1. Cardiovascular Health Research Unit, Seattle, WA IOM recommendations on drug safety: relevance for vaccines? Bruce M Psaty, MD, PhD

2. CHRU Drugs and vaccines: prevention DrugsVaccines PaymentAd hocVFC program Rx durationLongShort Rapid uptakeDTCAGuidelines Phase III standardSurrogatesClinical benefit PM safety eventsUncommonRare Injury compTort lawNo-fault system Orenstein WA. Health Affairs 2005; 24: 599-610.

3. CHRU US drug-safety system Pharmaceutical industry lacks a symmetric interest in safety and efficacy Since 1960s, approval marks transition from evaluation to marketing With rapid approvals since 1992, current post-market system--AERS plus PM commitments--could hardly be weaker Steenburg C. Food Drug Law 2006; 61: 295-384.

4. CHRU Guidance to assess safety For new drugs intended for long-term use in non-life threatening conditions –1500 subjects exposed –300 to 600 subjects for 6 months –100 subjects for 1 year Rofecoxib NDA as example –58 studies in 5771 patients –3629 received rofecoxib 1 day or more –752 received usual doses for 1 year Guidance ICH E1a, 1995. Villalba M. Review of Vioxx, 1999.

5. CHRU US post-market safety system FDA-based part of the system –AERS and some observational studies Industry-based part of the system –PM commitments and other studies 66% of med officers lack confidence that the “FDA adequately monitors the safety of prescription drugs … on the market” OIG Report. OEI-01-01-00590. March 2003.

6. CHRU Post-market commitments Agreed to by sponsors pre-approval For one sponsor, 7 of 11 PMCs identified within 3 weeks of approval Designed by sponsors, who often lack an imaginative interest in safety studies Reviewed by OND medical officers, who often don’t know what studies to request OIG report. FDA review process, March 2003.

7. CHRU Industry-funded studies MEDAL program with 24,913 subjects –Compared etoricoxib and diclofenac –Similar pain relief, GI and CV AEs Diclofenac as comparator –Best selling NSAID world-wide –COX2 selectivity similar to celecoxib –Compared with naproxen, 70% increase in vascular events Psaty BM. N Engl J Med 2007; 356: 328-30.

8. CHRU Lifecycle approach On-going evaluation of safety and efficacy of drugs during their market life Systematic approach to identifying and translating safety signals into high- quality studies Pursuit and management of emerging knowledge about risks and benefits

9. CHRU IOM recommendations New funding, preferably from general revenues rather than user fees New authorities for the FDA –Labeling and post-market studies –New enforcement tools Black triangle and restricted direct to consumer advertising

10. CHRU IOM recommendations Leadership promoting a culture of safety Access to new tools and new data Integration of ODS/OSE in OND reviews and shared for post-market decisions Development and use of risk-benefit analyses

11. CHRU Some potential remedies Congressional legislation –Clinical trials registration (S467) –Grassley-Dodd bill (S468) –Kennedy-Enzi bill (S484) –PUDFA reauthorization in 2007 Wise drug use by physicians & patients –Suspend use of some drugs –Use well-studied drugs