CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`201688s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`Date
`August 20, 2012
`From
`Eileen Navarro, IVID
`Cross-Disci line Team Leader Review
`
`
`
`NBA #
`Sun lement#
`
`A licant
`
`NBA 201, 688 (IND 64409)
`8000
`
`Novartis Pharmaceuticals Co oration
`
`Date of Submission
`
`PDUFA Goal Date
`
`21-DEC—2011
`
`19-OCT-2012
`
`GRMP Goal Date
`
`l6-SEP-2012
`
`Proprietary / Established TOBI PodhalerTM
`S ‘
`names
`Tobram cin
`
`Dosage forms / Strength
`
`Four - 28 mg capsules administered twice daily, in two
`inhalations per tablet for a total of 4 capsules (8 inhalations) per
`dose in a 28 day cycle of treatment followed by 28 days off
`treatment.
`
`Proposed Indication(§)
`Recommended:
`
`Treatment of CF patients with chronic P. aeruginosa infections.
`A I IT'OVG] with Postmarketin ' Re m'rements
`
`0 Summary:
`The drug product proposed in this NDA505b(l) submission, TOBI® PodhalerTM (tobramycin
`inhalation powder), is a dry powder formulation, intended as alternative to the currently
`marketed product tobramycin solution in saline. It is the first antimicrobial powder developed
`for any respiratory indication. At issue is whether the this alternative formulation, delivered
`via a novel device, affords similar benefits and assures similar safety as the identical drug
`substance marketed as a liquid solution, so as to serve as a treatment alternative for cystic
`fibrosis in patients ages 6 and older, who are chronically colonized with Pseudomonas
`aemginosa. One of two placebo controlled trials concludes significant benefit using the FEVl
`increment endpoint at 1 month, whereas the other trial failed recruitment goals and the
`difference favoring the new drug was not statistically conclusive of a benefit. In a large
`comparative safety study, cough and upper airway adverse reactions, none serious, were seen
`with TIP compared to TOBI. A similar increment in FEVl was seen with TIP compared to the
`standard of care, and notwithstanding a greater need for rescue oral antimicrobial, rates of
`hospitalization and intravenous antibiotic therapy were similar between the two study aims.
`Three deaths, all in the TIP arm are attributed to breakthrough infectious exacerbation of CF.
`Following treatment, more resistant P. aeruginosa isolates were seen in the TIP aim; the
`increment in MIC for this small number of isolates was disproportionately higher than seen
`with TOBI. There are no minimum inhibitory concentrations MC) standards established for
`resistance in P aeruginosa airway infections; resistance as defined by MICs for systemic
`infections has not been shown to correlate with treatment failures in CF and other airway
`infections. Increased adherence was not seen with TIP, compared to TOBI, despite the shorter
`drug administration time, and the portability and simplified maintenance of the inhaler.
`A single placebo-controlled (2301) study provides a direct measure of treatment effect in this
`drug development program, for an endpoint demonstrated to correlate in the long term with
`increased survival. The applicant also concludes noninferior efficacy of TIP relative to TOBI,
`
`Page 1 of 24
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`Reference ID: 31 98426
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`Cross Discipline Team Leader Review
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`using the same pulmonary flmction endpoint, in a comparative trial (2302) although the
`margin of benefit was not justified sufficiently apriori. The Agency, however, has adequate
`experience in placebo controlled trials for this endpoint in this indication, to put this proposed
`margin for a treatment effect in context, as it has in the past]. Nonetheless, data from the NDA
`provides little information on pulmonary drug delivery from the inhaler in patients with
`limited puhnonaiy flows (such as in pediatric patients with FEVl <40% of predicted or the
`frail elderly). As well there is limited long term follow up to assess impact of resistance
`development, no instructions for use demonstrated to predictably limit errors of use, limited
`long terms outcome assessment for clinically relevant endpoints such as exacerbation rate,
`hospitalization, rescue antimicrobial use and death. Given the limits of information in the drug
`development program, the Division should require postmarketing studies that fill the gap in
`information, and craft a label that conveys these gaps. Foreign regulators in the EU required a
`postmarketing study in pediatric patients that would assess usability in the younger age group
`and assess long term efficacy of the product over 48 weeks (6 cycles). The applicant plans a
`“real world study in the US (Study C2407), contingent upon US approval that would compare
`(m4)
`m4)
`safety (
`) and other clinical efficacy endpoints
`
`comparator be TOBI .
`
`with an approved inhaled product”. I recommend that the
`M“) also be assessed in this study and that the
`
`1 Response to GAO inquiry — NI margins for antiflmgal agents
`
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`Reference ID: 31 98426
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`Cross Discipline Team Leader Review
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`Cross Discipline Team Leader Review Template
`1. Introduction
`
`
`The drug product proposed in this NDA505b(1) submission, TOBI® PodhalerTM (tobramycin
`inhalation powder), is a dry powder formulation is intended as an alternative to the currently
`marketed inhalation solution TOBI® with the same active ingredient, tobramycin. The
`applicant of this New Drug Application (NDA) presents two placebo controlled trials
`conducted mainly in pediatric patients and one comparative safety trial largely in adults, to
`provide evidence of the safety and efficacy of TOBI Podhaler (referred to as TIP in the rest of
`this document), a powder formulation of tobramycin for the management of cystic fibrosis
`patients with Pseudomonas aeruginosa. TIP is a dry powder packaged in a hard capsule. Drug
`delivery for this new powder formulation of tobramycin is via a handheld, manually operated,
`breath-activated T-326 dry powder inhaler (DPI). The inhaler is intended for replacement
`every 7 days. TIP is to be administered as four capsules equaling 112 mg of tobramycin twice
`daily for repeated cycles of 28 days on drug and 28 days off drug. TIP is marketed in Canada,
`Chile, Colombia, Germany, The Netherlands, Norway, Denmark, Ireland, and the UK
`countries.
`2. Background
`
`
`CF is an orphan disease, there are 30 000 patients in the US with this autosomal recessive
`disease. The ion transport defects in cystic fibrosis (CF) lead to low volumes of fluids essential
`to the function of mucosal surfaces and secretory organs. In the lung, the small volumes of
`thick viscid mucus predispose to chronic infections with Pseudomonas aeruginosa. Antibiotics
`to treat P. aeruginosa pulmonary infections have resulted in improved pulmonary function (as
`measured by FEV1) and a corollary increase in survival in patients with CF. As treatment of
`episodic exacerbations of CF with antipseudomonal antibiotics has proven beneficial, the
`chronic intermittent use of antibiotics for chronic suppression of P. aeruginosa is standard of
`care. CFF guidelines strongly recommend chronic use of inhaled tobramycin in CF patients 6
`years and older with FEV1% predicted <40 to 692 and persistent P. aeruginosa in airway
`cultures. The CFF also recommends inhaled tobramycin use in asymptomatic CF patients 6
`year older; however, the evidence supporting this recommendation is weaker. The duration of
`‘chronic’ therapy is not defined. In clinical practice, patients generally remain on cycled
`inhaled antibacterial drugs indefinitely.
`
`Three drugs, belonging to three different antimicrobial classes, are approved for the treatment
`of Pseudomonas aeruginosa in CF.
`Ciprofloxacin, a fluoroquinolone antimicrobial, is approved for the treatment of acute
`pulmonary exacerbations in CF patients 5-17 years, based on a comparative study
`demonstrating improved symptoms of exacerbation in 67 patients who receive d ciprofloxacin
`10mg/kg/dose q8h IV for one week followed by ciprofloxacin tablets 20mg/kg/dose q12h to
`
`2 Flume PA, O’Sullivan BP, Robinson KA, et al Cystic Fibrosis Pulmonary Guidelines: Chronic Medications for
`Maintenance of Lung Health Am J Respir Crit Care Med 176:957-969, 2007
`
`Page 3 of 24
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`Reference ID: 3198426
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`Cross Discipline Team Leader Review
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`complete 10—21 days treatment. Concerns regarding chondrotoxicity limit long term use of
`this drug class in pediatric patients.
`For the chronic suppression ofP. aeruginosa, liquid formulations of the aminoglycoside
`tobramycin (TOBI®) and the monobactam aztreonam (Cayston®) are approved for use by
`inhalation with nebulizers. TOBI® (NDA 50 753) is specifically indicated for use with the Pari
`LC Plus nebulizer and Pulmo—aide air compressor. The treatment dose is 300 mg inhaled
`delivered in 15 minutes twice daily for repeated cycles of 28 days on drug and 28 days off
`drug. Cayston® (NDA 50814) is formulated for inhalation via the Altera nebulizer (75mg
`delivered in 2-3 minutes per dose TID). Although the indication of use for Cayston differs
`from TOBIc (to improve respiratory symptoms in CF patients with P. aeruginosa for a single
`28 day cycle of therapy), in the clinical setting, it is often used in a manner similar to TOBI®.
`The intravenous formulations of both drugs are also used off-label to treat acute exacerbations
`of CF. Cayston was filed as a 505b2, allowing FDA to rely in part on the finding of
`effectiveness of the parenteral formulation aztreonam; in the EU, the drug is labeled for use
`only in patients 18 and older. In the current NDA, the applicant similarly references the
`effectiveness of TOBI although studies supporting TIP efficacy were conducted and stand on
`their own.
`
`Given the microenvironment in thick dry mucus secretions of the CF patient, the chronic use
`of inhaled hypertonic saline is recommended by the CF foundation to improve lung function
`and to reduce exacerbations ('il’i‘i mm). A concern regarding the use of this tobramycin powder
`formulation, is that the powder may be less efficacious than TOBIQ which is a liquid solution
`in saline. While the serum pharmacokinetic studies indicate that absorption of the powder TIP
`is more efficient than that of the inhaled solution, activity at the endobronchial and peripheral
`airways is not known to correlate with serum PK of topically acting products in CF (Ilnd 1mm").
`
`3. CMCIDevice
`
`TIP is the first antimicrobial powder formulation developed for inhalation and similar to
`TOBI, is intended for chronic use. Dr. Mark Seggel finds that sufficient information is
`provided in the NDA to assure the identity, strength, quality, purity, and potency of the drug
`product and that the labels have provide requisite information (e.g., description, how supplied,
`storage statements). He recommends approval pending favorable GMP inspections as reflected
`in a recommendation from the Office of Compliance. The quality product microbiology
`reviewer Stephen E. Langille, PhD. likewise recommends approval.
`
`Drug Substance: The drug substance, tobramycin, is identical to that used to manufacture the
`approved TOBI (NDA 50—753, referenced by the applicant, who also provides references the
`DMF of the two drug substance manufacturers,
`are
`GDNIF
`0(0) and
`mo (DMF mo)
`There are no inspectional issues related to the drug substance.
`
`(I!) (4)
`
`(I!) (4)
`
`with
`antibiotic mixed
`Drug Product: The API Tobramycin is a
`sulfuric acid (salt forming and pH adjustment), DSPC and calcium chloride (wall forming )
`and perflubron (porefonning agent
`mg). Spray driying yields
`mu)
`particles with porous structure which is dispensed into capsules. TOBI® PodhalerrM
`capsules each contain 28 mg of tobramycin powder (corresponds to a target delivered dose of
`25.5 mg tobramycin per capsule).
`
`Page 4 of 24
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`Reference ID: 31 98426
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`Cross Discipline Team Leader Review
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`Two powder formulations were used in the drug development of TIP. The first formulation
`TS-001 was used in the normal volunteer phase 1 study 0001NH-007 whereas CN 1-002 was
`used in the dose ranging phase 1 and in all phase 3 studies (C2301, C2302 and 2303). Due to
`the
`on“) Dr. Seggel raised early concern that
`(am)
`could contribute to product
`‘"""
`, reducing overall efficacy of
`the product. The manufacturing process for CN 1-002 was further modified to reduce
`variability in powder characteristics as the sponsor prepared to scale up manufcturing; FDA
`required an additional placebo controlled study (C2303) to bridge the safety and efficacy of
`this final product with that seen in the two other phase 3 studies. Dr. Seggel concludes that the
`final product addresses previous concerns about stability and product quality attributes.
`Further, the bridging serlnn pharmacokinetics of tobramycin was shown to be unaltered due to
`the change in manufacturing process (see Dr. Ryan’s Clinical Pharmacology review for
`details).
`
`Mr. Sugato De, consultant reviewer from CDRH for the Podhaler device, concludes that the
`device engineering is adequate. Other CDRH colleagues, Dr. Quynh Nguyen and the DMEPA
`reviewer, Dr. Alex Winiarski, who reviewed the Human Factors study, likewise do not
`H-I-i—l-H-Hrecommend device approval. The issues raised in the course of the development
`of TIP are summarized below:
`
`Deliveg Device: The inhaler device PodhalerTM, referred to as T-326 preapproval, is a hand
`held, breath—actuated oral inhaler replaced every 7 days.
`
`To administer a TIP dose, the patient must remove the mouthpiece of the T-326, load a single
`TIP capsule into the inhaler chamber, screw the mouthpiece back on, pierce the capsule by
`pressing down on the blue button, inhale twice (counting to 5 after each inhalation) and check
`the capsule to determine if the capsule was emptied. These 5 steps must be repeated an 4 times
`to administer a full dose (4 TIP capsules=112 mg). Two such doses are administered daily for
`one 28-day on—therapy cycle.
`
`To assess suitability of the device and its ability to deliver TIP, the applicant conducted a study
`in normal volunteers (Study IN—007) and in CF patients (TIP001) comparing the systemic
`exposure, sputum exposure and the lung deposition between TIP and TOBI formulations as the
`parameters of interest to aid in dose selection. Study IN-007 is not summarized in any of the
`CDRH reviews and the sponsor’s characterization of the study is abridged below:
`0
`Study IN—007 assessed lung distribution, pharmacokinetics and safety of ascending
`doses of radiolabeled TIP and TOBI® in healthy adults volunteers who were not receiving
`bronchodilators or other medications. While a greater distribution of tobramycin (measured as
`Table 1 Percent of total radioactivity in normal volunteers
`
`—m
`
`%
`
`Page 5 of 24
`
`Reference ID: 31 98426
`
`radioactivity)
`
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`Cross Discipline Team Leader Review
`
`
`
`
`
` •
`
` Study TSB-001 was designed to derive optimal flow and performance characteristics of the
`simulated device in delivery of TIP to smaller subjects and/or subjects with more
`restrictive lung disease. CF patients aged 6 to 53 years, (mean age 20 years, 20% of whom
`had FEV< 40% of predicted) were enrolled, of whom only 27% of patients were capable of
`inspiratory volumes of 2 liters. While all patients achieved a peak flow rate of
` the
`minimum peak flow rate required to utilize the device, the lowest values approaching this
`limit were seen in the youngest age group. The study did not include pediatric CF patients
`with the full range of inspiratory flow profiles, 2 patient 6-10 years had an FEV1 <60%
`predicted, and none had an FEV1<40% predicted. This study was not described in the
`review by Mr. Sugato De and portions relevant to understanding device use are reproduced
`below. The study report (Page 30 CSR TBM100ctsb001) concludes:
`“The 6-10 year old age group is representative of both the youngest age group currently
`approved for the therapeutic use of Tobramycin (TOBI®) and the lower volumes and flows
`attained by the CF population. In order to be certain that virtually all CF patients can
`effectively use the T-326 inhaler, future in-vitro performance tests should utilize both the
`pediatric inspiratory flow profiles and volumes and flows common to this age group. “
`The team raised concerns about the performance of the inhaler for patients incapable of
`inspiratory volumes of 2 liters or peak flow rates of
`. The Pulmonary consultants
`consider this limitation less meaningful for US CF pediatric patients, who are likely to be
`healthier and to have FEV1 > 40% predicted.
`
`Page 6 of 24
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`Reference ID: 3198426
`
`6
`
`was seen in the lung and mouth with TIP compared to TOBI® (table), it required more than a
`single inhalation to deliver the required dose (data not shown). The reported lung deposition
`for TOBI in this study was about half that predicted from published data and the TOBI NDA.
`The sponsor concluded that better lung distribution could be achieved with >1 inhalation per
`capsule and that 4 capsules should constitute the dose for TIP. The AE rate from these
`exposures in shown in Table 2, reproduced from the sponsor’s complete study report and
`provides early indication of the relative rates of adverse reactions between the two drug
`formulations.
`
`
`
`
`
`
`
`
`
`Table 2 Adverse Events by Treatment
`Number (%) AE
`by subject
`5/14 (35.7)
`4/12 (33.3)
`3/13 (23.0)
`
`AE Incidence
`
`12
`8
`3
`
`TIP 1 inhalation (18 mg)
`TIP inhalation (18 x 6 =72 mg)
`TOBI (300 mg)
`
`(b) (4)
`
`(b) (4)
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`

`

`Cross Discipline Team Leader Review
`
`•
`CDTL comment:
`Studies INH-001 and TSB-001 assess drug delivery through the device and the clinical
`data need to be viewed with an understanding of the limitations of the device delivery
`
`
`
`Page 7 of 24
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`Reference ID: 3198426
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`Cross Discipline Team Leader Review
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`system to appreciate its labeling implications. Study INH-001 concludes that more than
`one inhalation is needed to deliver the drug – instructions for use should clarify that a
`full dose consists of 4 capsules and that each capsule should be emptied by effective
`inhalation. Study TSB-001 assessed delivery in only 2 pediatric patients with
`FEV1<60% predicted and none belowFEV1<40% predicted. Note that the CF
`foundation strongly recommends use of inhaled antibiotics in patients with severe (<40%
`predicted) to moderately severe disease (<70%), based on their FEV1. Although it is
`probably true that most US cystic fibrosis pediatric patients would have mild to
`moderately severe CF, some patients with severe CF or those that are poorly nourished
`with low BMI, may not derive full benefit. I requested Drs. Mishra and Kadoorie to
`perform an analysis of the primary endpoint stratified by age and severity of lung
`function to determine the proportions of patients with limited pulmonary reserve as well
`as the benefit derived from TIP inhalation in these patient subgroups. Dr. Mishra looked
`at the mean and range of change in FEV1 in 2301 and 2302 and found 3 TIP treated
`subjects in 2301, all of whom derived benefit and in 2302 where the mean FEV 1
`increased was ~12% over baseline, thus no concerns are raised regarding limited benefit
`in patients with diminished pulmonary reserve. Dr. Kadoorie’s analysis is pending at the
`time of this review.
`To extend labeling to pediatric patients with FEV1 <40% predicted, I recommend either
`an in-vitro study (as per the study INH-007 conclusions) or restricted labeling until
`efficacy and safety is established in such patients.
`
`In his review of the descriptive information for the proposed inhaler and the data
`characterizing its performance, Mr. Sugato De, M.S., Biomedical engineer (ODE/
`DAGID/ARDB) concludes that the applicant has demonstrated the ability of the device to
`deliver the respirable product from an engineering standpoint. Based on both the simulated
`flow rate study and the results of the Phase I clinical study, he concludes that the information
`is adequate to assess delivery delivers of the target dose (with a mass-median aerosol diameter
`between
` over the batches of products studied) and assess the device for mechanical
`safety and reliability. However he concludes that the biocompatibility testing is insufficient
`and that approval cannot be recommended; the device is categorized as an externally
`communicating device with tissue contact and that there is a potential for chemical leachants
`entering the patients airway. They consider the information submitted to be minimally
`acceptable testing and not sufficient to validate biocompatibility for an externally
`communicating device with tissue contact. If CDER agrees with the device categorization,
`subchronic toxicity, genotoxicity and implantation tests would be conducted by the sponsor. If
`the leachables and extractables are shown to be below a threshold known to be associated with
`toxicity, then additional testing may not be necessary. He recommended that the
`biocompatibility testing be selected in accordance with ISO 10993 with attention to
`appropriate duration and level of contact of the device and that cumulative duration of use be
`considered in determining patient contact. The Pulmonary (Dr. Peri Prasad) and DAIP (Dr.
`Mark Seggel) chemists, do not agree with this categorization. Consistent with the Pulmonary
`drug product review team viewpoint, classification of the dry powder inhaler as an “externally
`communicating” is not warranted. Dr. Seggel writes” The gas path and [dry] drug product
`contact surfaces are the same material. ..(L)ow levels of extractables (were) observed
`
`Page 8 of 24
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`Reference ID: 3198426
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`8
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`(b) (4)
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`

`Cross Discipline Team Leader Review
`
`in controlled extraction studies. ..Assessment of extracts per ISO 10993 (cytotoxicity,
`sensitization, and irritation) and USP <88> (acute systemic toxicity) is routinely considered
`sufficient for demonstrating biocompatibility of dry powder inhalers and other inhalation
`devices. The results of these tests on T-326 components were negative”. Dr. Amy Ellis,
`toxicologist agrees with their assessment.
`Mr. De concludes
`“The Center for Devices and Radiological Health (CDRHrecognizes that there are a range
`of human factors and clinical efficacy concerns with the proposed product. Specifically, the
`human factors study results demonstrate patterns of failures, use errors and operational
`difficulties. These issues are expected to lead to modifications to product labeling and also
`user training. In addition, a number of these issues may reasonably lead to design changes
`that may affect the performance of the proposed device.”
`
`CDTL comment: I agree with the CDER reviewers for the following reasons:
`a) total time of exposure to the device is brief per dose
`b) the device does require contact with the pseudostratified epithelium in the lips during the
`process of inhalation. This is not analogous to the mucosal exposures to the buccal ,
`nasopharyngeal, lanryngeal and tracheal epithelium that occurs with an endotracheal tube or to
`the endovascular exposure seen with intravenous catheters, for which such studies are required.
`c) device is discarded after 7 days and formulation is a dry powder, so possibility of breakdown
`and leaching /extracting of device plastic components is anticipated to be minimal
`d) potential for inhalation of fragments is minimal given the filter
`e) the product has been marketed worldwide for a total of 83.15 patient treatment years and Dr.
`Shrimant Mishra’s review of the postmarketing experience finds no unusual adverse events
`implying mucosal incompatibility with the device (lip swelling, pain etc). Local tolerability issues
`(dysphonia and dysgeusia) are attributed to the drug rather than the device and although more
`frequent with TIP compared to TOBI, have been reported with other inhaled antibiotic products
`as well.
`At the time of this review, DAIP has not been in receipt of the labeling modifications, user
`training and design changes from CDRH referred to in Dr. Sugato De’s review.
`
`Table 3 Human Factors, Usability and Comprehension of Instructions for Use
`The applicant sites the following device usability evaluation studies in their NDA:
`Study No.
`
`
`
`
`Study Title
`
`
`TBM100 Formative adult usability report
`Adult usability study
`TBM100 EU Readability report
`
`TBM100C Consultation w/ patients target groups
`
`TBM100 Formative child usability report
`Child CF study Report
`TBM100 EU summative child usability report
`T-326 Inhaler usability evaluation in children
`TBM100 US summative usability report
`
`TOBI Podhaler (T-326 inhaler) usability evaluation final report
`TBM100 Packaging evolution report
`Packaging and IFU evolution - technical memo
`TBM100 Usability summary report
`TOBI Podhaler Human Factors Engineering/
` Usability Engineering report
`The studies were designed to assess the ability of different subgroups to properly use the
`combination of drug and device, to demonstrate successful performance of all essential and
`critical tasks associated with complete drug delivery per dose by representative users, to obtain
`subjective measures using rating scales/questionnaires and assess comprehension of the
`instructions for use of the drug- device product.
`Dr. Quyhn Nguyen, who reviewed the human factors and usability of the device T326
`(TBM100 US summative usability report) with Dr. Aleksander Winiarski , DMEPA reviewer
`
`
`
`Page 9 of 24
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`Cross Discipline Team Leader Review
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`recommend against approval due to the unacceptable error rate for several individual steps in
`dosing TIP, the limitations of the study assessing instructions for use, the inability to provide
`assurance regarding safe and effective drug-device use. In this study, patients and their adult
`caregivers, in the case of pediatric patients, were provided the instructions for use, interviewed
`and trained by a representative, and their initial use observed for errors. A 5-day at home use
`was then conducted, with commercial weekly patients packs containing empty capsules. This
`was followed by a post 1 week dosing observation, followed by a second interview. More
`patients in this study (N=50) had a diagnosis of asthma than cystic fibrosis (N=12). This is
`notable in that patients with asthma often use powder formulations (such as corticosteroids)3,
`some using similar dry powder inhalers; whereas CF patients have not.
`Initial Training and Use
`The applicant reports that 85% of subjects followed the correct dosing procedures on the first
`attempt, and the FDA reviewers disagree as the study assessed only 3 of the 5 dosing steps
`and the tasks of “inhaling twice from each capsule” and “removing and visually inspecting the
`capsule to ensure the capsule is pierced and empty” were not tested. In the FDA review, over
`half of subjects did not correctly administer the dose (53%, 33/62), despite the fact that all
`participants were trained on the use of the product and received the IFU immediately prior to
`commencing the study. IFU use was not formally observed. The types of errors observed
`within the various age groups on the first attempt is shown below:
`
` Table 4 Age-Related Frequency of Various Types of Dosing Errors
`Age
`Number of
`Not
`Not
`Not
`Not
`Not
`group
`subjects with
`Removing
`Completely
`Inhaling
`Inhaling
`Checking
`(years)
`at least one
`Capsules
`Piercing
`from 4
`Twice from
`Capsule
`error
`Capsules
`Capsules*
`Each
`Capsule
`11/15 (73%)
`15
`3
`8
`2
`2
`0
`6 to 8
`14
`5
`4
`3
`2
`10/15 (67%) 0
`9 to 12
`8
`5
`3
`0
`0
`13 to 17 4/15 (27%) 0
`10
`7
`2
`1
`0
`Over 18 8/16 (50%) 0
`47
`20
`17
`6
`4
`Total
`33/64 (52%) 0
`The error rate was highest in the youngest age groups, with errors leading to incomplete
`dosing predominating. While certain use errors increased in incidence from initial assessment
`to post one week, the error that could read to incomplete dosing, i.e. checking that capsule was
`pierced was of most concern (initial test 17% to 34%). In a separate study, testing whether
`patients would re-inhale a capsule that was partially full, 11% of subjects did not re-inhale, so
`examining a capsule may not result in a full dose.
`CDTL comment:
`The instructions for use that could limit such errors were not considered adequate and
`not formally tested. At the advisory committee meeting, the sponsor showed an
`instructional video that I considered effective in providing instructions, and could
`potentially address the limitations of the IFU. I discussed this with Dr. Winiarski and his
`supervisor Dr. Carol Holquist, who are open to reviewing other instructional materials.
`Similar such materials are already widely available as YouTube videos on the internet
`although their attribution is not known. A PMC is recommended to develop digital
`
`3 http://www.mayoclinic.com/health/asthma-inhalers/HQ01081, accessed August 22, 2012.
`
`Total
`number of
`critical
`errors**
`
`Page 10 of 24
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`Cross Discipline Team Leader Review
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`media that supports the training needs of patients on the use of this drug-device
`combination. In the interim, the review team has proposed changes to the IFU in concert
`with DMEPA, CDRH, DPDP, DCDP, DMPP.
`
`Facilities review/inspection and other issues
`The product quality microbiology reviewer recommends approval of the NDA. ```The clinical
`inspections for the drug product have been completed (see review by Dr. Janice K. Pohlman,
`DGCP, OSI). Dr. Pohlman finds no violations that alter the conclusions of efficacy and safety.
`A US investigator, Dr. David E. Geller, who enrolled patients into the safety trial 2302, is cited
`for violations regarding human subject protection in a study unrelated to this submission; this
`finding do not alter the ability to rely on the data from this site. The device inspection, which
`the OC has recently required, will likely not be completed as of the PDUFA date.
`4. Nonclinical Pharmacology/Toxicology
`The reader is referred to the toxicology review by Dr. Amy Ellis who concludes that the
`toxicology studies suggest that repeated dosing with TIP will not cause greater systemic or
`pulmonary toxicity related to tobramycin than the currently marketed drug TOBI®.
`In the toxicology studies, rats were dosed using nose-only inhalation and the dogs were dosed
`using a face mask. The animals received drug by breathing a test atmosphere containing the
`suspended TIP for up to 3 hours (rats) or 45 minutes (dogs) rather than by oral rapid inhalation
`of the total dose in two breaths as humans would. The concentration of TIP in the test
`atmosphere in the rat study was about 1 mg/L and the concentration of TIP in the test
`atmospheres in the dog study ranged from about 2.5-3.0 mg/L. The highest inhaled dose of
`tobramycin base used in the 26-week rat study was approximately 38 mg/kg/day and the
`highest inhaled dose of tobramycin base used in the 4-week dog study was approximately 28
`mg/kg/day. The pulmonary deposited doses for rats and dogs are assumed to be 10% and 20%
`of the inhaled dose, respectively. There were no clinical signs of tobramycin toxicity in either
`species in any of the inhalation toxicity studies conducted with TIP. Histopathologic findings
`in the respiratory tissues of the rats dosed with TIP for up to 26 weeks were similar to those
`observed following chronic treatment with TOBI® solution given by nebulization.
`Kidney changes identical to those observed in older rats as age-related nephropathy were
`observed at a greater incidence in TIP treated rats than controls. There were fewer findings in
`dogs dosed with TIP for up to 4 weeks. Nonclinical issues with the DSPC excipient and its
`degradant (S-Lyso-PC) have been addressed to the clinical pharmacologist’s satisfaction
`through the conduct of appropriate invivo and invitro studies.
`CDTL comment: In humans, the dose regimen is to inhale the contents of 4 capsules of TIP twice
`daily, for a total of 224 mg tobramycin powder. This is an inhaled dose of 11.2 mg/kg in a child
`weighing 20 kg. The high particle volume delivered in 2 breaths is not similar to that of inhaling
`powder in the ambient atmosphere for 30 minutes to one hour. However, feasibility limits the
`conduct of testing oral inhalation in the animal models.
`5. Clinical Pharmacology/Biopharmaceutics
`The pharmacology of TIP was described in 5 clinical studies, the first in normal adults (INH
`007) and the rest in patients with CF (TPI 001, C2301, C2303, C2302). Dr. Ryan Owen
`recommends approval based on his review of these studies. He finds the dose ranging study
`TP