# Presentation: 387528

## Generic Topical DermatologicDrug Products:Issues and Opportunities

- Jonathan Wilkin, M.D.
- Director, Division of Dermatologic and
- Dental Drug Products, FDA

## Magnitude of the Issue

- Most dermatologic diseases are common, chronic and costly (3 C’s)
- Topical dermatologic products are often the mainstay of control
- Generic topical dermatologic drug products may lower costs and increase availability to patients

## Historical Difficulties

- Demonstration of bioequivalence to Reference Listed Drug (RLD) generally requires clinical trials(s) [320.24 (b) (4)]
- Clinical reports of lesser effectiveness
- Noticeable difference in vehicle properties
- Bad press

## Noticeable Difference in Vehicle Properties 

- Traditionally focus has been limited to
- Q1 - qualitative sameness
- and
- Q2 - quantitative sameness
- Vehicle properties, including drug delivery, also depend on
- “Q3” - structural (phasic) sameness

## Q3 Sameness and the Law of Duncan Hines and Wilkin

- Physical structure of topical dermatologic 	  	drug products matters.

## 314.94 (a) (9) (v)

- Inactive ingredients for topical products may not be the same as for the RLD.
- Q1 and Q2 are not essential.

## Manufacturing Process

- Propriety information not available to generic manufacture.
- Even when Q1 and Q2 are identical, the product may have very different physical properties, e.g., viscosity, which may affect product performance.

## The Question:

- How to ensure that information for approval of a generic topical dermatologic product is _necessary_ and _sufficient_ to establish that it is equivalent to the reference listed drug is a problem of regulatory science related to _Regulatory_ _Elegance._

## “Elegance” in the Sense of

- The synthesis of an organic chemical in the fewest steps with the highest yield
- The mathematical proof with the fewest assumptions and the fewest logical steps

## Regulatory Elegance

- Is the identification of the simplest information structure required for a regulatory decision.
- Is not the absence of “regulatory creep” ; it is the opposite.
- Demands focus on the 3 R’s

## The 3 R’s of Regulatory Elegance

- Reduction - number or extensiveness of required test
- Refinement - optimization of test design for maximum information at minimum cost
- Replacement - substitution of a simpler, cheaper, more informative test

## Possible Information Structures for Generic Topical Dermatological Drug Products

- Short term - Reduction and Refinement
- 		Average scalar (nonquantal) outcomes 				per patient over several time points to 				reduce intrasubject variability 					(increasing power and decreasing 				number of subjects)
- Long term- Replacement
- 		Develop alternative methods to assess 				Q3 sameness and bioequivalence.

## Alternative Methods for Bioequivalence of Topical Dermatological Drug Products

- 	Substantiation of performance parameters [211.194 (a) and USP (1225)]
- 1.  accuracy		6.  linearity
- 2.  precision 		7.  range
- 3.  specificity		8.  ruggedness
- 4.  limit of detection	9.  robustness
- 5.  limit of quantitation

##  Validation of Utility

- 	1.  intralaboratory reproducibility
- 	2.  interlaboratory reproducibility
- 	3.  demonstration of replaceability

## “Controlled Artifact” Stage

- Substantiation of performance parameters
- Reproducibility both intralaboratory and interlaboratory
- Awaiting the essential final validation step:  demonstration of replaceability

## Guild of Alternative Method Enthusiasts and Researchers 

- Intellectual bias - often “sold” on method at “Controlled Artifact” stage
- Conflict of interest - financial gain if method adopted
- Absolutely essential in reaching the goal of acceptable alternative methods
- “Replaceability” - needs peer review

## Validation:  Peer-Reviewed Demonstration of Replaceability 

- 1.  Does method make biological sense?
-     (e.g., Does the method use healthy skin with an intact stratum corneum barrier for products intend for diseased skin without an intact stratum corneum barrier?

## Validation (continued)

- 2.  Can the method reproducibly demonstrate 1)equivalence between the RLD and a clinically demonstrated bioequivalent product and 2)superiority (or inferiority) to a clinically - demonstrated superior (or inferior) bioinequivalent product in an adequate, well-controlled, and blinded comparative study with at least three arms:  RLD, clinically bioequivalent  product, and clinically bioinequivalent product?

## Conclusions

- 	1.  There is a compelling public health need 	    for good quality generic topical 		   dermatological drug products.
- 	2.   In the short term, reduction and 			   refinement of clinical trial designs 		   may decrease development costs and 	   provide sufficient evidence.

## Conclusions 

- 	3.  In the long term, replacement of clinical 		   trials by alternative methodologies 			   supplemented by the demonstration of 		   sameness in physical properties may 			  decrease development time and costs 			  even further, providing the greatest 			  regulatory elegance.