March 16, 2011

Letter to FDA on Indacaterol Maleate (Arcapta Neohaler)

July 31, 2012 FDA Response to our Letter on Indacaterol Trials (PDF)

Janet Woodcock, M.D.
Director
Center for Drug Evaluation and Research
Food and Drug Administration
Department of Health and Human Services
WO51/Room 6133
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002

Dear Dr. Woodcock:

These comments from the Public Citizen Health Research Group are being submitted in follow-up to our testimony presented at the March 8, 2011 meeting of the Food and Drug Administration (FDA) Pulmonary-Allergy Drugs Advisory Committee (PADAC) regarding the drug indacaterol maleate (Arcapta™ Neohaler™).

(1) We urge FDA to (a) reject the March 8 PADAC recommendation to approve indacaterol at a dose of 75 mcg daily, and (b) not approve the New Drug Application for indacaterol – even at the 75 mcg dose – because the lowest dose that provides the desired efficacy at the lowest possible risk in the chronic obstructive pulmonary disease (COPD) population has not been determined.

(2) Further long-term, placebo-controlled, phase 3 studies of indacaterol, in which placebo-control subjects with moderate to severe COPD are randomized to groups that receives substandard (placebo) care for prolonged periods of time, must not be conducted.

FDA Should not Approve Indacaterol, Even at the 75 mcg Dose

Prior FDA Review of Indacaterol

The FDA did not approve Novartis’s original application for use of indacaterol at doses of 150 and 300 mcg for COPD because of clinical deficiencies. In particular, the agency concluded that the data submitted did not show meaningful efficacy differences between the proposed doses and a lower dose of 75 mcg, and was concerned about higher frequencies of serious adverse events compared to control subjects in COPD and asthma subjects treated with indacaterol.[1]

The new data submitted by the sponsor and discussed at the March 8 PADAC meeting document the same concerns regarding a possible unfavorable risk:benefit relationship of indacaterol, even at the proposed 75 mcg dose.

Benefit Assessment

For study B2356, a key short-term dose-ranging study in subjects with moderate to severe COPD, the trough FEV1-difference from placebo was identical at the 37.5 and 75 mcg doses (see figure 5-11 below excerpted from Novartis briefing document).[2]

 

Also, peak FEV1-difference from placebo in the first 4 hours post the morning dose on day 14 in study B2356 showed no statistically significant differences between the 37.5 and 75 mcg doses (see figure 5-13 below excerpted from Novartis briefing document).[3]

The FDA review noted the following regarding the comparison of the 75 and 150 mcg doses of indacaterol:

On cross study comparison, which has limitations, the bronchodilatory effect sizes do not show a clear efficacy advantage of the 150 mcg dose over the 75 mcg dose.[4]

The FDA statistical reviewer also noted the following regarding data comparing different doses of indacaterol in COPD patients:

[In] study B2356….The dose of 150 mcg appeared to achieve its maximum bronchodilation effect more rapidly than the other doses, but lost its advantage after two weeks of treatment. Considering indacaterol is proposed to be used as a long term maintenance bronchodilator treatment, the 150 mcg dose’s rapid effect in day 1 may not be important, especially balancing with safety concerns on higher dose. From the week 2 data, it appears indacaterol 37.5 mcg, 75 mcg, and 150 mcg once daily worked equally well in terms of bronchodilatory effect.[5] [emphasis added]

At this time there is no evidence of any efficacy advantage of the 75 mcg dose over the 37.5 mcg dose, or any dose in between. Thus, the lowest effective dose of indacaterol in patients with moderate to severe COPD has not been established.

Risk Assessment

The phase 3 COPD studies testing indacaterol were not sufficiently powered to detect serious adverse events that may have major adverse public health consequences if the drug is prescribed to millions of COPD patients over many years. Therefore, significant weight must be given to any signal suggesting safety concerns, particularly since indacaterol is not a breakthrough drug and offers no clinically significant advantages over available FDA-approved long-acting bronchodilators.

Such an adverse safety signal has been identified in the FDA’s analysis of data from the sponsor’s blinded adjudicated analysis comparing indacaterol-treated patients to controls with respect to respiratory-related death, hospitalization, and intubation in all blinded, randomized, controlled trials of 7 or more days of treatment in both asthma and COPD subjects. The FDA medical officer noted the following regarding this data:      

Although the magnitude of the signal is not large, there does appear to be a numerical trend of increasing incidence of acute respiratory-related events, particularly those that were adjudicated as having been COPD-related, as the dose of indacaterol rises from 75 mcg to 300 mcg. This increase…is driven primarily by an increase in acute-respiratory related hospitalizations….The possibility that such a signal may exist in COPD rather than asthma further underscores the importance of selecting the lowest effective dose of a beta-agonist bronchodilator.[6] [emphasis added]

The dose versus toxicity-response curve for indacaterol is not yet well-defined, but from a public health standpoint, it is reasonable to assume a 37.5 mcg dose will have a lower probability of serious toxicity than a 75 mcg dose.

One supplementary trial submitted to FDA (study B2341) also revealed concerning adverse safety signals. This study, which randomized 1134 subjects with moderate to severe COPD to indacaterol plus tiotropium or placebo plus tiotropium (an ethically designed study), revealed the following:

The most frequent adverse event was cough, which occurred more frequently in the combination group (10.4% versus 3.7%)…Likewise, discontinuations due to AEs occurred more frequently in the combination group, with 21 (3.7%) versus 9 (1.6%). There were two on-treatment deaths in the trial, both in the combination group. Cause of death was anaphylaxis 30 minutes after receiving ceftriaxone for a COPD exacerbation and myocardial infarction.[7]

This data is consistent with results of a prior meta-analysis by Salpeter et al which showed that inhaled anticholinergics significantly reduced severe exacerbations and respiratory deaths in patients with COPD, whereas β-agonists were associated with increased risk of respiratory deaths.[8]

Concerns about Indacaterol Use in Patients with Asthma

As the FDA is well aware, once approved for the proposed use in COPD patients, indacaterol will be used off-label in asthmatics. Inhaled long-acting β-agonists (LABAs) have been linked to severe asthma exacerbations and asthma-related deaths.[9] In discussing the safety concerns identified in studies of indacaterol in asthmatic patients, the FDA review noted that:

The two deaths in patients with asthma while receiving indacaterol with background of concurrent ICS treatment is concerning. The deaths are reminiscent of asthma-related deaths seen with other LABAs…. The possible imbalance of SAEs related to asthma exacerbation further supports the safety concerns for indacaterol.[10]

Recommendations

In the interests of protecting the public health, the FDA should reject the recommendation of the PADAC to approve indacaterol at the 75 mcg dose and not approve indacaterol at any dose because:

(1) There is no evidence of any efficacy advantage of the 75 mcg dose over the 37.5 mcg dose, or any dose in between. Thus, the lowest effective dose of indacaterol in patients with moderate to severe COPD has not been established

(2) The available data from the studies on indacaterol fail to provide sufficient information to determine whether indacaterol is safe in the intended COPD patient population, even for the 75 mcg dose. The dose versus toxicity-response curve for indacaterol is not yet well-defined, but from a public health standpoint, a 37.5 mcg dose likely will have a lower probability of serious toxicity than the 75 mcg dose.

(3) Indacaterol offers no clinically significant advantages over available FDA-approved long-acting bronchodilators.

(4) Once approved, the drug will certainly be used off-label in asthmatics, who would be placed at increased risk of serious adverse events, including death, from indacaterol, as has been seen with other LABAs. 

Further Long-Term, Placebo-Controlled Trials Testing Indacaterol Must not be Permitted

Standard Treatment for Moderate to Severe COPD

Moderate to severe COPD is a serious, life-threatening illness for which regular use of one or more bronchodilators has been the mainstay of treatment. Since at least 2005, the Global Initiative for Chronic Obstructive Lung Disease, a well-recognized authoritative source for COPD management, has had guidelines stating that “regular treatment with one or more long-acting bronchodilators,” supplemented with a short-acting β-agonists when needed for acute symptoms and daily inhaled corticosteroids for patients who have frequent exacerbations, should be used to treat moderate to severe COPD.[11]

Six Unethical Studies in Which Placebo-Control Subjects Received Prolonged Substandard Care

Despite sponsor and investigator awareness of these standard COPD treatment guidelines,[12],[13] Novartis conducted at least 6 pivotal long-term phase 3, placebo-controlled studies (B2335[14], B2334[15], B2346[16], B2336[17], B2354[18], and B2355[19]) in subjects with moderate to very severe COPD, apparently with the endorsement of the FDA.

These studies were unethical primarily because a total of more than 1700 subjects with a serious, life-threatening disease were assigned to placebo groups that received substandard care for prolonged periods of time ranging from 3 to 12 months. In particular, while placebo subjects were permitted to use daily inhaled steroids and short-acting β-agonists for rescue use, they were not permitted to use any LABAs or short- or long-acting inhaled anticholinergics.

Furthermore, based on available data at the time of study initiation, there appeared to be no reasonable state of uncertainty on the part of the investigators regarding the comparative merits of the indacaterol – or the active FDA-approved long-acting bronchodilators used in three of the long term trials – and placebo. As a result, these studies, particularly the most recent ones and the three that used FDA-approved active comparators, lacked equipoise and were therefore unethical.[20]

As the sponsor stated in its briefing document, “[o]ptimizing bronchodilation is essential to the management of COPD” [21] [emphasis added]. Not surprisingly, administration of placebo in place of long-acting bronchodilators clearly did not optimize bronchodilation.

Predictably, in all 6 studies, placebo subjects had worse COPD management based on multiple outcome measures than indacaterol subjects or subjects treated with an FDA-approved active comparator. In addition, an analysis of these studies reveals a trend toward an increased death rate in the placebo subjects (0.64%) versus subjects in all active treatment groups combined (0.21%). An analysis by Novartis of subject deaths for the entire COPD safety population and related control subjects showed a similar trend toward an increased death rate in placebo subjects.[22] Among the causes of the 14 placebo-subject deaths noted by Novartis were cardiac arrest, cardio-respiratory arrest, COPD, multiorgan failure, and myocardial infarction. It is highly plausible that substandard care leading to respiratory failure, hypoxemia, and/or respiratory acidosis contributed to the death of some placebo subjects.

The scientific question of whether indacaterol was better than placebo for treating moderate to severe COPD was not an important or clinically useful question, given the existing state of knowledge about COPD treatment at the time these studies were conducted. Rather, the important question is whether indacaterol is at least as good as currently available bronchodilator therapy.

Recommendations

Further long-term placebo-controlled trials, involving the withholding of standard bronchodilator therapy, must not be conducted in subjects with moderate to severe COPD. Any ongoing such studies should be terminated immediately.

Thank you for taking our comments into account.

Sincerely,

Michael A. Carome, M.D.
Deputy Director

Sidney M. Wolfe, M.D.
Director
Health Research Group

cc: Dr. Margaret A. Hamburg, Commissioner, FDA
Dr. Badrul A. Chowdhury, Director, Division of Pulmonary, Allergy, and Rheumatology Products, Center for Drug Research and Development, FDA

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