NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Co-published by National Institutes of Health (US), Bethesda (MD).

Response Biomarker

Published ; Last Update: September 17, 2021.

Definition

A biomarker used to show that a biological response, potentially beneficial or harmful, has occurred in an individual who has been exposed to a medical product or an environmental agent.

  • Pharmacodynamic biomarker: A response biomarker that indicates biologic activity of a medical product or environmental agent without necessarily drawing conclusions about efficacy or disease outcome or necessarily linking this activity to an established mechanism of action. Potential uses of a pharmacodynamic biomarker include establishing proof-of-concept, assisting in dose selection or measuring a response to medical products or environmental agents, including the use as a measure of potential harm. In some cases, such measures may be secondary endpoints in clinical trials and may be described in labeling.
  • Surrogate endpoint biomarker: A response biomarker that is an endpoint used in clinical trials as a substitute for a direct measure of how a patient feels, functions, or survives. A surrogate endpoint does not measure the clinical benefit of primary interest in and of itself, but rather is expected to predict that clinical benefit or harm based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence.

From a U.S. regulatory standpoint, surrogate endpoints and potential surrogate endpoints can be characterized by the level of clinical validation:

  • validated surrogate endpoint
  • reasonably likely surrogate endpoint
  • candidate surrogate endpoint

Examples

The use of a biomarker as a pharmacodynamic biomarker or surrogate endpoint depends on its specific context of use, as demonstrated by the examples below:

Pharmacodynamic biomarkers

  • Circulating B lymphocytes may be used as a pharmacodynamic biomarker when evaluating patients with systemic lupus erythematosus to assess response to a B-lymphocyte stimulator inhibitor (Stohl and Hilbert 2012).
  • Sweat chloride may be used as a pharmacodynamic biomarker when evaluating patients with cystic fibrosis, to assess response to cystic fibrosis transmembrane regulator (CFTR) potentiating agents (Durmowicz et al. 2013; Mayer-Hamblett et al. 2016).
  • International normalized ratio (INR) may be used as a pharmacodynamic biomarker when evaluating a patient’s response to warfarin treatment for prevention of thrombosis (Holbrook et al. 2012).
  • Urinary level of glycosaminoglycans may be used as a pharmacodynamic biomarker when evaluating the response to enzyme replacement therapy for patients with mucopolysaccharidosis type 1 (Jameson et al. 2016).
  • Left ventricular ejection fraction may be used as a pharmacodynamic biomarker when evaluating the influence of extracorporeal membrane oxygenation (ECMO) on cardiac function (Kimball et al. 1991).
  • Fluoroestradiol F 18 levels visualized by positron emission tomography (PET) may be used as a pharmacodynamic biomarker to detect the response of estrogen receptor (ER)-positive lesions to endocrine therapy in patients with recurrent or metastatic breast cancer (Liao et al. 2016).
  • Phospho-AKT levels may be used as a pharmacodynamic biomarker to measure inhibition of downstream PI3K signaling as a response to anti-cancer PI3K inhibitors in paired tumor samples when evaluating target engagement of these drugs (Morschhauser et al. 2020).
  • High-sensitivity C-reactive protein, interleukin-6, fibrinogen, soluble intercellular adhesion molecule-1) and an oxidative stress biomarker (F2-isoprostane), maybe used as pharmacodynamic biomarkers when evaluating inflammation associated with former or current use of tobacco or ENDS (Electronic Nicotine Delivery Systems) (Christensen et al. 2021).

Surrogate endpoints

  • Hemoglobin A1c (HbA1c) reduction is a validated surrogate endpoint for reduction of microvascular complications associated with diabetes mellitus and has been used as the basis for approval of drugs intended to treat diabetes mellitus (American Diabetes Association 2016).
  • HIV-RNA reduction is a validated surrogate endpoint for human immunodeficiency virus (HIV) clinical disease control and has been used as the basis for approval of drugs intended to treat HIV (DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents 2019).
  • Low-density lipoprotein (LDL) cholesterol reduction is a validated surrogate endpoint for reduction of cardiovascular events and has been used as the basis for approval of statins and other LDL-lowering drugs such as PCSK9 inhibitors and ezetimibe. (Stone et al. 2014).
  • Blood pressure reduction is a validated surrogate endpoint for reduction in rates of stroke, myocardial infarction, and mortality and has been used as the basis for the approval of drugs and in pivotal trials of medical devices intended to treat hypertension (James et al. 2014).
  • Biochemical evidence of a clinically significant degree of improvement in alkaline phosphatase (ALP) at 12 months demonstrated in adequate and well controlled studies has been considered a reasonably likely surrogate endpoint to predict decreased risk of liver transplant or death and has supported/ been the basis for evaluating the efficacy for an accelerated approval of a drug to treat adults with primary biliary cirrhosis (Murillo Perez et al. 2020; Lammers et al. 2014).
  • Outcome following 6-month of treatment (i.e., sputum culture status and infection relapse rate) have been considered a reasonably likely surrogate endpoint to predict the resolution of pulmonary tuberculosis and have supported accelerated approval of drugs to treat tuberculosis. (Meyvisch et al. 2018)
  • For more examples of reasonably likely and validated surrogate endpoints see the Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure (U.S. Food and Drug Administration 2021)

Explanation

A response biomarker is used to show that a biological response, potentially beneficial or harmful, has occurred in an individual who has been exposed to a medical product or an environmental agent. A pharmacodynamic biomarker is a response biomarker that indicates biological activity of a medical product or environmental agent without necessarily drawing conclusions about efficacy or disease outcome or necessarily linking this activity to an established mechanism of action. It is often very difficult to statistically power an early phase clinical trial to demonstrate a meaningful change in a clinical outcome, and many clinical outcomes require a long period of time before a meaningful change can be demonstrated. Pharmacodynamic biomarkers may be useful to establish proof-of-concept, i.e. that a medical product produces a pharmacologic response in humans. This information can be used to more specifically guide dose-response studies to determine which doses should be considered in trials that evaluate a clinical outcome. For example, B-lymphocyte suppression has been used to find doses of B-lymphocyte targeted therapies required to maximally reduce this cell population, which is presumed to underlie the clinical benefits of these drugs in treating cancer. Pharmacodynamic biomarkers can provide evidence of target engagement; however, it may not always be possible to separate the direct biological effect of an agent from spontaneous changes in disease or medical condition.

An important use of response biomarkers is as Biomarkers of Potential Harm (BOPH), which measure effects consistent with harm due to exposure. These include early biological effects, alterations in morphology, structure, or function, and clinical symptoms (Stratton et al. 2001). An emerging application of BOPH is as response biomarkers for assessing potential health risks of new and novel tobacco products in the absence of long-term epidemiological evidence. A set of biomarkers, rather than a single biomarker, may be necessary to represent the multiple mechanisms by which tobacco causes diseases (Chang et al, 2019).

Response biomarkers that are intended to predict a clinical benefit in clinical trials may be considered as candidate, reasonably likely, or validated surrogate endpoints depending on the level of evidence.

Outside of medical product development, response biomarkers can also be used in clinical care settings. The main utility of response biomarkers in clinical practice is to guide dosing or continued use of a medical product. For example, the biomarker HbA1c is used to evaluate diabetes control following treatment with an antihyperglycemic agent. Such biomarkers may be used to gauge the level of response so that individual drug doses can be altered, or to identify whether therapies need to be added, subtracted, or replaced. Similarly, biomarkers of coagulation are used to monitor warfarin therapy and adjust doses so that the biomarkers are kept within specific ranges. Because these biomarkers have been shown to correlate with clinical outcomes in atrial fibrillation, measuring coagulation parameters and adjusting warfarin doses can reduce the likelihood of bleeding complications and decrease the likelihood of stroke. In almost all cases in the clinical setting, response biomarkers are monitored because there is, or is thought to be, a link between the biomarker and clinical outcomes.

References

  • American Diabetes Association. Standards of Medical Care in Diabetes – Diabetes Care. 2016 Jan;39 (Suppl 1). Accessed December 2016. http://care​.diabetesjournals​.org/content/39/Supplement_1.
  • Chang CM, Cheng YC, Cho M, Mishina EV, Del Valle-Pinero AY, van Bemmel DM, Hatsukami DK. Biomarkers of Potential Harm: Summary of an FDA-Sponsored Public Workshop. Nicotine & Tobacco Research, 2019, 3–13. [] [PubMed: 29253243]
  • Christensen CH, Chang JT, Rostron BL, Hammad HT, van Bemmel DM, Del Valle-Pinero AY, Wang B, Mishina EV, Faulcon LM, DePina A, et al. Biomarkers of Inflammation and Oxidative Stress among Adult Former Smoker, Current E-Cigarette Users-Results from Wave 1 PATH Study. Cancer Epidemiol Biomarkers Prev. 2021 July; doi: 10.1158/1055-9965.EPI-21-0140 (online ahead of print) [] [PMC free article: PMC8500540] [PubMed: 34289969] [CrossRef]
  • DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 2019. Accessed February 2021. https:​//clinicalinfo​.hiv.gov/sites/default​/files/guidelines/documents​/AdultandAdolescentGL.pdf.
  • Durmowicz AG, Witzmann KA, Rosebraugh CJ, Chowdhury BA. Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest. 2013 Jan;143(1):14–8. CrossRef [PubMed: 23276841]
  • Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2) Suppl: e152S–e184S. [PMC free article] [] [CrossRef] [PMC free article: PMC3278055] [PubMed: 22315259]
  • James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507–20. CrossRef [PubMed: 24352797]
  • Jameson E, Jones S, Remmington T. Enzyme replacement therapy with laronidase (Aldurazyme®) for treating mucopolysaccharidosis type I. Cochrane Database Syst Rev. 2016 Apr 1;4:CD009354. CrossRef [PubMed: 27033167]
  • Kimball TR, Daniels SR, Weiss RG, Meyer RA, Hannon DW, Ryckman FC, Tian J, Shukla R, Schwartz DC. Changes in cardiac function during extracorporeal membrane oxygenation for persistent pulmonary hypertension in the newborn infant. J Pediatr. 1991 Mar;118(3):431–6. CrossRef [PubMed: 1999787]
  • Lammers WJ, van Buuren HR, Hirschfield GM, Janssen HL, Invernizzi P, Mason AL, Ponsioen CY, Floreani A, Corpechot C, Mayo MJ, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014 Dec;147(6):1338–49.e5. CrossRef [PubMed: 25160979]
  • Liao GJ, Clark AS, Schubert EK, Mankoff DA. 18F-Fluoroestradiol PET: Current Status and Potential Future Clinical Applications. J Nucl Med. 2016 08;57(8):1269-1275. [] [CrossRef] [PubMed: 27307345]
  • Mayer-Hamblett N, Boyle M, VanDevanter D. Advancing clinical development pathways for new CFTR modulators in cystic fibrosis. Thorax. 2016 May;71:454–461. PMC free article CrossRef [PMC free article: PMC4853537] [PubMed: 26903594]
  • Meyvisch P, Kambili C, Andries K, Lounis N, Theeuwes M, Dannemann B, Vandebosch A, Van der Elst W, Molenberghs G, Alonso A. Evaluation of six months sputum culture conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial. PLoS One. 2018;13(7):e0200539. CrossRef [PMC free article: PMC6053142] [PubMed: 30024924]
  • Morschhauser F, Machiels JP, Salles G, Rottey S, Rule SAJ, Cunningham D, Peyrade F, Fruchart C, Arkenau HT, Genvresse I, et al. On-Target Pharmacodynamic Activity of the PI3K Inhibitor Copanlisib in Paired Biopsies from Patients with Malignant Lymphoma and Advanced Solid Tumors. Mol Cancer Ther. 2020 02;19(2):468-478. [v] [CrossRef] [PubMed: 31619463]
  • Murillo Perez CF, Harms MH, Lindor KD, van Buuren HR, Hirschfield GM, Corpechot C, van der Meer AJ, Feld JJ, Gulamhusein A, Lammers WJ, et al. Goals of Treatment for Improved Survival in Primary Biliary Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization of Alkaline Phosphatase. Am J Gastroenterol. 2020 07;115(7):1066-1074. [] [CrossRef] [PubMed: 32618657]
  • Stohl W, Hilbert DM. The discovery and development of belimumab: the anti-BLyS-lupus connection. Nat Biotechnol. 2012 Jan 9;30(1):69–77. PMC free article CrossRef [PMC free article: PMC3264947] [PubMed: 22231104]
  • Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25) Suppl 2:S1–45. CrossRef [PubMed: 24222016]
  • Stratton K, Shetty P, Wallace R, Stuart Bondurant. Institute of Medicine. Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction. Washington, DC: National Academy Press; 2001. [] [PubMed: 25057541]
  • U.S. Food and Drug Administration. Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure. Accessed 14 September 2021. Last updated September 2021. https://www​.fda.gov/drugs​/development-resources​/table-surrogate-endpoints-were-basis-drug-approval-or-licensure.