Use of Real World Data and Real World Evidence to Support Regulatory Decision Making for Drug and Biological Products

FDA issued the draft guidance as part of its Real World Evidence (RWE) Program to satisfy, in part, the mandate under 26 section 505F of the FD&C Act to issue guidance about the use of RWE to help support approval of a new indication for a drug already approved under section 505(c) of the FD&C Act or to help support post-approval study requirements.

Regulatory Considerations

Applicability of 21 CFR Part 312: applicability of part 312 (Investigational New Drug Application) to studies involving the use of Real-World Data (RWD).

1. FDA regulations under part 312 outline procedures and requirements governing the use of investigational new drugs, including the requirements for an IND submission to and review by the FDA.
2. FDA recognizes the potential utility of using RWD in interventional studies; for example, to identify potential participants for a randomized controlled trial, to ascertain endpoints or outcomes (e.g., the occurrence of stroke or other discrete events, hospitalization, survival) in a randomized controlled trial, or to serve as a comparator arm in an externally controlled trial, including historically controlled trials.
3. Non-interventional studies analyze data reflecting the use of a marketed drug administered in routine medical practice, according to a medical provider’s clinical judgment and based on patient characteristics, rather than the assignment of a participant to a study arm according to a research protocol.
    

Regulatory Considerations for Non-Interventional (Observational) Studies

    1. Transparency Regarding Data Collection and Analysis

Sponsors should engage with FDA in the early stages of designing a non-interventional study intended to support a marketing application. Sponsors should provide draft versions of their proposed protocol and statistical analysis plan (SAP) for Agency review and comment, prior to finalizing these documents and before conducting the study analyses.

To adequately assess the results of a non-interventional study supporting a marketing application, FDA must be confident that particular data sources or databases were not selected, or that specific analyses were not conducted, to favor a certain conclusion. Therefore, the protocol and SAP should be finalized prior to conducting the pre-specified analyses listed in the protocol and SAP. The sponsor should provide evidence that the protocol and SAP were finalized prior to reviewing the outcome data of a study and before performing the pre-specified analyses. In addition, any revisions to the protocol should be date-stamped, and the rationale for each change should be provided.

• FDA recognizes that access to and evaluation of relevant data sources or databases are important steps in the design of a study and in evaluating a study’s feasibility. Evaluations of data sources or databases for study design or feasibility purposes serve as a first step to (1) learn about the suitability of the data source or database to address the research question being posed and (2) estimate the statistical precision of a potential study without evaluating outcomes for treatment arms.

• Sponsors should describe in the study protocol all the data sources accessed when designing the study, as well as results from feasibility evaluations or exploratory analyses of those data sources. Sponsors should provide a justification for selecting or excluding relevant data sources from the study. FDA recommends that sponsors generate audit trails in their datasets that can track access to and analyses performed on relevant data sources.

• Sponsors should document all analyses performed on the data during the study design phase, including feasibility evaluations and exploratory analyses. Sponsors should also demonstrate that the choice of the final analytic dataset and the conduct of final analyses align with the research question of interest and do not favor particular study findings.

• Sponsors should describe patient characteristics of the source population (i.e., the population from which the study population is drawn) and the study population (i.e., the population for which analyses are conducted) and note any differences that may impact the final study findings.

• To ensure transparency regarding their study design, sponsors should post their study protocols on a publicly available website, such as ClinicalTrials.gov or the web page for the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) for post-authorization studies.
 

    2. RWD Data Access

• In the early stages of designing a non-interventional study intended for use in a marketing application, sponsors should discuss with the relevant review division the expectations regarding access to RWD for their development program. Sponsors must ensure that they are able to submit patient-level data for any RWD that have been analyzed as part of the clinical study included in a marketing application when required under 21 CFR 314.50 and 601.2.

• If certain RWD is owned and controlled by third parties, sponsors should have agreements in place with those parties to ensure that all relevant patient-level data can be provided to FDA and that source data necessary to verify the RWD is made available for inspection as applicable.

• Sponsors should ensure that RWD and associated programming codes and algorithms submitted to FDA are documented, well-annotated, and complete, which would allow the FDA to replicate the study analysis using the same dataset and analytic approach.
 

    3. Study Monitoring

• When a non-interventional study does not include any additional ancillary activities, study monitoring generally may be focused on maintaining the reliability of the RWD and data integrity, beginning with the extraction of the data from its origin (i.e., data accrual) through data curation and transformation and reporting of results. When a non-interventional study includes additional protocol-specified activities and procedures, study monitoring should also ensure that applicable human subject protections are met and data integrity is maintained

• FDA encourages sponsors to use a risk-based quality management approach to study oversight. This approach focuses sponsor oversight activities on preventing or mitigating important and likely risks to study quality in most instances, and on processes critical to human subject protection that are relevant when ancillary protocol-specified activities or procedures are included in a non-interventional study3
 

    4. Safety Reporting

• Applicants of NDAs and BLAs and other responsible parties are subject to regulatory requirements regarding post-marketing safety reporting. Given that non-interventional studies examine the use of a drug in routine medical practice, the Agency requires that relevant adverse events be submitted to FDA in accordance with post-marketing safety reporting regulations.

• For non-interventional studies, FDA recognizes that sponsors will often use only a subset (often called an analytic dataset) of a larger real-world dataset to conduct their analyses to support labeling changes. If the sponsor is conducting a study to support a specific labeling change (e.g., a new indication), FDA does not expect the sponsor to search the entire database regarding all uses of the product for adverse events that would meet the reporting requirements under FDA’s post-marketing reporting regulations. Nonetheless, if a sponsor identifies adverse events that are subject to post-marketing reporting requirements during the course of conducting a non-interventional study, such events must be reported in accordance with applicable post-marketing reporting requirements.
 

    5. Other Sponsor Responsibilities

• For a marketing application containing a non-interventional study submitted to support regulatory decisions regarding the safety or effectiveness of a product, the electronic systems used by the sponsor to manage the data and produce required records must comply with 21 CFR part 11. 19

• Sponsors who submit non-interventional studies for regulatory review should take responsibility for all activities related to the design, conduct, and oversight of the studies. These activities should include, but not be limited to: − Selecting researchers qualified by training and experience to perform study-related activities and confirming that researchers have the skills and information needed to perform their roles in the study; − Ensuring that the study is conducted in accordance with the final protocol and statistical analysis plan and documenting any deviations; − Maintaining and retaining adequate study records;− Ensuring that FDA can access and verify relevant records, such as source records of study analyses; − Ensuring appropriate monitoring of the study, including (when applicable) selecting a monitor qualified by training and experience for studies requiring additional data collection (e.g., patient-reported outcomes or laboratory assessments)

• FDA expects that the sponsor will retain and make available to the Agency upon request a log of any researcher or researchers who have significant involvement in the design or conduct of the study. The log should contain information on researchers, including − Researcher’s name and affiliations; − Description of roles or activities performed; − Qualifications regarding education, training, and experience to perform the proposed study role

 • If sponsors engage third parties (e.g., data vendors or contract research organizations) to perform certain study-related tasks, sponsors should document the roles and responsibilities of the organization or organizations performing the tasks. These documents should be made available to FDA upon request. Sponsors should remain responsible for all study-related activities unless a sponsor has transferred its responsibility to a contract research organization.