clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s, a surrogate endpoint (or surrogate marker) is a

measure of effect An outcome measure, endpoint, effect measure or measure of effect is a measure within medical practice or research, (primarily clinical trials) which is used to assess the effect, both positive and negative, of an intervention or treatment. Measures ...

of a specific treatment that may correlate with a ''real''

clinical endpoint Clinical endpoints or clinical outcomes are outcome measures referring to occurrence of disease, symptom, sign or laboratory abnormality constituting a target outcome in clinical research trials. The term may also refer to any disease or sign th ...

but does not necessarily have a guaranteed relationship. The

National Institutes of Health The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in 1887 and is part of the United States Department of Health and Human Service ...

(USA) defines surrogate endpoint as "a

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

intended to substitute for a clinical endpoint". 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

statistically significant In statistical hypothesis testing, a result has statistical significance when a result at least as "extreme" would be very infrequent if the null hypothesis were true. More precisely, a study's defined significance level, denoted by \alpha, is the ...

number of endpoints. The

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

and other regulatory agencies will often accept evidence from

s that show a direct clinical benefit to surrogate markers.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

s from

Electroencephalography Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignal, bio signals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in ...

( qEEG),

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...

PET A pet, or companion animal, is an animal kept primarily for a person's company or entertainment rather than as a working animal, livestock, or a laboratory animal. Popular pets are often considered to have attractive/ cute appearances, inte ...

, 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. In this context, the term ''Prentice criteria'' is used. 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. 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.

Examples

Cardiovascular disease

A commonly used example is

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

. While elevated cholesterol levels increase the likelihood for

heart disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina pectoris, angina, myocardial infarction, heart attack), heart failure, ...

, 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 Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease hyperlipidemia, elevated lipid levels. It is also used to decrease t ...

(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 Preventive healthcare, or prophylaxis, is the application of healthcare measures to prevent diseases.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental health a ...

. In another case,

AstraZeneca AstraZeneca plc () (AZ) is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, UK. It has a portfolio of products for major diseases in areas includi ...

was accused of marketing

rosuvastatin Rosuvastatin, sold under the brand name Crestor among others, is a statin medication, used to prevent cardiovascular disease in those at high risk and treat dyslipidemia, abnormal lipids. It is recommended to be used with dietary changes, exer ...

(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.

Cancer

Progression Free Survival is a prominent example in

Oncology Oncology is a branch of medicine that deals with the study, treatment, diagnosis, and prevention of cancer. A medical professional who practices oncology is an ''oncologist''. The name's Etymology, etymological origin is the Greek word ὄγ ...

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 Bevacizumab, sold under the brand name Avastin among others, is a monoclonal antibody medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and use ...

(Avastin) initially gained approval from the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

, but subsequently had its license revoked. More patient focused surrogate endpoints may offer a more meaningful alternative such as Overall Treatment Utility.

Infectious disease

In HIV/AIDS medicine, CD4 counts and viral loads are used as surrogate markers for drug approval for clinical trials. In hepatitis C medicine, the surrogate endpoint "Sustained Virological Response" has been used for the approval of expensive drugs known as Direct Acting Antivirals. The validity of this surrogate endpoint for predicting clinical outcomes has been challenged. 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.

Alzheimer's disease

A recent study showed that plasma biomarkers have the potential to be used as surrogate biomarkers in

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

(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. In 2021, the FDA came under heavy criticism for the approval of an alzheimer's drug called

Aduhelm Aducanumab, sold under the brand name Aduhelm, is an anti-amyloid drug designed to treat Alzheimer's disease. It is a monoclonal antibody that targets aggregated forms (plaque) of amyloid beta (Aβ) found in the brains of people with Alzheime ...

based on a surrogate endpoint that was later shown to be based on fraudulent data.

Reporting Guidelines

Reporting surrogate endpoints in

randomized controlled trials A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...

is an emerging source of concern for

clinicians A clinician is a health care professional typically employed at a skilled nursing facility or clinic. Clinicians work directly with patients rather than in a laboratory, community health setting or in research. A clinician may diagnose, treat a ...

and

epidemiologists Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and determinants of health and disease conditions in a defined population, and application of this knowledge to prevent diseases. It is a cornerstone o ...

. This issue has been addressed in two reporting guidelines called

CONSORT __NOTOC__ Consort may refer to: Music * "The Consort" (Rufus Wainwright song), from the 2000 album ''Poses'' * Consort of instruments, term for instrumental ensembles * Consort song (musical), a characteristic English song form, late 16th–earl ...

and SPIRIT, which will help

researchers Research is creative and systematic work undertaken to increase the stock of knowledge. It involves the collection, organization, and analysis of evidence to increase understanding of a topic, characterized by a particular attentiveness to ...

report surrogate endpoints in randomized controlled trials.

References

{{Medical research studies Medical terminology Epidemiology Biomarkers Medical statistics Clinical trials Endings