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Methods for evaluating allergic rhinitis medications
Guest editorial
Methods for evaluating allergic rhinitis medications In the design of a clinical trial the initial 2 steps in planning are defining the study goals and the methods to be used in attaining them. The goals that should receive specific attention in the evaluation of allergic rhinitis medications have been addressed by both the Food and Drug Administration Center for Drug Evaluation and Research (CDER)1 and the Allergic Rhinitis and Its Impact on Asthma (ARIA) Committee of the European Academy of Allergy and Clinical Immunology.2 The CDER guidance points out the “paramount” importance of placebo control in the performance of allergic rhinitis studies. This is because of the subjective nature of the assessments and spontaneous disease variability. However, a positive-control study may be sufficient when seeking to demonstrate drug superiority over an approved active control. Other recommendations exist, such as the minimal duration of the study and steps that enhance allergen exposure and the verification of adequate exposure and study medication compliance. The CDER specifically addresses data analysis issues and encourages frequent data analysis, thus providing information on the timing of maximal effect (when the primary efficacy end point demonstrates the greatest numerical difference from placebo in change from baseline). Further, they point out the importance of determining the onset of action and the duration of effect as measured by instantaneous symptom scores at the end of dosing schedules. The document selects 3 study designs that have been used to determine onset of study drug action: standard phase 3 allergic rhinitis trials, single-dose parallel group, placebo-controlled park setting study, and inhalation chamber study, commonly called an Environmental Exposure Unit study. The ARIA committee has recommended that an internationally accepted, valid definition of the specific properties of medications used in the treatment of allergic rhinitis be developed. Further they suggest that end points that best attest to those properties be incorporated into clinical trial design guidelines. It is apparent that no single study can accomplish these goals and that multiple approaches will be required. The CDER guidance described herein was issued in April 2000 for comment purposes only, whereas the ARIA proposal was published in 2003. It is useful to combine the information from these 2 publications to evaluate past and current methods used in the performance of allergic rhinitis clinical trials.
VOLUME 96, FEBRUARY, 2006
With the growing interest in the methods used to study medications for allergic rhinitis, a well-documented review of these methods is a must. This issue of the Annals provides for the readership an excellent historical review of clinical research methods used in the evaluation of allergic rhinitis treatments. This article also describes the strengths and weaknesses of the different study methods. The article by Day and colleagues3 goes into thoughtful detail, often viewed as too long for journal publication. To their credit, the editors of this journal grasp the importance of the exceptionally documented review provided by this article to allergist and trainees in the field of allergy. Some might say tell me what time it is, don’t build me a clock. The authors of this article built a clock that tells perfect time, past and present. The future of clinical trials will require sponsors, such as pharmaceutical companies, to broaden their outcome requirements to demonstrate not just equality but superiority outcomes. In a more thorough manner than has been done before, these will need to include quality of life, side effect profile, and especially economic superiority as the federal government increases its financial responsibilities for cost of patient medications. It becomes apparent that the superior not comparable medication will be selected for coverage. This alone may further enhance medical outcomes. PHILIP KORENBLAT, MD Washington University School of Medicine in St Louis St Louis, Missouri REFERENCES 1. US Department of Health and Human Services, Food and Drug Administration, and Center for Drug Evaluation and Research (CDER). FDA Draft Guidance for Industry-Allergic Rhinitis: Clinical Development Programs for Drug Products. Washington, DC: Center for Drug Evaluation and Research; April 2000. 2. Bousquet J, Van Cauwenberge, Bachert C, et al. Requirements for medications commonly used in the treatment of allergic rhinitis: European Academy of Allergy and Clinical Immunology (EAACI), Allergic Rhinitis and its Impact on Asthma (ARIA). Allergy. 2003;58:192–197. 3. Day JH, Ellis AK, Rafeiro E, Ratz JD, Briscoe MP. Experimental models for the evaluation of treatment of allergic rhinitis. Ann Allergy Asthma Immunol. 2006;96:263–278.
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Methods for evaluating allergic rhinitis medications In the design of a clinical trial the initial 2 steps in planning are defining the study goals and the methods to be used in attaining them. The goals that should receive specific attention in the evaluation of allergic rhinitis medications have been addressed by both the Food and Drug Administration Center for Drug Evaluation and Research (CDER)1 and the Allergic Rhinitis and Its Impact on Asthma (ARIA) Committee of the European Academy of Allergy and Clinical Immunology.2 The CDER guidance points out the “paramount” importance of placebo control in the performance of allergic rhinitis studies. This is because of the subjective nature of the assessments and spontaneous disease variability. However, a positive-control study may be sufficient when seeking to demonstrate drug superiority over an approved active control. Other recommendations exist, such as the minimal duration of the study and steps that enhance allergen exposure and the verification of adequate exposure and study medication compliance. The CDER specifically addresses data analysis issues and encourages frequent data analysis, thus providing information on the timing of maximal effect (when the primary efficacy end point demonstrates the greatest numerical difference from placebo in change from baseline). Further, they point out the importance of determining the onset of action and the duration of effect as measured by instantaneous symptom scores at the end of dosing schedules. The document selects 3 study designs that have been used to determine onset of study drug action: standard phase 3 allergic rhinitis trials, single-dose parallel group, placebo-controlled park setting study, and inhalation chamber study, commonly called an Environmental Exposure Unit study. The ARIA committee has recommended that an internationally accepted, valid definition of the specific properties of medications used in the treatment of allergic rhinitis be developed. Further they suggest that end points that best attest to those properties be incorporated into clinical trial design guidelines. It is apparent that no single study can accomplish these goals and that multiple approaches will be required. The CDER guidance described herein was issued in April 2000 for comment purposes only, whereas the ARIA proposal was published in 2003. It is useful to combine the information from these 2 publications to evaluate past and current methods used in the performance of allergic rhinitis clinical trials.
VOLUME 96, FEBRUARY, 2006
With the growing interest in the methods used to study medications for allergic rhinitis, a well-documented review of these methods is a must. This issue of the Annals provides for the readership an excellent historical review of clinical research methods used in the evaluation of allergic rhinitis treatments. This article also describes the strengths and weaknesses of the different study methods. The article by Day and colleagues3 goes into thoughtful detail, often viewed as too long for journal publication. To their credit, the editors of this journal grasp the importance of the exceptionally documented review provided by this article to allergist and trainees in the field of allergy. Some might say tell me what time it is, don’t build me a clock. The authors of this article built a clock that tells perfect time, past and present. The future of clinical trials will require sponsors, such as pharmaceutical companies, to broaden their outcome requirements to demonstrate not just equality but superiority outcomes. In a more thorough manner than has been done before, these will need to include quality of life, side effect profile, and especially economic superiority as the federal government increases its financial responsibilities for cost of patient medications. It becomes apparent that the superior not comparable medication will be selected for coverage. This alone may further enhance medical outcomes. PHILIP KORENBLAT, MD Washington University School of Medicine in St Louis St Louis, Missouri REFERENCES 1. US Department of Health and Human Services, Food and Drug Administration, and Center for Drug Evaluation and Research (CDER). FDA Draft Guidance for Industry-Allergic Rhinitis: Clinical Development Programs for Drug Products. Washington, DC: Center for Drug Evaluation and Research; April 2000. 2. Bousquet J, Van Cauwenberge, Bachert C, et al. Requirements for medications commonly used in the treatment of allergic rhinitis: European Academy of Allergy and Clinical Immunology (EAACI), Allergic Rhinitis and its Impact on Asthma (ARIA). Allergy. 2003;58:192–197. 3. Day JH, Ellis AK, Rafeiro E, Ratz JD, Briscoe MP. Experimental models for the evaluation of treatment of allergic rhinitis. Ann Allergy Asthma Immunol. 2006;96:263–278.
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