6 FEBRUARY 2022 – In 2021, the FDA published three (3) draft guidance documents that are intended to provide sponsors, researchers, and other interested stakeholders with considerations when proposing to use real world data (e.g., electronic health records and medical claims data) in clinical studies submitted to FDA in support of a regulatory decision regarding the effectiveness and safety of a drug (e.g., as part of a new drug application (NDA) or biologics license application (BLA)).

1. 1. Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [Link] [1]
   2. Draft FDA Guidance Data Standards for Drug and Biological Product Submissions Containing Real-World Data (October 2021) [Link] [2]
   3. Draft FDA Guidance – Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products (September 2021) [Link] [3]

The emphasis on the intended purpose of the clinical studies is important because it determines which legal standards are applicable to the study (see Figure 1).  There are additional regulatory requirements, recommendations and considerations for non-interventional studies that are designed with the intent of supporting an NDA or BLA. 

Figure 1 – Applicability of Code of Federal Regulations (CFRs) to Non-Interventional Studies Based on Whether Results are Intended to Support a New Drug Application (NDA)

We have created a consolidated version of these three (3) FDA Guidance documents to help provide an overview of the current (draft) FDA guidance and considerations for sponsors who are intending to use non-interventional study data to support regulatory submissions to the FDA [Link] [4].  

Definitions – Interventional Study versus Non-Interventional Study

Interventional study: An Interventional study (also referred to as a clinical trial) is a study in which participants, either healthy volunteers or volunteers with the disease being studied, are assigned to one or more interventions, according to a study protocol, to evaluate the effects of those interventions on subsequent health-related biomedical or behavioral outcomes. One example of an interventional study is a traditional randomized controlled trial, in which some participants are randomly assigned to receive a drug of interest (test article), whereas others receive an active comparator drug or placebo. Clinical trials with pragmatic elements (e.g., broad eligibility criteria, recruitment of participants in usual care settings) and single-arm trials are other types of interventional study designs.

Ref: Section II of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [1]

Link: https://www.fda.gov/media/154714/download  

Non-Interventional Study: A non-interventional study (also referred to as an observational study) is a type of study in which patients received the marketed drug of interest during routine medical practice and are not assigned to an intervention according to a protocol. Examples of non-interventional study designs include:

(1) observational cohort studies, in which patients are identified as belonging to a study group according to the drug or drugs received or not received during routine medical practice, and subsequent biomedical or health outcomes are identified, and 

(2) case-control studies, in which patients are identified as belonging to a study group based on having or not having a health-related biomedical or behavioral outcome, and antecedent treatments received are identified.

Ref: Section II of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [1]

Link: https://www.fda.gov/media/154714/download  

Applicability of 21 CFR Part 312 [Investigational New Drug Application] to Non-Interventional Studies

According to the recent FDA guidance, non-interventional studies are not clinical investigations as defined under § 312.3 and do not require an IND [ref 1].  This is a much appreciated clarification on the applicability of 21 CFR 312 to non-interventional studies!

Ref1: Section III.A of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021) [1]

Link: https://www.fda.gov/media/154714/download  

Although many non-interventional studies involve only the analysis of data reflecting the use of a marketed drug in routine medical practice, certain non-interventional studies include ancillary protocol-specified activities or procedures (e.g., questionnaires, laboratory tests, imaging studies) that collect additional data to help address questions of interest in these studies. FDA does not consider these types of studies to be clinical investigations under part 312, and an IND is not required [ref 1].

Ref1: Section III.B.1 of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021)

Link: https://www.fda.gov/media/154714/download  

Satisfying the Applicable Legal Standards

Regardless of a study’s interventional or non-interventional design, the evidence submitted by a sponsor in a marketing application to support the safety and/or effectiveness of a drug must satisfy the applicable legal standards for the application to be approved or licensed [ref 1].

Ref1: Section III.B.1 of the Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (December 2021) [1]

Link: https://www.fda.gov/media/154714/download   

The three (3) draft FDA guidance documents lay out the recommendation and considerations when proposing to use real world data (e.g., electronic health records and medical claims data) in clinical studies submitted to FDA in support of a regulatory decision regarding the effectiveness and safety of a drug (e.g., as part of a new drug application (NDA) or biologics license application (BLA)) [1] [2] [3].  In particular, these include:

• • Early engagement with the FDA
  • Transparency regarding data collection and analysis
  • Posting study protocols and results on a publicly available database such as clinical trials.gov
  • Ensuring the reliability and relevance of the data 
  • Appropriateness of data sources
  • Previous experience with data sources
  • Missing data
  • Validation
  • Data Quality During Data Accrual, Curation, and Transformation into the Final Study-Specific Dataset
  • Ability to Submit Patient-Level RWD to FDA
  • Data Access Agreements
  • Documentation of Processes for Managing Real-World Data
  • Considerations for Conforming Real-World Data to Currently Supported FDA Study Data Standards
  • Considerations for Mapping Real-World Data to Study Data Submission Standards
  • Considerations for Data Transformations
  • Data Management Processes and Maintaining Data Integrity During Data Curation and Transformation
  • Study Monitoring 
  • Risk-Based Quality Management Approach to Study Oversight [Risk-Based Monitoring]
  • Safety Reporting
  • Compliance with 21 CFR 11
  • Sponsor Responsibilities – Design, Conduct, and Oversight of Non-Interventional Studies
  • Sponsor Responsibilities – Responsibilities Logs and Documented Roles and Responsibilities

There is a lot to digest and it should be remembered that these are still draft guidance documents that are subject to stakeholder feedback.  Even so, this does represent FDAs current thinking on these topics and provides a very comprehensive overview of what study sponsors need to consider and address when designing non-interventional studies with a view to generating real world evidence to support any aspects of a new drug application.

References

1. Draft FDA Guidance – Considerations for the Use of Real-World Data and Real- World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (8 December 2021)

Link: https://www.fda.gov/media/154714/download 

2. Draft FDA Guidance Data Standards for Drug and Biological Product Submissions Containing Real-World Data (October 2021)

Link: https://www.fda.gov/media/153341/download 

3. Draft FDA Guidance – Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products (September 2021)

Link: https://www.fda.gov/media/152503/download 

4. Consolidated FDA Guidance on Using RWD and RWE to Support Regulatory Submissions (February 2022)

Link: https://rwr-regs.com/mp-files/rwr-insights-consolidated-fda-guidance-on-using-rwd-and-rwe-to-support-regulatory-submissions.docx/ 

Useful Resources

FDA Webpage – Real World Evidence

Link: https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence 

FDA Webpage – 21st Century Cures Act Deliverables

Link: https://www.fda.gov/regulatory-information/21st-century-cures-act/21st-century-cures-act-deliverables