# Presentation: 128067

## Why Highly Variable 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**
**October 6, 2006**

## I have made two previous presentations on this topic to ACPS

**November 29, 2001**
- Individual Bioequivalence:Have the Opinions of the Scientific Community Changed?
**April 14, 2004**
- Bioequivalence of Highly Variable (HV) Drugs: Clinical ImplicationsWhy HV Drugs are Safer
*Many of the slides today are the same as presented in my previous appearances*

## 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 are considering  another 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.             (Nov. 29, 2001 & April 14, 2004)

## 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**
**Cyclosporine (Neoral Package Insert)   20-50                   9-21**
**Digoxin****	****	****	****	****          52**
**Furosemide****	****                                              59                      15**
**Levothyroxine sodium****	****	****          20****	****          <20**
**Phenytoin sodium****	****	****	****          51****	****         10-15**
**Theophyllin sustained release                    31                   11-14                                   Warfarin sodium****	****	****	****          53****	****           6-11**
**       **Black numbers** **(Benet, Transplant. Proc. 31: 1642-44. 1999)

## 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 and proof nonexistent**
**  ****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.

## “Drug A”The Poster Drug for High Variability

-    A repeat measures study of “Drug A” 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 “Drug A” Capsules,    200 mg would require dosing in **300** postmenopausal women to achieve adequate statistical power

## Pharmacogenetics                       and Highly Variable Drug Safety

- Should pharmacogenetics be considered in setting the criteria?
- For some drugs, high variability may be the result of genetic polymorphisms

## Can we make some general conclusions as to when metabolic and transporter genetic polymorphisms will be important clinically in terms of drug disposition?

****** ****CYP 2D6    ****For sure****       ******** MDR1       ****No**
****** ****CYP 2C19  Yes               ******** OATPs     Yes**
****** ****CYP 2C9    Yes               ******** OCTs        Yes**
****** ****CYP 3A4     ****No ****               ******** OATs       Probably**
****** ****CYP 1A2     Maybe         ******** MRP2       Maybe**
****** ****UGT 1A1     Maybe         ******** Other ABC**
****** ****NAT2           No                   transporters   ??**

## What are the Substrate Characteristics that Result in Pharmacogenetic Variance  Affecting Pharmacokinetics?

- Substrate is BCS Class 1
- Genetic variants exhibit very wide differences in phenotype activity, preferable at one extreme marked effect and the other extreme no effect
- For an enzyme, protein is not present or not active extrahepatically, especially not present in the gut.
- For a Class 2, 3 or 4 substrate, efflux transporter effects are minimal.
- Compounds are primarily a substrate for a single metabolic enzyme, a single uptake transporter or a single efflux transporter
- The primary genetic variable potentially affecting substrate pharmacokinetics is not embedded.

## Cytochrome P450 2D6 Substrates

- Appear to be predominantly Class 1 substrates
- Therefore there will be no transporter interplay            (We are unaware of a CYP2D6 substrate that has been shown to be an efflux transporter substrate)
- Therefore they will exhibit good absorption
- The enzyme shows marked genetic differences in enzyme activity between EMs and PMs                  (i.e., marked activity vs. no activity)
- There is no significant gut CYP2D6 activity
- Many CYP2D6 substrates have minimal metabolism by other enzymes
-   **All factors that minimize nongenetic variability**

## Yet, many CYP 2D6 substrates have qualified generic substitutes on the market 

**The question should not be if such drugs are eligible for scaling in bioequivalence assessment or even if such drugs should be eligible for approval as generic equivalents**
**Rather this is a labeling issue.  If genetic polymorphisms are critical to drug dosing this should be true for the innovator as well as the generic**

## Recommendationsof the FDA Expert Panel on Individual Bioequivalence to this Advisory Committee (April 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%)

## My Recommendations           April 14, 2004

- •  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%.

## It is important to note that when I presented the recommendations of the Expert Panel (2001) as well as my own recommendations (2004) to the ACPS, the following were also stated:

- There is no scientific basis or rationale for the point estimate recommendations
- 2.  There is no belief that addition of the point estimate criteria will improve the safety of approved generic drugs
- 3. The point estimate recommendations are only “political” to give greater assurance to clinicians and patients who are not familiar (don’t understand) the statistics of highly variable drugs

## Conclusions

- Highly variable narrow therapeutic index drugs  are limited, at most, to a few cancer treatments but I am unaware of any documentation of highly variable narrow therapeutic index drugs.
- Highly variable drugs on the market are the safest drugs because marked swings in systemic drug levels have been shown to not affect safety and efficacy in individual patients
- High variability can result from a number of environmental and genetic factors, none of which appear to require any special considerations not already found in the labeling of the innovator drug