# Presentation: 027756

## Comments on FDA’s Risk Management Concept Paper	April 10, 2003

- Gerald Faich MD MPH
- 	Pharmaceutical Safety Assessments
- 	610-664-1088
- 	gfaich@yahoo.com

**Notes:**

GAF background
FDA 1983-1990—Office Directorafety reporting, epi programs, staff expansion
Since FDA
CEO “COVANCE” 
Consult to >20 companies and >40 projects/issue
U Penn

## Risk Management Concepts

**Most important safety initiative in many years**
**Tremendous potential **
**Concise and well written- ****      ****pretest and evaluation   ****	****sections**
**Support ISPE comments**

## Concepts to Practice-implications and concerns

**FDA processes and communication to sponsors, timing**
**Labeling and education research**
**Consequences of restrictive marketing**

## 1. FDA processes and communication with sponsors

**Coordination during NDA review**
**Timing-the earlier the better, time for pretest, signal need to sponsor**
**Assure that risk review and planning is not seen as duplicative of ISS**

## Levels of risk management

**Level 1-improve labeling **
**Level 2-go beyond labeling-education, Medguide, etc**
**Level 3-restrict prescribing, dispensing, distribution**
**Level 4-documentation of level 3**

## Level 1 will require labeling and education research

**Level 1 aims to improve the impact of information already in the label.**
**Improving design and content of labeling**
**Do we know how to write an effective label?**
**Need cognitive research**
**Evaluate labels impact**
**Survey knowledge, attitude and practice **

## 

**Label Comprehension**
**Readability, Comprehension, Overloading**
**Cognitive research**

****

**Ruth S. Day, Duke University**

- FDA Arthritis Advisory Committee
-  March 5, 2003

## Labeling

**Need to validate utility of risk interventions in the label**
**EG liver enzyme monitoring**
**Does it make us or the patient feel better? **
**Does it reduce liver failure**
**What level of labeling compliance 100%, 50% can be achieved**

## Wording in "Dear doctor" letters: Clin Pharmacol Ther 2002 Dec;72(6):735-42   Weatherby LB, Nordstrom BL, Fife D, Walker AM.
Methods
    Automated database 
RESULTSA highly publicized letter was associated with a  decline (58%) in the concomitant dispensing rate of explicitly contraindicated drugs and cisapride  

CONCLUSIONS Explicit, well-publicized drug warnings can change prescriber behavior

**Methods**
**    ****Automated database **
**RESULTS****A highly publicized letter was associated with a  decline (58%) in the concomitant dispensing rate of explicitly contraindicated drugs and cisapride  **
**CONCLUSIONS**** ****Explicit, well-publicized drug warnings can change prescriber behavior**

## Risk Management Program (level 2,3,4)

**Definition:**** Strategic program to decrease product risk **_**by interventions beyond the PI**_
**Eg education for HCs or pts**
**Processes to increase compliance**
**Systems to modify prescribing dispensing and use **
**Must identify the risk to be reduced**
**Targeted program**
**Specific measurable objectives eg physician knowledge, pt knowledge**

## Level 2 Interventions beyond labelFurther education

**How to communicate effectively?**
**Test the intervention-**
**pilot test preapproval**
**modify as results come in**
** **

## Interventions to Enhance Patient Adherence. McDonald. JAMA 2002:288:2868-79.

**Review of RCTS examining interventions to improve pt compliance**
**“****Current methods of improving medication adherence for chronic health problems are complex, labor intensive and not predictably effective.”**

## Barriers: Clinical Practice Guidelines Experience

**Lack of awareness**
**Lack of familiarity**
**Disagreement with recommendation**
**Disbelief outcome will occur**
**Inertia/experience of previous practice**
**External factors:inconvenience, time consuming, costly**

## Levels 3 and 4-restrictions and documentation	

**Apply judiciously**
**Will limit use**
**Likely will be effective but if barriers to accept will shift prescribing to other products**

## Alosetron (Lotronex) 	

**Rx for IBD withdrawn after ischemic bowel necrosis and severe constipation reports Nov 2002**
**Remarketed in Jan 2002 with RM Plan **
**Targetted to assuring use in women with diarrheal dominant disease and to detecting early warning signs**
**Components**
** ****Label change-black box, Med Guide**
**Physician attestation-qualified sticker for Rxes**
**Physician-patient agreement**
**Targeted**

## Overly restrictive?	Dofetilide

**Atrial fibriallation.**
**QT prolongation**
**Modify dose according to renal status and Qt prolongation**
**Initiate in hospital**
**Register physicians, patients, hospital pharmacies**
**Very little use**

## Conclusions

**Applaud the concepts**
**Early communicate with industry in general and particular. **
**Coordination within FDA**
**Test labeling and other interventions-what works and what doesn’t**