0
Correspondence |

ResponseResponse FREE TO VIEW

Anthony G. Durmowicz, MD; Kimberly A. Witzmann, MD; Curtis J. Rosebraugh, MD; Badrul A. Chowdhury, MD, PhD
Author and Funding Information

From the Division of Pulmonary, Allergy, and Rheumatology Products (Drs Durmowicz, Witzmann, and Chowdhury), Office of New Drugs, and the Office of Drug Evaluation 2 (Dr Rosebraugh), Center for Drug Evaluation and Research, US Food and Drug Administration.

Correspondence to: Anthony Durmowicz, MD, US Food and Drug Administration, Division of Pulmonary, Allergy, and Rheumatology Products, White Oak Bldg 22, Room 3318, 10903 New Hampshire Ave, Silver Spring, MD 20993-0002; e-mail: anthony.durmowicz@fda.hhs.gov


Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The views expressed in this letter are those of the authors and do not necessarily reflect the views or policies of the US Food and Drug Administration.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(4):1418-1419. doi:10.1378/chest.13-1517
Text Size: A A A
Published online
To the Editor:

We thank Dr Heltshe and colleagues for their letter in response to our article to CHEST in which we noted the lack of correlation between a change in sweat chloride and improvement in FEV1 in individual patients with cystic fibrosis (CF) who received ivacaftor in phase 3 clinical trials.1 They suggest that this lack of correlation between changes in sweat chloride in the ivacaftor trials should not diminish the potential usefulness of sweat chloride for predicting clinical outcomes.

Regarding the usefulness of using change in sweat chloride as an end point, it should be pointed out that it was and continues to be used effectively by companies developing therapies that target the CF transmembrane conductance regulator gene or protein. For example, for the ivacaftor program, it was used to establish proof of principle of drug activity, as a pharmacodynamic biomarker to select and enrich CF patient study populations that may best respond to the drug, and, in association with change in FEV1, as a factor in dose selection.

The implicit issue in the correspondence appears to be the extent to which change in sweat chloride could be used as a primary end point to establish efficacy for regulatory purposes (ie, approval of a drug for marketing). Such qualification of a pharmacodynamic biomarker as a surrogate end point is a high bar to achieve, as robust scientific evidence would be needed that demonstrates that changes in sweat chloride beyond a specific level in a specific CF population would predict clinical benefit to the same extent that a clinical end point (an improvement in how a patient feels, functions, or survives) would.2 Because of such a high level of evidence required, most pharmacodynamic biomarkers are used, as has been the case to date for the ivacaftor program, to guide drug development, whereas clinical end points (or in the case for ivacaftor, the surrogate end point, FEV1) provide the basis for regulatory approval. With the arrival and continued development of a new class or classes of CF therapies that have the potential to address the central defect that results in CF, we, like the CF community, are happy that we have reached such a time that we can have a discussion on the use of change in sweat chloride or other possibly more accurate pharmacodynamic biomarkers that may reflect CF transmembrane conductance regulator function3 as end points in clinical trials.

References

Durmowicz AG, Witzmann KA, Rosebraugh CJ, Chowdhury BA. Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest. 2013;143(1):14-18. [CrossRef] [PubMed]
 
Draft Guidance for Industry: Qualification Process for Drug Development Tools. Silver Spring, MD: US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER); 2010.
 
Quinton P, Molyneux L, Ip W, et al. β-Adrenergic sweat secretion as a diagnostic test for cystic fibrosis. Am J Respir Crit Care Med. 2012;186(8):732-739. [CrossRef] [PubMed]
 

Figures

Tables

References

Durmowicz AG, Witzmann KA, Rosebraugh CJ, Chowdhury BA. Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest. 2013;143(1):14-18. [CrossRef] [PubMed]
 
Draft Guidance for Industry: Qualification Process for Drug Development Tools. Silver Spring, MD: US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER); 2010.
 
Quinton P, Molyneux L, Ip W, et al. β-Adrenergic sweat secretion as a diagnostic test for cystic fibrosis. Am J Respir Crit Care Med. 2012;186(8):732-739. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543