FDA approves new use of transplant drug based on real-world evidence

The US FDA recently approved a new use of a transplant drug based on real-world evidence (RWE). It provides an opportunity to learn more above the use of real world data (RWD) and real world evidence (RWE) in drug reegistration.

Approval of Prograf in combination with other immunosuppressants for a new indication

Prograf (tacrolimus) in combination with other immunosuppressant drugs was approved for the new indication of preventing organ rejection in adult and pediatric patients receiving lung transplantation.

The approval was based on a non-interventional (observational) study providing real-world evidence (RWE) of effectiveness. This is the first time that an immunosuppressant drug has been approved to prevent lung transplant rejection. Prograf is the only approved immunosuppressant drug product for this population. 

Why is this approval significant?

The approval is 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. It also demonstrates how real-world evidence (RWE) can play a significant role in regulatory decision-making when appropriate

About real-world data (RWD) and real world evidence (RWE)

The FDA’s defines RWE and RWD as follows:

RWE is the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from the analysis of RWD.

RWD is defined as 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.

The link between RWD and RWE

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.

What legislation underpins the use of RWE?

The 21st Century Cures Act (Cures Act) was signed into law in 2016. It 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.

Through which study designs can RWE be generated and what regulatory requirements must it meet?

RWE can be generated through a variety of study designs, including randomized controlled clinical trials and observational studies.

Any use of RWD and RWE to support a regulatory decision is subject to FDA’s legal and scientific evidentiary standards. 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.

Regulatory Decision-Making for the New Prograf Indication
  • 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.
What was used as confrmatory evidence of the effectiveness of Prograf?

Randomised 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.  

The use of RWD and RWE in drug development

This approval has the scope to prompt stakeholders to consider the role that RWD can play in various study designs.

Since 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 in question led to the observed outcome or if other factors which led a practitioner to select a particular drug for a patient influenced the outcome.

Whilst the above concerns were addressed adequately in the Prograf study, randomised 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.  

This approval of a new indication for Prograf demonstrates that a non-interventional study has the potential to meet FDA’s regulatory standards for an adequate and well-controlled clinical study.

Source: FDA website