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  1. 1. ATACAND ® (candesartan cilexetil) Cardiovascular and Renal Drugs Advisory Committee Bethesda, Maryland July 18, 2002 C
  2. 2. ATACAND ® Introduction and Regulatory Overview Cindy Lancaster, MS, MBA, JD Director, Regulatory Affairs AstraZeneca C
  3. 3. Agenda for Presentation <ul><li>Regulatory Overview Cindy Lancaster, MS, MBA, JD Director, Regulatory Affairs AstraZeneca </li></ul><ul><li>Comparison of Vasilios Papademetriou, MD, Antihypertensive Efficacy DSc, FACC of Candesartan Cilexetil Professor of Medicine and Losartan Georgetown University </li></ul><ul><li>Epidemiologic and Clinical William B. Kannel, MD, FACC Significance of Incremental Professor of Medicine and Changes in Blood Public Health Pressure Boston University School of Medicine </li></ul><ul><li>Summary Cindy Lancaster, MS, MBA, JD Director, Regulatory Affairs AstraZeneca </li></ul>
  4. 4. Consultant and Sponsor Representatives <ul><li>Consultant </li></ul><ul><li>Donald Vidt, MD, FACC </li></ul><ul><ul><li>Principal Investigator for Study 230 </li></ul></ul><ul><ul><li>Consultant, Department of Hypertension and Nephrology, The Cleveland Clinic Foundation </li></ul></ul><ul><ul><li>Professor of Medicine, Ohio State University </li></ul></ul><ul><li>AstraZeneca </li></ul><ul><li>Eric Michelson, MD, FACC </li></ul><ul><ul><li>Senior Director, Clinical Research </li></ul></ul><ul><li>Conrad Tou, PhD </li></ul><ul><ul><li>Associate Director, Biostatistics </li></ul></ul><ul><li>Jennifer Sugg, MS </li></ul><ul><ul><li>Senior Statistical Scientist </li></ul></ul><ul><li>Glenn Carlson, MD </li></ul><ul><ul><li>Senior Director, Medical </li></ul></ul>
  5. 5. Introduction <ul><li>ATACAND ® (candesartan cilexetil) </li></ul><ul><li>Selective AT 1 subtype angiotensin II receptor antagonist (ARB) </li></ul><ul><li>June 1998—Approved for the treatment of hypertension </li></ul><ul><li>Can be used alone or in combination with other antihypertensive agents </li></ul><ul><li>Usual recommended starting dose: 16 mg QD </li></ul>
  6. 6. Regulatory History Agency Interactions (1) <ul><li>Original NDA </li></ul><ul><li>Included 1 positive comparative study versus losartan, SH-AHM-0001 </li></ul><ul><ul><li>Randomized, double-blind, multicenter, placebo-controlled, parallel-group, 8-wk duration </li></ul></ul><ul><ul><li>Patients (N = 337) with a mean diastolic blood pressure of 95 to 114 mm Hg </li></ul></ul><ul><ul><li>Compared candesartan cilexetil 8 and 16 mg QD, losartan 50 mg QD, and placebo </li></ul></ul><ul><ul><li>The proposed labeling did not include comparator text versus losartan </li></ul></ul>
  7. 7. Regulatory History Agency Interactions (2) <ul><li>Study 175—positive results versus losartan </li></ul><ul><li>available in 1998 </li></ul><ul><li>Randomized, double-blind, multicenter, titration-to-effect, parallel-group, 8-wk duration </li></ul><ul><li>Patients (N = 332) with a mean diastolic blood pressure of 95 to 114 mm Hg </li></ul><ul><li>Initiated treatment with candesartan cilexetil 16 mg QD or losartan 50 mg QD </li></ul><ul><li>After 4 wk, patients with a mean sitting DBP ≥ 90 mm Hg were titrated to candesartan cilexetil 32 mg QD or losartan 100 mg QD </li></ul>
  8. 8. Regulatory History Agency Interactions (3) <ul><li>August 1998 meeting with the Agency </li></ul><ul><li>Discussed use of SH-AHM-0001 and Study 175 to support a comparator claim versus losartan for the treatment of hypertension </li></ul><ul><ul><li>SH-AHM-0001 </li></ul></ul><ul><ul><ul><li>A starting dose comparison does not provide a meaningful comparison because the starting dose is an arbitrary point and does not represent how the drugs perform over their dose ranges </li></ul></ul></ul><ul><ul><li>Study 175 </li></ul></ul><ul><ul><ul><li>It was not a forced-titration design. Only poor responders would be titrated to the highest dose of the drugs in a titration-to-effect study </li></ul></ul></ul>
  9. 9. Regulatory History Agency Interactions (4) <ul><li>Agency requirements to support comparator claim: </li></ul><ul><li>Establish bioequivalence of losartan and overencapsulated tablets used in blinding of comparator product </li></ul><ul><li>Study candesartan cilexetil and losartan at the maximum approved doses for the treatment of hypertension </li></ul><ul><li>Statistically significant results replicated in adequate and well-controlled trials </li></ul><ul><li>If once-daily dosing is studied, then the limitations should be clearly stated in promotional claims </li></ul><ul><li>Acceptable study designs: parallel dose-response or forced-titration </li></ul>
  10. 10. Description of Comparative Trials in Labeling <ul><li>Results of a specific dosing regimen of once-daily administration at the maximum approved dose from 2 clinical trials with hypertensive patients </li></ul><ul><li>Once-daily administration is an appropriate dosing regimen for candesartan cilexetil and losartan because: </li></ul><ul><ul><li>Both drugs are regularly prescribed for use once daily </li></ul></ul><ul><ul><li>Once-daily administration is the dosing regimen primarily used in on-going and completed studies </li></ul></ul><ul><li>Statistically greater blood pressure reduction was demonstrated with candesartan cilexetil compared with losartan at the maximum approved dose when administered once daily </li></ul><ul><li>The proposed labeling is specific to effects on blood pressure reduction </li></ul>
  11. 11. Labeling <ul><li>PROPOSED ADDITION TO CLINICAL PHARMACOLOGY, Clinical Trials subsection (for insertion after the first paragraph in this section): </li></ul><ul><li>“ Two identically designed, concurrently conducted, 8-week, multicenter, double-blind, randomized, forced-titration studies were performed to compare the antihypertensive efficacy of candesartan cilexetil and losartan at their once-daily maximum doses. Candesartan cilexetil initiated at 16 mg once daily and forced- titrated at 2 weeks to 32 mg once daily was statistically significantly more effective than losartan 50 mg once daily forced-titrated at 2 weeks to 100 mg once daily in reducing systolic and diastolic blood pressure at 8 weeks. In these studies, both agents were well tolerated.” </li></ul><ul><li>Currently approved labeling—INDICATIONS AND USAGE: </li></ul><ul><li>“ ATACAND is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.” </li></ul>
  12. 12. Regulatory Precedent <ul><li>Comparator Claim for ZESTRIL ® /Prinivil ® (lisinopril): </li></ul><ul><li>CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Hypertension   </li></ul><ul><li>“ . . . In controlled clinical studies, ZESTRIL 20-80 mg has been compared in patients with mild to moderate hypertension to hydrochlorothiazide 12.5-50 mg and with atenolol 50-200 mg; and in patients with moderate to severe hypertension to metoprolol 100-200 mg. It was superior to hydrochlorothiazide in effects on systolic and diastolic pressure in a population that was ¾ Caucasian. ZESTRIL was approximately equivalent to atenolol and metoprolol in effects on diastolic blood pressure, and had somewhat greater effects on systolic blood pressure.” </li></ul>
  13. 13. Labeling <ul><li>Proposed labeling is consistent with: </li></ul><ul><li>The general requirements of the content and format of labeling for human prescription drugs </li></ul><ul><li>Guidance during the design of the CLAIM program from the Division on how these studies should be described in labeling </li></ul><ul><li>Placement of comparator information in labeling of other antihypertensive products: </li></ul><ul><ul><li>ZESTRIL ® , COZAAR ® , ACCUPRIL ® , ALTACE ® , DIOVAN ® , TEVETEN ® </li></ul></ul><ul><li>AstraZeneca will continue to work with the Division to finalize labeling </li></ul>