1. Department of Health and Human Services Center for Drug Evaluation and Research 1 Clinical Trial Design and Patient Safety: Future Directions for COX-2 Selective NSAIDs Robert J. Temple, M.D. Associate Director for Medical Policy Center for Drug Evaluation and Research U.S. Food and Drug Administration February 18, 2005

2. Department of Health and Human Services Center for Drug Evaluation and Research 2 Issues of Interest 1.Main Issue Effect of COX-2 selective NSAIDs on CV outcomes, especially death,stroke, NFAMI. Sub-issues include: Single drug effects Class effects/differences Little long-term data on non-selective NSAIDs (and they vary in selectivity), the most likely comparator agents in symptomatic patients

3. Department of Health and Human Services Center for Drug Evaluation and Research 3 Issues of Interest Possible differences in sub-populations at different risk Mechanistic considerations – platelet effect and/or BP effect Possible relation to dose and/or dose interval Duration of studies needed to detect effects

4. Department of Health and Human Services Center for Drug Evaluation and Research 4 Other Issues 2.Actual advantages of “selective” agents and alternatives (particularly adding a PPI to any NSAID). On GI symptoms On ulcers and bleeding Potential suppression of GI polyps (potential benefit vs colorectal cancer) properly monitored patients, real world setting Compared to NSAIDS plus anti-ulcer drugs [misoprostil, possibly PPIs]

5. Department of Health and Human Services Center for Drug Evaluation and Research 5 CV Effects Aren’t all the questions answered? The data do not seem wholly consistent to me, and there are several possible reasons: There are real differences between drugs and doses, Even the best controlled studies sometimes give different answers Small effects are difficult to evaluate in epidemiologic (and even controlled) studies Effects are population dependent. I therefore assume there is more to learn

6. Department of Health and Human Services Center for Drug Evaluation and Research 6 Pharmacology 1.Platelet effects Worry: decreased prostacyclin from COX2 inhibition (prostacyclin is vasodilator and platelet inhibitor) tilts toward platelet aggregation but with no lowering of thromboxane A 2 (COX 1 mediated - which inhibits platelet aggregation) to reverse the tilt. Net increase in thrombotic tendency, especially in people at higher risk (predisposed) Can dose-relationship for these effects be better defined?

7. Department of Health and Human Services Center for Drug Evaluation and Research 7 Pharmacology Would seem that ASA 81 mg should fully reverse this making the COX-2 selective agents identical to non-selectives. But the parecoxib CABG data (on ASA) and ASA-using subgroups in APPROVE suggest this is not so. 2. BP and Fluid Retention Effects Could some of the findings reflect increased BP, interference with BP drugs, or interaction of BP and platelet effects?

8. Department of Health and Human Services Center for Drug Evaluation and Research 8 Pharmacology 2.BP and Fluid Retention Effects Occam’s razor guides us towards platelets, but drugs can have multiple effects. There is no doubt NSAIDs generally, including some COX-2 selective agents, have effects on BP. These include: Reversing effects of antihypertensives, especially ACEI’s, AIIB’s, BB’s Elevating BP to a modest degree generally Reports of HT in trials

9. Department of Health and Human Services Center for Drug Evaluation and Research 9 Pharmacology 2.BP and Fluid Retention Effects All data on BP effects need to be considered, but if increased BP results from fluid retention, would expect: 1.Dose-response relationship 2.Perhaps b.i.d. > o.d. (less recovery) Need to look at 24 hour effects

10. Department of Health and Human Services Center for Drug Evaluation and Research 10 Effect of Elevated BP Impact of “hypertension” is well-recognized; benefit of lowering BP (systolic or diastolic) with variety of drugs is clear. Less recognized is effect of higher “normal” BP. Effect of BP elevation seems to be similar over broad range: JNC VII describes doubled risk of death from ischemic heart disease and stroke for every 20 mmHg systolic and 10 mmHg diastolic, starting as low as 115/75 McMahon, Peto, et.al. showed a doubled risk of stroke for every 7-8 mmHg and of AMI for every 10-11 mmHg

11. Department of Health and Human Services Center for Drug Evaluation and Research 11 Effects of Elevated BP (cont.) Vosan, et.al., (Framingham) compared event rates in patients starting with optimal, normal, and high normal BP Optimal: DBP<80; SBP<120 Normal: DBP 80-84; SBP 120-129 High NL: DBP 85-89; SBP 130-139 [If D and S disagree, higher category]

12. Department of Health and Human Services Center for Drug Evaluation and Research 12 Effects of Elevated BP (cont.) Collins, et.al. estimate stroke reduction of about 40% with DBP changes of 5-6 mmHg, but a smaller effect on CHD, about 14% – Perhaps related to excess dose of diuretics in the major trials. More recent studies (SHEP, Syst-Eur) have shown larger effects in systolic HT, but there are few low-dose placebo controlled diuretic studies in other kinds of HT. The BP Lowering Treatment Trialists Collaboration shows similar results, with an 8 mmHg systolic reduction giving about a 40% reduction in stroke and a 20-25% reduction in CHD, CV death Conclusion: A 5-6 mmHg long-term increase in BP could lead to a 25-30% increase in CV events and a 50-60% increase in stroke

13. Department of Health and Human Services Center for Drug Evaluation and Research 13 Effects of Elevated BP (cont.) The risk of increased BP extends into the “normal” BP range. But risk tells only about fractional increase. What is the actual consequence (e.g., events per 1000 patient years)? For low risk patients (SBP 135, no diabetes, etc.) with a rate of about 100 CV events per 1000 patient years, not so different from patients in e.g., VIGOR estimated that a 15 mmHg decrease would save about 20 CV disease events per 1000 patient years, obviously a substantial benefit Alderman, based on the McMahan and Peto data

14. Department of Health and Human Services Center for Drug Evaluation and Research 14 BP Elevation – CAMELOT 1,991 patients with known CAD and DBP < 100 mmHg randomized to amlodipine 10 mg, enalapril 20 mg, placebo, giving differences of 5.5/3.1 (amlodipine) and 5.6/3.0 (enalapril) Events:CV death NFMI Resuscitated arrest Coronary revascularization Angina Hospitalization CHF Hospitalization Stroke (F or NF) TIA New peripheral vascular disease

15. Department of Health and Human Services Center for Drug Evaluation and Research 15 BP Elevation – CAMELOT AmlodipinePlaceboEnalapril Total Events HR vs. plbo 110 (16.6%) 0.69 151 (23.1%) --- 136 (20.2%) 0.85 NFMI, stroke, TIA, CV death 253725 Second line omits angina-related, CHF, PVD, leaving about 33% reduction [angina-related events could reflect amlodipine’s anti-anginal effect].

16. Department of Health and Human Services Center for Drug Evaluation and Research 16 Pharmacology There are many studies addressing the BP effects of selective and non-selective NSAIDs; vary from 0 - 5-6 mmHg, probably dependent on starting BP and whether patients are on anti-hypertensives. But little firm data: 1)pinning down effects of dose and dose-interval (important if effect is primarily due to fluid retention) and 2)examining 24-hour effects with ABPM

17. Department of Health and Human Services Center for Drug Evaluation and Research 17 Assessment of CV Effects What can be studied? Given VIGOR and consistent epidemiology, I would say outcome studies of 50 mg rofecoxib would be hard to support. What about rofecoxib 25 mg and various doses of celecoxib and new selective or non-selective NSAIDs? What you could do depends on what you believe and the perceived gaps in data.

18. Department of Health and Human Services Center for Drug Evaluation and Research 18 Assessment of CV effects 1. Suppose you believe... CV risk of 200-400 mg celecoxib not so clear (only one polyp study says there is risk of 200-400 b.i.d.; other polyp study (o.d. dosing), Alz study, CLASS, both with b.i.d. dosing say there isn’t) Class effect uncertain (above bullet, lumiracoxib not clear), or at least not present at some doses in some settings More needs to be known about L-T use of all NSAIDs New COX-2 selective agents could be developed Pharmacology gives hypotheses that need to be tested clinically

19. Department of Health and Human Services Center for Drug Evaluation and Research 19 Assessment of CV Effects Then could consider “ALLHAT”-like long-term study of CV and GI risk, including, for example: – Ibuprofen – Naproxen – Diclofenac – Celecoxib – possibly > 1 dose – (?) Aspirin full dose plus a PPI (if PPI can be shown to prevent ulcers) – we know ASA does not increase risk – (?) APAP plus added codeine, if OA New single agent could be compared to naproxen and (I’d wish) either ASA/PPI or APAP codeine

20. Department of Health and Human Services Center for Drug Evaluation and Research 20 Assessment of CV Effects Population: – Need for chronic pain meds – OA and RA (stratify) – Range of risk best Could do low/no risk study first, with interim look. This group would not get low dose ASA – Known CAD risk patients must get low dose ASA probably with all treatments except full dose ASA, although benefit seems uncertain

21. Department of Health and Human Services Center for Drug Evaluation and Research 21 Assessment of CV Effects Sample Size: Studies with 1000/group vs placebo appear to have shown effects (they are not too rare to study in RCTs). ASA & PPI group should serve as placebo group (but could be superior to placebo, a problem).

22. Department of Health and Human Services Center for Drug Evaluation and Research 22 Comparison with ASA or APAP may not need large samples, but drug-drug comparisons will need quite large groups (the NSAID groups can be made larger than the ASA and APAP groups). Need to decide the magnitude of difference you want to detect/rule out and size accordingly.

23. Department of Health and Human Services Center for Drug Evaluation and Research 23 Assessment of CV Effects Endpoints (would be DMC, interim evaluations, etc): CV death Stroke AMI Bleeding What to do about BP? First thought is to monitor and treat BP> 120/80 but that’s not standard practice; Would treating only at 130/90 be acceptable? Define 2 nd treatment for failure/intolerance Follow to end of study (ITT vs per protocol)

24. Department of Health and Human Services Center for Drug Evaluation and Research 24 Assessment of CV Effects Why do it at all (who needs them)? My answer: It’s not just about nominal COX-2 selectivity NSAIDs have wide range of COX-2 selectivity (diclofenac is reasonably selective). – Need to study drugs with a range of selectivity, perhaps range of COX-2 potency Selectivity may not be the only issue We need to understand effects of the whole class, which is widely used clinically, and understand short and long term risks.

25. Department of Health and Human Services Center for Drug Evaluation and Research 25 Assessment of CV Effects 2. Suppose you believe... CV risk is increased with all of the COX-2 selective agents (ignoring for now which ones are actually selective) Mechanism is platelet effect There still could be differences among the drugs

26. Department of Health and Human Services Center for Drug Evaluation and Research 26 Assessment of CV Effects Then you could consider trial of COX-2 selective agents given with 80 mg ASA: - ibuprofen - naproxen - celecoxib plus 80mg ASA - aspirin full dose plus PPI (if PPI is shown to prevent ulcers) But only if short term study shows celecoxib plus 80 mg ASA still has favorable effect on GI symptoms compared to, say, naproxen