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New draft guidance on financial disclosure
The Food and Drug Administration (FDA) has issued new draft guidance, "Financial Disclosure by Clinical Investigators, Guidance for Clinical Investigators, Industry, and FDA Staff." The document is now available from FDA's web site at the following link: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM256525.pdf
This guidance is intended to assist clinical investigators, industry, and FDA staff in interpreting and complying with the regulations governing financial disclosure by clinical investigators, 21 CFR part 54.
Comments to the draft guidance are due by July 25, 2011.
Rilpivirine approved for HIV treatment
On Friday, May 20, 2011, the Food and Drug Administration (FDA) approved rilpivirine (Edurant®) 25 mg tablets, a new non-nucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of HIV. Rilpivirine is an antiviral drug that helps to block reverse transcriptase, an enzyme necessary for HIV replication. The recommended dose of rilpivirine is one 25 mg tablet once daily taken orally with a meal.
INDICATIONS AND USAGE:
Rilpivirine, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV 1) infection in antiretroviral treatment naïve adult patients (patients who have never taken HIV therapies, and are starting HIV therapy for the first time).
The following points should be considered when initiating therapy with rilpivirine: More rilpivirine treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the start of therapy.
The observed virologic failure rate in rilpivirine treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz.
More subjects treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz.
RESULTS OF CLINICAL TRIALS AND CLINICAL VIROLOGY SUMMARY:
The approval of rilpivirine is based on Week 48 safety and efficacy analyses from 2 randomized, double blind, active controlled, Phase 3 trials in treatment naïve subjects and Week 96 safety and efficacy analyses from a Phase 2b trial in treatment-naïve subjects.
The Phase 3 trials (TMC278-C209: ECHO and TMC278-C215: THRIVE) compared rilpivirine to efavirenz in antiretroviral-naïve HIV-1 infected subjects with HIV-1 RNA ≥ 5000 copies/mL and no NNRTI resistance. Both trials were identical in design, with the exception of the background regimen (BR). In TMC278 C209, the BR was fixed to the nucleoside (tide) reverse transcriptase inhibitors (N(t)RTIs), tenofovir disoproxil fumarate plus emtricitabine. In TMC278 C215, the BR consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load. In TMC278 C215, randomization was also stratified by N(t)RTI BR.
The Week 48 efficacy outcome for the pooled data from TMC278-C209 and TIMC278-C215 are as follows.
Overall, the proportion of subjects with HIV RNA < 50 copies/mL was 83% for rilpivirine-based regimen compared to 80% for efavirenz based regimen. The predicted difference (95% CI) of response rates is 2.0 (-2.1; 6.1). The overall virologic failure rate was 13% for the rilpivirine compared to 9% for the efavirenz. The proportion of patients who discontinued study due to an adverse event or death was 2% for rilpivirine and 7% for efavirenz.
Response rate was also calculated by baseline plasma viral load. For subjects with baseline plasma viral load ≤ 100,000 copies/mL, >100,000 to ≤ 500,000 copies/mL and > 500,000 copies/mL, the proportion of subjects with HIV RNA < 50 copies/mL was 89%, 78% and 65% for rilpivirine compared to 83%, 78% and 73% for efavirenz respectively.
The virologic failure rate by baseline plasma viral load is as follows. For subjects with baseline plasma viral load ≤ 100,000 copies/mL, the proportion of subjects with virologic failure was 5% for both rilpivirine and efavirenz. For subjects with baseline plasma viral load >100,000 to ≤ 500,000 copies/mL and > 500,000 copies/mL, the proportion of subjects with virologic failure was 20% and 29% for rilpivirine compared to 11% and 17% for efavirenz, respectively.
In the pooled resistance analysis from the Phase 3 Studies C209 and C215, the emergence of resistance among subjects was greater in the rilpivirine arm compared to the efavirenz arm. In the combined studies, 41% (38/92) of the virologic failures in the rilpivirine arms had genotypic and phenotypic resistance to rilpivirine compared to 25% (15/60) of the virologic failures in the efavirenz arms who had genotypic and phenotypic resistance to efavirenz. Moreover, resistance to a background drug (emtricitabine, lamivudine, tenofovir, abacavir or zidovudine) emerged in 48% (44/92) of the virologic failures in the rilpivirine arms compared to 15% (9/60) in the efavirenz arms.
Emerging NNRTI substitutions in the rilpivirine virologic failures included V90I, K101E/P/T, E138K/G, V179I/L, Y181I/C, V189I, H221Y, F227C/L and M230L, which were associated with a rilpivirine phenotypic fold change range of 2.6 - 621. The E138K substitution emerged most frequently on rilpivirine treatment commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V and the tenofovir resistance-associated substitutions K65R or N emerged more frequently in rilpivirine virologic failures compared to efavirenz virologic failures.
Cross-resistance to efavirenz, etravirine and/or nevirapine is likely after virologic failure and development of rilpivirine resistance. In the pooled analyses of the Phase 3 clinical trials, 38 rilpivirine virologic failure subjects had evidence of rilpivirine resistance. Of these subjects, 89% (n = 34) were resistant to etravirine and efavirenz, and 63% (n = 24) were resistant to nevirapine. In the efavirenz arm, none of the 15 efavirenz-resistant virologic failures were resistant to etravirine at failure. Subjects experiencing virologic failure on rilpivirine developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had a higher likelihood of cross-resistance to all NNRTIs in the class than subjects who failed on efavirenz.
Rilpivirine is contraindicated with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs:
The anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin the antimycobacterials rifabutin, rifampin, rifapentine proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, the glucocorticoid systemic dexamethasone (more than a single dose), St John's wort.
WARNINGS AND PRECAUTIONS:
The Warnings and Precautions for rilpivirine include fat redistribution, immune reconstitution syndrome and the following:
Drug Interactions: Caution should be given to prescribing rilpivirine with drugs that may reduce the exposure of rilpivirine.
In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Rilpivirine should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.
Depressive Disorder: The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with TRADENAME. During the Phase 3 trials (N = 1368), the incidence of depressive disorders (regardless of causality, severity) reported among rilpivirine (n = 686) or efavirenz (n = 682) was 8% and 6%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among rilpivirine or efavirenz was 1% in each arm. Suicide attempt was reported in 2 subjects in the rilpivirine arm while suicide ideation was reported in 1 subject in the rilpivirine arm and in 3 subjects in the efavirenz arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to rilpivirine, and if so, to determine whether the risks of continued therapy outweigh the benefits.