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Over the past few decades, the US Food and Drug Administration (FDA) has increasingly relied on surrogate measures such as blood tests instead of clinical outcomes for medication approvals. But critics say the agency lacks consistent standards to ensure the surrogate aligns with clinical outcomes that matter to patients — things like improvements in symptoms and gains in function.
Sometimes those decisions backfire. Consider: In July 2021, the FDA approved aducanumab for the treatment of Alzheimer’s disease, bucking the advice of an advisory panel for the agency that questioned the effectiveness of the medication. Regulators relied on data from the drugmaker, Biogen, showing the monoclonal antibody could reduce levels of amyloid beta plaques in blood — a surrogate marker officials hoped would translate to clinical benefit.
The FDA’s decision triggered significant controversy, and Biogen in January announced it is pulling it from the market this year, citing disappointing sales.
Although the case of aducanumab might seem extreme, given the stakes — Alzheimer’s remains a disease without an effective treatment — it’s far from unusual.
“When we prescribe a drug, there is an underlying assumption that the FDA has done its due diligence to confirm the drug is safe and of benefit,” said Reshma Ramachandran, MD, MPP, MHS, a researcher at Yale School of Medicine, New Haven, Connecticut, and a coauthor of a recent review of surrogate outcomes. “In fact, we found either no evidence or low-quality evidence.” Such markers are associated with clinical outcomes. “We just don’t know if they work meaningfully to treat the patient’s condition. The results were pretty shocking for us,” she said.
The FDA in 2018 released an Adult Surrogate Endpoint Table listing markers that can be used as substitutes for clinical outcomes to more quickly test, review, and approve new therapies. The analysis found the majority of these endpoints lacked subsequent confirmations, defined as published meta-analyses of clinical studies to validate the association between the marker and a clinical outcome important to patients.
In a paper published in JAMA, Dr. Ramachandran and her colleagues looked at 37 surrogate endpoints for nearly 3 dozen nononcologic diseases in the table.
Approval with surrogate markers implies responsibility for postapproval or validation studies — not just lab measures or imaging findings but mortality, morbidity, or improved quality of life, said Joshua D. Wallach, PhD, MS, assistant professor in the department of epidemiology at the Emory Rollins School of Public Health in Atlanta and lead author of the JAMA review.
Dr. Wallach said surrogate markers are easier to measure and do not require large and long trials. But the FDA has not provided clear rules for what makes a surrogate marker valid in clinical trials.
“They’ve said that at a minimum, it requires meta-analytical evidence from studies that have looked at the correlation or the association between the surrogate and the clinical outcome,” Dr. Wallach said. “Our understanding was that if that’s a minimum expectation, we should be able to find those studies in the literature. And the reality is that we were unable to find evidence from those types of studies supporting the association between the surrogate and the clinical outcome.”
Physicians generally do not receive training about the FDA approval process and the difference between biomarkers, surrogate markers, and clinical endpoints, Dr. Ramachandran said. “Our study shows that things are much more uncertain than we thought when it comes to the prescribing of new drugs,” she said.
Surrogate Markers on the Rise
Dr. Wallach’s group looked for published meta-analyses compiling randomized controlled trials reporting surrogate endpoints for more than 3 dozen chronic nononcologic conditions, including type 2 diabetes, Alzheimer’s, kidney disease, HIV, gout, and lupus. They found no meta-analyses at all for 59% of the surrogate markers, while for those that were studied, few reported high-strength evidence of an association with clinical outcomes.
The findings echo previous research. In a 2020 study in JAMA Network Open, researchers tallied primary endpoints for all FDA approvals of new drugs and therapies during three 3-year periods: 1995-1997, 2005-2007, and 2015-2017. The proportion of products whose approvals were based on the use of clinical endpoints decreased from 43.8% in 1995-1997 to 28.4% in 2005-2007 to 23.3% in 2015-2017. The share based on surrogate endpoints rose from 43.3% to roughly 60% over the same interval.
A 2017 study in the Journal of Health Economics found the use of “imperfect” surrogate endpoints helped support the approval of an average of 16 new drugs per year between 2010 and 2014 compared with six per year from 1998 to 2008.
Similar concerns about weak associations between surrogate markers and drugs used to treat cancer have been documented before, including in a 2020 study published in eClinicalMedicine. The researchers found the surrogate endpoints in the FDA table either were not tested or were tested but proven to be weak surrogates.
“And yet the FDA considered these as good enough not only for accelerated approval but also for regular approval,” said Bishal Gyawali, MD, PhD, associate professor in the department of oncology at Queen’s University, Kingston, Ontario, Canada, who led the group.
The use of surrogate endpoints is also increasing in Europe, said Huseyin Naci, MHS, PhD, associate professor of health policy at the London School of Economics and Political Science in England. He cited a cohort study of 298 randomized clinical trials (RCTs) in JAMA Oncology suggesting “contemporary oncology RCTs now largely measure putative surrogate endpoints.” Dr. Wallach called the FDA’s surrogate table “a great first step toward transparency. But a key column is missing from that table, telling us what is the basis for which the FDA allows drug companies to use the recognized surrogate markers. What is the evidence they are considering?”
If the agency allows companies the flexibility to validate surrogate endpoints, postmarketing studies designed to confirm the clinical utility of those endpoints should follow.
“We obviously want physicians to be guided by evidence when they’re selecting treatments, and they need to be able to interpret the clinical benefits of the drug that they’re prescribing,” he said. “This is really about having the research consumer, patients, and physicians, as well as industry, understand why certain markers are considered and not considered.”
Dr. Wallach reported receiving grants from the FDA (through the Yale University — Mayo Clinic Center of Excellence in Regulatory Science and Innovation), National Institute on Alcohol Abuse and Alcoholism (1K01AA028258), and Johnson & Johnson (through the Yale University Open Data Access Project); and consulting fees from Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC outside the submitted work. Dr. Ramachandran reported receiving grants from the Stavros Niarchos Foundation and FDA; receiving consulting fees from ReAct Action on Antibiotic Resistance strategy policy program outside the submitted work; and serving in an unpaid capacity as chair of the FDA task force for the nonprofit organization Doctors for America and in an unpaid capacity as board president for Universities Allied for Essential Medicines North America.
A version of this article appeared on Medscape.com.
Over the past few decades, the US Food and Drug Administration (FDA) has increasingly relied on surrogate measures such as blood tests instead of clinical outcomes for medication approvals. But critics say the agency lacks consistent standards to ensure the surrogate aligns with clinical outcomes that matter to patients — things like improvements in symptoms and gains in function.
Sometimes those decisions backfire. Consider: In July 2021, the FDA approved aducanumab for the treatment of Alzheimer’s disease, bucking the advice of an advisory panel for the agency that questioned the effectiveness of the medication. Regulators relied on data from the drugmaker, Biogen, showing the monoclonal antibody could reduce levels of amyloid beta plaques in blood — a surrogate marker officials hoped would translate to clinical benefit.
The FDA’s decision triggered significant controversy, and Biogen in January announced it is pulling it from the market this year, citing disappointing sales.
Although the case of aducanumab might seem extreme, given the stakes — Alzheimer’s remains a disease without an effective treatment — it’s far from unusual.
“When we prescribe a drug, there is an underlying assumption that the FDA has done its due diligence to confirm the drug is safe and of benefit,” said Reshma Ramachandran, MD, MPP, MHS, a researcher at Yale School of Medicine, New Haven, Connecticut, and a coauthor of a recent review of surrogate outcomes. “In fact, we found either no evidence or low-quality evidence.” Such markers are associated with clinical outcomes. “We just don’t know if they work meaningfully to treat the patient’s condition. The results were pretty shocking for us,” she said.
The FDA in 2018 released an Adult Surrogate Endpoint Table listing markers that can be used as substitutes for clinical outcomes to more quickly test, review, and approve new therapies. The analysis found the majority of these endpoints lacked subsequent confirmations, defined as published meta-analyses of clinical studies to validate the association between the marker and a clinical outcome important to patients.
In a paper published in JAMA, Dr. Ramachandran and her colleagues looked at 37 surrogate endpoints for nearly 3 dozen nononcologic diseases in the table.
Approval with surrogate markers implies responsibility for postapproval or validation studies — not just lab measures or imaging findings but mortality, morbidity, or improved quality of life, said Joshua D. Wallach, PhD, MS, assistant professor in the department of epidemiology at the Emory Rollins School of Public Health in Atlanta and lead author of the JAMA review.
Dr. Wallach said surrogate markers are easier to measure and do not require large and long trials. But the FDA has not provided clear rules for what makes a surrogate marker valid in clinical trials.
“They’ve said that at a minimum, it requires meta-analytical evidence from studies that have looked at the correlation or the association between the surrogate and the clinical outcome,” Dr. Wallach said. “Our understanding was that if that’s a minimum expectation, we should be able to find those studies in the literature. And the reality is that we were unable to find evidence from those types of studies supporting the association between the surrogate and the clinical outcome.”
Physicians generally do not receive training about the FDA approval process and the difference between biomarkers, surrogate markers, and clinical endpoints, Dr. Ramachandran said. “Our study shows that things are much more uncertain than we thought when it comes to the prescribing of new drugs,” she said.
Surrogate Markers on the Rise
Dr. Wallach’s group looked for published meta-analyses compiling randomized controlled trials reporting surrogate endpoints for more than 3 dozen chronic nononcologic conditions, including type 2 diabetes, Alzheimer’s, kidney disease, HIV, gout, and lupus. They found no meta-analyses at all for 59% of the surrogate markers, while for those that were studied, few reported high-strength evidence of an association with clinical outcomes.
The findings echo previous research. In a 2020 study in JAMA Network Open, researchers tallied primary endpoints for all FDA approvals of new drugs and therapies during three 3-year periods: 1995-1997, 2005-2007, and 2015-2017. The proportion of products whose approvals were based on the use of clinical endpoints decreased from 43.8% in 1995-1997 to 28.4% in 2005-2007 to 23.3% in 2015-2017. The share based on surrogate endpoints rose from 43.3% to roughly 60% over the same interval.
A 2017 study in the Journal of Health Economics found the use of “imperfect” surrogate endpoints helped support the approval of an average of 16 new drugs per year between 2010 and 2014 compared with six per year from 1998 to 2008.
Similar concerns about weak associations between surrogate markers and drugs used to treat cancer have been documented before, including in a 2020 study published in eClinicalMedicine. The researchers found the surrogate endpoints in the FDA table either were not tested or were tested but proven to be weak surrogates.
“And yet the FDA considered these as good enough not only for accelerated approval but also for regular approval,” said Bishal Gyawali, MD, PhD, associate professor in the department of oncology at Queen’s University, Kingston, Ontario, Canada, who led the group.
The use of surrogate endpoints is also increasing in Europe, said Huseyin Naci, MHS, PhD, associate professor of health policy at the London School of Economics and Political Science in England. He cited a cohort study of 298 randomized clinical trials (RCTs) in JAMA Oncology suggesting “contemporary oncology RCTs now largely measure putative surrogate endpoints.” Dr. Wallach called the FDA’s surrogate table “a great first step toward transparency. But a key column is missing from that table, telling us what is the basis for which the FDA allows drug companies to use the recognized surrogate markers. What is the evidence they are considering?”
If the agency allows companies the flexibility to validate surrogate endpoints, postmarketing studies designed to confirm the clinical utility of those endpoints should follow.
“We obviously want physicians to be guided by evidence when they’re selecting treatments, and they need to be able to interpret the clinical benefits of the drug that they’re prescribing,” he said. “This is really about having the research consumer, patients, and physicians, as well as industry, understand why certain markers are considered and not considered.”
Dr. Wallach reported receiving grants from the FDA (through the Yale University — Mayo Clinic Center of Excellence in Regulatory Science and Innovation), National Institute on Alcohol Abuse and Alcoholism (1K01AA028258), and Johnson & Johnson (through the Yale University Open Data Access Project); and consulting fees from Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC outside the submitted work. Dr. Ramachandran reported receiving grants from the Stavros Niarchos Foundation and FDA; receiving consulting fees from ReAct Action on Antibiotic Resistance strategy policy program outside the submitted work; and serving in an unpaid capacity as chair of the FDA task force for the nonprofit organization Doctors for America and in an unpaid capacity as board president for Universities Allied for Essential Medicines North America.
A version of this article appeared on Medscape.com.
Over the past few decades, the US Food and Drug Administration (FDA) has increasingly relied on surrogate measures such as blood tests instead of clinical outcomes for medication approvals. But critics say the agency lacks consistent standards to ensure the surrogate aligns with clinical outcomes that matter to patients — things like improvements in symptoms and gains in function.
Sometimes those decisions backfire. Consider: In July 2021, the FDA approved aducanumab for the treatment of Alzheimer’s disease, bucking the advice of an advisory panel for the agency that questioned the effectiveness of the medication. Regulators relied on data from the drugmaker, Biogen, showing the monoclonal antibody could reduce levels of amyloid beta plaques in blood — a surrogate marker officials hoped would translate to clinical benefit.
The FDA’s decision triggered significant controversy, and Biogen in January announced it is pulling it from the market this year, citing disappointing sales.
Although the case of aducanumab might seem extreme, given the stakes — Alzheimer’s remains a disease without an effective treatment — it’s far from unusual.
“When we prescribe a drug, there is an underlying assumption that the FDA has done its due diligence to confirm the drug is safe and of benefit,” said Reshma Ramachandran, MD, MPP, MHS, a researcher at Yale School of Medicine, New Haven, Connecticut, and a coauthor of a recent review of surrogate outcomes. “In fact, we found either no evidence or low-quality evidence.” Such markers are associated with clinical outcomes. “We just don’t know if they work meaningfully to treat the patient’s condition. The results were pretty shocking for us,” she said.
The FDA in 2018 released an Adult Surrogate Endpoint Table listing markers that can be used as substitutes for clinical outcomes to more quickly test, review, and approve new therapies. The analysis found the majority of these endpoints lacked subsequent confirmations, defined as published meta-analyses of clinical studies to validate the association between the marker and a clinical outcome important to patients.
In a paper published in JAMA, Dr. Ramachandran and her colleagues looked at 37 surrogate endpoints for nearly 3 dozen nononcologic diseases in the table.
Approval with surrogate markers implies responsibility for postapproval or validation studies — not just lab measures or imaging findings but mortality, morbidity, or improved quality of life, said Joshua D. Wallach, PhD, MS, assistant professor in the department of epidemiology at the Emory Rollins School of Public Health in Atlanta and lead author of the JAMA review.
Dr. Wallach said surrogate markers are easier to measure and do not require large and long trials. But the FDA has not provided clear rules for what makes a surrogate marker valid in clinical trials.
“They’ve said that at a minimum, it requires meta-analytical evidence from studies that have looked at the correlation or the association between the surrogate and the clinical outcome,” Dr. Wallach said. “Our understanding was that if that’s a minimum expectation, we should be able to find those studies in the literature. And the reality is that we were unable to find evidence from those types of studies supporting the association between the surrogate and the clinical outcome.”
Physicians generally do not receive training about the FDA approval process and the difference between biomarkers, surrogate markers, and clinical endpoints, Dr. Ramachandran said. “Our study shows that things are much more uncertain than we thought when it comes to the prescribing of new drugs,” she said.
Surrogate Markers on the Rise
Dr. Wallach’s group looked for published meta-analyses compiling randomized controlled trials reporting surrogate endpoints for more than 3 dozen chronic nononcologic conditions, including type 2 diabetes, Alzheimer’s, kidney disease, HIV, gout, and lupus. They found no meta-analyses at all for 59% of the surrogate markers, while for those that were studied, few reported high-strength evidence of an association with clinical outcomes.
The findings echo previous research. In a 2020 study in JAMA Network Open, researchers tallied primary endpoints for all FDA approvals of new drugs and therapies during three 3-year periods: 1995-1997, 2005-2007, and 2015-2017. The proportion of products whose approvals were based on the use of clinical endpoints decreased from 43.8% in 1995-1997 to 28.4% in 2005-2007 to 23.3% in 2015-2017. The share based on surrogate endpoints rose from 43.3% to roughly 60% over the same interval.
A 2017 study in the Journal of Health Economics found the use of “imperfect” surrogate endpoints helped support the approval of an average of 16 new drugs per year between 2010 and 2014 compared with six per year from 1998 to 2008.
Similar concerns about weak associations between surrogate markers and drugs used to treat cancer have been documented before, including in a 2020 study published in eClinicalMedicine. The researchers found the surrogate endpoints in the FDA table either were not tested or were tested but proven to be weak surrogates.
“And yet the FDA considered these as good enough not only for accelerated approval but also for regular approval,” said Bishal Gyawali, MD, PhD, associate professor in the department of oncology at Queen’s University, Kingston, Ontario, Canada, who led the group.
The use of surrogate endpoints is also increasing in Europe, said Huseyin Naci, MHS, PhD, associate professor of health policy at the London School of Economics and Political Science in England. He cited a cohort study of 298 randomized clinical trials (RCTs) in JAMA Oncology suggesting “contemporary oncology RCTs now largely measure putative surrogate endpoints.” Dr. Wallach called the FDA’s surrogate table “a great first step toward transparency. But a key column is missing from that table, telling us what is the basis for which the FDA allows drug companies to use the recognized surrogate markers. What is the evidence they are considering?”
If the agency allows companies the flexibility to validate surrogate endpoints, postmarketing studies designed to confirm the clinical utility of those endpoints should follow.
“We obviously want physicians to be guided by evidence when they’re selecting treatments, and they need to be able to interpret the clinical benefits of the drug that they’re prescribing,” he said. “This is really about having the research consumer, patients, and physicians, as well as industry, understand why certain markers are considered and not considered.”
Dr. Wallach reported receiving grants from the FDA (through the Yale University — Mayo Clinic Center of Excellence in Regulatory Science and Innovation), National Institute on Alcohol Abuse and Alcoholism (1K01AA028258), and Johnson & Johnson (through the Yale University Open Data Access Project); and consulting fees from Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC outside the submitted work. Dr. Ramachandran reported receiving grants from the Stavros Niarchos Foundation and FDA; receiving consulting fees from ReAct Action on Antibiotic Resistance strategy policy program outside the submitted work; and serving in an unpaid capacity as chair of the FDA task force for the nonprofit organization Doctors for America and in an unpaid capacity as board president for Universities Allied for Essential Medicines North America.
A version of this article appeared on Medscape.com.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Over the past few decades, the US Food and Drug Administration (FDA) has increasingly relied on surrogate measures such as blood tests instead of clinical outco</metaDescription> <articlePDF/> <teaserImage/> <teaser>As the FDA’s use of surrogate endpoints in the drug approval process is increasing, researchers are concerned important postapproval or validation studies are lacking.</teaser> <title>Follow-Up Outcomes Data Often Missing for FDA Drug Approvals Based on Surrogate Markers</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>rn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>im</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>chph</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>endo</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>cpn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>skin</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>fp</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>card</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>hemn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>mdid</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>mdemed</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle/> <copyrightStatement/> </publicationData> <publicationData> <publicationCode>mdsurg</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle/> <copyrightStatement>2018 Frontline Medical Communications Inc.,</copyrightStatement> </publicationData> <publicationData> <publicationCode>nr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle>Neurology Reviews</journalTitle> <journalFullTitle>Neurology Reviews</journalFullTitle> <copyrightStatement>2018 Frontline Medical Communications Inc.,</copyrightStatement> </publicationData> <publicationData> <publicationCode>ob</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>oncr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>pn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term>26</term> <term canonical="true">21</term> <term>6</term> <term>34</term> <term>9</term> <term>13</term> <term>15</term> <term>5</term> <term>18</term> <term>51892</term> <term>58877</term> <term>52226</term> <term>22</term> <term>23</term> <term>31</term> <term>25</term> </publications> <sections> <term canonical="true">27980</term> <term>39313</term> </sections> <topics> <term canonical="true">38029</term> <term>27442</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Follow-Up Outcomes Data Often Missing for FDA Drug Approvals Based on Surrogate Markers</title> <deck/> </itemMeta> <itemContent> <p>Over the past few decades, the US Food and Drug Administration (FDA) has <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/989725">increasingly relied</a></span> on surrogate measures such as blood tests instead of clinical outcomes for medication approvals. But critics say the agency lacks consistent standards to ensure the surrogate aligns with clinical outcomes that matter to patients — things like improvements in symptoms and gains in function.</p> <p>Sometimes those decisions backfire. Consider: In July 2021, the FDA <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/952502">approved aducanumab</a></span> for the treatment of <span class="Hyperlink">Alzheimer’s disease</span>, bucking the advice of an advisory panel for the agency that questioned the effectiveness of the medication. Regulators relied on data from the drugmaker, Biogen, showing the monoclonal antibody could reduce levels of amyloid beta plaques in blood — a surrogate marker officials hoped would translate to clinical benefit.<br/><br/>The FDA’s decision triggered <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/972583">significant controversy</a></span>, and Biogen in January announced it <span class="Hyperlink"><a href="https://www.medscape.com/s/viewarticle/biogen-drops-alzheimers-drug-aduhelm-ending-17-year-chapter-2024a100025r">is pulling it</a></span> from the market this year, citing disappointing sales.<br/><br/>Although the case of aducanumab might seem extreme, given the stakes — Alzheimer’s remains a disease without an effective treatment — it’s far from unusual.<br/><br/>“When we prescribe a drug, there is an underlying assumption that the FDA has done its due diligence to confirm the drug is safe and of benefit,” said Reshma Ramachandran, MD, MPP, MHS, a researcher at Yale School of Medicine, New Haven, Connecticut, and a coauthor of a recent review of surrogate outcomes. “In fact, we found either no evidence or low-quality evidence.” Such markers are associated with clinical outcomes. “We just don’t know if they work meaningfully to treat the patient’s condition. The results were pretty shocking for us,” she said.<br/><br/>The FDA in 2018 released an <span class="Hyperlink"><a href="https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure">Adult Surrogate Endpoint Table</a></span> listing markers that can be used as substitutes for clinical outcomes to more quickly test, review, and approve new therapies. The analysis found the majority of these endpoints lacked subsequent confirmations, defined as published meta-analyses of clinical studies to validate the association between the marker and a clinical outcome important to patients.<br/><br/>In <span class="Hyperlink"><a href="https://jamanetwork.com/journals/jama/article-abstract/2817850?resultClick=1">a paper</a></span> published <span class="Hyperlink">in </span><em>JAMA</em>, Dr. Ramachandran and her colleagues looked at 37 surrogate endpoints for nearly 3 dozen nononcologic diseases in the table.<br/><br/>Approval with surrogate markers implies responsibility for postapproval or validation studies — not just lab measures or imaging findings but mortality, morbidity, or improved quality of life, said Joshua D. Wallach, PhD, MS, assistant professor in the department of epidemiology at the Emory Rollins School of Public Health in Atlanta and lead author of the <em>JAMA</em> review.<br/><br/>Dr. Wallach said surrogate markers are easier to measure and do not require large and long trials. But the FDA has not provided clear rules for what makes a surrogate marker valid in clinical trials.<br/><br/>“They’ve said that at a minimum, it requires meta-analytical evidence from studies that have looked at the correlation or the association between the surrogate and the clinical outcome,” Dr. Wallach said. “Our understanding was that if that’s a minimum expectation, we should be able to find those studies in the literature. And the reality is that we were unable to find evidence from those types of studies supporting the association between the surrogate and the clinical outcome.”<br/><br/>Physicians generally do not receive training about the FDA approval process and the difference between <span class="Hyperlink"><a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/biomarker">biomarkers</a></span>, <span class="Hyperlink"><a href="https://www.annualreviews.org/docserver/fulltext/statistics/10/1/annurev-statistics-032921-035359.pdf?expires=1715040933&id=id&accname=guest&checksum=B808A6F92AA256F76794D6A7F3E72EEC">surrogate markers</a></span>, and <span class="Hyperlink"><a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/clinical-endpoint#:~:text=Clinical%20endpoints%2C%20defined%20as%20characteristics,of%20drug%20therapy%20%5B1%5D.">clinical endpoints</a>,</span> Dr. Ramachandran said. “Our study shows that things are much more uncertain than we thought when it comes to the prescribing of new drugs,” she said.<br/><br/></p> <h2>Surrogate Markers on the Rise</h2> <p>Dr. Wallach’s group looked for published meta-analyses compiling randomized controlled trials reporting surrogate endpoints for more than 3 dozen chronic nononcologic conditions, including <span class="Hyperlink">type 2 diabetes</span>, Alzheimer’s, kidney disease, <span class="Hyperlink">HIV</span>, <span class="Hyperlink">gout</span>, and lupus. They found no meta-analyses at all for 59% of the surrogate markers, while for those that were studied, few reported high-strength evidence of an association with clinical outcomes.<br/><br/>The findings echo previous research. In a <span class="Hyperlink"><a href="https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2764603">2020 study</a></span> in <em>JAMA Network Open</em>, researchers tallied primary endpoints for all FDA approvals of new drugs and therapies during three 3-year periods: 1995-1997, 2005-2007, and 2015-2017. The proportion of products whose approvals were based on the use of clinical endpoints decreased from 43.8% in 1995-1997 to 28.4% in 2005-2007 to 23.3% in 2015-2017. The share based on surrogate endpoints rose from 43.3% to roughly 60% over the same interval.<br/><br/>A <span class="Hyperlink"><a href="https://www.sciencedirect.com/science/article/pii/S0167629616304830">2017 study</a></span> in the <em>Journal of Health Economics</em> found the use of “imperfect” surrogate endpoints helped support the approval of an average of 16 new drugs per year between 2010 and 2014 compared with six per year from 1998 to 2008.<br/><br/>Similar concerns about weak associations between surrogate markers and drugs used to treat cancer have been documented before, including in a <span class="Hyperlink"><a href="https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30076-6/fulltext">2020 study</a></span> published in <em>eClinicalMedicine</em>. The researchers found the surrogate endpoints in the FDA table either were not tested or were tested but proven to be weak surrogates.<br/><br/>“And yet the FDA considered these as good enough not only for accelerated approval but also for regular approval,” said Bishal Gyawali, MD, PhD, associate professor in the department of oncology at Queen’s University, Kingston, Ontario, Canada, who led the group.<br/><br/>The use of surrogate endpoints is also increasing in Europe, said Huseyin Naci, MHS, PhD, associate professor of health policy at the London School of Economics and Political Science in England. He cited a <span class="Hyperlink"><a href="https://jamanetwork.com/journals/jamaoncology/fullarticle/2777587">cohort study</a></span> of 298 randomized clinical trials (RCTs) in <em>JAMA Oncology</em> suggesting “contemporary oncology RCTs now largely measure putative surrogate endpoints.” Dr. Wallach called the FDA’s surrogate table “a great first step toward transparency. But a key column is missing from that table, telling us what is the basis for which the FDA allows drug companies to use the recognized surrogate markers. What is the evidence they are considering?”<br/><br/>If the agency allows companies the flexibility to validate surrogate endpoints, postmarketing studies designed to confirm the clinical utility of those endpoints should follow.<br/><br/>“We obviously want physicians to be guided by evidence when they’re selecting treatments, and they need to be able to interpret the clinical benefits of the drug that they’re prescribing,” he said. “This is really about having the research consumer, patients, and physicians, as well as industry, understand why certain markers are considered and not considered.”<br/><br/>Dr. Wallach reported receiving grants from the FDA (through the Yale University — Mayo Clinic Center of Excellence in Regulatory Science and Innovation), National Institute on Alcohol Abuse and Alcoholism (1K01AA028258), and Johnson & Johnson (through the Yale University Open Data Access Project); and consulting fees from Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC outside the submitted work. Dr. Ramachandran reported receiving grants from the Stavros Niarchos Foundation and FDA; receiving consulting fees from ReAct Action on Antibiotic Resistance strategy policy program outside the submitted work; and serving in an unpaid capacity as chair of the FDA task force for the nonprofit organization Doctors for America and in an unpaid capacity as board president for Universities Allied for Essential Medicines North America. <br/><br/></p> <p> <em>A version of this article appeared on <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/surrogate-markers-used-many-new-drug-approvals-lack-follow-2024a10009f6">Medscape.com</a></span>.</em> </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM JAMA