FDA AIDAC 7/10/021 NDA 21-242 Rectal Artesunate Integrated Safety Rosemary Johann-Liang, M.D....
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Transcript of FDA AIDAC 7/10/021 NDA 21-242 Rectal Artesunate Integrated Safety Rosemary Johann-Liang, M.D....
FDA AIDAC 7/10/02 1
NDA 21-242
Rectal Artesunate
Integrated Safety
Rosemary Johann-Liang, M.D.
Division of Special Pathogen and Immunological Drug Products
FDA AIDAC 7/10/02 2
Proposed Indication
“Single 10 mg/kg dose of artesunate rectal capsules
in the initial management of acute malaria in patients who cannot take medication by mouth and for whom parenteral treatment is not available”
FDA AIDAC 7/10/02 3
Implications of the Indication
• In the “field”• Empiric Therapy (other severe febrile
illnesses included)• Severe disease (unable to take PO)• Mainly very young children
FDA AIDAC 7/10/02 4
SAFETY SUBMISSIONS
• WHO-Sponsored Studies • Safety Review of published and unpublished
safety information on studies of Artemisinin Derivatives
• Summary of the data presented to the Chinese Authorities in 1989
• Neurotoxicity (WHO-sponsored consultation)
FDA AIDAC 7/10/02 5
WHO-sponsored Studies
FDA AIDAC 7/10/02 6
WHO-sponsored StudiesAll hospitalized patients
M alaysia, Thailand, Ghana, M alaw i, South Africa, Kenya, Brazil
2 Bioavailability2 Bioequivalency
3 "pivotal" clinical studies(2 pediatric, 1 adult)
3 publishedre-analysis studies
3 other clinical studies( 1 pediatric, 2 adult)
healthy volunteersn=66
childrenn=166 total, n=8 less than 2 years
m oderately severen=344
severe m alarian=91, n=5 from clinical
Safety Database: 13 study reportsn=501, n=435 w / m alaria, n=319 in clinical studies
FDA AIDAC 7/10/02 7
WHO-sponsored Studies: Clinical
Rectal Artesunate ComparatorAdults N=153 pts
148: Mod Severe Dz5: Severe Dz
N = 14 ptsAll: Severe DzAll: IV quinine
Children (<15 yrs)
N=166 ptsAll: Mod Severe Dz
N=8 for < 2 years old
N = 39 ptsAll: Mod Severe Dz17: PO Artesunate22: IV quinine
FDA AIDAC 7/10/02 8
WHO-sponsored Studies: AE
Children RectalArtesunate
Comparator(17 PO AS; 22 QN)
Overall AE 33 AE / 166 pts(20%)
10 AE / 39 pts(26%)
GI AE(nausea, vomiting,abdominal pain)
14 AE / 166 (8%) 5 AE / 39 (12%)
CNS AE(H/A, impairedconsciousness,convulsions)
10 AE / 166 (6%) 2 AE / 39 (5%)
FDA AIDAC 7/10/02 9
WHO-sponsored studies: Deaths
DHA level2 hrs: 2002 ng/m l (652+/-353.2)4 hrs: 977 ng/m l (396.8+/-545.2)
1 Pediatric Death3 y/o boy: 11.5 m g/kg x 1probable cause of death
W HO: "iatrogenic water intoxication"
3 Add. Deaths in P ivotal TrialsAll 3 w ith severe m alaria
1 death in AS; 2 IV quinine armW HO: Due to underlying m alarial dz
3 deaths in re-analysis studiespatients w ith severe m alaria
cause not determ inedall 3 had cleared their parasitem ia
In to ta l: 7 /501 (1 .4% )1/275 (.36% ) Modera te Severe D z
6/91 (6% ) Severe Ma la ria
FDA AIDAC 7/10/02 10
WHO-sponsored Studies: Labs
• Laboratory monitoring was limited. Only one clinical study had comprehensive labs recorded (CBC, Chem, LFTs)
• HCT ( n= 250) Overall, transient decrease at 12-24 hours with rise to baseline by day 7, to normal by day 28
• SGOT / SGPT (n= 48) Only monitored in 1 study. 3 patients with rise over 3X UL after normal baseline, peaking day 7-14, falling by day 21
• ECG (n=48) Only monitored in 1 study. No significant abnormalities noted
FDA AIDAC 7/10/02 11
WHO-sponsored studies : Dose
• PK and clinical studies: one rectal dose majority receiving 10 mg/kg (6.8 to 22.2 mg/kg)
• Re-analysis studies: repeated rectal dosing over 3-4 days with mean doses between 25-32 mg/kg total dose (11.3 to 45.7 mg/kg)
• Maximum dose exposure for Adults– 45.7 mg/kg total dose given over 4 days in 8 divided doses
• Maximum dose exposure for Children– 21.4 mg/kg with the longest duration of exposure of 7 days
(rectal dose x 1 followed by oral dosing: study 5)
FDA AIDAC 7/10/02 12
WHO-sponsored Studies: Special Populations
• < 2 years: only 8 of 166 children • > 50 years: only 6 of 153 adults with malaria• Renal & Hepatic impairment: not specifically studied• Pregnant: not included in studies
– preclinical: consistent findings of impaired fetal survival; no evidence of teratogenicity
– clinical from literature: no evidence of fetal injury or impairment of maternal health
FDA AIDAC 7/10/02 13
WHO-sponsored Studies: Safety Summary
• Very small safety database, all open-labeled • Studies mainly non-comparative• Safety assessment not available for special populations,
in particular very young children• Dose exposure: mainly 1 rectal dose at 10 mg/kg• Overall, no unusual or serious pattern of adverse
events; but minimal numbers for comparison• Overall, no unusual or serious laboratory abnormalities;
but monitoring was sparse• Deaths on study few but not all with clear etiology
FDA AIDAC 7/10/02 14
Safety Review of Published and Unpublished Clinical Studies on
Artemisinin Derivatives
FDA AIDAC 7/10/02 15
WHO- Safety Review: Types of Clinical Studies
Artem isinin Derivatives
Phase In=8
129 patients
N oncom parativen=33
4186 patients
C om parative, N Rn=11
1476 patients
C om parative, Rn=78
7848 patients
safety Inform ationn=130
13,639 patients
Clinical S tudiesn=169
151 pub; 18 unpub15,498 patients
FDA AIDAC 7/10/02 16
WHO-Safety Review: Disease Population
Artesunate N = 6158
56%
1%
15%
28%
uncompmoderatesevereother
ArtemisininsN = 13,520
20%
7%
0%
73%
uncompmoderatesevereother
FDA AIDAC 7/10/02 17
WHO-Safety Review: Adverse Events
Pooling of adverse events across studies: problem aticNo Raw data: Data not review ed by FDA
Safety Review states
Severe M alaria"Few er incidence of hypoglycem ia,skin reactions, tinnitus, d izziness
than quinine"
Uncom plicated m alaria"Less pruritis than chloroquine
Less nausea, d izziness, tinnitus than quinineLess vom iting than m efloquine"
Com parative Studiesm ost com m on AE (in the order of <1%)
to be m ild G I events(nausea, vom iting, d iarrhea, Abd pain)
FDA AIDAC 7/10/02 18
WHO-Safety Review: Laboratory and ECG Abnormalities
Laboratory abnormalities in the order of 1%• neutropenia• reticulocytopenia• eosinophilia• anemia• transaminitis• culture-negative pyuria• hemoglobinuriaFew cases of elevated bilirubin
ECG abnormalities in the order of 1%• bradycardia• prolongation of QT interval
Few cases of 1st degree AV block, atrial extra-systoles and T-wave abnormalities
FDA AIDAC 7/10/02 19
WHO-Safety Review: Neurological Assessments
• Majority: no neurological assessments • Dizziness most common
• *Price R et al. Adverse Effects in Patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Hyg. 1999:60; 547-55– Patients with uncomplicated malaria– “ Neurologic examination could be performed reliably only in
patients >5 years old”• Human Histopathology ( Hien et al 1999, artemether: n=6)
FDA AIDAC 7/10/02 20
WHO-Safety Review: reassurance
• comprehensive effort• relatively few side effects reported• lack of evidence: an association between
artemisinin derivatives and increased neurological AE/ sequelae (in people with malaria)
FDA AIDAC 7/10/02 21
WHO-Safety Review: problems
• Methodological deficiences– drug vs. disease effects– uncertainty of pooling AEs
#s for moderate/severe disease # for neurological assessment especially in young
children• No raw data for FDA to review• Not GMP: sub-potent content of active ingredient
Newton P et al. Fake Artesunate in Southeast Asia. Lancet 2001 Jun 16; 357 (9272):1904
FDA AIDAC 7/10/02 22
Artemisinin Neurotoxicity
Class effect: Artemisinin (QHS, qinghaosu), Artemether (AM),
Arteether (AE) , Dihydroartemisinin (DHA)
Symptomatic: apathy, unsteadiness, collapse, coma, deathNeuropathological: chromatolysis, unique pattern of neuronal necrosis in brainstem nuclei (vestibular, cochlear, olivary, red and others)
FDA AIDAC 7/10/02 23
Preclinical evidence: neurotoxicity margin of safety
• WHO-sponsored expert consultation: Conclusions about AS– Limited Information for AS– No neuronal necrosis at 420 mg/kg IM x 1 or 200 mg/kg/day
PO x 5-7d• WHO: Briefing Package regarding WHO-sponsored toxicology
– total 210-300 mg/kg via IV / PO– 21 to 30 fold greater than total proposed human dose
• FDA: BSA conversion to Human Equivalent Dose (HED)– 35-50 mg/kg (only 3-5 times)
FDA AIDAC 7/10/02 24
Preclinical evidence: margin of safety
BSA conversionof Rat 45-75 m g/kg
HED: 7.5 - 12.5 m g/kg IM
NOAELrat: 45-75 m g/kg IM x 1 or over 7d
dog: 3 - 6.25 m g/kg/day x 7dm onkeys: 100 m g/kg IM x 1 or over 7d
1998 W HO sponsoredexpert review of path m aterial
all available info. for AM, AE
BSA conversionof Rat 75 or 150 m g/kg
HED: 12 and 25 m g/kg PO
Not specific Neurotox studyUnexplained rat deaths
1/16 rat on day 4: 75m g/kg 2/16 rat on day 3: 150 m g/kg
preclinicalW HO-sponsored
toxicology studies for AS
Artem isinin N europathology
FDA AIDAC 7/10/02 25
Neurotoxicity: clinical experience
WHO-sponsored studies• Neurological assessments
performed for studies 5, 6, 7 only (should give 164 rectal AS recipients tested / 501 total, but missing data common)
• Young patients: assessments not reliable
• No pattern of neurological abnormalities was identified
Literature/actual usage• Main argument for the safety of
artesunate• Large body of experience• No evidence of neuro toxicity with
AS used in patients with malaria• Minority were moderate/severe dz• Main Ref. to Price et al study but
children <5 did not get neurological assessments
• Adults Highest Dose: 45.7 mg/kg (n<30)• Children Highest Dose: 57 mg/kg (n<30)
FDA AIDAC 7/10/02 26
Neurotoxicity: What do we know
• Neurotoxicity: dose-dependent• Lipid soluble derivatives: AE, AM • Water soluble derivatives: AS, AL• Most Neurotoxic: DHA > AE, AM >>AS, AL• Conversion to DHA: AS > AE, AM >> AL• Faster Elimination: AS >> AE, AM• Lipid soluble agents produce much longer periods of DHA activity. • Critical factor leading to neurotoxicity: Sustained level rather than peak
level
FDA AIDAC 7/10/02 27
Neurotoxicity: What we don’t know
• Safety margin from preclinical clinical not determined yet and may not be as “wide”. HED: one rectal dose OK but unclear with repeated dosing.
• AS elimination faster: IV > PO > Rectal; With repeated dosing, could rectal formulation also act as “depot” , causing sustained levels?
• Brainstem nuclei affected: species specific? Humans?• DHA Tissue Distribution to parasitized cells, a buffer?• Empiric Use in febrile children (especially if repeated dosing and no buffer of
parasitized cells): Sustained CNS DHA levels be possible?
FDA AIDAC 7/10/02 28
Lack of information: populationsCan we make the link?
W HO conclusionshighly favorable safety profile
num ber of AE sm allno consistent pattern of toxicity identified
All hospitalized patientsAll w ith proven m alaria
m ainly m oderately-severe diseaseonly 8 patients < 2 years of age
NDA application
little inform ation availableeven in the large body of clinical experience
none in the W HO-specific studies of this NDA...to draw upon for safety evaluation for proposed indication
In the "field"em piric therapy
severe disease, unable to take POm ainly very young children
Proposed Indication
FDA AIDAC 7/10/02 29
Safety Summary: Benefit / Risk
WHO Statements
• highly favorable safety profile
• number of AE small• no consistent pattern
of toxicity identified
Uncertainties
• Neurotoxicity, safety margin
• Population for proposed indication
FDA AIDAC 7/10/02 30
Safety Summary: Benefit/Risk
• Impact of the disease malaria to individual human suffering and global public health
• Proposed rectal dose (10 mg/kg x1) within safety limits of collective current knowledge
• Uncertainties and concerns expand if higher doses or repeated dosing becomes an issue