# Presentation: 232689

## SOME ISSUES ON THE DETERMINATION 

**OF BIOEQUIVALENCE**
**FOR HIGHLY VARIABLE DRUGS**
- _Laszlo Endrenyi_
- University of Toronto
- _Laszlo Tothfalusi_
- Semmelweis University of Budapest

- FDA/CDER
- Advisory Committee on
-    Pharmaceutical Sciences
- Rockville, MD
- October 6, 2006

## SYNOPSIS

- 1.  What kinds of replicate designs should be applied?
- 2.   Should there be a constraint on the estimated ratio
- 		of geometric means?

## USUAL METHOD OF EVALUATION:UNSCALED AVERAGE BIOEQUIVALENCE

-              	1/BEL  GMR  BEL
- BEL:  BE limit  -  Usually 1.25
- GMR: Ratio of geometric means
- 	     	- lgBEL  log(GMR)  lgBEL
- 		- lgBEL  mT - mR  lgBEL
- lgBEL: logarithm of BEL
- mT, mR:  Estimated logarithmic means

## AN APPROACH FOR HIGHLY VARIABLE DRUGS:SCALED AVERAGE BIOEQUIVALENCE

- Difference between logarithmic means is _normalized by __estimated variation__:_
- 			- lgBELsc   (mT - mR)/s  lgBELsc
- A general procedure was suggested for setting BE limits (BELsc)
**Advantages:**
- - Statistical power is independent of variation
- - Statistical power is, with same sample size, much higher than of unscaled average BE
- - Interpretation: Compare expected change due to switching with expected difference between replicate administrations
- - Interpretation: Standardized effect size, as in clinical comparisons

## REPLICATE STUDY DESIGNS FORAPPLYING SCALED AVERAGE BIOEQUIVALENCE

- Difference between logarithmic means is _normalized by __estimated variation__:_
- 			- lgBELsc   (mT - mR)/s  lgBELsc
- s:  Often regarded as within-subject variation of reference product (sWR)
- For estimating sWR a single-sequence 3 period design could be sufficient:
- 				RRT

## REPLICATE STUDY DESIGNS FORAPPLYING SCALED AVERAGE BIOEQUIVALENCE

- An additional goal:
- 	To compare variations of the two drug products:
- 				 sWT/sWR
- 	Could identify highly variable _drug products_
- Replications of _both_ RR and TT are required
- For example:
- 				RRT
- 				TTR

## REPLICATE STUDY DESIGNS FORAPPLYING SCALED AVERAGE BIOEQUIVALENCE

- Refine the additional goal:
- 	To compare variations of the two drug products:
- 				 sWT/sWR
- 	_within the same subject_
- More effective identification of highly-variable drug products
- Also: can identify (some) outlying observations
- Example of study design:
- 				RTRT
- 				TRTR

## REPLICATE STUDY DESIGNS FORAPPLYING SCALED AVERAGE BIOEQUIVALENCE

**NOTE:**
**	**3- and 4-period designs require approximately the _same_ number of observations

## SHOULD THERE BE A CONSTRAINT ON  GMR?

- Concern about possibly large deviations between estimated logarithmic means
- 	   [i.e., about log(GMR)]
- 	   L. Benet, AAPS Workshop on Individual BE, 1999.
- Concern about interpretation to physicians

## SHOULD THERE BE A CONSTRAINT ON  GMR?

- Larger deviation between the (logarithmic) means arises as a natural, direct consequence of the higher variability

- Larger deviations occur at higher variations
- They would be _truncated _by GMR constraint
**Moreover:**

## QUALITY CONTROL ORTHERAPEUTIC SURROGATE?

_***QUALITY CONTROL***_***	******	******	***_***THERAP. SURROGATE***_
**   ****HIGH SENSITIVITY****	****	****	****CLINICAL RELEVANCE**
**   ****HIGH STATISTICAL POWER****	**
**    ****Young, healthy (male) volunteers           *****  Heterogeneous study popul'n**
***   Single dosing****	****	****	****     ****	****   ****Steady state****     **
**    ****Cmax/AUC****	****	****	**** ****	*****   Cmax **
***   Parent drug****	****	****	****     ****	****    ****Active metabolite**
**    Recommendations of FDA*
-      **Does one guidance/method satisfy both goals?**

- BioInternational 1994:: Both!
- But: Ambivalence

## Slide 12

| 

     Endpoint |          Goal of the study
Therapeutic            Quality  Control
Equivalence 
         =                              =
New Drugs               Generic Drugs   |  |
| --- | --- | --- |
| Pharmacodynamic
           and 
     Therapeutic

  Pharmacokinetic
(AUC, Cmax, Css) | Phase III or Phase IV cal | Inhalation devices
Nasal and dermatological products |
|  | Product labelling trials:                                              Interaction and food effect
Patient subpopulation trials: Renal, hepatic impairment
New ER   formulations 
Dose linearity
 | Generic drug
development (including food effect) |

## SHOULD THERE BE A CONSTRAINT ON  GMR?

- Possible concern about large estimated GMR may possibly apply to the introduction of generic products,
- but _NOT_ during the development of new drugs.
- Therefore:  a secondary regulatory criterion should _NOT_ be generally invoked

## CONCLUSIONS

- 	3- or preferably 4-period study designs in which both the
-     reference and test products are replicated (RR _and_ TT), enable the comparison of within-subject variations and the identification of highly-variable drug products.
- A constraint of the estimated ratio of geometric means is
- 	not warranted scientifically or, generally, for the sake
-    of public relations.