Transcript Slide 1

Date 01.12.2008
Drug regulatory process, the
supporting information
systems, and the Escherproject
Tommi Tervonen
Faculty of Economics and Business
University of Groningen
[email protected]
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
Preclinical
trials
Clinical trials
Phase I
Phase II
Phase III
Drug lifecycle
Launch
Development
Marketing
Phase IV clinical trials
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
Preclinical
trials
Clinical trials
Phase I
Phase II
Phase III
Launch
Development
Marketing
Phase IV clinical trials
Compound
DBs
Pre/clinical trial DBs
Time
SmPC DBs
ADR DBs
CPOEs
Date 01.12.2008
DIS
Class
Compound
Compound
CT
CT
CT
CT
CT
CT / SmPC
Name
Cambridge structural
database
NCI 3D database
clinicaltrials.gov
Janus
EudraCT
Cochrane
clinicalstudyresults.org
NCI Drug
Dictionary/thesaurus
Data
Type
(Structural/Trial/Reg
ulative/Patient)
Details
S
S
T
T, R
T
T
T
T, R
SmPC
Drug Information Online
R
SmPC
R
SmPC
RxList
Lung Association of
Saskatchewan lung
disease drug repository
SmPC
SmPC
SmPC
ADR
ADR
ADR
CPOE
Drug Digest
DailyMed
EMEA EPAR
MedEffect
FDA ADR
EMEA ADR
Various
R
R
R
R
R
R
R, P
R
Molecule crystal structures
Molecular 3d structures
Only CT settings and objectives
Not functional yet
No public functionality*
CT Meta-analyses
Detailed clinical study results
SmPC and clinical trials for cancer
drugs
SmPC, drug interactions, condition
medication, pill labeling
SmPC, drug interactions, condition
medication, pill labeling
SmPCs for drugs with indication in
lung diseases
SmPC, drug interactions, pill
labeling
Detailed SmPC
EPAR, incl. detailed SmPC
Superficial ADR
ADR quarterly reports
No public functionality*
SmPC through internal SmPC DB
Organization
Quanti
tative
(Yes/N Aggregat
o)
ed/Raw
Name
Non-profit
(Yes/No)
Y
Y
N
Y
N
Y
N
R
R
A
A, R
A
A
A
CCDC
NCI
NIH / FDA
FDA
EMEA
Cochrane
PhRMA
N
Y
Y
Y
Y
Y
N
N
A
Y
N
A
NCI
Micromedex,
Cerner Multum,
Wolter Kluwer,
and others
N
N
A
RxList, Inc.
N
A
Lung Association
of Saskatchewan
Y
NLM
EMEA
Health Canada
FDA
EMEA
Various
N
Y
Y
Y
Y
Y
N
N
N
N
Y
N
N
N
N
A
A
A
A
A
A
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
Regulatory
Logic
Data and
evidence
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
Preclinical
trials
Clinical trials
Phase I
Phase II
Phase III
Launch
Development
Marketing
Phase IV clinical trials
Compound
DBs
Pre/clinical trial DBs
Time
SmPC DBs
ADR DBs
CPOEs
Date 01.12.2008
>Dose-response curve-fitting with various A-II
antagonists
Dose (mg/d)
100
200
300
0
0
0
-2
-2
-4
-6
-8
-10
Trough DBP (mm Hg)
8
16
24
32
-4
-6
-8
Dose (mg/d)
0
-10
50
100
Dose (mg/d)
150
200
0
0
0
-12
-2
Similar compounds,
partially different
indications, totally different
clinical data!
-4
-6
-8
-2
Trough DBP (mm Hg)
-12
Trough DBP (mm Hg)
Trough DBP (mm Hg)
0
Dose (mg/d)
-4
-6
-8
-10
-10
-12
-12
80
160
240
320
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” benefitrisk 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
Rank acceptability indices
80
CAS
50
DAK
30
b9
CAS
DAK
TAN
RAB
b1
OUJ
b3
MAR
Rank
AGA
b5
BEN
b7
Alternative
BEN
60
40 Acceptability
FEZ
Choosing a location
for a new cargo
airport in Morocco
with SMAA
70
TAN
AGA
RAB
20
OUJ
10
MAR
0
FEZ
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
Why Agile?
Date 01.12.2008
Date 01.12.2008
>How to model relevant data (SmPC)?
5.1 Pharmacodynamic properties
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.>
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.
…
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 multidisciplinary, 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 PhDstudent (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
>/dev/null