Cialis NDA Issues Include Back Pain At 20 Mg Dose, FDA Documents Show

FDA's safety questions about Lilly/Icos' erectile dysfunction agent Cialis focus on back pain reported at the starting dose initially proposed by the companies.

In clinical trials of a 20 mg dose, there was a 10% rate of back pain reported, FDA documents state.

In an April 2002 "approvable" letter, FDA told the company that "10 mg would be an appropriate starting dose for most men with erectile dysfunction." In addition, FDA told the company that "a range of dosage strengths are needed to promote effective treatment of the spectrum of erectile dysfunction and to promote safety through use of the lowest effective dose."

FDA also deemed a 5 mg and 10 mg dose to be approvable, although those doses were not initially included in the NDA.

Lilly has described the "approvable" letter in general terms as seeking confirmatory clinical pharmacology data and an "extra margin of protection" in the event that patients take it recreationally (¹ (Also see "Lilly Cialis Delay Clears Space For Bayer Nuviva: Extra FDA Caution Cited" - Pink Sheet, 6 May, 2002.), p. 26).

Lilly is confident that the issues raised by the agency have been resolved in its response to the "approvable" letter. The company expects approval of Cialis by the end of the year.

FDA's discussion of the Cialis starting dose issue was posted on the agency's website in background materials for a Nov. 17-18 Pharmaceutical Sciences/Clinical Pharmacology Subcommittee meeting.

FDA will be presenting the committee with a proposal for "End-of-Phase IIa Meetings" to discuss "exposure-response" analyses for investigational products.

The background materials included eight case studies (intended to be redacted) where, in the agency's view, an early discussion of exposure response could have prevented a setback.

For Cialis, FDA maintains that an early meeting with sponsors to talk about exposure-response and dose selection "would have resulted in a better NDA package that would include a wider safe and effective dose range with the necessary supportive information (such as chemistry) on all doses."

Another high-profile case cited by the agency is Merck's follow-on COX-2 inhibitor Arcoxia (etoricoxib).

FDA's materials reveal that one issue in the review was the agency's desire to see data on a 60 mg b.i.d. dose for dental pain in addition to Merck's proposed once-daily 120 mg dose.

The "60 mg dose beat placebo during the first 24 hours of the study," FDA noted. "Since drug toxicity is usually dose dependent, the sponsor may consider studying 60 mg b.i.d. dosing for a better benefit/risk ratio."

Merck conducted a PK/PD study to support its proposed dose, but the review deemed the analysis "inadequate."

FDA noted that Merck "withdrew the application and planned to re-submit with a new indication and a more complete safety assessment regarding cardiovascular side effects."

Merck withdrew the Arcoxia NDA in March 2002, citing a desire to supplement the application with clinical data to support an ankylosing spondylitis indication.

The company subsequently acknowledged that the agency also wanted additional data on cardiovascular safety and acute pain (² (Also see "Merck Arcoxia 6,000-Patient Trial Will Study GI, Cardiac Events" - Pink Sheet, 17 Jun, 2002.), p. 15).

Merck plans to resubmit the Arcoxia NDA by the end of the year.

Forest's lercanidipine has also been delayed because FDA believes there is insufficient data to justify a proposed once-daily dosing regimen. "Although there is no doubt that lercanidipine lowers blood pressure, there are inadequate data on dose response, particularly regarding the relative effectiveness of once-daily and twice-daily dosing," FDA's 2002 "approvable" letter states.

Forest said it may have to reformulate lercanidipine (³ (Also see "Forest Lercanidipine Options Include Reformulation, Confirmatory U.S. Trial" - Pink Sheet, 27 Jan, 2003.), p. 28).