U.S. flag An official website of the United States government
  1. Home
  2. Drugs
  3. News & Events for Human Drugs
  4. From Our Perspective
  5. FDA Approval Demonstrates the Role of Real-World Evidence in Regulatory Decision-Making on Drug Effectiveness
  1. From Our Perspective

FDA Approval Demonstrates the Role of Real-World Evidence in Regulatory Decision-Making on Drug Effectiveness

Ozlem Belen, MD, MPH
Ozlem Belen, MD, MPH
John Concato, MD, MPH, MS
John Concato, MD, MPH, MS
Stefanie Kraus, JD, MPH
Stefanie Kraus, JD, MPH

Ozlem Belen, MD, MPH, Deputy Director of the Division of Rheumatology and Transplant Medicine, Office of New Drugs

John Concato, MD, MPH, MS, Associate Director of Real-World Evidence Analytics, Office of Medical Policy

Stefanie Kraus, JD, MPH, Senior Regulatory Counsel, Office of Regulatory Policy

FDA recently approved Prograf (tacrolimus) in combination with other immunosuppressant drugs for the new indication of preventing organ rejection in adult and pediatric patients receiving lung transplantation. This action marked the first approval of an immunosuppressant drug to prevent lung transplant rejection. The approval is also significant because it reflects how a well-designed, non-interventional (observational) study relying on fit-for-purpose (i.e., reliable and relevant) real-world data (RWD), when compared to a suitable control, can be considered adequate and well-controlled under FDA regulations.

Real-World Evidence and Its Role in Regulatory Decisions

As demonstrated by the Prograf approval for the indication of preventing organ rejection in adult and pediatric patients receiving lung transplants, real-world evidence (RWE) can play a significant role in regulatory decision-making when appropriate. According to FDA’s definition, RWE is the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from the analysis of RWD.

FDA defines RWD as data about a patient's health status and/or the delivery of health care routinely collected from a variety of sources, including health care provider records, medical and pharmacy claims, and disease registries. RWD can also be collected outside the health care setting — for instance, data from mobile technologies that gather biometric information.

Fit-for-purpose RWD may be used to generate RWE that FDA can consider when making regulatory decisions about the safety and effectiveness of medical products — such as identifying new safety issues with a drug after it is approved or helping to determine the effectiveness of a drug for a new indication or patient population.

The 21st Century Cures Act (Cures Act), signed into law in 2016, is designed to accelerate medical product development and bring new innovations and advances faster and more efficiently to patients who need them. The Cures Act required FDA to publish a framework for a program to evaluate the use of RWE in regulatory decision-making; FDA published the framework for its RWE Program in December 2018.

As part of its RWE Program, FDA committed to understanding the full potential of RWD and RWE in regulatory decision-making. The agency has been holding workshops, funding demonstration projects, creating mobile and web applications that can collect RWD, and engaging with sponsors on the topic.

Regulatory Decision-Making for the New Prograf Indication

Any use of RWD and RWE to support a regulatory decision is subject to FDA’s legal and scientific evidentiary standards. RWE can be generated through a variety of study designs, including randomized controlled clinical trials and observational studies. When included in a marketing application as an adequate and well-controlled study as part of demonstrating substantial evidence of effectiveness, such a study must meet FDA’s regulatory requirements under 21 CFR 314.126.

FDA determined that the non-interventional study supporting the Prograf approval for the lung transplantation indication, when compared with historical controls, met FDA’s evidentiary standards for an adequate and well-controlled study. Specifically, the non-interventional study used RWD from the U.S. Scientific Registry of Transplant Recipients, supported by the Department of Health and Human Services. The data were collected on all lung transplants in the U.S. and were supplemented by information from the Social Security Administration’s Death Master File as a trusted repository of mortality data. A dramatic improvement in outcomes was observed among lung transplant patients receiving Prograf as part of their immunosuppression regimen compared to the well-documented natural history of patients receiving a transplanted lung with no or minimal immunosuppressive therapy. The clinical benefit seen with the tacrolimus-containing immunosuppressive regimen was so large compared to these controls that bias was highly unlikely to explain the outcome differences.

Randomized controlled trials of Prograf used in other solid organ transplant settings provided confirmatory evidence of effectiveness. Additional clinical trial evidence from research publications supported the independent contribution of Prograf as part of a multidrug immunosuppressive regimen.  

It is important to note that Prograf should only be prescribed by physicians experienced in immunosuppressive therapy and organ transplant management, and patients receiving the drug should be treated in facilities equipped and staffed with adequate laboratory and supportive medical resources. Prograf is associated with increased risk of developing lymphoma and other malignancies and is also associated with increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections (infectious that occur more often or are more severe in people with weakened immune systems).

The Future of RWD and RWE in Drug Development

This approval may prompt stakeholders to consider the role that RWD can play in various study designs. Given that treatment assignment in a non-interventional study is based on clinical judgment rather than a protocol-based assignment, confounding and other sources of bias can create challenges in determining whether the drug led to the observed outcome or if other factors that led a practitioner to select a particular drug for a patient influenced the outcome. Although these concerns were addressed in the Prograf study, randomized and other types of clinical trials are still generally the most reliable way to assess the potential effectiveness of a drug and these trials will remain a critical part of the drug development process. Accordingly, FDA will continue to individually review each drug development program and marketing application that includes RWE based on legal and scientific standards.  

As the approval of a new indication for Prograf demonstrates, a non-interventional study has the potential to meet FDA’s regulatory standards for an adequate and well-controlled clinical study. As research methods and technologies continue to evolve and RWD data quality and methods of analysis improve, RWD and RWE may play an increasing role in FDA’s regulatory decisions.  

Back to Top