Level 1 A true clinical efficacy measure
(When evidence establishing risk is acceptable in the context of evidence of benefit)
Death {Death or Hospitalization}, in Heart Failure {Death, Lung Transplantation or Hospitalization for Pulmonary Arterial Hypertension} in PAH {Cardiovas Death, Stroke, or Symptomatic Myocardial Infarction}, in Acute Coronary Syndrome {Stroke or Systemic Embolic Event}, in Atrial Fibrillation Progression to EDSS 7 (i.e., becoming wheel chair bound), in Multiple Sclerosis 15 Letter Loss in Best Corrected Visual Acuity, in Age Related Macular Degeneration {Cough, Dyspnea, Chest Pain, or Fever (if defined as symptomatic warmth & chills)}, in Community-Acquired Bacterial Pneumonia Pain or Loss of Joint Function, in Osteo-Arthritis or Rheumatoid Arthritis Symptomatic Bone Fractures Pain in the area of skin lesions, in Acute Bacterial Skin and Skin Structure Infections
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Level 2 A validated surrogate (for a specific disease setting and class of interventions.)
(When interventions are safe, with strong evidence that risks from off target effects are acceptable)
HbA1c for clinical effects on long term risk of microvascular complications, in T2DM {Death or Cancer Recurrence}, in Adjuvant Colorectal Cancer, with 5-Fluorouracil based regimens Systolic and Diastolic Blood Pressure, in Multiple Classes of Anti-hypertensives >40 meter improvements in 6 Minute Walk Distance, in Pulmonary Arterial Hypertension HIV infection, if the mechanisms of the HIV prevention intervention only reduce susceptibility rather than impacting disease progression or infectiousness should infection occur
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Level 3 A non-validated surrogate, yet one established to be ‘reasonably likely to predict clinical benefit’ (for a specific disease setting and class of interventions)
(When interventions are safe, with evidence that risks from off target effects are acceptable)
Large and Durable effects on Viral Load, in Some Treatment of HIV infection Settings Durable Complete Responses, in Some Hematologic Oncology Settings Large Effects on Progression-Free-Survival, in Some Solid Tumor Oncology Settings
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Level 4 A correlate that is a measure of biological activity, but not established to be at a higher level.
CD-4, in HIV infected patients Fever (if defined as elevated body temperature), in Community Acquired Bacterial Pneumonia Decolonization of VRE, in the Gastro-Intestinal Tract to prevent VRE bacteremia Decolonization of Staphylococcus aureus, in Preventing Wound or Bloodstream Infections Hematocrit levels, in Chemotherapy-Induced Anemia or in End Stage Renal Disease Antibody Levels and Cell Mediated Immune Responses, in Vaccines for Prevention of HIV Urine GAG and Urine KS, in Rare Disease Settings such as MPS-I, MPS-II and MPS-IV PSA levels or Prostate Cancer Biopsy, in Prevention of Prostate Cancer Symptoms or Death Detecting Asymptomatic Ulcers on Endoscopy, in Prevention of Symptomatic Ulcers FEV-1 and FVC, in Pulmonary Diseases Silent Myocardial Infarction, in Cardiovascular Disease Asymptomatic Fracture Rate, in Prevention of Symptomatic Disease Negative Cultures & Polymerase Chain Reaction Tests, in Treating Various Infectious Diseases
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