from new molecules to
leads for innovation
studies on the post-innovation
learning cycle for pharmaceuticals
Lay-out inside work:
The work presented in this thesis was performed at the Division of Pharmaco-
epidemiology & Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences,
Faculty of Science, Utrecht University, The Netherlands.
CIP-gegevens Koninklijke Bibliotheek, Den Haag
From new molecules to leads for innovation – Studies on the Post-Innovation
Learning Cycle for Pharmaceuticals
Thesis Utrecht University – with ref. – with summary in Dutch
© 2008 Pieter Stolk
Francis te Nijenhuis, zonnezijn creaties, 's-Hertogenbosch
Francis te Nijenhuis, zonnezijn creaties, 's-Hertogenbosch
Optima Grafische Communicatie, Rotterdam
From new molecules to leads for innovation –
Studies on the Post-Innovation Learning Cycle
Van nieuwe moleculen tot aanwijzingen voor innovatie –
Studies aan de post-innovatie leercyclus voor geneesmiddelen
(met een samenvatting in het Nederlands)
ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van
de rector magnificus, prof.dr. J.C. Stoof, ingevolge het besluit van het college
voor promoties in het openbaar te verdedigen op maandag 15 september 2008
des middags te 4.15 uur
geboren op 21 augustus 1978 te Rotterdam
Prof.dr. H.G.M. Leufkens
Dr. E.R. Heerdink
Dit proefschrift werd (mede) mogelijk gemaakt met financiële steun van het
Ministerie van Volksgezondheid, Welzijn en Sport.
Embedding new drugs in the health system
2.1 Changes in the defined daily dose: CYP2D6/CYP3A
metabolism as an indicator for dose setting problems
2.2 Variability in use of newly approved drugs with or
without an orphan designation
2.3 Rare essentials: drugs for rare diseases as essential
Effects of policy (interventions) on the use of drugs in clinical
3.1 Impact analysis of the discontinuation of reimbursement:
the case of oral contraceptives
3.2 Variable access to clopidogrel in a harmonised EU market
3.3 Between country variation in the utilisation of
antihypertensive agents: guidelines and clinical practice
3.4 Seige-cycles as a learning device in pharmacovigilance
Pharmacoepidemiology as a learning device in pharmaceutical
4.1 The association between exposure to COX-2 inhibitors
and schizoprenia deterioration: a nested case-control
4.2 Taking low dose aspirin is associated with more stable
drug treatment for lithium users
List of co-authors 211
List of publications 217
About the author 221
The pharmaceutical arena is evolving constantly: new drugs enter the market
while older ones are discontinued, clinical practice changes, health care budgets
rise and fall, and public health needs are redefined. Against this background, the
achievement of three main policy goals related to pharmaceuticals has to be
1. To ensure patient access to safe and effective medicines that are used in
the context of a high quality delivery system;
2. To allocate scarce resources in a health system in such a way that
pharmaceutical spending remains sustainable, while optimal health
outcomes for the individual patient are achieved;
3. To create an environment where innovation is rewarded, and the aims of
(national) industrial policies are achieved.
The ways in which societies reconcile these three goals are manifold, leading to a
variety of health systems, allocation policies, and usage patterns.
several important issues have converged that pose important challenges to the
fulfilment of the main policy goals. For example, there are growing concerns
about the ability of the current system to satisfactorily respond to issues
surrounding drug safety. This may lead to a decrease in the trust that patients and
health professionals have in the health system as a vehicle to deliver high quality
expenditures due to demographic developments and the increasing per unit
treatment costs of new drugs.
containment. Also, the number of innovative drugs coming to the market is
decreasing and profit margins for companies are under pressure, which will
change the structure of the industry in the coming years.
extent or source of the dearth of drug innovation is unknown, changing
regulatory requirements may be a key issue.
discussion about whether or not innovation is matched to real public health
needs. This was analysed in detail in the 2004 report of the World Health
Organisation (WHO) ‘Priority medicines for Europe and the world’.
mismatch not only relates to diseases that are highly prevalent in low- and
middle-income countries, but also to diseases that affect patients around the
world (e.g. Alzheimer’s disease, stroke and the orphan diseases).
6,7 Furthermore, governments are faced with growing health care
8 This leads to strong incentives for cost
9,10 Although the precise
11 Moreover, there is a continuing
Between these challenges that confront regulators worldwide there are many
cross-links: interventions to address one issue often have a broader impact as
well. An example for this can be found in a recent retrospective cohort study of
patients with acute coronary syndrome, discharged from hospital and receiving
posthospital treatment with clopidogrel (Plavix
study, an increase in mortality in the first 90 days after the discontinuation of
clopidogrel was found.
alternatives such as acetyl salicylic acid, this drug has been a frequent target for
cost containment interventions by regulators and third party payers. Therefore,
reimbursement policies may have played a role in determining the duration of
use for individual patients. One of the authors of the study, Dr. John Rumsfeld,
remarked: “Cost must be an issue here. If clopidogrel cost the same amount as
aspirin, perhaps we would be recommending indefinite use of this drug as
This example shows that careful assessment of the possible impact of regulatory
intervention on the usage environment is warranted. Ideally, proposals for policy
changes should be backed up by information about current use or the impact of
prior interventions. In his evaluation of regulatory requirements during the
development phase, Rawlins has proposed two criteria to evaluate all
regulation? And, does each regulatory requirement offer value for money? To
answer these questions in a satisfactory way, information from the usage
environment is needed.
Furthermore, data form the usage environment can also provide important
information and incentives for drug development and innovation. The study on
the clinical impact of the discontinuation of clopidogrel described above is such
an example. New insights from drug use in clinical practice is one of the three
main routes for ‘post-innovation innovation’: the discovery of new indications
after market entry.
example through pharmacoepidemiological studies, can contribute to the learn-
confirm cycle of drug development.
To assist in thinking about the usage environment of drugs in a comprehensive
manner that includes regulation, clinical outcomes, and incentives for
innovation, we propose a conceptual learning cycle for pharmaceuticals that
incorporates all these elements. Results from studies on this learning cycle can be
®), an antiplatelet drug. In the
13 Because of the high costs of clopidogrel compared to
15 is there a clear evidence-base to support the continuing of the
17 In this way, insights from use in clinical practice, for
helpful in designing future policies, as well as identifying opportunities for
optimising drug use and the innovation process.
THE LEARNING-CYCLE FOR PHARMACEUTICALS – A CONCEPTUAL
The cycle that we want to use as the conceptual framework is described in
Figure 1. The framework contains a ‘pre-innovation’ phase and a ‘post-
innovation’ phase. The distinction between innovation and post-innovation is
based on the work of David Banta, who places the moment of ‘innovation’ at
the start of clinical use.
part of the cycle that begins with the embedding of a new drug in the existing
health care system, and ends with the leads for innovation that arise from use in
19 In this thesis we want to focus on the ‘post-innovation’
FIGURE 1 - A proposed learning cycle for pharmaceuticals
The first step in the cycle is when a drug receives a market authorisation by a
regulator such as the European Medicines Agency (EMEA) or the US Food and
Drug Administration (FDA) (Section 1). At this moment, the new drug or drug
class must be embedded in the existing regulatory and health system. For
example, payers have to make a decision about whether or not the drug should
be reimbursed, and professional organisations have to make a decision about the
role of a drug in clinical practice.
In the next section of the cycle, the drug is taken up and used in clinical practice
by patients and health professionals (Section 2). During this period, more
information comes available about the benefits and risks of the new drug. Use in
clinical practice is heavily influenced by reimbursement policies and guidelines.
Based on the position that the drug attains in clinical practice and the outcomes
of drug treatment, the therapeutic needs of the population may change or leads
for new indications or future drugs are discovered; both of these provide
incentives for pharmaceutical research and development (Section 3) .
Next, we come to the drug development (pre-innovation) phase of the cycle
(Section 4). This section contains all drug discovery and clinical development
within academia and industry, including all pre-marketing activities of regulators
such as FDA, the EMEA and national authorities. Ideally, the product of this
process is marketed as a new drug, returning us to Section 1 of the learning cycle.
In this thesis we will use a variety of analysis tools to study the links between the
first three sections of the learning cycle for pharmaceuticals, the phase for post-
innovation learning. We will evaluate how these tools can best be used and
adapted for this purpose. The tools used in this thesis include
pharmacoepidemiological methods, multicountry comparisons and case studies.
We are especially interested in the international context, making use of the
natural variability of policy environments and health care systems.
POST-INNOVATION LEARNING FOR PHARMACEUTICALS (PILLS) -
OBJECTIVES OF THIS THESIS
A primary objective of this thesis is to develop a set of analytical tools to study
the post-innovation learning cycle of pharmaceuticals. With these tools we aim
to provide an evidence base for the formulation of policies that want to achieve a
sustainable balance between providing good quality health care, stimulating the
optimal allocation of scarce resources, and fostering an environment where
innovation is adjusted to real public health needs. Finally, we want to identify
directions for future research.
OUTLINE OF THIS THESIS
This thesis contains nine studies divided in three chapters. Each chapter is located
on a section of the post-innovation learning cycle presented in Figure 1.
In Chapter 2 we will focus on several challenges for policymakers that arise
from specific characteristics of new molecules, Section 1 in the cycle. An example
that we will study is the Defined Daily Dose (DDD), which plays an important
role in the price-setting systems of many countries. Also, we will explore the
implications of new therapeutic groups for policies of global organisations such as
the WHO. Finally we look at how the use of orphan drugs varies in different EU
Chapter 3 focuses on the relationship between regulation and use in clinical
practice, represented by Section 2 in the cycle. Firstly, we look at a policy
interventions at the micro level: the discontinuation of the reimbursement of oral
contraceptives. In the second study we use a macro perspective by looking at the
relationship between guideline preferences and the use of antihypertensives in
clinical practice in a multicountry setting. Another macro level study looks at
challenges to the payers in the health system. Here we look at the differences
between the EMEA market authorisation, the national reimbursement conditions
and actual use in nine EU member states. Finally, we use a life-cycle perspective
to look at how signals from the usage environment are translated into a
regulatory response for two drug safety cases, the market withdrawal of
Serotonin Inhibitors (SSRIs) in children.
In Chapter 4 we present two studies that show how information from actual use
in clinical practice can provide leads for drug development, the third section in
the cycle. We concentrate on the field of psychiatry and two classes of drugs that
have been linked to possible beneficial effects in patients with severe psychiatric
®), an expensive antithrombotic drug that poses special
®) and the safety issues surrounding suicide and Selective
illness: cyclooxygenase-2 (COX-2) inhibitors in schizophrenia, and non-steroidal
anti-inflammatory drugs (NSAIDs) in bipolar disorder.
In Chapter 5 the results from the earlier chapters are discussed in the context of
the post-innovation learning cycle and, based on this, we will provide a synthesis
and directions for future research.
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