1. Artesunate Rectal Capsules For the initial management of acute malaria in patients who cannot take medication by mouth and for whom parenteral treatment is not available A marketing authorisation application by the World Health Organization, submitted simultaneously to the FDA, MCA, and Swissmedic

2. Rectal Artesunate: Evaluation by Swissmedic Application History –Submission received –Discussion in Swiss „Advisory Committee“ –First comment sent to WHO –Additional material received „rolling review“ –Advice from external experts in tropical medicine obtained –Additional discussions with WHO 25.04. 00 07.11. 00 20.12. 00 22.03./02.08/ 24.09. 01/ 24.06.02 Dec 00/ Dec 01 / Jan 02 last: 10.12.01

3. Main Issues after Clinical Evaluation The Basics: To obtain approval a drug must provide more benefit than harm when used –as intended? –in real world! Some extrapolation always necessary based on recent experience

4. Normal cascade Benefit-risk in clinical trial situation Benefit-risk in intended use Benefit-risk in actual use Extrapolation to target population Experience on difference of intended vs. actual use

5. Usual Situation: Clinical Trial Intended Use Actual Use Clinical trial population and administration circumstances not too different from i.use Quite good experience on the unlabeled use to be expected (depending on drug up to appr. 50%), in most cases indications near labeled use

6. Rectal artesunate: Studies 5,6,7 Intended Use Actual Use Clinical trial population and administration circumstances very different from intended use Very little experience on the unlabeled use to be expected

7. Rectal artesunate: Studies 5,6,7 I.Use A.Use Clinical trial population and administration circumstances very different from i.use Very little experience on the unlabeled use to be expected In addition bioequivalence between galenical formulation F2 and F3 is not shown Formulation F2 Formulation F3

8. Rectal artesunate: Studies 5,6,7 Intended Use Actual Use Study 13 Clinical trial population and administration circumstances very different from i.use Very little experience on the unlabeled use to be expected

9. Rectal artesunate: Studies 5,6,7 Intended Use Actual Use Study 13 Formulation F2 Formulation F3 Bioequivalence would no longer be an issue

10. Rectal Artesunate: Study 13 Placebo controlled, randomised, double blind projected enrollment 10‘000 of ~ target population Clear efficacy related endpoints To be halted by Independent Monitoring Committee if „proof beyond reasonable doubt“ that Rectal Artesunate is indicated or contraindicated

11. Study 13 Still ongoing, blinded. What do we know already? 120 day safety update: – 3366 patients enrolled as of March 2002 – 56% aged below 12 months – 74% P. falciparum positive smears – 11.6% unconscious, 22.8% with convulsions – 99 = 2.9% (4% children, 1% adults) died – at least 4 cases of bacterial meningitis

12. Study 13 –The Monitoring Committee did not stop the trial after 3366 patients What can we conclude? –Is the advantage of using rectal artesunate as important as results of studies 5,6, 7 and others would suggest? –Is the inappropriate (and possibly counter-productive) use - even in this trial - so widespread that a possible beneficial effect of artesunate is diluted? –If use in young children - 56% patients aged below 12 months - is so high even in a trial, is there any point in restricting treatment to those aged 12 months and over?

13. Rectal artesunate Current considerations of Swissmedic: –No major concerns about toxicity if used as intended –Bioequivalence of Clin. Trial Formulation and Market Formulation not shown (but may be less important)

14. Rectal artesunate Current considerations of Swissmedic: –Concerns about benefit risk relation in actual use see also FDA-Briefing material: „Patients in the field might get a false sense of security after rectal treatment and fail to present for definitive therapy The diagnosis of malaria was confirmed in study patients. This would not be the case in the bush where malaria might be confused with meningitis, typhoid fever and a host of other febrile illnesses“

15. Rectal artesunate Would it not be wiser to wait for the results of study 13 before taking a decision?