is a thorough qt study cost-effective?no new non-cardiac drug approved after 1998, the year when...
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Is a Thorough QT Study
Cost-effective?
By Rashmi Shah
Historical development
Cisapride
CPMP PtC versus ICH E14
Alternatives 4
3
2
1
European Union and CPMP
Sertindole and mizolastine (1995-1996)
- Disagreement among Member States
1991 Terodiline withdrawn from the market
1989 + Ongoing issues with terfenadine and
astemizole
1994 SWORD study with d-sotalol discontinued
1994-5 Emergence of halofantrine and cisapride
as torsadogens
European Union and CPMP
Sertindole and mizolastine (1995–1996)
1991 Halofantrine approved in the UK
1994 14 reports [8 fatal]
1995 33 reports
CPMP Points to Consider – in effect from 1998
Post-implementation survey by R Shah in 1999
Cisapride
1994: 2 reports of TdP in US
07 2000 Withdrawn from the market
01 1995 12 reports
04 1996 57 reports
06 1997 131 reports
05 1998 273 reports [70 fatal]
09 1999 288 reports
01 2000 341 reports [80 fatal]
1998 Approved in the EU [40mg/daily]
1993 Approved in the US [80mg/daily]
03 2000 High profile death
? Health Canada
Draft guidance
03 2001
Wysowski D et al, 2001
Cisapride
Was this based on CPMP PtC recommendations?
Cisapride
Or, was this the birth of the Thorough QT Study?
CPMP PtC versus ICH E14-compliant TQT
Aspect of study CPMP PtC TQT
Placebo-controlled study
Supratherapeutic dose Preclinical
Assay sensitivity Preclinical
Measurements around Cmax
Steady state conditions
Cardiologists to read manually
Threshold value of regulatory concern No data to support 5 (10) ms
Outlier analysis
PK/PD analysis
Use of inhibitors
Implications for Phase II/III studies
Regulatory implications
Roles of stereoisomers / metabolites / X /
Shah RR, 2002
CPMP Points to Consider
No new non-cardiac drug approved after 1998, the year
when CPMP guidance came into effect, has been
withdrawn as a result of its QT-liability.
To this extent, the CPMP guidance had achieved its objectives
without the need for a prescribed thorough QT study.
Advantages of a Thorough QT Study
Estimate QT effect accurately
To what benefit?
Sertindole versus thioridazine [QTc 30ms]
Would another TQT with identical protocol replicate
the effect? TQT is not the be all and end all
Would a formal TQT with assay sensitivity have altered
the course of events with cisapride? We will never know
Cost of TQT is driven by ECGs and QT corrections
Preclinical studies will identify potent torsadogens
Is there a more effective way of spending US$ 2 million?
Think of ondansetron and targeted pharmacovigilance
For discussion
So, we have 2 questions before us:
Is a TQT cost-effective?
- Jacoline will talk to this
If we conclude that it is, we can all have early lunch
If we conclude it is not, we need to consider alternatives
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