Life Science Momentum - Ronald van der Geest & Inez de Greef Success criteria in new-age product development programs
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Success criteria in new-age product development programs Ronald van der Geest & Inez de Greef Life Science Momentum November, 2010
No improvements until now have been achieved in
bringing drugs faster to patients
LSM 2010
Success criteria in new-age product
development programs
1. Technical project development related criteria
2. Project management/operational criteria
LSM 2010
Part 1: Technical project development
related criteria
• Advanced decision tools based on pharmacometrics have been
developed and (partially) implemented throughout the development
process in recent years, backed by regulatory bodies
• 1st example: Use of Clinical Utility Index (CUI): Multi-attribute
Approach to Drug Development Decisions or quantification of your
target product label
• 2nd example: Conducting exposure-response analysis to prevent the
need for additional trials
• 3rd example: Accelerating drug development through a model-based
approach to understanding dosing before it was tested in patients
LSM 2010Utilization of pharmacometrics allows for a
more efficient drug development process
Propose best doses
The cost of PM
Estimate effect size is marginal
compared to the
final cost of a
Rescue discarding good drug
trial. In most
cases, the level
Target patient selection
of effort for PM
is as low as 1
Maximize value of prior data
person for 2-6
months
Drug approval
Labeling
LSM 2010The Clinical Utility Index, a Method for
Balancing Efficacy and Safety in Drug
Development Decision Making
Placeholder for PKPD slides
LSM 2010Using quantitative data to understand when to
(dis)continue development
Clinical utility index for lead and follow-up compound
PM approach and impact
Lead compound Follow-up compound
Sponsor wanted to compare two
potential insomnia compounds
Clinical Utility Index (CUI) was developed
using various measures of residual
U
C
I
sedation and efficacy
Dose-response analyses were conducted
on each end point, using sensitivity
Probability of observing a difference at peak clinical utility Dose, analysis to determine the degree of
clinical meaning in CUI
index (CUI) value mg
Peak CUI values were observed at doses
viable for lead compound and not viable
for follow-up compound, leading to an
expedited and quantitative decision to
continue development with lead
compound
Difference in CUI
SOURCE: Reprinted by permission from Macmillan Publishers Ltd: Clinical Pharmacology & Therapeutics, Ouellet D, Werth J, Parekh N, Feltner D, McCarthy B and
LSM 2010
Lalonde, RL; The Use of a Clinical Utility Index to Compare Insomnia Compounds: A Quantitative Basis for Benefit–Risk Assessment (reference citation),
March 2009 copyright (year of publication)Conducting exposure-response analysis to
prevent the need for additional trials
Symptom score
PM approach and impact
160
150 Sponsor had inconclusive results from
two registration trials in patients with a
140 debilitating neurological disorder
without approved treatments
130
Key question was: is there adequate
120 evidence of effectiveness in the current
clinical trial database?
110
Analysis conducted by 1 person for
100Accelerating drug development through a model-based
approach to understanding dosing before it was tested
in patients
PM approach and impact
Simulated and observed viral load for 2 dosage regimens
Sponsor needed to select a range of active oral
doses for clinical phase IIa trials of a novel anti-HIV
drug, maraviroc
PK/PD model to link plasma concentration to
inhibition of viral replication was adapted for short-
term treatment based on disease model
parameters from literature and preclinical data
o
p
c
/s
ei
The model predicted the effect on viral load of
different doses, resulting in a range of possible
D
active oral doses used in the design of phase IIa
ff
i
trials
Time, days
Solid lines: Measured Dotted lines:
Simulated Bold: 100 mg 2x / day Narrow:
25 mg 1x / day
SOURCE: Reprinted by permission from Macmillan Publishers Ltd: Clin Pharmacol Ther, Rosario MC, Jacqmin P, Dorr P, van der Ryst E, Hitchcock C. A
9
pharmacokinetic-pharmacodynamic disease model to predict in vivo antiviral activity of maraviroc, (reference citation), 2005 Nov;78(5):508-19, copyright
year of publication)Success of these technical tools highly depend
on acceptance by management & project
teams and the level at which these experts
are empowered to implement
LSM 2010Part 2: Project management &
operational criteria
CEO
Development management board
Protocol review committee
Core development
team
Sub teams
Cases known whereby protocols or
pivotal development decisions Collaborative teams
need to be signed off 12-15
….
development layers
LSM 2010Project management & operational criteria
Development plans for highly
comparable programs
• Program I:
development plan of a global pharma company in the 90’s
as line extension of orally delivered CNS drug
• Program II:
development plan of a global pharma company in early
2000 as line extension of orally delivered CNS drug
• Program III:
development plan of a mid-sized pharma company in
early-mid 2010 as line extension of oral/IV administered
CNS drug
• Program IV (too early to disclose plan outcomes):
development plan of a virtual development setting as line
extension of oral/IV administered CNS drug
LSM 2010Program comparison
Program I (1996) Program II (2002) Program III (2008)
4 phase I trials 6 phase I trials 2 phase I trials
1 phase II trial 0 phase II trials 1 phase II trial
2 phase III trials 2 phase III trials
2 open label trials
development duration: development duration: development duration:
Est. 5-6 yrs Est. 4 yrs Est. 2 yrs
Est. budget: Est. budget: Budget:
105 M 60 M 15 M
LSM 2010Associated regulatory landscape
• 505B2 (FDA, 1999)
“Application for which one or more of the investigations relied upon by the
applicant for approval were not conducted by or for the applicant and for
which the applicant has not obtained a right of reference or use from the
person by or for whom the investigations were conducted”
The application should at least include:
- A Bioavailability/Bioequivalence (BA/BE) study comparing the proposed
product to the listed drug (if any).
- Studies necessary to support the change or modification from the listed drug
or drugs (if any). Complete studies of safety and effectiveness may not be
necessary if appropriate bridging studies are found to provide an adequate
basis for reliance upon FDA’s finding of safety and effectiveness of the listed
drug(s)
• Similar regulations are provided through EMA, so called Hybrid
application
LSM 2010Evolving companies (classic)
• Classic virtual Biotech model
Project team /
management
team
LSM 2010Evolving companies (classic)
• Classic virtual Biotech model - evolved
Project team /
management
team
LSM 2010Novel development models
• Some dynamic graphics on novel development paradigms
IP,
capital,
FLEX- Project
program
team team
management
LSM 2010Evolving development models
compared to classic CEO
Development management board
Protocol review committee
Core development
team
Sub teams
IP, Collaborative teams
capital,
FLEX- Projec
program
team t team ….
manageme
nt
LSM 2010Evolution of models over time:
moving from flex teams to in-house staff
In-house team
Flex team
Key challenge: maintaining the entrepreneurial spirit
and team empowerment while growing the
organization
LSM 2010Conclusions
• Current development programs highly benefit from novel
M&S technologies in term of adding knowledge, informed
decision taking, improved trial design and chance of success.
• Implementation of flexible organizational structures and
team empowerment are expected to further shorten
timelines and reduce budgets and will ultimately bring
products to patients faster.
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