Editing Surrogate endpoint

{{Short description|Biomarker proxy outcome measure}}
In [[clinical trial]]s, a '''surrogate endpoint''' (or '''surrogate marker''') is a [[Outcome measure|measure of effect]] of a specific treatment that may correlate with a ''real'' [[clinical endpoint]] but does not necessarily have a guaranteed relationship. The [[National Institutes of Health]] (USA) defines surrogate endpoint as "a [[biomarker]] intended to substitute for a clinical endpoint".<ref>{{cite journal|last1=De Gruttola|first1=Victor G|last2=Clax|first2=Pamela|author3-link=David DeMets|last3=DeMets|first3=David L|last4=Downing|first4=Gregory J|last5=Ellenberg|first5=Susan S|last6=Friedman|first6=Lawrence|last7=Gail|first7=Mitchell H|last8=Prentice|first8=Ross|author8-link=Ross Prentice|last9=Wittes|first9=Janet|author9-link=Janet Wittes|last10=Zeger|first10=Scott L|title=Considerations in the Evaluation of Surrogate Endpoints in Clinical Trials|journal=Controlled Clinical Trials|volume=22|issue=5|year=2001|pages=485–502|issn=0197-2456|doi=10.1016/S0197-2456(01)00153-2|pmid=11578783 }}</ref><ref>{{cite journal | author = Cohn JN | title = Introduction to Surrogate Markers | journal = Circulation | volume = 109 | pages = IV20&ndash;1 | date = 2004 | doi =  10.1161/01.CIR.0000133441.05780.1d | pmid=15226247 | issue = 25 Suppl 1 | doi-access = free }}</ref>

Surrogate markers are used when the primary endpoint is undesired (e.g., death), or when the number of events is very small, thus making it impractical to conduct a clinical trial to gather a [[statistical significance|statistically significant]] number of endpoints. The [[Food and Drug Administration|FDA]] and other regulatory agencies will often accept evidence from [[clinical trial]]s that show a direct clinical benefit to surrogate markers.<ref name=cr>[http://www.crmagazine.org/archive/spring%202009/Pages/AnImperfectSubstitute.aspx Alexandra Goho, "An Imperfect Substitute" ''CR Magazine'', Spring 2009]</ref>

Surrogate endpoints can be obtained from different modalities, such as, behavioural or cognitive scores, or [[biomarker]]s from [[Electroencephalography]] ([[Quantitative electroencephalography|qEEG]]), [[MRI]], [[Positron emission tomography|PET]], or biochemical biomarkers.

A correlate does not make a surrogate. It is a common misconception that if an outcome is a correlate (that is, correlated with the true clinical outcome) it can be used as a valid surrogate endpoint (that is, a replacement for the true clinical outcome). However, proper justification for such replacement requires that the effect of the intervention on the surrogate endpoint predicts the effect on the clinical outcome: a much stronger condition than correlation.<ref>{{cite journal|last1=Fleming|first1=Thomas R.|title=Surrogate End Points in Clinical Trials: Are We Being Misled?|journal=Annals of Internal Medicine|volume=125|issue=7|year=1996|pages=605–613|doi=10.7326/0003-4819-125-7-199610010-00011|pmid=8815760 |s2cid=12267404 }}</ref><ref>{{cite journal|last1=Prentice|first1=Ross L.|author1-link=Ross Prentice|title=Surrogate endpoints in clinical trials: Definition and operational criteria|journal=Statistics in Medicine|volume=8|issue=4|year=1989|pages=431–440|doi=10.1002/sim.4780080407|pmid=2727467 }}</ref> In this context, the term ''Prentice criteria'' is used.<ref>{{Cite journal|last1=O'Quigley|first1=John|last2=Flandre|first2=Philippe|date=March 2006|title=Quantification of the Prentice Criteria for Surrogate Endpoints|journal=Biometrics|volume=62|issue=1|pages=297–300|doi=10.1111/j.1541-0420.2006.00538.x|pmid=16542258 |s2cid=19927364 }}</ref>

The term "surrogate" should not be used in describing endpoints. Instead, descriptions of results and interpretations should be formulated in terms that designate the specific nature and category of variable assessed.<ref>{{cite journal|last1=Sobel|first1=Burton E.|last2=Furberg|first2=Curt D.|title=Surrogates, Semantics, and Sensible Public Policy|journal=Circulation|volume=95|issue=6|year=1997|pages=1661–1663|doi=10.1161/01.CIR.95.6.1661|pmid=9118540 }}</ref>

A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint.<ref>Temple RJ. A regulatory authority's opinion about surrogate endpoints. Clinical Measurement in Drug Evaluation. Edited by Nimmo WS, Tucker GT. New York: Wiley; 1995.</ref>

== Examples ==
=== Cardiovascular disease ===
A commonly used example is [[cholesterol]].  While elevated cholesterol levels increase the likelihood for [[cardiovascular disease|heart disease]], the relationship is not linear - many people with normal cholesterol develop heart disease, and many with high cholesterol do not.  "Death from heart disease" is the endpoint of interest, but "cholesterol" is the surrogate marker.  A clinical trial may show that a particular drug (for example, [[simvastatin]] (Zocor)) is effective in reducing cholesterol, without showing directly that simvastatin prevents death.  Proof of Zocor's efficacy in reducing cardiovascular disease was only presented five years after its original introduction, and then only for [[secondary prevention]].<ref>{{cite journal |vauthors=Pedersen TR, Olsson AG, Faergeman O, etal |title=Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)|journal=Circulation|year=1998|volume=97|pages=1453–1460|pmid=9576425|issue=15|doi=10.1161/01.cir.97.15.1453|doi-access=free}}</ref> In another case, [[AstraZeneca]] was accused of marketing [[rosuvastatin]] (Crestor) without providing hard endpoint data, relying instead on surrogate endpoints. The company countered that rosuvastatin had been tested on larger groups of patients than any other drug in the class, and that its effects should be comparable to the other statins.<!--
  --><ref name="lancetoped">{{cite journal | author =Horton, Richard  | title = The statin wars: why AstraZeneca must retreat | journal = Lancet | volume = 362 | issue = 9393 | page = 1341 | date=October 25, 2003 | pmid=14585629  | doi = 10.1016/S0140-6736(03)14669-7| s2cid = 39528790 | doi-access = free }}<br><!--
  -->{{cite journal | author = McKillop T | title = The statin wars | journal = Lancet | volume = 362 | issue = 9394 | page = 1498 | date=November 1, 2003 | pmid = 14602449 | doi = 10.1016/S0140-6736(03)14698-3| s2cid = 5300990 | doi-access = free }}</ref>

=== Cancer ===
[[Progression Free Survival]] is a prominent example in [[Oncology]] contexts. There are examples of cancer drugs approved on the basis of progression-free survival failed to show subsequent improvements in overall survival in subsequent studies. In breast cancer, [[Bevacizumab]] (Avastin) initially gained approval from the [[Food and Drug Administration]], but subsequently had its license revoked.<ref>{{cite journal|title=Changing End Points in Breast-Cancer Drug Approval — The Avastin Story|journal=NEJM|volume=365|issue=2|pages=e2|doi=10.1056/NEJMp1106984|pmid=21707384|year=2011|last1=d'Agostino|first1=Ralph B.}}</ref><ref>{{cite journal|url=http://www.bmj.com/content/343/bmj.d4244|title=FDA committee votes to withdraw bevacizumab for breast cancer|journal=BMJ|volume=343|pages=d4244|doi=10.1136/bmj.d4244|pmid=21729988|year=2011|last1=Lenzer|first1=J.|s2cid=206893438 }}</ref> More patient focused surrogate endpoints may offer a more meaningful alternative such as [[Overall Treatment Utility]].<ref>{{cite journal|vauthors=Handforth C, Hall PS, Marshall HC, Collinson M, Jones M, Seymour MT|title=Overall treatment utility: a novel outcome measure reflecting the balance of benefits and harms from cancer therapy|journal=European Journal of Cancer|date=2013|volume=49|issue=S2|page=346}}</ref><ref>{{cite journal|vauthors=Hall PS, Lord SR, Collinson M, Marshall H, Jones M, Lowe C, Howard H, Swinson D, Velikova G, Anthoney A, Roy R, Seymour M | title=A randomised phase II trial and feasibility study of palliative chemotherapy in frail or elderly patients with advanced gastroesophageal cancer (321GO)|journal=British Journal of Cancer|date= 2017 |volume=116|issue=4|pages=472–478|doi=10.1038/bjc.2016.442| pmid=28095397| pmc=5318975}}</ref>

=== Infectious disease ===
In HIV/AIDS medicine, CD4 counts and viral loads are used as surrogate markers for drug approval for clinical trials.<ref>{{cite book |last1=Epstien |first1=Stephen |title=Impure Science: AIDS, Activism, and the Politics of Knowledge |date=1998 |publisher=University of California Press |location=Berkeley |isbn=0-520-20233-3 |pages=270–276}}</ref>

In hepatitis C medicine, the surrogate endpoint "Sustained Virological Response" has been used for the approval of expensive drugs known as [[Direct-acting antivirals|Direct Acting Antivirals.]] The validity of this surrogate endpoint for predicting clinical outcomes has been challenged.<ref>{{cite journal |last1=Koretz |first1=Ronald |title=Is Widespread Screening for Hepatitis C Justified? |journal=British Medical Journal |date=January 13, 2015 |volume=350 |pages=g7809 |doi=10.1136/bmj.g7809|pmid=25587052 |s2cid=36816304 }}</ref><ref>{{cite web |title=Expert: SVR does not equate to a cure in HCV |url=https://www.healio.com/news/hepatology/20160413/expert-svr-does-not-equate-to-a-cure-in-hcv |website=Helio}}</ref>

For several vaccines (anthrax, hepatitis A, etc), the induction of detectable antibodies in blood is used as a surrogate marker for vaccine effectiveness, as exposure of individuals to an actual pathogen is considered unethical.<ref>{{cite web |title=Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure |date=28 February 2022 |url=https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure |archive-url=https://web.archive.org/web/20191213221500/https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure |url-status=dead |archive-date=December 13, 2019 |publisher=Food and Drug Administration}}</ref>

=== Alzheimer's disease ===
A recent study<ref>{{cite journal | vauthors = Ferreira PL, Ferrari-Souza JP, Tissot C, Bellaver B, Leffa D, Lussier FZ, Povala G, Therriault J, Benedet AL, Ashton NJ, Cohen AD, Lopez OL, Tudorascu D, Klunk WE, Soucy JP, Gauthier S, Villemagne V, Zetterberg H, Blennow K, Rosa-Neto P, Karikari TK, Pascoal TA | display-authors = 6 | title = Potential Utility of Plasma P-Tau and Neurofilament Light Chain as Surrogate Biomarkers for Preventive Clinical Trials | journal = Neurology | date = March 2023 | volume = 101 | issue = 1 | pages = 38–45 | pmid = 36878697 | doi = 10.1212/WNL.0000000000207115 | pmc = 10351303 }}</ref> showed that plasma biomarkers have the potential to be used as surrogate biomarkers in [[Alzheimer's disease]] (AD) clinical trials. More specifically, this study demonstrated that plasma p-tau181 could potentially be used to monitor large-scale population interventions targeting preclinical AD individuals.

==Criticism==
There have been a number of instances when studies using surrogate markers have been used to show benefit from a particular treatment, but later, a repeat study looking at endpoints has not shown a benefit, or has even shown a harm.<ref>{{cite journal |vauthors=Psaty BM, Weiss NS, Furberg CD, etal | title=Surrogate end points, health outcomes, and the drug approval process for the treatment of risk factors for cardiovascular disease | journal=JAMA | year=1999 | volume=282 | pages=786&ndash;790|doi=10.1001/jama.282.8.786 | pmid=10463718|issue=8| s2cid=16582482 | url=https://cdr.lib.unc.edu/downloads/08612v188 }}</ref> In 2021, the FDA came under heavy criticism for the approval of an alzheimer's drug called [[Aducanumab|Aduhelm]] based on a surrogate endpoint that was later shown to be based on fraudulent data.<ref>{{cite news |title=Three F.D.A. Advisers Resign Over Agency's Approval of Alzheimer's Drug |url=https://www.nytimes.com/2021/06/10/health/aduhelm-fda-resign-alzheimers.html |work=New York Times |date=2 September 2021}}</ref><ref>{{cite news |last1=Glenza |first1=Jessica |title=Critical elements of leading Alzheimer's study possibly fraudulent |url=https://www.theguardian.com/society/2022/jul/23/alzheimers-study-fraudulent |work=The Guardian |date=23 July 2022}}</ref>

==Reporting Guidelines==
Reporting surrogate endpoints in [[randomized controlled trials]] is an emerging source of concern for [[clinicians]] and [[epidemiologists]]. This issue has been addressed in two reporting guidelines called [[CONSORT]] and [[Standard Protocol Items Recommendations for Interventional Trials|SPIRIT]],<ref>{{cite journal |vauthors=Manyara AM, Davies P, Stewart D, Weir CJ, Young AE, Blazeby J, Butcher NJ, Bujkiewicz S, Chan AW, Dawoud D, Offringa M, Ouwens M, Hróbjartssson A, Amstutz A, Bertolaccini L, Bruno VD, Devane D, ((Faria CDCM)), Gilbert PB, Harris R, Lassere M, Marinelli L, Markham S, Powers JH, Rezaei Y, Richert L, Schwendicke F, Tereshchenko LG, Thoma A, Turan A, Worrall A, Christensen R, Collins GS, Ross JS, Taylor RS, Ciani O | title=Reporting of surrogate endpoints in randomised controlled trial reports (CONSORT-Surrogate): extension checklist with explanation and elaboration | journal=BMJ | year=2024 | volume=386 | pages=e078524|doi=10.1136/bmj-2023-078524 | pmid=38981645 | pmc=11231881 }}</ref><ref>{{cite journal |vauthors=Manyara AM, Davies P, Stewart D, Weir CJ, Young AE, Blazeby J, Butcher NJ, Bujkiewicz S, Chan AW, Dawoud D, Offringa M, Ouwens M, Hróbjartssson A, Amstutz A, Bertolaccini L, Bruno VD, Devane D, ((Faria CDCM)), Gilbert PB, Harris R, Lassere M, Marinelli L, Markham S, Powers JH, Rezaei Y, Richert L, Schwendicke F, Tereshchenko LG, Thoma A, Turan A, Worrall A, Christensen R, Collins GS, Ross JS, Taylor RS, Ciani O| title=Reporting of surrogate endpoints in randomised controlled trial protocols (SPIRIT-Surrogate): extension checklist with explanation and elaboration | journal=BMJ | year=2024 | volume=386 | pages=e078525|doi=10.1136/bmj-2023-078525| pmid=38981624 | pmc=11231880 }}</ref> which will help [[researchers]] report surrogate endpoints in [[ randomized controlled trials]].

==See also==
*[[FDA Accelerated Approval Program]] based on surrogate endpoints

==References==
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{{Medical research studies}}

[[Category:Medical terminology]]
[[Category:Epidemiology]]
[[Category:Biomarkers]]
[[Category:Medical statistics]]
[[Category:Clinical trials]]
[[Category:Endings]]