Effient Approval Was Prolonged, But FDA Requirements May Help Sponsors

FDA's approval of Lilly/Daiichi Sankyo's Effient (prasugrel) NDA took longer than either the sponsors or FDA review management liked. Approval took more than a year-and-half to accomplish, with changes occurring to the very last day, July 10.

The final approval package, however, including labeling, post-marketing tests and post-marketing risk management programs, may create a surprisingly solid platform for a product that had the misfortune of attracting a difficult public image throughout its review.

Effient has significance to the whole industry as the first, truly high-profile product to emerge from a tough review conducted under the post-REMS FDA approval process.

Although Wall Street has generally cooled to the commercial prospects for the product and scaled back peak projections to the $1 billion range, it is still clearly a major commercial launch for the sponsors.

It should be watched closely to see whether the FDA controls around the product act to offset the publicity over safety concerns that came up during clinical trials and the protracted regulatory review.

The Effient launch will be a test case to see whether controls negotiated with a stronger FDA may help the sponsors overcome the safety concerns that came up during clinical trials and the protracted regulatory review.

The agency is using its full range of safety powers granted by the FDA Amendments Act to help Lilly/Daiichi Sankyo control the bleeding risk for Effient: mandatory postmarket trials and a Risk Evaluation and Mitigation Strategy involving a Medication Guide and a communication plan (see (Also see "Effient REMS: FDA Role In Intro Grows; No Safe Use Restrictions" - Pink Sheet, 20 Jul, 2009.) ).

The agency worked with the sponsors to design six postmarketing trials (two mandatory) - including a potential way to control excess bleeding.

Those programs modify the safeguards the agency has also built in to the approved labeling: an extensive boxed warning on the increased bleeding risk, with specific directions to minimize the potential risk (Also see "Effient Labeling Could Give Edge Against Plavix Through Pharmacogenetics" - Pink Sheet, 10 Jul, 2009.).

FDA's review documents are clear that efficacy was not an issue for prasugrel - the agency approached the review from the start as an effort to understand and balance the bleeding risk versus the benefits of the drug's effect on reduction of thrombotic cardiovascular events.

The sense on FDA's part that the review issues were clearer than the length of the process would suggest is reflected in a comment from late in the spring by the head of the reviewing division that handled the prasugrel application.

In an April 29 memo supporting approval, Cardiovascular and Renal Products Division Director Norman Stockbridge expressed frustration that the timelines for making decisions had not been handled better.

"This has not been a well-managed review process," Stockbridge said in a memo released with the NDA approval documents.

The issues in the Effient review, Stockbridge wrote, "were pretty clear early enough to have allowed us to meet the original PDUFA (user fee) goal."

"What has been missing," the FDAer said candidly, "is a clear means or will to declare an end to discussions and to allow the regulatory process to complete. No one associated with this review should feel good about this."

Stockbridge may have been unduly harsh on FDA's handling of the review, because the agency had to coordinate with the sponsors on the mandated post-marketing trials and the communication plan.

For a drug with the visibility and commercial potential of Effient, both the sponsors and regulators would want to negotiate the requirements more carefully.

Determining that spontaneous adverse event reporting "will not be sufficient to assess a known serious risk of major bleeding and a signal of a serious risk of increased incidence of malignancies" - and because FDA's new Sentinel pharmacovigilence system required under FDAAA has not yet been established - the agency has determined that "only a clinical trial (rather than a non-clinical or observational study)" will be enough to elucidate the safety issues.

But that study is not a major, large-population study. FDA, instead, is requiring the sponsor to do a small, 28-patient lab study to determine what steps can reverse excess bleeding if it occurs.

Thus, the first required postmarket trial is aimed at better understanding the connection of the platelet inhibition and the bleeding; specifically to study the effects of adding additional platelets to a patient who has received prasugrel and see how long it takes to return to normal clotting.

Understanding how the platelet inactivation effect holds up after additional platelets are infused should give FDA - and clinical practitioners - some guide as to how to control major bleeding events caused by prasugrel administration.

The requirement is for an open-label trial of ex vivo reversal of platelet inhibition by exogenous platelets as a function of time and plasma level of prasugrel active metabolite in 28 normal volunteers given a single 60 mg loading dose of prasugrel plus 325 mg of aspirin. A protocol submission is due in September and the final report is expected in September 2011.

For Lilly and Daiichi, the study requirement is quite manageable and could lead to useful information that could help control excess bleeding incidents.

The other mandatory trial is aimed to keep track of the suggestion of a relationship of prasugrel with malignant tumors. FDA did not feel concerned enough about the potential association to include language about malignancy in the warnings/ precautions section of labeling. The mandatory Phase IV trial to clarify the signal requires the sponsors to continue work on a trial Lilly already has under way.

FDA is asking the firms to gather baseline cancer history and cancer adverse event data from the TRILOGY trial under way in 10,300 ACS patients who are being managed medically (without coronary revascularization). TRILOGY is aimed at expanding prasugrel's indication. The study will be completed by December 2012; the final report is due a month later.

On top of the required postmarketing trials, which are aimed at the known serious risks, FDA has also asked for four postmarketing commitments that do not fall under the agency's mandatory trial authority.

Two of the postmarketing commitments are part of a pathway to develop a different formulation of the prasugrel drug product.

Daiichi reports that the alternate formulation will significantly reduce or eliminate the conversion of salt to base. FDA's review documents note that correcting the instability would increase bioavailability in patients using proton pump inhibitors, so there might be greater platelet inhibition.

FDA is asking for the new formulation to be submitted as an sNDA with development, manufacture, control and stability information. The reformulation development should be completed quickly: bioequivalence studies will be completed in August. The final report is expected at FDA in December.

The other pair of postmarketing commitments should help Lilly and Daiichi build better evidence toward closer identification of the ideal Effient patient population.

A bonus element of the final labeling was the inclusion of an analysis of the pivotal trial that showed that the prasugrel active metabolite works in patients who do not respond to Plavix due to a genetic variant to the CYP2C19 allele.

Thirty percent of the population has the decreased function in the CYP2C19 pathway, and thus a natural lowered response to clopidogrel. The opportunity gets bigger because that pathway can also be blocked by use of proton pump inhibitors (Also see "Lilly, Daiichi Explore Pharmacogenomic Marker For Prasugrel" - Pink Sheet, 11 May, 2009.).

Lilly and Daiichi have already completed a trial comparing the original and reformulated versions of prasugrel in the presence and absence of proton pump inhibitors; FDA has set a December deadline for that report. FDA is also asking the companies to collect baseline samples in TRILOGY for genotyping CYP450 enzymes, "to allow a comparison of effectiveness and bleeding in prasugrel and clopidogrel subgroups by metabolizer status." That analysis will come in with the full TRILOGY results, in January 2013.

- Mary Jo Laffler ([email protected]) and Cole Werble ([email protected])