People rely on the U.S. Food and Drug Administration (FDA) to ensure that the drugs and biologics they use have been shown to be safe and effective. Clinical trials are conducted to demonstrate that new medical products deliver a positive balance of benefit and risk.
What are clinical trial endpoints?
A clinical trial’s endpoints measure the outcomes in the trial. When a trial evaluates the efficacy of a new medical product or a new use for an approved product, investigators may choose endpoints that directly measure the clinical outcome they want to study. Alternatively, they may choose an endpoint that is a substitute, or “surrogate”, for the outcome they want to study:
- Clinical outcomes directly measure whether people in a trial feel or function better, or live longer. The benefit or likely benefit of a therapy, as measured by clinical outcomes (e.g., improvement in symptoms), is assessed to determine whether it outweighs any adverse effects (e.g., drug-induced liver injury).
- Surrogate endpoints may be used instead of clinical outcomes in some clinical trials. For example, surrogate endpoints are used when the clinical outcomes, like strokes, might take a very long time to study, or in cases where the clinical benefit of improving the surrogate endpoint, such as controlling blood pressure, is well understood. They are also used in cases where conducing a clinical endpoint study would be unethical. Before a surrogate endpoint can be accepted in place of a clinical outcome, extensive evidence must accumulate, including evidence from epidemiological studies and clinical trials. Usually clinical trials are needed to show that the surrogate endpoint can be relied upon to predict, or correlate with, clinical benefit in a context of use. Surrogate endpoints that have undergone this extensive testing are called validated surrogate endpoints and these are accepted by the FDA as evidence of benefit. Between 2010 and 2012, the FDA approved 45 percent of new drugs based on a surrogate endpoint. Sometimes surrogate endpoints can support an accelerated approval with lesser evidentiary support, when they are “reasonably likely to predict a clinical benefit”, as described below.
Why are surrogate endpoints important for medical product development?
When a surrogate endpoint clearly predicts a beneficial effect through appropriate studies, its use generally allows for more efficient drug development programs. For example, many clinical trials, using a range of different blood pressure lowering medications, have demonstrated that reducing systolic blood pressure reduced the risk of stroke. Hence, measurement of reduction in the surrogate endpoint of systolic blood pressure can stand in for the clinical outcome of stroke, and clinical trials targeting the reduction of risk of stroke can be conducted more rapidly in smaller populations using this validated surrogate endpoint.
What is a biomarker?
Some surrogate endpoints are a small subclass of biomarkers. More generally, a biomarker is a defined characteristic that is objectively measured as an indicator of normal biological processes, pathologic processes, or responses to an exposure or intervention, including therapeutic interventions.1,2 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 .
There are many different types (e.g., molecular, histologic, radiographic, or physiologic characteristics), classes (e.g., efficacy response, safety, diagnostic)1, and uses of biomarkers (e.g., enrichment, predictive, prognostic), including use as outcomes for clinical trials to support drug and biologic approvals.
What is biomarker qualification?
Many biomarkers used today have been developed for use with a specific disease or as part of the development program for a specific drug. The Biomarker Qualification Program was established to support FDA's work with external stakeholders to develop biomarkers that aid in the drug development process. Through this program biomarker developers may request regulatory qualification of a biomarker for a particular context of use in drug development.
What is the difference between biomarkers and clinical outcome assessments?
Biomarkers should not be confused with clinical outcome assessments (COAs), a parameter that describes or reflects how an individual feels or functions, or how long the person lives. Although COAs are often used to determine whether or not a drug used in a clinical trial provides a treatment benefit, unlike biomarkers, COAs are measured using a report generated by a clinician, patient, non-clinician observer, or a performance-based assessment. For further information on COAs, FDA has created a COA Compendium that summarizes COA information for many different diseases and conditions.
How can biomarkers be used as surrogate endpoints?
A surrogate endpoint is a clinical trial endpoint used as a substitute for a direct measure of how a patient feels, functions, or survives. A surrogate endpoint does not measure the clinical benefit of primary interest in and of itself, but rather is expected to predict that clinical benefit. In general, the predictive nature of a surrogate endpoint is determined through the evaluation of epidemiologic, therapeutic, pathophysiologic, or other scientific evidence.1,3 Surrogate endpoints can be characterized by the level of clinical validation:
- Candidate surrogate endpoint
- Reasonably likely surrogate endpoint
- Validated surrogate endpoint
Candidate surrogate endpoints are still under evaluation for their ability to predict clinical benefit, while validated surrogate endpoints are supported by a clear mechanistic rationale and clinical data providing strong evidence that an effect on the surrogate endpoint predicts a specific clinical benefit. Regarding reasonably likely surrogate endpoints, see the next section.
What is the challenge of using novel biomarkers as reasonably likely surrogate endpoints in medical product development?
Reasonably likely surrogate endpoints are supported by strong mechanistic and/or epidemiologic rationale, but the amount of clinical data available is not sufficient to show that they are a validated surrogate endpoint . Reasonably likely surrogate endpoints can be used to support FDA’s Accelerated Approval program, which is intended to provide patients with serious diseases more rapid access to promising therapies.
In the post-marketing setting, additional data has been collected to determine if the reasonably likely surrogate endpoint, in fact, predicts the clinical benefit1,1,2This approach underscores the importance of continued evaluation in the post-market phase when products are approved based upon reasonably likely surrogate endpoints that have not been validated. It also underscores the need to rigorously evaluate and sometimes re-evaluate surrogate endpoints clinically, based on current scientific understanding.
List of surrogate endpoints used for traditional and accelerated approval
Surrogate endpoints are used in clinical trials submitted to support either traditional or accelerated approval of drugs and biologics. Under Section 507 of the Federal Food, Drug, and Cosmetic Act, as amended by the 21st Century Cures Act, FDA must make public a list of “surrogate endpoints which were the basis of approval or licensure (as applicable) of a drug or biological product.” FDA’s Surrogate Endpoint Table:
- Includes surrogate endpoints that sponsors have used as primary efficacy clinical trial endpoints for approval of new drug applications (NDAs) or biologics license applications (BLAs).
- Includes surrogate endpoints that the Agency 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.
- Is intended to provide greater clarity for drug developers, and will help facilitate discussions of potential surrogate endpoints with FDA review divisions, potentially speeding up drug and biologic development.
Type C meeting for discussion of novel surrogate endpoints
Ongoing discussions between FDA and sponsors are an important part of any drug development program. For a new biomarker intended as a surrogate endpoint, early consultation gives the division an opportunity to provide input and guidance at the beginning of the process of biomarker development, and to work collaboratively with the sponsor over the course of development.
Based on our PDUFA VI Commitment letter.4 , we intend to utilize the type C meeting process to engage with sponsors who would like to employ a biomarker as a surrogate endpoint that has not been used previously as the primary basis for product approval in the proposed context of use. This meeting will apply to new surrogate endpoints in support of either accelerated or traditional approval.
The purpose of this meeting is to discuss the feasibility of the surrogate as a primary efficacy endpoint, identify any gaps in knowledge that may exist, and discuss how those gaps could be addressed. Depending on the level of evidence provided, the outcome of this meeting may be that the sponsor needs to conduct further investigations to address issues raised by the Agency before the surrogate endpoint can be used as the primary basis for product approval.
This meeting is expected to occur when the sponsor has preliminary clinical study results that show that the proposed biomarker responds to the candidate drug at doses that appear to be generally tolerable. To qualify for this consultation, requests for this Type C meeting should be accompanied by the complete meeting background package.4
Please refer to the link below for a summary of content areas that a sponsor may want to consider including in the meeting background package when they submit their Type C meeting request to FDA.
The background package must be comprehensive and formatted according to the guidelines in the FDA PDUFA meetings guidance.5
2 FD&C Act section 507(e)(1);
3 FD&C Act section 507(e)(9);