# Presentation: 918962

## Rationale and Context:  Pravastatin-Aspirin Overview

**Fred T. Fiedorek, M.D.**
**Vice President, Clinical Design & Evaluation and Exploratory Development****Pharmaceutical Research Institute****Bristol-Myers Squibb**

## Pravastatin-Aspirin Advisory Committee – Jan 18, 2002 and Today:  Requisites for a Combination Product

**Pravastatin-Aspirin Advisory Committee – ****Jan 18, 2002 and Today:  ****Requisites for a Combination Product**

**Different mechanisms of action of components**
**No PK interaction between components**
**Both components contribute to efficacy, in this case with clinical outcome event reduction**
**Addresses a medical need**
**Appropriate dose combinations available**
**Acceptable safety and tolerability profile**

## Context:  Current FDA Fixed-Dose Combination Regulation Established 1971

**Context:  Current FDA Fixed-Dose ****Combination Regulation Established 1971**

- “. . . two or more drugs may be combined in a single dosage form when _each component makes a contribution_ to the claimed effects and the _dosage of each component_ (amount, frequency, duration) is such that the combination is _safe and effective_ for a _significant patient population_ requiring such concurrent therapy as defined in the labeling for the drug.”  														21 C.F.R. § 300.50 (a)
- 						      (Underlined emphasis added)

## Fixed-Dose Combination Goals Cited by FDA in 1971 Regulations Remain Relevant Today   

**Fixed-Dose Combination Goals Cited by FDA in 1971 Regulations Remain Relevant Today   **

**Four Key Components – Still a Valid Framework **
**Efficacy – Through complementary mechanisms for secondary prevention in CHD patients**
**Safety – In CHD patients, including in clinical situations surrounding surgery **
**Contribution – (A + B > both A and B alone)**
**Medical Need – Demonstrated population at risk****	**

## Comprised of component drugs at selected doses previously approved by the FDA
Labeled only for secondary prevention, an indication previously approved for each component
Practice patterns and medical guidelines support concurrent use

**Comprised of component drugs at selected doses previously approved by the FDA**
**Labeled only for secondary prevention, an indication previously approved for each component**
**Practice patterns and medical guidelines support concurrent use**

**. . . *****Plus***** for Pravastatin-Aspirin   **

## Risk of a CHD Event Based on Placebo Event Rates

**History of acute MI**
**LIPID****	****	****	****	****	****31%**
**CARE****	****	****	****	****	****26%**
**4S****	****	****	****	****	****51%**
**Revascularization procedure****	****	****25-30%**
**Stable angina pectoris****	****	****	****20%**
**	****	****	****www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm**

_**DIAGNOSIS**__**	**__**10-year Risk of CHD Event**_
_**	**__**	**__**(MI and CHD Death)**_

**Risk of a CHD Event ****Based on Placebo Event Rates**

## Conclusions

**Pravastatin-Aspirin:  A rational combination product supported through evidence-based medicine**
**Three doses of pravastatin to be provided: 40mg, 80mg and 20mg**
**Safety of aspirin and favorable benefit:risk profile in CHD patients**
**Possible advantages of prescription aspirin in a clearly labeled combination product relative to ****OTC preparations**

**Conclusions**