DRUG DEVELOPMENT RESEARCH 62:71–75 (2004)

DDR
Editorial
Applying Pharmacogenomics in Drug Development:
Call for Collaborative Efforts
David Gurwitzn
Department of Human Genetics and Molecular Medicine, Sackler Faculty of Medicine,
Tel-Aviv University, Tel-Aviv, Israel

Strategy, Management and Health Policy

Enabling Preclinical Development Clinical Development

Technology, Preclinical Toxicology, Formulation Phases I-III Postmarketing
Genomics, Research Drug Delivery, Regulatory, Quality, Phase IV
Proteomics Pharmacokinetics Manufacturing

ABSTRACT Personalized medicine remains the long-awaited next revolution in medicine. So far,
progress towards this change has been much slower than hoped, given that our entire DNA sequence has
been publicly available since April 2001. Three years down the road, it has become clear that the
expectations for fast progress in medicine were excessive, and that our genome is by far more complex
than originally perceived. Moreover, it seems that both the medical profession and health care systems, as
well as pharmaceutical companies, are too conservative for modifying diagnostic and treatment protocols
following the gain of new pharmacogenomics knowledge that has the potential to drastically reduce the
incidence rates of adverse drug reactions. The next few years may well be a crucial turning point for the
use of pharmacogenomics data in drug development. The transformation will hopefully begin with the
availability of FDA approved rapid and reliable diagnostic screening tools for CYP450 alleles, along with
new FDA guidelines favoring the approval process for drug applications supported by valuable genomic
information related to toxic reactions. The current theme issue, a focused snapshot for mid-2004,
highlights some of the vital topics in clinical genetics and informatics that together will hopefully form a
platform for future joint efforts to identify the most valuable genotype/drug response phenotype
correlations. Dialogue and collaboration between regulatory agencies and the pharmaceutical industry, as
well as within the pharmaceutical sector, will be indispensable for advancing beyond this turning point
towards genuine personalized medicine. Drug Dev. Res. 62:71–75, 2004. c 2004 Wiley-Liss, Inc.

Key words: adverse drug reactions; CYP450; genotype/drug response phenotype databases; personalized medicine;
pharmacogenomics consortium

REDUCING ADR AS THE PRIMARY OBJECTIVE
In recent years, it has become obvious that the
inter-individual diversity of the human genome,
harboring over 10 million single nucleotide polymorph-
isms (SNPs), and the level of intricate polymorphic
gene interplay participating in the etiology of common
diseases, is much higher than originally perceived.
Accordingly, it is now evident that the use of
pharmacogenomics information during drug develop-
ment for polygenic diseases will be far more complex
than previously expected [Bartfai, 2004; Evans and
Relling, 2004; Roses et al., 2004]. This will be especially
true for inherited traits determining disease severity, as
well as drug efficacy, as numerous ‘‘protective alleles’’
can modify the deleterious effects of just a few disease-
promoting alleles. The collective analysis of raw
genotype/phenotype correlation data already generated
during the past 10 years of clinical genetics research
might be beyond our computing power. This is
n
Correspondence to: David Gurwitz, Department of
Human Genetics and Molecular Medicine, Sackler Faculty of
Medicine, Tel-Aviv University, Tel-Aviv, 69978 Israel.
E-mail: gurwitz@post.tau.ac.il
Published online in Wiley InterScience (www.interscience.wiley.
com) DOI: 10.1002/ddr.10368

c 2004 Wiley-Liss, Inc.
72 GURWITZ
reflected in the scientific literature: the PubMED
database contains roughly 200,000 articles that relate
genes to drugs (see Altman et al., pages 81–85, this
issue). Small clinical studies on complex disorders,
often analyzing data from merely a few hundred
patients, rather add confusion by the lack of powerful
statistics or attention to ethnic background. Altogether,
this indicates that true personalized medicine, where
genotyping (possibly of the entire patient genome) will
allow the choice of the best drug for each patient
without the need for costly ‘‘trial and error’’ drug
prescription periods, is decades away. Yet, one aspect of
tools for individualizing drug prescription is soon
expected: chip-based DNA screening tools for single-
gene polymorphic alleles affecting drug metabolism,
and thereby drug safety. The first genes to be screened
by such tools would most likely include the CYP450
gene family, in particular, CYP2D6, CYP2C19, and
CYP2C9 [Evans and Relling, 2004] (Roche Diagnostics
AmpliChip CYP450). Roche Diagnostics has already
developed a specific chip for the rapid detection of
CYP2D6 ‘‘poor metabolizer’’ alleles. Their web site
currently states that ‘‘Roche is working to obtain
approval in the United States and Europe for a clinical
diagnostic version of the test in 2004.’’ nHopefully, the
FDA Office of In Vitro Diagnostic Device Evaluation
and Safety (OVID) will ultimately approve CYP450 and
similar diagnostic tests (Roche Diagnostics original
application was rejected in July 2003). Endorsement of
CYP450 ‘‘poor metabolizer’’ allele diagnostics by
national health authorities should hopefully open the
door for similar diagnostic tests designed for additional
drug metabolizing and drug transporter genes.
Eventually, the availability of such DNA chip-
based diagnostics, if sufficiently affordable and if
embraced by the medical community, would allow a
drastic reduction in the alarmingly high current rates of
adverse drug reactions (ADRs). Indeed, this is the most
urgent aspect for the personalized medicine vision.
Meta-analysis of published studies indicates that nearly
6% of all hospital admissions to internal medicine
wards are due to ADRs [Muehlberger et al., 1997].
Studies show yet higher 14% ADR-related admission
rates in geriatric medicine wards [Hallas et al., 1993]. A
recent German study confirmed the 6% ADR rate as a
primary cause for new hospital admissions, and,
moreover, specified that 23% of hospitalized patients
in internal medicine wards suffered from one or more
ADRs [Dormann et al., 2004]. As most ADRs reflect
poor drug metabolism phenotypes, leading to elevated
n
Note added in proof: On September 1, 2004, Roche
Diagnostics has announced that its AmpliChip CYP450 Test had
been approved for diagnostic use in the European Union.
and harmful drug levels, we can at least look forward
for considerably reduced ADRs rates once common
‘‘poor drug metabolizer’’ phenotypes become amenable
to prior diagnosis by simple laboratory tools. Hopefully,
these aspects of personalized medicine will soon arrive
at the clinic.
IMPROVING DRUG EFFICACY
ADRs are only one side of the coin, certainly being
the most dangerous one. The other facet, less risky for
patients but nonetheless more challenging, is addressing
the poor efficacy and the insufficient post-marketing
follow-up for newly introduced drugs [Deyo, 2004].
Improving drug efficacy would be possible by tailoring
treatment protocols and drug choice for each patient,
but the required informatics would be most demanding.
The amounts of genotype/drug response phenotype data
that need to be accumulated and analyzed, and the
resources required for data analysis, are huge. Ideally,
comprehensive data sets should be collected without
particular hypotheses in mind, so that no bias is
introduced (Altman et al., pages 81–85, this issue).
Other, less elaborate routes for overcoming data over-
flow should examine specific pharmacodynamic hypoth-
eses related to the drug’s mechanism, and should focus
on those parts of our genome that are most likely to yield
significant clues to patient variation in drug efficacy.
It is often difficult to predict which sets of genes
would prove most significant for predicting drug
efficacy during drug development, especially when its
mode of action is not obvious. However, it is rational to
expect that for many drugs, polymorphic immunity-
related genes would prove vital for gaining insight into
the inter-patient variability in drug efficacy. Such gene
sets might include genes for cytokines, cytokine
receptors, and hormones and neurotransmitter recep-
tors participating in the regulation of the delicate
immune balance. Both general and adaptive immunity
participate in key aspects of health and disease, as
reflected in several reviews featured in the present
issue. Hence, at least certain segments of the mysteries
of the considerable patient heterogeneity in drug
efficacy should become more perceptible once larger
studies on drug efficacy phenotype vs. immune
genotypes become available. After all, the immune
system is the major player in most chronic diseases;
thus, it is likely to play a key role in the therapeutic
efficacy (or lack thereof) of many current and future
drugs. Notably, the adaptive immune system has been
implicated in psychiatric disorders [Kipnis et al., 2004],
a discipline eagerly awaiting the vital insight expected
from the deciphering of the human genome. Indeed,
psychiatry, where objective diagnostic tools are pro-
foundly lacking, seems to be the medical discipline in
 PHARMACOGENOMICS IN DRUG DEVELOPMENT
most urgent need of credible genotype/drug response
phenotype studies [Gurwitz and Weizman, 2004].
The present issues of Drug Development Re-
search also review the potential of expression genomics
in drug development (see Chin et al., pages 124–133,
this issue). The authors have successfully employed the
technology to elucidate new networks of regulatory
genes, shedding light on the renowned anti-cancer
potential of the green tea polyphenol, epi-gallocatechin
gallate. The arrival of Affymetrix whole-genome DNA
arrays and similar products will boost the potential of
such powerful technologies for elucidating complex
sub-cellular control mechanisms and their role in
disease, allowing the screening of large chemical
libraries for potential new lead compounds.
CALL FOR CONSORTIUM EFFORTS
Drug development has become extremely costly;
estimates for cost vary but are at least several hundred
million US dollars for bringing a single new drug from
bench to market [Bartfai, 2004]. There are fears that
future requirements to employ pharmacogenomics
data will drive development costs higher, while
reducing market size due to lower numbers of potential
patients. However, pharmaceutical companies will
apparently be able to charge prime prices for
pharmcogenomics-tailored drugs, owing to their super-
ior efficacy, thereby compensating for the smaller
patient numbers qualifying for a given drug [Bartfai,
2004]. The FDA is already under rising criticism for
insufficient requirements of post-marketing follow-up
[Deyo, 2004; Griffin et al., 2004] as well as slow drug
approval rates in spite of recent measures for speeding
up the review process [Reichert, 2003]. Concurrently,
pharmaceutical companies are under increased pres-
sure to openly share their clinical trials data [Lancet
editorial, June 12, 2004]. Indeed, in the aftermath of
the paroxetine for adolescents scandal, GSK has
announced that its entire clinical trials data for
marketed drugs will be made open, and available on-
line as ‘‘the GSK Clinical Trial Register’’ [Giles, 2004;
GSK press release, June 18, 2004]. This is a welcome
step, although it remains to be seen how comprehen-
sive these data will be and whether pharmacogenomics
data would be included. Moving towards a pharmco-
genomics-oriented drug market will put further pres-
sures on the approval process, and must, therefore,
include continued dialogue between the pharmaceu-
tical industry and regulatory agencies (see Hall et al.,
pages 102–111, this issue). Thorough discussion of
relevant ethical aspects is needed to watch over a
correct practice of research and clinical trials in
accordance with accepted international guidelines and
regulation. This dialogue will have to continue in step
73
with ongoing developments in pharmacogenomics
knowledge and diagnostic tools, in order to establish
trust in the options of personalized medicine by both
health professionals and society at large (see Lunshof
and de Vert, pages 112–116, this issue).
Other essential ingredients for a successful shift
beyond the turning point towards personalized medi-
cine must include collaborative measures for open data
sharing between pharmaceutical companies and the
scientific community on pharmacogenomics aspects of
the drug efficacy. While the latter statement may not
seem obvious, there are sound reasons to believe that
such data sharing will nevertheless be vital for
implementing personalized medicine. Measures for
joint studies on drug efficacy might include, but not be
limited to, agreements between companies and govern-
ment regulators on shared platforms for patient
genotyping and for genotype/drug response phenotype
data collection, analysis, and submission. Moreover, the
means must also be found for exploiting the huge
amounts of patient phenotypic data already being
collected during large clinical trials, for the benefit of
all parties, rather than keeping the data locked in
corporation files and away from the reach of open
scientific research [Collier and Iheanacho, 2002].
Hopefully, the open sharing of such genotype/drug
response phenotype databases, evidently with provi-
sions to ensure absolute patient anonymity, would
promote better medical treatment.
A fine example for a collaborative genotype/
phenotype database effort is the newly established
Public Population Project in Genomics at the Uni-
versity of Montreal (P3G). The project aims to establish
an international consortium for collaboration in popu-
lation genomics, by developing coordination and
standardization for genotype/phenotype correlation
data, thereby providing a resource for data sharing
between large human genomics projects. This public
project illustrates the pathway that the pharmaceutical
industry should take, even though data-sharing intui-
tively seems in contradiction with private sector
interests. Hopefully, large pharmaceutical companies
will, in due course, be willing to join similar
consortiums and share their huge bio-bank pharmaco-
genomics data, accumulated during completed clinical
trials. A potential necessary first step might include the
fostering of mechanisms for public sharing of post-
marketing genotype/drug response phenotype data of
already approved drugs. Subsequent steps should
ideally be modeled on the successful Wellcome Trust
SNP Consortium database [1999], where major phar-
maceutical companies participate in funding. An
important consideration at this point is that the
complexity of data relevant for drug efficacy is so large
74 GURWITZ
that it might be far beyond the capacity of a single
pharmaceutical company to achieve significant insight
without such collaborative efforts. In the long run, such
shared databanks should facilitate drug development
efforts for complex disorders; thus, mutual benefit is
expected for both the pharmaceutical industry and
society.
STROKE PHARMACOGENOMICS
A case in point for a desperately needed
international shared genotype/phenotype database
concerns the development of drugs for reducing
secondary brain damage following ischemic stroke.
Ischemic stroke is among the major causes of mortality
and severe morbidity among the elderly. It is also
among the most costly, with annual costs estimated at
approximately 3% of total health care expenditures
across eight countries [Evers et al., 2004]. Rates of
stroke are escalating in Western societies along with the
increased life span and the well-publicized obesity
epidemic. There is an urgent need to establish a
worldwide database of stroke pharmacogenomics,
cataloging risk gene alleles in various ethnic popula-
tions. A practical database should also include com-
prehensive statistics for gene alleles correlated with
favorable or poor outcomes following various pharma-
co-therapeutic interventions immediately following
stroke. Data should include various anti-thrombotic,
anti-inflammatory, and neuroprotective interventions.
Induced hypothermia, emerging as a novel post-
traumatic treatment for reducing secondary neuronal
cell death, should also be studied with respect to
genotype/outcome measures phenotype [Suzuki et al.,
2003]. A comprehensive stroke database would even-
tually allow fast and effective individualized treatment
during the first 6–72 h following stroke onset, the brief
‘‘open window’’ available for reducing secondary brain
damage. Later interventions are less likely to affect the
secondary damage, but should also be included in the
database. Indeed, ischemic stroke is a unique case
where ‘‘trial and error’’ classical medicine has no place,
as there are no ‘‘second chances’’ following erroneous
early decisions. Pharmacogenomics, therefore, could
be of vital importance in early clinical decision-making
for stroke patients. Such an open-access database will
also enable, besides the early identification of at-risk
individuals, more favorable risk-lowering drug treat-
ments, as well as allowing early and individually
optimized treatment soon following the onset of
ischemic stroke. Favorably, such a stroke database
would be an international effort, including as many
ethnic groups as possible, so that the most crucial
genetic risk factors, which might differ among ethnic
groups, will be correctly identified and globally useful.
Numerous genes are seemingly involved in stroke
genetics; this means that in order to be useful, large
numbers of patients, clearly over 10,000, must be
recruited and followed for outcome measures following
the various treatments. Such efforts are unfeasible
without international collaboration.
EDUCATING SOCIETY
The incorporation of pharmacogenomics into the
drug development process will mean far more than the
generation of elaborate genomic data. The expected
change towards individualized therapies will call for
reformation of teaching curricula for physicians and
health care providers [Gurwitz et al., 2003] and there
will also be a substantial need for educating society to
adapt to the far-reaching changes in pharmacotherapy
[Frueh and Gurwitz, 2004]. To begin moving towards
this objective, continued dialogue between pharma-
ceutical companies and the FDA (or national drug
agencies outside the Unites States) as well as
collaborative agreements within the industry, should
benefit all parties. The benefits will extend to our
graying society, whose health-care bills keep escalating,
further endangering the viability of national health-care
systems worldwide. Drug companies themselves will
also benefit, as otherwise it would become prohibitive
to generate the required data for developing effective
genotype-tailored new treatments. The pharmaceutical
industry has much to gain from collaborative utilization
of pharmacogenomics data, should we be wise enough
to devise adequate mechanisms for sharing it for the
benefit of all parties. Hopefully, we shall soon witness
the turning point towards this direction.
ACKNOWLEDGMENTS
I am grateful to Jeantine Lunshof for valuable
discussions.
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