Surrogate endpoint

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In clinical trials, a surrogate endpoint (or surrogate marker) is a 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". [1] [2]

Contents

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 number of endpoints. The FDA and other regulatory agencies will often accept evidence from clinical trials that show a direct clinical benefit to surrogate markers. [3]

Surrogate endpoints can be obtained from different modalities, such as, behavioural or cognitive scores, or biomarkers from Electroencephalography (qEEG), MRI, 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. [4] [5] In this context, the term Prentice criteria is used. [6]

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. [7]

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. [8]

Examples

Cardiovascular disease

A commonly used example is cholesterol. While elevated cholesterol levels increase the likelihood for 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. [9] 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. [10]

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. [11] [12] More patient focused surrogate endpoints may offer a more meaningful alternative such as Overall Treatment Utility. [13] [14]

Infectious disease

In HIV/AIDS medicine, CD4 counts and viral loads are used as surrogate markers for drug approval for clinical trials. [15]

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. [16] [17]

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. [18]

Alzheimer's disease

A recent study [19] 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. [20] In 2021, the FDA came under heavy criticism for the approval of an alzheimer's drug called Aduhelm based on a surrogate endpoint that was later shown to be based on fraudulent data. [21] [22]

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 SPIRIT, [23] [24] which will help researchers report surrogate endpoints in randomized controlled trials.

See also

Related Research Articles

<span class="mw-page-title-main">Statin</span> Class of drugs to lower cholesterol

Statins are a class of medications that reduce illness and mortality in people who are at high risk of cardiovascular disease.

Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins, such as cholesterol, in the blood (hyperlipidemia). The American Heart Association recommends the descriptor 'lipid lowering agent' be used for this class of drugs rather than the term 'hypolipidemic'.

<span class="mw-page-title-main">Fibrate</span> Class of chemical compounds

In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid. They are used for a range of metabolic disorders, mainly hypercholesterolemia, and are therefore hypolipidemic agents.

<span class="mw-page-title-main">Heart Protection Study</span>

The Heart Protection Study was a randomized controlled trial run by the Clinical Trial Service Unit, and funded by the Medical Research Council (MRC) and the British Heart Foundation (BHF) in the United Kingdom. It studied the use of the cholesterol lowering drug, simvastatin 40 mg and vitamin supplementation in people who were at risk of cardiovascular disease. It was led by Jane Armitage, an epidemiologist at the Clinical Trial Service Unit.

<span class="mw-page-title-main">Atorvastatin</span> Cholesterol-lowering medication

Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.

<span class="mw-page-title-main">Simvastatin</span> Lipid-lowering medication

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 elevated lipid levels. It is also used to decrease the risk of heart problems in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Rosuvastatin</span> Statin medication

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 abnormal lipids. It is recommended to be used together with dietary changes, exercise, and weight loss. It is taken orally.

<span class="mw-page-title-main">Ezetimibe/simvastatin</span> Drug combination used for the treatment of dyslipidemia

Ezetimibe/simvastatin is a drug combination used for the treatment of dyslipidemia. It is a combination of ezetimibe and the statin drug simvastatin.

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 that strongly motivates withdrawal of an individual or entity from the trial, then often termed a humane (clinical) endpoint.

In medicine, a biomarker is a measurable indicator of the severity or presence of some disease state. It may be defined as a "cellular, biochemical or molecular alteration in cells, tissues or fluids that can be measured and evaluated to indicate normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention." More generally a biomarker is anything that can be used as an indicator of a particular disease state or some other physiological state of an organism. According to the WHO, the indicator may be chemical, physical, or biological in nature - and the measurement may be functional, physiological, biochemical, cellular, or molecular.

<span class="mw-page-title-main">Hypocholesterolemia</span> Medical condition

Hypocholesterolemia is the presence of abnormally low (hypo-) levels of cholesterol in the blood (-emia). A defect in the body's production of cholesterol can lead to adverse consequences as well. Cholesterol is an essential component of mammalian cell membranes and is required to establish proper membrane permeability and fluidity. It is not clear if a lower than average cholesterol level is directly harmful; however, it is often encountered in particular illnesses.

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is present, as demonstrated by laboratory testing, radiologic testing, or clinically. Similarly, "disease-free survival" is the length of time after patients have received treatment and have no detectable disease.

An imaging biomarker is a biologic feature, or biomarker detectable in an image. In medicine, an imaging biomarker is a feature of an image relevant to a patient's diagnosis. For example, a number of biomarkers are frequently used to determine risk of lung cancer. First, a simple lesion in the lung detected by X-ray, CT, or MRI can lead to the suspicion of a neoplasm. The lesion itself serves as a biomarker, but the minute details of the lesion serve as biomarkers as well, and can collectively be used to assess the risk of neoplasm. Some of the imaging biomarkers used in lung nodule assessment include size, spiculation, calcification, cavitation, location within the lung, rate of growth, and rate of metabolism. Each piece of information from the image represents a probability. Spiculation increases the probability of the lesion being cancer. A slow rate of growth indicates benignity. These variables can be added to the patient's history, physical exam, laboratory tests, and pathology to reach a proposed diagnosis. Imaging biomarkers can be measured using several techniques, such as CT, PET, SPECT, ultrasound, electroencephalography, magnetoencephalography, and MRI.

Critical Path Institute (C-Path) is a non-profit organization created to improve the drug development process; its consortia include more than 1,600 scientists from government regulatory and research agencies, academia, patient organizations, and bio-pharmaceutical companies.

Alirocumab, sold under the brand name Praluent, is a medication used as a second-line treatment for high cholesterol for adults whose cholesterol is not controlled by diet and statin treatment. It is a human monoclonal antibody that belongs to a novel class of anti-cholesterol drugs, known as PCSK9 inhibitors, and it was the first such agent to receive FDA approval. The FDA approval was contingent on the completion of further clinical trials to better determine efficacy and safety.

The United States Food and Drug Administration (FDA) initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate endpoints. Drug approval typically requires clinical trials with endpoints that demonstrate a clinical benefit, such as increased survival for cancer patients. Drugs with accelerated approval can initially be tested in clinical trials that use a surrogate endpoint, or something that is thought to predict clinical benefit. Surrogate endpoints typically require less time, and in the case of a cancer patient, it is much faster to measure a reduction in tumor size, for example, than overall patient survival.

Aducanumab, sold under the brand name Aduhelm, is a monoclonal antibody 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 Alzheimer's disease to reduce its buildup. It was developed by Biogen and Eisai. Aducanumab is given via intravenous infusion.

<span class="mw-page-title-main">Obeticholic acid</span> Chemical compound

Obeticholic acid (OCA), sold under the brand name Ocaliva, is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It is used as a medication used to treat primary biliary cholangitis. Intercept Pharmaceuticals Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.

Bempedoic acid, sold under the brand name Nexletol among others, is a medication for the treatment of hypercholesterolemia.

References

  1. ↑ De Gruttola, Victor G; Clax, Pamela; DeMets, David L; Downing, Gregory J; Ellenberg, Susan S; Friedman, Lawrence; Gail, Mitchell H; Prentice, Ross; Wittes, Janet; Zeger, Scott L (2001). "Considerations in the Evaluation of Surrogate Endpoints in Clinical Trials". Controlled Clinical Trials. 22 (5): 485–502. doi:10.1016/S0197-2456(01)00153-2. ISSN   0197-2456. PMID   11578783.
  2. ↑ Cohn JN (2004). "Introduction to Surrogate Markers". Circulation. 109 (25 Suppl 1): IV20–1. doi: 10.1161/01.CIR.0000133441.05780.1d . PMID   15226247.
  3. ↑ Alexandra Goho, "An Imperfect Substitute" CR Magazine, Spring 2009
  4. ↑ Fleming, Thomas R. (1996). "Surrogate End Points in Clinical Trials: Are We Being Misled?". Annals of Internal Medicine. 125 (7): 605–613. doi:10.7326/0003-4819-125-7-199610010-00011. PMID   8815760. S2CID   12267404.
  5. ↑ Prentice, Ross L. (1989). "Surrogate endpoints in clinical trials: Definition and operational criteria". Statistics in Medicine. 8 (4): 431–440. doi:10.1002/sim.4780080407. PMID   2727467.
  6. ↑ O'Quigley, John; Flandre, Philippe (March 2006). "Quantification of the Prentice Criteria for Surrogate Endpoints". Biometrics. 62 (1): 297–300. doi:10.1111/j.1541-0420.2006.00538.x. PMID   16542258. S2CID   19927364.
  7. ↑ Sobel, Burton E.; Furberg, Curt D. (1997). "Surrogates, Semantics, and Sensible Public Policy". Circulation. 95 (6): 1661–1663. doi:10.1161/01.CIR.95.6.1661. PMID   9118540.
  8. ↑ 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.
  9. ↑ Pedersen TR, Olsson AG, Faergeman O, et al. (1998). "Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)". Circulation. 97 (15): 1453–1460. doi: 10.1161/01.cir.97.15.1453 . PMID   9576425.
  10. ↑ Horton, Richard (October 25, 2003). "The statin wars: why AstraZeneca must retreat". Lancet. 362 (9393): 1341. doi: 10.1016/S0140-6736(03)14669-7 . PMID   14585629. S2CID   39528790.
    McKillop T (November 1, 2003). "The statin wars". Lancet. 362 (9394): 1498. doi: 10.1016/S0140-6736(03)14698-3 . PMID   14602449. S2CID   5300990.
  11. ↑ d'Agostino, Ralph B. (2011). "Changing End Points in Breast-Cancer Drug Approval — The Avastin Story". NEJM. 365 (2): e2. doi:10.1056/NEJMp1106984. PMID   21707384.
  12. ↑ Lenzer, J. (2011). "FDA committee votes to withdraw bevacizumab for breast cancer". BMJ. 343: d4244. doi:10.1136/bmj.d4244. PMID   21729988. S2CID   206893438.
  13. ↑ Handforth C, Hall PS, Marshall HC, Collinson M, Jones M, Seymour MT (2013). "Overall treatment utility: a novel outcome measure reflecting the balance of benefits and harms from cancer therapy". European Journal of Cancer. 49 (S2): 346.
  14. ↑ Hall PS, Lord SR, Collinson M, Marshall H, Jones M, Lowe C, Howard H, Swinson D, Velikova G, Anthoney A, Roy R, Seymour M (2017). "A randomised phase II trial and feasibility study of palliative chemotherapy in frail or elderly patients with advanced gastroesophageal cancer (321GO)". British Journal of Cancer. 116 (4): 472–478. doi:10.1038/bjc.2016.442. PMC   5318975 . PMID   28095397.
  15. ↑ Epstien, Stephen (1998). Impure Science: AIDS, Activism, and the Politics of Knowledge. Berkeley: University of California Press. pp. 270–276. ISBN   0-520-20233-3.
  16. ↑ Koretz, Ronald (January 13, 2015). "Is Widespread Screening for Hepatitis C Justified?". British Medical Journal. 350: g7809. doi:10.1136/bmj.g7809. PMID   25587052. S2CID   36816304.
  17. ↑ "Expert: SVR does not equate to a cure in HCV". Helio.
  18. ↑ "Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure". Food and Drug Administration. 28 February 2022.
  19. ↑ Ferreira PL, Ferrari-Souza JP, Tissot C, Bellaver B, Leffa D, Lussier FZ, et al. (March 2023). "Potential Utility of Plasma P-Tau and Neurofilament Light Chain as Surrogate Biomarkers for Preventive Clinical Trials". Neurology. 101 (1): 38–45. doi:10.1212/WNL.0000000000207115. PMC   10351303 . PMID   36878697.
  20. ↑ Psaty BM, Weiss NS, Furberg CD, et al. (1999). "Surrogate end points, health outcomes, and the drug approval process for the treatment of risk factors for cardiovascular disease". JAMA. 282 (8): 786–790. doi:10.1001/jama.282.8.786. PMID   10463718. S2CID   16582482.
  21. ↑ "Three F.D.A. Advisers Resign Over Agency's Approval of Alzheimer's Drug". New York Times. 2 September 2021.
  22. ↑ Glenza, Jessica (23 July 2022). "Critical elements of leading Alzheimer's study possibly fraudulent". The Guardian.
  23. ↑ 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 (2024). "Reporting of surrogate endpoints in randomised controlled trial reports (CONSORT-Surrogate): extension checklist with explanation and elaboration". BMJ. 386: e078524. doi:10.1136/bmj-2023-078524. PMC   11231881 . PMID   38981645.
  24. ↑ 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 (2024). "Reporting of surrogate endpoints in randomised controlled trial protocols (SPIRIT-Surrogate): extension checklist with explanation and elaboration". BMJ. 386: e078525. doi:10.1136/bmj-2023-078525. PMC   11231880 . PMID   38981624.
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