Risk–Benefit Assessment

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Chapter: Pharmacovigilance: Withdrawal of Terodiline: A Tale of Two Toxicities

Despite the fact that QT interval is not a very reliable surrogate of torsade de pointes, it is neverthe-less true that drugs that prolong QT interval are considered more likely to cause torsade de pointes in susceptible patients than drugs that do not.


RISK–BENEFIT ASSESSMENT

Despite the fact that QT interval is not a very reliable surrogate of torsade de pointes, it is neverthe-less true that drugs that prolong QT interval are considered more likely to cause torsade de pointes in susceptible patients than drugs that do not. There-fore, QT interval prolongation has been used in distin-guishing safer drugs from those that are less safe within the same class. Not surprisingly, regulatory authorities are reluctant to approve drugs that prolong the QT interval when the potential benefits are very modest, and especially when alternatives without the QT-liability are already available. For example, ebas-tine (a non-sedating H1-antihistamine) has not been approved in the United States because of its abil-ity to prolong the QT interval, although there are no documented reports of torsade de pointes associated with its extensive use elsewhere. The reason is almost certainly the availability of alternatives without such a liability. However, it should not be assumed that just because a drug prolongs the QT interval, it might not be approvable.

A number of factors determine whether drugs that prolong the QT interval can be approved, particularly because the QT-liability of a drug does not neces-sarily translate into a proarrhythmic activity (Shah, 2002; 2004). In contrast to ebastine, drugs such as ziprasidone or arsenic trioxide that prolong the QT interval to a much greater extent have nevertheless been approved, because they were considered to have an acceptable risk–benefit profile. Arsenic trioxide illustrates particularly well how even a drug with very marked potential to prolong the QT interval, and actu-ally induce torsade de pointes, may be approved with specific guidelines associated with its clinical use, if it is shown to fulfil an unmet need. Arsenic triox-ide (‘Trisenox’) was approved in September 2000 in the United States and in October 2001 in the EU for its remarkable efficacy in induction of remission and consolidation in patients with a specific form of acute promyelocytic leukaemia who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy. Protease inhibitors are another class of drugs that block hERG, prolong the QT interval and induce torsade de pointes (Anson et al., 2005). However, their clinical benefits far outweigh their very small proarrhythmic risk.

With respect to risk–benefit analysis of a drug that actually induces torsade de pointes and other ventric-ular tachyarrhythmias, the benefit offered by the new drug merits very careful assessment. Furthermore, the risk of torsade de pointes is not an ‘all-or-none’ effect. Depending on the benefit offered by the drug, an inci-dence of 1 in 3000 might be unacceptable whereas an incidence of 1 in 500 000 may be considered acceptable with a whole range of risk–benefit in between. As stated earlier, risk–benefit analysis in drug development and the regulatory approval process includes not only the alternatives already available, but also the seriousness of the condition under treat-ment. For relatively benign indications such as hay fever or gastroparesis, a risk of proarrhythmias even as low as 1 in 100 000 recipients is unlikely to be acceptable.

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