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1991 Terodiline withdrawn from the market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07 2000 Withdrawn from the market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Draft guidance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withdrawn as a result of its QT-liability.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