# Presentation: 070769

## Comments on FDA’s Pharmacovigilance and Pharmacoepidemiologic Assessment Concepts

- Testimony April 11, 2003
- Gerald Faich MD MPH
- 	Pharmaceutical Safety Assessments
- 	610-664-1088
- 	gfaich@yahoo.com

**Notes:**
Applaud FDA’s effort to promote pv and pe.
Generally agree with all in document

## General Comments

**Thoughtful, useful**
**Addresses the need to balance  PE (structured studies) and PV (particularly use of spontaneous reports)**

## RESPONSES TO 4 of 6 QUESTIONS FOR THE PUBLIC WORKSHOP

**1.  **_**Spontaneous report quality**_
**2.  **_**Data mining **_**-What are possible advantages or disadvantages for  signaling?**** **
**3. **_**Causality Assessments-**_** advantages or disadvantages ?**
**4.  **_**Registries**_**-when useful?**
**Comments about Large Simple Safety Studies**

**Notes:**
Quality of case reports—get most info at first encounter, resistance after this. Cannot rely on MD intake, so use trained hc with branching script. Also collect info with logic which drives toward obtaining key info and automatically generates missing info request. E.g. safety trak and portal

Data mining—false signals, confounding by indication, stay in general indication class

Causality assessment-not routine, mainly when signal. Trials a special case—will overload under proposed “cannot r/o” approach

Registries-large and long comments

Additional pe studies—limitations and use of LSSTs when have the concern 

## 1. Quality of case reports

**We have concentrated on reporting elements, standardized coding and requirements. ****Now need to look at content.**
**Most information will be obtained during first encounter, resistance after this.**
** ****Need a trained health care provider for initial intake, not an MD.**

## Quality of case reports- Improving content and completeness

**Intake with a central computer-assisted interview  process **
**built-in structure,  logic and range checks (not merely word processing)**
**e.g.. prespecify part of anatomy then give choices**
**Automatically generate missing information request**

## Traditional Paper Approach vs. Technology

- Fax   >  Log  >  Write up  >  Code  >  Enter  >  Verify  >  Review
- Mail

**Paper Based Process**

**Electronic Process, e.g., SafetyTrak****®**** **

**Traditional Paper Approach vs. Technology**

**Notes:**
Inverted triangle D/E=10-15/day; SM’s=8/day; MD’s =20/day
Most expensive labor used less frequently
For call cases, nurses take cases directly and enter on line to one of our desktop applications.
Through the appropriate investigative questioning we minimize follow-up, one of our value added goals.
Pooled labor allows us to manage the volume variations which pharma can’t

## International Society of Pharmavigilance (ISoP):Draft Points to considerParis Jan. 2003

- Panel-Ralph Edwards,Gerry Faich,
-  Hugh Tilson

## ISoP POINT TO CONSIDER Pharmacovigilance signal detection

**Report volume for a drug is affected by, v****olume of use, publicity, type and severity of the event and other factors, therefore**** the reporting rate is not a true measure of the rate or the risk **
**Spontaneous reporting is a method with a high sensitivity and low specificity.**** **
**An observed event may be due to the indication for therapy rather than the therapy itself (e.g. suicide after anti-depressant ); therefore ****observed associations should be viewed as signal, and causal conclusions drawn with caution**

## 2. Data mining

**The database has **
**evolved over time—volume, quality, requirements, waivers**
**Numerous nonbiologic influences affect reporting-labeling, publicity**
**Reported AEs are greatly affected by the indication and patient population**
**Thus false signals are inevitable**

## Data mining –Limitation Examples and a Suggestion

_**Claritin and arrhythmias**_** (channeling and need for detailed data not in data base)**
**	****Increased number of reports due to preexisting condition. Selection of high risk patients for the drug deemed safest for them.**
_**Prozac and suicide**_** (confounding by indication) Large increase in reports following publicity and stimulated reporting**

## Data Mining

**Largely restrict within therapeutic class**
**Yogi Berra was right “If I hadn’t believed it, I wouldn’t have seen it”**

## 3. Causality assessment 

**No standardized method that is reproducible (Koch-Weser 1968).**** **
**Time and resource consumptive **
**particularly distinguishing between probable and possible. **
_**Routine**_** assessment dropped at FDA in 1983 because of its limited value and because it was a major source of delay in entry and contributed to backlogging.**
**Information often lacking**

## 3. Causality assessment 

**For spontaneous reports, do whenever a signal is under investigation, but not be routine   **
**Whenever causality assessed, always note results are **_**preliminary**_** in order to assist in interpreting patterns of reporting and do not represent definitive conclusions (secondary incomplete records, legal implications)**
**For serious trial ADR reports, causality assessments need to be done. The Tome (new requirements) calls for submission to FDA when causality cannot be ruled out. This could clog the system and undermining the value of expedited reporting.**

## 4. Registries

**Follow large number of exposed patients often for extended periods of time for particular outcomes**
**Recent examples- lymphoma and infections after exposure to drugs potentially affecting the immune system**
**Issues-sizing (power), feasibility, data collection**

## 4. Registries-Issues-sizing (power), duration, feasibility, data collection

**Sizing****-need to recognize that will need 10s of thousands over many years to rule out risk of 3-fold. If one insists on ruling out a 2- fold risk, study may become infeasible**
**Duration****-drop outs are a fact of life. Anticipate 20% per year. Thus very long follow-up (except NDI) may not be feasible—5 years yes, 10 years maybe**
**Data collection**** –direct-to-patient calls to find sentinel events (e.g. hospitalization or biopsy)**

##  Other Suggestions/responses-LSSTs

- LSSTs done in the periapproval period must draw upon pharmacoepidemiology (like cohort studies-broad inclusion criteria, simple focused data collection)
- Traditional epi studies, even using automated databases,  will be delayed until enough penetration of the drug of interest into populations which can be studied
- Both LSSTs and registries need to consider apply technology and direct-to-patient methods.

## Smoking Cessation Study: 10,000 pt. Registered/7000 pts surveyed in <5 months.

**Patients**
**Investigators**
**Study Coordinators**
**Pharmacists**
**Physicians**
**Consumers**

**Menu-Driven**
**Easy Data-Tables**
**Thesauri**
**Drop-Downs**
**Standardizations**
**Auto-QC**
**Auto-Narrative**
**Global Access**
**Multilingual**

**Notes:**
How does SafetyTrak work?
The portal supports all three value propositions—this is the postmarketing solution
The data come in from a variety of sources
The call is answered by the CRC/DE/monitor agent
CSR logs onto onto SafetyTrak anywhere in the world (could interface with a CRM system)
SafetyTrak walks them through the interview with
Drop down menus
Requiring basic fields
Automatically creates the narrative

Maintains the data in the SafetyTrak database for viewing until 
It is pushed via E2B transfer into your safety system

It is your system that creates MedWatch forms, reports, etc.
Maximizes the efficiency of our medically trained safety specialists—valuing their time—thus reducing costs for us both

Data accessible on a need to know basis
Real time
E2B transfer

## Post-NDA tools

**Utilization **

**External **
**Databases**:

-    **Passive surveillance**                        (AERS)

**Background                                         rates**

-      **Active**
**Surveillance**

## Summary

**For spontaneous case reports, the means to improve content is to standardize and improve intake   **
**Data mining likely will generate many false positives and affirmations of what was previously known**
**Causality assessments should largely be reserved refining  important signals **
**Registry challenges of size, duration and data collection are markedly intertwined with feasibility issues**
**Large safety trials need epidemiologic input**
**PE-PV concept paper is excellent**

## GAF Background

**FDA 1983-1990—Office Director****safety reporting, epi programs**
**Since FDA**
**Senior positions in CROs, safety consultant to >20 companies and >40 projects/issue**
**IDMCs**
**U Penn**