Issues in Generic Substitution: Safety/Efficacy, Cost Savings and Supply Robert J. Herman, MD, FRCPC Professor, Department of Medicine University of Calgary

1)Know the science behind the Canadian Guidelines and policies for mandatory substitution of generic for brand name pharmaceutical products 2) Understand that provisions exist in the Guideline for dealing with critical drugs and complex delivery systems 3)Recognize that there are risks to this system and when and how to challenge these regulatory decisions when an issue of individual patient safety overrides population needs and policies No Disclosures

TESTING OF BIOEQUIVALENCE Examine the rate and extent of absorption of a TEST DRUG compared to a known REFERENCE DRUG, which has a proven record of safety and efficacy in patients

Extent:Ratio AUC Test / Reference Rate: Ratio C max Test / Reference Equivalency Range is defined as % This is the minimal clinically important difference For AUC, the 90% Confidence Interval of the ratio must fall within the equivalency boundary of % For Cmax, point estimate of the ratio must fall within the equivalency boundary of %

Absolute (100%) equivalence can never be demonstrated The true difference lies somewhere within the range of the Confidence Interval Point Estimate of the Mean Difference (A - B) Mean Difference (A - B) 

Special Considerations 1)Drugs that have topical effects or cannot be measured within the systemic circulation May accept equivalence testing on the basis of a pharmacodynamic (drug effect) studies 2)Drugs that have controlled release BE must be studied in both fasting and fed states 3)Drugs with unusual PK properties May require steady-state studies 4)Critical Dose Drugs (cyclosporine, digoxin, flecainide, lithium, sirolimus, tacrolimus, theophylline and warfarin) Require a narrower equivalency band to ensure BE AUC 90% CI within % Cmax 90% CI within % Require BE studies both fasting and fed and in special circumstances, at steady-state

Risks Change in the Canadian Reference Standard can lead to ‘BE creep’ Cost of generics must be less than the cost of 35% of the innovator brand Limited numbers of suppliers Other individual differences

BE only assesses the active medicinal ingredient and for this there is a no clinically meaningful difference

Cross Section of Adalat and Mylan Tablets

BP Profiles on 2 Agents in 1st Normotensive

Cumulative Dose Response Curve % of Individuals Responding Frequency Distribution Cumulative Frequency Distribution Log Dose

Bioequivalence is a compromise Risk/Benefit vs Cost

Minimum Criteria for the Design of a Good Equivalency Study 1) A priori choice of a valid equivalency range 2) Sample Size based on a null hypothesis of non- equivalence 3) Conclusions based on Confidence Interval Testing 4) Adequate study rigor applied comparison to a drug with proven safety/efficacy similar design and outcomes as the original studies the same doses and dosing regimens inclusion/exclusion criteria use of same concomitant medication