NDA 22-307/S-000 EFFIEN'J'TM (prasugrel) Known versus unknown function of genotypes of interest -7 - To assess the impact of the predicted metabolic phenotypes on the clinical outcome, the sponsor classified patients with an IM2C9 genotype and a normal CYP2C19 as missing due to their potential confounding effect for clinical outcome. The sponsor excluded these patients from the clinical outcome analysis. Thus, the reduced metabolizers include those patients who either are homozygous null CYP2C 19 or have combination genotypes with heterozygous CYP2C19 (IM2CI9) and the presence ofa reduced-function CYP2C9 allele (IM2C9). This subset is called "GVC Evaluable (GVCE) patients". References: Wilkison GR. 2005. Drug metabolism and variability among patients in drug response. New England Journal of Medicine 352(21):2211-2221. Lynch T, Price A. 2007. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. American Family Physician 76(3):391-396.
Transcript
NDA 22-307/S-000 EFFIEN'J'TM (prasugrel)
Known versus unknown function of genotypes of interest
-7 -
To assess the impact ofthe predicted metabolic phenotypes on the clinical outcome, thesponsor classified patients with an IM2C9 genotype and a normal CYP2C19 as missingdue to their potential confounding effect for clinical outcome. The sponsor excludedthese patients from the clinical outcome analysis. Thus, the reduced metabolizers includethose patients who either are homozygous null CYP2C19 or have combination genotypeswith heterozygous CYP2C19 (IM2CI9) and the presence ofa reduced-function CYP2C9allele (IM2C9). This subset is called "GVC Evaluable (GVCE) patients".
References:
Wilkison GR. 2005. Drug metabolism and variability among patients in drug response.New England Journal ofMedicine 352(21):2211-2221.
Lynch T, Price A. 2007. The effect ofcytochrome P450 metabolism on drug response,interactions, and adverse effects. American Family Physician 76(3):391-396.
,hic and Baseline Characteristics between ITT oatientsand GVCE oat'DTable 2 - ----- - -----UAINSTEMI STEMI . ALLACS
* primary analysis, reported by the sponsor and replicated by the statistical reviewer Ququan LlU.** ifprimary analysis is significant, then, perform the test in ACS ITT patient population, reported by the sponsor and replicated bythe statistical reviewer Ququan Liu.The analysis results are extracted from Reviewer Tables 5-10, and sponsor's Tables TAAL 11.15, 11.34, and sponsor's Figure ll.a.
-------------------------------,,;,--------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.------------------------------------------------.._-----/s/
Sue Jane Wang5/7/2008 07:42:57 AMBIOMETRICSSecondary statistics genomic review and evaluation
Indication: Treatment of subjects with acute coronary syndromes (ACS)
Reviewer: Ququan Liu
Background:
A question was raised recently from the review team on how benefit/risk of the test drug shouldbe evaluated (benefit: reduction of clinical events, risk: bleeding).
Statistical Analysis:
Assessment ofbenefit/risk is a clinical judgment and it is very subjective. A statistical approachusing hazard function is used to assess whether risk is increasing or decreasing over time for theclinical endpoint or bleeding.
1. Clinical Endpoint: The hazard function plot indicates that the hazard's patterns appear to besimilar in both treatment groups. The hazard is high at the early time where most eventsoccurred. The hazard is decreasing over time: declines dramatically at the early time andthen slowly (Figure 1, Table 1).
Figure 1 Hazard Function of Clinical Endpoint
.1111& \iit.l!
i_.0&,.
I~-·
•. 00001..,- ..-- ---. --.- ..,..,..... -.-J
T bi 1 H d· cr' lEd .a e azar m lllica n IpomtPrasugrel Clopidogrel
Interval Day Number Number Hazard Number Number Hazard[Lower, Upper) Failed Censored Failed Censored
2. Bleeding Events: The bleeding events were classified into three groups: TOO Major, TIMIMinor, or TM Major/ Minor. The hazard function plots indicate that the hazard is high at theearly time where most bleeding events occurred. The hazard i(generally decreasing over time,but appears to fluctuate after the early time (Figures 2-4, Tables 2-4).
----------------_.------.-- -------------.--------._------------.._-------_ _--_.._------- --_..---_._--.This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.
/s/
Ququan Liu6/4/2008 04:44:35 PMBIOMETRICS
James Hung6/7 /2008 10: 00: 16 AMBIOMETRICS
DEPARTMENT OF HEALTH AND HUMAN SERVICESPUBLIC HEALTH SERVICEFOOD AND DRUG ADMINISTRATIONCENTER FOR DRUG EVALUATION AND RESEARCH
STATISTICAL REVIEW AND EVALUATION
Addendum
NDA/Serial Number:
Drug Name:
Indication(s):
Applicant:
Date(s):
Review Priority:
Biometrics Division:
Statistical Reviewer:
Concurring Reviewers:
Medical Division:
Clinical Team:
Project Manager:
Keywords:
22-307 / S 000
EFFIENTTM (prasugrel hydrochloride) Tablets
Treatment of subjects with acute coronary syndromes (ACS)
Eli Lilly
Date ofDocument: December, 26 2007
PDUFA Due Date: June 26, 2008
Priority
Biometrics I, HFD-710
Ququan Liu,M.D., M.S.
James Hung, Ph.D.
Division ofCardio-Renal Drug Products, HFD-IIO
Karen Hicks, M.D, Norman Stockbridge, M.D., Ph.D.
Meg Pease-Fye, M.S.
EFFIENTTM, Prasugrel, ACS
Background:
The medical reviewer, Dr. Karen Hicks requested to look into whether heterogeneity oftreatment effects is present in the following subgroups: GPlIb/IIIa inhibitors use; troponin levelat baseline; and GPlIbnIla inhibitors use and troponin level at baseline in different genders.
Statistical Analysis:
Both test for interaction and subgroup analysis are conducted. All these analyses areexploratory.
There was no evidence suggesting large heterogeneity in the prasugrel effect relative toc1opidogrel, regardless of GPlIb/IIIa inhibitors use, troponin level at baseline and genders. Theresults are summarized in the following tables.
Table 1 Interaction Test nTI)Interaction Effect
Treatment*GPIIbnIa inhibitors prior to and during PClTreatment*GPIIblIla inhibitors prior to and during PCl* TroponinTreatment*GPIIblIla inhibitors up to cath labTreatment*GPlIbnIa inhibitors up to cath lab * Troponin
0.62910.53490.92900.5244
P-value
Table 2 Subgroup Analysis:Use of GPIIbIIIIa Inhibitors prior to and during PCl
![NDA22-307CS-747(Prasugrel) Page 17 of19€¦ · Peto, Richards, and].Wahrendorf, "Guidelines for ~ sensitive significance test for ~. nic effects in long-teun :inimal experiments",](https://static.documents.pub/doc/80x56/5f8bd40793b5233bf205eaeb/nda22-307cs-747prasugrel-page-17-of19-peto-richards-andwahrendorf-guidelines.jpg)
