed SmPC

N

A

NLM

Y

SmPC

EMEA EPAR

R

EPAR, incl. detailed SmPC

Y

A

EMEA

Y

ADR

MedEffect

R

Superficial ADR

N

A

Health Canada

Y

ADR

FDA ADR

R

ADR quarterly reports

N

A

FDA

Y

ADR

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 for

reforming the regulatory

process is to limit

the linear growth

of 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
Time
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
Trough DBP (mm Hg)
Dose (mg/d)
-12
-10
-8
-6
-4
-2
0
0
8
16
24
32
Trough DBP (mm Hg)
Dose (mg/d)
-12
-10
-8
-6
-4
-2
0
0
50
100
150
200
Trough DBP (mm Hg)
Dose (mg/d)
-12
-10
-8
-6
-4
-2
0
0
80
160
240
320
Trough DBP (mm Hg)
Similar compounds,
partially different
indications, totally different
clinical data!

Date 01.12.2008

Escher
-
project

Workpackages 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
BEN
CAS
DAK
TAN
AGA
RAB
OUJ
MAR
FEZ
0
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 01.12.2008

Why Agile?

Date 01.12.2008

>
How to model relevant data (SmPC)?

5.1 Pharmacodynamic properties

Pharmacotherapeutic 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 erection

process. Its effect is more potent on PDE5 than on other
known phosphodiesterases. There is a 10
-
fold

selectivity over PDE6 which is involved in the
phototransduction pathway in the retina. At maximum

recommended 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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