Artesunate Rectal Capsules

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
Extrapolation to target population
Benefit-risk in intended use
Experience on difference of intended vs. actual
use

• Benefit-risk in actual use

5
Usual Situation
Clinical Trial
IntendedUse
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
Actual Use
Studies 5,6,7
Intended 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
A.Use
Studies 5,6,7
Formulation F3
I.Use
Formulation F3
Formulation F2
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
8
Rectal artesunate
Actual Use
Studies 5,6,7
IntendedUse
9
Rectal artesunate
Actual Use
Studies 5,6,7
Study 13
IntendedUse
Formulation F3
Formulation F3
Formulation F2
Formulation F3
Bioequivalence would no longer be an issue
10
Rectal Artesunate Study 13

• Placebo controlled, randomised, double blind
• projected enrollment 10000 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?