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A regulatory perspective on real-world evidence for biopharmaceuticals​

Executive Summary
A crucial point in time to look at the exciting possibilities with Real World Data (RWD) and Real World Evidence (RWE) from a regulatory vantage point. The growing emphasis on RWE by regulatory agencies has fueled a new optimism and provided an impetus for a new regulatory framework. Limitations crop up as “traditional“ randomized clinical trials may not be feasible, unethical, or extremely challenging to conduct in certain situations. In those cases, possibilities with RWD as a source for external controls emerge. While providing the detailed stance of various Health authorities for RWE across the globe, this paper discusses the unique challenges of RWE from a regulatory perspective and the future of RWE application against the backdrop of emerging comprehensive initiatives.


Limitations imply possibilities! This quote can explain the rising traction for Real World Data (RWD) in healthcare. It is an critical time to consider use of RWD and Real World Evidence (RWE) given the increased guidance from across global regulatory authorities. But what is RWD? In 2016 the United States Food and Drug Administration (USFDA) passed the 21st Century Cures Act. The Cures Act states that “Real-world data are data related to a patient's health status and/or the delivery of health care routinely collected from a variety of sources”. RWD can provide important information about patient experience and treatment requirements. The Cures Act additionally provides guidance on the use of real-world evidence, which states it is “the clinical evidence regarding the usage and potential benefits/risks of a medical product derived from the analysis of RWD.”
There are a spectrum of RWD sources available at our disposal:
Clinical and medical record data from electronic health records (EHRs), prescriptions, pharmacy, lab, and imaging studies
Payer and regulatory data from claims and government datasets
Data from disease, device, patient, and specialty clinical registries
Patient-sourced data from patient surveys, feedback forms, biometric wearables, and population health measures
But to use the data as evidence, it must be analyzed to address a specific research question to ensure the generated results are robust and reliable. It is therefore being explored extensively across the pharmaceutical and clinical arenas, adding value at every stage of the pharmaceutical life cycle.

Some examples in the usage of RWD / RWE include:


Disease etiology and onset evaluation
Insights on therapeutic strategy
Clinical trial design considerations


Forecast on treatment effect
Comparator arms in clinical trials or as a control
Assist in endpoint identification for clinical trials
Post-marketing safety surveillance activities
Patient population insights
To understand the increasing attention toward RWD/RWE, one needs to look at the overall development in the application approach and how regulatory decisions can be supported.

Evolution of RWD/RWE application

Initially, Health Authorities began the use of Real-World Data post-authorization to supplement insights on already approved products. In recent years, Real-world data (RWD) and Real-world evidence (RWE) have played an increasingly important role in regulatory decision-making pre-approval. Early examples include the accelerated approvals of Genzyme's alglucosidase alfa formulations for Pompe disease by the FDA in 2006.2 With the onset of the Covid-19 pandemic, the regulators have been focused in assessing the applicability of RWE in accelerated drug/vaccine approval. There is now an increased release of guidance and regulations for pre-marketing authorization indicating an evolving trend across regulators.

Exciting possibilities with RWD/RWE to support Regulatory decisions

A paradigm for novel uses of RWE, in preauthorization regulatory decision-making3, is emerging. Traditional randomized clinical trials may be extremely challenging to conduct and, in those cases, possibilities with RWD as a source for external controls emerge. RWD can be leveraged to:
Interpret data from a single-arm trial
Support expedited approval
Support label expansion3
In some cases, analyses of RWD may provide similar or even superior characteristics compared to the information collected and analyzed through a traditional clinical trial.5 For example, RWD collected within a registry using a randomized exposure assignment can provide sufficient data for powered subgroup analysis. This approach may support the evidence required to expand a product's label/indication for use.
Separately, as an example, the recent approval of Palbociclib in combination with endocrine therapy for male breast cancer and the inclusion of RWE in the label of paliperidone palmitate for schizophrenia are examples of how RWE as evidence for label expansion influenced regulatory decisions.5

Following pointers emerge as the drivers of RWD acceptability especially when observed against the backdrop of limitations of traditional randomized clinical trials:

Usage of RWD for rare or orphan diseases, significant unmet needs, or where randomized controlled trials (RCT) are unfeasible.
In certain cases, RCT lacks reflection on the circumstances under which patients are treated
RWE can be impactful when combined with literature searches and clinician feedback. it can help in identifying opportunities for innovation that improve patient care and identify unmet clinical needs
RWE provides additional context and greater external generalizability to the benefit-risk assessment, thereby leading to improved regulatory decisions.
Because of these possibilities, one can understand the attention of the USFDA and European Medicines Agency (EMA) to consider RWE insights. The Cures Act Cures Act also helps accelerate product development and bring innovations and advances to patients who need them. The Cures Act modernizes clinical trial designs using RWE and clinical outcome assessments.
Recently an article by Bolislis W, et al. 2020,6 provided an overview of approved products that have used RWD for new drug approvals (1998–2018) and line extensions (2012–2019). Figure 1 represents the number of applications filed for different type of approvals (line extension, safety and efficacy updates, patient population expansion) between 2012 and 2019 to regulatory bodies based on RWD.

Figure. 1. Real-world data application in line extensions submitted between 2012 and 2019, including one on a device

Real-world data application in line extensions
Source: Bolislis W et al. Use of Real-world Data for New Drug Applications and Line Extensions, Clinical Therapeutics, 42(5), 2020, 926-938.6  

What is the current stance of Health Authorities for RWE across the globe?

Global regulators such as the US FDA, Health Canada, Japan’s Pharmaceutical and Medical Devices Agency (PMDA), EMA, and China’s National Medical Products Agency (NMPA) are all leaders in delivering guidance in the use of RWD as a means of supporting regulatory decision making. The US FDA and Health Canada are already accepting observational data to support efficacy determinations. The EMA is assessing the use of registry data for rare diseases however there are already examples of RWE data but a standard is needed to improve the approach.
A number of guidance documents have been issued to develop a framework for evaluating the use of RWD/RWE in regulatory decisions. Some examples of these are listed below:


The 21st Century Cures Act (Cures Act) considers RWE to support the approval of a new indication for a drug already approved under section 505(c) of the FD&C Act or to satisfy post-approval study requirements.7 The US FDA since then published several draft guidance documents on the use of RWD/ RWE including:
Assessing data from electronic health records and claims databases
Assessing registries to support regulatory decision-making for drug and biological products
Considerations for the use of RWD/RWE to support regulatory decision-making for drugs and biological products
Data standards for drug and biological product submissions containing RWD
Guidance on submitting documents utilizing RWE with a uniform format to track regulatory submissions for investigational new drug application (IND), new drug application (NDA) or biologics license application (BLA), or for line extensions including labeling changes.8,9 
For medical devices, the FDA issued a final guidance4 in August 2017 on using RWE to support regulatory decision-making for medical devices, including software that meets the definition of a device.
Following an investment of approx. $3 million to get the National Evaluation System for health Technology (NEST) off the ground, FDA issued final guidance on using RWE to support regulatory decision-making for medical devices. NEST aims to research medical technologies using retrospective and active sources of RWD4,10 
Historically, oncology and rare diseases have been the only settings where FDA has accepted RWE to support drug approvals for efficacy. One such example, is Blincyto1 (blinatumomab) that was initially approved by the US FDA under the ‘accelerated approval’ designation. It was based on historical data retrieved from over 2,000 patient records from European Union (EU) and U.S. clinical study and treatment sites.11  

2. EMA

The EMA supports regulatory decisions in the development/pre-authorization stage.3 The EMA conducted an analysis of regulatory submissions from 2018 – 201917 where characteristics of RWE were included in new marketing authorization applications (MAAs) or extensions of indication (EOIs) to the EMA. For MAAs, 63 of 158 products (39.9%) contained RWE with a total of 117 studies. For 31.7% of these products, the RWE submitted was derived from data collected before the planned authorization. The most common data sources were registries (60.3%) followed by hospital data (31.7%). The EMA regulators further intend to ensure the value of RWE for decision-making on the development, authorization, and supervision of medicines in Europe is well defined by 2025. The EU is funding a growing number of initiatives linked to RWE.
The EMA Cross-Committee Task Force on Registries with the European Medicines Regulatory Network published draft guidance on registry-based studies in September 2020. The objective is to provide recommendations on key methodological aspects specific to the use of patient registries by marketing authorization applicants and holders (MAAs/MAHs) planning to conduct studies.
European Medicines Regulatory Network (EMRN) strategy emphasizes that by 2025 the use of RWE will have been enabled, and the value will have been established across a spectrum of use cases.12 Creating the Data Analytics and Real World Interrogation Network (DARWIN EU) will be vital to delivering this vision. It will be launched in 2022 to onboard data partners and drive the conduct of studies requested by regulators.13  

3. Health Canada

In 2019, Health Canada announced that they are in use of RWE for regulatory decisions to improve the extent and rate of access to prescription drugs in Canada. This is in partnership with the Canadian Agency for Drugs and Technologies in Health (CADTH) and the Institut national d'excellence en santé et en services sociaux (INESSS).14 The initiatives undertaken are:
Invite industry partners’ submissions to encourage RWE submissions with an aim to expand evidence-based indications for populations often excluded from clinical trials or for drugs and diseases where clinical trials are unfeasible or unethical
The Health Canada project on ‘Strengthening the use of RWE for Drugs’ is an initiative under the Regulatory Review of Drugs and Devices which aims to optimize the consideration of RWE across the drug life cycle.
Health Canada is working with partners, including industry and HTA organizations, to establish an approach for RWE across the drug life cycle that is systematic and transparent.

4. Japan PMDA

The Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) are actively promoting the utilization of RWD and RWE in their regulatory decision-making processes.15  
In 2014, PMDA published its first RWD-related Guidelines for the Conduct of Pharmacoepidemiological Studies in Drug Safety Assessment with Medical Information Databases.
Between 2017 and 2021, both MHLW and PMDA released a series of documents on post-marketing studies in Japan (including collecting information using RWD)
In 2021, the PMDA established its RWD working group to discuss regulatory issues related to RWD/RWE, such as data reliability standards and methodological approaches and seeks to continuously promote utilization of RWD in the Japanese regulatory framework.

5. China NMPA

The RWE regulatory landscape in China has been dynamic and rapidly evolving. The key initiatives are:
In August 2018, the Wu Jieping Medical Foundation released China’s Real World Research Guide, and several articles explaining the application of RWD including technical specifications, research design, data management, and statistical analysis
Till date, NMPA has published three RWE guidelines:
January 2020: Guidelines for Real-World Evidence to Support Drug Development and Review (Interim)
August 2020: Guidelines for Using RWE for Supporting Pediatric Drug Research & Development and Evaluations (Interim)
April 2021: Guidelines for RWD Used to Generate RWE (Interim) discusses RWD applicability and data curation, data security, and data quality.
Initiation of 3-year NMPA RWE project, which aims to study worldwide RWE policies, collect use cases, and research data standardization
Similarly, within the context of regulatory decision-making by other regulatory agencies such as Australia TGA, South Korea MFDS and Taiwan FDA, the concept of utilizing of RWE to support drug development is gaining interest.

Six unique challenges posed by RWE in Regulatory decision making

Real-world evidence raises different considerations in the context of regulatory decision-making which depends not only on the evaluation of the methodologies employed to generate evidence but also consideration of the reliability and relevance of RWD used to derive RWE.1
Quality of real-word data sources
Variability between different data sources
Lack of essential data elements (lack of standardization in collecting data)
Lack of standardization of RWE analytics
Risk of publication bias
Restricted access to RWD

Quality of real-world data sources

The quality of RWE can vary significantly across sources. Lack of completeness in the data provided can have only limited value for the analysis intended to be performed to demonstrate sufficient statistical evidence.

Variability between different data sources

Methods are needed to address duplication of patient information and to link data about a single patient across data sources.

Lack of essential data elements (lack of standardization in collecting data)

Data sources such as EHRs and medical claims data may not capture all essential data elements needed to answer the question of interest. Different health care systems use EHRs in different formats that are not standardized making it difficult to collect data across varying records.

Lack of standardization of RWE analytics

Variation in analysis methodology, poor-quality analyses, limited transparency into methods, and bias in results still require standardization.

Risk of publication bias

Publication of favorable results while excluding negative findings can be more serious with RWE studies than RCT, as registration of RWE studies in public registries/platforms are limited. Very few RWE studies are publicly registered with posting of complete results.

Restricted access to RWD

In many countries, access to RWD such as claims data, national health check-up data, and electronic medical record data are restricted.

Expect accretion in RWE application with comprehensive initiatives emerging

It is important to harmonize international regulatory requirements and many regulators have taken various initiatives to promote the utilization of RWD/ RWE for regulatory decision-making at the pre- and post-approval stages of a drug. All regulatory bodies of advanced countries are working towards issuing guidance documents that should be employed to define the collection, analysis, and reporting of RWD along with greater transparency around RWE study design and results.
USFDA’s RWE Program focuses on exploring the potential of RWD/RWE to support regulatory decisions about product effectiveness, label changes/ updates, or adding safety information. It provides an opportunity to improve the reliability and relevance of RWD sources. The US FDA has stated that the selection of appropriate RWD sources should be premised on the regulatory question of interest and should be collected and maintained in a way that provides an appropriate level of reliability and quality.1
Real-World Evidence Transparency Initiative is a collaborative effort between the International Society for Pharmacoepidemiology (ISPOR), the Duke-Margolis Center for Health Policy, and the National Pharmaceutical Council, since 2019. The objective of this initiative was to promote a culture of transparency for study analysis and reporting of hypothesis evaluating RWE studies on treatment effects. In turn, this can enable decision-makers to evaluate the quality of the methods used and the applicability of the evidence that results from the RWE studies. Registration of studies, as recommended by the ISPOR collaboration, is an essential first step towards improving transparency and trust in non-interventional research for hypothesis testing.5, 16
The existing registries, such as Clinical Trials. gov and the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance Post-Authorization Study [EU-PAS] currently lack many features needed to improve transparency as the focus is on studies that collect primary data. The intention of the RWE collaborative initiative is to encourage researchers to post their studies in existing study registries. The eventual goal is to work with the study registry hosts in evaluating the potential to optimize treatment effectiveness (HETE) RWE studies and through this initiative identify the most ‘fit for use’ study registration site for HETE RWE studies that can accommodate noninterventional secondary data research. The ISPOR collaborative initiative is also working with health agencies, such as the USFDA is developing a structured protocol and reporting template, to avoid duplication and create synergies where possible.


While clinical trials remain the gold standard for evaluation of treatment efficacy, there is increasing potential in using RWE to support regulatory decisions about the effectiveness of drug products, label changes, or adding safety information. The growing emphasis on RWE by regulatory agencies has fueled a new optimism and provided an impetus for a new regulatory framework. A significant amount of precedent data exists for regulatory bodies’ acceptance of RWE for drug approvals. Furthermore, the volume and diversity of RWD have been growing exponentially, as electronic medical records have made information increasingly accessible and useful for outcomes research and regulatory purposes.16
While RWE offers tremendous potential, it also presents challenges such as biases due to lack of randomization, data reliability, and the potential for spurious results due to data mining. Despite having at least two decades of significant data capabilities in healthcare, a standard approach is still required to improve collection, integration, analysis and reporting. Continued efforts by the industry in partnership with health authorities are needed to harmonize principles for the regulatory use of RWD. All regulators including USFDA are committed to explore ways and taking initiatives to pilot projects to further understand the potential and optimize the use of RWE for regulatory decisions.


Framework for FDA’s Real-World Evidence Program.  https://www.fda.gov/media/120060/download. 2018 Dec
O’Donnell JC, Le TK, Dobrin R, Higashi M, Pereira A, Wagner S, Yang A, Hukkelhoven M. Evolving use of real-world evidence in the regulatory process: a focus on immuno-oncology treatment and outcomes. Future Oncol. 2021 Jan;17(3):333-347. doi: 10.2217/fon-2020-0591
Burcu M, Dreyer NA, Franklin JM, Blum MD, Critchlow CW, Perfetto EM, Zhou W. Real-world evidence to support regulatory decision-making for medicines: Considerations for external control arms. Pharmacoepidemiol Drug Saf. 2020 Oct;29(10):1228-1235. doi:10.1002/ pds.4975
Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices Guidance for Industry and Food and Drug Administration Staff.   https://www.fda.gov/media/99447/download. 2017 Aug 31
Orsini LS, Berger M, Crown W, Daniel G, Eichler HG, Goettsch W, Graff J, Guerino J, Jonsson P, Lederer NM, Monz B, Mullins CD, Schneeweiss S, Brunt DV, Wang SV, Willke RJ. Improving Transparency to Build Trust in Real-World Secondary Data Studies for Hypothesis Testing-Why, What, and How: Recommendations and a Road Map from the Real-World Evidence Transparency Initiative. Value Health. 2020 Sep;23(9):1128-1136. doi:10.1016/j.jval.2020.04.002
Bolislis WR, Fay M, Kühler TC. Use of Real-world Data for New Drug Applications and Line Extensions. Clin Ther. 2020 May;42(5):926- 938. doi:10.1016/j.clinthera.2020.03.006
Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drugs and Biologics Guidance for Industry.  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/submitting-documents-using-real-world-data-and-real-world-evidence-fda-drugs-and-biologics-guidance. 2019 May
Brennan Z. RWE Submissions: FDA Drafts Guidance. https://www.raps.org/news-and-articles/news-articles/2019/5/rwe-submissions-fda-drafts-guidance. 2019 May 08
Rachal M. Pandemic pushes FDA to ‘accelerate’ real-world evidence efforts, Hahn says.  https://www.medtechdive.com/news/fda-coronavirus-diagnostics-real-world-evidence/580123/. 2019 Jun 19
Gökbuget N, Kelsh M, Chia V, Advani A, Bassan R, Dombret H, Doubek M, Fielding AK, Giebel S, Haddad V, Hoelzer D, Holland C, Ifrah N, Katz A, Maniar T, Martinelli G, Morgades M, O’Brien S, Ribera JM, Rowe JM, Stein A, Topp M, Wadleigh M, Kantarjian H. Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia. Blood Cancer J. 2016 Sep 23;6(9):e473. doi:10.1038/bcj.2016.84
Arlett P, Kjaer J, Broich K, Cooke E. Real-World Evidence in EU Medicines Regulation: Enabling Use and Establishing Value. Clin Pharmacol Ther. 2022 Jan;111(1):21-23. doi: 10.1002/cpt.2479
A vision for use of real-world evidence in EU medicines regulation.   https://www.ema.europa.eu/en/news/vision-use-real-world-evidence-eu-medicines-regulation. 2021 Nov 24
Sem E, Han F, Beauregard AC. Real-World Evidence Regulatory Landscape in Asia Pacific: Australia, China, Japan, South Korea, and Taiwan.  https://globalforum.diaglobal.org/issue/june-2022/real-world-evidence-regulatory-landscape-in-asia-pacific-australia-china-japan-south-korea-and-taiwan/
BLA : Biologics License Application
EHRs : Electronic Health Records
EMA : European Medicines Agency
EU-PAS : European Network of Centers for Pharmacoepidemiology and Pharmacovigilance Post-Authorization Study
EU : European Union
HTA : Health Technology Assessment
HETE : Hypothesis Evaluating Treatment Effectiveness
ISPOR : International Society for Pharmacoepidemiology
IND : Investigational New Drug
MAAs/MAHs : Marketing Authorization Applicants/Holders
NEST : National Evaluation System for Health Technology
NMPA : National Medical Products Agency
NDA : New Drug Application
PMDA : Pharmaceutical and Medical Devices Agency
RCT : Randomized Controlled Trials
RWD : Real-World Data
RWE : Real-World Evidence
USFDA : United States Food and Drug Administration
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