Surrogate Endpoints Part 3 Akbar soltani Assistant Professor

Surrogate End-points Part (3) Akbar soltani Assistant Professor of Medicine and Endocrinology Evidence-Based Medicine Working Team (EBMWT) Tehran University of Medical Sciences (TUMS) Shariati Hospital EBMWT. EMRC A. SOLTANI TUMS

How to Use an Article Measuring the Effect of an Intervention on Surrogate End Points EBMWT. EMRC A. SOLTANI TUMS

Clinical Scenario You are a physician seeing a 62 -year-old woman with postmenopausal osteoporosis. Her bone mineral density as measured by dual-energy X-ray absorptiometry is 2. 5 standard deviations below the mean value in premenopausal women and, though she does not suffer from back pain, a spinal radiograph shows an old vertebral fracture. Although she has not yet experienced problems as a result of her vertebral fracture, she is disturbed by the prospect that she may end up like her mother whose osteoporotic fractures have resulted in severe, chronic, back pain. EBMWT. EMRC A. SOLTANI TUMS

Clinical Scenario The patient suffers from reflux esophagitis and a past endoscopy has revealed non-specific gastritis. A specialist had prescribed alendronate which the patient had to stop after several weeks because of dyspepsia. She has searched the Web, and discovered a new drug, raloxifene, and wonders whether this drug might be an alternative. You promise to examine the literature and to get back to her. Using Medline you identify a study of raloxifene for the treatment of osteoporosis demonstrating an effect on bone mineral density. You are wondering whether this warrants administration to lower your patient's risk of osteoporotic fracture. EBMWT. EMRC A. SOLTANI TUMS

Is there a strong association between the surrogate end point and the clinical end point? EBMWT. EMRC A. SOLTANI TUMS

How strong is the effect, measured as RR or OR? Whereas weak associations in observational studies can Easily be due to bias large amount of bias would be Necessary to produce strong association. HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

RR more than 3 in cohort studies OR greater than 4 in case control studies provide strong Support for causation EBMWT. EMRC A. SOLTANI TUMS

Is there a consistent association between the surrogate end point and the clinical end point? EBMWT. EMRC A. SOLTANI TUMS

Consistent observation of association in different populations and with different study design s also lends support to a real effect. HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

Is there a independent association between the surrogate end point and the clinical end point? EBMWT. EMRC A. SOLTANI TUMS

It should be a true predictor of disease (or risk of disease) and not merely express exposure to a covariable. When a surrogate is associated with an outcome after adjusting For multiple other potential prognostic factors we call the association Independent. HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

DISEASE SURROGATE HBA 1 C EBMWT. EMRC LDL A. SOLTANI OUTCOME BMD TUMS

Returning to the scenario, you are wondering if you can substitute bone mineral density for fractures or health-related quality of life in considering whether to recommend raloxifene. . Furthermore, after considering other risk factors for osteoporotic hip fractures including maternal history of hip fracture, previous fractures from any site, poor self rated health, use of long acting benzodiazepines, impaired visual function, and reduced physical activity, bone mineral density continued to predict the risk of hip fracture. EBMWT. EMRC A. SOLTANI TUMS

Is there a temporal association between the surrogate end point and the clinical end point? EBMWT. EMRC A. SOLTANI TUMS

The most important criteria for causation Is chicken egg question. HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

Does increased exposure result in more of the outcome? EBMWT. EMRC A. SOLTANI TUMS

Biologic gradient(dose- response relation) HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

Does the association make sense? Biologic plausibility is another weak Criterion , limited by our knowledge. HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

Factor Favors Surrogate Does Biological plausibility • Epidemiologic evidence extensive and consistent • Quantitative epidemiologic relationship • Credible animal model shows drug response • Well-understood disease pathogenesis • Drug mechanism of action well understood • Surrogate relatively late on biological path EBMWT. EMRC A. SOLTANI TUMS

Does Not Favor Surrogate Biological plausibility • Inconsistent epidemiology • No quantitative epidemiologic relationship • No animal model • Pathogenesis not clear • Novel actions not previously studied • Surrogate remote from clinical outcome EBMWT. EMRC A. SOLTANI TUMS

The surrogate end point should be reliable, reproducible, clinically available, easily quantifiable HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

It should be sensitive—a "positive" result in the surrogate end point should pick up all or most patients at increased risk of adverse outcome Or capture most of the patients Paradox for definitions HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

It should be specific—a "negative" result should exclude all or most of those without increased risk of adverse outcome HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

There should be a precise cut off between normal and abnormal values. HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

• It should have an acceptable positive predictive value—a "positive" result should always or usually mean that the patient thus identified is at increased risk of adverse outcome HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

• It should have an acceptable negative predictive value—a "negative" result should always or usually mean that the patient thus identified is not at increased risk of adverse outcome HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

Evaluation may require comprehensive review of observational studies of the relation between the surrogate and the target EBMWT. EMRC A. SOLTANI TUMS

Bone mineral density is a moderately strong, independent predictor of fracture and meets our first category of criteria for an acceptable surrogate end point. EBMWT. EMRC A. SOLTANI TUMS

Is there evidence from randomized trials in other drug classes that improvement in the surrogate end point has consistently lead to improvement in the target outcome? EBMWT. EMRC A. SOLTANI TUMS

• pathophysiologic studies • ecological studies • and cohort studies are insufficient to establish that the link between surrogate and clinically important outcomes is ironclad HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

Surrogate end points can only be considered validated when their relationship with the clinically important outcome has been firmly established in long-term randomized trials HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

Although sodium fluoride increased bone mineral density at the lumbar spine by 35% over 5 years, more vertebral and non-vertebral fractures occurred in the intervention group than in the placebo group. EBMWT. EMRC A. SOLTANI TUMS

Inferences on the basis of unchanged bone density may also be problematic: Calcium and vitamin D in the elderly showed virtually no change in bone density, but a reduction in fracture risk of 50%. EBMWT. EMRC A. SOLTANI TUMS

Increase in bone mineral density as a surrogate end point has shown an inconsistent relation to osteoporotic fractures. outcome in several classes (supports more general use) EBMWT. EMRC A. SOLTANI TUMS

One trial of a drug from a single class does not provide much information about the validity of the surrogate end point because the evaluated therapy may in fact work through a mechanism completely independent of the surrogate. In other words, surrogate end points are best validated as “risk factors” by multiple trials using drugs from a variety of drug classes. outcome in several classes (supports more general use) EBMWT. EMRC A. SOLTANI TUMS

Is there evidence from randomized trials in the same drug class that improvement in the surrogate end point has consistently lead to improvement in the target outcome? EBMWT. EMRC A. SOLTANI TUMS

Analogy The argument for the approval of a new drug (1) in large, long-term clinical trials, drug A reduces both the surrogate end point and the disease incidence; (2) in short-term trials, drug B reduces the level of the surrogate end point; (3) in clinical practice, drug B will behave like drug A in its effect on disease incidence. EBMWT. EMRC A. SOLTANI TUMS

ALENDRONATE Vs RISEDRONATE ALENDRONATE Vs RALOXIFEN outcome with other drugs of same pharmacologic class (supports surrogate in class) HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

Clinicians are in a stronger position relying on surrogate end points if the new drug they are considering is from a class of drugs in which the relation between changes in the surrogate and changes in the target has been verified in randomized trials EBMWT. EMRC A. SOLTANI TUMS

Returning to the scenario because of the inconsistent relation between increase in bone mineral density and fracture reduction we would be reluctant to offer patients a new anti-osteoporotic agent solely on the basis of effect on BMD. EBMWT. EMRC A. SOLTANI TUMS

Selected examples of applied validity criteria for the critical evaluation of studies using surrogate end points Types of intervention (References) Surroga End Criterion 1 te point (References) end point Criterion 2 (References) Criterion 3 (References) Raloxifene Bone mineral density Is there evidence from randomized trials in other drug classes that improvement in the surrogate end point has consistently lead to improvement in the target outcome? Is there evidence from randomized trials in the same drug class that improvement in the surrogate end point has consistently lead to improvement in the target outcome? EBMWT. EMRC Oste opor otic fract ures Is there a strong, independent, consistent association between the surrogate end point and the clinical end point? A. SOLTANI TUMS

How large, precise, and lasting was the treatment effect? EBMWT. EMRC A. SOLTANI TUMS

If an intervention shows • large reductions in the surrogate end point • the 95% confidence intervals around those large reductions are narrow • the effect persists over long period • our confidence that the target outcome will be favorably affected increases. EBMWT. EMRC A. SOLTANI TUMS

Positive effects that are smaller, with wider confidence intervals, and shorter duration of follow up, leave us less confident. HBA 1 C EBMWT. EMRC LDL A. SOLTANI BMD TUMS

Returning to our scenario, the trial of raloxifene in osteoporotic women demonstrated that after two years of treatment raloxifene-treated patients in the group receiving the highest dose showed an increase in bone mineral density at the lumbar spine of 2. 2%(SE 0. 3) compared to a slight decrease in the control group 0. 8% (SE 0. 3). EBMWT. EMRC A. SOLTANI TUMS

Ideally, the investigators would have provided us with a confidence interval around the 3. 0% difference in percentage change in bone mineral density in the treatment and control groups. As we will illustrate when we consider weighing benefits and harms, the magnitude of the effect on the surrogate may (or may not) help us estimate the size of possible impact on the target outcome. EBMWT. EMRC A. SOLTANI TUMS

Are the likely treatment benefits worth the potential harms and costs? EBMWT. EMRC A. SOLTANI TUMS

When the data available are limited to the effect on a surrogate end point, estimating the extent to which treatment will reduce clinically important outcomes becomes a challenge. EBMWT. EMRC A. SOLTANI TUMS

One approach is to extrapolate from randomized trials in a similar patient population that provides both surrogate end point clinical outcome data EBMWT. EMRC A. SOLTANI TUMS

ALENDRONATE Vs RISEDRONATE ALENDRONATE Vs RALOXIFEN vs TAMOXIFEN EBMWT. EMRC A. SOLTANI TUMS

alendronate increase vertebral bone density by 7. 5% over two years raloxifene increase 3. 0% over the same time frame. EBMWT. EMRC A. SOLTANI TUMS

Even if a surrogate end point meets all of these criteria, inferences about a treatment benefit may still prove misleading. EBMWT. EMRC A. SOLTANI TUMS

Furthermore, difficulties in estimating the magnitude of effects on clinically important end points compromises economic analysis examining the cost-effectiveness of alternative management strategies. EBMWT. EMRC A. SOLTANI TUMS

waiting for randomized trials investigating the effect of the intervention on important outcome is the only ironclad solution to the surrogate outcome dilemma. EBMWT. EMRC A. SOLTANI TUMS

when patients' risk of serious morbidity or mortality are high can we wait and see? EBMWT. EMRC A. SOLTANI TUMS

Risk-benefit, public health considerations 1 -the effect of the intervention on the surrogate end point is large 2 -the patient's risk of the target outcome is high 3 -the patient places a high value on avoiding the target outcome EBMWT. EMRC A. SOLTANI TUMS

4 -there are no satisfactory alternatives clinicians can recommend therapy on the basis of randomized trials evaluating only surrogate end points. 5 -Large safety database 6 -Short-term use 7 -Difficulty of studying clinical end point (rare, delayed) EBMWT. EMRC A. SOLTANI TUMS

Risk-benefit, public health considerations 1. Nonserious disease and alternative therapy with different pharmacologiaction known to affect outcome 2. Little safety data 3. Long-term use 4. Easy to study clinical end point (short-term study) 5. Long-delayed, small effect in healthy people EBMWT. EMRC A. SOLTANI TUMS

Treatment recommendations based on surrogate outcome effects can never be strong. EBMWT. EMRC A. SOLTANI TUMS

Resolution of the Scenario We have found a strong, consistent, independent and biologically plausible association between bone mineral density and vertebral and nonvertebral fractures. Randomized trials, however, have failed to show a consistent association between increased bone density and reduced fracture across all drug classes. EBMWT. EMRC A. SOLTANI TUMS

Resolution of the Scenario Our judgment is that a number of options (including a trial of etidronate, offering hormone replacement therapy, calcium and vitamin D, calcitonin, or suggesting only a balanced diet and exercise) would be reasonable. Data indicating a reduction in fracture rate with raloxifene, which a preliminary report suggest may soon be available would greatly strengthen the case for including raloxifene as one of the options. EBMWT. EMRC A. SOLTANI TUMS

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THANK YOU EBMWT. EMRC A. SOLTANI TUMS