Table 1

Rationale for using surrogate outcomes discussed in drug medical reviews (n=11)

DiseaseDrug nameYear approvedRationale for using surrogate outcomesThe rationale is based on: ‘treatment effects on the surrogate outcome predict treatment effects on the patient-centred outcome’ (highest level of evidence using the International Conference on Harmonisation guidelines for the conduct of clinical trials for the registration of drugs (ICH-9) criteria for surrogacy)Evidence cited to support the use of surrogate outcome
Chronic obstructive pulmonary disease (COPD)TUDORZA PRESSAIR2012Overall, the committee's view was that the Applicant's data for the primary end point of trough forced expiratory volume in one second (FEV1) demonstrated statistical significance, and that these results were clinically meaningful…Comments were made that the results for other measures of efficacy (eg, the St George's Respiratory Questionnaire (SGRQ) and COPD exacerbations), while generally not statistical significant, were nonetheless trending in a direction to support the results for the primary end point… Several comments were made regarding the limitations of FEV1-based end points and the importance of evaluating patient-centred outcomes.”NoNone
Diabetes (type 1 or 2)APIDRA2004GHb (note: glycosylated haemoglobin) results were reported as glycated haemoglobin A1c (HbA1c) equivalents and are directly traceable to the Diabetes Control and Complications Trial (DCCT) reference, for which the relationship between mean BG (blood glucose) (measured by HbA1c) and the risk for vascular complications has been established.”UnclearDiabetes control and complications trial29
Diabetes (type 1 or 2)SYMLIN2005FDA (note: Food and Drug Administration) accepts reduction in HbA1c as a measure of efficacy in trials of new antidiabetic agents. This use of HbA1c as a surrogate end point reflects the finding that long-term reduction of HbA1c decreases the risk of diabetic complications, particularly retinopathy.”YesNone
Diabetes (type 1 or 2)EXUBERA2006“An ideal trial would use diabetic complications as end points, but the trial size and duration needed for use of such end points would be very large. There is some controversy about whether HbA1c is truly a good marker of the risk for complications of diabetes. However, the correlation of HbA1c with risk for the development of microvascular disease in type 1 diabetics is well-established (Jeffcoate 2004), and thus HbA1c is a good surrogate end point for the trials of inhaled insulin in type 1 diabetics.”NoJeffcoate 200430
Diabetes (type 2)JANUVIA2006HbA1c is generally considered the most reliable surrogate of glycaemic control, and ultimately predicts late chronic complications of T2DM (type 2 diabetes mellitus) microvascular and macrovascular, as demonstrated in the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS).”UnclearDiabetes control and complications trial and UK Prospective diabetes study14 29
Diabetes (type 2)JANUMET2007HbA1c is generally considered the most reliable surrogate of glycaemic control, and ultimately predicts late chronic complications of T2DM (type 2 diabetes mellitus) microvascular and macrovascular, as demonstrated in the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS).”UnclearDiabetes control and complications trial and UK Prospective diabetes study14 29
Diabetes (type 2)VICTOZA2010HbA1c has excellent reliability, predicts several diabetes-specific complications and provides the current basis for treatment decisions (American Diabetes Association 2008)… Lowering HbA1c reduces microvascular complications in patients with type 1 and type 2 diabetes (Diabetes Control and Complications Trial Research Group 1993, UK Prospective Diabetes Study (UKPDS) Group 1998) and possibly macrovascular complications in patients with type 1 diabetes (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group 2005).”YesDiabetes control and complications trial, UK Prospective diabetes study and diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) study14 29
Diabetes (type 2)BYDUREON2012HbA1c has excellent reliability, predicts several diabetes-specific complications and provides the current basis for treatment decisions (American Diabetes Association 2006)…Lowering HbA1c reduces microvascular complications in patients with type 1 and type 2 diabetes (Diabetes Control and Complications Trial Research Group 1993, UK Prospective Diabetes Study (UKPDS) Group 1998). There is weaker evidence showing that lowering HbA1c reduces macrovascular complications in patients with type 1 diabetes (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group 2005).”YesDiabetes control and complications trial, UK Prospective diabetes study and diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) study14 29
GlaucomaALPHAGAN P2005Elevated IOP (intraocular pressure) presents a major risk factor in glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.”NoNone
GlaucomaQOLIANA2006“Elevated intraocular pressure is an aetiological factor in glaucomatous cupping. Higher intraocular pressure corresponds with a greater frequency of optic nerve damage. Medical therapy for open-angle glaucoma is aimed at lowering the intraocular pressure below a level that is likely to produce further optic nerve damage.”UnclearNone
GlaucomaLUMIGAN2010Intraocular pressure (IOP) is currently the accepted standard for establishing the efficacy of ocular hypotensive medications. IOP is a surrogate end point for potential visual function loss.”UnclearNone