# Presentation: 519052

## Practical Experiences in Active Safety Surveillance

**CDER Drug Safety & Risk Management **
**Advisory Committee Meeting **
**May 18-19, 2005**

**Notes:**
[Customer-Oriented Title Page]

## Background 

- Establishing product safety requires studies with **large** patient numbers and **long** periods of follow-up;
- Quintiles is a leading provider of services that capture and consolidate these large data sets for industry and government around the world.
- Our practical experience in this area may be valuable when considering relative obstacles to best practice safety surveillance.

## Questions to be addressed 

- Is more pre-approval data collection a viable solution?
- How practical are retrospective techniques in establishing safety?
- What practical obstacles exist for prospective safety surveillance?

## Is more pre-approval data as a viable solution? 

- Median patients per NDA (3000-5000)
- ~$5,000 per patient
- 100-150 patients / month recruitment in Phase II/III
- Phase III normally completed within 3 years
- Naturalistic studies, by definition, not possible
- Increasing exposure data requirements to 25,000 patients would:
- Increase cost of drug development by over $100m
- Delay approval of new drugs by up to 5 years

## Post-Approval Retrospective Experience - 1 

- Quintiles has experience applying retrospective techniques to different data sets for safety surveillance purposes:
- Prospective research databases (registries/SEER/NHANES)
- Prospective administrative databases (Verispan, Kaiser etc.)
- Case notes / charts
- Key take away points:
**Sufficient consistent data needs to be available for analysis...**
**...****Still predicated on quality prospective data collection**

## Challenges:
Data simply not available (AE summary, diagnosis, con meds, LOT)
Proxies for safety endpoints not always appropriate 
Representativeness of data / Confounders / Significance
High patient attrition rates without termination summaries
Administrative databases apply non-clinical judgement to reporting
Selection bias / lack of appropriate controls / controlling variables

Tenuous use of data proxies – identifying signals that don’t exist
Lack of termination data – missing signals that may exist 

- Data simply not available (AE summary, diagnosis, con meds, LOT)
- Proxies for safety endpoints not always appropriate
- Representativeness of data / Confounders / Significance
- High patient attrition rates without termination summaries
- Administrative databases apply non-clinical judgement to reporting
- Selection bias / lack of appropriate controls / controlling variables
- Tenuous use of data proxies – identifying signals that don’t exist
- Lack of termination data – missing signals that may exist

**Post-Approval Retrospective Experience - 2 **

## Low physician motivation / research infrastructure (50% of 20%)
Low presentation of patient benefit (cf. risk management)
Fragmented pharmacy / reimbursement environment (cf. UK/AU)
Haphazard IRB environment (local/central) (cf. France)
Inconsistent IRB decision making – eg. informed consent
Confusion regarding AE / safety / monitoring processes – industry defaults to higher cost and complexity solutions
HMO / Doctor swapping / attrition rates

- Low presentation of patient benefit (cf. risk management)
- Fragmented pharmacy / reimbursement environment (cf. UK/AU)
- Haphazard IRB environment (local/central) (cf. France)
- Inconsistent IRB decision making – eg. informed consent
- Confusion regarding AE / safety / monitoring processes – industry defaults to higher cost and complexity solutions
- HMO / Doctor swapping / attrition rates

**What are the obstacles to prospective research? **

## Recommendations 

- Facilitating more post-approval prospective research is the only way to definitively improve drug safety without compromising patient access to treatment.
- Increase investigator motivation for participation
- Negotiated, published risk management / surveillance plans
- Label warning for prescribing physicians
- Decrease administrative overhead
- Single central IRB for observational safety research
- FDA statement for informed consent, monitoring and safety reporting
- Standardized pharmaceutical reimbursement record keeping, opportunities to use linkage as a trigger for patient follow-up