FDA Cardio-Renal Drug Products Division Director Douglas Throckmorton, MD, is the chair of an agency working group that is attempting to provide clear advice to industry on how to assess drugs that prolong the QT interval.

The working group hopes to produce a written guidance in the near future. The guidance development effort will be one of Throckmorton's early priorities as division director.

Throckmorton was named division director April 8; he has been serving as acting director since the retirement of Raymond Lipicky, MD, on Feb. 28 (¹ Also see "Cardio-Renal Division Acting Director To Be Throckmorton; Lipicky Retires" - Pink Sheet, 18 February, 2002., p. 21).

The agency moved quickly to name a permanent successor to Lipicky, who had by far the longest tenure of any division director when he retired.

QT prolongation was a factor in three recent product withdrawals ( Posicor , Seldane and Hismanal ). Under Lipicky, the Cardio-Renal Division served as a consultant to other review divisions on the issue. Lipicky himself helped block the approval of Abbott's antipsychotic Serlect , which he termed a "dangerous drug" during an advisory committee review.

Two years ago, Throckmorton, along with Maryann Gordon, MD, conducted a cardiovascular safety review of Pfizer's antipsychotic Geodon (then known as Zeldox ) to assess the risks from the QT prolongation associated with the drug.

During a July 2000 Psychopharmacologic Drugs Advisory Committee review, Throckmorton presented an analysis of cardiovascular drugs that prolong the QT interval, including McNeil's angina drug Vascor (bepridil), and two anti-arrhythmics, Pfizer's Tikosyn (dofetilide) and Berlex' Betapace (sotalol) (² Also see "Zeldox QTc Prolongation Is Less Severe Than Serlect, Pfizer Tells Committee" - Pink Sheet, 24 July, 2000., p. 5).

"To summarize the experience of the Division of Cardio-Renal Drug Products...regarding compounds that prolong QT," Throckmorton said, "the use of cardiovascular drugs that prolong the mean QT in a dose-dependent fashion has been associated with an increased risk for torsades and sudden death."

"That risk appears to be continuous, and over a broad dose range. There doesn't seem to be an upper limit where the risk does not continue to increase," he added.

Throckmorton recommended that without demonstration of greater efficacy than existing antipsychotics, Geodon should not be approved or should be relegated to second-line use.

Throckmorton also indicated that studies quantifying the risk of QT prolongation in patients at risk for a cardiac event as well as in the drug's intended patient population could increase the likelihood that the agency would approve Geodon.

Geodon was approved with an indication that stopped short of a second-line designation, but recommended that doctors first consider prescribing antipsychotic agents associated with lower rates of QT prolongation (³ Also see "Pfizer Ziprasidone Labeling Stops Short Of Second-Line Use; QT Effect Noted" - Pink Sheet, 12 February, 2001., p. 9).

Geodon's contraindication for drugs affecting QT intervals was strengthened and expanded in a labeling revision approved in February (⁴, p. 17).

Another early priority for Throckmorton as division director will be coordinating the Center for Drug Evaluation & Research's role in reviewing drug-coated stents.

Currently, the Center for Devices & Radiological Health acts as the lead center for drug-coated stent reviews, with the Cardio-Renal Division serving as consultants.

Throckmorton joined FDA in 1996 as a medical officer in the Cardio-Renal Division. He was appointed deputy director in August 2000.

Prior to joining FDA, Throckmorton was a staff nephrologist at the Veteran's Administration Medical Center in Augusta, Ga.

Throckmorton was one of the medical reviewers for Scios' acutely decompensated congestive heart failure therapy Natrecor (nesiritide). The drug was approved Aug. 10, 2001, after being deemed "not approvable" in April 1999 pending additional safety data (⁵ [A#00630340006], p. 11).

FDA Working On QT Interval Guidance Under Cardio-Renal’s Throckmorton

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