Novartis’ experience with its chronic obstructive pulmonary disease drug Arcapta Neohaler is a reminder that while quality-of-life data is nice to have, particularly from a competitive standpoint, it often plays merely a supporting role to clinical efficacy when it comes to product approval.

In the case of Arcapta (indacaterol), FDA’s Pulmonary-Allergy Drugs Advisory Committee concluded March 8 that although QoL data supported a claim for improved health status with the 150 mcg dose, this was not enough to overcome the lack of data showing superior efficacy to the 75 mcg dose.

Despite a stronger endorsement for a QoL claim for the 150 mcg dose, the committee found differently on the clinical efficacy evidence, with 11 of 17 members saying there was no advantage for the higher dose over the lower dose. The panel also backed the 75 mcg dose while recommending against approval of the higher dose (Also see "Arcapta Quality Of Life Data For High Dose Cannot Overcome Efficacy Questions" - Pink Sheet, 8 March, 2011.).

Novartis is seeking approval of both the 75 and 150 mcg doses but prefers the latter, asserting it provides optimal efficacy. However, the higher dose is also important for the company’s lifecycle development plans for the long-acting beta-adrenergic agonist (Also see "COPD Drug Dose Selection May Face Greater Scrutiny In Arcapta’s Wake" - Pink Sheet, 14 March, 2011.).

SGRQ Claim Would Be A First

In arguing its case for approval of the higher dose, Novartis hoped that QoL data from the St. George’s Respiratory Questionnaire would help tip the scales toward an efficacy advantage for 150 mcg.

The SGRQ comprises 16 questions that assess disease symptoms, disturbances to patients' daily physical activity and the impact of disease on the patient. The instrument is frequently used as a QoL assessment in clinical trials, Novartis says in briefing documents for the advisory committee meeting.

FDA’s 2007 draft guidance on COPD drug development allows for use of the SGRQ and other health-related QoL instruments as secondary efficacy endpoints

However, no bronchodilators in the U.S. have been approved with claims for QoL improvement based upon the SGRQ. The advisory committee was asked whether SGRQ data supported claims for improved health status for both doses.

The minimal clinically important difference (MCID) from placebo in the SGRQ total score is considered to be a reduction of four units. Two of three studies of indacaterol 150 mcg crossed this threshold, while the two studies of the 75 mcg dose both fell short.

David Morris, Novartis’ respiratory franchise head, said that while the total SGRQ score is important, so is the impact across the instrument’s individual components. Indacaterol 150 and 75 mcg delivered substantial benefit with regard to symptoms, and there was a trend toward benefit of 150 mcg on the components that measure activity and impact, he said. “We’re seeing a clear trend of supportive efficacy of the 150 mcg dose across multiple domains.”

No QoL Differences Among Doses

However, FDA questioned whether the data supported an SGRQ claim for either dose.

FDA reviewers noted that across various studies, indacaterol 75, 150 and 300 mcg doses were each associated with statistically significantly better SGRQ total scores than placebo, although there was no significant difference among the indacterol doses themselves. Furthermore, the confidence intervals for the three doses were wide and overlapped considerably, and the percentages of patients for whom an improvement in SGRQ score was considered clinically important were similar.

Notably Boehringer Ingelheim GMBH/Pfizer Inc.'s long-acting antimuscarinic antagonist Spiriva (tiotropium), which was used as an active comparator in some indacaterol studies, did not show a significant improvement in SGRQ total score over placebo.

As the only once-daily bronchodilator approved for COPD, tiotropium would be a prime competitive target for indacaterol, which is also being proposed for once-daily dosing. A QoL labeling claim for indacaterol could provide a marketing advantage.

In votes of 10-7 and 13-4, the committee found the data supported an SGRQ-related QoL claim for the 75 and 150 mcg doses, respectively.

Committee member Thomas Platts-Mills, University of Virginia, concluded the data supported an SGRQ claim for both doses, although he did so “reluctantly” for the lower dose. “I think the data for 150 mcg is stronger and clearer and I’d hate to imply that 75 is the final answer,” he said.

On the other side of the coin was committee member Daren Knoell, Ohio State University, who did not think the SGRQ claim was supported for either dose.

Knoell said he was surprised FDA asked the committee to vote on the lower dose because there was no evidence, based on the total score MCID of -4, that 75 mcg provided a benefit. As for the 150 mcg dose, he said: “I really don’t believe that this is ready for prime time product labeling. It was two out of three trials, the two that showed, if you accept the cut-off of 4, a large, large variation in my opinion and an unacceptable level as of yet.”

By Sue Sutter

Arcapta Quality-Of-Life Benefit For Higher Dose Isn't Enough Given Efficacy Data

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