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Surrogate Endpoint (Marker): Definition and Examples

“As per National Cancer Institute : In clinical trials, an indicator or sign used in place of another to tell if a treatment works. Surrogate endpoints include a shrinking tumor or lower biomarker levels.

They may be used instead of stronger indicators, such as longer survival or improved quality of life, because the results of the trial can be measured sooner.

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The use of surrogate endpoints in clinical trials may allow earlier approval of new drugs to treat serious or life-threatening diseases, such as cancer. Surrogate endpoints are not always true indicators or signs of how well a treatment works.

In other words, a surrogate endpoint (or surrogate marker) in clinical trials is a measure of the efficacy of a particular treatment that may correspond with a true therapeutic outcome, but may not actually have a assured relation.

Surrogate endpoints may be used in its place of clinical outcomes in some clinical trials.

For example, surrogate endpoints are used where clinical results, such as strokes, may take a long time to research, or when the health advantage of changing the surrogate endpoint is well known, such as managing blood pressure.

These are also seen in situations where it would be unethical to perform a therapeutic conclusion test. Extensive data must gather, including results from epidemiological research and clinical experiments, until a alternative conclusion can be recognized in favour of a clinical result.

Clinical studies are typically used to show that the surrogate endpoint can be used to forecast, or compare with, clinical benefit in a context of use. Surrogate endpoints that have completed this comprehensive evaluation are considered approved surrogate endpoints, and the FDA recognizes these endpoints as evidence of gain.

Between 2010 and 2012, the FDA approved 45 percent of new drugs based on a surrogate endpoint. Often surrogate endpoints will help rapid acceptance with less proof help because they “possibly predict a therapeutic gain.”

Why are surrogate endpoints important for medical product development?

When a surrogate endpoint clearly predicts a beneficial effect through appropriate studies, its use normally allows for more efficient drug development programs.

For example, many clinical trials, using a range of different blood pressure lowering medications, have demonstrated that reducing systolic blood pressure reduced the risk of stroke.

Measurement of decrease in the surrogate endpoint of systolic blood pressure will also reflect the clinical outcome of the stroke, and clinical trials aimed at decreasing the risk of stroke can be carried out more rapidly in smaller populations using this validated surrogate endpoint.

Adult Surrogate Endpoint Table

Adult Surrogate Endpoint Table

Disease or UsePatient PopulationSurrogate EndpointType of approval appropriate forDrug mechanism of action
Acute Bronchospasm  Patients with acute bronchospasm associated with reversible obstructive airway disease or exerciseForced expiratory volume in 1 second (FEV1)TraditionalBeta-2 adrenergic agonist
Anthrax vaccinePersons at high risk of exposure to anthraxAnti-protective antigen antibody response             TraditionalInduction of immunity
Acute BronchospasmPatients with acute bronchospasm associated with reversible obstructive airway disease or exerciseForced expiratory volume in 1 second (FEV1)TraditionalBeta-2 adrenergic agonist
Benign hematologyPatients with Thrombocytopenia due to immune (idiopathic) thrombocytopenia or chronic hepatitis CPlatelet count responseTraditionalMechanism agnostic*
Benign hematology       Patients with sickle cell disease        Hemoglobin response rateAcceleratedHemoglobin S polymerization inhibitor
Cancer: hematological malignanciesPatients with Acute Lymphoblastic LeukemiaSerum asparaginaseTraditionalAsparagine-specific enzyme
Cancer: solid tumors Patients with breast cancer; neuroblastomaEvent-free survival (EFS)˟Accelerated/Traditional§Mechanism agnostic*
Cushing’s diseasePatients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative    Urine free cortisol TraditionalSomatostatin analog
Diphtheria vaccine (in combination vaccines)Persons to be immunized against diphtheriaAnti-diphtheria toxoid antibody             TraditionalInduction of immunity
Exocrine pancreatic insufficiencyPatients with exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditionsFecal coefficient of fat absorptionTraditionalCombination of porcine-derived lipases, proteases, and amylases
Fabry diseasePatients with Fabry diseaseHistological reduction of GL-3 inclusion burden in biopsied kidney interstitial capillaries (KIC)AcceleratedEnzyme replacement therapy, chaperone therapy
GoutPatients with goutSerum uric acidTraditionalXanthine oxidase inhibitor; URAT1 inhibitor
Hepatitis A (Hep A) vaccinePersons to be immunized against Hep AAnti-Hep A antigen antibody             TraditionalInduction of immunity
Hepatitis B (Hep B) vaccinePersons to be immunized against Hep BAnti-Hep B antigen antibodyTraditionalInduction of immunity
Hepatitis C Virus (HCV)Patients with HCV infection with or without cirrhosisSustained viral response (HCV-RNA)TraditionalAntiviral
Hepatitis D Virus (HDV)Patients with HDV infection with or without cirrhosis>2 log reduction in HDV-RNA plus normalization of ALT or HDV below the LLOQ˟AcceleratedAntiviral
Human Immunodeficiency Virus-1 (HIV-1)Patients with HIV-1Undetectable plasma HIV RNA              TraditionalAntiviral
Human PapillomavirusPersons (18 through 45 years of age) to be immunized against human papillomavirusCervical intraepithelial neoplasiaTraditionalInduction of immunity
Hyperkalemia    Patients with hyperkalemiaSerum potassiumTraditionalPotassium salts
Influenza vaccinePersons to be immunized against influenza Hemagglutination inhibition antibody               AcceleratedInduction of immunity
Japanese encephalitis vaccinePersons to be immunized against Japanese encephalitisNeutralizing antibodyTraditionalInduction of immunity
Lipodystrophy   Patients with congenital or acquired generalized lipodystrophySerum hemoglobin A1C, fasting glucose and triglyceridesTraditionalTraditionalLeptin analog
Male hypogonadotropic hypogonadism with inferilityMen with selected cases of hypogonadotropic hypogonadism with inferilitySperm parametersTraditionalGonadotropin

Pediatric Surrogate Endpoint Table

Disease or UsePatient PopulationSurrogate EndpointType of approval appropriate forDrug mechanism of action 
AcromegalyPatients with acromegaly who don’t respond to or cannot undergo other standard therapiesSerum growth hormone and serum insulin-like growth factor-I  (IGF-1)TraditionalSomatostatin analog 
Acute Bronchospasm              Patients with acute bronchospasm associated with reversible obstructive airway disease or exerciseForced expiratory volume in 1 second (FEV1)TraditionalBeta-2 adrenergic agonist 
Benign hematologyPatients with Thrombocytopenia due to immune (idiopathic) thrombocytopenia or chronic hepatitis CPlatelet count responseTraditionalMechanism agnostic* 
Benign hematologyPatients with anemia due to (1) chronic kidney disease, (2) chemotherapy-induced anemia, (3) zidoviduine in patients with HIV-infectionHematologic response and reduction in transfusionTraditionalMechanism agnostic* 
Cancer: hematological malignanciesPatients with Acute Lymphoblastic LeukemiaSerum asparaginaseTraditionalAsparagine-specific enzyme 
Cancer: hematological malignanciesPatients with chronic myeloid leukemia; hypereosinophilic syndrome/chronic eosinophilic leukemiaMajor hematologic responseAccelerated/Traditional§               Mechanism agnostic* 
Cancer: solid tumors              Patients with breast cancer; renal cell carcinoma; pancreatic neuroendocrine tumor; soft tissue sarcoma; ovarian, fallopian tube, or primary peritoneal cancer; prostate cancer; thyroid cancer; colorectal cancer; non-small cell lung cancer; head and neck cancer; uberous sclerosis complex; merkel cell carcinoma; basal cell carcinoma; urothelial carcinoma; cervical cancer; endometrial cancer;  hepatocellular carcinoma; fallopian tube cancer; melanoma; astrocytoma; gastrointestinal stromal tumorsProgression free survivial (PFS)     TraditionalMechanism agnostic* 
Cancer: solid tumorsPatients with breast cancer; ovarian cancer; renal cell carcinoma; pancreatic neuroendocrine cancer; colorectal cancer; head and neck cancer; non-small cell lung cancer; small cell lung cancer; melanoma; tuberous sclerosis complex-associated SEGA and renal angiomyoliploma; merkel cell carcinoma; unresectable or metastatic cutaneous basal cell carcinoma; urothelial carcinoma; cervical cancer; endometrial cancer;  hepatocellular carcinoma; fallopian tube cancer; microsatellite instability-high cancer; gastric cancer; thyroid cancer; astrocytoma; AIDS -related Kaposi’s sarcoma; unresectable or metastatic cutaneous squamous cell carcinoma; neurotrophic receptor tyrosine kinase ( NTRK) gene fusion without a known acquired resistance mutationDurable objective overall response rate (ORR)Accelerated/Traditional§               Mechanism agnostic* 
Chronic kidney diseasePatients with chronic kidney disease secondary to multiple etiologiesEstimated glomerular filtration rate or serum creatinineTraditionalMechanism agnostic* 
Cytomegalovirus (CMV)CMV seropositive and hematopoietic transplant recipients requiring prophylaxisPlasma CMV-DNA exceeding threshold for starting treatmentTraditionalAntiviral 
CystinuriaPatients with cystinuriaUrinary cystineTraditionalReducing and complexing thiol 
Cystic fibrosisPatients with cystic fibrosisForced expiratory volume in 1 second (FEV1)TraditionalCystic fibrosis transmembrane conductance regulator potentiator 
Diphtheria vaccine (in combination vaccines)Persons to be immunized against diphtheriaAnti-diphtheria toxoid antibody               TraditionalInduction of immunity 
Duchenne muscular dystrophy (DMD)               Patients with DMD who have aPatients with DMD who have a confirmed mutation of the DMD gene that is amenable to exon 51 skippingSkeletal muscle dystrophinAcceleratedAntisense oligonucleotide 
Fabry diseasePatients with Fabry diseaseHistological reduction of GL-3 inclusion burden in biopsied kidney interstitial capillaries (KIC)AcceleratedEnzyme replacement therapy, chaperone therapy 
Human Immunodeficiency Virus-1 (HIV-1)Patients with HIV-1Undetectable plasma HIV RNATraditionalAntiviral 
Human Immunodeficiency Virus-1 (HIV-1)Patients at high risk of sexually acquired HIV-1Serum HIV antibodyTraditionalAntiviral 
Human PapillomavirusPersons (18 through 45 years of age) to be immunized against human papillomavirusCervical intraepithelial neoplasiaTraditionalInduction of immunity 
Hypercholesterolemia              Patients with heterozygous familial and nonfamilial hypercholesterolemiaSerum LDL-C TraditionalLipid-lowering 
HypertensionPatients with hypertensionBlood pressureTraditionalMechanism agnostic* 
Influenza vaccinePersons to be immunized against influenza Hemagglutination inhibition antibody             AcceleratedInduction of immunity 
Interoperative hemorrhagePatients who require reduction of blood pressure to reduce bleeding during surgeryBlood pressureTraditionalVasodilator 
What is the purpose of the Surrogate Endpoint Table?

FDA’s surrogate endpoint table provides important information for drug developers on endpoints that may be considered and discussed with the FDA for individual development programs.

This table also fulfills a 21st Century Cures Act requirement to publish a list of the  “surrogate endpoints which were the basis of approval or licensure (as applicable) of a drug or a biological product” under both accelerated and traditional approval pathways.

Section 3011 of the 21st Century Cures Act established section 507 of the Federal Food , Drug and Cosmetic Act (FD&C Act), which allows the FDA to provide a list of “surrogate endpoints that were the basis for the approval or licensing (as applicable) of a medication or biological product” under both accelerated and conventional authorisation requirements.

This surrogate endpoint table includes surrogate endpoints that sponsors have used as primary efficacy clinical trial endpoints for approval of new drug applications (NDAs) or biologics license applications (BLAs).  

The table also includes surrogate endpoints that may be appropriate for use as a primary efficacy clinical trial endpoint for drug or biologic approval, although they have not yet been used to support an approved NDA or BLA.
This list facilitates consideration of potential surrogate endpoints when developers are designing their drug development programs. 

What are the key considerations of the surrogate endpoint table?

The table is intended to act as a reference guide to help inform the discussion of potential surrogate endpoints with the related analysis divisions of the Center for Biologics Evaluation and Research (CBER) or the Center for Drug Evaluation and Research (CDER), with the goal of encouraging the production of drugs.

The acceptability of these alternative endpoints should be assessed on a case-by – case basis for use in a particular medication or biological research programme. It is context-dependent, partly depending on the disorder, patient population observed, clinical mode of action and availability of existing therapies.

A particular surrogate endpoint that may be suitable for use in a particular drug or biologic clinical development program, should not be supposed to be appropriate for use in a different program that is in a different clinical setting.

Similarly, composite endpoints with biomarker surrogate endpoints are not used, nor are clinical outcome tests.

If multiple biomarker surrogate endpoints is composed of a single endpoint, the information is included in the table.

Separate adult and pediatric sections are provided.  Pharmacokinetic endpoints that have supported extrapolation from the adults to children are not included in the pediatric section.  

If a surrogate endpoint was previously used to promote accelerated approval of a drug or biologic but subsequent confirmatory trials did not show the predicted therapeutic benefit, the surrogate endpoint would no longer be approved for this use and would not be included on the table.

Other Important facts about Surrogate Endpoints:

A surrogate endpoint is a clinical trial endpoint used as a alternative for a direct measure of how a patient feels, functions, or survives.

A surrogate endpoint does not measure the clinical benefit of the primary interest in and of itself, but rather is expected to predict that clinical benefit.  

Generally, the predictive nature of a surrogate endpoint is determined during the evaluation of epidemiologic, therapeutic, pathophysiologic, or other scientific evidence.

Surrogate endpoints can be characterized by the level of clinical validation:

  • Candidate surrogate endpoint
  • Reasonably likely surrogate endpoint
  • Validated surrogate endpoint

Candidate surrogate endpoints are still under evaluation for their capacity to predict clinical benefit, while validated surrogate endpoints are supported by the clear mechanistic rationale and clinical data providing strong evidence that an effect on surrogate endpoint predicts a specific clinical benefit.”

https://www.fda.gov/drugs/development-resources/surrogate-endpoint-resources-drug-and-biologic-development

https://www.cancer.gov/publications/dictionaries/cancer-terms/def/surrogate-endpoint

https://www.nuventra.com/resources/blog/surrogate-endpoints-benefits-and-criticisms/

https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure

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