Japanese Journal of Statistics and Data Science

https://doi.org/10.1007/s42081-022-00156-0

ORIGINAL PAPER
Data Science: Present and Future

Real world data and data science in medical research:

present and future

Kanae Togo1 · Naohiro Yonemoto1

Received: 13 December 2021 / Revised: 18 February 2022 / Accepted: 20 March 2022

© The Author(s) 2022

Abstract
Real world data (RWD) are generating greater interest in recent times despite being
not new. There are various purposes of the RWD analytics in medical research as
follows: effectiveness and safety of medical treatment, epidemiology such as inci-
dence and prevalence of disease, burden of disease, quality of life and activity of
daily living, medical costs, etc. The RWD research in medicine is a mixture of digi-
tal transformation, statistics or data science, public health, and regulatory science.
Most of the articles describing the RWD or real-world evidence (RWE) in medi-
cal research cover only a portion of these specializations, which might lead to an
incomplete understanding of the RWD. This article summarizes the overview and
challenges of the RWD analysis in medical fields from methodological perspectives.
As the first step for the RWD analysis, data source of the RWD should be compre-
hended. The progress of the RWD is closely related to the digitization, especially of
medical administrative data and medical records. Second, the selection of appropri-
ate statistical and epidemiological methods is highly critical for an RWD analysis
than those for randomized clinical trials. This is because it contains greater varie-
ties of bias, which should be controlled by balancing the underlying risk between
treatment groups. Last, the future of the RWD is discussed in terms of overcoming
limited data by proxy confounders, using unstructured text data, linking of multiple
databases, using the RWD or RWE for a regulatory purpose, and evaluating values
and new aspects in medical research brought by the RWD.

Keywords Real world data · Medical database · Observational study · Causal

inference · Bias

* Kanae Togo
[email protected]
1
Health and Value, Pfizer Japan Inc., Tokyo, Japan

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 Japanese Journal of Statistics and Data Science

1 Introduction

In the field of medical research, randomized clinical trials (RCTs) are the golden stand-
ard to estimate the causal inference between treatment interventions and outcomes.
Real world data (RWD) are the data relating to patient health status and/or the delivery
of the healthcare, routinely collected from a variety of sources regardless of the size of
data (Hiramatsu et al., 2021; US Food & Drug Administration, 2018). Data from obser-
vational studies are also considered as RWD. The RWD are mutually complementary
to limitations of RCTs, such as a small sample size of trials, participants with limited
age groups including a smaller number of people, or no older people and minors, par-
ticipants with limited complications, short follow-up duration, etc.
The RWD are generating greater interest in recent times although the RWD has been
used since more than decades ago. Progress of the RWD is closely related to digiti-
zation, especially of medical administrative data and medical records. The UK estab-
lished the first European electronic health records (EHR) database of Clinical Practice
Research Datalink (CPRD) in 1987. In the US, the HITECH Act was enacted in 2009,
providing funds toward encouraging medical practices to better adopt and make mean-
ingful use of the EHR (Menachemi & Collum, 2011). In Japan, electronic claim of
public health insurance was legalized in 1976, finally becoming an obligation in 2011.
At present, the National Database of Health Insurance Claims and Specific Health
Checkups of Japan (NDB) cover 99% of claims in Japan.
Various purposes of analysis using the RWD (hereafter, RWD analysis) in medical
research include effectiveness and safety of medical treatment, epidemiology such as
incidence and prevalence of disease, burden of disease, quality of life and activity of
daily living, and medical costs. As an example of comparative effectiveness, long-term
survival advantage among patients who underwent coronary-artery bypass grafting
(CABG) was shown compared with percutaneous coronary intervention (PCI), using
a large study population of 189,793 patients in total, from claims and patient regis-
try databases (Weintraub et al., 2012). These days, the RWD and real-world evidence
(RWE) are used for regulatory submission (Feinberg et al., 2020), as well as for other
activities during clinical development and post-launch of drugs in the pharmaceutical
industry (Fig. 1) (Togo et al., 2019).
The RWD in medicine is a mixture of digital transformation, statistics, data science,
public health, reimbursement, pricing of products and regulatory science. Unfortu-
nately, most of the articles describing the RWD in medical research cover only a por-
tion of these specializations and that might lead to RWD’s incomplete understanding.
Further, describing various sources of the RWD and relating analytic issues as biases
(systematic errors) remain insufficient as well. Therefore, this article summarizes the
overview of data source of the RWD and challenges of the RWD analysis in medical
fields from methodological perspectives.

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Fig. 1  Use of real-world data during clinical development and post-launch in pharmaceutical industry

2 Source of RWD

There are two approaches to collecting RWD: primary and secondary data collection
(Schneeweiss & Patorno, 2021). Primary data are collected directly from study par-
ticipants for the purposes of the study, and may be collected either retrospectively
(via patient charts or other data sources), or prospectively (Mueller et al., 2018).
Secondary data are obtained from existing health care data collection infrastruc-
tures, such as administrative claims databases, EHR databases, existing patient reg-
istries or study cohorts, or individual patient medical records.
Major data sources of secondary data are presented in Table 1 (Nabhan et al.,
2019). Each database of secondary data has strengths and limitations. The over-
view of medical databases in Japan is annually surveyed by the Japanese Society
for Pharmacoepidemiology and provided on the website (Pharmacoepidemiology &
Database Taskforce, Japanese Society for Pharmacoepidemiology, 2021). The larg-
est medical database in Japan is the National Database of Health Insurance Claims
and Specific Health Checkups of Japan (NDB), which covers approximately 99% of
health insurance claims in Japan. Although its use was limited to certain organiza-
tions for public welfare and academic institutions, NDB has been open to private
companies for research of public health since October 2020 (Kaneyama et al., 2017;
Kohsaka et al., 2021).
When selecting an appropriate data source for a research, protection of data pri-
vacy is one of the key elements, as well as strengths and limitations of each data
source. The RWD includes medical data with sensitive personal information. There-
fore, data privacy has to be protected for any types of data source in compliance
with national data protection laws such as the US Health Insurance Portability and
Accountability Act (HIPAA), the EU General Data Protection Regulation (GDPR),
and the Japan Act on the Protection of Personal Information (Personal Information
Protection Commission, Government of Japan, 2020; Office of Civil Rights, Depart-
ment of Health and Human Services, 2002; The European Parliament & the Council
of the European Union EUR-Lex, 2019; Wirth et al., 2021). In Japan, medical data

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Table 1  Major data sources of secondary data (Nabhan et al., 2019)

Data source Description

Administrative claims database A health insurance claim is a request made for direct payment or
reimbursement for medical services from hospitals, clinics, phar-
macy. Claims data are systematic and well-structured. Large claims
databases are available in many countries. However, claims are
recorded to maximize the reimbursement and the data sometimes
might be unrepresented as the disease name of clinical practice
EHR database (Evans, 2016) An EHR is an individual patient health record. A typical EHR may
include a patient’s medical history, diagnoses, treatment plans,
immunization dates, allergies, radiology images, pharmacy records,
and laboratory and test results. Although EHR databases are more
likely to capture important health information about patients than
administrative data, most of that information is unstructured
Patient registry A patient registry is defined as an organized system that collects
data and information on a group of people defined by a particular
disease or condition, and that serves a pre-determined scientific,
clinical and/or public health (policy) purpose (European Medical
Agency, 2020). In addition to its use as secondary data, a registry-
based study is another way of leveraging registry system. Registry
often includes clinical outcomes, but missing data is common
Wearable, censor Sensors and/or software apps on smartphones and tablets that can
collect health‐related data remotely i.e., outside of the healthcare
provider’s office (Izmailova et al., 2018). These provide monitoring
treatment response, including the monitoring of efficacy and safety
of treatment, and monitoring of patient‐reported outcomes and/or
quality of life measures

is regarded as sensitive information and consent from patients (opt-in consent) is

required to use such data for secondary purposes unless it is anonymized according
to the act. However, for academic research, medical information regarding public
health can be used with opt-out consent to provide patients an opportunity to refuse
inclusion in the research (Ministry of Education, Culture, Sports, Science and Tech-
nology et al., 2021). Although database linkage enables large data creation, a wide
range of personal information makes data linkage difficult, or at times, even impos-
sible, because of data privacy.

3 Statistical and epidemiological methods for the RWD analysis

Although the RWD can be leveraged for various research questions, the selection of
appropriate statistical and epidemiological methods is highly critical than those for
RCTs. In traditional clinical trials, randomization has long been an essential tool for
minimizing bias by balancing underlying risk between treatment groups (Sherman
et al., 2016). Among dozens of biases that have been defined, the major biases are
the selection bias and the information bias (Table 2) (Rothman et al., 2008). A bias
needs to be prevented by adequate designing of the study, since bias once identified,

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 Table 2  Biases in the RWD analysis
Description Example of limitation due to secondary data

Selection bias Bias that results from procedures used to select participants and from factors that influence Insurance claims data, based on worker’s
study participation association, consists of relatively young
Japanese Journal of Statistics and Data Science

and healthier people. The population of

EHR depends on the types of hospitals
(Rothman et al., 2008)
Information bias (Measure- Systematic error such as self-reporting or recall bias, measurement error bias, confirmation Diagnosis for reimbursement, validity of
ment error, misclassifica- bias (investigator belief) (Althubaiti, 2016; Rothman et al., 2008). Immortal time bias is defined outcome, misclassification of drug
tion) also a kind of information bias where immortal time is a span of time in the observation or exposure especially time-varying exposure
follow-up period during which the study outcome could not have occurred (Suissa, 2008) due to limited data
Confounding Confounding is related independently to both, the exposure and the outcome. It may create Limited data of potential confounders
an apparent association or mask a real one (Strom et al., 2019). Confounding by indication
can occur when participants, who undergo treatment, are more likely to have an underlying
condition

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cannot be reverted. Confounding is another challenge in the RWD analysis. It can be

controlled either in the study design or in its analysis.
Basic principles to prevent a bias and confounding in design are random alloca-
tion (generally not applicable in RWD), subject selection or localization, stratifica-
tion, and matching. Common epidemiological study designs using these principles
are cohort studies of new-user design, nested case–control studies, and self-control
studies (Table 3) (Strom et al., 2019). Furthermore, study designs for regulatory
decision making in combination with clinical trials emerge (Table 3) (Baumfeld
et al., 2020), whereas the purpose of those designs is to support the evidence from
clinical trials rather than to prevent bias. The epidemiological study designs are
adaptive to the studies for regulatory decision making as well.
Statistical methods should be carefully selected in the RWD analysis for causal
inference and estimation of treatment effect, as well as the study design. We sum-
marize some statistical methods.

3.1 Stratification, matching, and weighting using propensity score

Propensity score is the probability of treatment assignment (Z = 1 for treated, Z = 0

for control) conditional on measured baseline
( covariates
) (X) and the propensity
score for subject i (i = 1, …, n) is ei = Pr Zi = 1||Xi (Rosenbaum & Rubin, 1983).
The propensity score is often applied to stratification and matching to balance large
numbers of covariates. However, the balancing between treatment groups using pro-
pensity score requires the assumption of no unobserved confounders which is rarely
true in research using the RWD. Other difficulty is the distribution of propensity
scores. It often does not overlap adequately between treatment groups when the
treatment choice is strongly related with patient backgrounds.
Inverse probability weighting (IPW) using propensity score, or inverse prob-
ability of treatment weighting (IPTW) is an alternative method to estimate treat-
ment effect with covariate (adjustment.
) ( The)inverse probability of treatment weight
is defined as wi = Zi ∕ei + 1 − Zi ∕ 1 − ei . The weight can be highly large when
a subject has very low propensity score. A number of alternatives
( ) are
( proposed
) to
stabilize weights such as wi = Pr(Z = 1)Zi ∕ei + Pr(Z = 0) 1 − Zi ∕ 1 − ei , where
Pr(Z = 1) and Pr(Z = 0) are the marginal probability of treatment and control in the
overall sample (Austin & Stuart, 2015).
A large number of RWD studies with application of propensity have been pub-
lished, but only a few reviews suggested the pitfall and the guidance (Austin, 2007;
Yao et al., 2017; Zakrison et al., 2018).

3.2 Structural models and doubly robustness

The difficulty of a RWD analysis, in addition to that caused by non-randomization,

is bias due to time-varying exposures and confounders. These effects post-treatment
initiation are not considered in Intent-to-Treat approach, which is generally employed
in RCTs. Marginal structural models produce consistent estimates of the average
causal treatment effects even in the presence of treatment changes, time-dependent

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 Table 3  Study designs using the RWD (Baumfeld et al., 2020; Strom et al., 2019)
Description Limitation

Epidemiological study design

Cohort studies of new-user design Identifying patients who start a new drug and begin follow-up Secondary data requires the assumption that the first use of the
after initiation. Those patients have been evaluated by physi- drug after a certain period of no drug use is regarded as a new
cians who concluded that the patients might benefit from a use
newly prescribed drug. This makes treatment groups highly
similar in characteristics that might not have been observed
in the database
Japanese Journal of Statistics and Data Science

Nested case–control studies Selecting all cases in the cohort, then randomly selecting one Whenever the disease to be investigated is changed, controls
or more controls from risk-set for each case. The antecedent need to be re-selected, as well as the cases. Whereas, the
exposure is compared between cades and controls case–control study can easily consider many exposures
Self-control studies This is a design where comparisons between exposures are This design can only deal with an acute adverse event, a short
made within subjects, thus significantly attenuating the wash-out period of exposure and requires precise data of
problem of confounding exposure
Study designs for regulatory decision making in combination with clinical trials
External control arm for clinical trials Participants are selected from a cohort of RWD to be balanced Differences in unmeasured confounders between the arms of
with subject of a clinical trial in backgrounds for comparing clinical trial and the external control remain even after adjust-
key efficacy or safety outcomes ing all measured confounders
Pragmatic studies A randomized clinical trial incorporating pragmatic design This is the most feasible in health care systems with reliable and
elements. The intervention should be delivered as in clinical accessible electronic health records that capture the events of
practice (Ford & Norrie, 2016) interest, which is at present are challenging in many countries
Long‐term follow‐up studies Post‐marketing requirement studies of safety and effectiveness Regulators or companies may prefer RCTs due to feasibility
outcomes of interest require longer follow‐up durations (e.g., level of measurement and/or monitoring)

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confounders, and missing at random study dropout as application of inverse-proba-

bility weighting (Faries et al., 2014). Structural nested mean model is also applied
to time-varying exposures and confounders, and are fitted using g-estimation. This
model is better tailored for dealing with failure of the standard assumptions of no
unmeasured confounders (Vansteelandt & Sjolander, 2016). Several applications of
time-depending confounders have been reported in a wide range of diseases (Clare
et al., 2019; Yang et al., 2014). Of these, one example is the comparative effective-
ness study of angiotensin receptor blockers (ARBs), in patients with chronic heart
failure (CHF), using a national cohort of beneficiaries of the US Department of Vet-
erans Affairs medical care system (Desai et al., 2012). A marginal structural model
in reducing mortality in CHF included the time-dependent confounder of hospitali-
zation, which lies on the causal pathway from treatment to death. ARB treatment
history and hospitalization were defined on monthly basis.
The idea of doubly robustness is to combine outcome and exposure modelling
in a fashion that provides a valid estimate if either model is correct. For example,
matching using propensity scores in a model for exposure, and then regressing
outcomes on exposure and covariates in the matched sample. Robins et al. (1994)
developed an improved augmented inverse probability weighting (AIPW) using the
process of double robustness property involving 2 basic steps: first, fitting a propen-
sity score model, and then fitting
( models
) that estimate the outcome Yi under treat-
ment and control conditions, f Z ||Xi (Kurz, 2021; Qi & Sun, 2014; Robins et al.,
1994). The average treatment effect of AIPW can be estimated by
[ ] [( ) ]
1 ∑ Zi Yi Zi − ei ( | ) 1 ∑ 1 − Zi Yi Zi − ei ( | )
− f 1|Xi − − f 0|Xi .
n i ei ei n i 1 − ei ei

3.3 Instrumental variable

Instrumental variable is the approach without assuming potential unobserved con-

founders. Instrumental variables naturally create quasi-random treatment choice and
is related to the interested treatment. The instrumental variable estimator is simple:
(E[Y|T = 1 ] − E[Y|T = 0 ])∕(E[Z|T = 1 ] − E[Z|T = 0 ]), where T is the instrumen-
tal variable (Strom et al., 2019). An example of instrumental variable is site-level
preference for the use of embolic protection devices (EPD) for assessing causality of
EPD use during transcatheter aortic valve replacement (TAVR) on in-hospital stroke
(Butala et al., 2021). However, the difficulty in finding a valid instrumental variable
is the reason for its relatively limited use (Faries et al., 2014).

3.4 Machine learning, AI

At times, the RWD is a large and high-dimensional data. Machine learning methods
are used for identifying groups with disease prognostic or treatment response from
a large data (Bakouny & Patt, 2021; Bica et al., 2021) In addition, machine learn-
ing and deep learning are leveraged for propensity score estimation. Application of

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AI to the RWD is an intensive research field to use complex RWD including texts,
images, voice data, etc. Disease diagnosis from image data and outcomes, such as
treatment response and adverse effects, extracted from physician notes are popular
and practical themes using AI.

3.5 Sensitivity analysis

Although it may be strange to deal with sensitivity analysis along with the meth-
ods mentioned above, it is worth referring to sensitivity analysis to understand the
robustness of a study’s findings in a RWD analysis. Sensitivity analysis for quantify-
ing a bias is sometimes called bias analysis. For unobserved confounders, external
adjustment is to adjust relative risk using external evidence. For misclassification of
disease or exposure, statistics can be adjusted using sensitivity and specificity esti-
mated in a validation study or external literatures. For assessing the effect of a bias
in the study design, definitions of baseline period, outcomes, and exposure can be
varied in the sensitivity analysis (Rothman et al., 2008). Causal effects estimated in
observational studies are not binary signals, with or without statistical significance,
but are numerical quantities. To quantify the effect as unbiasedly and precisely as
possible, multiple studies using the different RWD sources, and meta-analysis of
them could provide a highly reliable estimate (Hernán, 2021). The practical imple-
mentation, and quite a few assumptions of the sensitivity and bias analysis are con-
tinuously discussed.

4 Discussion

There are several approaches to overcome the limited data of a RWD database.
Although administrative database has limited information, high dimensional propen-
sity score approach can be exploited by applying proxy confounders of variables
created from a large quantity of structured data, such as disease and prescription
records (Bosco-Lévy et al., 2021). For the EHR, unstructured text data including
physician’s progression notes and repots of test results is drawing attention. Clinical
outcomes are derived from unstructured medical records using retrospective review
and automated analysis, using natural language processing and AI. This is critical
for the progress of comparative effectiveness research using the RWD. Linking mul-
tiple databases enables patient follow-up for a long period of time, or covers a wide
range of personal information. The data privacy regulation in each country makes
data linking difficult or at times, even impossible. As a countermeasure for medical
research, in Japan, “Act on Anonymized Medical Data That Are Meant to Contrib-
ute to Research and Development in the Medical Field” (Next Generation Medical
Infrastructure Law) was enforced in 2018 that allows certified enterprises to deal
with identifiable medical information from multiple facilities.
In drug development, pharmaceutical companies and regulatory authorities con-
sider utilizing an external control arm for a non-randomized clinical trial of a sin-
gle arm when randomization may not be feasible or ethical (Nishioka et al., 2021;

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US Food & Drug Administration, 2018) Bias is greater problematic in compari-

son between treatment arms from clinical trial and the RWD, than the comparison
between treatment arms within a database of the RWD. However, there is a strong
need of the external control arm in rare disease area, and regulatory guidance has
been issued in several countries. In Japan, the Ministry of Health, Labour, and Wel-
fare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) have
been working to promote the RWD use for regulatory decision making. They have
issued several guidelines, including the RWD use for post-marketing surveillance
and registry data use for drug applications (Nishioka et al., 2021; Ishii et al., 2021).
The RWD provides new aspects on medical research. Research using the RWD
provides results with an increased speed. It is based on larger data than research
using primary data collection, with a relatively low cost, once the platform is estab-
lished. Demands of rapid RWE in post-marketing safety surveillance are increasing
considerably after the COVID-19 pandemic (Naidoo et al., 2021). For example, a
study to explore the frequency and severity of myocarditis after COVID-19 vaccina-
tion used the data until May 24, 2021 from the database of Clalit Health Services in
Israel, and the results were published in the New England Journal of Medicine just
after about 4.5 months from the data period (Barda et al., 2021). Another aspect is
new technologies as means of collecting the RWD novel outcomes created by digital
devices, such as mobility and sleep by wristwatch type wearable and ECG by skin
patch, yielding new values of drug effectiveness. These data from new technologies
provide opportunities to apply new methodologies of data science dealing with large
data of intensive longitudinal time periods (Izmailova et al., 2018).
There still exists large potential for improvement in the ways of demonstrating the
reliability or degree of bias, and the uncertainty about the evidence obtained from
the new types of RWD. We would rather quantify them for considering the effect on
decision making, than emulating the inference of RCTs. Moreover, the RWD reflect
“real world” of local regions, and it is important to understand the local healthcare
system and clinical practices to evaluate values for reimbursement and pricing.
Therefore, Statistics and data science have opportunities for contributing toward pre-
senting new methodologies for the RWD.

5 Conclusion

The RWD is not new, but rapidly evolving in terms of data source, digital devices for
data collection, application fields, and regulations. Statistics and data science should
be updated corresponding to these rapid changes for various sources and settings in
the RWD. We emphasize on improving methodologies for explaining relevance of
the obtained evidence including biases and uncertainty.

Author contribution All named authors meet the International Committee of Medical Journal Editors
(ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole,
and have given their approval for this version to be published.

Funding No funding was received to assist with the preparation of this manuscript.

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Data availability statement No data was generated and analyzed.

Declarations

Conflict of interest KT and NY are employees of Pfizer Japan and shareholders of Pfizer.

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