By Stacy Cline Amin, Morrison & Foerster; former chief counsel of the FDA
Health policy experts have talked excitedly about the potential for real-world evidence (RWE) to transform healthcare delivery and drug development for years. But the regulatory framework has remained in a state of infancy, despite Congress’s focus on developing alternative data sources to speed drug development. However, the COVID-19 pandemic has brought new urgency to the FDA’s efforts to advance RWE into its toddler growth spurt.
The first major leap forward occurred in the 21st Century Cures Act of 2016. While developing this law, Congress spent years studying why drug development takes so long and what needed to change to bring innovations to patents faster and more efficiently. What we discovered through that deliberative process were key drawbacks to the “gold standard” traditional randomized, controlled clinical trials that FDA required for a new drug approval. Among those drawbacks:
- The costs of traditional drug development are enormous, with the median cost of a Phase 3 clinical trial exceeding $100 million and the cost of bringing a new drug to market exceeding $1.3 billion.
- Trials designed to support regulatory approvals are framed to produce clear answers to narrow research questions defined at the outset of a trial. This framing doesn’t always reflect real-world medical practice or the wealth of information that could be useful to informing that practice.
- Participants in these trials often do not reflect the diversity of the real world and the settings in which treatment occurs, and they can differ in terms of sociodemographic characteristics, the likelihood of disease recovery or recurrence, comorbidities or conditions, and likelihood of treatment adherence.
- The cost and time involved in a trial often means limited numbers of patients enrolled and limiting assessment of the trial to intermediate or surrogate outcomes rather than full recovery or prevention or more significant improvements.
In response, the 21st Century Cures Act added Section 505F to the Federal Food, Drug, and Cosmetic Act, which requires FDA to evaluate the potential for RWE to support the approval of new indications in previously approved drugs and to support post-approval study requirements. Some in Congress and the healthcare industry would have gone much further, advocating for RWE to support conditional approvals, but this language was a compromise to take baby steps toward considering the use of RWE for regulatory decisions.
The statute defined RWE broadly to mean data regarding usage derived from sources other than randomized clinical trials. The law required FDA to publish draft guidance within five years that would inform when drug sponsors may rely on RWE for approvals and post-approval studies and the appropriate standards and methodologies for collection and analysis of such RWE. FDA has taken its mandate seriously, with leadership at the agency fully supportive of the goals of advancing RWE.
COVID-19 Spurs FDA To Look For Alternative Sources Of Data
COVID-19 has been the single greatest catalyst for the advancement of RWE. I lived through those dark early days of the pandemic, when the scientists at our public health agencies struggled to understand the virus – how it transmitted, how it impacted the body, and why some people responded so severely worse to infection than others.
In March 2020, FDA’s access to real-time clinical data was haphazard at best. The agency would hear anecdotal reports from sources at random, but there was no infrastructure in place to receive real-time data from the vast network of interoperable health reporting systems that the agency needed.
Moreover, FDA was faced with implementing an extremely flexible, vague emergency use authority that required little more than “the potential benefits” of a medical product “outweigh the potential risks.” Legal arguments could be made, and were made by many, that in the face of lockdowns and mass catastrophic death, with no approved or authorized therapeutics and very few possibilities in the pipeline, nearly anything with a strong safety profile and a glimmer of efficacy in the data would meet the emergency use standard.
Without time for the gold standard of blinded controlled clinical trials, FDA had to pivot to finding and using data sources that it never previously would have relied on for regulatory decisions. Some of those decisions have been criticized in hindsight, but what everyone seems to agree on is that FDA desperately needed more access to more data.
What I can say from my experience at FDA is that the agency experienced a cultural shift in its willingness to consider and even rely on RWE to inform policy and regulatory decision-making. The agency also undertook huge efforts during that time to improve its access to such data. Those efforts were led by Dr. Amy Abernethy to advance collaborations with public and private partners to collect and analyze a variety of real-world data sources.
It has been heartening to see this work continue with exciting recent announcements from FDA:
- The PDUFA (Prescription Drug User Fee Act) VII commitment letter included FDA’s commitment to continue working with stakeholders on the use of RWE to support efficacy and safety information, particularly with respect to rare and ultra-rare diseases.
- In July 2021, FDA announced the approval of a new use of a transplant drug, Prograf, based on an observational study that provided RWE of effectiveness. The drug was approved for use in combination with other drugs to prevent organ rejection in patients receiving lung transplants.
- Most recently, FDA expanded a research collaboration agreement with healthcare analytics company Aetion to study COVID-19 medical products and develop a framework and infrastructure that will support FDA’s data modernization goals.
New FDA Documents Provide Guidance For Using RWE
FDA’s recent work has also included two draft guidance documents, required by the 21st Century Cures Act, that provide critical information to developers trying to use RWE. Both guidances have a 60-day comment period and have generated significant stakeholder interest.
The first draft guidance, Real World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products, issued in September 2021. This guidance provides considerations when sponsors or others are intending to use electronic health records (EHRs) or medical claims data in clinical studies to support a regulatory decision on effectiveness or safety.
The guidance discusses three key factors in relying on these kinds of data: 1) that the data sources appropriately address the study question and population, 2) that the study develops and validates definitions for study design elements, and 3) the importance of data provenance and quality.
FDA advises that for all studies using EHRs, sponsors should seek the relevant review division’s input on protocols and statistical analysis plans before conducting the study. The guidance also discusses considerations for assessing the relevance and reliability of the data in a protocol submitted to the agency, including the appropriateness and limitations of certain data sources; time periods for ascertainment of study design elements; definitions for study design elements (such as inclusion/exclusion criteria) and validation studies; and quality assurance and quality control procedures. The guidance then provides detailed recommendations for each of those categories.
Stakeholders were still excitedly digesting the September guidance when FDA dropped a second draft guidance on October 21, Data Standards for Drug and Biological Product Submissions Containing Real-World Data. This guidance addresses real-world data (RWD) from EHRs, medical claims data, data from product and disease registries, patient generated data, and data from alternative sources that can provide information on health status, such as mobile devices.
RWD that comes from these sources to support NDAs, ANDAs, BLAs, and certain INDs must be in an electronic format that FDA can process as part of a normal drug application that is submitted electronically, consistent with the technical recommendations made in previous FDA guidance for electronic submissions.
FDA recognizes the difficulty of standardizing data derived from RWD sources given the variety of sources and their inconsistent formats, standards, terminologies, exchange formats, methodologies and algorithms, and other aspects that can impact data quality. FDA advises that for now, sponsors should submit data using the formats described in the Study Data Catalog, but FDA intends to issue further guidance on this or update the catalog in the future.
FDA also notes in the guidance that it realizes there are differences between RWD sources and FDA-supported data standards. For example, how race/ethnicity or male/female is recorded could vary. FDA recommends that sponsors document how they choose to submit data and provide a general description of the approach with a data dictionary.
Based on continued interest from Congress and the healthcare industry in the development of RWE policies and the urgency of identifying diverse real-world data sources to further inform FDA’s science-based response to the COVID-19 public health emergency, I expect RWE to continue to be top of mind for FDA leadership.
About The Author:
Stacy Cline Amin co-leads Morrison & Foerster’s FDA Regulatory & Compliance practice. She previously served as chief counsel of the U.S. Food and Drug Administration and chief counsel of the Senate Health Committee. She provides clients with an insider’s perspective on regulatory and compliance issues, enforcement actions, and litigation challenges.