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More information on indacaterol maleate (Arcapta Neohaler)

More Information on Ethics and Clinical Trials

Letter to OHRP on Unethical Trials of Indacaterol Maleate (Arcapta Neohaler)

March 16, 2011

Jerry Menikoff, M.D., J.D.
Director
Office for Human Research Protections
Department of Health and Human Services
1101 Wootton Parkway
Suite 200
Rockville, MD 20852

Kristina Borror, Ph.D.
Director, Division of Compliance Oversight
Office for Human Research Protections
Department of Health and Human Services
1101 Wootton Parkway
Suite 200
Rockville, MD 20852

Dear Drs. Menikoff and Borror:

We hereby request that the Office for Human Research Protections (OHRP) conduct a compliance oversight evaluation of the following research studies for any U.S. institution that was engaged in the research and held an applicable Federalwide Assurance at the time the research was conducted:

(1) 26 week efficacy, safety and tolerability study of indacaterol in patients with chronic obstructive pulmonary disease (COPD); sponsor: Novartis; ClinicalTrials.gov identifier: NCT00463567; Novartis study number: B2335;[1],[2]

(2) Efficacy and safety of indacaterol in patients with COPD; sponsor: Novartis; ClinicalTrials.gov identifier: NCT00624286; Novartis study number: B2346;[3],[4]

(3) 12-week efficacy of indacaterol; sponsor: Novartis; ClinicalTrials.gov identifier NCT01072448; Novartis study number: B2354;[5] and

(4) Comparison of efficacy of indacaterol versus placebo over 12 weeks; sponsor; Novartis; ClinicalTrials.gov identifier: NCT01068600; Novartis study number: B2355.[6]

We allege that each of the above-referenced studies, as conducted, was unethical and failed to satisfy the following requirements of the Department of Health and Human Services regulations at 45 CFR part 46:

(1) 45 CFR 46.111(a)(1): The research as conducted failed to minimize risks to subjects because study design was unsound and unnecessarily exposed subjects to risk. In particular, in each study large numbers of placebo-control subjects with moderate to severe COPD were randomized to a study group that received substandard (placebo) care for up to 3 to 6 months.

(2) 45 CFR 46.116(a)(1) and (2): It is likely that the IRB-approved informed consent process and document failed to adequately describe the procedures involved in the research and reasonably foreseeable risks and discomforts to the subjects with respect to the placebo-control group subjects.

The following discussion provides a detailed overview of the rationale for our allegations.

Failure to Minimize Risks to Subjects

Standard Treatment for Moderate to Severe COPD

Moderate to severe COPD is a serious, life-threatening illness for which regular treatment with one or more long-acting bronchodilators, such as long-acting β-adrenergic agonists (LABAs)(e.g., salmeterol and formoterol) or long-acting anticholinergic agents (e.g., tiotropium), has been the mainstay of treatment for many years. 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.[7]

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

Despite sponsor and investigator awareness of these standard COPD treatment guidelines and the importance of optimizing bronchodilation in moderate to severe COPD[8],[9], the 6 pivotal, long-term, phase 3, placebo-controlled studies listed in the Table below were conducted in subjects with moderate to very severe COPD, apparently with the endorsement of the FDA (studies B2334 and B2336 were conducted entirely outside the U.S.).

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 (if already on such steroids at a stable dose at the time of study enrollment) and short-acting β-agonists for rescue use, they were not permitted to use any LABAs or short- or long-acting inhaled anticholinergics or to start inhaled corticosteroids.

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.[10]

As the sponsor stated in a briefing document recently submitted to the FDA, “[o]ptimizing bronchodilation is essential to the management of COPD” [11] [emphasis added]. Not surprisingly, administration of placebo in place of long-acting bronchodilators clearly did not optimize bronchodilation.

TABLE: Description of Long-Term Randomized, Placebo-Controlled Studies Testing Indacaterol

Study #

Dates of Enrollment

Active Treatment Intervention

# of Placebo Subjects

Duration

B2335[12]

April 07-August 08

Indacaterol 150 mcg (N=416)

Indacaterol 300 mcg (N=416)

Tiotropium 18 mcg (N=415)

418

6 months

B2334[13]

?-2008

Indacaterol 300 mcg (N=437)

Indacaterol 600 mcg (N=425)

Formoterol 12 mcg bid (N=434)

432

12 months

B2346[14]

?-2008

Indacaterol 150 mcg (N=211)

205

3 months

B2336[15]

Nov 2007-Jan 2009

Indacaterol 150 mcg (N=330)

Salmeterol 50 mcg (N=333)

335

6 months

B2354[16]

?-2010

Indacaterol 75 mcg (N=163

160

3 months

B2355[17]

?-2010

Indacaterol 75 mcg (N-159)

159

3 months


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.[18] 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.

Inadequate Informed Consent of Subjects

While adequate informed consent would not have been sufficient to make these studies ethical, it is likely that subjects were not informed that they had a 25 to 50% chance of being assigned a substandard treatment regimen for 3 or 6, and that they were almost certainly likely to experience more shortness of breath, more dyspnea on exertion, decreased exercise tolerance, more frequent COPD exacerbations, and an increased risk of death since they would not be receiving the usual standard medical care with regular use of long-acting bronchodilators. 

FDA Involvement

It is our understanding that OHRP routinely refers complaints about industry-sponsored clinical trials to FDA for review and action. In this case, it is clear that FDA has a conflict of interest and should not be asked to investigate our allegations because Novartis conducted these placebo-controlled trials with the full knowledge and endorsement of the FDA. Therefore, since FDA is complicit in this unethical research, we urge OHRP to take the lead in investigating our allegations. We acknowledge that OHRP may need FDA’s assistance in identifying the U.S. institutions that were engaged in each of the above-referenced studies since, except for study B2335, the citations on ClinicalTrials.gov do not provide the specific names of the research institutions enrolling subjects for each study.  

Please note that OHRP may share our complaint letter with identifiers with anyone. We will be posting a copy on our website as well.

We look forward to OHRP’s thorough and careful investigation of our allegations. Please contact us if you have any questions or need additional information.

Sincerely,

Michael A. Carome, M.D.
Deputy Director

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

Enclosures:

(1) ClinicalTrial.gov citations for studies NCT00463567, NCT00624286, NCT01072448, and NCT01068600.

(2) Donohue JF, Fogarty C, Lotvall J, et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med. 2010;182:155-162.

(3) Feldman G, Siler T, Prasad N, et al. Efficacy and safety of indacaterol 150 μg once-daily in COPD: a double-blind, randomized, 12-week study. BMC Pulm Med. 2010;10:11.

cc: Honorable Kathleen Sebelius, Secretary of Health and Human Services


[1] ClinicalTrials.gov citation for NCT00463567. http://clinicaltrials.gov/ct2/show/study/NCT00463567?term=b2335&rank=2&show_locs=Y#locn. Accessed March 14, 2011.

[2] Donohue JF, Fogarty C, Lotvall J, et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med. 2010;182:155-162.

[3] ClinicalTrials.gov citation for NCT00463567. http://clinicaltrials.gov/ct2/show/study/NCT00463567?term=b2335&rank=2&show_locs=Y#locn. Accessed March 14, 2011.

[4] Feldman G, Siler T, Prasad N, et al. Efficacy and safety of indacaterol 150 μg once-daily in COPD: a double-blind, randomized, 12-week study. BMC Pulm Med. 2010;10:11.

[5] ClinicalTrials.gov citation for NCT01072448. http://clinicaltrials.gov/ct2/show/study/NCT01072448?term=b2354&rank=1&show_locs=Y#locn. Accessed March 14, 2011.

[6] ClinicalTrials.gov citation for NCT01068600. http://clinicaltrials.gov/ct2/show/study/NCT01068600?term=b2355&rank=1&show_locs=Y#locn. Accessed March 14, 2011.

[7] Global Initiative for Chronic Obstructive Lung Disease.  Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease; 2005-2010 updates. Available at http://www.goldcopd.com/. Accessed March 4, 2011. 

[8] Novartis. Indacaterol (QAB149) in Chronic Obstructive Pulmonary Disease (NDA 22-383) Briefing Document. February 1, 2011. Web page 112. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM245639.pdf. Accessed March 4, 2011.

[9] Dahl R, Chung KF, Buhl R, et al. Efficacy of a new once-daily long-acting inhaled β2-agonist indacaterol versus twice-daily formeterol in COPD. Thorax. 2010;65:473-479.

[10] Freedman B. Equipoise and the ethics of clinical research. NEJM. 1987;317:141-145.

[11] Novartis. Indacaterol (QAB149) in Chronic Obstructive Pulmonary Disease (NDA 22-383) Briefing Document. February 1, 2011. Web page 14. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM245639.pdf. Accessed March 4, 2011.

[12] Donohue JF, Fogarty C, Lötvall J, et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med. 2010;182(2):155-62.

[13] Dahl R, Chung KF, Buhl R, et al. Efficacy of a new once-daily long-acting inhaled β2-agonist indacaterol versus twice-daily formeterol in COPD. Thorax. 2010;65:473-479.

[14] Feldman G, Siler T, Prasad N, et al. Efficacy and safety of indacaterol 150 microg once-daily in COPD: a double-blind, randomised, 12-week study. BMC Pulm Med. 2010;10:11.

[15] Kornmann O, Dahl R, Centanni S, et al. Once-daily indacaterol versus twice daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir J 2011; 37:273-279.

[16] Food and Drug Administration. Pulmonary-allergy drugs advisory committee briefing materials for March 8, 2011. Web pages 130-141. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM245637.pdf. Accessed March 4, 2011.

[17] Food and Drug Administration. Pulmonary-allergy drugs advisory committee briefing materials for March 8, 2011. Web pages 111-129. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM245637.pdf. Accessed March 4, 2011.

[18] Novartis. Indacaterol (QAB149) in Chronic Obstructive Pulmonary Disease (NDA 22-383) Briefing Document. February 1, 2011. Web page 82. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM245639.pdf. Accessed March 4, 2011.

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