Surrogate end-points

Fleming TR and DeMets DL (1996) Surrogate end points in clinical trials Are we being misled Annals of Internal Medicine, 125, 605-613... 

Use of a surrogate end point that is quick and easy to obtain Permeation experiments using a radiolabeled, fluorescent, HPLC-detectable, or radio immuno assay/enzyme linked immuno sorbent assay-detectable marker necessitate the need of extensive sample handling and sample analysis. This accentuates the cost of sample analysis and overall time spent in characterizing the efficacy of formulations. Furthermore, current state of the art fluidics systems put a fundamental limit on the number of samples handled in a given time. 

Accelerated drug approval program Mechanism to accelerate approval of products designed to treat life-threatening or seriously debilitating diseases based on modified criteria for marketing approval for example, the use of surrogate end points. 

Approval based on a surrogate end point or on an effect on a clinical end point other than survival or irreversible morbidity... 

Kelloff GJ, Bast RC Jr, Coffey DS, et al., Biomarkers, surrogate end points, and the acceleration of drug development for cancer prevention and treatment an update prologue. Clin. Cancer Res. 2004 10 3881-3884. 

XVIII. Surrogate End Points in Clinical Trials of ACE Inhibition ... 

NSAID comparators (relative risk 0.45) (Langman et al, 1999). Thus, the surrogate end points of intact gastric mucosal prostaglandin synthesis, normal upper GI endoscopy, normal intestinal permeability, and lack of fecal red blood cell loss were predictive of the clinical outcomes seen in the phase II and III studies. 

Several studies have confirmed the antihypertensive efficacy of ARBs, although blood pressure reduction is only a surrogate end-point. In contrast, during the past few years clinical outcome trials have confirmed the value of these agents in hard end-points , for example target organ protection. 

Accelerated development/review can be used under two special circumstances (a) when approval is based on evidence of the product s effect on a surrogate end point, and (b) when the FDA determines that safe use of a product depends on restricting its distribution or use. A surrogate end point is a laboratory finding or physical sign that may not be a direct measurement of how a patient feels, functions, or survives but is still considered likely to predict therapeutic benefit for the patient. 

SiAMON, D.). (2004). Rationale for biomarkers and surrogate end points in mechanism-driven oncology drug development. Clin. Cancer Res. 10, 3885-3896. 

The effects of methoxamine have been examined in a double-blind, placebo-controUed trial in only six women (1). There was httle effect on maximum urethral pressure, the surrogate end-point used in the trial. The drug was given by intravenous infusion at a maximum dose of 1.0 mg/70 kg/minute. There was a significant rise in sys-tohc blood pressure of about 13 mmHg and a fall in pulse rate of some 18 beats/minute. All subjects taking methoxamine had headache, cold extremities, and piloerection. The authors understandably concluded that this is not a very promising treatment for stress incontinence. 

Wagner JA, Williams SA, Webster CJ. Biomarkers and surrogate end points for fit-for-purpose development and regulatory evaluation of new drugs. Clin Pharmacol Ther. 

The randomized controlled trial (RCT) is the de facto standard for studies of the health effects of medical interventions. In these studies, patients are randomized to receive either a therapy to be tested or an alternative (either a placebo or a conventional treatment), and an outcome is measured. RCTs have been used to evaluate therapeutic interventions, including drugs, radiation therapy, and surgical interventions, among others. The measured outcomes vary from hard evidence, such as mortality and morbidity, to softer evidence, such as patient-reported satisfaction and surrogate end points typified by markers of disease activity... 

For example, zidovudine (azidothymidine) was approved under these regulations as a treatment for AIDS after an NDA that contained only one well-controlled trial in its support, and various in vitro and uncontrolled human data as confirmatory moreover, CD4 lymphocyte counts were accepted as a surrogate end point in the clinical trial. 

Accelerated, Sub-part H, approvals rely less on clinical data than an ordinary approval. On the efficacy side, this might include, for example, the use of a surrogate end point instead of a disease outcome (for example, an antihypertensive drug can be approved without ap- value for reduction of stroke). On issues of tolerability, an accelerated approval almost always means a database with fewer patients than would be otherwise desirable. It is in this latter case that FDA will mandate a special risk management program. The Agency... 

The first step in making this decision is to consider the clinical value of the beneficial outcomes reported. Are the outcomes demonstrating improvements important to the patients For example, a drug therapy that improves left ventricular ejection fraction (a surrogate end point) does not have the same clinical value as a drug that is shown to decrease mortality or improve functional status (primary end points) in an individual with heart failure. 

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