New Year New FDA Strategic Framework on Real World Evidence Program


Today there remains an ever-growing ability to generate, collect, and store vast amounts of health-related data. Availability of such data has opened the doors for the opportunity to leverage this information when developing drugs, for example in designing clinical trials. Having all this data at our fingertips is exciting as it has many potential uses but also leads to many questions: How can we best use this data for good? When is it appropriate to use this type of data? Are there standards for how to analyze the data? How can we guarantee the data is of the highest quality? How do we ensure the data is both reliable and relevant? These types of discussion are by no means new topics in the regulatory world. There have been numerous ongoing discussions regarding how to leverage this vast amount of available information and the appropriate ways to integrate it into the regulatory-life cycle. Many strides have already taken place to assess the use of health-related data as evidence for safety of certain drugs. Now, progressing forward, we begin to step into the realm of how to use such data when establishing evidence for drug efficacy. On 06 December 2018 the United States Food and Drug Administration (FDA) announced the release of a strategic framework to evaluate the potential use of real-world evidence (RWE) to support regulatory decisions on the development of drugs and biologics. The RWE program is issued in response to the 21st Century Cures Act. Specifically, the program is designed to incorporate a framework where RWE may be used to (1) support approval of a new indication and (2) support or satisfy postapproval study requirements for both drugs and biologics.[1] Medical devices, however, are not within the scope of this framework. RWE can support a new indication only for drugs or biologics already approved under section 505(c) of the Federal Food, Drug, and Cosmetic Act. Similarly, RWE used to support a new indication for biologic products will be applicable for biologics licensed under section 351 of the Public Health Service Act.


The FDA defines:

  • Real world data (RWD) as “data relating to patient health status and the delivery of health care routinely collected from a variety of sources.”[[1]]
  • Real world evidence (RWE) as “clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of RWD.”[1]

Reasons for Capturing RWD

RWD is collected for a number of different reasons. Some example uses are to develop analysis infrastructures to support study designs (i.e., randomized trials or observational studies), collecting data to generate RWE, and for improving efficiency of clinical trials.[[2]Current Use The FDA already considers RWD and RWE in evaluation safety for drugs, devices, and biologics. Current uses of RWD and RWE include:

  • The Sentinel System, which evaluates drug or biologic safety by monitoring electronic health and administrative data.[[3]] In some cases, the Sentinel System has accelerated and provided more effective postmarketing evaluations, saving time and money.[2, [4]]
  • The FDA-Catalyst program, part of the sentinel initiative, surveys and researches medical products on the market by obtaining patient reported information (PRO) via smart devices (e.g., FDA MyStudies mobile application project).[4, [5]]
  • The Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) use pharmacoepidemiologic research projects to conduct safety monitoring.[4]
  • CDER uses RWD from the Center for Disease Control and Prevention (CDC) and Prevention National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance Project to investigate drug abuse, misuse, etc.[4]
  • CBER also uses RWD for focused surveillance of existing databases (e.g., vaccine safety using the Post-Licensure Market Rapid Immunization Safety Monitoring (PRISM) or Blood components and blood derived products with Blood Surveillance Continuous Active Surveillance Network (BloodScan)).[4]
  • FDA issued The Best Practices for Conducting and Reporting Pharmacoepidemilogic Safety Studies Using Electronic Healthcare Data[6] which describes utilizing RWD from electronic healthcare systems.[4] 

Sources for RWD

RWD can be obtained from a number of sources; such as, electronic health records (EHR), administrative and medical claims databases, product and disease registries, patient-generated data, and other sources (i.e., mobile devices).[4] Part of the scope of the RWE program will be to evaluate what types of RWD are acceptable and whether RWE is properly generated from RWD.

Benefits of Using RWD and RWE

Using RWE can aid in supporting a product’s effectiveness. Some of the benefits of using RWD and RWE are:

  • Faster approval for label modifications or revisions (e.g., adding or changing an indication; modifying dose, dose regimen, or route of administration; safety and efficacy information).
  • Faster data collection
  • Improvements for cost savings (e.g., preventing the need for extended clinical trials)
  • Collecting data more representative of actual use in the target population
  • Proving more information to patients and providers

Implementation of the Framework

The FDA’s goal is to develop a platform that integrates RWE into the drug development and regulatory life-cycle.[1, 2] Table 1 summarizes the plan for the multifaceted program which engages various stakeholders, issues new guidance documents for developers, and assess the type of RWD and RWE being generated to develop standards for appropriate use across disciplines.

Table 1. Implementation of the Strategic Framework.

GuidanceHow to assess reliability and relevance of RWD from electronic healthcare data used to generate RWE on a product’s effectiveness·         RWD sources include medical claims, EHRs, registries, and international electronic healthcare data ·         Reliability regarding data accrual and control ·         Will build upon Pharmacoepidemiologic Guidance[[6]]
GuidancePotential gaps in RWD sources and strategies to address themHow to use other RWD sources (mobile technologies, electronic PROs, wearables and biosensors) to generate RWE that may be difficult to demonstrate solely using RWD sources (EHRs and medical claims)
GuidanceConsideration for designing clinical trials that include pragmatic design elements and that generate evidence of effectiveness for regulatory decisionsWhile evidence from traditional clinical trials are not considered RWE, hybrid (or pragmatic) trial designs and observational studies are potential sources capable of generating RWE
GuidanceUse of RWD to generate external control armsA potential guidance for historical controls used as external control arms using data from past traditional clinical trials.[6, [7]]
GuidanceHow observational studies can be used to generate RWE to support product effectivenessBuild off Pharmacoepidemiologic Guidance[7] to support changes in labeling that require evidence of effectiveness
GuidanceDifferent study designs using RWD to generate RWE to determine effectivenessWill build off available guidance documents such as Use of Electronic Informed Consent[[8]], Electronic Source Data in Clinical Investigations[[9]], and Use of Electronic Health Records in Clinical Investigations[[10]]
GuidanceUsing different sources of RWD to generate RWE regarding safety and effectivenessThis is a potential guidance to be issued after FDA evaluates whether the current available guidances collectively do not provide sufficient information to developers.[6]
AssessmentFDA will conduct a variety of assessments to integrate usage of RWD and RWE in the drug development and regulatory process·         Data standards ·         Implementation strategies ·         Identifying gaps ·         Recommending paths forward
ConsultationEngagement of internal and external stakeholders to include senior leadership input into the evaluation of RWE and promote shared learning and consistency when applying the framework·         Internal – RWE evidence subcommittee of leadership (CDER and CBER) ·         External – representatives from industry, academia, medical professional and consumer organizations, patient advocacy groups, disease research foundations, etc. ·         Consultation formats: public workshops, public-private partnerships, etc.

CBER = Center for Biologics Evaluation and Research; CDER = Center for Drug Evaluation and Research; EHR = Electronic health record; PRO = Patient reported outcome; RWE = Real world evidence; RWD = Real world data; Italicization indicates a potential guidance Currently, there are a number of guidance documents pertaining to use of RWD and RWE which focus on the product’s safety rather than efficacy. These guidances will be leveraged to create new guidance documents that describe acceptable use of RWE to support efficacy claims.


The FDA intends to allow RWE to support approval of new indications and support or satisfy postapproval study requirements for both drugs and biologics. The new RWE program will be implemented through the utilization of a multifaceted framework. The framework outlines a number of guidance documents, their plans to engage experts across specialties and fields, and various assessments to produce acceptable standards for developers (e.g., so that the RWE submitted in the FDA package supplements the totality of evidence for efficacy). Together each of these components will provide appropriate integration of RWE for routine use in the drug development and regulatory process.

[[1]] “Real World Evidence”. The U.S. Food & Drug Administration. 12 December 2018. [[2]] “Statement from FDA Commissioner Scott Gottlieb, M.D., on FDA’s new strategic framework to advance use of real-world evidence to support development of drugs and biologics”. The U.S. Food & Drug Administration. 06 December 2018. [[3]] “Sentinel System Overview.” CDER FDA Presentation. 2017. [[4]] “Framework for FDA’s Real-World Evidence Program”. The U.S. Food & Drug Administration. December 2018. [[5]] “Collection of Patient-Provided information through a Mobile Device Application for Use in Comparative Effectiveness and Drug Safety Resarch.” FDA-Catalyst Project. 03 January 2017. [[6]] “Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data.” Guidance for Industry and FDA Staff. May 2013. [[7]] “E 10 Choice of Control Group and Related Issues in Clinical Trials”. FDA Guidance for Industry. May 2001 [[8]] “Use of Electronic Informed Consent Questions and Answers.” FDA Guidance for Institutional Review Boards, Investigators, and Sponsors. December 2016. [[9]] “Electronic Source Data in Clinical Investigations.” FDA Guidance for Industry.  September 2013. [[10]] “Use of Electronic Health Record Data in Clinical Investigations.” FDA Guidance for Industry. July 2018.

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