18 July, 2002
The Cardio-Renal Advisory Committee is asked to opine on the relative antihypertensive efficacy of an antihypertensive regimen containing candesartan compared withand a regimen containing losartan at a dose of 100 mg per day. Specific guidance is sought on the adequacy of the current program to support a claim of superior efficacy for candesartan when compared with losartan, as well as guidance on how to describe any relevant differences in labellinglabeling. Specific guidance is also sought and on the adequacy of the advice that we have given sponsors, intended to guide future development programs. There is little published experience or relevant guidance, but this issue is briefly addressed in ICH guidance E-10 (Choice of Control Groups and Related Issues in Clinical Trials).
In the past, the Agency has told sponsors that demonstrating superiority to another antihypertensive medication on blood pressure lowering, when both were appropriately dosed, was a relevant clinical benefit, and that such a claim required the following data:
1) Evaluation of the antihypertensive effects of the respective drugs at the highest approved doses. If the comparison was not done with the approved product, bioequivalence of the study formulation and the approved product must be demonstrated. If the comparison is not done with the approved product, bioequivalence of the study formulation and the approved product must be demonstrated. Our recommendation has been that this evaluation should include at least two forced-titration trials to adequately assess the drug’s relative antihypertensive effects. We have also said that, unless a placebo group is included in the trials, no information about absolute antihypertensive efficacy can be inferred; , only comparative antihypertensive effect.
2) Data comparing the safety of the two agents, providing evidence that they do not significantly differ with regard to adverse effects not captured by changes in blood pressure.the 'superior' agent is not inferior with respect to safety.
The present sponsor has provided data from three randomized trials, including two forced-titration trials. These were conducted comparing candesartan force-titrated to a dose of 32 mg per day and losartan force-titrated to a dose of 100 mg per day. The Agency and the sponsor have agreement with regard toagree on the numerical results of the efficacy analyses for the three trials. OverallAt the end of 8 weeks, candesartan 32 mg reduced diastolic BPblood pressure by around 3/32 mmHg more at trough than did losartan 100 mg, when both were given once per day.
Do you recommend approval of candesartan for superior antihypertensive efficacy when compared with losartan? If so, how should the findings of these trials be included in the approved labeling…
- Regarding the candesartan development program:
- The sponsor compared once per day dosing for both products, although the labeling for both includes the possibility that twice per day dosing may be more effective.
- Did the program compare the highest labeled dose of candesartan with the highest labeled dose of losartan?
- There was no significant change in mean BP when patients were titrated from 16 to 32 mg of candesartan and from 50 to 100 mg of losartan.
- How do you explain this?
- Is this observation relevant for the relative efficacy of these two products?
- There was no significant change in blood pressure when patients in either treatment group were titrated from the starting dose to the target dose.
- How do you explain this?
- Is this observation relevant to the superiority claim? <What are you expecting the Cmte to say?>
Regarding relative antihypertensive efficacy, compare the benefits of being ‘superior’ in lowering BP compared with another approved antihypertensive drug to lowering BP compared with placebo:
- More beneficial than lowering BP to an equal degree with compared with placebo.
- Equal to being superior in lowering BP to an equal degree when compared with placebo.
- Less beneficial than lowering BP to an equal degree when compared with placebo.
- Overall, candesartan reduced diastolic BP by around 3 mm Hg at the trough measurement relative to losaratan in the two forced-titration studies. Are these differences in BP lowering reported in these trials for candesartan and losartan clinically meaningful?
- Which of the following are necessary or sufficient to establish a claim of relative superiority for an antihypertensive? The response for each question need not be mutually exclusive.
- Diastolic pressure at trough?
- Systolic pressure at trough?
- Diastolic pressure throughout the dosing interval?
- Systolic pressure throughout the dosing interval?
- 24-hour mean ABPM?
- Other measures of effectiveness?
- The sponsor compared once-daily dosing for both products, although both products are labeled for once- or twice-daily dosing. Is a once-daily comparison a legitimate basis for a superiority claim?
- Which of the following are necessary or sufficient to establish a claim of relative superiority for a once-daily antihypertensive?
- Beating the comparator's highest approved once-daily dose?
- Beating the comparator's most effective approved regimen?
- Beating the comparator when it is dosed to its maximum effect, perhaps outside the approved dose range?
- Beating the comparator when used with other approved agents [(e.g., diuretics, beta blockers])?
- Beating the comparator in special populations (e.g., blacks, elderly)?
- Is it possible to claim superiority if…
- … the comparator has other outcome benefits not demonstrated by the test drug …
- O… on clinical endpoints in hypertensive patients (e.g., stroke reduction)?
- … iIn other populations (e.g., (e.g., heart failure, post-MImyocardial infarction, diabetic nephropathy)?
- … the comparator has fewer potential pharmacokinetic interactions such as CYP 2D6 or CYP 3A4 inhibition?
- In most cases, comparative data have not revealed differences between pharmacologically similar drugs. Should wethe Division encourage more comparative studies? Can the estimate of effect versus placebo be made?
- Overall, candesartan reduced diastolic BP by around 2 mmHg more at trough than did losartan, an amounteffect size that would be sufficient for approval whenif a drug were compared with placebo.
- Is this difference clinically meaningful for a comparison between two antihypertensives?
- What comparative safety data would be necessaryAre the comparative safety data submitted by the sponsor sufficient to show that the expected reduction in cardiovascular risk would not be offset by other risks of candesartan?
- Would your answer regarding the need for comparative safety data be different if the two drugs were from different drug classes (e.g., calcium-channel blocker and diuretic)?
- Is the comparison between candesartan and losartan fair, as defined by ICH E-10?
The sponsor has summarized the available safety data from the submitted trials in your briefing book. Consider the importance of relative safety in assessing superiority claims for antihypertensives with extensive post-marketing safety databases.
- Are the submitted data adequate to compare the safety of losartan and candesartan?
- If not, what additional information is needed?
- Would your answer change if the comparator was from a different drug class (e.g., calcium-channel blocker)?
- If so, are there safety concerns that undermine or enhance the relative risk/benefit ratio for candesartan when compared with losartan?
Do you recommend approval of candesartan as having demonstrated superior antihypertensive efficacy when compared with losartan?
7.1. of candesartan?
7.2. of losartan?
7.3. oOf combination products containing candestartan or losartan?
The advice given to sponsors seeking to assess relative antihypertensive efficacy is summarized above.
- If so, how should the findings of these trials be included in the approved labeling:
- For Candesartan?
- How should the potential use of losartan 50 mg BID be reflected in the label?
- For Losartan?
- How should the relative antihypertensive effect of two drugs be made: trough DBP, 24-hour ABPM, other method?
- Are there additional requirements you would recommend?