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US Postmarketing Requirements Status as of 08-Jul-2013 TRADE NAME (generic name) CANCIDAS (caspofungin acetate) DUE DATE STATUS EXPLANATION OF STATUS PMR DESCRIPTION 31-Jul-2020 Pending DULERA (mometasone furoate (+) formoterol fumarate) 31-Jul-2012 Submitted DULERA (mometasone furoate (+) formoterol fumarate) 30-Nov-2014 Released PMR 1658-2 Deferred pediatric trial under PREA to compare the pharmacokinetics of DULERA with and without a spacer in children 5 to 11 years of age. Final Report Submission DULERA (mometasone furoate (+) formoterol fumarate) 31-Mar-2014 Released PMR 1658-3 Deferred pediatric trial under PREA to evaluate the effects of DULERA on the HPA axis in children 5 to 11 years of age. In lieu of an HPA axis study, you may provide robust data to demonstrate that the systemic exposure of mometasone from DULERA is comparable or lower than that from the mometasone dry powder inhaler. Final Report Submission DULERA (mometasone furoate (+) formoterol fumarate) 31-Aug-2014 Ongoing PMR 1658-4 Deferred pediatric trial under PREA to evaluate the safety and efficacy of multiple doses of mometasone MDI in children 5 to 11 years of age with asthma. Final Report Submission DULERA (mometasone furoate (+) formoterol fumarate) 31-Jan-2017 Pending DULERA (mometasone furoate (+) formoterol fumarate) 31-Mar-2017 Pending DULERA (mometasone furoate (+) formoterol fumarate) 30-Jun-2017 Pending PMR 1658-5 Deferred pediatric trial under PREA to evaluate the safety and efficacy of DULERA compared to mometasone MDI in children 5 to 11 years of age with asthma. This study will be 12- 26 weeks duration. Final Report Submission PMR 1658-6 Deferred pediatric trial under PREA to evaluate the longterm safety of DULERA in children 5 to 11 years of age with asthma. This study will be 26 weeks duration with a 6 month extension. Final Report Submission PMR 1751-1 A randomized, double-blind, 26-week, active-controlled clinical trial comparing Dulera (mometasone furoate and formoterol fumarate) Inhalation Aerosol and mometasone furoate to evaluate the risk of serious asthma outcomes (hospitalizations, intubation, death) in 11,700 adult and adolescent patients 12 years of age and older with persistent asthma. Final Report Submission PMR 1 Deferred pediatric study under PREA for the treatment of candidemia and Candida infections in pediatric patients ages 0 to 3 months. Final Report Submission PMR 1658-1 Deferred pediatric trial under PREA to compare the pharmacodynamics of DULERA with and without a spacer in children 5 to 11 years of age. Final Report Submission Page 1 of 10 US Postmarketing Requirements Status as of 08-Jul-2013 TRADE NAME (generic name) EMEND (aprepitant) DUE DATE STATUS EXPLANATION OF STATUS PMR DESCRIPTION 31-Oct-2013 Ongoing One study completed and reported, two studies ongoing. EMEND (aprepitant) 31-Oct-2013 Ongoing One study completed and reported, two studies ongoing. EMEND (aprepitant) 31-Jan-2020 Ongoing One study ongoing and another one planned. EMEND for Injection (fosaprepitant dimeglumine) 31-Dec-2017 Ongoing One Study ongoing and another planned EMEND for Injection (fosaprepitant dimeglumine) 31-May-2014 Ongoing PMR 1663-1 A PK/PD study to characterize aprepitant PK parameters following administration of a single dose of intravenous fosaprepitant, in combination with a 5HT3 antagonist and dexamethasone, in pediatric cancer patients ages 0 to 17 years undergoing treatment with highly emetogenic chemotherapy. You must conduct this study with an age appropriate formulation. Final Report Submission EMEND for Injection (fosaprepitant dimeglumine) 31-Dec-2017 Pending PMR 1663-2 An adequate, placebo-controlled, double-blind, randomized, add-on design, superiority study to evaluate the safety and efficacy of a single dose of intravenous fosaprepitant, in combination with a 5HT3 antagonist, as compared to standard therapy (a 5HT3 antagonist) in pediatric cancer patients ages 0 to 17 years undergoing treatment with highly emetogenic chemotherapy. You must conduct this study with an age appropriate formulation. Final Report Submission ISENTRESS (raltegravir potassium) 30-Apr-2013 Submitted PMR 1395-7 Deferred pediatric studies in patients 2 years to 17 years of age for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin until December 31, 2007. Final Report Submission PMR 331-1 Deferred pediatric study under PREA for the use of Emend (aprepitant) in the prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy in pediatric patients 6 months to less than 17 years of age. Final Report Submission PMR 574-1 Deferred pediatric study under PREA for the treatment of post-operative nausea and vomiting pediatric patients ages 0 to less than 17 years of age. Final Report Submission PMR 1450-1 A study in adolescents and younger pediatric patients receiving emetogenic chemotherapy (HEC or MEC) to evaluate fosaprepitant PK, safety, and tolerability. Final Report Submission PMR 1880-1 Conduct a clinical trial to evaluate the effect of coadministration and staggered administration of calcium- or magnesium/aluminum-containing antacids on the pharmacokinetics of raltegravir in HIV-infected subjects on a stable raltegravir-containing regimen. Final Report Submission Page 2 of 10 US Postmarketing Requirements Status as of 08-Jul-2013 TRADE NAME (generic name) ISENTRESS (raltegravir potassium) DUE DATE STATUS EXPLANATION OF STATUS PMR DESCRIPTION 30-Jun-2011 Fulfilled ISENTRESS (raltegravir potassium) 30-Jun-2011 Delayed ISENTRESS Chewable Tablets (raltegravir potassium) 31-Jan-2015 Released PMR 1846-1 Deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric subjects from ages 0 to <4 weeks of age. The study will determine the safety, antiviral activity and pharmacokinetic profile of raltegravir in neonates. The antiviral activity will be based on the results of virologic response over at least 24 weeks of dosing and safety will be monitored for a minimum of 24 weeks. Final Report Submission ISENTRESS Chewable Tablets (raltegravir potassium) 31-Jan-2015 Pending PMR 1881-1 Deferred pediatric study under PREA to evaluate the safety and pharmacokinetics of raltegravir in HIV-exposed neonates (born to HIV-infected mothers). This multiple-dose pharmacokinetic and safety study will evaluate raltegravir in addition to the standard of care in HIVexposed neonates from ages 0 to 4-6 weeks. HIV-exposed neonates will have safety assessments, on or off treatment (as appropriate), for a minimum of 24 weeks after start of raltegravir therapy. Final Report Submission JANUMET (sitagliptin phosphate (+) metformin hydrochloride) 15-Jun-2011 Fulfilled Per FDA letter dated 02/01/2013, this PMR 1603 A 3-month pancreatic safety study in a diabetic rodent model PMR has been fulfilled. treated with sitagliptin. Final Report Submission PMR 582-2 Deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric subjects from 2 to 18 years of age. This study will determine raltegravir exposure (pharmacokinetic profile) followed by 24 weeks of dosing. Efficacy will be based on viral load reduction through 24 weeks of dosing and safety will be monitored for a minimum of 24 weeks to support raltegravir dose selection, safety, and efficacy in this population. Final Report Submission FDA acknowledged new target date of 1/5/2015 for study report. PMR 582-3 Deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric subjects from 4 weeks to 2 years of age. This study will determine raltegravir exposure (pharmacokinetic profile) followed by 24 weeks of dosing. Efficacy will be based on viral load reduction through 24 weeks of dosing and safety will be monitored for a minimum of 24 weeks to support raltegravir dose selection, safety, and efficacy in this population. Final Report Submission Page 3 of 10 US Postmarketing Requirements Status as of 08-Jul-2013 TRADE NAME (generic name) JANUMET (sitagliptin phosphate (+) metformin hydrochloride) DUE DATE STATUS EXPLANATION OF STATUS 25-Apr-2018 Ongoing JANUMET XR (sitagliptin phosphate (+) metformin hydrochloride) 01-Jun-2014 Pending PMR 1802-1 A pharmacokinetic study of JANUMET XR in pediatric patients 10 through17 years of age (inclusive) with type 2 diabetes mellitus. Final Report Submission JANUMET XR (sitagliptin phosphate (+) metformin hydrochloride) 01-Mar-2017 Released Released and replaced with new PMR 1802-3 PMR 1802-2 A 54-week, randomized, double-blind placebo-controlled trial to evaluate the efficacy and safety of JANUMET XR vs. metformin in pediatric patients who are inadequately controlled on diet and exercise. You must also evaluate whether pediatric patients can safely swallow JANUMET XR over the course of the trial. Final Report Submission JANUMET XR (sitagliptin phosphate (+) metformin hydrochloride) 01-Mar-2017 Pending PMR 1802-3 A 54-week, randomized, double-blind placebo-controlled trial to evaluate the efficacy and safety of JANUMET XR versus metformin extented-release in pediatric patients who are inadequately controlled on metformin immediate release. You must also evaluate whether pediatric patients can safely swallow JANUMET XR over the course of the trial. Final Report Submission JANUVIA (sitagliptin phosphate) JANUVIA (sitagliptin phosphate) 15-Jun-2011 Fulfilled 25-Apr-2018 Ongoing JUVISYNC (sitagliptin phosphate (+) simvastatin) 31-Jul-2015 Pending NOXAFIL (posaconazole) 15-Sep-2011 NOXAFIL (posaconazole) 20-Oct-2011 One study completed and reported, one study ongoing. PMR DESCRIPTION PMR 856-1, Deferred pediatric study under PREA for the treatment of type 2 diabetes in pediatric patients ages 11 to 16, inclusive. Final Report Submission Per FDA letter dated 02/01/2013, this PMR has been fulfilled. One study completed and reported, one study pending. PMR 1602 A 3-month pancreatic safety study in a diabetic rodent model treated with sitagliptin. Final Report Submission PMR 224-1, Deferred pediatric study under PREA for the treatment of type 2 diabetes in pediatric patients ages 11 to 16, inclusive. Final Report Submission PMR 1826-1 A randomized, double-blind, active-controlled clinical trial to study the effect of sitagliptin and simvastatin fixed-dose combination versus sitagliptin on glycemic control in type 2 diabetic patients on background metformin therapy. Final Report Submission Delayed FDA acknowledged new target date of 4/15/2016 for study report. PMR 28-3 Deferred pediatric study under PREA for the prophylaxis of invasive Aspergillis and Candida infections in patients, who are at risk of developing these infections in pediatric patients two years to twelve years of age. Final Report Submission Delayed FDA acknowledged new target date of 7/1/2017 for study report. PMR 864-1 Deferred pediatric study under PREA for the treatment of oropharyngeal candidiasis in pediatric patients ages zero to sixteen years of age. Final Report Submission Page 4 of 10 US Postmarketing Requirements Status as of 08-Jul-2013 TRADE NAME (generic name) PEGINTRON (peginterferon alfa-2b) DUE DATE STATUS EXPLANATION OF STATUS PMR DESCRIPTION 31-Mar-2014 Ongoing PMR Completion of the 5-year follow-up observational study of subjects enrolled in Part 2 of the pediatric study P02538, to assess long-term or delayed toxicity including the effect of PegIntron on height and weight and the durability of treatment response. Submit data for at least 50 pediatric subjects completing the 5 year follow-up. Final Report Submission SAPHRIS (asenapine maleate) 01-Dec-2016 Ongoing SAPHRIS (asenapine maleate) 01-Dec-2016 Ongoing PMR 1496-1 A deferred pediatric study under PREA for the treatment of schizophrenia in pediatric patients ages 13 to 17 years. A study to obtain pharmacokinetic data and provide information pertinent to dosing of asenapine sublingual tablets in the relevant pediatric population. Final Report Submission PMR 1496-2 A deferred pediatric study under PREA for the treatment of schizophrenia in pediatric patients ages 13 to 17 years. A study of the efficacy and safety of asenapine sublingual tablets in the relevant pediatric population. Final Report Submission SAPHRIS (asenapine maleate) 01-Dec-2016 Ongoing PMR 1496-3 A deferred pediatric study under PREA for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder ages 10 to 17 years. A study to obtain pharmacokinetic data and provide information pertinent to dosing of asenapine sublingual tablets in the relevant pediatric population. Final Report Submission SAPHRIS (asenapine maleate) 01-Dec-2016 Ongoing SINGULAIR (montelukast sodium) 31-Dec-2009 Fulfilled SINGULAIR (montelukast sodium) 31-Dec-2009 Fulfilled SINGULAIR (montelukast sodium) 31-Dec-2009 Fulfilled PMR 1496-4 A deferred pediatric study under PREA for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder ages 10 to 17 years. A study of the efficacy and safety of asenapine sublingual tablets in the relevant pediatric population. Final Report Submission PMR Deferred pediatric study under PREA for the prevention of exerciseinduced bronchoconstriction in pediatric patients ages 4 - 14 years of age. NDA 20-829. Final Report Submission PMR Deferred pediatric study under PREA for the prevention of exerciseinduced bronchoconstriction in pediatric patients ages 4 - 14 years of age. NDA 20-830. Final Report Submission PMR Deferred pediatric study under PREA for the prevention of exerciseinduced bronchoconstriction in pediatric patients ages 4 - 14 years of age. NDA 21-409. Final Report Submission Page 5 of 10 US Postmarketing Requirements Status as of 08-Jul-2013 TRADE NAME (generic name) SYLATRON (peginterferon alfa-2b) DUE DATE STATUS EXPLANATION OF STATUS PMR DESCRIPTION 30-Dec-2011 Fulfilled PMR #1 To develop a validated, sensitive, and accurate assay for the detection of neutralizing antibodies to peginterferon alfa-2b, including procedures for accurate detection of neutralizing antibodies to peginterferon alfa-2b in the presence of peginterferon alfa-2b levels that are expected to be present in the serum or plasma at the time of patient sampling. In the event such an assay cannot be developed, evidence of due diligence in attempting to develop the assay will be provided. Final Report Submission SYLATRON (peginterferon alfa-2b) 15-Jul-2020 Ongoing PMR #2 To conduct a randomized, multicenter, observation-controlled trial of peginterferon alfa-2b as adjuvant therapy in 1200 patients with ulcerated primary cutaneous melanoma with negative sentinel lymph node biopsy (T1b-T4bN0M0) randomized 1:1 to peginterferon alfa-2b 3.0 mcg/kg SC administered weekly for 24 months or observation alone for 24 months. The trial will characterize toxicity of treatment, specifically debilitating fatigue, depression, and anorexia, and evaluate relapse-free survival (RFS). Secondary endpoints will include overall survival. The trial will be powered to detect an increase in RFS rate by 6.8% at 2 years, by 9.4% at 5 years, and by 10% at 10 years. The trial will be powered to detect a hazard ratio of 0.7 for overall survival. The trial design and statistical analysis plan must adequately address the comments provided to you in our December 10, 2010, letter to IND 7194 regarding proposed trial 18081. Final Report Submission SYLATRON (peginterferon alfa-2b) 31-May-2014 Pending PMR #3 To conduct a clinical trial that will assess the effect of peginterferon alfa-2b on the QT/QTc interval. This QT assessment must be performed in an adequate number of subjects receiving the highest clinical dose approved and at the steady state maximum therapeutic exposure that is anticipated in patients with melanoma to ensure that changes of 20 ms in QTc interval can be excluded. ECG with timematched PK samples will be collected at the anticipated steady state concentration and across the entire dosing interval at steady state. ECGs will be collected in replicates and centrally read. Statistical analyses will include central tendency analysis, concentration-QT analysis and categorical analysis. Final Report Submission Page 6 of 10 US Postmarketing Requirements Status as of 08-Jul-2013 TRADE NAME (generic name) SYLATRON (peginterferon alfa-2b) DUE DATE STATUS EXPLANATION OF STATUS PMR DESCRIPTION 30-Apr-2012 Fulfilled PMR #4 To conduct an assessment of anti-drug antibody (ADA) and neutralizing ADA responses to peginterferon alfa-2b with validated assays capable of sensitively detecting ADA responses in the presence of peginterferon alfa-2b levels that are expected to be present at the time of patient sampling. ADA responses will be evaluated in all available samples from Trial EORTC 18991. Samples tested positive for binding ADA will be evaluated for neutralizing ADA responses. The final report will include information on the level of peginterferon alfa-2b in each patient's test sample at each sampling time point. Final Report Submission SYLATRON (peginterferon alfa-2b) 31-May-2014 Pending PMR #5 To conduct a drug interaction trial in 24 healthy subjects receiving subcutaneous peginterferon alfa-2b 6 mcg/kg once weekly for four weeks with probe substrates for multiple cytochrome P450 enzymes administered before the first dose and after the last dose of peginterferon alfa-2b. Pharmacokinetic blood and urine samples will be collected after the administration of the probe substrates and peginterferon alfa-2b (up to 168 hours) to measure enzyme activities and peginterferon alfa-2b systemic exposure. Final Report Submission SYLATRON (peginterferon alfa-2b) 31-Aug-2013 Ongoing PMR #6 To conduct a dedicated clinical trial assessing the safety and pharmacokinetics (PK) of peginterferon alfa-2b in accordance with the FDA Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function - Study Design, Data Analysis and Impact on Dosing and Labeling. The renal function subgroups should have similar demographic characteristics with respect to age, gender and weight. The number of patients enrolled in the trial should be sufficient to detect clinically important PK differences that would warrant dosage adjustment recommendation. The frequency and duration of blood sampling should be sufficient to accurately estimate relevant PK parameters for the parent drug. A data analysis plan should be included in the final protocol submitted to FDA. Final Report Submission Page 7 of 10 US Postmarketing Requirements Status as of 08-Jul-2013 TRADE NAME (generic name) VICTRELIS (boceprevir) DUE DATE STATUS EXPLANATION OF STATUS PMR DESCRIPTION 31-May-2013 Released PMR 1767-01 Conduct a single-dose pharmacokinetics study of boceprevir in treatment naïve pediatric subjects 3 through 17 years of age to determine weight-based dosing for children that will result in exposures similar to those observed in adults. Final Report Submission. VICTRELIS (boceprevir) 31-Jul-2012 Fulfilled VICTRELIS (boceprevir) 31-Oct-2015 Released PMR 1767-10 Conduct an in vivo drug-drug interaction trial between boceprevir and a selective serotonin reuptake inhibitor (SSRI) (e.g. escitalopram). Final Report Submission PMR 1767-2 Conduct a trial to evaluate safety and treatment response of boceprevir in combination with pegylated interferon and ribavirin as measured by sustained virologic response (SVR) in pediatric subjects 3 through 17 years of age, including previously untreated subjects and those who have failed a prior course of pegylated interferon and ribavirin therapy. This trial should include at least 5 years follow-up of pediatric subjects to characterize long-term safety of boceprevir, including growth assessment and sexual maturation in pediatric subjects, to determine the durability of response and to characterize boceprevir resistanceassociated substitutions. Final Report Submission VICTRELIS (boceprevir) 31-Jul-2012 Fulfilled PMR 1767-3 Conduct a study to assess the impact of boceprevir treatment-emergent NS3 amino acid substitutions (those that have been observed but not characterized phenotypically) on the anti-HCV activity of boceprevir in the HCV replicon system. Potentially novel resistanceassociated substitutions should also be evaluated. The HCV replicon genotype/subtype background used should be consistent with the background in which the specific substitutions have been observed in treated patients. Evaluations should include HCV replicons with previously characterized resistance-associated substitutions spanning the range of susceptibilities as reference standards. Specific examples of substitutions to be assessed include the following: a. D168N, with and without linked R155T, genotype 1a replicon b. V107I, with and without linked V36M+R155K, genotype 1a replicon c. P146S, with and without linked V36M+R155K, genotype 1a replicon d. I170V, genotype 1a replicon e. V36M, R155K and V36M+R155K, genotype 1a replicon Final Report Submission Page 8 of 10 US Postmarketing Requirements Status as of 08-Jul-2013 TRADE NAME (generic name) VICTRELIS (boceprevir) DUE DATE STATUS EXPLANATION OF STATUS PMR DESCRIPTION 30-Apr-2013 Fulfilled PMR 1767-4 Conduct pooled analyses to characterize the impact of detectable baseline boceprevir resistance-associated polymorphisms on the efficacy of boceprevir + Peg-IFNa/RBV treatment regimens among subjects who (1) respond relatively poorly to the Peg-IFNalpha/RBV 4week lead-in (e.g., <1 log10 IU/mL decline, greater than or equal to 1 log10 IU/mL to <2 log10 IU/mL decline, etc.), or (2) have an unfavorable IL28B genotype (if data are available). These pooled analyses should be conducted using data from the following completed and currently ongoing boceprevir clinical trials: P03523, P05216, P05101, P05411, P05685, and P06086. These analyses should be completed, and a study report submitted, within 9 months of collection of SVR outcome data from these clinical trials. Final Report Submission VICTRELIS (boceprevir) 31-Jul-2012 Fulfilled PMR 1767-5 Conduct a study to analyze NS3/4A protease cleavage sites for the presence of boceprevir treatment-emergent substitutions for a selected subset of subjects (n~10) representative of the virologic failure responses and NS3 protease resistance patterns observed in Phase 3 trials. An additional subset of subjects (n~10) who experienced virologic failure, but for whom no clear resistance-associated substitutions in NS3/4A were detected, should also be analyzed for the presence of boceprevir treatment-emergent substitutions in NS3/4A protease cleavage sites. Final Report Submission VICTRELIS (boceprevir) 31-Jul-2012 Fulfilled PMR 1767-6 Report results from ongoing clinical trial P05063 regarding the long-term persistence of amino acid substitutions that emerged in boceprevir-treated subjects from the following Phase 2 and Phase 3 trials conducted to date: P03523, P03659, P05216 and P05101. For long-term, follow-up analyses of subjects from the Phase 3 trials (P05216 and P05101), if available, the same assay/vendor used initially to identify the treatment-emergent substitutions should continue to be used to monitor the persistence of the substitutions in the follow-up period. The persistence of detectable amino acid substitutions should be assessed for a treatment-free follow up period of approximately 2 years. Final Report Submission Page 9 of 10 US Postmarketing Requirements Status as of 08-Jul-2013 TRADE NAME (generic name) VICTRELIS (boceprevir) DUE DATE STATUS EXPLANATION OF STATUS PMR DESCRIPTION 31-Jul-2012 Fulfilled PMR 1767-7 Conduct an in vivo drug-drug interaction trial between boceprevir and an oral contraceptive containing a progesterone component other than drospirenone. Final Report Submission VICTRELIS (boceprevir) 31-Mar-2012 Fulfilled VICTRELIS (boceprevir) 30-Apr-2012 Fulfilled VICTRELIS (boceprevir) 31-Aug-2016 Ongoing PMR 1767-8 Conduct an in vivo drug-drug interaction trial between boceprevir and methadone. Final Report Submission PMR 1767-9 Conduct an in vivo drug-drug interaction trial between boceprevir and a sensitive substrate of p-glycoprotein (e.g. digoxin). Final Report Submission PMR 2034-1 Evaluate single-dose pharmacokinetics (PK) of boceprevir in treatment-naïve pediatric subjects 3 through 17 years of age to determine weight-based dosing for children that will result in exposures similar to those found to be safe and effective in adults. Using dose(s) selected based on the PK evaluation and agreed upon with the FDA, evaluate safety and treatment response of boceprevir in combination with pegylated interferon and ribavirin. Treatment response should be measured by sustained virologic response (SVR) in all pediatric subjects including previously untreated subjects and those who have failed a prior course of pegylated interferon and ribavirin therapy. Final Report Submission VICTRELIS (boceprevir) 31-Aug-2021 Ongoing PMR 2034-2 Collect long-term safety data for subjects enrolled in the pediatric boceprevir safety and treatment trial. Data collected should include at least 5 years of follow-up in order to characterize the longterm safety of boceprevir in pediatric patients, including growth assessment, sexual maturation and characterization of boceprevir resistance-associated substitutions in viral isolates from subjects failing therapy. Long-term Final Report Submission ZETIA (ezetimibe) 31-Dec-2019 Released PMR 1806-1 Pediatric Plan in Adolescents at High Risk for Cardiovascular Disease with Primary Hypercholesterolemia. Final Report Submission Page 10 of 10