1	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
2	Topics Chronology of Vioxx Other COX-2 Inhibitors Future plans
3	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
4	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
5	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
6	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
7	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
8	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
9	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
10	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
11	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
12	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?
13	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
14	What About Other COX-2s?
15	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
16	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
17	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)
18	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
19	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
20	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