# Presentation: 499558

## Bioequivalence of Highly Variable (HV) Drugs: Clinical ImplicationsWhy HV Drugs are Safer

**Leslie Z. Benet, Ph.D.**
**Professor of Biopharmaceutical Sciences**
**University of California San Francisco**
**FDA Advisory Committee for Pharmaceutical Science**
**Rockville, MD**
**April 14, 2004**

## The Current U.S. Procrustean Bioequivalence Guidelines

-    The manufacturer of the test product must show using two one-sided tests that a 90% confidence interval for the ratio of the mean response
-    (usually AUC and Cmax) of its product to that of
-    the reference product is within the limits of 0.8 and 1.25 using log transformed data.
**    ****(Procrustean ******** marked by an arbitrary, often ruthless disregard for individual differences or special circumstances.)**
**     ****Note: BCS is a non-Procrustean advance**
**     ****We should consider other non-Procrustean advances**

## Bioequivalence IssuesWhat are we trying to solve?

- For all drugs, but particularly for NTI drugs, practitioners need assurance that transferring a patient from one drug product to another yields comparable safety and efficacy (switchability).
- For wide-therapeutic index, highly variable drugs we should not have to study an excessive number of patients to prove that two equivalent products meet preset (one size fits all) statistical criteria.
- To give patients and clinicians confidence that a generic equivalent approved by the regulatory authorities will yield the same outcome as the innovator product.

## Why is meeting bioequivalence criteria a 

**relatively minor concern for drugs with **
**narrow therapeutic indices?**

**   ****By definition, approved drugs **
**         ****with narrow therapeutic **
**         ****indices exhibit small **
**         ****intrasubject variability.**
**   ****If this were not true, patients **
**         ****would routinely experience **
**        ****cycles of toxicity and lack of **
**         ****efficacy, and therapeutic **
**         ****monitoring would be useless.**

## NTI Drugs Frequently Proposed 

**to Limit Generic Substitution **

**	****	****	****	****	****        ****CV%**
**	****	****	****	****      ****Inter****	****        Intra**
**	****	****	****	****    ****Subject****	****       Subject**
**Carbamazepine****	****	****	****38**
**Conjugated Estrogens****	****	****42****	****	****14-15**
**Digoxin****	****	****	****	****52****	**
**Levothyroxine sodium****	****	****20****	****	****<20**
**Phenytoin sodium****	****	****	****51****	****	****10-15**
**Theophyllin sustained                      31                    11-14**
**release****	****	****                                    ****	****	**
**Warfarin sodium****	****	****	****53****	****	****6-11**

## Individual Bioequivalence (IBE)

**	****	****	********WR****2**

**Individual Bioequivalence (IBE)**

**                  **_**Initial Promises for IBE**_
**  ****Addresses the correct question (switchability)**
**  ****Considers subject by formulation interaction (********D ****)**
**  ****Incentive for less variable test product**
**  ****Scaling based on variability of the reference product**
**   ****both for highly variable drugs and for certain **
**   ****agency-defined narrow therapeutic range drugs**
**  ****Encourages use of subjects more representative of **
**   ****the general population**

##  Re-examination of the Initial Promises for IBE

**  ****Addresses the correct question (switchability)—****Necessity questionable**
**  ****Considers subject by formulation interaction—****Unintelligible parameter**
**  ****Incentive for less variable test product—****ABE with scaling could also solve this issue**** **
**  ****Scaling based on variability of the reference product both for highly variable drugs and for certain agency-defined narrow therapeutic range drugs– ****ABE with scaling could also solve this issue**
**  ****Encourages use of subjects more representative of the general population—****Failed**

## Highly Variable Drugs (CV>30%)

- For wide-therapeutic index highly variable drugs we should not have to study an excessive number of patients to prove that two equivalent products meet preset (one size fits all ) statistical criteria.
- This is because ,by definition, highly variable approved drugs must have a wide therapeutic index, otherwise there would have been significant safety issues and lack of efficacy during Phase 3
- Highly variable narrow therapeutic index drugs are dropped in Phase 2 since it is not possible to prove either efficacy or safety.

## ProgesteroneThe Poster Drug for High Variability

-    A repeat measures study of Prometrium® 2x200 mg capsules in 12 healthy post-menopausal females yielded:
-            **Intrasubject CV for AUC of 61%**
**           ****Intrasubject CV for C****max**** of 98%**
**    **A generic company calculated that a 2 period crossover  BE study for Progesterone Capsules,    200 mg would require dosing in **300** postmenopausal women to achieve adequate statistical power

## Recommendationsof the FDA Expert Panel on Individual Bioequivalence to this Advisory Committee on November 21, 2001 

- Sponsors may seek bioequivalence approval using either ABE or IBE (with SxF deleted)
- Scaling of ABE should be considered.
- If an IBE study is carried out and the test product fails, the data or a subset of the data may not be reanalyzed by ABE for approval
- A point estimate criteria on mean AUCs of ±15% and on mean Cmax of ±20% should be required for both ABE and IBE.
- Consideration should be given for narrower point estimate criteria for NTI drugs (e.g., AUC ±10%, Cmax ±15%)

## Recommendations

- •  Methodology should be developed to allow approvals based on weighting of average bioequivalence analyses for highly variable drugs (i.e., WR> 30%).
- •  A point estimate criteria on mean AUCs of ±10% and on mean Cmax of ±15% should be required for NTI drugs where WR  20%.
- •  A point estimate criteria on mean AUCs of ±15% and on mean Cmax of ±20% should be required for all other drugs, including NTI drugs where WR> 20%.