# Presentation: 053793

## Observations on Concept Paper IPre marketing Risk AssessmentGlenn Gormley MD, PhDAstraZeneca

## General Comments to Concept Paper I

**Members of PhRMA share a mutual interest in bringing safer and more effective drugs to the market as rapidly as possible and embrace the importance of risk management**
**While most of the suggestions in this paper are reasonable there is little or no clarity on how to determine when to incorporate specific points into a development plan.**
**  **
**This paper is useful in defining the concepts relevant to pre marketing risk assessment, but it does not provide sufficient guidance on when to utilize them**

## General Comments to Concept Paper I

**Several proposals have the potential to change the standard for FDA approval of new drugs or new indications.**
**We do not believe that this forum is appropriate to effect any changes in these standards**
**There is little evidence that the risk management strategies proposed will result in safer drugs reaching the market compared to current standards**

## Specific Challenges to Concept Paper I

- IIIA appropriate size of pre marketing safety database
**(line 79) Increasing the size of the required database above ICH guidelines without specifically defining the concern and objective, is not likely to add significant reassurance for patient safety.**
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**(line 94) Requiring substantial representation of patients exposed above the highest proposed dose may not be ethical if dose dependent toxicity is significant**
**(line 136) requiring larger databases when there is the potential for rapid exposure to a large population appears to be a highly subjective requirement dependent on the final label**

## Specific Challenges to Concept Paper I

- IIIB  characteristics of an ideal database
- (line 174) Use of a range of doses in phase III.
**Most development programs rely on adequate dose ranging studies in phase IIb to identify the most likely dose(s).  **
**The limited patient exposure in phase II minimizes toxicity to excessive doses, and limits treatment with ineffective or sub therapeutic doses.  **
**Phase III is designed to evaluate only  the relevant doses to provide adequate exposure.   In many cases that may be a single dose.  **

## Specific Challenges to Concept Paper I

**IIID  Use of comparative safety data**
**(line 238)  When there is a well established product with minimal toxicity to treat the condition of interest.**
**comparative safety trials are not generally required**
**the suggestion is that this standard could change to ****a relative one**** requiring demonstration of  “a comparably benign safety profile”.  **
**This suggestion does not take into account a potential difference in efficacy that might make a difference in the safety profile acceptable**

## Specific Challenges to Concept Paper I

**IIIE  Special considerations for optimal risk assessment.****  **
**(line 279)  “A large, simple safety study (LSSS) conducted prior to approval designed to assess few outcomes in a large number of patients. “  **
** ****Prior to the conclusion of Phase III, it would rarely be possible or ethical to conduct a large simple study.**
**To do such a study requires knowing the dose(s) that have demonstrated favorable risk/benefit and requires substantial knowledge of the safety profile. **
** ****A well designed phase III program should address the issues relevant for approval.  ****A pre-approval LSSS requirement appears to add an additional post phase III requirement for approval****. **
**In some cases, a  LSSS may be appropriate as a phase IV commitment as part of an ongoing risk management program**

## Need for clarity in Concept Paper I

**Dr. McClellan**** has advocated the use of Phase IV studies to accelerate the approval process while this paper appears to require more work prior to approval that was traditionally done in phase IV.  ****How should we interpret these messages?**
**When the concept paper uses terms such as: “ ideally, would suggest, case-by-case, should consider, could be useful,  in certain circumstances,”  is industry to assume that these issues are best addressed with the agency at appropriate times in the development process?**