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Transcript of FDA AIDAC 7/10/021 NDA 21-242 Rectal Artesunate Integrated Safety Rosemary Johann-Liang, M.D....
![Page 1: FDA AIDAC 7/10/021 NDA 21-242 Rectal Artesunate Integrated Safety Rosemary Johann-Liang, M.D. Division of Special Pathogen and Immunological Drug Products.](https://reader035.fdocuments.in/reader035/viewer/2022081504/56649da15503460f94a8d67b/html5/thumbnails/1.jpg)
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
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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”
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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
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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• WHO-Sponsored Studies • Safety Review of published and unpublished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)
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FDA AIDAC 7/10/02 5
WHO-sponsored Studies
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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
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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
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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%)
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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
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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
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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)
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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
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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
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FDA AIDAC 7/10/02 14
Safety Review of Published and Unpublished Clinical Studies on
Artemisinin Derivatives
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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
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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
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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)
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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
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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)
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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)
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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
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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)
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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)
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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
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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)
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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
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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?
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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
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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
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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