Current challenges of the proposed framework for the pharmaceutical industry

The new draft framework leaves some significant gaps with regard to a defined approach that pharmaceutical manufacturers should take in their RWE trial design for regulatory approval. The guidelines do not yet completely define the RWE trial design approaches that are approvable, nor the regulatory submission process. The FDA had an open comment period and is expected to finalize RWE guidance in the future.


The FDA has stated they will review RWE submissions on a case-by-case basis and will use three criteria for evaluation:


  1. If the RWD selected is fit for use to generate data for product effectiveness decisions
  2. If the study design used to generate RWE can provide robust scientific evidence to help address the regulatory question
  3. If the execution of the studies generating RWE meets FDA regulatory requirements


The last criterium forms a catch-22 as the current FDA regulatory requirements regarding RWE do not specifically outline use in regulatory approval. Several FDA regulations and guidance documents are available for the use of electronic data, eHealth records in clinical investigations, electronic informed consents Q&A’s that could potentially be used for the FDA RWE program. These include Electronic Source Data in Clinical Investigations and Use of Electronic Health Records in Clinical Investigations, among others. Per the draft guidance: “FDA has gained considerable experience assessing electronic health care data (e.g., EHRs, medical claims data, registries) through experience with the Sentinel System and other data systems.” The FDA will be using this experience to guide their perspective on data submissions within the RWE Program.

Pharmaceutical manufacturers must seek guidance from the FDA for each trial design proposed to ensure regulatory processes are met. With this draft framework publication, a number of areas are yet to be defined, according to the FDA. The FDA has stated the intention to updated and design guidance on how to include RWD to design both randomized and non-randomized hybrid clinical trials as well as observational studies. To achieve this, the FDA directly outlines in the draft guidance the factors that would need to be considered such as:


a. Types of interventions or therapeutic areas for which routine clinical data could be used

b. The reliability and quality of data collected from the routine clinical care settings

c. If outcomes are rare, the number of patients need to be tested

d. How to account for variations in routine clinical practice

e. The extent to which randomization can and should be included

The FDA provided this draft framework with an 8-week period solicitation period for suggestions and feedback. A mature form of the framework is expected in the future. The FDA states that the RWE Program “…will involve the establishment of demonstration projects, engagement with stakeholders intended to promote shared learning and consistency in applying the framework, and the development of guidance documents to assist sponsors interested in using RWE to support their work.” The RWE framework will also include data standards for collection, analysis and submission of RWD. The need for RWE data may spur the need to develop a common data model (CDM) in order to work with RWD across different sources. The CDM would unify terminology, vocabularies, and coding schemes. It will be incumbent on pharmaceutical manufacturers and clinicians to remain actively involved in the development of the final FDA RWE guidance.

The FDA intends to review gaps in both the RWE Framework and in RWE data systems as well as the interoperability and provide strategies to address them. The following summarizes gaps currently identified by the FDA which may need to be addressed while framing guidance for the RWE program.


1. Lack of enough data showing concordance between the results of traditional clinical trials vs. observational studies

2. Lack of reporting requirements for various observational studies

3. Lack of data recording standards and interoperability across various health care data collection systems

4. Challenges in integrating data for the same patient across various data sources

5. Challenges in collecting data from electronic patient reported outcomes, wearables, biosensors and mobile app


Interestingly, the RWE framework also opens the door for possible inclusion of data derived from outside of the United States of America. The continued evaluation and publication of data and systems gaps with strategic recommendations by the FDA will have to address how to support these issues and how to address HIPPA within RWE.