# Presentation: 714897

## Drug Regulation in Controversy: VioxxNovember 10, 2004

**Sandra L. Kweder, M.D.**
**Deputy Director, Office of New Drugs**
**Center for Drug Evaluation and Research Food and Drug Administration**

## Topics

- Chronology of Vioxx
- Other COX-2 Inhibitors
- Future plans

## COX-2 Inhibitors

- 1990s: tremendous hope of reducing GI morbidity and mortality
- 1998 Vioxx NDA was large
-  > 5000 pts
- Exposure up to 86 weeks, with 371 and 381 patients taking 12.5 and 25 mg/day for one year or longer; 272 patients took 50 mg for at least six months
- No CV signals in clinical trials, but reviewed carefully because of concern of pro-thrombotic effects *in vitro*

## Vioxx 1999

- January
- Vioxx GI Outcomes Research trial begins (VIGOR)
- April - Arthritis Advisory Committee
- Efficacy and multiple safety components
- May – Vioxx NDA approved
- Acute pain, dysmenorrhea, OA
- November
- Colon polyp prevention study (APPROVe) submitted

## Vioxx 2000

- March – Preliminary results of VIGOR submitted to IND
- Analyses of serious CV events in all NDA studies, placebo controlled Alzheimer studies and ADVANTAGE, which was almost complete
- Letters to all investigators with information
- Informed consent documents modified
- Multiple public venues for data

## Vioxx 2000 (continued)

- June
- APPROVe protocol changed to allow use of low dose aspirin
- June – VIGOR to FDA as NDA supplement
- Decrease in risk of gastroduodenal perforations, ulcers and bleeds compared to naproxen
- Increase in CV thrombotic events, mostly MI 0.5% V vs. 0.1% not used
- November – NEJM publication of VIGOR

## Vioxx 2001

- February
- Arthritis Advisory Committee reviews VIGOR
- Risk/Benefit review – still positive
- Recommend _labeling_ & additional studies of CV risk
- February**
- NDA for Rheumatoid Arthritis submitted
- N=1100 taking 25 or 50 mg vs naproxen for 3-12 months
- Fall
- APPROVe completes enrollment
- Labeling discussions with Merck ongoing

## Vioxx 2001 (continued)

- All Vioxx _protocols_ reviewed
- Alzheimer's, polyps, prostate cancer
- Focus on CV endpoint definition & adjudication
- Review of data sources for more definitive answer
- NDA supplement for RA
- Interim analyses of other clinical trials
- FDA sought large database to conduct retrospective data review
- Contract with Kaiser

## Vioxx 2002

- Label discussions between FDA and Merck
- Ongoing data review by FDA
- Mixed picture of CV risk
- Merck submits more data from ongoing Alzheimer’s Disease trials
- 2800 patients on Vioxx 25 mg vs placebo
- No excess of CV events
- April
- Label for RA, GI safety benefit and CV risk approved
- CV risk in “Precautions” and other sections
- 50 mg dose should not be used for more than 5 days

## Vioxx 2003-2004

- 2003
- Continued focus on ongoing trials and data collection and assessment for CV safety
- August 2004
- FDA Kaiser cohort analysis neared completion
- Abstract presented at ISPE
- Shows risk of 50 mg dose (confirms VIGOR)
- Risk for 25 mg dose similar to other NSAIDS
- September 2004
- APPROVe 36 month study results reviewed by DSMB
- Merck decision to withdraw Vioxx

## What Did APPROVe Show?

**Vioxx** **25** **mg** per day significantly increases risk of serious CV events (MI and stroke) compared to placebo
- Risk appears after patients are taking drug for 18 months
- Definitive confirmation of risk not evident until 36 month assessment

## Do Cox-2 Selective Agents Have a Different CV Risk Profile?

- No definitive evidence – except Vioxx
- Agents differ in degree of selectivity
- Dose response may be an important factor
- Traditional NSAIDs may differ in CV toxicity profiles
- Mechanism for the risk remains unclear
- platelet effect?
- blood pressure?
- Other?

## Difficulties in Evaluation

- Placebo controlled data most interpretable because CV effects of comparators not established
- Issue of naproxen control loomed over VIGOR
- Other NSAID controls would have similar concerns
- VIGOR suggested risk seems to be highest after months on treatment
- Hard to do long term placebo controlled trials in arthritis
- Trials in high risk groups for long periods are of concern
- High CV risk groups take ASA, which might have mitigated any adverse risk with Vioxx

## What About Other COX-2s?

## Celecoxib (Celebrex)

- Approved in 1998
- No CV risk in NDA
- Development program
- Large scale placebo-controlled trials for prevention of colon polyps/cancer (n=3600) and Alzheimer’s disease
- Independent DSMBs for these studies with special emphasis on cardiovascular events. Both DSMB’s get monthly data updates; have issued statements to investigators that they are aware of rofecoxib W/D and have determined there is no indication for stopping these trials
- Meet again in late fall

## Valdecoxib (Bextra)

- NDA database of 8,000
- No CV signal in oral studies at doses in range and above those approved
- No CV signal in IV studies in post operative pain
- Excess CV events and death in single IV study in post-CABG patients
- IV and follow-on po in post-op studies were 2-4X that in oral only studies

## FDA Next Steps

- Arthritis Advisory Committee in early 2005
- Share all available data on Vioxx and other drugs
- Seek advice on additional steps and studies needed
- Other COX-2s
- Accumulating data re: celecoxib via placebo controlled trials
- Explore ways of further evaluation of valdecoxib
- Scrutiny of new agents (some approved in Europe)

## FDA Safety Initiative 2004

- Search for Director, Office of Drug Safety
- Institute of Medicine Study
- Assess full spectrum of drug safety in the US
- To include operations between Office of New Drugs and Office of Drug Safety
- New procedure for review of differing professional opinions
- When usual processes are not satisfactory to parties
- Focused effort to bring safety matters to public Advisory Committee meetings for review

## Summary

- Vioxx experience complex from scientific and regulatory standpoint
- Data were mixed from very early on
- Definitive trials in arthritis extremely challenging
- Difficulty in requiring 3 year placebo controlled safety studies prior to approval
- Placebo controlled data offered best hope for definitive answers
- The experience will be applied to review additional COX-2 inhibitors over next few months
- Public discussion essential – Advisory Committee

## Summary (continued)

- Learning from experience is a part of public accountability
- Role for external scrutiny (IOM), particularly of broader picture of our ability to be effective in identifying and following up on safety issues