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Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure

What is the purpose of the Surrogate Endpoint Table?

FDA’s surrogate endpoint table provides valuable information for drug developers on endpoints that may be considered and discussed with FDA for individual development programs. This table also fulfills a 21st Century Cures Act requirement to publish a list of “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 mandates that the FDA publish a list of “surrogate endpoints which were the basis of approval or licensure (as applicable) of a drug or biological product” under both accelerated and traditional approval provisions. The Surrogate Endpoint Table below fulfils this legislative requirement and is intended to provide valuable information for drug developers on endpoints that may be considered and discussed with FDA for individual development programs.

According to section 507(e)(9) of the FD&C Act “[t]he term ‘surrogate endpoint’ means a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure, that is not itself a direct measurement of clinical benefit, and—

‘‘(A) is known to predict clinical benefit and could be used to support traditional approval of a drug or biological product; or

‘‘(B) is reasonably likely to predict clinical benefit and could be used to support the accelerated approval of a drug or biological product in accordance with section 506(c).’’

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. We believe that this list should facilitate 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 serve as a reference guide to help inform discussion of potential surrogate endpoints with relevant Center for Biologics Evaluation and Research (CBER) or Center for Drug Evaluation and Research (CDER) review divisions, with the intended goal of facilitating product development.
  • The acceptability of these surrogate endpoints for use in a particular drug or biologic development program will be determined on a case-by-case basis. It is context dependent, relying in part on the disease, studied patient population, therapeutic mechanism of action, and availability of current treatments. A particular surrogate endpoint that may be appropriate for use in a particular drug or biologic clinical development program, should not be assumed to be appropriate for use in a different program that is in a different clinical setting.
  • The table does not include composite endpoints that are a combination of biomarker surrogate endpoints and clinical endpoints.  Likewise, composite endpoints of biomarker surrogate endpoints and clinical outcome assessments are also not included.  If a composite endpoint was composed of multiple biomarker surrogate endpoints, that information is included on the table.   
  • Separate adult and pediatric sections are provided.  Pharmacokinetic endpoints that have supported extrapolation from adults to children are not included in the pediatric section.  
  • If a surrogate endpoint was previously used to support accelerated approval of a drug or biologic but subsequent confirmatory trials failed to demonstrate the expected clinical benefit, the surrogate endpoint would no longer be accepted for this use and it was not included on the table.

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What are the table’s limitations?

  • This table reflects surrogate endpoints that have either been already used in development programs for drugs that have been approved, or surrogate endpoints that FDA has indicated acceptance of in guidances or other documents.  FDA encourages development of novel surrogate endpoints, and strongly encourages sponsors to seek advice from the relevant CBER or CDER division of such novel endpoints early in development by scheduling a PDUFA VI Type C SE meeting to discuss the use of a novel surrogate endpoint in their planned clinical trials. The acceptability of a surrogate endpoint for an individual drug or biologic development program will be determined on a case by case basis.
  • The Surrogate Endpoint Table is not a replacement for discussions with appropriate CBER or CDER review divisions.  Sponsors are reminded that surrogate endpoints provided in this table are intended to facilitate but not replace discussions of individual drug development programs between the sponsor and the appropriate review division.
  • The table does not include surrogate endpoints that may have been accepted for past programs but are no longer acceptable as an endpoint to support registration.  As scientific understanding, clinical information, and technology evolve, a previously used surrogate endpoint may no longer be considered sufficiently robust or appropriate for use in current programs.   

The SE table was last updated July 23, 2018 and will be updated by CBER and CDER every 6 months to reflect current thinking as mandated by section 507 of the FD&C Act.

Footnotes

# Surrogate endpoint is part of a composite of biomarker surrogate endpoints.

* Mechanism agnostic refers to cases where there are many mechanisms of action associated with a surrogate endpoint, so it is not directly related to a particular causal pathway.

§ Endpoints based on changes in tumor burden may be used for both traditional and accelerated approval depending on context of use, including factors such as disease, effect size, effect duration, residual uncertainty and benefits of other available therapy.

˟ The agency anticipates that this surrogate endpoint could be appropriate for use as a primary efficacy clinical trial endpoint for drug or biologic approval, although it has not yet been used to support an approved NDA or BLA.

¤ Bone mineral density is an acceptable primary endpoint for establishing efficacy for the treatment of male or glucocorticoid-induced osteoporosis after efficacy based on new morphometric vertebral fractures has been established in postmenopausal women.    

Downloadable Table of Surrogate Endpoints (XLS - 41 KB)

Adult Surrogate Endpoint Table

Disease or Use  Patient Population  Surrogate endpoint  Type of approval appropriate for  Drug mechanism of action 
Disease or Use  Patient Population  Surrogate endpoint  Type of approval appropriate for  Drug mechanism of action 
 Alpha-1-antitrypsin deficiency Patients with congenital alpha-1 antitrypsin deficiency Plasma alpha-1 proteinase inhibitor Traditional Alpha-1 protease inhibitor augmentation
Acetylglutamate Synthase deficiency Patients with hyperammonemia due to N-acetylglutamate synthase deficiency Plasma ammonia  Traditional Carbamoyl Phosphate Synthetase 1 (CPS 1) activator
Acromegaly  Patients with acromegaly who don't respond to or cannot undergo other standard therapies Serum Insulin-like growth factor-I (IGF-1) Traditional Growth hormone receptor antagonist
Acromegaly  Patients with acromegaly who don't respond to or cannot undergo other standard therapies Serum growth hormone and serum insulin-like growth factor-I  (IGF-1)  Traditional Somatostatin analog
Acute Bronchospasm Patients with acute bronchospasm associated with reversible obstructive airway disease or exercise Forced expiratory volume in 1 second (FEV1) Traditional  Beta-2 adrenergic agonist
Anthrax vaccine Persons at high risk of exposure to anthrax Anti-protective antigen antibody response Traditional Induction of immunity
Anticoagulation reversal (needed due to life-threatening or uncontrolled bleeding) Patients treated with a direct or indirect FXa inhibitor when reversal of anticoagulation is needed Percent change in anti-FXa activity, from baseline to nadir Accelerated Binding and sequestering FXa inhibitors
Asthma Patients with asthma Forced expiratory volume in 1 second (FEV1)   Traditional  Corticosteroid; Beta-2 adrenergic agonist
Benign hematology Patients with Thrombocytopenia due to immune (idiopathic) thrombocytopenia or chronic hepatitis C Platelet count response Traditional  Mechanism agnostic*
Benign hematology Patients with chronic iron overload or non-transfusion-dependent thalassemia syndromes Serum ferritin and liver iron concentration  Accelerated/Traditional§  Iron chelator
Benign hematology Patients with anemia due to (1) chronic kidney disease, (2) chemotherapy-induced anemia, (3) zidoviduine in patients with HIV-infection Hematologic response and reduction in transfusion Traditional Mechanism agnostic*
Benign hematology Patients with severe aplastic anemia Hematologic response  Traditional Mechanism agnostic*
Benign hematology Patients with venous thromboembolism (VTE)/pulmonary embolism Total venous thromboembolism and all-cause death# Traditional Anticoagulant
Benign hematology Patients with methemoglobinemia Serum methemoglobin Accelerated Oxidation-reduction agent    
Benign hematology Patients in need of reversal of anticoagulant effects for emergency surgery/urgent procedures and in life-threatening or uncontrolled bleeding. Change in coagulation factors  Traditional  Humanized monoclonal antibody fragment 
Cancer: hematological malignancies  Patients with Acute Lymphoblastic Leukemia  Serum asparaginase  Traditional  Asparagine-specific enzyme
Cancer: hematological malignancies  Patients with diffuse large B-cell lymphoma Event-free survival (EFS) ˟ Traditional Mechanism agnostic*
Cancer: hematological malignancies  Patients with chronic myeloid leukemia; hypereosinophilic syndrome/chronic eosinophilic leukemia  Major hematologic response Accelerated/Traditional§  Mechanism agnostic*
Cancer: hematological malignancies  Patients with acute myeloid leukemia and acute lymphoblastic leukemia Durable complete remission rate Accelerated/Traditional§  Mechanism agnostic*
Cancer: hematological malignancies  Patients with acute lymphoblastic leukemia; myelodysplastic/myeloproliferative diseases; chronic myeloid leukemia Major hematologic response and cytogenic response Accelerated/Traditional§  Mechanism agnostic*
Cancer: hematological malignancies  Patients with B-cell precursor acute lymphoblastic leukemia in first or second complete remission Minimal residual disease response rate  Accelerated Mechanism agnostic*
Cancer: hematological malignancies  Patients with T-cell lymphoma;  B-cell lymphoma; mantle cell lymphoma; classical Hodgkin lymphoma; anaplastic large cell lymphoma and mycosis fungoides; non-Hodgkin lymphoma; multiple myeloma; chronic myeloid leukemia; acute lymphoblastic leukemia; chronic lymphocytic leukemia; accute myeloid leukemia; small lymphocytic lymphoma; Waldenström’s macroglobulinemia; marginal zone lymphoma; follicular lymphoma Durable objective overall response rate (ORR) Accelerated/Traditional§  Mechanism agnostic*
Cancer: hematological malignancies  Patients with multiple myeloma; mantle cell lymphoma; classical Hodgkin lymphoma; follicular lymphoma;  B cell lymphoma; systemic anaplastic large cell lymphoma; chronic myeloid leukemia; chronic lymphocytic leukemia; cutaneous T cell lymphoma; all other non-Hodgkin lymphoma; chronic lymphocyic leukemia; mycosis fungoides  Progression free survivial (PFS) Traditional Mechanism agnostic*
Cancer: solid tumors Patients 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;  urotherlial carcinoma; unresectable or metastatic cutaneous squamous cell carcinoma; neurotrophic receptor tyrosine kinase ( NTRK) gene fusion without a known acquired resistance mutation Durable objective overall response rate (ORR) Accelerated/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 tumors Progression free survivial (PFS) Accelerated/Traditional§  Mechanism agnostic*
Cancer: solid tumors Patients receiving adjuvant therapy following complete surgical resection of colon cancer; colorectal cancer;  melanoma; renal cell cancer; gastrointestinal stromal tumor; breast cancer and adjuvant therapy for stage III non-small cell lung cancer Disease-free survival (DFS) Accelerated/Traditional§  Mechanism agnostic*
Cancer: solid tumors Patients with breast cancer; neuroblastoma Event-free survival (EFS)˟ Accelerated/Traditional§  Mechanism agnostic*
Cancer: solid tumors Patients with breast cancer Pathological complete response Accelerated Mechanism agnostic*
Cancer: solid tumors Patients with nonmetastatic castrate-resistant prostate cancer Metastasis-free survival Accelerated/Traditional§  Mechanism agnostic*
Cancer: solid tumors Patients with advanced prostate cancer Plasma testosterone levels Traditional Gonadotropin-releasing hormone antagonist
Chronic kidney disease  Patients with chronic kidney disease secondary to multiple etiologies  Estimated glomerular filtration rate or serum creatinine  Traditional Mechanism agnostic*
Chronic obstructive pulmonary disease (COPD) Patients with COPD Forced expiratory volume in 1 second (FEV1) Traditional  Long-acting beta2-adrenergic agonist; Anticholinergic; Phosphodiesterase 4 inhibitor
Cushing's disease  Patients with Cushing’s disease  Urine free cortisol   Traditional Somatostatin analog 
Cushing's syndrome Patients with endogenous Cushing’s syndrome Urine free cortisol ˟   Traditional   Cortisol synthesis inhibitor 
Cystic fibrosis Patients with cystic fibrosis Forced expiratory volume in 1 second (FEV1) Traditional  Cystic fibrosis transmembrane conductance regulator potentiator
Cystinuria Patients with cystinuria Urinary cystine Traditional Reducing and complexing thiol
Cytomegalovirus (CMV)  CMV seropositive and hematopoietic transplant recipients requiring prophylaxis   Plasma CMV-DNA exceeding threshold for starting treatment Traditional Antiviral
Diphtheria vaccine (in combination vaccines) Persons to be immunized against diphtheria  Anti-diphtheria toxoid antibody  Traditional Induction of immunity
Duchenne muscular dystrophy (DMD) Patients with DMD who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping Skeletal muscle dystrophin Accelerated Antisense oligonucleotide
Exocrine pancreatic insufficiency Patients with exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions Fecal coefficient of fat absorption  Traditional Combination of porcine-derived lipases, proteases, and amylases
Fabry disease Patients with Fabry disease GL-3 inclusion score in renal interstitial capillary endothelial cells or plasma GL-3 levels Accelerated Agalsidase beta
Female hypogonadotropic
hypogonadism
Infertile women with hypogonadotropic hypogonadism Follicle size, serum estradiol and progesterone# Traditional Gonadotropin
First aid antiseptic; Health care antiseptic; Consumer antiseptic General public, consumers, and health care professionals Bacterial count Traditional and Monograph 
Antimicrobial 
Gout Patients with gout Serum uric acid Traditional  Xanthine oxidase inhibitor; URAT1 inhibitor
Hepatitis A (Hep A) vaccine Persons to be immunized against Hep A  Anti-Hep A antigen antibody   Traditional Induction of immunity
Hepatitis B (Hep B) vaccine Persons to be immunized against Hep B Anti-Hep B antigen antibody  Traditional Induction of immunity
Hepatitis B Virus (HBV) Patients with HBV infection with or without cirrhosis  Undetectable plasma HBV-DNA Traditional  Antiviral
Hepatitis C Virus (HCV) Patients with HCV infection with or without cirrhosis Sustained viral response (HCV-RNA)  Traditional  Antiviral 
Hepatitis D Virus (HDV) Patients with HDV infection with or without cirrhosis ≥ 2 log reduction in HDV-RNA plus normalization of ALT ˟ Accelerated Antiviral
Hepatorenal syndrome  Patients with hepatorenal syndrome type 1 Serum creatine ˟ Traditional Vasopressin analog
Hereditary orotic aciduria Patients with hereditary orotic aciduria  Neutrophil count and percent neutrophils, white blood cell count, and mean corpuscular volume  Traditional Acetylated uridine
Homozygous sitosterolemia (phytosterolemia) Patients with homozygous sitosterolemia (phytosterolemia) Plasma sitosterol and campesterol Traditional Dietary cholesterol absorption inhibitor
Human Immunodeficiency Virus-1 (HIV-1) Patients with HIV-1 Undetectable plasma HIV RNA Traditional Antiviral 
Human Immunodeficiency Virus-1 (HIV-1) Patients at high risk of sexually acquired HIV-1  Serum HIV antibody  Traditional Antiviral 
Human Immunodeficiency Virus-1 (HIV-1) Highly treatment-experienced  HIV-1 patients  Greater than 0.5 log reduction in plasma HIV RNA Traditional Antiviral 
Human Papillomavirus Persons (18 through 45 years of age) to be immunized against human papillomavirus Cervical intraepithelial neoplasia Traditional Induction of immunity
Hypercholesterolemia Patients with heterozygous familial and nonfamilial hypercholesterolemia Serum LDL-C   Traditional Lipid-lowering
Hypercholesterolemia  Patients with homozygous familial hypercholesterolemia Serum LDL-C  Traditional Lipid-lowering 
Hyperkalemia  Patients with hyperkalemia Serum potassium Traditional Potassium binder
Hyperphosphatemia Dialysis patients with hyperphosphatemia  Serum phosphate  Traditional Phosphate binder
Hypertension  Patients with hypertension  Blood pressure Traditional Angiotensin II receptor blocker; Dihydropyridine calcium channel blocker; Renin inhibitor; Aldosterone antagonist; Vasodilator; Dihydropyridine calcium channel blocker
Hypertriglyceridemia Patients with severe hypertriglyceridemia Serum triglycerides Traditional  Lipid-lowering
Hypokalemia  Patients with hypokalemia Serum potassium  Traditional Potassium salts
Hyponatremia  Patients with hypervolemic and euvolemic hyponatremia Serum sodium Traditional Vasopressin receptor antagonist
Hypotension Patients with distributive shock Blood pressure Traditional Alpha  and beta adrenergic agonist; Vasopressin analog
Hypothyroidism Patients with hypothyroidism Serum thyroid-stimulating hormone (TSH) Traditional Thyroid hormone analog 
Idiopathic pulmonary fibrosis   Patients with idiopathic pulmonary fibrosis Forced vital capacity (FVC)   Traditional  Pyridone; Kinase inhibitor
Influenza vaccine Persons to be immunized against influenza   Hemagglutination inhibition antibody  Accelerated Induction of immunity
Interoperative hemorrhage Patients who require reduction of blood pressure to reduce bleeding during surgery Blood pressure Traditional Vasodilator
Japanese encephalitis vaccine Persons to be immunized against Japanese encephalitis  Neutralizing antibody  Traditional Induction of immunity
Lipodystrophy Patients with congenital or acquired generalized lipodystrophy Serum hemoglobin A1C, fasting glucose and triglycerides  Traditional  Leptin analog
Lysosomal Acid Lipase (LAL) deficiency Patients with LAL deficiency Serum LDL-c levels Traditional Hydrolytic lysosomal cholesteryl ester-specific enzyme
Male hypogonadotropic hypogonadism Men with selected cases of hypogonadotropic hypogonadism Sperm count Traditional Gonadotropin
Meningococcal ACYW-135 Persons to be immunized against meningococcal meningitis Serum bactericidal antibody  Traditional Induction of immunity
Meningococcal Group B Vaccine Persons (18 through 25 years of age) to be immunized against meningococcal meningitis Serum bactericidal antibody  Traditional Induction of immunity
Monkeypox vaccine Persons to be immunized against monkeypox Vaccinia-neutralizing antibody Traditional Induction of immunity
Mycobacterium avium complex (MAC) lung disease  Patients with MAC lung disease  Sputum culture conversion to negative by six months  Accelerated Antimicrobial 
Nephropathic cystinosis Patients with nephropathic cystinosis White blood cell cystine and serum creatinine# Traditional Cystine depleting agent
Nonalcoholic steatohepatitis (NASH) Precirrhotic NASH patients with liver fibrosis Histopathologic findings of either 1) resolution of steatohepatitis with no worsening of fibrosis OR 2) improvement of fibrosis with no worsening of steatohepatitis OR 3) Both# Accelerated Anti-fibrotic; Anti-inflammatory
Opioid use disorder Patients with opioid use disorder Urine toxicology test for opioids Traditional Partial opioid agonist
Osteoporosis Postmenopausal women with osteoporosis New morphometric vertebral fractures Traditional Estrogen agonist/antagonist; Parathyroid hormone analog; Bisphosphonate; RANK ligand (RANKL) inhibitor
Osteoporosis Patients with glucocorticoid induced osteoporosis Bone mineral density¤  Traditional Bisphosphonate; Parathyroid hormone analog; RANKL inhibitor
Osteoporosis Men with osteoporosis Bone mineral density¤  Traditional  Parathyroid hormone analog; Bisphosphonate; RANK ligand (RANKL) inhibitor
Paget's disease Patients with Paget's disease Serum alkaline phosphatase Traditional Bisphosphonate
Peri-implantitis Patients with peri-implantitis Probing pocket depth ˟ Traditional Antimicrobial
Periodontitis Patients with chronic periodontitis with a mean probing pocket depth of greater than 5mm  Probing pocket depth Traditional Antimicrobial
Pertussis (in combination vaccines) Persons (18 through 64 years of age) to be immunized against pertussis Serum antibody concentrations Traditional Induction of immunity
Phenylketonuria Patients with hyperphenylalaninemia due to tetrahydrobiopterin-responsive phenylketonuria Plasma phenylalanine  Traditional Phenylalanine hydroxylase activator
Pneumococcal conjugate vaccine Persons ( ≥ 50 years of age) to be immunized against pneumonia and invasive disease Opsonophagocytic antibody response Accelerated  Induction of immunity
Polio vaccine Persons to be immunized against polio  Neutralizing antibody response Traditional Induction of immunity
Polycystic kidney disease Patients with autosomal dominant polycystic kidney disease with or without associated polycystic liver disease  Total kidney volume ˟ Accelerated  Mechanism agnostic*
Preterm birth Women with a singleton pregnancy who have a history of singleton spontaneous preterm birth Delivery prior to 37 weeks gestation Accelerated  Progesterone analog
Primary biliary cholangitis Patients with primary biliary cholangitis Serum alkaline phosphatase and bilirubin# Accelerated Farnesoid X receptor (FXR) agonist
Primary glomerular diseases associated with significant proteinuria Patients with primary glomerular disease associated with significant proteinuria   Proteinuria (urinary protein/creatinine ratio) ˟ Accelerated  Mechanism agnostic*
Primary Hemophagocytic Lymphohistiocytosis (HLH) Patients with HLH Overall Response Rate Traditional Interferon gamma blocking antibody
Primary hyperoxaluria type 1 (PH1) Patients with primary hyperoxaluria type 1 (PH1) Urinary oxalate˟ Traditional siRNA against hyroxyacid oxidase 1 gene 
Primary hyperparathyroidism  Patients with hypercalcemia due to primary hyperparathyroidism  Serum calcium  Traditional Calcium-sensing receptor agonist
Pulmonary multi-drug resistant tuberculosis (TB) Patients with pulmonary multi-drug resistant TB Time to sputum culture conversion to negative Accelerated Antimicrobial 
Pulmonary tuberculosis  Patients with active or latent pulmonary tuberculosis Time to sputum culture conversion to negative Traditional Antimicrobial 
Rabies immune globulin Patients with suspected exposure to a rabid animal Rabies neutralizing activity and antibody response Traditional Passive immunity
Rabies Vaccine Persons to be immunized against rabies Neutralizing antibody  Traditional Induction of immunity
Secondary hyperparathyroidism associated with chronic kidney disease Patients with secondary hyperparathyroidism associated with chronic kidney disease  Serum intact parathyroid hormone (iPTH)   Traditional Calcium-sensing receptor agonist; Vitamin D3 analog
Smallpox vaccine Persons to be immunized against smallpox Vaccinia-neutralizing antibody Traditional Induction of immunity
Smallpox vaccine Persons to be immunized against smallpox Vaccination site take reaction (replicating smallpox vaccines only) Traditional Induction of immunity
Supportive cancer care Patients with delayed methotrexate clearance due to impaired renal function Plasma methotrexate Traditional  Carboxypeptidase
Supportive cancer care Patients with  leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of uric acid. Serum uric acid Traditional  Uric acid specific enzyme
Supportive cancer care Patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs  Duration of severe neutropenia  Traditional  Leukocyte growth factor
Systemic sclerosis-associated interstitial lung disease ( SSc-ILD) Patients with SSc-ILD Forced vital capacity (FVC)   Traditional  Kinase inhibitor
Testosterone deficiency  Men with primary or hypogonadotropic hypogonadism Serum testosterone Traditional Androgen, GnRH analog
Tetanus vaccine Persons to be immunized against tetanus Anti-tetanus toxoid antibody  Traditional Induction of immunity
Tobacco dependence Cigarette smokers  Exhaled carbon monoxide Traditional Smoking cessation 
Type 1 diabetes mellitus  Patients with type 1 diabetes mellitus Serum hemoglobin A1C  Traditional  Glucose-lowering 
Type 1 Gaucher disease   Patients with Type 1 Gaucher disease Spleen volume, liver volume, hemoglobin and platelet count# Traditional Glucosylceramide synthase inhibitor; Hydrolytic lysozomal glucocerebroside-specific enzyme
Type 2 diabetes mellitus  Patients with type 2 diabetes mellitus Serum hemoglobin A1C  Traditional  Glucose-lowering 
X-linked hypophosphatemia  Patients with X-linked hypophosphatemia  Serum phosphate Traditional Fibroblast growth factor 23 inhibitor
Yellow fever  vaccine Persons to be immunized against yellow fever Neutralizing antibody  Traditional Induction of immunity

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Pediatric Surrogate Endpoint Table

Disease or Use  Patient Population  Surrogate endpoint  Type of approval appropriate for Drug mechanism of action Age range 
Acetylglutamate Synthase deficiency Patients  with hyperammonemia due to N-acetylglutamate synthase deficiency Plasma ammonia  Traditional Carbamoyl Phosphate Synthetase 1 activator From birth to less than 18 years of age
Acromegaly  Patients with acromegaly who don't respond to or cannot undergo other standard therapies Serum Insulin-like growth factor-I (IGF-1)  Traditional Growth hormone receptor antagonist 2 years to less than 18 years
Acute bronchospasm Patients with acute bronchospasm associated with reversible obstructive airway disease or exercise Forced expiratory volume in 1 second (FEV1) Traditional  Beta-2 adrenergic agonist 5 years and older
Asthma Patients with asthma Forced expiratory volume in 1 second (FEV1) Traditional  Corticosteroid; Beta-2 adrenergic agonist; Anticholinergic 4 years and older
Benign hematology Patients with thrombocytopenia due to immune (idiopathic) thrombocytopenia or chronic hepatitis C Platelet count Traditional Thrombopoietin receptor agonist 1 year and older
Benign hematology Patients with chronic iron overload or non-transfusion-dependent thalassemia syndromes Serum ferritin and liver iron concentration Accelerated/Traditional§  Iron chelator 2 years or older for chronic iron overload and 10 years older for Non-transfusion-dependent thalassemia syndromes
Benign hematology Patients with severe aplastic anemia Hematologic response  Traditional Thrombopoietin receptor agonist 1 year and older
Benign hematology Patients with venous thromboembolism (VTE)/pulmonary embolism Total VTE and all-cause death  Traditional Anticoagulation All pediatric age groups
Benign hematology Patients with methemoglobinemia Serum methemoglobin Accelerated Oxidation-reduction agent     All pediatric age groups
Cancer: hematological malignancies  Patients with acute lymphoblastic leukemia; B-cell lymphoma Durable objective overall response rate (ORR) Accelerated/Traditional§  Mechanism agnostic* 1 to 21 years
Cancer: hematological malignancies  Patients with acute lymphoblastic leukemia Event Free Survival Accelerated/Traditional§  Mechanism agnostic*  1 to 21 years
Cancer: hematological malignancies  Patients with chronic myeloid leukemia Major hematologic and cytogenic response Accelerated/Traditional§  Mechanism agnostic* 3 to 20 years 
Cancer: hematological malignancies  Patients with Acute Lymphoblastic Leukemia  Serum Asparaginase  Traditional  Asparagine-specific enzyme All pediatric age groups
Cancer: solid tumors Patients with tuberous sclerosis complex with subependymal giant cell astrocytoma; merkel cell carcinoma; neurotrophic receptor tyrosine kinase ( NTRK) gene fusion without a known acquired resistance mutation   Durable objective overall response rate (ORR) Accelerated  Mechanism agnostic* 1 year and older; 12 years and older; 28 days and older 
Cancer: solid tumors Patients with metastatic melanoma Progression Free Survival Accelerated Mechanism agnostic* 12 years and older
Chagas disease  Patients with Chagas disease Immunoglobulin G antibody negative against the recombinant antigens of T. cruzi Accelerated Antimicrobial 2 to 12 years
Chronic kidney disease  Patients with chronic kidney disease secondary to multiple etiologies  Estimated glomerular filtration rate or serum creatinine  Traditional Mechanism agnostic*  
Cystic fibrosis  Patients with cystic fibrosis Forced expiratory volume in 1 second (FEV1) Traditional  Cystic fibrosis transmembrane conductance regulator potentiator 2 years and older
Cystinuria Patients with cystinuria Urinary/urine cystine Traditional Reducing and complexing thiol 9 years and older
Cytomegalovirus (CMV)  CMV seropositive and hemotopoietic transplant recipients requiring prophylaxis   Plasma CMV-DNA exceeding threshold for starting treatment Traditional Antiviral 12 years and older
Diphtheria vaccine (in combination vaccines) Persons to be immunized against diphtheria Anti-diphtheria toxoid antibody  Traditional Induction of immunity 6 weeks and older
Diphtheria, tetanus, pertussis, polio, haemophilus type b disease, and hepatitis B vaccine  Patients to be immunized against diphtheria, tetanus, pertussis, polio, haemophilus type b disease, and hepatitis B vaccine  Neutralizing antibody  Traditional Induction of immunity 6 weeks to <5 years of age
Duchenne muscular dystrophy (DMD) Patients with DMD who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping Skeletal muscle dystrophin Accelerated Antisense oligonucleotide Mean age 8.9 years
Exocrine pancreatic insufficiency Patients with exocrine pancreatic insufficiency due to cystic fibrosis Fecal coefficient of fat absorption  Traditional Reducing and complexing thiol 6 months and older 
Fabry disease Patients with Fabry disease GL-3 inclusion score in renal interstitial capillary endothelial cells and/or plasma GL-3 levels Accelerated Agalsidase beta 8 years and older
First aid antiseptic; Health care antiseptic; Consumer antiseptic General public, consumers, and health care professionals Bacterial count  Traditional and Monograph  
Antimicrobial 
All pediatric age groups
Haemophilus B conjugate vaccine Persons to be immunized against Haemophilus B Anti-polyribosyl-ribitol-phosphate antibody concentrations Accelerated Induction of immunity 6 weeks to 71 months 
Hepatitis A (Hep A) vaccine Persons to be immunized against Hep A  Anti-Hep A antigen antibody  Traditional Induction of immunity 12 months and older
Hepatitis B (Hep B) vaccine Persons to be immunized against Hep B  Anti-Hep B antigen antibody  Traditional Induction of immunity All pediatric age groups
Hepatitis B Virus (HCV) Patients with HBV Serum HBV DNA Traditional  Antiviral 2 years and older
Hepatitis C Virus (HCV) Patients with HCV  with or without cirrhosis Sustained viral response (HCV-RNA)  Traditional  Antiviral 3 years and older
Hereditary orotic aciduria Patients with hereditary orotic aciduria  Neutrophil count and percent neutrophils, white blood cell count, and mean corpuscular volume  Traditional Acetylated uridine 2 months to 12 years
Homozygous sitosterolemia (phytosterolemia) Patients with homozygous sitosterolemia (phytosterolemia) Plasma sitosterol and campesterol  Traditional Dietary cholesterol absorption inhibitor  
Human Immunodeficiency Virus-1 (HIV-1) Patients with HIV-1  Undetectable plasma HIV-RNA Traditional Antiviral  Patients infected since birth
Human Immunodeficiency Virus-1 (HIV-1) Highly treatment experienced HIV-1 patients  Greater than 0.5 log reduction in plasma HIV RNA Traditional Antiviral  Patients infected since birth
Human papillomavirus Persons to be immunized against human papillomavirus Cervical intraepithelial neoplasia Traditional Induction of immunity 9 through 17 years
Hypercholesterolemia Patients with heterozygous familial hypercholesterolemia Serum LDL-C  Traditional Lipid-lowering  
Hypercholesterolemia  Patients with homozygous familial hypercholesterolemia Serum LDL-C  Traditional Lipid-lowering   
Hyperkalemia  Patients with hyperkalemia Serum potassium Traditional Potassium binder  
Hyperphosphatemia Patients with chronic kidney disease on dialysis with hyperphosphatemia Serum phosphate  Traditional Phosphate binder  
Hypertension  Patients with hypertension  Blood pressure Traditional Mechanism agnostic*  
Hypokalemia  Patients with hypokalemia Serum potassium  Traditional Potassium salts  
Hyponatremia  Patients with hypervolemic and euvolemic hyponatremia Serum sodium Traditional Vasopressin receptor antagonist  
Hypothyroidism Patients with hypothyroidism Thyroid-stimulating hormone (TSH) Traditional  Thyroid hormone analog  
Influenza vaccine Persons to be immunized against influenza  Hemagglutination inhibition antibody  Accelerated Induction of immunity  6 months and older
Japanese encephalitis vaccine Persons to be immunized against Japanese encephalitis  Neutralizing antibody  Traditional Induction of immunity 2 months and older
Lipodystrophy Patients with congenital or acquired generalized lipodystrophy Serum hemoglobin A1C , fasting glucose and triglycerides  Traditional  Leptin analog  
Lysosomal Acid Lipase (LAL) deficiency Patients with LAL deficiency Serum LDL-c levels Traditional Hydrolytic lysosomal cholesteryl ester-specific enzyme 1 month and older
Meningococcal A C Y W-135 vaccine Persons to be immunized against meningococcal meningitis   Serum bactericidal antibody  Traditional Induction of immunity 2 months and older
Meningococcal B vaccine Persons to be immunized against meningococcal meningitis Serum bactericidal antibody  Traditional Induction of immunity 10 to 25 years
Nephropathic cystinosis Patients with nephropathic cystinosis White blood cell cystine and serum creatinine# Traditional Cystine depleting agent 6 years and older
Pertussis (in combination vaccines) Persons to be immunized against pertussis Serum antibody concentrations Traditional Induction of immunity 6 weeks and older
Phenylketonuria  Patients with hyperphenylalaninemia due to tetrahydrobiopterin-responsive phenylketonuria Plasma phenylalanine  Traditional Phenylalanine hydroxylase activator  1 month to 16 years
Polio vaccine  Persons to be immunized against polio Neutralizing antibody  Traditional Induction of immunity 6 weeks and older
Precocious puberty Patients with central precocious puberty Serum luteinizing hormone  Traditional Gonadotropin releasing hormone (GnRH) agonist  
Primary glomerular diseases associated with significant proteinuria Patients with primary glomerular disease associated with significant proteinuria   Proteinuria (urinary protein/creatinine ratio) ˟ Accelerated  Mechanism agnostic*  
Primary Hemophagocytic Lymphohistiocytosis (HLH) Patients with HLH Overall Response Rate Traditional Interferon gamma blocking antibody Birth to 13 years of age
Primary hyperoxaluria type 1 (PH1) Patients with primary hyperoxaluria type 1 (PH1) Urinary oxalate˟ Traditional siRNA against hyroxyacid oxidase 1 gene   
Pulmonary Arterial Hypertension  Patients with PAH Pulmonary vascular resistance  Traditional Endothelin receptor antagonist  
Pulmonary Tuberculosis (TB)  Patients with latent pulmonary TB  Time to sputum culture conversion to negative Traditional Antimicrobial  12 years and older
Rabies immune globulin Patients with suspected exposure to a rabid animal Rabies neutralizing activity and antibody response Traditional Passive immunity  
Rabies vaccine Persons to be immunized against rabies Neutralizing antibody  Traditional Induction of immunity All pediatric age groups
Secondary hyperparathyroidism associated with chronic kidney disease  Patients with secondary hyperparathyroidism associated with chronic kidney disease  Serum intact parathyroid hormone (iPTH)   Traditional Vitamin D analog  
Tetanus vaccine (alone or in combination vaccines) Persons to be immunized against tetanus Anti-tetanus toxoid antibody  Traditional Induction of Immunity 6 weeks and older
Type 1 diabetes mellitus  Patients with type 1 diabetes mellitus Serum hemoglobin A1C Traditional  Glucose-lowering 6 to 15 years
Type 1 Gaucher disease   Patients with type 1 Gaucher disease Spleen volume, liver volume, hemoglobin and platelet count# Traditional Hydrolytic lysozomal glucocerebroside-specific enzyme 4 to 17 years 
Type 2 diabetes mellitus  Patients with type 2 diabetes mellitus Serum hemoglobin A1C Traditional  Glucose-lowering 10 to 16 years
X-linked hypophosphatemia  Patients with X-linked hypophosphatemia  Serum phosphate Traditional Fibroblast growth factor 23 inhibitor 1 year and older 
Yellow fever vaccine Persons to be immunized against yellow fever Neutralizing antibody  Traditional Induction of immunity 9 months and older

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