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I am writing a paper for HMS Beagle (http://hmsbeagle.com), a webzine for
biomedical researchers. The topic of the paper is to be PK/PD simulation
using Pharsight Trial Designer. I am looking for individuals that: (1) are
familiar with the program (2) have done a clinical trial simulation with the
program (3) have any opinions about the program (e.g. how it compares to
other simulation programs commonly used) or (4) would like to comment about
the importance (or irrelevance) of clinical trial simulation software.
Thanks in advance for considering my request.
Regards,
Dylan Bulseco, Ph.D.
Software Editor, HMS Beagle
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Dylan A. Bulseco, PhD * bulseco.-a-.os.com
Worcester Foundation for Biomedical Research * bulseco.-at-.sci.wfbr.edu
222 Maple Ave, Shrewsbury, MA 01545 * www.wfbr.edu/~bulseco
ph: 508.793.0945 * FAX: 508.842-9632 * http://biomednet.com/hmsbeagle
====>Soon to be Department of Pharmacology, UMASS Medical School<===~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
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Dear Dylan,
I've been doing a good bit or work on simulation of trials. The
division of clinical pharmacology at Georgetown has been working with a
company called MGA in Concord MA (www.mga.com), developing a product
called ACSL BioMed, specifically for these simulations. Please note that
this is NOT a project of the Center for Drug Develoment Science at
Georgetown, although the CDDS has a strong interest in Simulation.
Another company, SCI in Apex, NC (http://www.sciconsulting.com/) also has
a product for this purpose, called Forecaster. We have actually
simulated a number of trials, and are currently conducting one of those,
so, we'll soon be able to comment about whether we were smart enough to
do this in a meaningful way. Another person who has given this a lot of
thought is Bill Gillespie, of Globomax (a small CRO in Columbia MD).
Please contact me if you have any questions.
Mark
Mark Sale M.D. Assistant Professor of Medicine
Georgetown University 202-687-8242
msale.-at-.medlib.georgetown.edu
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Dylan,
> The topic of the paper is to be PK/PD simulation
> using Pharsight Trial Designer. I am looking for individuals that: (1)
> are familiar with the program (2) have done a clinical trial simulation with
> the program (3) have any opinions about the program (e.g. how it compares to
> other simulation programs commonly used) or (4) would like to comment
> about the importance (or irrelevance) of clinical trial simulation software.
The following comments should be assessed in light of the following:
1. The Pharsight clinical trial simulator code is based on that developed
for the European Centre for Pharmaceutical Medicine RIDO program (see
below). I was the principal designer of the RIDO simulator program.
2. I own shares in Pharsight Inc.
3. I am a member of the Pharsight scientific advisory board.
Familiarity and Clinical Trial Simulation Experience
===================================================I am currently engaged in projects using Pharsight as follows:
1. To evaluate the power of the enrichment design used in several
pivotal studies of tacrine in Alzheimer's disease. This study includes
an assessment of the power of different analysis methods (mainly ANOVA
and NONMEM) and how these influence the ability to detect key covariate
influences on effectiveness.
2. To simulate the progression of Parkinson's disease based on data in
the literature with a view to developing clinical trials which can
distinguish symptomatic from protective drug effects.
3. To compare the predictions of different sets of PK parameters for
paracetamol (acetaminophen) in relation to a set of concentrations
measured in children after accidental overdose.
Each of these projects has provided an interesting challenge for
simulating drug responses and clinical trial designs.
Features of Pharsight that I have not yet explored include the ability
to simulate a variety of patterns of compliance, missing observations
and errors in recorded vs actual sampling times. It also has a flexible
and sophisticated system for defining the distribution of covariates in
the study population and the correlation between covariates. These
should prove very valuable in attempting to mimic real world clinical
trial behaviour. Finally, some simple kinds of adaptive trial designs are
possible which allow the dose to be varied according to prior responses.
Pharsight Release 1.0 has proven to be relatively easy to use (given my
prior experience with RIDO). Two PhD students working with me have
quickly been able to take on projects 2 and 3 above and work
independently.
Other Simulation Programs
========================RIDO: RIDO aims to teach scientific drug development based on PKPD
principles as exemplified through a clinical trial simulator. The
clinical trial simulator will be distributed with a multimedia CDROM
based teaching program. It offers a Windows based GUI to allow a user to
define a study population, treatments (dose, size, formulation, etc),
and responses (conc, effects). Variability in outcome is determined by
sampling PKPD parameters from specified distributions plus the influence
of covariates (age, weight, sex, smoking, renal function) and random
measurement error. The results of the simulation are presented
graphically with simple comparative statistics. Further analysis is
linked to a set of population PKPD models which allow parameter
estimation and model based hypothesis testing using NONMEM. There is a
limited attempt to estimate the cost of alternate trial designs based on
costs of subjects, staff, drug supplies and response measurements.
ACSL BioMed: I have no experience of this program but I have seen
demonstrations. It appears to have many features similar to Pharsight
but I have no familiarity with how they compare.
NONMEM: Many features of clinical trial designs can be simulated and
analysed using NONMEM. The main drawback of NONMEM is the lack of a
convenient method for defining clinical trial designs and for
introducing sources of variability such as compliance, missing
observations, imprecise recording of sample times.
Others: There are many programs able to simulate individual PKPD
responses that can be used to gain insight into drug responses. However,
the key feature of clinical trials is the behaviour of a population of
diverse individuals which requires special attention when attempting to
distinguish signal from noise (statistical hypothesis testing) and in
determining how to predict the ways that individuals will have different
responses (essential for informative product details). Other simulation
programs do not offer practical ways to simulate realistic PKPD
responses and popln variability.
Importance
=========My personal scientific efforts over the last 4 years have been heavily
involved with the development of clinical trial simulation software. The
release of RIDO, Pharsight, ACSL BIOMED have opened up the
opportunity to test the value of this technique against real world
needs. My own prediction of the value is inevitably biased but I cannot
see how thinking more deeply about how to do an experiment and testing
alternatives can fail to add value to an already very complex area of
activity.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.html
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Nick Holford has recently asked for comments and insights into the
Pharsight Simulator. More Importantly than that, it would be of great
value to hear thoughts, opinions, and EXPERIENCES on clinical trial
simulation in general. A recent article in Applied Clinical Trials said
that there "seems to be [a] fear of being left behind should clinical
trial simulation reach its potential and become a strategic and
competitive advantage. There is evidence of defensive investments by
companies fearing that a rapid advancement of simulation technology
would put them at a competitive disadvantage." This might seem an
overstatement since the vast majority of people I have talked to about
this have never even heard of it. That might be changing however. Carl
Peck is organizing a conference on this topic in November at Georgetown.
Among those that have formed INFORMED opinions on this topic the utility
of it is mixture of those who believe that it will be the next big thing
(that its use will speed drug development through identifying those
trials with a greater likelihood of failure a priori) to those who
believe that we can never possibly know what will happen in a complex
clinical trial. Most likely is that the utility of clinical trial
simulation will fall somewhere in between. I for one would like to hear
more from individuals about this topic and what they think its potential
will be in the future.
I would also like to point out two things to the group (if they didn't
already know).
1.) Pharsight is not the only clinical trial simulator on the market.
MGA's ACSL Biomed Simulator is another very good program which is
considerably cheaper than the price of Pharsight.
2.) Neither of these programs is necessary to do clinical trial
simulation. A programming language, such as S-plus or Gauss, and a good
programmer is all that is really necessary. What these packages do is
take alot of the headache out of writing your own code for you.
Peter L. Bonate, Ph.D.
Hoechst Marion Roussel
Clinical Pharmacokinetics
P.O. Box 9627 (F4-M3112)
Kansas City, MO 64134
fax: 816-966-6999
phone: 816-966-3723
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Thank you Peter,
(The usual disclaimer:) I am a co-developer of MGA's simulation product
ACSL BioMed. Thanks for pointing out the Pharsight is not the only
simulation program. Not only is it not the only, it was not the first (ACSL
BioMed version 1.0 released July 1996), and it has fewer installed sites (I
beleive, but I may be wrong) than ACSL BioMed. Clearly, this area is quite
full of far to much hype and marketing at the moment. My usual
recomendation to people is that they think very carefully before making a
decision, first about whether to do simulation, then if they decide to do
it, about who, how and what software to use. I think both companies (and
others such as SCI's program Forecaster) should make software available for
a long, FREE evaluation period. I think 2 months is probably a reasonable
lenght of time to decide it this technology is useful and how it fits into a
drug development plan. Comments from Pharsight or MGA?
Mark Sale M.D. Assistant Professor Medicine
Georgetown University msale.aaa.medlib.georgetown.edu
Bonate, Peter, HMR/US wrote:
> PharmPK - Discussions about Pharmacokinetics
> Pharmacodynamics and related topics
>
> Nick Holford has recently asked for comments and insights into the
> Pharsight Simulator. More Importantly than that, it would be of great
> value to hear thoughts, opinions, and EXPERIENCES on clinical trial
> simulation in general. A recent article in Applied Clinical Trials said
> that there "seems to be [a] fear of being left behind should clinical
> trial simulation reach its potential and become a strategic and
> competitive advantage. There is evidence of defensive investments by
> companies fearing that a rapid advancement of simulation technology
> would put them at a competitive disadvantage." This might seem an
> overstatement since the vast majority of people I have talked to about
> this have never even heard of it. That might be changing however. Carl
> Peck is organizing a conference on this topic in November at Georgetown.
>
> Among those that have formed INFORMED opinions on this topic the utility
> of it is mixture of those who believe that it will be the next big thing
> (that its use will speed drug development through identifying those
> trials with a greater likelihood of failure a priori) to those who
> believe that we can never possibly know what will happen in a complex
> clinical trial. Most likely is that the utility of clinical trial
> simulation will fall somewhere in between. I for one would like to hear
> more from individuals about this topic and what they think its potential
> will be in the future.
>
> I would also like to point out two things to the group (if they didn't
> already know).
> 1.) Pharsight is not the only clinical trial simulator on the market.
> MGA's ACSL Biomed Simulator is another very good program which is
> considerably cheaper than the price of Pharsight.
> 2.) Neither of these programs is necessary to do clinical trial
> simulation. A programming language, such as S-plus or Gauss, and a good
> programmer is all that is really necessary. What these packages do is
> take alot of the headache out of writing your own code for you.
>
> Peter L. Bonate, Ph.D.
> Hoechst Marion Roussel
> Clinical Pharmacokinetics
> P.O. Box 9627 (F4-M3112)
> Kansas City, MO 64134
> fax: 816-966-6999
> phone: 816-966-3723
>
> Also see: http://www.cpb.uokhsc.edu/pkin/pkin.html
>
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>
> PharmPK - Discussions about Pharmacokinetics
> Pharmacodynamics and related topics
>
> Nick Holford has recently asked for comments and insights into the
> Pharsight Simulator.
Not me. I did not ask for comments and insights. My recent posting was
in response to a request for such comments and insights from a reporter
for HMS Beagle.
Your other comments are well taken.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.html
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Mark Sale's idea is a good one. When a program costs $10,000 dollars or
more, a lot of research should go into whether and how it benefits a
company. Also, making available to the public who has purchased what
product is also useful (but it is doubtful that many software companies
would supply this information). And if you really want to challenge a
company give them a one year money back guarantee. IF your product
doesn't save the company at least the price of the product in a year (by
supposed cost savings from the design and efficiency of a clinical
trial) then return the product for a refund.
Just a thought...
Peter L. Bonate, Ph.D.
Hoechst Marion Roussel
Clinical Pharmacokinetics
P.O. Box 9627 (F4-M3112)
Kansas City, MO 64134
fax: 816-966-6999
phone: 816-966-3723
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Over the course of 20 years, MGA has been providing simulation
technology to a wide variety of industries. Last year we introduced
ACSL BioMed to the pharmaceutical industry and have been working
closely with customers to insure that they realize the full
potential of this new technology. Our experience in conducting
evaluations have lead to one evaluation approach which
offers a high success rate for both the customer and vendor.
This approach we'll call "The Model This Session". This is a
short one or two day event where the customer provides data (before
hand) to the software vendor so that the vendor has a clear
understanding of what the customer would like to model. The vendor
then meets with the customer and together they begin to create the
simulation model. Once the model is created, simulations can be run,
results analyzed and conclusions drawn. At the conclusion of this
session, a presentation should be made to the customer's
department/management.
The benefits here are; shorten evaluation time, intensive
one on one session where customer and vendor learn software
capabilities/applicabilities, customer gains understanding of the
support level the vendor can offer, minimal impact/risk on the part of
the customer and vendor.
This approach has worked well in helping organizations decide whether
or not to take the next step in applying this technology to real
programs.
The comments regarding how a company should review software are all
valid and we certainly agree with them. Whenever you introduce new
techology into an industry, appropriate expectations must be set and
both the vendor and customer must do their best to communicate their
needs in order to achieve success (success=clear understanding of how
a software tool may or may not benefit the customer).
If this does not happen, our experience shows that the evaluation
will take on a life of its own with no end in sight. Both the
customer and vendor will waste time and money and in the end, both
walk away from the ordeal putting the blame for failure of the
evaluation, on each other. Properly conducted evaluations are your
best "Money Back Guaranties".
Most software vendors and many of their customers would agree
that the best way to evaluate any sophisticated software program is
through some type of cooperation between the customer and vendor.
Since all evaluations cost both parties time and money, emphasis must
be put on defining what is to be done, time frame, support needed
during evaluation phase and customer training. The length of an
evaluation need not be long if together the customer and vendor have
worked out evaluation criteria which will answer the question to the
satisfaction of the customer and his/her management.
Lastly, we do (as much as the customer will let us), publicize names
of customers using our technology. In our case, many of our customers
have agreed to talk with other prospective buyers and write papers
discussing the work they are involved with as well. In fact, it's in
the vendor's best interest to have his customer's names publicized.
If a vendor refuses to provide company names or references....watch
out....they might be selling vaporware!
Dan
*****************************************
Dan C. Cui
V.P. Sales
MGA Software, Inc.
200 Baker Ave.
Concord, MA 01742
978-369-5115 ext. 228
978-369-0013 fax
dancui.-a-.mga.com
*****************************************
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