Selling Safety

[Guest guest]

Hi All,

To whom are we and will the Federal Drug Agency listening?

What about the " a 2- to 4-kg increase in weight " ?

Selling Safety—Lessons From Muraglitazar

M. Brophy, MD, FRCPC, PhD

JAMA. 2005;294:2633-2635.

Peroxisome proliferator–activated receptors (PPARs) are nuclear cell

transcription

factors with isoform agonists that exhibit clinical benefit. The PPAR-gamma

agonists

increase insulin sensitivity, explaining the antidiabetic action of the

thiazolidinediones rosiglitazone and pioglitazone. PPAR- agonists, including the

fibrates, increase fatty acid oxidation, leading to a decrease in plasma

triglycerides and a modest increase in high-density lipoprotein cholesterol.

Muraglitazar is the first dual-PPAR agonist to be considered for general

marketing

both as monotherapy and combined therapy by the US Food and Drug Administration

(FDA). Given the emerging epidemic of type 2 diabetes, it is easy to understand

the

enthusiasm for this new class of drugs. Tight glycemic control reduces diabetic

microvascular complications, although both old1 and new2 studies have failed to

convincingly show decreased macrovascular complications of stroke, cardiac

disease,

and peripheral vascular disease.

On September 9, 2005, an FDA advisory committee reviewed muraglitazar’s efficacy

and

safety data and recommended approval3 and on October 18, 2005, it was reported

that

the FDA issued an " approvable letter " for this drug.4 However, in this issue of

JAMA, Nissen and colleagues5 have reanalyzed these data and challenge the

advisory

board’s recommendation. Courtesy of a transparent FDA approval process that

provides

online submission information,3 Nissen et al were able to contrast the 2374

patients

taking muraglitizar at 5 mg or less vs the combined 1351 patients exposed to

either

placebo or pioglitazone. Their analysis demonstrated a 2.23 (95% confidence

interval, [CI], 1.07-4.06) increased risk in the composite outcome of death,

myocardial infarction, or stroke and a 7.4 (95% CI, 0.97-56.8) relative risk of

congestive heart failure (CHF).

The authors rightly mention that a potential limitation of their analysis was

their

use of simple proportion tests and not the more informative survival time

analysis.

Nevertheless they feel confident in recommending that approval of muraglitazar

be

delayed pending a dedicated cardiovascular trial. In contrast, the sponsor’s

presentation to the advisory committee concluded that no significant excess risk

of

deaths or cardiovascular events occurred with muraglitazar treatment.6 While

there

may be disagreement over which analysis to believe, a consensus should exist

that

these differences indicate less than robust data.

Is it possible, at least partially, to reconcile these radically different

interpretations of the same data? Unlike the report by Nissen et al, the sponsor

presented the data as 3, not 2, distinct groups and calculated event rates per

patient year of exposure (Table), thereby logically weighting by duration of

exposure. However the 495 patients, representing 990 patient-years of exposure,

with

subtherapeutic doses of 2.5 mg or less were maintained in the denominator. Since

FDA

approval was not sought for these small doses of muraglitazar, the inclusion of

these data in the safety analysis for the proposed marketed doses may be

questioned.

Because there were no associated cardiovascular events among these patients, the

effect is a dilution of the clinically pertinent risk estimate. The recalculated

event rate for the proposed marketed doses of muraglitazar is 97 events per 2447

patient-years, an excess of 20% compared with placebo alone and an excess of 67%

compared with the combined placebo-pioglitazone control group. There is obvious

variability in cardiovascular event rates across the 5 different trials, but

this

heterogeneity can only be properly explored with further studies.

Muraglitazar users also had a 2- to 4-kg increase in weight, a 10% incidence of

edema, and 13 adjudicated cases of CHF (compared with 1 case in the control

group)

despite the strict exclusion of all patients with moderate or severe baseline

CHF.

Although patients with mild CHF symptoms (New York Heart Association class I and

II)

were eligible, only 25 were recruited and since their CHF risk was increased

10-fold, the sponsor’s claim that safety has been demonstrated for this group

rings

hollow. Systematic baseline ejection fractions were not recorded but none of the

patients had a value below 40%, implying that CHF risk prediction for future

muraglitazar users will likely be problematic. These elevated CHF rates are

possibly

related to increased circulating volume and have been consistently observed with

other PPAR- agonists.2, 7 Moreover, the rates from these clinical trial data may

be

underestimates of the true population risk because unselected diabetic

populations

are likely to be older and have an increased possibility of occult CHF that may

be

more prone to drug-induced decompensation. Combining the CHF cases with the

other

cardiovascular events reveals that the total muraglitazar cardiovascular risk

exceeds the placebo risk and the combined control group risk by 35% and by 89%,

respectively (Table).

Although hepatotoxicity has not been observed with muraglitazar (unlike the

first

PPAR- troglitazone, withdrawn due to liver toxicity), carcinogenicity has been a

concern in animal studies involving other dual-PPAR agonists. The sponsor’s

presentation to the advisory committee concluded that cancer rates were not

increased. However, 34 cancers were reported among 3125 patients (3471

patient-years

of exposure) in the muraglitazar group for an incidence of 9.8 per 1000

patient-years (95% CI, 6.7-13.3), whereas 1 cancer was reported among 528

placebo

patients (332 patient-years exposure), for an incidence rate of 3.0 per 1000

patient-years (95% CI, 0.1-21.3). Although the CIs overlap, this is a worrisome

observation that requires immediate further study as a very large increase in

cancer

risk cannot be excluded with the limited available data. Animal work showing

urinary

bladder carcinomas in muraglitazar-treated rats within 6 to 15 months of

follow-up

at doses only 7 to 8 times of those given to humans6 may have a clinical

correlate

in the increased bladder cancer risk observed with pioglitazone.2

Generically, there are specific methodological decisions in the sponsor’s FDA

application that may foster an illusion of safety. The following are several,

perhaps unintended but nevertheless disingenuous, methods observed in the

application that may have contributed to an overestimate of the safety profile:

1.Selecting a study population unlikely to have adverse outcomes but

nonrepresentative of potential future users (eg, exclusion of elderly patients,

even

though more than one third of type 2 diabetes occurs in this group)

2. Conducting underpowered studies increasing the failure rate to detect

meaningful

safety differences (ie, maximizing rather than minimizing type II errors)

3. In contrast to efficacy determinations, reporting individual rather than

composite safety outcomes to decrease the likelihood of establishing statistical

significance (eg, separate cardiovascular events from CHF)

4. Limiting preapproval peer-review publication of results so as to minimize

scrutiny and debate of both methods and results (eg, of all submitted data only

1

study of 340 patients has been published8)

5. Evoking biological implausibility of safety concerns by the use of surrogate

measures (eg, treatment reduces C-reactive protein [CRP]) implying safety,

despite

no proof that CRP reduction is clinically correlated with improved safety)

6. Recording outcomes only in patients who are fully compliant with prescribed

treatment because this self-selected group will likely have fewer adverse events

(eg, unknown impact of the nonanalysis of the 15% discontinued cases)

7. Ignoring the totality of the evidence by excluding consideration of

confirmatory

safety signals seen in studies of similar molecules (eg, CHF and bladder cancer

outcomes with pioglitazone)

8. Diverting attention to unproven but potential benefits by concentrating on

reductions in surrogate laboratory values (eg, hemoglobin A1C) rather than in

meaningful patient health outcomes.

Risk-benefit assessment is a dynamic process with few absolutes. A new drug for

a

uniformly fatal disease with no other treatment options is likely, even in the

presence of some treatment risks, to be approved by regulators and accepted by

patients. Conversely for muraglitazar, for which no meaningful outcome benefits

have

been demonstrated and other treatments exist, the safety standards should be

proportionally higher and importantly less uncertainty should be tolerated about

suspected risks.

What future studies are now required to allay these safety concerns? The sponsor

has

proposed a pharmacovigilance (observational) study of muraglitazar compared with

conventional type 2 diabetes treatments in 15 000 patients with annual

questionnaires during 5-year follow-up. While well-performed observational

studies

may provide useful information on drug safety, residual concerns will generally

remain due to possible selection or channeling biases. A large premarketing

safety

trial as proposed by Nissen et al will provide more secure evidence and has an

additional advantage of limiting risk only to study participants while safety

concerns are being assessed.

In conclusion, although muraglitazar may yet prove to be a valuable addition to

the

clinical armamentarium, the meticulous examination of the current evidence by

Nissen

and colleagues should focus serious attention on the potential cardiovascular

risks

of this drug. Residual safety concerns surrounding carcinogenicity also have not

been completely resolved. The question now is which safety message will the FDA

buy?

Al Pater, PhD; email: old542000@...

__________________________________

Start your day with - Make it your home page!

http://www./r/hs