Welcome to the CDER Small Business and Industry Assistance (SBIA) Podcast Series.

Today’s topic is ‘FDA Facilitates the Use of Surrogate Endpoints in Drug Development’.

We would like to introduce Dr. Abena Agyeman, Science Policy Analyst for the Biomarker Development and Regulatory Science Team in FDA’s Center for Drug Evaluation and Research, Office of New Drugs.

Thanks for having me! To enhance the use of surrogate endpoints, in drug development, expand existing transparency initiatives, and facilitate the development of new and innovative products for patients, the FDA has made available a Table of Surrogate Endpoints (or SEs) That Were the Basis of Drug Approval or Licensure. This table lists SEs the FDA has accepted or could accept as primary efficacy endpoints in drug development programs. FDA is also accepting Type C IND meeting requests focused on potential novel SEs that may be used in drug development programs.

An SE is a substitute for measuring a clinical outcome studied in a trial and is not itself a direct measure of clinical benefit but is known to predict clinical benefit.  Before an SE can be accepted in place of a clinical outcome, there must be extensive evidence showing that it can be relied upon to predict, or correlate with clinical benefit.  From a regulatory standpoint, SEs can be characterized by the level of clinical validation:

• Validated SEs that can reliably predict a clinical outcome, are accepted by FDA as evidence of benefit, and can be used to support traditional approval. They are supported by a clear mechanistic rationale and clinical data providing strong evidence that an effect on the SE has a specific clinical benefit.
• Reasonably likely SEs are reasonably likely to predict a clinical benefit. They are supported by strong mechanistic and/or epidemiologic rationale, but the amount of clinical data available is not sufficient to show that they are validated. They can be used to support accelerated approval, but post-approval clinical trials are needed to show that these SEs can be relied upon to predict, or correlate with, clinical benefit.
• Candidate SEs are still under evaluation for their ability to predict clinical benefit.

SEs may be used when testing new therapies and new indications for existing therapies. When an SE shows a beneficial effect through appropriate studies, its use may allow clinical trials to be conducted in smaller numbers of patients over shorter periods of time.

Whereas clinical outcomes directly measure efficacy, SEs involve measuring a substitute that predicts the clinical outcome. SEs may be a good alternative in cases where it may take a long time to see an effect in treatment for a disease, where the clinical benefit of improving the SE is well understood, or when conducting a clinical endpoint study would be unethical.

Some SEs are a small subclass of biomarkers. In general, a biomarker is a defined characteristic that is objectively measured as an indicator of a normal biological process, a pathologic process, or a response to an exposure or intervention, including a therapeutic intervention. In a drug development context, biomarkers may be used for several different purposes, such as identifying patients for clinical trial enrollment, monitoring the safety of a therapy, or finding out if a treatment is having the desired effect on the body. The Biomarker Qualification Program allows drug developers to request regulatory qualification of a biomarker for a particular context of use in drug development. 

The Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure lists SEs that sponsors have used as primary efficacy clinical trial endpoints for approval of new drug applications (NDAs) or biologics license applications (BLAs). It also includes SEs that FDA anticipates could be appropriate for use as a primary efficacy clinical trial endpoint for drug or biologic approval, although they have not yet been used to support an approved NDA or licensed BLA. 

The information in the table is intended to provide greater clarity for drug developers on SEs that may be considered and discussed with FDA for individual development programs.

Note that:

• The information is intended to facilitate but not replace discussions of individual drug development programs between the sponsor and the appropriate review division.
• The acceptability of the SEs for use in a particular drug or biologic development program will be determined on a case-by-case basis and is context-dependent.
• An SE should not be assumed to be appropriate for use in a different program and/or in a different clinical setting.
• If an SE was previously used to support accelerated approval of a drug or biologic but subsequent confirmatory trials failed to demonstrate the expected clinical benefit, it would no longer be accepted for this use and is not included on the table.
• The table also does not include SEs that may have been accepted for past programs but are no longer acceptable as an endpoint to support registration. It also does not include product names or composite endpoints that are a combination of biomarker SEs plus clinical endpoints or clinical outcome assessments.
• Separate adult and pediatric sections are provided. Pharmacokinetic endpoints that have supported extrapolation from adults to children are not included in the pediatric section.  

When an SE clearly predicts a beneficial effect through appropriate studies, its use generally allows for more efficient drug development programs. The use of SEs for certain clinical studies has helped to expedite drug development. As science and technology advance, increased use of biomarkers and SEs will hopefully facilitate the more efficient development of safe and effective medical products.

A link to the full SBIA Chronicles article and more information about CDER’s SBIA Program can be found at: www.fda.gov/cdersbia. Thanks for tuning in!