Size of the Safety Database:Population Considerations

Richard O’Brien

Foundation for Innovative New Diagnostics

TB Drug Forum

Arlington, VA

December 6-7. 2005

Safety Database• Complication of information related to drug

safety collected during clinical development• Major items

– Serious Adverse Event (AE): death, including life-threatening event, hospitalization, disability, birth defect

– Discontinuations due to adverse events

• Other: common AE*s, laboratory data, vital signs, ECG, Phase 1 safety data, pregnancies, overdose experience, drug-drug interaction, dose dependency re AEs

*any adverse finding temporarily associate with drug use, Including signs, symptoms, lab/VS/ECG, etc., or cluster of events

Sources of Safety Data

• Phase I trials– Common AEs– Lab, vital sign, and/or EKG data– Metabolic profile, AEs in special populations

• Phase II/III randomized controlled trials– Common AEs, serious less common AEs (maybe)– Discontinuations due to AEs– Lab, vital sign, and EKG data

• Phase II/III Open Label trials– Serious AEs

NDA Safety Review

• Required by FDC Act, section505– Includes “all tests reasonable applicable to show…

drug is safe…under…proposed labeling”– Results show “drug is safe under such conditions”

• To critically examine sponsor’s claim of safety– To assess adequacy of testing for safety: numbers

of patients, duration of exposure, quality of data– To identify safety issues that could affect approval

• To identify safety issues to be described in product label

Risk Factors to Explore

• Patient factors– Age– Gender– Race– Genetic vulnerability– Comorbid illness

• Drug factors– Dose– Plasma level– Duration– Concomitant

medications

Safety Database: Numbers of Patients

• Generally accepted that premarketing safety database is not able to detect rare SAEs

• ICH guidelines for chronically administered drug:– 300-600 patients for 6 months– 100 patients for 1 year– 1500 total patients

• If labeling will recommend dose range:– How much exposure was observed at highest

dose?• Subgroup analyses problematic

Probability of Observing AEs Event Sample Size Probability of observingRate > 1 event > 2 events

1% 500 0.99 0.96

0.5% 500 0.92 0.711000 0.99 0.96

0.1% 1500 0.78 0.443000 0.95 0.80

0.01% 6000 0.45 0.1210,000 0.63 0.2620,000 0.86 0.59

Subpopulations of special interest in TB trials

• Extremes of age, especially children• Patients with comorbid conditiions

– hepatic or renal impairment– HIV infection

• Pregnant/lactating women• Different races/ethnicities• Different disease forms• Differing severity of disease • Different geographic regions

Hepatic Toxicity in South Indian TB Patients Treated with H,R,Z*

• Data from studies of 1686 TB patients with TB treated at TRC with SCC regimens

• Hepatitis usually accompanied by jaundice• Rates varied by site of disease

– 16-39% in children with TBM– 10% in spinal TB– 2-8% in pulmonary TB

• Rates varied by acetylator phenotype– 11% in 317 slow acetylators– 1% in 244 rapid acetylators

*Parthasarathy eta al. Tubercle 1986;67:99-108.

Urinary Excretion of Toxic Metabolites of INH by Acetylator Status*

All differences statistically significant, p < 0.01-0.05

*Peretti et al. Eur J Clin Pharmacol 1987;33:283-6.

Slow Acetylators (7) Rapid Acetylators (5) % Dose in 24 hr % Dose in 24 hr

Isoniazid 32.4 (+ 4.0) 9.2 (+ 2.9)Acetylisoniaizid 25.9 (+ 3.4) 42.9 (+ 7.1)Acetlyhydrazine 3.1 (+ 1.0) 1.6 (+ 0.4)Diacetylhydrazine 5.1 (+ 2.4) 22.6 (+ 3.9)Hydrazine 1.0 (+ 0.3) 0.4 (+ 0.1)

Hepatic Toxicity Children in U.S. Treated with Short-Course Therapy*• Survey of state TB programs following

ATS/CDC recommendation on SCC• 874 reports from children treated 1977-79• 16 hepatotoxic reactions (15/430, 3.3% in

430 children on SCC)• Half in the first month, all in the first 10 wks• Higher in those on high HR doses and on

those with disseminated TB• Recommendations on limiting doses and

monitoring those with serious disease

*O’Brien el al. Pediatrics 1983;72:491-9.

TBTC Study 22: Relationship of Acetylator Status to Outcome in

HIV-Negative Patients* Failure/Relapse Cured

Fast 13 (59%) 9 (41%)

Medium 13 (35%) 24 (65%)

Slow 8 (25%) 24 (75%)

P=0.04, chi square

*Weiner et al. AJRCCM 2003;167:1341-7.

Isoniazid-Related Hepatitis in USPHS Cooperative Surveillance Study*

• 18,838 patients in IPT in 21 HDs in U.S.• Age most significant hepatitis risk factor

– 0.1% among persons < 20 yr– 2.3% among persons 50-64 yr

• Related to alcohol consumption– 0.6 % in non-drinkers vs. 2.7% in daily drinkers

• Eight hepatitis deaths– 5 in black women– 7 in one geographic region

*Kopanoff et al. ARRD 1978;117:991-1001.

Isoniazid-Related Hepatitis among Pregnant and Postpartum Hispanics*

• CDC investigation following 2 INH-related hepatitis deaths in post-partum women

• 3,681 women on IPT in pre-natal clinic• Control group: 3948 women in earlier study• Rate of hepatitis increased 2.5-fold among

prenatal/postpartum women– For 15-34 yr: 0.3 % vs. 0.06%– For 35-44 yr: 2.3% vs. 0.9%

*Franks et al. Pub Health Rpt 1989;104:151-5.

2RZ-Related Hepatitis

• Addition of PZA to INH/RIF in SCC did not increase rate of hepatitis in CDC Study 21– Enrolled 1451 newly diagnosed PTB patients– 2.4% in 2HRZ/4HR vs 3.6% in 9HR*

• No increased hepatotoxicity in studies of 2RZ LTBI Rx in HIV+ patients– International study enrolled 1583 patients**– Randomized to 2RZ and 9H– Abnormal LFTs in 1.4% on 2RZ and 3.3% on 9H

*Combs et al. Ann Int Med 1990;112:397-406.**Gordin et al. JAMA 2000;283:1445-50 and

Multicenter CT of 2RZ in HIV-Negative Patients*

• 589 HIV- adults eligible for LTBI treatment in 3 centers

• Randomized to 2RZ and 6H• Hepatoxicity in persons completing treatment

– 16/207 (7.7%) for 2RZ– 2/204 (1%) for 6H

• No difference in rate of completion of treatment

*Jasmer et al. Ann Int Med 2002;137:640-7.

Toxic Hepatitis Among HIV+ and HIV- Patients in Barcelona*

*P Sanchez. Personal communication.

Drug Regimen Toxic Hepatitis

HIV+ (%), RR (CI) HIV- (%) RR (CI)

2RZ (n=281) 4(3.5),1.5(0.2-17) 12(11),4.4(1.3-19)

6-9H (n=320) 2(2) 3(3)

P = 0.7 P = 0.015

Initial Report of Fatal Hepatitis with 2RZ*

* MMWR Weekly Report. 2001;50;289-91.

0

2

4

6

8

10Ja

n

Apr

Jul

Oct

Jan

Apr

Jul

Oct

Jan

Apr

Jul

Oct

Jan

Apr

Jul

Oct

Jan

Apr

Jul

Oct

Cas

es

1999 2000 2001 2002

Known case: Captured by survey

Additional case: Detected by survey

Known case: NOT captured by survey

Survey Periods

Cases of Serious 2RZ-Related Hepatitis, 1999-2003*

2003

MMWR8

MMWR9 MMWR10 MMWR11

CDC/ATS endorsement4

x

x x x

x

x

x

x

x xx

x

Additional case: Verispan® search

Known case: Pre or Post-survey period

*McElroy et al. Clin Inf Dis 2005;41:1125-33.

CDC Survey of 2RZ Use

• Survey of state/city TB controllers on 2RZ use between Jan 2000 and June 2002

• 110/139 responded (79%), 87 (79%) used 2RZ in 8087 patients

• Rates per 1000 initiations– Asymptomatic AST > 5 times ULN: 25.6– Symptomatic hepatitis: 18.7– Hospitalization for hepatitis: 2.8– Death from hepatitis: 0.9 (vs. 0.0-0.3 for INH)

• Completion rate: 64%

Acquired RIF-Resistance in HIV+ Patients*

TBTC Study 22 included an arm which evaluated the once-weeklyINH-Rifapentine regimen in HIV+ persons

*Vernon et al. Lancet 1999;353:1843-7.

Acquired RIF-Resistance in Study 22 Item Treatment Arm

INH+RPT INH+RIF Both

Enrolled 36 35 71

Completed Rx 30 31 61

Relapsed1 5 3 8

RMR relapse2 4 0 4

1p=0.47, Fisher’s Exact Test2p=0.05, Fisher’s Exact Test

Acquired RIF-Resistance in Study 22HIV+ Patients in Rifapentine Arm

Group RIF-R No RIF-R P value

Number 4 25

Age (mean/sd) 31+10 43+14 0.10

CD4 (mean/sd) 57+88 227+189 0.03

EPTB 75% 12% 0.02

Use of azoles 75% 8% 0.01

Acquired RIF-Resistance in TBTC Study 23*

• Single arm study of largely intermittent rifabutine in HIV+ persons

• 169 eligible patients enrolled and treated• 9 patients had culture+ relapse (6) or failure (3)

– Overall rate of relapse (5%) not higher than expected

– 12% in pts with CD4<100 vs 0% in pts > 100

• 8/9 had acquired rifampin resistance• Resulted in change in ATS/CDC/IDSA

treatment recommendations for HIV+ TB Pts

*Burman et al. AJRCCM. E-Pub Aug 18, 2005

Summary• Only more common adverse events will be detected

during clinical development• Safety data from populations of great interest difficult

to obtain• Cannot predict toxicity indirectly, e.g., HRZ vs. RZ

hepatoxicity• Discussions about acceptable rates of serious AEs

for new TB drugs are needed (> 1/50,000 not acceptable for less serious condition, those with other therapeutic options

• Post-approval/marketing (Phase IV) studies are needed. May be difficult to estimate true rate of uncommon AEs, but planning should begin now