CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202895Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`Clarification to Amendment 2 to MOR of NBA 202-895
`
`Dec. 13, 2011
`
`As per FAX to Applicant from the Agency regarding storage
`temperature reports in the EMA inspections:
`
`0 Please clarify whether any “M"
`data has been generated at either
`
`darunavir and ritonavir long term stability
`(5)“)
`
`0 In regards to darunavir/ritonavir samples from the TMCl l4—C228 trial that
`were stored at
`(W), please provide information on the following: a) the
`number of trial sites and the number of subjects at each site that had
`darunavir/ritonavir samples stored at m“), b) the total number of
`darunavir/ritonavir samples at each trial site that had samples stored at -
`00(4)
`-
`.
`, and c) the max1mum length of time
`
`In Amendment 2 the following statement was made:
`“The Applicant’s response to the Division’s RFI for the first question is the
`subject of this amendment. The Chemistry Reviewer, Dr. M Paciga, will
`provide an in depth review of stability and temperature issues, however his
`assessment indicated that based on stability data and reported temperature
`deviations sigpjficant changes in product gualig or performance are not
`expected.”
`
`Clarification as per Chemistry Reviewer:
`
`There were 2 stability/storage temperature issues identified during the clinical
`site inspections:
`
`1) storage and stability of drug product (darunavir oral suspension, and possibly
`ritonavir) at temperatures in the range of 10-30degC; and
`
`2) storage of blood/plasma PK samples at "’m’degC rather than -20degC.
`
`It is unlikely that storage of the drug product over the range of temperatures
`noted (all above refrigeration or freezing) before administration to patients would
`adversely affect product quality or performance.
`
`Storage of drug product at "’m’degC would likely impact product performance.
`On the other hand, storage of plasma at (”m’degC would not likely adversely
`impact chemical stability of the analytes (darunavir, metabolites).
`
`Reference ID: 3057892
`
`

`

`deg and product
`Note: MOR #2 refers erroneously to storage at
`quality/performance. As noted above plasma storage at
` would not affect
`plasma quality not drug quality. Drug product stored at specified range of
`temperatures was also not affected.
`
`Regina Alivisatos, MD
`
`
`Reference ID: 3057892
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`M R ALIVISATOS
`12/13/2011
`
`Reference ID: 3057892
`
`

`

`NDA/ 202-895/Major Amendment
`
`1
`
`Medical Officer Review
`
`Amendment to Review of NDA 202-895
`
`Date
`
`November 20, 2011
`
`Re - ina Alivisatos, M.D.
`
`Subject
`Medical Officer Review Amendment
`NDA # and Sun lement #
`NDA 202895/000 and SNDA 21976/S-20
`
`A licant
`
`Tibotec Inc.
`
`March 29, 2011
`Date of Ori_ ' I al Submission
`Se Itember 30, 2011
`Ori '_ 'nal PDUFA Goal Date
`Se tember 28, 2011
`Date of Ma'or Amendment
`
`Revised PDUFA Date
`December 30, 2011
`
`Proprietary Name / Established
`S ‘
`names
`
`Dosage forms / Strength
`
`Prezista (danmavir)
`
`New proposed dosage form: Oral Suspension
`Approved dosage forms: 300 mg tablets, 150 mg
`tablets
`
`
`
`Proposed Indication(s)
`Recommended:
`
`Treatment of HIV infection
`
`Approval
`
`This is the second amendment to the NDA package. The first, authored by the Cross
`Discipline Team Leader, Dr. Yodit Belew, dated September 26, 2011, had as its subject
`the revised dosing recommendation made by the Division for subjects weighing 10 to less
`than 15 kg. This recommendation was subsequently accepted by the Applicant.
`Specifically, the Division recommended that for subjects 3 years of age and older and
`weighing 10 to less than 15 kg, the dose should be calculated based on darunavir 20
`mg/kg co—administered with ritonavir 3mg/kg.
`
`Several reasons led to this change in dosing recommendation to 20/3 mg/kg instead of the
`Applicant’s proposed
`(hm) in subjects weighing 10— <15 kg. The primary reason
`was the Division’s assessment of a revision to the population PK analysis submitted by
`the Applicant to correct for an error, primarily in subjects weighing 10 - <15 kg. In this
`revised analysis, these subjects would have mean AUC exposure that is 53% higher that
`the targeted mean adults exposure value. As the lower dose did not present similar
`pharmacokinetic concerns and had similar efficacy and safety it was determined that this
`dose was the appropriate one to be included in labeling.
`
`In addition because of concerns that the initial dosing device supplied by the Applicant
`could lead to dosing errors, the device was changed to an
`(m4) syringe device. Details
`of this device were provided in the major amendment under review including instructions
`for use. Both the device and the instructions are acceptable to the Division as well as to
`DRISK and DMEPA.
`
`The current amendment to the MOR has been included because of the, unsolicited by the
`Division, submission on September 27, 2011 (SNDA 202-895/SN 41) by the Applicant of
`clinical sites inspection reports from the EMA for the ARIEL study (TMCl 14-C228).
`The ARIEL study was the primary pharmacokinetic and clinical study submitted in both
`
`Reference ID: 3051423
`
`

`

`NDA/ 202-895/Major Amendment
`
`2
`
`the US and Europe in support of dosing recommendations for subjects weighing between
`10 and 20 kg. The site reports generated concerns regarding the quality of the data
`submitted in support of the NDA submission from 3 of the sites including the Kenya site
`(N = 6), and two South African sites (Drs. Violari and Moultrie (N = 9). As the PDUFA
`due date of September 30, 2011 did not allow adequate time for review of the data as well
`as for the submission of additional explanatory data from the Applicant, the site
`inspection submission was deemed a major amendment and the review time was
`extended (FAX communication to Tibotec 9/29/11). In a FAX dated October 6, 2011 the
`Agency requested that the Applicant supply the following:
`
`0 Provide a copy of your assessment to the inspection reports issued by the EMA
`(CHIVIP). In addition, submit your rationale for using/accepting the data fiom the
`three sites inspected in support of pediatric labeling for children 3 to <6 years of
`age.
`
`0 Please clarify whether any mu) darlmavir and ritonavir long term stability data
`has been generated at either
`(no)
`
`0
`
`In regards to darunavir/ritonavir samples from the TMCl l4-C228 trial that were
`stored at mu), please provide information on the following: a) the number of trial
`sites and the number of subjects at each site that had darunavir/ritonavir samples
`stored at M“), b) the total number of darunavir/ritonavir samples at each trial site
`that had samples stored at M“) and c) the maximum length of time
`
`The Applicant’s response to the Division’s RFI for the first question is the subject of this
`amendment. The Chemistry Reviewer, Dr. M Paciga, will provide an in depth review of
`stability and temperature issues, however his assessment indicated that based on stability
`data and reported temperature deviations significant changes in product quality or
`performance are not expected.
`
`Review of Response to RFI Question 1:
`
`A single study "IMCI l4—C228 was submitted in support of use of darunavir in the
`pediatric population ages 3 — < 6 years (NDA 202-895). Study TMC114-C228 is the only
`study conducted in this age group and the patients were treated with a new oral solution
`formulation.
`
`Study 'IMC 1 14-C228 is an ongoing, open-label, Phase 2 trial to evaluate the
`pharmacokinetics, safety, and antiviral activity to support dose recommendations by body
`weight of damnavir in combination with low—dose ritonavir (DRV/r) and other
`antiretroviral (ARV) agents, in treatment—experienced HIV-l infected children ages from
`3 to < 6 years and weighing between 10 and < 20 kg. In addition, efficacy, safety and
`tolerability of DRV/r are being evaluated in combination with other ARVs over a 48-
`week treatment period. The study was conducted in two parts. The first two weeks of the
`
`Reference ID: 3051423
`
`

`

`NDA/ 202-895/Major Amendment
`
`3
`
`TMC114-C228 trial were designed to support dose recommendations of DRV/r in the
`studied population. The pharmacokinetic profile of DRV/r dosed twice daily at the
`initially selected dose at steady-state in the studied population was evaluated at Week 2.
`Safety, tolerability and antiviral activity were also assessed at the Week 2 timepoint.
`Based on the PK analyses and simulations, dosing was adjusted primarily at or around
`week 12 of treatment. It should be noted that although these adjustments were made,
`they were made based on inaccurate information due to the omission of certain data.
`Follow-up analyses revealed that these adjustments ultimately led to unacceptably high
`Cmax and AUC in the lower weight band but were acceptable in the upper band. Two
`weeks after the dose adjustment, an additional pharmacokinetic assessment was
`performed, followed by another planned pharmacokinetic assessment at Week 24. Safety
`and tolerability, as well as antiviral activity, were also evaluated at these time points. The
`mean duration of DRV/r treatment from trial start up to the cut-off date of the Week-24
`analysis was 30.5 weeks.
`
`Subjects received DRV/r according to their body weight. The initial dose of DRV was 20
`mg/kg in combination with ritonavir 3 mg/kg. According to their body weight, subjects
`received a DRV dose between 200 and 380 mg twice daily and a ritonavir dose between
`32 and 48 mg twice daily. DRV/r was taken together with an optimized background
`regimen (OBR).
`
`Twenty-seven treatment-experienced subjects (15 male and 12 female) were enrolled in
`the study and were stratified by weight and received DRV/r according to their respective
`weight band- 14 subjects (51.9%) in the 10 to < 15 kg weight group, and 13 subjects
`(48.1%) in the 15 to < 20 kg weight group. At the time of the Week-24 analysis, 1 subject
`had prematurely discontinued (due to an AE [vomiting], grade 2, not related to DRV).
`
`The primary efficacy endpoint in this trial was plasma viral load < 50 copies/mL at Week
`24. In the initial analysis, the virologic response defined as the percentage of subjects
`with a confirmed virologic response (plasma viral load < 50 copies/mL) was 59% (16/27)
`based on the FDA snapshot analysis. Nine subjects were classified as virologic failures
`and there was one each with missing data and no data because of early discontinuation.
`
`In Table 1 below is the distribution of patients by country. As noted above concerns
`regarding the integrity of the submitted data were raised by the EMA inspectors for the
`Kenyan and the South African sites. In dispute are 16 patients, 6 from Kenya and 10 from
`S Africa. An initial review of the inspection reports raised serious concerns about the
`Kenyan site whereas there were fewer issues noted from the S African sites.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3051423
`
`

`

`NDA/ 202-895/Major Amendment
`
`4
`
`Country
`
`Argentina
`Brazil
`Kenya
`South Africa
`India
`
`Subjects enrolled in Trial 228
`Number of
`Number of
`Subjects Enrolled
`Sites
`
`Enrolling
`3
`4
`3 (2 enrolled)
`6
`2
`6
`3
`10
`1
`1
`
`Number
`Prematurely
`Discontinued
`0
`1
`0
`0
`0
`
`
`The Applicant also submitted a Marketing Authorization Application (MAA) to EMA on
`May 4, 2011. The application consisted of trial TMC114-C228 which was also submitted
`to the US FDA. As a part of the MAA review process, between August 24 and
`September 2, 2011, the EMA Inspectorate conducted clinical site inspections at three
`sites in Kenya and S. Africa (Dr. Kimutai, Dr. Moultrie, and Dr. Violari) that were part of
`the TMC114-C228 study. The inspection reports were provided to the Applicant on Sept
`26, 2011 and subsequently provided to NDA 202-895 (sequence 0041) on Sept 29, 2011.
`The initial inspection reports consisted of multiple minor and few major and critical
`issues as defined by the EMA for each site. A finding that was common to each of the
`three inspection reports, involved inconsistencies in data in the Week 24 dataset when
`compared to the Week 48 dataset. Other issues included:
`
`
`• Lack of calibration of storage area thermometers (minor)
`• Storage temperature went below the recommendations of the sponsor (minor).
`• Lack of documentation of lower temperatures in the monitoring reports
`• No timely notification of temperature excursion(major)
`• No timely evaluation of the usage of IMP was performed by investigator site and
`sponsor (major).
`
` number of issues were specific to the Kenya site and included:
`
`• No PPB approval for the conduct of the trial from 1st September 2010 to 24th
`November 2010 due to delay in renewal (major)
`•
`Investigator TMF was not adequately maintained
`• Monitoring not adequate
`• The site was closed on the 21st June 2011, despite the fact that all necessary
`documents were not in the appropriate files
`• Ethics correspondence, including letters from the ERC (dated 24th August 2011 and
`June 24th 2011) and a notification to the ERC regarding trial closure (dated 21st June
`2011) were misfiled in the Temperature and Humidity Log Section.
`• Correspondence was not filed in chronological order.
`• Correspondence was filed in duplicate within the same section of the file, for
`example, letters to the ERC dated 28th September 2009, regarding submission of
`KEMRI protocol Version 2.0, and, dated 29th September, regarding clarification of
`approved protocols and PILs.
`
` A
`
`
`
`Reference ID: 3051423
`
`

`

`NDA/ 202-895/Major Amendment
`
`5
`
`• Correspondence was filed in duplicate across different sections for no logical reason.
`For example the Continuing Review Reports were filed in the section entitled
`“interim, annual and final reports‟ and section entitled “cover letter, application
`forms section‟.
`• Letters were on file in duplicate, but with different handwritten dates on the letters.
`For example the letter to the PPB regarding resubmission of IB, Safety Updates and
`Insurance for the trial.
`• A document entitled “KEMRI SSC Protocol \ 1570 Reviewer comments (Site
`responses embedded in bold), signed and dated by Kimutai 11th March 2009, was on
`file with the PPB correspondence.
`Issues with consent form review committee make-up as well as with the consent
`form itself and the procedures followed in obtaining informed consent. Issues
`included translation, omission of dosing instructions, the performance of genetic
`testing etc. (Critical)
`Inaccurate documentation in the eCRF of the physical exam findings at screening,
`at baseline, similar issues for previous treatments and medical history,
`
`•
`
`•
`
`
`
`The inspection reports were reviewed by the Applicant and responses were provided to
`the EMA on Oct 31, 2011 and to the Division on November 9. 2011.
`
`For the Kenya site, a review of the Applicant’s responses revealed that most of the issues
`were acknowledged as indicative of “sloppy work”. Corrective actions taken for future
`projects included a commitment by the Applicant to ensure adequate training of all
`personnel involved in a trial as well as the hiring of a specific onsite clinical monitor who
`will ensure timely and adequate documentation of all parts of the trial. Issues such as
`inadequate representation of pediatricians of the informed consent committee were also
`acknowledged and will be avoided in future trials.
`
`Comment: The Division acknowledged that the Applicant will in the future correct the
`issues that were found by the EMA inspectors however the informed consent issues are
`deemed too significant to allow for the inclusion of the data from the Kenya site into the
`data used to make a final decision regarding the approvability of the application.
`
`With regards to the inconsistencies found between the 24 and 48 week datasets across the
`sites, Tibotec performed a detailed assessment of both datasets. Overall, there were 228
`inconsistencies in the Week-24 dataset for the entire trial that were already corrected
`prior to inspection, by the time of the Week-48 analysis. When excluding the
`inconsistencies for laboratory data (a local laboratory was used for the site of Dr. Kimutai
`in Kenya, and the
` laboratory for the other sites), 130 corrected inconsistencies
`were shown to be related to the inspected sites (3 sites, 15 subjects) and 47 corrected
`inconsistencies were related to the non-inspected sites (8 sites, 12 subjects). The
`inconsistencies identified are either additions or corrections of the Week-24 dataset,
`generally pertaining to screening and baseline data.
`
`
`Reference ID: 3051423
`
`(b) (4)
`
`

`

`NDA/ 202-895/Major Amendment
`
`6
`
`There were no consequences of the inspection findings on the handling on the safety of
`the subjects in the trial (the trial subjects were monitored according to local medical
`standards). There were no negative consequences for the pharmacokinetic/efficacy/safety
`conclusions of the primary Week-24 and Week-48 analyses and the local Kenyan lab
`results did not affect the main objective of the trial.
`
`Comment: From a clinical standpoint the inclusion of all patients who received any dose
`of study drug in the safety analysis is standard procedure and the exclusion of any of the
`27 treated subjects would be unreasonable. From an efficacy standpoint however, the
`Kenya site patients were excluded for the reasons stated above. It should also be noted
`however that as per the Clinical Pharmacology Reviewer, Dr. Stanley Au, all Kenyan
`patients’ data was previously excluded from the PK analyses and therefore no changes in
`the PK conclusions were expected.
`
`The revised efficacy analysis excluding the three Kenyan patients originally included in
`the analysis (one virologic failure and two successes) is as follows:
`
`Virologic Response Defined as % of Patients with Viral Load less than 50 copies/mL
`(FDA snapshot analysis/Original Dataset)
`Week 24
`
`n (%)
`
`Virologic Success
`Virologic Failure
`No virologic data week 24-discontinued due to AE/death
`Missing data week 24
`N = # of responders, n = # of patients
`
`Virologic Response Defined as % of Patients with Viral Load less than 50 copies/mL
`(FDA snapshot analysis/Revised Dataset)
`Week 24
`
`n (%)
`
`DRV/r
`N = 27
`16 (59.3)
`9 (33.3)
`1 (3.7)
`1 (3.7)
`
`DRV/r
`N = 24
`14 (58.3)
`8 (33.3)
`1 (3.7)
`1 (3.7)
`
`Virologic Success
`Virologic Failure
`No virologic data week 24-discontinued due to AE/death
`Missing data week 24
`N = # of responders, n = # of patients
`
`
`Therefore the exclusion of the Kenya patients did not substantively alter the efficacy
`analysis.
`
`Conclusion and Recommendations: The Applicant submitted a response to the EMA
`inspection reports and deficiencies found at three of the sites where trial TMC114-C228
`took place. The inspection reports and the response constituted a major amendment to the
`
`Reference ID: 3051423
`
`

`

`NDA/ 202-895/Major Amendment
`
`7
`
`NDA package. After review of both the inspection reports and the responses the
`Reviewer concluded that the Applicant performed inadequate monitoring at the
`respective sites, however generally the deficiencies did not affect the PK, efficacy and
`safety conclusions drawn from trial 228 regarding dosing in pediatric patients ages 3 – 6
`and weighing between 10 and < 20 kgs. It was necessary to exclude the patients from the
`Kenya site because of significant deficiencies in the informed consent process. The
`exclusion of these patients did not affect the efficacy, safety or pharmacokinetic
`conclusions of trial TMC114-C228.
`
`The Reviewer recommends an approval of NDA 202-895 with labeling as agreed upon
`including dosing for patients weighing between 10 - < 15 kg at the 20/3 mg/kg dose level
`and the exclusion of the Kenya patienys’ data from the efficacy analyses presented in
`labeling.
`
`Reference ID: 3051423
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`M R ALIVISATOS
`12/13/2011
`
`Reference ID: 3051423
`
`

`

`NDA 202-895/SNDA 21976/S-20/Darunavir
`Pediatric dosing ages 3 – 6
`Oral suspension and tablet formulations
`
`CLINICAL REVIEW
`Application Type NDAs 202-895 and 21-976
`
`
`1
`
`
`
`
`Submission Number 000 and S-20
`Submission Code Type 3 and SE5
`
`Letter Date March 29, 2011/June 28, 2011
`Stamp Date March 30, 2011
`PDUFA Goal Date September 30, 2011
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reviewer Name Regina Alivisatos, M.D.
`
` Review Completion Date July 30, 2011
`
`
`
`
`
`
`Established Name Darunavir
`(Proposed) Trade Name PREZISTA
`Therapeutic Class Protease Inhibitor
`Applicant Tibotec
`
`Priority Designation P
`
`
`
`
`
`Formulation Oral Suspension 100 mg/ml
`
` Tablets 400 mg
`
`Dosing Regimen Twice daily (BID)
` Indication Treatment of HIV-1 Infection
`
`
`
`
`Reference ID: 3067080
`
`

`

`NDA 202-895/SNDA 21976/S-20/Darunavir
`Pediatric dosing ages 3 – 6
`Oral suspension and tablet formulations
`
` Intended Population Pediatric Population 3 - < 6 years
`of Age
`
`2
`
`
`
`
`Reference ID: 3067080
`
`

`

`3
`
`2
`
`3
`
`4
`
`NDA 202-895/SNDA 21976/S-20/Darunavir
`Pediatric dosing ages 3 – 6
`Oral suspension and tablet formulations
`
`TABLE OF CONTENTS
`1
`RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ..........................................................................5
`1.1
`Recommendation on Regulatory Action.....................................................................................................5
`1.2
`Risk Benefit Assessment ............................................................................................................................7
`1.3
`Recommendations for Postmarketing Risk Management Activities ..........................................................8
`1.4
`Recommendations for other Post Marketing Study Commitments.............................................................8
`INTRODUCTION AND REGULATORY BACKGROUND.........................................................................8
`2.1
`Product Information....................................................................................................................................8
`2.2
`Tables of Currently Available Treatments for Proposed Indications........................................................10
`2.3
`Availability of Proposed Active Ingredient in the United States..............................................................11
`2.4
`Important Safety Issues with Consideration to Related Drugs .................................................................11
`2.5
`Summary of Presubmission Regulatory Activity Related to Submission.................................................11
`2.6
`Other Relevant Background Information .................................................................................................13
`ETHICS AND GOOD CLINICAL PRACTICES.........................................................................................13
`3.1
`Submission Quality and Integrity .............................................................................................................13
`3.2
`Compliance with Good Clinical Practices................................................................................................13
`3.3
`Financial Disclosures................................................................................................................................14
`SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES......14
`4.1
`Chemistry Manufacturing and Controls ...................................................................................................14
`4.2
`Clinical Microbiology...............................................................................................................................14
`4.3
`Preclinical Pharmacology/Toxicology......................................................................................................15
`4.4
`Clinical Pharmacology .............................................................................................................................15
`4.4.1 Mechanism of Action...........................................................................................................................15
`4.4.2
`Pharmacodynamics ..............................................................................................................................15
`4.4.3
`Pharmacokinetics.................................................................................................................................16
`SOURCES OF CLINICAL DATA .................................................................................................................16
`5.1
`Tables of Clinical Studies.........................................................................................................................16
`5.2 Review Strategy…………………………………………………………………………………………17
`5.2
`Discussion of Study TMC114-C112 ........................................................................................................17
`REVIEW OF EFFICACY...............................................................................................................................19
`6.1
`Indication..................................................................................................................................................20
`6.1.1 Methods ...............................................................................................................................................20
`6.1.2 Demographics......................................................................................................................................21
`6.1.3 Baseline HIV Characteristics...............................................................................................................21
`6.1.4
`Patient Disposition...............................................................................................................................24
`6.1.5 Analysis of Primary Endpoint(s) .........................................................................................................24
`6.1.6 Analysis of Secondary Endpoint(s)......................................................................................................26
`6.1.7 Other Endpoints...................................................................................................................................27
`6.1.9 Analysis of Clinical Information Relevant to Dosing Recommendations ...........................................31
`6.1.10
`Discussion of Persistence of Efficacy and/or Tolerance Effects.....................................................33
`6.1.11
`Additional Efficacy Issues/Analyses...............................................................................................33
`REVIEW OF SAFETY....................................................................................................................................33
`7.1
`Methods....................................................................................................................................................34
`7.1.1 Clinical Studies Used to Evaluate Safety.............................................................................................34
`7.1.2 Adequacy of Data ................................................................................................................................34
`7.2
`Adequacy of Safety Assessments .............................................................................................................34
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations............34
`
`5
`
`6
`
`7
`
`
`
`
`Reference ID: 3067080
`
`

`

`4
`
`NDA 202-895/SNDA 21976/S-20/Darunavir
`Pediatric dosing ages 3 – 6
`Oral suspension and tablet formulations
`
`7.2.2
`Explorations for Dose Response..........................................................................................................35
`7.2.3
`Special Animal and/or In Vitro Testing...............................................................................................35
`7.2.4 Routine Clinical Testing ......................................................................................................................35
`7.2.5 Metabolic, Clearance, and Interaction Workup ...................................................................................35
`7.2.6
`Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .........................................35
`7.3
`Major Safety Results ................................................................................................................................35
`7.3.1 Deaths ..................................................................................................................................................35
`7.3.2 Nonfatal Serious Adverse Events (SAEs)............................................................................................36
`7.3.3 Dropouts and/or Discontinuations .......................................................................................................37
`7.3.4
`Significant (Grade 3 and/or 4) Adverse Events ...................................................................................37
`7.3.5
`Submission Specific Primary Safety Concerns....................................................................................39
`7.4
`Supportive Safety Results.........................................................................................................................43
`7.4.1 Common Adverse Events ....................................................................................................................43
`7.4.2
`Laboratory Findings.............................................................................................................................46
`7.4.3 Vital Signs ...........................................................................................................................................46
`7.4.4
`Electrocardiograms (ECGs).................................................................................................................46
`7.4.5
`Immunogenicity...................................................................................................................................46
`7.5
`Other Safety Explorations ........................................................................................................................47
`7.5.1 Dose Dependency for Adverse Events.................................................................................................47
`7.5.2 Drug-Demographic Interactions ..........................................................................................................47
`7.5.3 Drug-Disease Interactions....................................................................................................................47
`7.5.4 Drug-Drug Interactions........................................................................................................................47
`7.6
`Additional Safety Explorations.................................................................................................................47
`7.6.1 Human Carcinogenicity .......................................................................................................................47
`7.6.2 Human Reproduction and Pregnancy Data..........................................................................................47
`7.6.3
`Pediatrics and Effect on Growth..........................................................................................................47
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...............................................................48
`7.7
`Additional Submissions............................................................................................................................48
`POSTMARKETING EXPERIE