Journal of

Personalized
Medicine

Review
A State-of-the-Art Roadmap for Biomarker-Driven Drug
Development in the Era of Personalized Therapies
Victoria Serelli-Lee 1,2, * , Kazumi Ito 1,3 , Akira Koibuchi 1,4 , Takahiko Tanigawa 1,5 , Takayo Ueno 1,6 ,
Nobuko Matsushima 1,7 and Yasuhiko Imai 1,6, *

1 Clinical Evaluation Sub-Committee, Medicinal Evaluation Committee, Japan Pharmaceuticals Manufacturers

Association, 2-3-11, Nihonbashi Honcho, Chuo-ku, Tokyo 103-0023, Japan; [email protected] (A.K.);
[email protected] (T.T.); [email protected] (T.U.); [email protected] (N.M.)
2 Eli Lilly Japan K.K., 5-1-28 Isogamidori, Chuo-ku, Kobe 651-0086, Japan
3 Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;
[email protected]
4 Astellas Pharma Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan
5 Bayer Yakuhin Ltd., 2-4-9, Umeda, Kita-ku, Osaka 530-0001, Japan
6 Bristol Myers Squibb K.K., 6-5-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 163-1334, Japan
7 Janssen Pharmaceutical K.K., 3-5-2, Nishikanda, Chiyoda-ku, Tokyo 101-0065, Japan
* Correspondence: [email protected] (V.S.-L.); [email protected] (Y.I.)

Abstract: Advances in biotechnology have enabled us to assay human tissue and cells to a depth
and resolution that was never possible before, redefining what we know as the “biomarker”, and
how we define a “disease”. This comes along with the shift of focus from a “one-drug-fits-all” to a
“personalized approach”, placing the drug development industry in a highly dynamic landscape,
having to navigate such disruptive trends. In response to this, innovative clinical trial designs have
been key in realizing biomarker-driven drug development. Regulatory approvals of cancer genome
sequencing panels and associated targeted therapies has brought personalized medicines to the clinic.
Citation: Serelli-Lee, V.; Ito, K.; Increasing availability of sophisticated biotechnologies such as next-generation sequencing (NGS) has
Koibuchi, A.; Tanigawa, T.; Ueno, T.; also led to a massive outflux of real-world genomic data. This review summarizes the current state of
Matsushima, N.; Imai, Y. A State-of- biomarker-driven drug development and highlights examples showing the utility and importance
the-Art Roadmap for Biomarker- of the application of real-world data in the process. We also propose that all stakeholders in drug
Driven Drug Development in the Era development should (1) be conscious of and efficiently utilize real-world evidence and (2) re-vamp
of Personalized Therapies. J. Pers. the way the industry approaches drug development in this era of personalized medicines.
Med. 2022, 12, 669. https://
doi.org/10.3390/jpm12050669 Keywords: biomarker-driven drug development; real-world data/evidence; personalized medicine;
Academic Editor: Stefania Nobili genome medicine; data ecosystem; ecosystem for personalized therapies; disease blueprint; clinical
trial renovation; Japan
Received: 26 January 2022
Accepted: 15 April 2022
Published: 21 April 2022

Publisher’s Note: MDPI stays neutral 1. Introduction

with regard to jurisdictional claims in
The aim in drug development is to validate a clinically efficacious dose of a new drug
published maps and institutional affil-
for a defined disease state, i.e., finding the dose that will be effective for a defined group
iations.
of patients while causing the least side effects. In drug development today, where a large
proportion of new drug entities are targeted agents with specific molecular targets, the
interpretation of this aim should be re-defined and the approach to drug development
Copyright: © 2022 by the authors.
transformed. There are two parts to this transformation:
Licensee MDPI, Basel, Switzerland. “Clinically efficacious dose”—it is well established that there are individual differences
This article is an open access article that lead to differences in clinical efficacy and severity of side effects caused by drugs. In
distributed under the terms and oncology, clinical biomarkers are used to identify individuals who may respond better
conditions of the Creative Commons to targeted therapies. Pharmacogenomic (PGx) markers are also widely used now to
Attribution (CC BY) license (https:// determine dosages or identify patients who may have an adverse side effect to a drug.
creativecommons.org/licenses/by/ “Defined disease state”—in May 2017, the Food and Drug Administration (FDA) ap-
4.0/). proved pembrolizumab for microsatellite instability-high (MSI-H) or mismatch repair

J. Pers. Med. 2022, 12, 669. https://doi.org/10.3390/jpm12050669 https://www.mdpi.com/journal/jpm

J. Pers. Med. 2022, 12, 669 2 of 16

deficient (dMMR) solid tumors—the first regulatory approval of an indication defined by

biomarkers [1]. This signified the beginning of biomarker-based diagnoses in the clinic.
The biomarker is at the core of the two concepts. Identifying clinically significant
biomarkers and ensuring that there are robust methods of evaluating it is central to patient
safety and delivering clinical efficacy.
Biomarker-driven drug development embeds our knowledge of disease etiology
into clinical trial designs with the aim of de-risking the process and improving success
rates [2–4]. Over the past two decades, with advances in biotechnology, drug development
and healthcare has greatly advanced especially in the field of genomic and precision
medicine. Specifically, in recent years comprehensive genome profiling (CGP) using next-
generation sequencing (NGS) has provided the ability to molecularly profile cancers. This
provides information on the complexity of the disease and potentially identifies actionable
mutations to which available targeted therapies can be prescribed. Nevertheless, clinical
efficacy percentages even within the biomarker-selected population are sub-optimal. This
suggests the heterogenous nature of disease manifestations in different individuals, the
details of which are still unknown.
Using an array of next-generation technologies, biomarker assays today can generate
high-resolution data that provide biological information down to the single-cell level [5–8].
Accumulating omics data, clinical data, electronic health records and wearable device data
are contributing to the “data overload” [9] in healthcare. The ability to apply analytics and
artificial intelligence (AI) to mine this real-world data (RWD) for insights is accelerating the
progress of our understanding of various disease etiologies and drug interactions [10], and
is changing the way we approach science and drug development.

2. Background
Amidst this dynamic landscape, the Japan Pharmaceuticals Manufacturers Association
(JPMA) had put together a working group to address the topic of “Clinical Biomarkers
in Personalized Therapies”. The aim of the working group was to increase awareness
and advocate for transformation in this field. The group comprised representatives from
pharmaceutical organizations. We summarized the current state of biomarker-driven drug
development as a “Personalized therapy ecosystem” (PTE) and represented this pictorially
(Figure 1). The PTE was conceived based on examples of the use of RWD/evidence
(RWD/E) in the process of drug development, which we review in the sections below. Since
the PTE comprises multiple stakeholders involved in biomarker and drug development,
the goal of this review is to engage with all stakeholders to instill a common understanding.
Our working group had also conducted a survey (via a questionnaire sent to partic-
ipating member companies of the JPMA) on the biopharmaceutical industry in Japan in
2020. The survey assessed the current use of biomarkers and the application of RWD in
drug development. Full results were shared at the 42nd Annual Scientific Meeting of the
Japanese Society of Clinical Pharmacology and Therapeutics [11]. The survey revealed key
issues and challenges faced by drug makers in Japan, which are the basis of our proposals.
In this review, the lifecycle of a biomarker is broken down into three stages—discovery,
translation and qualification. In each of these stages, we briefly review current practices
that support our idea of a PTE.
By the juxtaposition of traditional/current drug development processes with latest
breakthrough concepts in the field, we propose a new “state-of-the-art” roadmap for drug
development, in the era of personalized therapies.
 J. Pers. Med. 2022, 12, 669 3 of 16
J. Pers. Med. 2022, 12, 669 3 of 16

Figure 1. Personalized therapy ecosystem (PTE). A pictorial representation of a PTE. A biomarker

“lifecycle” is broken down into 3 stages—discovery, translation and qualification. Biomarker testing
Figure 1. Personalized therapy ecosystem (PTE). A pictorial representation of a PTE. A biomarker
in the clinic is
“lifecycle” generates real-world
broken down into 3data/evidence (RWD/E)
stages—discovery, that feeds
translation and back into (supports)
qualification. all stages
Biomarker test-
of
ingbiomarker-driven drug development.
in the clinic generates Increased efficiency
real-world data/evidence (RWD/E) in that
development
feeds backleads
into to more clinically
(supports) all
validated
stages of biomarkers that can
biomarker-driven be used
drug in clinical Increased
development. practice. efficiency in development leads to more
clinically validated biomarkers that can be used in clinical practice.
3. Definitions and Scope
“Clinical biomarkers”,
In this review, as defined
the lifecycle in the BEST
of a biomarker (Biomarkers,
is broken down intoEndpointS and other
three stages—discov-
Tools) [12] resource,
ery, translation andput together byIn
qualification. theeach
FDA-National Institutes
of these stages, of Health
we briefly (NIH)
review Biomarker
current prac-
working group, is “ a defined
tices that support our idea of a PTE. characteristic that is measured as an indicator of normal
biological
By theprocesses, pathogenic
juxtaposition processes, or responses
of traditional/current to an exposure
drug development or intervention,
processes with latest
including therapeutic interventions. Molecular, histologic, radiographic,
breakthrough concepts in the field, we propose a new “state-of-the-art” roadmap or physiologic
for drug
characteristics
development, in arethe
types
era ofofpersonalized
biomarkers. therapies.
A biomarker is not an assessment of how an
individual feels, functions, or survives”. In our proposed PTE, we use this broad definition
and use the termand
3. Definitions “biomarker”
Scope to refer to all quanta of measurements—from single molecular
targets to whole genome sequence, to multiplex biomarker algorithms, to omics-signatures,
“Clinical biomarkers”, as defined in the BEST (Biomarkers, EndpointS and other
to high resolution medical images and digital biomarkers.
Tools) [12] resource, put together by the FDA-National Institutes of Health (NIH) Bi-
We refer to a wholistic biomarker assessment of an individual’s disease state as a
omarker working group, is “ a defined characteristic that is measured as an indicator of
disease blueprint, which we define as the true omni-level etiology of an individual’s disease
normal biological processes, pathogenic processes, or responses to an exposure or inter-
state. Like an architectural blueprint provides all the details required to construct a building,
vention, including therapeutic interventions. Molecular, histologic, radiographic, or phys-
a disease blueprint reveals the pathophysiology of a disease. Depending on the disease, this
iologic characteristics are types of biomarkers. A biomarker is not an assessment of how
blueprint could be derived via the integration of various types of biomarker information—
an individual feels, functions, or survives”. In our proposed PTE, we use this broad defi-
next-generation mutli-omic assay data, medical images and even ambulatory vital sign
nition and use the term “biomarker” to refer to all quanta of measurements—from single
measurements. With this blueprint at hand, targeted therapies can be accurately prescribed
molecular targets to whole genome sequence, to multiplex biomarker algorithms, to om-
to patients. In the management of chronic diseases, the blueprint may also guide treatment
ics-signatures, to high resolution medical images and digital biomarkers.
strategies, ensuring optimization.
We concept
The refer to aofwholistic biomarker
“personalized assessment
approach” or “rightof an individual’s
drug disease state
to right patient” takesas ona
disease blueprint,
several which in
nomenclatures wethe
define as the true omni-level
literature—“targeted etiology
therapy”, of an individual’s
“precision medicine” disease
and
“personalized medicine”. In this review, we utilize various nomenclatures depending ona
state. Like an architectural blueprint provides all the details required to construct
building,
the context.a disease blueprintPTE,
In our proposed reveals
the the
termpathophysiology of a disease.
“personalized therapy” refersDepending on the
to a therapeutic
disease, this blueprint could be derived via the integration
method or drug prescribed to a patient based on their disease blueprint. of various types of biomarker
information—next-generation
An “ecosystem” typically refers mutli-omic assay data, medical
to an interconnected network. images and it even
In biology, is a
ambulatory
network vital sign measurements.
of interdependent With this
living organisms. blueprint
In our proposed at PTE,
hand,alltargeted therapies
stakeholders can
in drug
be accurately prescribed to patients. In the management of chronic
development—drug makers, in vitro diagnostic (IVD) makers, biotechnology industry, diseases, the blueprint
may also guide
healthcare industrytreatment strategies,
and supporting ensuring optimization.
infrastructure, regulatory agencies, academia, patients
The concept of “personalized approach”
and advocacy groups—are participating members. or “right drug to right
All members patient” takes for
are interdependent on sev-
the
eral nomenclatures in the literature—“targeted therapy”,
unified benefit of eventually delivering personalized therapies to patients. “precision medicine” and
J. Pers. Med. 2022, 12, 669 4 of 16

The scope of our review encompasses various aspects of biomarker-driven drug

development for all relevant stakeholders to understand and consider. Since cancer is the
most mature therapeutic area practicing targeted therapies, most of our cited examples
are oncology related. However, we do not limit our recommendations and discussion
to oncology.

4. Discovery
Biomarker discovery ties in closely with new drug discovery. Identifying biologically
relevant and druggable targets for diseases is a key challenge in drug development. Evi-
dence shows that deep understanding of disease pathophysiology is an important factor of
success [13–15]. There are limitations to extrapolating efficacy, ADME (absorption, distribu-
tion, metabolism and excretion) and toxicity profiles of drugs in humans from nonclinical
studies using traditional phenotypic animal disease models and/or immortalized cell lines.
This section summarizes current RWD/E-driven approaches taken in this area. A summary
of the approaches is presented in Table 1.

Table 1. Summary of approaches taken in biomarker and drug target discovery.

Approach Specific Method Source of Data/Samples Applications in Drug Development

• Genome-wide • Large-scale omics data • Insights into
association studies initiatives (e.g., 100,000 biology/disease pathology
(GWAS) genomes project, • New target identification
Computational • Quantitative systems ToMMo, etc.) • Identify disease-associated
pharmacology (QSP) • Curated omics databases biomarkers
• Network modeling (e.g., TCGA, JGCA, • Drug repurposing
SCRUM-Japan, etc.)

• Patient-derived • Biobanks • New target screen-

xenograft models • Clinical trial banked ing/identification/optimization
Experimental • Patient-derived iPSC samples • In vitro disease modeling
models

4.1. Big Data and Computational Approaches

Large-scale, nationwide initiatives to sequence the genomes of large populations
provide a valuable data source to mine for research and target identification. Examples
include government-led initiatives such as the 100,000 Genomes Project (UK) [16] and the
million-genome Precision Medicine Initiative (US). In Japan, the Tohoku Medical Megabank
(ToMMo) Project is the largest cohort, comprising clinical, genomic and multi-omics data
from more than 150,000 participants [17].
Genomic analyses such as genome-wide association studies (GWAS) are traditionally
conducted on large cohort data to identify quantitative trait loci in specific populations,
which may shed insight into disease mechanisms. More recently, GWAS is further combined
with functional genomic strategies to shed further insight into disease pathology [18].
Disease-specific molecular profiles have been identified in publicly available databases,
and such insights are used for discovery, repurposing and development [19,20].
Quantitative systems pharmacology (QSP) is a powerful method whose use signifies
a paradigm shift from a single gene to a multi-modal approach. QSP integrates pharma-
cokinetic and pharmacodynamic data with the “system” being studied. It also provides a
quantitative framework for the integration of diverse omics data sources and translation
of molecular data to clinical outcomes. Multi-omics data are increasingly being used to
deepen our understanding of the pathophysiology of diseases and are suggested to be
novel tools for discovery of drug targets and disease-associated biomarkers [21–23].
Utilizing omics analyses and databases, biological networks can be mathematically
modeled, enabling quantitative analyses of normal biological regulation versus dysfunction
in pathophysiological states. Multi-scaled QSP-network models (i.e., mathematical models
J. Pers. Med. 2022, 12, 669 5 of 16

based on multiple temporal and spatial scales—molecules, cells, tissues, organs, organ-
isms, and patients) of networks involved in disease progression can be potentially used
to define a wholistic profile of a disease—or a disease blueprint. Well-established models
could potentially also provide the ability to predict the effects of a drug candidate on patho-
physiology [24,25], thus aiding in the optimization process. Most recently, the mapping of
the human interactome (genome-proteome interactions) has reached an extensive level of
53,000 high-quality protein-protein interactions [26]. The application of network science on
such models can transform the way biomarkers are discovered and even the way diseases
are defined [27].
Curated databases such as The Cancer Genome Atlas (TCGA) are an invaluable source
of knowledge and is becoming a key tool in biomarker discovery. It archives genomic,
transcriptomic, epigenetic and proteomic information collected from over 20,000 primary
cancers and matched normal samples for 33 cancer types [28]. On the TCGA website alone,
there are 72 listed publications during the period from 2008 through 2021. A crude search
on the PubMed Central database in January 2022 revealed 12,512 hits with “TCGA” found
in the title or abstract of the article. Further refinement of the search to look for mentions
in the “Methods” section revealed 328 hits, showing the value of TCGA data as a tool in
research. Other than being a source of RWD that can be mined for new discoveries [29–33],
it also acts as a useful reference dataset in clinical trials and biomarker/omics signature
validation studies [34–36].
In Japan, cancer precision medicine initiatives such as SCRUM-Japan [37] (solid tu-
mors) and MASTER KEY project [38] (rare cancers) are currently ongoing. These function
as screening platforms to identify cancer patients with actionable mutations who may be
eligible to participate in ongoing clinical trials. The accumulated genomic, transcriptomic,
and clinical data collected in these initiatives contribute to a growing clinico-genomic
database from which novel biomarkers have now been identified [39]. There is also an
effort to establish a Japanese Cancer Genome Atlas (JCGA) using data generated from
tumor samples collected from Japanese patients [40]. In this effort, clinical samples from
more than 5000 cancer patients were subject to DNA and RNA sequencing and gene ex-
pression profiling. Driver and actionable genomic alterations in cancer-related genes were
cross-referenced to existing databases and literature to form a curated catalogue of cancer
genome information.
Increases in the utilization and mining of such curated data may offer invaluable
insights into population-specific, disease outcome-related traits, and these should be lever-
aged where and when possible.

4.2. Experimental Approaches

Application of patient derived cells in in vitro studies and in vivo patient-derived
xenograft models is a powerful method for evaluating and optimizing drug candidates [41,42].
Human-induced pluripotent stem cells (hiPSCs) are also useful in the drug target discovery
process. hiPSCs, particularly when differentiated into three-dimensional multicellular models
such as spheroids or organoids, may be used as models to mimic in vivo pathophysiology
and pharmacological responsiveness. CRISPR/Cas9-based gene editing is more specific and
powerful than traditional knockout methods in producing loss-of-function phenotypes and
is now being employed to create isogenic disease models for drug screening [43] and target
identification [44]. By integrating the CRISPR/Cas9 screening output with other lines of data,
including real world patient data, a quantitative framework was generated for screening
drug candidates [45]. This example demonstrated the value of combining experimental and
computational data-driven approaches.
In Japan, clinical samples for research can be obtained via collaboration with academia,
from public biobanks, or by prospectively collecting stored specimens in clinical trials.
Samples in public biobanks come from hospitals and research institutions, where stake-
holders cooperate to collect and manage human tissue, cells and/or biofluid samples along
with donors’ background and health data [46,47]. However, processes for sample and
J. Pers. Med. 2022, 12, 669 6 of 16

information distribution from biobanks in Japan may sometimes be tangled and limita-
tions around personal data and privacy often apply for commercial use. On the contrary,
patient samples obtained from clinical trials can be used for research and development
(R&D) under appropriately documented informed consents. Here, although the necessary
patient information is appropriately collected and managed, sample size may sometimes
be limited.
It is therefore important for stored samples from public biobanks and/or clinical trial
sample repositories to be realistically available for discovery and translational research.

5. Translation
Translational research involves bringing scientific discoveries or basic research con-
cepts into the clinic. In this section we review the processes involved in taking a biomarker
from the R&D phase to its use in a clinical setting, including the technical assay validation
process. A well-established process is the development of a companion diagnostic (CDx).
A large part of this process is the selection and analytical validation of an appropriate assay
method to measure the biomarker of interest. Complementary diagnostics, biomarkers of
prognostic value, PGx biomarkers or biomarkers used as surrogate measures also require
robust assay methods to be available before implementation in clinical studies. The BEST
resource 2020 states that validation is important for ensuring that the test, tool or instru-
ment is adequate for its proposed use [12]. Validation of a biomarker in drug development
comprises of 2 main pillars:
(1) Analytical validation of the assay methodology to evaluate performance character-
istics such as precision, accuracy, specificity, selectivity, sensitivity, analytical range,
interference, and sample stability to broadly name a few [48,49]
(2) Clinical validation/qualification to demonstrate the relationship of a biomarker with
the clinical outcome it is posited to be associated with.
The spectrum of biomarkers used in drug development spans a wide range of defi-
nitions and intended applications (proposed use) frequently also referred to as context of
use (COU). The required rigor of analytical validation should correspond to the clinical or
regulatory risk associated with the COU of the biomarker. This ensures that the evidence
generated by the biomarker assay is sufficiently robust to support the intended application
or claim. This concept of “fit-for-purpose” is an iterative approach to biomarker validation.
For example, a biomarker assay validated for use in exploratory projects or early phase
trials may be basic or of less rigor, but as the role of the biomarker matures during drug
development, additional validation requirements may have to be reconsidered as the COU
and associated regulatory risks evolve. The intent of this fit-for-purpose concept which
was first proposed in 2005 [50], was to provide guidance and increase the efficiency of
incorporating biomarkers into drug development. This concept is now widely applied
and also described and applied in the FDA draft guidance, the “Biomarker Qualification:
Evidentiary Framework” [51].
Two industry white papers published by the Critical Path Institute extensively summa-
rize and provide recommendations for analytical validation of various types of biomarkers
based on assay method [48,49].
In a CDx development program, determining the clinically relevant threshold, some-
times known as “cut-point” or “cutoff” is a key requirement in clinical validation. This
threshold value should be clinically relevant in the appropriate patient population [52].
Ensuring good technical performance of the biomarker assay at and around the range of
the clinically relevant cut-point is crucial to accurately differentiate between the biomarker
“positive” and “negative” populations. This process and the qualification of the clinical
utility of the biomarker (reviewed in the next section) may be iterative. A well-known
case-study of cut-point establishment is in the case of PD-L1 as measured by IHC, as a CDx
for pembrolizumab [53].
In many cases, the process of analytical and clinical validation being iterative con-
tributes to the overall development process being labor- and cost-intensive. The FDA,
J. Pers. Med. 2022, 12, 669 7 of 16

recognizing that there is wealth of real-world clinical lab data that can be potentially uti-
lized as evidence to support the development of IVDs, issued two guidance’s—in August
2017, “Use of RWE to Support Regulatory Decision Making for Medical Devices” [54] and
then in April 2018, “Use of Public Human Genetic Variant Databases to Support Clinical
Validity for Genetic and Genome-based in vitro diagnostics” [55]. A report was also re-
cently published by the Medical Device Innovation Consortium on using RWE in pre- and
post-market regulatory decision making for IVDs [56].
A well-cited example of the use of RWD in supporting clinical performance valida-
tion is the MSK-IMPACT cancer panel [57]. The MSK-IMPACT cancer panel, originally a
laboratory-developed test, obtained authorization from the FDA under the 510(k) frame-
work in 2017. The source of evidence for clinical performance was from a clinical evidence
curation resource—OncoKB [58]. This example highlights synergies that can be achieved
when data are thoughtfully curated and appropriately shared—as these data become
the invaluable evidence that eventually support the broader use of the biomarker assay
in clinics.

6. Qualification
The “Qualification” of a biomarker demonstrates the clinical utility of the biomarker.
“Clinical utility” as defined by the National Cancer Institute’s (NCI) dictionary of genetic
terms is the “likelihood that a test will, by prompting an intervention, result in an im-
proved health outcome”. Depending on the purpose and COU of a biomarker, there are
various approaches to validating clinical utility of biomarkers in different settings and
disease populations.
Choice of study design is critical in demonstrating clinical relevance and utility. This
section reviews designs employed to test various biomarker hypotheses in different contexts.

6.1. Mendelian Randomization

Mendelian randomization (MR) is an instrumental variable approach widely used in
observational studies to strengthen causal inferences made retrospectively from data. It is
analogous to a randomized controlled trial, except that in MR, a germline genetic variant
that is known to be strongly associated with an exposure, is utilized as a proxy for the risk
factor of interest [59]. Mendelian randomization has been widely used in correlating disease
risk factors with biomarkers [60,61] and is used to aid in the identification of potential drug
targets or biomarkers. With the accumulation of genomic data in databases, data from
GWAS are also improving our understanding of genetic variants associated with diseases.
Using this knowledge in MR studies, causal relationships between a disease or clinical
outcome with a biomarker or risk factor of interest have been established [62,63].

6.2. Single Biomarker-Driven Clinical Trials

Pivotal clinical trials evaluating the use of a single-biomarker CDx with a therapeutic
product typically employ an “enrichment design” or a “biomarker-based strategy design”.
“Enrichment designs” enroll only biomarker-positive patients to evaluate the safety
and efficacy of the treatment in the biomarker-positive population. This design is evident
in the pivotal trial for trastuzumab in HER2-positive breast cancer patients [64]. Although
efficient if the biomarker correlates well with the disease etiology, this approach raises
the question of whether the investigational drug may also be potentially effective in the
biomarker-negative population, since data from this group of subjects are not obtained in
the study.
“Biomarker-based strategy design” randomizes subjects to either a biomarker-based
strategy arm or a control arm (non-biomarker-based strategy). The biomarker-based
strategy arm is further sub-divided into the biomarker-positive group, receiving the investi-
gational drug, while the biomarker-negative group receives standard of care. In the control
arm, subjects are assigned to the standard of care treatment. Some trial designs may also
include a sub-group within the control arm receiving an investigational drug [65]. In the
J. Pers. Med. 2022, 12, 669 8 of 16

case of developing a CDx, utilizing this design may generate robust data to support clinical
validation of the IVD, but the operational feasibility, scale and cost is high.
Still, several successful examples exist for biomarker-driven designs. Vemurafenib, a
tyrosine kinase inhibitor targeting previously untreated melanoma harboring the BRAF-
V600E-mutation, was shown to improve rates of overall survival and progression-free
survival [66]. Erlotinib and gefitinib are approved for epidermal growth factor receptor
mutation-positive bronchial carcinomas which occur in 10% of the Caucasian and 30% of
the Asian lung cancer patient population [67,68].
Having an analytically validated biomarker assay early in drug development and
successful partnership between drug and IVD makers in the case of a CDx development re-
mains a challenge that is widely discussed to date. We briefly comment on these challenges
in our discussion.
While trials selecting patients based on a single biomarker have demonstrated overall
benefit in clinical trials, there remains a sub-group of the selected patients who do not
experience clinical benefits. The need to assess biomarkers more comprehensively and
efficiently has presented drug trial sponsors with the challenge of looking for more efficient
and innovative ways of conducting clinical trials.

6.3. Master Protocols and Adaptive Trial Designs

Platform, basket and umbrella trials are typical formats for a “master protocol”. Ini-
tially designed and used in oncology trials, this design enabled the simultaneous evaluation
of multiple therapeutic drugs across multiple biomarker-defined populations in a single
clinical trial infrastructure. This approach is widely reviewed in the literature [69–72] and
will not be discussed in detail here. However, this strategy is now being employed in
therapeutic areas such as chronic pain management [73], autoimmune dysfunctions [74]
and COVID-19 [75], to name a few.
Bayesian adaptive trial design is used in evaluating personalized therapies in a range
of diseases [76–79]. This design uses an adaptive approach, which allows for real time out-
comes to influence ongoing treatment assignment probabilities, contributing to enhanced
flexibility and efficiency. By defining early stopping rules, ineffective treatments are also
terminated at an earlier point in time, such that more patients can be subsequently treated
with effective treatments. In adaptive trials, biomarkers are built into the protocol, to be
used in guiding patient treatments.

6.4. Evaluating Biomarkers in Personalized Therapies

Even after a CDx is approved and launched, delivering the treatment to patients in
the real-world clinic still presents as a hurdle [80]. There is a growing need to evaluate and
demonstrate the clinical utility of using biomarkers to guide treatment regimes in the clinic.
Many “precision medicine trials” in oncology have already been conducted or are
ongoing [81]. These trials molecularly profile patients’ tumor using methods such as NGS,
polymerase chain reaction, mass spectrometry and immunohistochemistry to evaluate
genomic, transcriptomic, or proteomic makeup. Based on actionable molecular alterations
or features, a molecular tumor board, or “expert panel” recommends a treatment regi-
men, or personalized therapy for patients. A prospective study conducted at two cancer
centers in the US—I-PREDICT—evaluated such a protocol on patients with refractory
malignancies [82]. A “matching score”, that evaluates the number of clinically actionable
genetic alterations with a matched therapy available for a patient is commonly used in such
trials to correlate with improvements in the disease control rate and survival parameters.
The I-PREDICT study described that in heterogenous cancers harboring multiple genetic
aberrations that have “matched therapies”, the administration of a combination of the
matched therapies resulted in better patient outcomes.
In Japan, the National Cancer Center had also initiated a personalized medicine
trial [83]. The primary objective of this prospective study was to evaluate the clinical utility
of performing a CGP panel at the time of initial diagnosis of patients with solid tumors,
J. Pers. Med. 2022, 12, 669 9 of 16

as compared to the current standard of performing a CGP test only after completion of
current standard of care.
A traditional single pharmaceutical-sponsored drug trial is relevant in establishing the
safety and efficacy of new targeted therapies. However, demonstrating that the biomarker-
based personalized approach confers more clinical benefit to patients over the standard of
care, although a key bridging step, is still a budding field in many regions.
Even while the science may support the motive to shift toward a personalized ap-
proach, from the patient and government perspectives, assessing the value and cost ef-
fectiveness of the approach is yet another complex issue. An overall study of the cost
effectiveness of precision medicine concluded that precision medicine interventions were
more effective than existing standard of care, but this study also highlighted the lack of
clinical data to support conclusions [84]. A specific study by Safonov et al. [85] developed
and used an analysis tool to evaluate cost-utility of predictive biomarkers in oncology. They
concluded that the value of a biomarker is driven primarily by clinical efficacy of the treat-
ment and treatment cost. Cost-effectiveness studies in specific disease settings may provide
the needed insight into the value of personalized therapies [86–89]. Cost effectiveness and
value of personalized approaches involving more complex and innovative biotechnologies
are also still yet to be studied in-depth. As newer approaches are available and clinical
utility validated, the ability to evaluate personalized approaches with respect to standard
of care will be important in translating the method from a hypothetical to a practical one.
Evolving complex trial designs mean the involvement of and collaboration between
multiple different stakeholders. On top of just genomic data, multiple modes of biomarker
information should ideally be comprehensively interpreted to diagnose a patient based
on their disease blueprint. Patient information may not only exist from clinical trials but
also possibly from health care databases. In recent years, wearable devices have also
made it possible to collect sequential, ambulatory data. For personalized approaches to be
efficiently delivered to patients, the industry will have to transform the way that clinical
efficacy is validated against a background of multimodal biomarker data.

7. Proposals
The benefits and challenges of biomarker-driven or personalized approaches are
apparent. In this review, we emphasized the importance of our proposed PTE framework.
In Japan, however, there are still gaps to be filled. In the survey that our working group
had conducted in 2020, one of the top challenges identified (via analysis of free text
comments) was the uncertainty of the actual uptake of biomarker testing in the clinic (i.e.,
reforming the standard of care). We inferred that this top challenge may be intertwined
with other challenges identified, such as high R&D costs involved in biomarker validation
and development [11]. Based on the reviewed content and insights obtained from the
survey, we make the following proposals.

7.1. RWD Usage

Since 2017, the Pharmaceuticals and Medical Devices Agency (PMDA) has issued
several guidance and points-to-consider documents relating to the use of real world data
and evidence in a regulatory setting [90], however no specific information or use-cases
were available on biomarker translation or qualification. Based on our survey, there are
two major areas in which improvement is needed in RWD usage:
(1) Access and (2) mining and utilization.
Access—As databases such as disease registries are established in Japan [17,91,92],
more biomarker, multi-omics data as well as electronic health data will accumulate. The
content of these databases should be poised to be shared openly and efficiently, such that
the curated data can be leveraged to its maximum.
Mining and Utilization—Data-driven and computational approaches provide deep
insight into disease pathophysiology and this insight is a factor of success in drug develop-
ment. Despite this, the usage of RWE in clinical development is still in its immature phases
J. Pers. Med. 2022, 12, 669 10 of 16

in Japan. AI and machine learning is being applied to biomedical data for integration and
modeling [93]. However, such capabilities may not typically be available within traditional
pharmaceutical organizations. The establishment of platforms for the effective mining
of biomedical big data will require significant scientific and technical expertise in new
fields. We emphasize that there are organizations taking the lead in this direction and have
reported positive results [14,15].
Latest computational approaches and algorithms as well as results should be shared
as openly as possible. Integration of healthcare data with quality control and analysis
processes could be also achieved by government-led efforts for increased standardization
and uniformity.

7.2. Regulations and Infrastructure

As the types and scope of biomarker use cases increase, there is a constant need for new
guidance and policy to guide the industry in the development process. For example, points
to consider when establishing and validating quantitative or semi-quantitative biomarker
cut points is a topic still requiring expert consensus. National regulatory bodies should
consider regularly updating policies and guidance coordinated with the latest biomarker
use cases, and in harmonization with efforts from other global agencies. There are currently
some gaps for instance, in the requirements of the CDx submission and approval pathways
among the health authorities in the US, Europe and Japan [94].
As pointed out earlier, studies that demonstrate value in biomarker-focused or per-
sonalized approaches over current standard of care, are lacking. In such cases, it is espe-
cially important for stakeholders including key opinion leaders, government agency, and
regulatory bodies to be aligned on the current unmet medical needs and agree on how
biomarker-driven approaches can (or cannot) help address these needs. A framework for
defining and evaluating “clinical benefit”, should be established, perhaps for each disease
setting. This will instill more clarity and assurance on the direction that the industry should
J. Pers. Med. 2022, 12, 669 11 of 16
take in R&D efforts.

7.3. Evolution of the “Clinical Trial”

7.3. Evolution of the “Clinical Trial”
Prospective
Prospective platform
platform and innovative
and innovative trialdescribed
trial designs designs in described in the Qualification
the Qualification sec- section
above will be crucial in evaluating the utility of a true disease blueprint-based
tion above will be crucial in evaluating the utility of a true disease blueprint-based diagnosis diagnosis in
the clinic.
in the clinic. In thisclimate,
In this climate, asmove
as we we move
away fromaway from the “one-drug-fits-all”
the “one-drug-fits-all” and turn to the and turn to the
“personalized approach”,
“personalized approach”, the “global clinical trial”
the “global becomes
clinical lacking
trial” and counterintuitive.
becomes lacking and counterintuitive.
While pharma-sponsored global clinical trials remain important in bringing new thera-
While pharma-sponsored global clinical trials remain important in bringing new therapeutic
peutic agents to market, new-age personalized medicine trial designs should aim to fulfil
agents
the localtoregulatory,
market, new-age personalized
infrastructural, and medicalmedicine
needs. Thetrial designs
industry should
therefore needsaimto to fulfil the local
regulatory, infrastructural,
re-evaluate collaboration and medical
frameworks, needs. Theinindustry
each stakeholder therefore and
drug development needs to re-evaluate
healthcare having
collaboration to pivot in terms
frameworks, of strategy
each to meetinthis
stakeholder need.
drug We summarizeand
development this con-
healthcare having to
cept in Figure 2.
pivot in terms of strategy to meet this need. We summarize this concept in Figure 2.

Figure 2.2.Roadmap
Figure Roadmapfor biomarker-driven drug development
for biomarker-driven for personalized
drug development fortherapies.
personalized therapies.
8. Discussion and Conclusions
As described thus far, reliable clinical biomarkers are at the core of personalized ther-
apy. There is accumulating scientific evidence now especially in oncology that using clin-
ically validated biomarkers to select patients for targeted therapies in precision medicine
trials result in better outcomes. Our working group also performed an in-depth review on
the medical needs for personalized approaches in non-oncology diseases [95].
While there is inertia to making significant investments in new technology and capa-
J. Pers. Med. 2022, 12, 669 11 of 16

8. Discussion and Conclusions

As described thus far, reliable clinical biomarkers are at the core of personalized
therapy. There is accumulating scientific evidence now especially in oncology that using
clinically validated biomarkers to select patients for targeted therapies in precision medicine
trials result in better outcomes. Our working group also performed an in-depth review on
the medical needs for personalized approaches in non-oncology diseases [95].
While there is inertia to making significant investments in new technology and capa-
bilities, there is evidence that high R&D investments reap high R&D output [96]. Simulta-
neously, to ensure that industry R&D investments can have the potential to be effectively
translated into improved healthcare practices, all stakeholders need to collaborate in new
and innovative ways to embrace change.
In three independent reviews by three pharmaceutical organizations, the authors
reported that leveraging some form of genomic data or experimental data-driven approach
in identifying the appropriate drug targets are an important part of organizational drug
development strategies [13–15]. An industry-wide review conducted by Shih et al. [97] also
corroborated the conclusion that therapies targeting well-validated biological mechanisms
were a common feature of successful projects. Additionally, in two of the reviews, the use
of validated biomarkers as intermediary outcome readouts was also part of the success
strategy. Projects with a patient selection strategy had a higher chance of success than those
without one [14]. Another common feature of the reported strategies is the “shift” that
organizations are making to focus on understanding disease heterogeneity to select higher
quality drug targets and refine patient selection strategies.
Although anecdotal, these examples support our concept of the importance of data-
driven approaches in refining biomarker-driven drug development.
Within the restraints of current industry practices and frameworks, it may be that
drug makers cannot “see the light at the end of the tunnel” and this is creating barriers to
investment decisions, especially in smaller organizations that have limited resources.
In 2010, a Biomarker Task Force comprising multi-disciplinary representatives from
the NCI and FDA, published a recommendation paper for incorporating biomarkers in
early phase clinical trials with the goal of identifying exciting and novel agents [98]. The
recommendations to sponsors revolved around the need for incorporating well thought-out
and prioritized biomarker plans in clinical development programs. Institutional investi-
gators were seen as a valuable collaborative resource for biomarker testing capabilities.
Eleven years on, the drug development industry has effectively brought the biomarker
into the clinic to provide personalized medicines to patients. Drug development programs
now also typically have an accompanying biomarker strategy. Biomarkers being validated
and tested in central reference laboratories are now a part-and-parcel of drug develop-
ment programs. Banking of clinical samples collected during clinical trials are a routine
procedure, and collaborations between sponsor and academia for exploratory biomarker
research are a norm.
The recommendation from 2010 to prioritize biomarkers based on “solid science and
the needs of patients” resounds with the central concept of our paper. In today’s context
we have more robust methods to achieve this by tapping on to the mass of biomedical big
data that is accumulating.
The personalized therapy approach is expected to increase the quality of diagnoses
and reduce or prevent the prescription of ineffective treatments. This could ultimately
translate to reductions in mortality rates, hospitalization periods and overall societal
burden. The use of RWD to make decisions in an evidence-based manner will also help
channel valuable resources into scientifically sound research causes. We encourage that all
involved in healthcare and drug development be conscious of the PTE—a framework that
links patients, clinicians, industry, academia, and government—and collaborate to bring
healthcare to the next level.
J. Pers. Med. 2022, 12, 669 12 of 16

Author Contributions: Conceptualization, K.I., T.T., A.K., T.U., Y.I. and N.M.; writing—original
draft preparation, V.S.-L., K.I., T.T., A.K. and T.U.; writing—review and editing, V.S.-L.; visualization,
V.S.-L.; supervision, N.M. and Y.I.; project administration, N.M.; funding acquisition, N.M. All authors
have read and agreed to the published version of the manuscript.
Funding: This work was funded by Japan Pharmaceuticals Manufacturers Association.
Conflicts of Interest: All authors are employees of their organizations listed in the author affiliations
section. This work is an effort of the authors’ participation as members on the Japan Pharmaceutical
Manufacturers’ Association clinical biomarkers taskforce.

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