Real World Data Part 4: How to Use it Properly

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In order to determine the suitability of RWD for regulatory decision-making, the FDA will assess the relevance and reliability of the source and its specific elements. Important factors associated with RWD relevance primarily are: 1) sufficient details 2) capability to address specific questions 3) interpretable using informed clinical/scientific judgement. Reliability of RWD is associated with data accrual and data assurance. Data assurance consists of the quality of data element population, adherence, completeness, consistency and program evaluation process.

Specifically, when RWE is intended to be used for purposes of evaluating a regulatory question, the following considerations for RWD should be put in mind:

  • In order to use RWD, the device must be sufficiently identified with the level of detail necessary to address the regulatory question. For example, to evaluate a particular device, the Unique Device Identifier (UDI) or serial/model number may be necessary to identify the device within a RWD source that contains data on many similar devices;
  • RWD should meet the criteria of relevance and reliability;
  • RWD should be presented to FDA according to recognized data standards (i.e. in standardized file formats and data structures, utilizing standardized variables and definitions, etc.) when applicable.
  • If RWE is derived from multiple RWD sources, each RWD source will be evaluated individually and together in the aggregate to determine the relevance and reliability of the RWD.
  • The methodology used to analyze RWD and assess clinically relevant differences as well as statistical significance should be scientifically robust.

To give some examples, FDA has been using RWD and RWE, derived from the Sentinel System, to eliminate the need for post-market studies on nine potential safety issues involving five products. This makes FDA’s post-market evaluation of safety timelier and more effective.

RWD may potentially be used as some or all of the evidence necessary for understanding medical device performance at different points in the TPLC. Some purposes for which RWD may potentially be used include the following:

  • for generating hypotheses to be tested in a prospective clinical study;
  • as a historical control, a prior in a Bayesian trial or as one source of data in a hierarchical model or a hybrid data synthesis;
  • as a concurrent control group or as a mechanism for collecting data related to a clinical study to support device approval or clearance in a setting where a registry or some other systematic data collection mechanism exists;
  • as evidence to identify, demonstrate, or support the clinical validity of a biomarker;
  • as evidence to support approval or granting of an Humanitarian Device Exemption, Premarket Approval Application (PMA), or De Novo request;
  • as support for a petition for reclassification of a medical device under section 513(e) or (f)(3) of the FD&C Act;
  • as evidence for expanding the labeling of a device to include additional indications for use or to update the labeling to include new information on safety and effectiveness
  • for public health surveillance efforts. Through ongoing surveillance, signals are at times identified that suggest there may be a safety issue with a medical device. RWE may be used to refine these signals for purposes of informing appropriate corrective actions and communication;
  • to conduct post-approval studies that are imposed as a condition of device approval or to potentially preclude the need for post-market surveillance studies ordered under section 522 of the FD&C Act;
  • in certain circumstances, for use in generating summary reports of Medical Device Reports (MDRs); and
  • to provide post-market data in lieu of some premarket data.

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Real World Data Part 3: Consider Relevancy

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Relevance and reliability of RWD

In order to determine the suitability of RWD for regulatory decision-making, the FDA will assess the relevance and reliability of the source and its specific elements. Important factors associated with RWD relevance primarily are: 1) sufficient details ; 2) capability to address specific questions; 3) interpretable using informed clinical/scientific judgement. Reliability of RWD is associated with data accrual and data assurance. Data assurance consists of the quality of data element population, adherence, completeness, consistency and the program evaluation process.

Specifically, when RWE is intended to be used for purposes of evaluating a regulatory question, the following considerations for RWD should be:

  • In order to use RWD, the device must be sufficiently identified with the level of detail necessary to address the regulatory question. For example, to evaluate a particular device, the Unique Device Identifier (UDI) or serial/model number may be necessary to identify the device within a RWD source that contains data on many similar devices;
  • RWD should meet the criteria of relevance and reliability;
  • RWD should be presented to FDA according to recognized data standards (i.e. in standardized file formats and data structures, utilizing standardized variables and definitions, etc.) when applicable.
  • If RWE is derived from multiple RWD sources, each RWD source will be evaluated individually and together in the aggregate to determine the relevance and reliability of the RWD.
  • The methodology used to analyze RWD and assess clinically relevant differences as well as statistical significance should be scientifically robust.

 

To give some examples, the FDA has been using RWD and RWE, derived from the Sentinel System, to eliminate the need for post-market studies on nine potential safety issues involving five products. This makes the FDA’s post-market evaluation of safety timelier and more effective.

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What to Know About the FDA’s Real World Evidence Framework

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This framework is for evaluating the potential use of Real World Evidence (RWE) to help support the approval of a new indication for drugs and biological products already approved or to help support or satisfy drug post-approval study requirements. This framework is also intended for application to biological products licensed.

What studies could be covered by the RWE program?

The FDA will consider the following trial designs to have the potential to generate RWE.

  • Hybrid design clinical trials. In a hybrid design clinical trial, certain elements could rely on the collection and analysis of RWD extracted from medical claims, EHRs, or laboratory and pharmacy databases. Hybrid trials could use RWD for one clinical outcome, (e.g. hospitalization, death), while other elements were more traditional (e.g. specified entry criteria, monitoring and collection of additional study endpoints by dedicated study personnel).
  • Pragmatic clinical trial. The pragmatic clinical trials can include some elements that more closely resemble routine clinical practice. The pragmatic trials often rely on RWD and have the potential to generate RWE.
  • Observational Study. For purposes of this framework, observational studies are non-interventional clinical study designs. FDA considers a retrospective observational study to be one in which the study identifies the population and determines the exposure/treatment from historical data (i.e. data generated prior to the initiation of the study). The variables and outcomes of interest are determined at the time the study is designed. In a prospective observational study, the population of interest is identified at the start of the study, and exposure/treatment and outcome data are collected from that point forward.

 

Observational clinical studies might be another way to generate RWE that is relevant to effectiveness determinations. Therefore, the RWE program will also consider the evaluation of observational clinical studies using RWD to support product effectiveness determinations.

 

When generating RWE, an attention should be paid to evaluating that RWE in the context of regulatory decision-making depends not only on the evaluation of the methodologies used to generate the evidence but also on the reliability and relevance of the underlying RWD.

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FDA Publishes Framework for Real-World Evidence Program

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In December of 2018, the FDA published their Framework for FDA's Real-World Evidence Program, which outlines the allowed usage of Real World Data (RWD) and Real World Evidence (RWE) in FDA submissions.

The sources of RWD and the application of RWE

The rationale for using Real-World Data (RWD) is to help support the approval of a new indication for a drug approved under the Federal Food, Drug, and Cosmetic Act (FD&C Act) and to help support or satisfy post-approval study requirements.

 

RWD can come from a number of sources, for example:

  • Electronic health records (EHRs)
  • Claims and billing activities
  • Product and disease registries
  • Patient-generated data including in home-use settings
  • Data gathered from other sources that can inform on health status, such as mobile devices;

 

The FDA uses RWD to monitor post-market safety and adverse events and to make regulatory decisions. At the same time, medical product developers use RWD and Real-World Evidence (RWE) to support clinical trial designs and observational studies to generate innovative, new treatment approaches.

 

In the “Guidance for Industry and Food and Drug Administration Staff : Use of Real World Evidence to Support Regulatory Decision –Making for Medical Device,” launched in 2017, the FDA stated that the above mentioned RWD sources can be used as data collection and analysis infrastructure to support many types of trial designs, including, but not limited to, randomized trials, such as large simple trials, pragmatic clinical trials, and observational studies (prospective and/or retrospective). Furthermore, the FDA has been implementing the National Evaluation System for health Technology (NEST) to leverage RWD in order to more quickly identify safety problems and to better understand the benefit-risk profile of devices used in clinical care.  Whether RWE provides an acceptable level of valid scientific evidence or not depends on whether the RWD are of sufficient quality, that is, whether RWD were accurately and reliably captured at clinically relevant time intervals throughout the device lifecycle. Under the right conditions, RWE may be suitable to support the clearance or approval of a new device, or the expansion of the indications for use of devices that are already on the market.

 

RWE may also be used to supplement the total evidence required for such clearances or approvals. Other applications of RWE in premarket decision-making may also be possible, particularly as RWD systems and analysis methodology advance.

 

Case study for using RWD and RWE in FDA New drug/device application

Though the program for using RWD and RWE is in process of awaiting public comments, the FDA has practiced RWD and RWE in previous approvals of drug applications. For example, in the October 18, 2018 meeting for Prucalopride (Motegrity), the FDA agreed to use the data from two non-interventional studies for a long-term safety submission. One of the studies is a non-interventional pharmacoepidemiology study that used national claims data from four European countries, and another one is a non-interventional epidemiologic study conducted to estimate the adjusted incidence ratio for MACE. In the same application, the FDA agreed to use the data from a phase 3 trial conducted in 1999 to support the generalizability of results from non-US pivotal studies to the US patients’ population.

 

With this successful case, we expect more and more new applications for drugs and medical devices using RWD and RWE. This will reduce the cost of drug development and shorten the time of new drug/device approval, especially in the data related to safety and benefit-risk assessment.

 

RWD and RWE: FDA’s focus  

At the end of 2018, the FDA published two documents regarding Real-World Data (RWD) and Real-World Evidence (RWE). The Statement on FDA’s new strategic framework to advance use of RWD and RWE support development of drugs and biologics was released on December 6, 2018. The framework for FDA’s Real-World Evidence Program was launched in FDA web site on December 19, 2018. The purposes of RWD and RWE are to help inform regulatory decisions around medical products as the collection of this data gets more widespread and reliable.

In terms of definition from the FDA, RWD are data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources. RWD offer new opportunities to generate evidence and better understand clinical outcomes. These data may be derived from a diverse array of sources, such as electronic health records (EHR), medical claims, product and disease registries, laboratory test results and even cutting-edge technology paired with consumer mobile devices.

RWE is the clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of RWD. Under the FDA’s RWE Program, evidence from traditional clinical trials will not be considered RWE. However, various hybrid or pragmatic trial designs and observational studies could generate RWE. The FDA’s RWE Program will cover clinical trials that generate RWE in some capacity (i.e., sources other than traditional clinical trials) and observational studies.

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