The public posting of a surrogate endpoint (SE) table for both reasonably likely and validated SEs was mandated by the 21st Century Cures Act of 2016 and was achieved in July 2018. The SE table increases transparency by informing stakeholders about the development of novel SEs. It also provides consistency in the application of existing endpoints to drug development programs, thus expediting drug development according to comprehensive criteria. A compiled list of SEs can thus assist in identifying potential case studies for the development of scientific policy around the acceptability of novel SEs. The SE table increases transparency and expedites drug development.
Understanding the Challenge
FDA has a long history of using judiciously reasoned surrogate endpoints (SEs) to expedite patient access to safe and effective treatments for serious conditions. SEs are biomarkers that are reasonably likely to predict a clinical benefit but are not themselves a measure of clinical benefit. Common examples include blood pressure, hemoglobin A1c, and HIV viral load. Section 3011 of the 21st Century Cures Act established Section 507 of the Federal Food, Drug, and Cosmetic Act of 1938 (FD&C Act) for the qualification of drug development tools. That section required FDA to create a list of “... surrogate endpoints which were the basis of approval or licensure (as applicable) of a drug or biological product...” for both traditional and accelerated approval.
Prior to this legislative requirement there had been multiple congressional requests for FDA to prepare an SE table over the years, but efforts to compile and tabulate SEs properly were hampered by various issues. One of those issues was the lack of standardized definitions for SEs, biomarkers, and drug development tools. Section 507 of the FD&C Act provided a number of definitions, including those pertinent to SEs, and mandated the establishment of a “taxonomy for the classification of biomarkers (and related scientific concepts) for use in drug development.” FDA’s work in response to that mandate resulted in creation of the BEST (Biomarkers, EndpointS, and other Tools) Resource.
FDA’s Work to Address Transparency and Expedite Drug Development: Establishing an SE Table
The CDER Office of New Drugs (OND) worked with the CDER and CBER review divisions to curate the SE list for both accuracy and completeness for subsequent publication on a CDER-hosted website. This project has allowed OND scientists to evaluate how SEs are used in drug approvals; to classify them using the current version of the BEST resource and the Section 507 definitions; and to look more broadly for SEs that are included in existing guidance and other internal resources. Although there is a misconception in the drug development community that SEs are used only in a few clinical areas, the SE table demonstrates that FDA uses SEs for many different diseases. As part of FDA’s commitment to transparency, the SE table is updated at six-month intervals to reflect current thinking and to fulfil the legislative mandate.
Although the requirement called for a list of those SEs used in traditional and accelerated approvals, OND staff worked further to include SEs mined from documentation (i.e., meeting minutes) from 2,444 end-of-phase-2 meetings, and from 219 special protocol assessment meetings, and from otherwise endorsed sources (e.g., guidance documents). We also relied on previous SE compilation efforts and divisional knowledge, especially for SEs in disease categories for which no new drug had been developed for some time (e.g., conditions related to thyroid disease ). Through close collaboration with CDER and CBER review divisions, OND ultimately compiled the SE table that was released on July 25, 2018.
A major consideration in the development of the SE table was to provide consistency across review division areas of expertise. This consideration, along with the goal of providing data as efficiently as possible, resulted in five column headings: disease/use, patient population, surrogate endpoint, type of approval appropriate for (accelerated or traditional), and drug mechanism of action. For each entry (i.e., row), the disease/use and patient population columns combined represent the indication in general terms. For the sake of conciseness, detailed qualifiers, such as time points for measurement, rates, and population characteristics were excluded whenever appropriate. Enough flexibility was nevertheless built into the table to allow for important details to be captured as appropriate for the given disease area. For example, oncology SEs were the most generalized, based on the many different SEs and patient population combinations in this space and in consideration of the ever-changing oncology landscape.
Highlights of the SE Table
There were 101 adult and 56 pediatric entries listed in the first release of the SE table. Since then, the table has been expanded and updated three times. Prior to the release of the table, there was the common misconception that FDA approved therapeutics based on few SEs (e.g. HIV viral load, blood pressure and hemoglobin A1c) in a small number of disease areas, but the table shows that SEs are used in many more different contexts than had been assumed. In conjunction with the release of the table, we established the Surrogate Endpoint Resources for Drug and Biologic Development website to provide a portal to SE-related resources at FDA. That website includes a link to the Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure webpage.
The SE table allows stakeholders to determine what SEs might reasonably be used for marketing applications, thereby enabling transparency and expediting future drug development. The table provides drug developers with information that can potentially accelerate their programs because the use of SEs can provide information on drug efficacy faster than clinical endpoints. The information in the table may also help facilitate the development of novel SEs, effectively providing a source of case studies for consideration in the development of scientific policy around the acceptability of novel SEs. A PDUFA VI-mandated Type C Surrogate Endpoint meeting was instituted in 2018 for sponsors that would like to employ a SE biomarker that has not been used as the primary basis for product approval in the proposed context of use. Together with the Considerations for Discussion of a New Surrogate Endpoint(s) at a Type C PDUFA Meeting Request document, which provides information on content areas that a sponsor should include in submitting a Type C SE meeting request, the SE table is an important resource for sponsors wishing to incorporate SEs effectively into their drug development programs.
How does the posting of a comprehensive Surrogate Endpoint (SE) Table support development of CDER- and CBER-regulated products?
The SE table project advances FDA’s mission to protect and promote public health by informing stakeholders about SEs that might reasonably advance and enhance scientific approaches to developing new drugs intended to satisfy FDA standards of safety and efficacy.
- Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics Guidance for Industry
- Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics
- CDER Small Business and Industry Association (SBIA) Chronicles Article and Podcast on Early Engagement with FDA to Discuss Novel Surrogate Endpoints