Confirming Hope: Validating Surrogate Endpoints to Support FDA Drug Approval Using an Inter-Agency Approach
To enable more timely access to new drugs and biologics, clinical trials are increasingly using surrogate markers in lieu of traditional clinical outcomes that directly measure how patients feel, function, or survive. Surrogate markers, such as imaging findings or laboratory measurements, are expected to predict clinical outcomes of interest. In comparison to clinical outcomes, surrogate markers offer an advantage in reducing the duration, size, and total cost of trials. Surrogate endpoints are considered to be “validated” if they have undergone extensive testing that confirms their ability to predict a clinical outcome. However, reviews of “validated” surrogate markers used as primary endpoints in trials supporting U.S. Food and Drug Administration (FDA) approvals suggest that many lack sufficient evidence of being associated with a clinical outcome.
Since 2018, FDA has regularly updated the publicly available “Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure”, which includes over 200 surrogate markers that have been or would be accepted by the agency to support approval of a drug or biologic. Not included within the table is information regarding the strength of evidence for each surrogate marker and its association with a clinical outcome. As surrogate markers are increasingly being accepted by FDA to support approval of new drugs and biologics, it is imperative that patients and clinicians understand whether such novel endpoints are reflective of meaningful clinical benefits. Thus, FDA, in collaboration with other agencies, should take steps to increase transparency regarding the strength of evidence for surrogate endpoints used to support product approvals, routinely reassess the evidence behind such endpoints to continue justifying their use in regulatory decision-making, and sunset those that fail to show association with meaningful clinical outcomes. Such transparency would not only benefit the public, clinicians, and the payers responsible for coverage decisions, but also help shape the innovation landscape for drug developers to design clinical trials that assess endpoints truly reflective of clinical efficacy.
Challenge and Opportunity
To receive regulatory approval by FDA, new therapeutics are generally required to be supported by “substantial evidence of effectiveness” from two or more “adequate and well-controlled” pivotal trials. However, FDA has maintained a flexible interpretation of this guidance to enable timely access to new treatments. New drugs and biologics can be approved for specific disease indications based on pivotal trials measuring clinical outcomes (how patients feel, function, or survive). They can also be approved based on pivotal trials measuring surrogate markers that are meant to be proxy measures and expected to predict clinical outcomes. Examples of such endpoints include changes in tumor size as seen on imaging or blood laboratory tests such as cholesterol.
Surrogate markers are considered “validated” when sufficient evidence demonstrates that the endpoint reliably predicts clinical benefit. Such validated surrogate markers are typically the basis of traditional FDA therapeutics approval. However, FDA has also accepted the use of “unvalidated” surrogate endpoints that are reasonably likely to predict clinical benefit as the basis of approval of new therapeutics, particularly if they are being used to treat or prevent a serious or life-threatening disease. Under expedited review pathways, such as accelerated approval that grant drug manufacturers faster FDA market authorization using unvalidated surrogate markers, manufacturers are required to complete an additional clinical trial after approval to confirm the predicted clinical benefit. Should the manufacturer fail to do so, FDA has the authority to withdraw that drug’s particular indication approval.
For drug developers, the use of surrogate markers in clinical trials can shorten the duration, size, and total cost of the pivotal trial. Over time, FDA has increasingly allowed for surrogate markers to be used as primary endpoints in pivotal trials, allowing for shorter clinical trial testing periods and thus faster market access. Moreover, use of unvalidated surrogate markers has grown outside of expedited review pathways such as accelerated approval. One analysis of FDA approved drugs and biologics that received “breakthrough therapy designation” found that among those that received traditional approval, over half were based on pivotal trials using surrogate markers.
While basing FDA approval on surrogate markers can enable more timely market access to novel therapeutics, such endpoints also involve certain trade-offs, including the risk of making erroneous inferences and diminishing certainty about the medical product’s long-term clinical effect. In oncology, evidence suggests that most validation studies of surrogate markers find low correlations with meaningful clinical outcomes such as overall survival or a patient’s quality of life. For instance, in a review of 15 surrogate validation studies conducted by the FDA for oncologic drugs, only one was found to demonstrate a strong correlation between surrogate markers and overall survival. Another study suggested that there are weak or missing correlations between surrogate markers for solid tumors and overall survival. A more recent evaluation found that most surrogate markers used as primary endpoints in clinical trials to support FDA approval of drugs treating non-oncologic chronic disease lack high-strength evidence of associations with clinical outcomes.
Section 3011 of the 21st Century Cures Act of 2016 amended the Federal Food, Drug, and Cosmetic Act to mandate FDA publish a list of “surrogate endpoints which were the basis of approval or licensure (as applicable) of a drug or biological product” under both accelerated and traditional approval pathways. While FDA has posted surrogate endpoint tables for adult and pediatric disease indications that fulfil this legislative requirement, missing within these tables is any justification for surrogate selection, including evidence supporting validation. Without this information, patients, prescribers, and payers are left uncertain about the actual clinical benefit of therapeutics approved by the FDA based on surrogate markers. Instead, drug developers have continued to use this table as a guide in designing their clinical trials, viewing the included surrogate markers as “accepted” by the FDA regardless of the evidence (or lack thereof) undergirding them.
Plan of Action
Recommendation 1. FDA should make more transparent the strength of evidence of surrogate markers included within the “Adult Surrogate Endpoint Table” as well as the “Pediatric Surrogate Endpoint Table.”
Previously, agency officials stated that the use of surrogate markers to support traditional approvals was usually based, at a minimum, on evidence from meta-analyses of clinical trials demonstrating an association between surrogate markers and clinical outcomes for validation. However, more recently, FDA officials have indicated that they consider a “range of sources, including mechanistic evidence that the [surrogate marker] is on the causal pathway of disease, nonclinical models, epidemiologic data, and clinical trial data, including data from the FDA’s own analyses of patient- and trial-level data to determine the quantitative association between the effect of treatment on the [surrogate marker] and the clinical outcomes.” Nevertheless, what specific evidence and how the agency weighed such evidence is not included as part of their published tables of surrogate endpoints, leaving unclear to drug developers as well as patients, clinicians, and payers the strength of the evidence behind such endpoints. Thus, this serves as an opportunity for the agency to enhance their transparency and communication with the public.
FDA should issue a guidance document detailing their current thinking about how surrogate markers should be validated and evaluated on an ongoing basis. Within the guidance, the agency could detail the types of evidence that would be considered to establish surrogacy.
FDA should also include within the tables of surrogate endpoints, a summary of evidence for each surrogate marker listed. This would provide justification (through citations to relevant articles or internal analyses) so that all stakeholders understand the evidence establishing surrogacy. Moreover, FDA can clearly indicate within the tables which clinical outcomes each surrogate marker listed is thought to predict.
FDA should also publicly report on an annual basis a list of therapeutics approved by the agency based on clinical trials using surrogate markers as primary endpoints. This coupled with the additional information around strength of evidence for each surrogate marker would allow patients and clinicians to make more informed decisions around treatments where there may be uncertainty of the therapeutic’s clinical benefit at the time of FDA approval.
Recently, FDA’s Oncology Center for Excellent through Project Confirm has made additional efforts to communicate that status of required postmarketing studies meant to confirm clinical benefit of drugs for oncologic disease indications that received accelerated approval. FDA could further expand this across therapeutic areas and approval pathways by publishing a list of ongoing postmarketing studies for therapeutics where approval was based on surrogate markers that are intended to confirm clinical benefit.
FDA should also regularly convene advisory committees to allow for independent experts to review and vote on recommendations around the use of new surrogate markers for disease indications. Additionally, FDA should regularly convene these advisory committees to re-evaluate the use of surrogate markers based on current evidence, especially those not supported by high-strength evidence demonstrating their association with clinical outcomes. At a minimum, FDA should convene such advisory committees focused on re-examining surrogate markers listed on their publicly available tables annually. In 2024, FDA convened the Oncologic Drugs Advisory Committee to discuss the use of the surrogate marker, minimal residual disease as an endpoint for multiple myeloma. Further such meetings including for those “unvalidated” endpoints would provide FDA opportunity to re-examine their use in regulatory decision-making.
Recommendation 2. In collaboration with the FDA, other federal research agencies should contribute evidence generation to determine whether surrogate markers are appropriate for use in regulatory decision-making, including approval of new therapeutic products and indications for use.
Drug manufacturers that receive FDA approval for products based on unvalidated surrogate markers may not be incentivized to conduct studies that demonstrate a lack of association between such surrogate markers with clinical outcomes. To address this, the Department of Health and Human Services (HHS) should establish an interagency working group including FDA, National Institutes of Health (NIH), Patient Centered Outcomes Research Institute (PCORI), Advanced Research Projects Agency for Health (ARPA-H), Centers for Medicare and Medicaid Services (CMS) and other agencies engaged in biomedical and health services research. These agencies could collaboratively conduct or commission meta-analyses of existing clinical trials to determine whether there is sufficient evidence to establish surrogacy. Such publicly-funded studies would then be brought to FDA advisory committees to be considered by members in making recommendations around the validity of various surrogate endpoints or whether any endpoints without sufficient evidence should be sunset. NIH in particular should prioritize funding large-scale trials aimed at validating important surrogate outcomes.
Through regular collaboration and convening, FDA can help guide the direction of resources towards investigating surrogate markers of key regulatory as well as patient, clinician, and payer interest to strengthen the science behind novel therapeutics. Such information would also be invaluable to drug developers in identifying evidence-based endpoints as part of their clinical trial design, thus contributing to a more efficient research and development landscape.
Recommendation 3. Congress should build upon the provisions related to surrogate markers that passed as part of the 21st Century Cures Act of 2016 in their “Cures 2.0” efforts.
The aforementioned interagency working group convened by HHS could be authorized explicitly through legislation coupled with funding specifically for surrogate marker validation studies. Congress should also mandate that FDA and other federal health agencies re-evaluate listed surrogate endpoints on an annual basis with additional reporting requirements. Additionally, through legislation, FDA could also be granted explicit authority for those endpoints where there is no clear evidence of their surrogacy to sunset them, thus preventing future drug candidates from establishing efficacy based on flawed endpoints. Congress should also require routine reporting from FDA on the status of the interagency working group focused on surrogate endpoints as well as other metrics including a list of new therapeutic approvals based on surrogate markers, expansion of the existing surrogate marker tables on FDA’s website to include the evidence of their surrogacy, and issuance of a guidance document detailing what scientific evidence would be considered by the agency in validating and re-evaluating surrogate markers.
Conclusion
FDA increasingly has allowed new drugs and biologics to be approved based on surrogate markers that are meant to be predictive of meaningful clinical outcomes demonstrating that patients feel better, function better, and survive longer. Although the agency has made more clear what surrogate endpoints could be or are being used to support approval, significant gaps exist in the evidence demonstrating that these novel endpoints are associated with meaningful clinical outcomes. Continued use of surrogate endpoints with little association with clinical benefit leaves patients and clinicians without assurance that novel therapeutics approved by FDA are meaningfully effective, as well as payers responsible for coverage decisions. Transparency of the evidence supporting clinical endpoints is urgently needed to mitigate this uncertainty around new drug approvals, including for drug developers as they continue clinical trials for therapeutic candidates seeking FDA approval. FDA should and in collaboration with other federal biomedical research agencies, routinely re-evaluate surrogate endpoints to determine their continued use in therapeutic innovation. Such regular re-evaluation that informs regulatory decision-making will strengthen FDA’s credibility and ensure accountability of the agency, tasked with ensuring the safety and efficacy of drugs and other medical products as well as with shaping the innovation landscape.
This memo produced as part of the Federation of American Scientists and Good Science Project sprint. Find more ideas at Good Science Project x FAS
Yes. In 2016, eteplirsen (Exondys 51) was granted accelerated approval for the treatment of Duchenne muscular dystrophy (DMD) against the recommendation of an advisory committee and FDA’s own scientific staff. Concerns were raised that the approval was based on a small clinical trial that showed that eteplirsen led to a small increase in protein dystrophin, a surrogate marker. Three additional approvals for similar DMD drugs have been made based on the same surrogate endpoint. However, no studies have been completed providing confirmation of clinical benefit.
In 2021, aducanumab (Aduhelm) was granted accelerated approval for the treatment of Alzheimer’s disease against the recommendation of an advisory committee and FDA’s scientific staff. Concerns were raised that the approval was based on a surrogate marker, beta-amyloid levels, which has not been found to correlate with cognitive or function changes for Alzheimer’s disease patients. In particular, FDA’s internal statistical review team found no association between changes to the surrogate marker and the clinical outcomes reported in pivotal trials.
Industry may claim that such re-evaluation and potential removal of continued unvalidated surrogate endpoints would slow down the pace of innovation and thus, patient access to novel therapeutics. However, it is more likely this would instead enable more efficient drug development in providing manufacturers, particularly smaller companies with surrogate endpoints that not only decrease the duration and cost of clinical trials, but that also have strong evidence of association with meaningful clinical outcomes. This may also mitigate the need for postmarketing requirements for manufacturers meant to confirm clinical benefit if adequate validation is conducted through FDA and other federal agencies.
No. Having FDA in collaboration with other federal health agencies to validate surrogate endpoints would not halt the use of unvalidated surrogate endpoints reasonably likely to predict clinical benefit. Expedited regulatory pathways such as accelerated approval that are codified by law allowing manufacturers to use unvalidated surrogate markers as endpoints in pivotal clinical trials will still be available for manufacturers. Instead, this creates a process for re-evaluation such that unvalidated surrogate endpoints are not forever left unvalidated, but instead examined within a timely manner to inform their continued use in supporting FDA approval. Ultimately, patients and clinicians want drugs that meaningfully work to treat or prevent against a disease or condition. Routine re-evaluation and validation of surrogate endpoints would provide assurance that for those therapeutics whose approval is based off of these novel endpoints that the FDA approved treatment is clinically effective.
FDA’s function as a regulator is to evaluate the evidence that is brought before them by industry sponsors. To do so effectively, the evidence must be available. This is often not the case, particularly for new surrogate markers as there may not be commercial incentive to do so, particularly if after approval, a surrogate endpoint is found to be not associated with a meaningful clinical outcome. Thus, the involvement of multiple federal biomedical research agencies including NIH and ARPA-H alongside FDA can play an instrumental role in conducting or funding studies demonstrating a clear association between surrogate marker and clinical outcome. Already, several institutes within the NIH are engaged in biomarker development and in supporting validation. Collaboration between NIH institutes with expertise as well as other agencies engaged in translational research with FDA will enable validation of surrogate markers to inform regulatory decision-making of novel therapeutics.
Under the Prescription Drug User Fee Act VII passed in 2022, FDA was authorized to establish the Rare Disease Endpoint Advancement (RDEA) pilot program. This program is intended to foster the development of novel endpoints for rare diseases through FDA collaboration with industry sponsors. with proposed novel endpoints for a drug candidate, opportunities for stakeholders including the public to inform such endpoint development, and greater FDA staff capacity to help develop novel endpoints for rare diseases. Such a pilot program could be further expanded to not only develop novel endpoints, but to also develop approaches for validating novel endpoints such as surrogate markers and communicating the strength of evidence to the public.
Payers such as Medicare have also taken steps to enable postmarket evidence generation including for drugs approved by FDA based on surrogate endpoints. Following the accelerated approval of aducanumab (Aduhelm), the Centers for Medicare and Medicaid Services (CMS) issued a national coverage determination under the coverage with evidence development (CED) program, conditioning coverage of this class of drugs to studies approved by CMS approved by FDA based on a surrogate endpoint with access only available through randomized controlled trials assessing meaningful clinical outcomes. Further evaluation of surrogate endpoints informing FDA approval can be beneficial for payers as they make coverage decisions. Additionally, coverage and reimbursement could also be tied to evidence for such surrogate endpoints, providing additional incentive to complete and communicate the findings from such studies.
As surrogate markers are increasingly being accepted by FDA to support approval of new drugs and biologics, it is imperative that patients and clinicians understand whether such novel endpoints are reflective of meaningful clinical benefits.
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