FDA Will Allow Observational Studies to Support Effectiveness Determinations, New Framework Says

Regulatory NewsRegulatory News | 06 December 2018 |  By 

The US Food and Drug Administration (FDA) on Thursday unveiled a new framework discussing how the agency will use real world evidence (RWE) and real-world data (RWD) to help companies win new indications for approved drugs and biologics, expand labels or satisfy post-approval study requirements.

As far as what the framework will guide FDA on specifically, the agency said its RWE program will evaluate the potential use of RWE to support changes to labeling about drug product effectiveness, including adding or modifying an indication, such as a change in dose, dose regimen or route of administration; new populations; or the addition of comparative effectiveness or safety information.

“The RWE framework will also consider the evaluation of observational clinical studies using RWD to support product effectiveness determinations,” FDA said.

For determinations on how to use RWE, the agency said it will consider the following on a case-by-case basis:
  • Whether the RWD are fit for use
  • Whether the trial or study design used to generate RWE can provide adequate scientific evidence to answer or help answer the regulatory question  
  • Whether the study conduct meets FDA regulatory requirements (e.g., for study monitoring and data collection)
“FDA intends to use this three-part approach to evaluate individual supplemental applications, as appropriate, and more generally to guide FDA’s RWE Program,” the framework says.

In addition to offering examples of current uses of RWD for evidence generation (more below), sections of the framework deal with assessing data reliability and relevance and addressing gaps in RWD sources.

Under the section on the potential for study designs using RWD to support effectiveness, the framework focuses on randomized designs using RWD, non-randomized trials, single-arm trials with RWD control and observational studies.

“In considering whether data gathered through observational study designs are appropriate to generate RWE for the purpose of supporting effectiveness determinations, FDA intends to evaluate multiple questions of interest that could affect the ability to draw a reliable causal inference, including, for example, the role of existing evidence (e.g., the natural history of the disease) and how the inclusion of a more diverse population can result in a heterogeneity of treatment effects making it difficult to detect smaller effect sizes,” the agency says.

But the agency also cautions that the potential lack of transparency, especially in retrospective observational studies, which do not have to be registered on clinicaltrials.gov, coupled with the fact that retrospective analyses can be conducted multiple times and relatively inexpensively with varying study design elements, “makes it possible to conduct numerous retrospective studies until the desired result is obtained and then submit only favorable results as if they were the result of a single study with a prespecified protocol.”

FDA said it will consider policies to prevent such practices, including recommendations from experts and other stakeholders. The agency also said it will issue guidance about observational study designs using RWD, including whether and how these studies might provide RWE to support product effectiveness in regulatory decisionmaking.

Background and Examples

The creation of this framework was built into the 21st Century Cures Act, which directed FDA to build an RWE program to include information describing sources of RWE, gaps in data collection, standards and methodologies for collecting and analyzing RWE, and priority areas, challenges and potential pilot opportunities to address the overarching Cures requirements.

For the purposes of this framework, FDA said it defines RWD and RWE as follows: 
  • RWD are data “relating to patient health status and/or the delivery of health care routinely collected from a variety of sources.”
  • RWE is the “clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of RWD.”
And the agency has already begun using RWD and RWE in some postmarket instances.

“To give some examples, our use of RWD and RWE, derived from our Sentinel system, eliminated the need for postmarketing studies on nine potential safety issues involving five products; making our postmarket evaluation of safety timelier and more effective,” FDA Commissioner Scott Gottlieb said in a statement.

In more cases, active post-market risk identification and analysis is replacing the need for randomized controlled post-marketing studies as a more effective, comprehensive, and achievable tool for post-market evaluation. And as a result, these tools are becoming an increasingly important part of pre-market reviews, Gottlieb noted.

In the premarket space in oncology, for example, Gottlieb said that FDA currently has new drug applications under review where RWD and RWE are “helping to inform our ongoing evaluation as one component of the total complement of information that we’re evaluating.”

RWD and RWE can be particularly helpful when evaluating treatments for uncommon conditions or rare tumor types. Across the pond, the European Medicines Agency said late last month that companies developing certain hemophilia treatments should collect data from patient registries rather than run small clinical trials.



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