Clinical Trial Design and Patient Safety: Future Directions for ...

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Department of Health and Human Services

Center for Drug Evaluation and Research

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 ResearchU.S. Food and Drug Administration

February 18, 2005

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Issues of Interest1. 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

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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

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Other Issues1. 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]

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CV EffectsAren’t all the questions answered? The data do not seem wholly consistent to me, andthere 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

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Pharmacology1. Platelet effects

Worry: decreased prostacyclin from COX2 inhibition (prostacyclin is vasodilator and platelet inhibitor) tilts toward platelet aggregation but with no lowering of thromboxane A2 (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?

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PharmacologyWould 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 EffectsCould some of the findings reflect increased

BP, interference with BP drugs, or interaction of BP and platelet effects?

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Pharmacology• 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

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Pharmacology

• 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 relationship2. Perhaps b.i.d. > o.d. (less recovery)

Need to look at 24 hour effects

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Effect of Elevated BPImpact 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

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Effects of Elevated BP (cont.)Vosan, et.al., (Framingham) compared event rates inpatients starting with optimal, normal, and highnormal BP

Optimal: DBP<80; SBP<120Normal: DBP 80-84; SBP 120-129High NL: DBP 85-89; SBP 130-139[If D and S disagree, higher category]

CV Events Women

Age-adjusted % in 10 years

Men Age-adjusted %

in 10 years Optimal 1.9 5.8 Normal 2.8 7.6 High NL 4.4 10.1

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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

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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

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BP Elevation – CAMELOT1,991 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 deathNFMIResuscitated arrestCoronary revascularizationAngina HospitalizationCHF HospitalizationStroke (F or NF)TIANew peripheral vascular disease

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BP Elevation – CAMELOT

253725NFMI, stroke, TIA, CV death

136 (20.2%)0.85

151 (23.1%)---

110 (16.6%)0.69

Total Events HR vs. plbo

EnalaprilPlaceboAmlodipine

Second line omits angina-related, CHF, PVD, leaving about 33% reduction [angina-related events could reflect amlodipine’s anti-anginal effect].

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PharmacologyThere are many studies addressing the BP effects ofselective and non-selective NSAIDs; vary from 0 - 5-6 mmHg, probably dependent on starting BPand whether patients are on anti-hypertensives.

But little firm data:7) pinning down effects of dose and dose-interval

(important if effect is primarily due to fluid retention) and

8) examining 24-hour effects with ABPM

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Assessment of CV EffectsWhat 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.

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Assessment of CV effects• 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

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Assessment of CV EffectsThen 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 OANew single agent could be compared to naproxen and (I’d wish) either ASA/PPI or APAP codeine

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Assessment of CV EffectsPopulation:

– 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

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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).

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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.

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Assessment of CV EffectsEndpoints (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 2nd treatment for failure/intolerance

Follow to end of study (ITT vs per protocol)

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Assessment of CV EffectsWhy 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.

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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

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Then you could consider trial of COX-2 selectiveagents 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

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