CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`202895Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Cross-Discipline Team Leader Review— Amendment
`
`
`Date
`December 8, 2011
`
`From
`Yodit Belew, M.D.
`
`Subject
`NDAIN DA #
`
`Cross-Discipline Team Leader Review Amendment
`202895/21976
`
`8-20 (to NDA 21976)
`Supplement #
`
`Applicant
`Tibotec, Inc.
`Date of Submission
`March 29, 2011
`PDUFA Goal Date
`Se otember 30, 2011
`
`
`Proprietary Name I
`Established USAN names
`
`Dosage forms I Strength
`
`Prezista(darunavir)
`
`New proposed dosage form: Oral Suspension
`A roved dosa-e forms: 600, 400, 150, 75 mo tablets
`
`
`
`Proposed lndication(s)
`Recommended:
`
`Treatment of HIV infection
`Approval
`
`This amendment summarizes two important events that occurred after review of the
`pediatric data to NDAs 202895 and 21976 were completed. The first section of this
`amendment addresses the revised dosing recommendations that have been made for
`children 3 years of age and older and weighing 10 to less than 15 kg. The second
`section addresses why an action was not taken on the PDUFA goal date, September 30,
`2011. Specifically, it discusses the information submitted by the Applicant which was
`considered a major amendment, what conclusions the review team reached after review
`of the information, and what the final recommendation is for the application.
`
`Section 1
`
`A revision to the dosing recommendation has been made by the Division and
`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 the recommendation that the 20/3 mg/kg instead of "M" mg/kg
`be approved for dosing in children 10— <15kg:
`
`o The Applicant submitted a revision to the population PK analysis to correct for an
`error, primarily in subjects weighing 10 - <15 kg.
`
`15 to <20 k --
`
`After Dose Ad'ustment
`10 to <15 k
`140%
`153%
`
`128%
`129%
`
`122%
`113%
`
`Table 1 Comparative result of the mean AUC in the initial and adjusted dosage regimens
`to the mean target adult exposure of 62.3 mcg/mL*hr
`— Before Dose Ad'ustment
`—_ 10 to <15 k
`Oriinal Anal sis
`107%
`111%
`107%
`110%
`Source: Applicant’s revised submission
`
`15 to <20 k
`104%
`
`Reference ID: 3058332
`
`

`

`Based on this revised analysis, subjects weighing 10 to <15 kg have mean AUC
`exposure that is 53% higher that the targeted mean adults exposure value.
`
`• Changes in the dosing device
`
`As discussed in the CDTL memo, DMEPA had recommended that the originally
`proposed
`be replaced by a syringe that is similar to what is currently available in
`the U.S. market. The Applicant submitted an alternative device (syringe) for marketing
`and has been accepted and recommended for approval by DMEPA. Although this
`syringe is similar to what is available in U.S. pharmacies, the dosing increments are
`much closer compared to the originally proposed
`. Therefore, less precision could
`be expected when drawing the medication. Although this decrease in precision is likely
`to be by small amounts, it can potentially add to the overall increased dose of darunavir
`25/3 mg/kg, in particular for those weighing 10 to <15 kg.
`
`In addition to the already higher exposure expected with the 25/3 mg/kg dosing, one
`could consider adding yet another level of complexity: a drug-drug-interaction scenario
`where the exposure could be further pushed to significantly higher exposure where no
`supportive safety data is available from the adult or pediatric trials.
`
`We therefore reevaluated the PK/PD, antiviral activity and safety data for the two doses
`as well as the adult trials C202 and C213.
`
`
`Pharmacokinetics The pre-defined targeted exposure was to be within 80%-130% of the
`mean adult AUC value (62.3) at the 600/100 mg dose. The mean AUC value at the 20/3
`mg/kg dose falls within this range. On the other hand, the mean AUC value at the 25/3
`mg/kg falls outside the range of the target- i.e. 53% higher than adult mean AUC. As
`previously discussed and demonstrated, the data analysis exposure-response/efficacy in
`the treatment experienced adults did not demonstrate a relationship for the two variables
`even when considering doses as low as 400 mg QD. Therefore the exposure-response
`information does not support the need for a higher darunavir dose. Had the 20/3 mg/kg
`yielded exposures below the targeted adult mean value, it would be reasonable to
`consider and accept the
` mg/kg in order to avoid under dosing in children. But such
`is not the case.
`
`The standard for pediatric HIV drugs approval within the Agency is primarily based on
`PK data- matching the pre-specified adult parameters. Efficacy (or antiviral activity) and
`safety data collected during the trials are used as supportive evidence. This is due to the
`nature of HIV pediatric trials- single arm, open label and not powered for true efficacy
`demonstration. In the case of C218, the primary endpoint- the pre-specified
`pharmacokinetic parameter was met with the 20/3 mg/kg dose.
`
`One of the concerns about selecting the 20/3 mg/kg dose is the lack of long term
`antiviral activity/efficacy data. In order to address this issue, we looked at the mean
`exposure period for the 20/3 dose and also considered the patient population – what the
`average age is at the 10-<15 kg weight band and compared it to the treatment
`experienced adult population from studies C202 and C213.
`
`Duration of exposure Although the 20/3 mg/kg dose is referred to as the initial dose
`(Week 2), the mean exposure time (weeks) for this dose is 12.9 weeks. Therefore there
`
`Reference ID: 3058332
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`is antiviral activity data for the 20/3 mg/kg dosing beyond a 2-week period. As
`summarized in the figure below, response rate was upward and positive during the first
`~16 weeks.
`
`
`
`Figure 1A and B: Virologic Response Defined as the Percentage of Subjects with Viral
`Load <50 copies/mL (A) and <400 copies/mL (B) [ITT- TLOVR) Over Time
`
`
`
`Patient population: The subjects enrolled in the adult clinical trials C202 and C213 were
`heavily treatment experienced. The mean time since first ART initiation (months) was
`114 for C202 and 112 for C213. In addition, based on baseline phenotypic data, overall,
`71% of the subjects in C202 and 63% of subjects in C213 were infected with virus
`resistant to all available PIs. Despite the significant amount of resistant viruses, 56-69%
`and 36-57% of the subjects had HIV-RNA <400 copies/mL and <50 copies/mL,
`respectively at the 600/100 mg dose. Similarly 52-68% and 37-54% of the subjects had
`HIV-RNA <400 copies/mL and <50 copies/mL, respectively, at the 400/100 mg dose
`(Table 2).
`
`
`Reference ID: 3058332
`
`

`

`Table 2 Virologic outcome at Week 24
`
`
`The pediatric subjects in the 10 - <15 kg weight band are not expected to have
`comparative levels of baseline resistance as they are considerably younger. The CDC
`growth chart (below) can be utilized to estimate the age range for this weight band.
`Based on the CDC growth chart, approximately 50% of children weigh 15 kg by age 3.5
`years and less than 3 percentile weigh 15 kg by age 5.5 years.
`
`
`
`
`
`
` AGE
`
`
`
`Therefore, many if not most children weighing 10- <15 kg should not be older than 4.5
`years of age. It is extremely unlikely that pediatric patients at such age will harbor
`resistant viruses to the same extend as the adult patients did. As evident by the baseline
`disease characteristics information obtained from trial C228, there is less resistance in
`this overall 3 to <6 years-old subject population compared to adults.
`
`According to the Applicant, the median number of ARVs previously used in the pediatric
`subjects enrolled in C228 was 4; the median number of PIs, NRTIs, and NNRTIs
`previously used was 1, 2, and 1, respectively. Eleven subjects (40%) had used no PI;
`twelve subjects (44%) had used 1 PI, and 4 subjects (15%) had used ≥ 2 PIs. The
`previous PI most frequently used was lopinavir; the previous NNRTI most frequently
`used was nevirapine.
`
`
`Reference ID: 3058332
`
`

`

`Protease mutations, primary PI mutations, PI RAMs, and DRV RAMs at baseline were
`collected. The majority of subjects had no primary PI mutations (23 subjects, 85.2%) and
`no DRV RAMs (25 subjects, 92.6%) at baseline; 21 subjects (77.8%) had ≥ 3 PI RAMs.
`The median number of primary PI mutations was 0 (range: 0 - 3), the median number of
`DRV RAMs was 0 (range: 0 - 2), and the median number of PI RAMs was 4 (range: 1 -
`13). DRV RAMs L76V and L33F were observed in 1 subject and L76V was observed in
`1 other subject (CRF ID 228-0015).
`
`Finally, the number of susceptible drugs per class at baseline was also provided.
`At baseline, all subjects enrolled in the trial were infected with virus susceptible to ≥ 5
`ARVs (including PIs, NRTIs, NNRTIs, fusion inhibitor, integrase inhibitor). All subjects
`were infected with virus susceptible to DRV and most subjects had also virus susceptible
`to the other commercially available PIs (ranging between 85.7% and 95.2% for the
`different PIs).
`
`In summary, based on the baseline genotypic and phenotypic resistance profile, the
`baseline IC50 is not expected to be higher than what was observed in trials C202 and
`C213. This is an important factor as response to treatment is related to inhibitory
`quotient (IQ)- the ratio between steady state trough concentration and baseline IC50 (see
`below).
`
`Pharmacometrics: Based on the adult data (C202 and C213), virologic response is
`related to the subject’s darunavir IQ- the higher the IQ, the more likely that a subject will
`respond. The IQ appears to be primarily influenced by baseline IC50. The 600/100 mg
`BID dose in adults correlated with an IQ sufficient enough to have an acceptable
`virologic success rate. Because the 20/3 mg/kg dose leads to exposures that are within
`80 to 130% range of the adult exposure (from the 600/100 mg BID dose), and because
`the IC50 is not expected to be higher in this age group, the long term efficacy or durability
`of the 20/3 mg/kg can be expected to be similar to what was observed in treatment
`experienced adults.
`
`
`
`Safety The overall mean duration of treatment from trial start up to the cut-off date of the
`analysis was 30.5 weeks. The mean duration of treatment after dose adjustment was
`18.4 weeks. Although the 25/3 mg/kg dose appears to be generally safe and well
`tolerated for the 18.4 weeks it was administered, sparse data is available for subjects
`weighing 10 to <15 kg and with exposure >130%. Post dose adjustment, 6 subjects out
`of a total of 9 in the 10 to < 15 kg group had exposures above 130% of the target range
`for adults. Although no significant adverse events were reported, the lack of sufficient
`number of subjects in that weight band supporting higher exposure is concerning.
`
`In conclusion, I recommend the approval of this pediatric NDA (202895) with the
`following dosing recommendations:
`• 10 kg to < 15 kg: darunavir 20 mg/kg with ritonavir 3 mg/kg twice daily
`• 15 kg to < 20 kg: darunavir 375 mg with 50 mg of ritonavir twice daily
`
`
`The Applicant agrees with the dosing recommendations. Labeling revisions to the dosing
`section of the USPI are currently underway.
`
`
`
`
`Reference ID: 3058332
`
`

`

`Section 2
`
` •
`
` Background
`
`
`Trial TMC114-C228 is an international trial evaluating the pharmacokinetic, antiviral
`activity and safety of darunavir in children 3 to less than 6 years of age. The study report
`was submitted to both the US and European regulatory agencies in support of dosing
`recommendations for subjects 3 to less than 6 years of age and weighing between 10
`and 20 kg.
`
`Twenty-seven subjects were enrolled and stratified by weight band- 14 subjects (52%) in
`the 10 to < 15 kg weight group, and 13 subjects (48%) in the 15 to < 20 kg weight group.
`Table 3 summarizes the distribution of subjects by country.
`
`Table 3 Subjects enrolled in Trial 228
`Number of
`Number of
`Sites
`Subjects Enrolled
`Enrolling
`
`3
`4
`3 (2 enrolled)
`6
`2
`6
`3
`10
`1
`1
`
`Number
`Prematurely
`Discontinued
`0
`1
`0
`0
`0
`
`Country
`
`Argentina
`Brazil
`Kenya
`South Africa
`India
`
`
`As a part of the review process for marketing authorization, the EMA Inspectorate
`conducted clinical site inspections at 3 locations. On September 27, 2011, unsolicited
`new information [submission number (SN) 41] was submitted by the Applicant to NDA
`202-895. The submission contained interim clinical sites inspection reports issued by the
`EMA for trial TMC114-C228.
`
`DAVP has not routinely requested clinical site inspections for pediatric trials of
`antiretroviral drugs unless there was a specific concern identified. It should also be noted
`that the FDA does not rely on inspections conducted by other regulatory agencies to
`make regulatory decisions. As such, although the inspection reports were taken into
`consideration and reviewed, the final regulatory decision by the FDA is independent of
`other agencies.
`
`The inspection reports generated concerns about the quality of the data from the 3 sites
`inspected by EMA: a Kenyan site, which enrolled six subjects, and two South African
`sites, which together enrolled nine subjects. Because the information was submitted 3
`days before the PDUFA goal date, there was insufficient time for review of the data.
`Therefore, the information submitted was deemed a major amendment and the review
`time was extended to December 30, 2011. Furthermore, the review team needed
`additional information from the Applicant in order to conduct an adequate review. After
`the Applicant submitted the additional information requested, a full review of the
`information was conducted by the review team, in consultation with the Office of
`Scientific Inspection (OSI).
`
`
`
`
`Reference ID: 3058332
`
`

`

` •
`
` Deficiencies identified by the report
`
`
`The inspection reports identified several issues, ranging from ‘minor’ to ‘critical’, although
`most were considered ‘minor’ by the inspectorate.
`
`In addition, there were 2 stability/storage temperature issues identified during
`inspections: 1) storage and stability of drug product (darunavir oral suspension, and
`possibly ritonavir) at temperatures in the range of 10-30º C and 2) storage of
`blood/plasma PK samples at
`º C rather than -20º C.
`
`Please refer to the amendments by the chemistry reviewer and the clinical
`pharmacology reviewer for further detail on the issues related to plasma sample storage
`and drug product stability. In summary, it is unlikely that, storage of the drug product
`over the range of temperatures noted, before administration to patients would adversely
`affect product quality or performance. Further, storage of plasma at
` C would not
`likely adversely impact chemical stability of the analytes (darunavir, metabolites).
`
`
`The following are among the clinical violations noted from the South African sites:
`
`
`Inconsistencies in data in the Week 24 dataset when compared to the source document and when
`compared to the subset data included in the Week 48 data
`
`o
` o Procedure for identifying and classifying protocol deviations were insufficient
`
`However, in addition to the data inconsistencies between source documents and
`datasets, the violations from the Kenyan sites appear to be more serious, and also
`include ethical violations:
`
`
`o
`
`Issues with the Informed Consent Form (ICF) which arose during language translation:
`(cid:131)
`The quality of translation was not adequately assessed.
`(cid:131)
`The ICF lacked dosing and storing instructions that were included in the master
`version.
`(cid:131) Risks associated with darunavir that were included in the master version were
`omitted.
`(cid:131) Risks associated with ritonavir that were included in the master version were omitted.
`(cid:131) Questionable if the signatures of the parents for some subjects were personally dated
`by the parents or the staff.
`(cid:131) Unclear if counselors who administered the ICF had medical background and/or if
`they received training for ICF administration
`
`o Subject identifiers on source documentation were not adequate.
`
` o
`
` The clinical site, in general lacked experience and there were insufficient monitoring visits from the
`clinical research organization (CRO)
`o Handling and processing of biological samples was not adequate. Issues with the local laboratory
`(which was used for diagnostics) included: lack of daily QC checks of analytical methods; failing to
`establish its own reference range but instead used outside laboratory reference ranges; incorrect
`patient identifiers were used on laboratory reports. Of note, per trial design, all laboratory testing were to
`be performed by a central laboratory (
`).
`
`
`
`
`
`
`
`Reference ID: 3058332
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`• Applicant’s response to the inspection reports
`
`The Applicant acknowledged the issues identified by the reports and believes it to be an
`indicative of “sloppy work” and plans to implement corrective actions for future projects.
`
`With regards to the inconsistencies found between the 24 and 48 week datasets across
`the sites, the Applicant performed a detailed assessment of the datasets. Per Applicant,
`the inconsistencies identified are either additions or corrections of the Week-24 dataset,
`generally pertaining to screening and baseline data. 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, safety and efficacy conclusions of the primary
`Week-24 and Week-48 analyses.
`
`
` DAVP’s review of the inspection report and Applicant’s response
`
`
`After reviewing the inspection reports and the Applicant’s response to the reports, the
`assessment made by the review team is that none of the issues identified in the two
`South African sites were considered significant enough to recommend exclusion of the
`data from these sites. The sites generally followed GCP and the data were not
`fraudulent or fabricated. In addition, there were no ethical violations related to the
`Informed Consent Form (ICF).
`
`In addition to the major laboratory and clinical site concerns, of paramount concerns of
`the Kenyan site are the violations relating to the ICF. Based on review of the report, the
`events appear to be due to ‘sloppy work’ but the investigator had good intent.
`Nonetheless, these violations can be considered as ethical violations. Although the
`violations did not necessarily lead to unsound clinical data, it is questionable if the data
`was ethically obtained and thus questions the usability of the data to support the
`application.
`
`Darunavir is an antiretroviral drug considered essential for this pediatric age group as it
`adds meaningful therapeutic benefit for treatment of HIV infection. Therefore, it is not
`without serious deliberation that the review team concluded the data from the Kenya site
`should be excluded. When considering the necessity of the data from this site, it is
`arguable that there is no critical need of the Kenyan data to justify its inclusion because
`adequate pharmacokinetic, safety and efficacy data exists from the other clinical sites.
`Therefore, the data from the Kenyan site should be excluded from analyses used to
`support dosing recommendation in this pediatric age group. The revised efficacy
`analysis after excluding the Kenyan data is comparable to the original result: 59%
`(original dataset) vs. 58% (revised dataset).
`
`
` •
`
` •
`
` Conclusions and recommendation
`
`
`In addition to the types of clinical trial violations, one has to consider the type of disease,
`the patient population for which the study was conducted and the unmet medical need
`that exists for the patient population. Consider the following: HIV infection is a life-
`threatening disease, if untreated; the pediatric patient population is in need of additional
`antiretroviral drugs; and darunavir has been shown to be safe and effective for treatment
`
`Reference ID: 3058332
`
`

`

`of HIV infection in patients 6 years of age and older. Therefore, the data from this trial
`should be considered crucial. Unless there is ethical misconduct or fraudulent data,
`every effort should be made to utilize the data. In addition, data collected from pediatric
`research subjects (i.e. children 3 to 6 years of age) who participated with full consent
`should not be easily discarded.
`
`As stated previously, the Kenya site violations are serious and question the ethics in
`which the trial was conducted. Therefore, the data from this site should be excluded.
`However, the violations from the South African sites do not lead to conclusions that
`question the integrity of the data. In lieu of the fact that the data remains
`uncompromised, there are no scientific or ethical bases to exclude the South African
`data from analyses.
`
`In summary, the trial results were re-analyzed excluding subjects from the Kenyan site.
`The final pharmacokinetic, safety and efficacy conclusions generally remained
`unchanged.
`
`The overall recommendation for this NDA application is approval. The Applicant has
`agreed with the recommendations made by the Division (i.e. exclusion of the Kenyan
`data). Labeling changes to reflect the revised number of subjects who contributed to the
`analyses have been made by the Applicant and are acceptable.
`
`
`
`
`Reference ID: 3058332
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`YODIT BELEW
`12/14/2011
`
`Reference ID: 3058332
`
`

`

`Cross-Discipline Team Leader Review
`
`_ Seotember 9. 2011
`_ Yodit Belew. M-D-
`m3_ Cross-Discipline Team Leader Review
`NDAIN DA #
`202895/21976
`
`Supplement #
`S—20 (to NBA 21976)
`
`Applicant
`Tibotec, Inc.
`Date of Submission
`March 29, 2011
`PDUFA Goal Date
`Se tember 30, 2011
`——
`
`
`
`Established USAN names
`
`New proposed dosage form: Oral Suspension
`A- oroved dosaoe forms: 300 m- tablets, 150 mo tablets
`
`Proposed lndication(s)
`Recommended:
`
`Treatment of HIV infection
`Approval
`
`1.
`
`Introduction
`
`This review summarizes the main issues for Tibotec’s NDA seeking approval for Prezista Oral
`Suspension in pediatric patients 3 to 6 years of age and for older pediatric patients who are
`unable to swallow tablets. This review highlights the supporting pharmacokinetic, safety and
`efficacy (antiviral activity) data. Of note, Prezista Tablet Formulation is approved for use in
`HIV infected children 6 years of age and older weighing at least 20 kg. This application
`extends the intended population to 3 years of age and weighing at least 10 kg, and provides
`alternative dosing formulations for older children who cannot take the tablet formulation.
`Additionally, the NDA was granted a priority review as it pertains to pediatric population.
`
`2. Background
`
`Prezista, originally approved in June 2006, is an important product for adults and pediatric
`patients receiving antiretroviral treatment for HIV-1 infection. Prezista is recommended as a
`preferred protease inhibitor for initiation of ART in naive adult and is recommended as an
`alternative regimen to pediatric patients 6 years of age and older. The recommended dose of
`Prezista in treatment naive and experienced adult patients with no darunavir resistance
`associated substitutions is 800 mg of darunavir co-administered with 100 mg of ritonavir once
`daily. In treatment experienced adult patients with one or more darunavir resistance
`associated substitutions, the recommended dosage regimen is 600 mg of darunavir co-
`administered with 100 mg of ritonavir twice daily. The weight based dosing recommended in
`pediatric patients 6 years of age and older and weighing at least 20 kg is summarized in
`Table 1. Once daily dosing is not approved for pediatric patients
`“M"
`
`Reference ID: 301 6386
`
`

`

`Table 1 Currently Approved Darunavir/ritonavir Dose for Pediatric Patients 6 to Less Than 18
`Years of Age Weighing at Least 20 kg
`Body Weight
`
`(Kg)
`≥ 20 kg – < 30 kg
`≥ 30 kg – < 40 kg
`≥ 40 kg
`
`(Ibs)
`≥ 44 lbs – < 66 lbs
`≥ 66 lbs – < 88 lbs
`≥ 88 lbs
`
`Dose
`
`375 mg PREZISTA/50 mg ritonavir twice daily
`450 mg PREZISTA/60 mg ritonavir twice daily
`600 mg PREZISTA/100 mg ritonavir twice daily
`
`
`The proposed dosing regimen for pediatric patients 3 to 6 years of age who weigh at least 10
`kg is also weight based:
`
`
` mg/kg with ritonavir 3 mg/kg twice daily
`• 10 kg to < 15 kg: darunavir
` kg: darunavir 375 mg with 50 mg of ritonavir twice daily
`• 15 kg to <
`
`
`This current application fulfills one of the outstanding postmarketing requirements under
`Pediatric Research Equity Act (PREA): ‘Deferred pediatric study under PREA for the
`treatment of HIV-1 infection in pediatric patients 3 to 6 years of age. Please evaluate dose
`requirements and safety in treatment-experienced pediatric patients 3 to 6 years of age with
`HIV-1 infection after preliminary review of data from the 6 to 17 year olds in trial TMC114-
`C212 with the Division of Antiviral Products (DAVP)’ [requirement/commitment Number 1
`under NDA 21976 S-6]. In addition, the current application, in combination with the previously
`submitted and reviewed pediatric study in children 6 years of age and older, fulfills the
`Pediatric Written Request issued in November 2006. The Applicant has been granted
`pediatric exclusivity.
`
`
`3. CMC
`
`
`With the exception of setting dissolution test acceptance criteria, no other issues have been
`identified by the CMC reviewer. Please refer to ONDQA’s review by Mark Seggel for full
`detail. The Applicant and the ONDQA review team have agreed to the establishment of an
`interim dissolution test acceptance criterion. A Q of % at 45 minutes will be accepted as the
`interim setting while the Applicant continues to collect dissolution profiles at release and on
`stability. Refer to ‘Recommendation for other Postmarketing Requirements and
`Commitments’ under Section 9 for additional details.
`
`In addition, the Division of Medication Error Prevention and Risk Management (DMEPA)
`identified potential dosing errors with use of the proposed dosing
`. The Applicant
`included a dosing devise
` as part of the packaging for Darunavir Oral Suspension.
`Therefore, the
` was reviewed by DMEPA. Please refer to review by Loretta Holmes,
`Pharm.D for details. In summary, DMEPA was concerned that the
` is not generally
`used in the US and thus may lead to dosing errors. In addition to the lack of familiarity,
`DMEPA is concerned that the device is confusing as the measurement markings are
`displayed on the
` (i.e. opposite to the typical syringe markings found
`in the U.S.). DMEPA also reviewed dosing errors reported (via AERS) for
`, a
`suspension medication
`. DMEPA identified 2 cases of
`dosing errors that appear to be related to parent/s being confused about the devise. DMEPA
`recommended that that the proposed dosing
` be replaced with a standard oral dosing
`syringe.
`
`
`
`Reference ID: 3016386
`
`2
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`The Applicant submitted a response to the concerns outlined by DMEPA. In summary, the
`Applicant believes it is in the ‘best interests’ of their patients and their caregivers to proceed
`with the originally submitted
`"M". Their proposal considers the following points:
`0 Dosing accuracy of the originally submitted
`0”“) is confirmed with the
`oral suspension throughout the range suggested for dosing at increments
`of 0.2 mL
`
`0
`
`(him with the correct dose is achieved without inverting
`Filling of the
`the
`M“). Other products currently on the US market employing the
`dosing configuration include
`“M“.
`"M", a written instructions
`. To assist caregivers in the proper use of the dosing
`and pictographs as an aid to understanding the correct use of the
`W"
`has been prepared.
`
`0)) (4)
`
`The Applicant also submitted an alternative dosing device- a syringe, similar to the standard
`oral dosing syringe used in the US, along with an adaptor to aid in drawing the medication
`directly from the bottle without spillage. A ‘Use for Instruction’ has also been included with the
`devise.
`
`“m" provides dosing measurement with such
`I agree with the Applicant that the original
`"’"4’ which is similar to the standard U.S.
`accuracy that it is superior to the alternative
`syringes. This is an important point to consider as it affects the daily administration of the
`medication. However, DMEPA remains concerned about potential dosing error because the
`devise differs from the standard syringe that patients are used to. The alternative dosing
`device is currently under review by CMC and DMEPA.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The Applicant submitted the results of a toxicology study conducted to fulfill a post-marketing
`requirement (PMR) issued at the time of an sNDA 21,976 approval (2008). The PMR
`requested that the Applicant "perform a nonclinical reproductive study in a relevant species
`which achieves an adequate AUC exposure margin (compared to human serum exposure) in
`order to establish the safety profile of darunavir in-utero’. Refer to Dr. Laine (Peyton) Myer’s
`review for further details. The Applicant conducted the study and confirmed the in-utero
`toxicity of darunavir - incomplete ossification of a number of bones and delayed thymus
`development. The Pharmacology/Toxicology review team has determined that the study
`fulfills the PMR requirement; the label has been updated with the new reproductive toxicology
`
`study information.
`
`5.
`
`Summary of Pharmacokinetic Data
`
`Two clinical studies were conducted under the current NDA— TMC114-0228 and TMC114—
`C169.
`
`Trial C169 was a bioequivalence trial comparing a darunavir oral suspension formulation to
`darunavir tablets in healthy adult subjects. The trial was considered a pivotal trial by the
`Agency as it provided linkage between the oral suspension and tablet formulation. This is
`
`Reference ID: 301 6386
`
`

`

`important as it would support allowing pediatric patients 6 years of age and older (and adult
`patients) who are unable to swallow tablets to be able to take the suspension formulation. Of
`note, the suspension formulation was used only in trial C228; no suspension formulation was
`used in trial C212 (pediatric patients 6 years of age and older) or in any of the HIV infected
`adult clinical trials. Therefore, a consultation for site investigation was issued by the Clinical
`Pharmacology Division to the Office of Scientific Investigations (OSI). Although no 483
`observation was issued, OSI recommended that the bioequivalence results of the trial not be
`accepted because the trial did not retain samples of the drug products (i.e. test drug-
`suspension formulation or the reference drug- tablet formulation). However, it was left up to
`the review team whether the multiple pharmacokinetic data of the suspension formulation
`could be used to support dosing recommendations. The Office of Clinical Pharmacology
`determined that it was acceptable to rely on the pharmacokinetic data from the multiple
`dosing portion of the trial.
`
`Despite this limitation of lack of supportive bioequivalence data, the review team was able to
`use alternative methods to allow dosing recommendations with the oral suspension
`formulation for older pediatric patients and adult patients. This recommendation is based on
`assumption that the two formulations have similar bioavailability. Please refer to the Clinical
`Pharmacology review for further details.
`
`In summary, comparing the exposure (AUC, Cmax) data of darunavir suspension in healthy
`volunteer adults to the historical exposure data of darunavir tablets in HIV infected adults, the
`suspension formulation leads to higher exposure ( AUC higher by up to 31%; Cmax higher by
`up to 35%). However, such increases are not anticipated to result in clinically significant
`safety issues based on review of previous adult darunavir exposure-safety data.
`
`If the two formulations generally lead to similar exposures in adults, similar conclusions can
`be reached in children- that is, the two formulations would lead to generally similar exposures.
`Additionally, although there is no pharmacokinetic data available comparing exposures