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

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

There are many options already on the markethttps://www.joslin.org/info/oral_diabetes_medications_summary_chart.html

Adverse outcomes of diabetes

Short term

• Hyperglycemiao DKAo HHNS

• Hypoglycemia

Long term

• Neuropathy

• Poor wound healing

• Retinopathy

• Nephropathy and renal failure

• Pregnancy complications

• Stroke

• Hypertension

• Heart disease and MIhttp://www.diabetes.org/living-with-diabetes/complications/

Diabetes-related morbidity and mortality

Mortality in 2010

• 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)

http://www.cdc.gov/nchs/fastats/diabetes.htm

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.

The reasons surrogates may not work

Surrogate markers of diabetes• Surrogates of blood sugar control

o Hemoglobin A1C (HgA1C)o Fasting plasma glucose

• Other surrogates specific to outcomeso 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.

● 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.

Results - CAST I & CAST II

Example 3: ILLUMINATE StudyBarter 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

Surrogates: biomarkers HDL and LDL

Results of torcetrapib therapyAfter 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•Flawed assumptions about HDL, LDL, and cardiovascular disease

FDA approval guidelines for accelerated approval

Accelerated Approval

• 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

http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm

Possible drawbacks to accelerated approval

• 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

http://content.healthaffairs.org/content/24/1/67.full

FDA assistance for breakthrough therapies

Breakthrough Therapy

• For drugs used to treat serious conditions in which preliminary evidence shows superiority over current treatment

• Uses a clinically significant endpoint (including surrogates)

• Facilitates research so drugs can be approved more efficiently

• Does not guarantee approval

FDA approval using surrogates for diabetes

• 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

• 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