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Meet our The use of
experts pharmacometrics
in drug development
The use of pharmacometrics
in drug development
Pharmacometrics and quantitative clinical pharmacology is now almost routinely integrated in the
process of drug development in many pharmaceutical companies. Nevertheless, this research area is
continuously evolving and shows increasingly high impact in supporting both in-house and regulatory
decision-making. Meet Celine Sarr and Jakob Ribbing, sharing their experiences about implementing
pharmacometrics in a variety of projects across many different therapeutic areas and organisations -
altogether corresponding to more than 3 decades of collective wisdom.
Can you briefly describe what pharmacom- in phase I, dose selection in phase II,
etrics is and how you have seen it evolving explaining variability in phase III, and
over the years? supporting marketing in phase IV.
Celine: Pharmacometrics is the modeling Jakob: The pre-clinical and early
of pharmacokinetics (PK), efficacy and development phases may require
safety endpoints in order to inform decisions application of more mechanistic models.
during drug development. Its usage can In phase 2, the primary endpoints are often
be extended to prediction of trial success, based on biomarkers. Pharmacometrics
sampling design, detection of subpopulation serves to integrate the accumulated
of responders, and support of pediatric information in a quantitative framework that
development. It has evolved over the years, contributes to informed decisions in each
originating from population PK studies, only step of development. Pharmacometrics may
requested by health authorities, to PKPD and be used for predicting the outcome of the
exposure-response studies. Most companies clinical endpoint and, ultimately, to calculate
are still not realizing the full potential of the probability of study success.
model-informed drug development (MIDD) How can pharmacometrics support the
yet. design and evaluation of clinical studies/
Jakob: When I got involved in this field, in decision making/labelling?
2000, pharmacometricians focused to a large Celine: By long-term interaction with the
extent on developing descriptive models clinical teams. Pharmacometrics has the
just for the sake of it. Within short, the work potential to impact everything from clinical
developed to answer specific questions. development plan and study designs to
Nowadays, the focus is more on extrapolation data analysis and reporting/interpretation.
(e.g. to a new population or different dosage Ultimately the results can be used to
regimens) or for aid in decision-making (e.g. inform or justify a decision or to provide a
whether to go forward with the next trial, treatment recommendation.
which trial design/population/regimens, etc.).
Jakob: Besides what already mentioned by
How can pharmacometrics be used across Celine, pharmacometrics can be applied
the different phases of drug development? for identification of subpopulations at risk
Celine: Pharmacometrics contributes to of sub-optimal exposure and/or response
PK description and some safety modeling (efficacy/safety), and consequently aid
approval of different doses in different sub- (based on efficacy or safety), and the need
populations. to allow flexible (down-titration) background
What impact can pharmacometrics have in treatment.
drug development? What data and input are needed to develop
Celine: There are many areas. My favourite a model?
one is supporting dose selection. Celine: We need longitudinal and individual
Jakob: If planned upfront, the benefits of data combined with treatment information,
applying pharmacometrics may contribute patient characteristics, time scale, and any
to approval of a dose that has not even been covariate that might have an impact on
investigated in the relevant patient population efficacy or safety.
(or subpopulation), waiver of studies Jakob: For the pharmacometric model,
(replaced by extrapolation analysis), etc. we often expect data from clinical or pre-
The savings may span from cost and time/ clinical studies on the individual level (i.e.
patent life, to patient lives (the number of not means per time point or treatment arm).
patients that receive a sub-optimal exposure/ For a so-called population model, repeated
treatment before approval). Even in case measures are required, e.g. measurement
of less successful drugs, it may aid in early over time in the same individual.
termination of the development program. What assumptions are often used when
Are there any differences in distinct developing pharmacometric models?
therapeutic areas or indications one should Celine: The main assumptions are that all
be aware of? individuals come from the same population
Celine: Oncology is still different, both in and that the data coming from the clinical
the sense that the optimal dose will not trial is representative of the disease studied.
necessarily be given (and the maximal Jakob: Most often, pharmacometric
tolerated dose will be given instead) and modeling is not restricted to a single
that generally it cannot be studied in healthy pre-specified model but is guided by the
subjects. available data and various assumptions.
Jakob: The availability of useful biomarkers The model building procedure should be
(or surrogate endpoints) differ across pre-specified, including the definition of
different indications. Likewise, the clinical acceptable criteria for model evaluation.
endpoints used may be more or less The more mechanistic knowledge is built
informative, ranging from patient-reported into the model, the more useful it often
scores to frequently and objectively measured tends to be for extrapolation outside of the
data on a continuous scale, or time to an studied data range. We also often assume
event, e.g. death. Other differences among that different studies or populations can be
therapeutic areas are the possibility to assign integrated by one model. We always try to
patients to placebo in acute and more long- justify and explicitly state the assumptions
terms trials, the requirement of flexible dosing made.
Choose this text
Who are the key stakeholders for successful expanding.
implementation of pharmacometrics? How do you think pharmacometric work is
Celine: The people who can influence the received by regulatory agencies?
analysis within the project team needs to have Celine: Authorities such as the FDA and
a good understanding of the work done, its EMA are increasingly promoting the use of,
limitations, and how to apply it. and need for, pharmacometrics to support
Jakob: It depends on the phase the regulatory interactions. Some embedded
compound is in, but for the typical project pharmacometrics, statistics, and medical
the key stakeholders are the clinical sub- experts within these agencies are doing
team (including clinician, statistician, clinical a good job informing other regulators of
pharmacologist/pharmacometrician), with the what can be achieved and what should be
support of the upper management (to make requested from the sponsors. We notice
it happen) and sometimes with vital input that companies receive from regulators
from other experts relevant to the program increasingly more review questions related
(e.g. on biomarkers, preclinical experiments, to pharmacometric topics.
regulatory, outcomes research/market Jakob: The escalating demand of more
access, pharmaceutical development, etc.). model-based analyses is one of the
What are your key recommendations drivers of the increasing activity in drug
regarding the successful implementation of development.
pharmacometric projects? How do you expect pharmacometrics will
Celine: Frequent team discussions and evolve over the coming years?
commitment are important before, during, and Celine: I hope it will evolve into more
after the actual conduct of the analysis. simulations, more success stories, and
Jakob: Focus on identifying the current and, more team engagement.
potentially, the following questions: plan Jakob: I expect modelling will continue to
to use relevant information and modelling increase efficiency in drug development.
techniques to answer these questions. If early
Can you share some examples of how you
enough, this would also include designing
now support clients with pharmacometrics?
experiments/trials for optimal information
content and understanding the market for Celine: I try to propose team engagement
setting the right targets. but first focusing on delivering within the
expected time.
Do you see any trends in the use of
pharmacometrics in pharma today? Jakob: I develop modelling frameworks for
predicting the long-term clinical endpoint,
Celine: The added value can be seen more
based on the biomarker response. This will
and more. It is progressing towards the
allow a more reliable go/no-go decision for
model-informed drug development paradigm,
phase III studies, based on the outcome
where decisions are routinely informed
of an earlier biomarker trial. Moreover,
by the application of quantitative models
the biomarker trial can be optimized in
for integration of data to be used for both
terms of design to ensure it is efficient
intrapolation and extrapolation.
to support that decision. Early unblinding
Jakob: It is increasingly focused, increasingly of data allows a fast turnaround of the
impactful, and the amount of work is also analysis. This is typically done for somephase IIb and III studies I get involved in. The
Pharmetheus reproducible reporting allows
much of the work to be done upfront (before
database lock). As consultants, it is easy for
us to restrict communication with the clinical
team and others who must not be unblinded
early.
Is there any difference in the support to large Dr. Céline Sarr
pharma vs small biotech?
Senior MIDD Consultant, at
Celine: Large pharmaceutical companies have Pharmetheus since 2016. Celine holds
internal pharmacometrics representatives a PharmD and obtained a PhD after
that know what the company wants. Smaller working with PK/PD models applied
companies may have to rely more on external to oncology drugs. Previously, she has
experts. been working as a Senior Consultant
at SGS Exprimo (2015-2016), as a
Jakob: Smaller companies, in which in- Senior expert modeler at Novartis,
house roles are less narrow, possibly need Switzerland (2013-2015), and as the
to be more innovative. However, these Cluster leader for the modeling and
companies sometimes suffer from a lack of simulation oncology business unit at
understanding of the process all the way to Novartis, US (2008-2013).
registration or of what is important for the
intended buyer (Big Pharma), as well as for
routine clinical care.
Is there any last piece of advice you can
provide to us?
Celine: Frequent meetings are important to
have an impact in any project. In general,
many pharmacometricians have a way to
present issues that is too technical to be
understood by other project representatives. Dr. Jakob Ribbing
All results presentation slides should be Senior MIDD Consultant, at
driven by a message, making it easier for the Pharmetheus since 2014. Jakob
audience to interpret the results and their holds a PhD in Biopharmaceutical
impact. sciences and a M.Sc. in Pharmacy.
Previously, he worked at Pfizer
(2007-2014), where he also was the
pharmacometrics subject-matter
expert for the allergy and respiratory
project portfolio.
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