Debate 1: Short term trials with
surrogate outcomes in diabetes
drug development
Group 6
Most common types of diabetes
Type 1
Pancreas does not
make any insulin
Completely dependent
on insulin
Type 2
Pancreas does not
make enough insulin
Can be treated with
lifestyle changes and
oral medication
Insulin used in severe
cases
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Current medications
• Insulins: rapid, short, and long acting
• Biguanides: metformin, metformin XR
• Sulfonylureas: glimepiride, glipizide, micronized glyburide
• Meglitinides: repaglinide
• D-phenylalanine derivatives: nateglinide
• Thiazolidinediones pioglitazone: pioglitazone
• DPP 4 inhibitors: sitagliptin, saxagliptin, linagliptin
• Alpha-glucosidase inhibitors: acarbose, miglitol
• Bile acid sequestrants: colesevelam
• Combination pills
https://www.joslin.org/info/oral_diabetes_medications_summary_chart.html
Adverse outcomes of diabetes
Short term
Hyperglycemia
o DKA
o HHNS
Hypoglycemia
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Long term
Neuropathy
Poor wound healing
Retinopathy
Nephropathy and renal failure
Pregnancy complications
Stroke
Hypertension
Heart disease and MI
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http://www.diabetes.org/living-with-diabetes/complications/
Diabetes-related morbidity and mortality
Mortality in 2010
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Number of deaths: 69,071
Deaths per 100,000 population: 22.4
Cause of death rank: 7
Diabetes related mortality mainly due to heart
disease, stroke and kidney dysfunction (chronic
diseases which takes years, often decades, to
develop)
Use of surrogates
What is surrogate?
Surrogate is a response variable, for which the test of a null hypothesis of no
relationship to the treatment groups under comparison is also a valid test of
the corresponding null hypothesis based on the true endpoint.
The reasons that surrogate may not work:
1. Surrogates do not describe direct clinical benefit to patients.
2. Overinterpretation of surrogates can lead to misinterpretation of the
evidence.
Surrogate markers of diabetes
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Surrogates of blood sugar control
o Hemoglobin A1C (HgA1C)
o Fasting plasma glucose
Other surrogates specific to outcomes
o HDL and LDL (heart disease)
o Protein loss in urine (kidney disease)
Example 1:Protein leak and kidney disease
Example 2: CAST (Cardiac Arrhythmic
Suppression Trial )
(NEJM 1989, 321:406-412, August 10 1989)
Purpose: Evaluate the effect of antiarrhythmic therapy in patients with
asymptomatic or mildly symptomatic ventricular arrhythmia after myocardial
infarction(MI). Did suppression of these ventricular arrhythmias truly
increase survival ?
Features: Multicenter randomized double blind placebo control study with 3
treatment arms. (Flecainide, Encainide and Moricizine used for ventricular
arrhythmia suppression).
Surrogate Endpoint:Suppression of ventricular arrhythmias.
Primary Endpoint: Death or cardiac arrest with resuscitation, either of which
are due to arrhythmias.
Results - CAST I & CAST II
● Total mortality for those with arrhythmia suppression with Encainide and
Flecainide was 2.5 times higher than that of the placebo group
● Excess of deaths from arrhythmia and non fatal cardiac arrests were
nearly 3.6 times higher in treatment groups
Both these drugs were terminated early from the study.
The study was then continued with only Moricizine (CAST II) but was also
unsuccessful and riddled with adverse effects. This was subsequently
terminated as well.
Example 3: ILLUMINATE Study
Barter et al. Effects of torcetrapib in patients at high risk for coronary events.
NEJM 357(21):2109-22, 2007.
Purpose: To assess the effectiveness of the drug torcetrapib on the disease
hyperlipidemia
Treatment: torcetrapib & atorvastatin
Placebo: atorvastatin only
Results of torcetrapib therapy
After 12 months:
•Statistically significant increase in HDL cholesterol (72%)
•Statistically significant decrease in LDL cholesterol (25%)
After 1.5 median years:
•Statistically significant higher mortality rate in the torcetrapib and atorvastatin
arm compared with the atorvastatin-only group.
Possible Explanations:
•Off-target effects of torcetrapib on blood pressure and the renin–
angiotensin–aldosterone system
FDA approval guidelines for accelerated
approval
Accelerated Approval
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Allows drugs for serious conditions (includes diabetes) that fill an unmet
medical need to be approved based on a surrogate endpoint or
intermediate clinical endpoint
FDA can then approve these drugs faster
Phase 4 confirmatory trials still required
Approval of a drug may be withdrawn if phase 4 trials don’t verify clinical
benefit/don’t demonstrate enough benefit to justify the drug’s risks
Possible drawbacks to accelerated approval
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Time between granting of marketing through accelerated approval and
completing validation trials may be longer than in normal approval process
Loss of sense of urgency since drugs already on market
Possible difficulties enrolling patients into clinical trials when the
experimental therapy is already available for use in non-research setting
Pharmaceutical companies would be liable for drugs allowed on the market
that are dangerous
FDA assistance for breakthrough therapies
Breakthrough Therapy
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For drugs used to treat serious conditions in which preliminary evidence
shows superiority over current treatment
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Uses a clinically significant endpoint (including surrogates)
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Facilitates research so drugs can be approved more efficiently
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Does not guarantee approval
FDA approval using surrogates for diabetes
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FDA-issued guidance for industry re: Evaluating cardiovascular risk in new
antidiabetic therapies to treat type 2 diabetes.
“HbA1c remains an acceptable primary efficacy endpoint for approval of
drugs seeking an indication to treat hyperglycemia secondary to diabetes
mellitus.”
“For cardiovascular endpoints…...events should include cardiovascular
mortality, myocardial infarction, and stroke”
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf
Conclusions
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A surrogate end-point is expected to predict clinical benefit (or harm, or
lack of benefit or harm) based on epidemiologic, therapeutic,
pathophysiologic, or other other scientific evidence’- Biomarker Definitions
Working Group
Validation of surrogate end-points requires a comprehensive
understanding of the causal pathways.
Diabetes is a multi-factorial disease with complex pathophysiology where
causal pathways are not clearly known and surrogate end-points may not
always be reflective of clinical outcomes.
Therefore, clinical outcomes are a better measure of drug efficacy and
should be used in clinical trials