CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-3 87
`
`OTHER REVIEWg S)
`
`

`

`22—387 TYVASO® (treprostinil) inhalation Solution
`
`Eroiect Manager Overview
`
`NDA 22-387 (pulmonary arterial hypertension)
`TYVASO® (treprostinil) Inhalation Solution
`Pharmacologic Class: Prostacyclin Analogue
`Combination Product: Drug + Device
`Chemical Classification: New formulation (chemical type 5)
`Orphan Designation
`
`Background:
`
`Remodulin® (treprostinil) for subcutaneous (NDA 21—272) and intravenous (NDA 21-272/5-002)
`administration was originally approved under Subpart H on May 21, 2002 (NDA 21—272) and
`November 24, 2004, respectively.
`
`The sponsor of Remodulin, United Therapeutics, submitted a New Drug Application (NDA) for
`Tyvaso® (treprostinil) inhalation Solution 0.6 mg/mL (supplied as 2.9 mL ampules) on June 30,
`
`2008. The studies were conducted under 1ND 70 362. The sponsor proposed to market the
`product for treatment of pulmonary arterial hypertension (WHO Group 1) in patients with NYi—lA
`Class ill
`r—f symptoms (same indication as Remodulin); however, the agreed upon indication
`will include use in Class 111 only.
`
`b‘4)
`
`The dosage and administration section of the labeling proposes four separate inhalation sessions
`per day (while awake). Each breath is expected to deliver a dose of approximately 6 mcg per
`breath.
`initial treatment would begin with three breaths (18 meg) and the maximal target dose per
`session is 54 mcg (9 breaths).
`
`The Tyvaso inhalation System involves use of a never-before cleared/marketed nebulizer device,
`The device, known as the Optineb R, a portable ultrasonic nebulizer, was submitted under the
`NDA. DCRP consulted CDRl-i including a bioengineer and a human factors analyst.
`
`The Division reviewed this NDA under the Good Review Management Principles and
`Practices—the NDA was assigned a Standard review (10—month clock), however, a 3—month
`clock extension was granted based on submission of new information related to the device.
`
`Note that the sponsor plans to implement what appears to be an extensive hands-on training
`program for patients receiving the Tyvaso inhalation System (drug/device) where nurses train
`patients one-on-one either in a clinic setting or at the patient’s home. Also, patients will be able
`to obtain the product only from specialty pharmacies (i.e., the product is not available through
`typical pharmacy distribution channels).
`
`NDA Reviews and Memos
`
`Division Director’s Memo #2
`
`Dr. Norman Stockbridge; July 28, 2009
`In his second memo, Dr. Stockbridge recommends approval.
`
`Division Director’s Memo #1
`Dr. Norman Stockbridge; April 25, 2009
`In Dr. Stockbridge’s initial DD memo, he recommended a Complete Response based on issues
`relating to manufacture of the drug substance (facility inspections), biocompatibility of the
`
`

`

`22-3 87 TYVASO® (treprostinil) Inhalation Solution
`
`nebulizer parts that come into human contact, and device-related problems. Although a Complete
`Response action was recommended, in response to the Division’s request, the sponsor submitted
`several amendments late in the review cycle (March/April) that, per the Division’s decision,
`triggered a 3-month clock extension. Therefore, no action had been taken with respect to the
`original PDUFA goal date, April 30, 2009. Adding three months to the PDUFA clock made the
`new goal date July 30, 2009.
`
`CDTL Memo #2
`
`Dr. Avi Karkowsky; July 27, 2009
`Dr. Karkowsky notes that there are problems with the device, however, many of the identified
`problems will be addressed through PMC 2, 3, and 4 (see approval letter). To address the
`inadequacies, the Division and the sponsor agreed to a timeline (see action letter) which would
`allow for marketing of the current version of the device for some period of time (i.e., < 2 years).
`Given his concerns for pulmonary toxicity based on human and animal data provided in the NDA,
`Dr. Karkowsky requested that the sponsor capture and track adverse events related to pulmonary
`toxicity via a postmarketing requirement (PMR).
`
`CDTL Memo #1
`
`Dr. Avi Karkowsky; April 19, 2009
`Dr. Karkowsky recommended a complete response for various reasons, some of which are:
`The device seems complex and cumbersome to assemble, use and clean
`An adequate human factors study had not been completed (see CDRH’s review)
`Biocompatibility data had not been submitted/reviewed
`Inspection facilities had not received an overall acceptable recommendation
`The benefit (increase in 6MWD) was relatively small and wanes at the interdosing
`interval; he also does not think the inhaled route should be automatically substituted for
`the SC/IV route of administration
`
`VVVVV
`
`Clinical Review; April 3, 2009
`Dr. Avi Karkowsky .
`Recommended Action: Approvable (pending issues identified in CDTL memo)
`Dr. Karkowsky emphasizes that Tyvaso was studied in patients on background therapies
`including sildenafil and bosentan and such information should be included in the indications
`section of the labeling. Furthermore, the waning of the treatment effect during the interdosing
`interval should be noted as well. His major concern regarding safety included adverse events
`related to irritation of the oro-nasopharynx and respiratory tree.
`
`QT Study; January 30, 2009
`Interdisciplinary Review Team for QT Studies
`The study failed to exclude a 10 ms increase in the QTc interval (results below).
`
`Table 1: The Point Estimates and the 90% Cls Corresponding to the Largest Upper Bounds for
`Treprostinil sodium (54 meg and 84 mcg) and the Largest Lower Bound for Moxifloxacin (FDA
`Anal sis)
`
`90% Cl (ms)
`Treatment
`AAQTCF (ms)
`
`
`
`
`Trefirostinil sodium 54 mcg
`o.4_
`__
`__
`( 3.5, 9.4)
`
`Treprostinil sodium 84 meg
`8.5
`( 5.8, 113)
`
`
`
`Moxiiioxacin 4b0‘ing*“""
`8.2 ( 5.8, 10.7)~
`
`
`’3 Multiple endpoint adjustment is not applied. The largest lower bound afler Bonferroni adjustment for 3 timepoints is 5.1 ms.
`
`

`

`p
`22-387 TYVASO® tre rostinil Inhalation Solution
`
`Statistical Review; April 7, 2009
`Dr. John Lawrence
`
`Dr. Lawrence notes that the primary endpoint of the study was change in exercise capacity at
`week 12 as measured by peak 6MWD. There was an approximately 20 m (95% Cl 8, 33)
`difference between treatment and placebo in 6MWD (p=0.004~). Looking across various
`subgroups, treatment effects appeared to be larger in the following subgroups of patients: those
`between 18—45 years of age; those whose baseline walk distances were in the bottom quartile
`(smallest baselines); and patients from the “rest of the world” (i.e., outside North America).
`
`Clinical Pharmacology; March 24, 2009
`Dr. Robert Kumi
`
`Recommended action: Approval pending confirmation from CDRH on the reliability (precision
`and accuracy) that the device can deliver the dose reported in the PK studies.
`In some studies, some subjects had undetectable or low treprostinil exposure compared to other
`subjects. The reason for these low exposures is unclear.
`
`Pharmacology Review; June 24, 2008
`Dr. Xavier Joseph
`Recommended action: Approval
`
`in his review, Dr. Joseph makes several recommendations for changes to the labeling but has no
`recommendations for additional nonclinical studies.
`
`Chemistry Review #2; July 23/24, 2009
`Dr. Monica Cooper
`Recommended action: Approval
`See review for details.
`
`Chemistry Review #1; March 24, 2009
`Dr. Monica Cooper
`Recommended action: Complete Response because of pending issues as noted below.
`
`1) All drug substance information is referenced to NDA 21 -272 (Remodulin lnj ection). A
`supplement for a new treprostinil drug substance manufacturing facility and
`—-
`process is
`currently pending (NDA 21-272/SCM-0l 0). The previous treprostinil drug substance
`manufacturing site
`._
`was closed in 2006. Given that no other drug substance
`manufacturer is provided in this submission, the current NDA cannot be approved until the
`supplemental NDA 21-272/SCM-OIO is approved.
`
`11(4)
`
`2) An information request letter was sent to the applicant on 13-Jan—2009 outlining the CMC
`information needed to complete this application. The Amendment dated 25-Feb-2009 included a
`partial response to these issues. An in-use stability study of the drug product in the proposed
`Optineb nebulizer has not been completed and submitted for our review.
`
`3) Evaluation of the Optineb nebulizer was consulted to CDRl-l. CDRl—l has not provided a
`recommendation at this time. However, an information request was sent to the applicant on 03—
`Mar—2009 that included several device issues. These issues are currently pending.
`
`4) The Office of Microbiology has not provided a recommendation on the sterility assurance of
`the drug product.
`
`

`

`22—387 TYVASO® (treprostinil) Inhalation Solution
`
`The Office of Compliance has given an acceptable recommendation for the manufacturing and
`testing facilities.
`
`Microbiology Review; March 24, 2009
`Dr. John Metcalfe
`
`Recommended action: Approval
`
`DMEPA Review #2
`
`in a review dated July 1, 2009, DMEPA found the proposed tradename, Tyvaso, acceptable.
`
`DMEPA Review #1
`
`in a review dated February 19, 2009, the Division for Medication Error Prevention and Analysis
`found that the proposed trade name Tyvaso does not appear to be vulnerable to name confusion
`that could lead to mediation errors.
`
`Division of Scientific Investigations (DSI)
`April 23, 2009; January 8, 2009
`Two sites were inspected as part of a data audit in evaluation of this NDA:
`> Numerous discrepancies were noted at Dr. McLaughlin’s site and DST did NOT consider
`the data to be reliable (0A1).
`> Dr. Bourge appeared to have conducted the study adequately and D81 considered the data
`reliable from this site (NAI).
`
`CDRH Review #2
`
`Mr. Sugato De; Mr. Ron Kaye
`Mr. De reviewed the biocompatibility information and found it acceptable; however, neither
`CDRH reviewer found the usability analysis and human factors study to be adequate. They also
`provide recommendations for changes to the proposed labeling.
`
`CDRH Review #1
`
`Mr. Sugato De; Mr. Ron Kaye
`The reviewers in the Center for Devices and Radiological Health (CDRH) do not find the
`proposed device to be approvable (see review for details).
`
`Action Items: An approval letter will be drafted for Dr. Stockbridge’s signature. The approval
`letter will include one PMR related to pulmonary toxicity and three PMCs related to re-
`engineering of the device. Labeling, including the Pl, PP], and instructions for use (TFU), is
`being finalized.
`
`by Dan Brum, Pl7arm.D., RAC
`July 29, 2009
`
`

`

`Submission
`Linked Applications Type/Number
`
`Sponsor Name
`
`Drug Name / Subject
`
`NDA 22387
`
`ORIG 1
`
`UNITED
`THERAPEUTICS
`CORP
`
`TREPROSTINIL FOR
`INHALATION
`
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`DANIEL BRUM
`
`07/29/2009
`
`

`

`“slum-15.0
`*3?
`’4
`
`~“Vna
`
`is,” {g DEPARTMENTOF HEALTHANDHUMANSERVICES
`
`
`
`M EM0RANDU M
`
`Food and Drug Administration
`Anesthesia and Respiratory Devices Branch
`Division of Anesthesiology, General Hospital, Infection Control and Dental Device
`Office of Device Evaluation
`9200 Corporate Boulevard
`Rockville, MD 20850
`
`NDA 22-387 — Regulatory Device Review
`
`Date: June 10, 2009
`
`To: Daniel Brum, Regulatory Project Manager (OND/ODEI/DCRP)
`From: Sugato De, Biomedical Engineer (ODE/DAGID/ARDB), Lead Reviewer
`
`Ronald Kaye, Human Factors Specialist (ODE/DAGID/GI—IDB)
`
`Applicant: United Therapeutics Corporation
`
`Device Name: Optineb-IR Ultrasonic Nebulizer (Tyvaso Inhalation Solution)
`—._—__..____—_____—_________
`Indication: Pulmonary Hypertension
`
`A. Executive Summafl
`
`In NDA 22-387, United Therapeutics Corporation has proposed a novel combination product intended for
`the delivery of treprostinil sodium (Tyvaso®) to patients with pulmonary arterial hypertension (PAH).
`Tyvaso is administered in a home-care setting to patients using the Optineb—IR Ultrasonic Nebulizer,
`manufactured by NebuTec.
`
`In this regulatory consult, the applicant’s responses to deficiencies raised in the April I, 2009 device
`consult will be reviewed. Specifically, the remaining concerns raised in the aforementioned letter relate to
`the completion of ongoing biocompatibility tests, the adequate completion of an adequate usability
`analysis, and the updated labeling for the proposed device. This memorandum includes the review of the
`biocompatibility test reports submitted for review on April 29, 2009, the Human Factors Study submitted
`on April 17, 2009 and the updated labeling submitted on May 7, 2009.
`
`The primary remaining concern at this point relates to the adequate completion of a comprehensive
`usability analysis incorporating the evaluation and prioritization of user-related risk. Following this
`evaluation, it is recommended that the applicant perform a comprehensive human factors study
`demonstrating the safe and effective simulated—use of the Optineb-IR device in an environment that
`approximates the intended home-care setting. The purpose of this study will be to evaluate the severity of
`the risks anticipated in the initial usability analysis, and to identify user-related risks that may have been
`unanticipated by the applicant. At the conclusion of these usability evaluations, the applicant should
`propose adequate mitigation measures for the identified user-related risks, and may be expected to modify
`and revalidate the proposed device as necessary to alleviate safety—related concerns regarding its use.
`
`

`

`Recommendations:
`
`The biocompatibility evaluation of the device has been adequately completed, and the findings
`have demonstrated that the proposed device is biocompatible in accordance with ISO 10993-1. ‘
`
`The Human Factors Study submitted by the applicant on April 17, 2009 is insufficient and does
`not adequately address any of the specific device-related concerns communicated to the applicant.
`
`We defer to CDER’S clinical review team regarding appropriate timing for the completion of a
`comprehensive usability analysis and human factors study. From a device review perspective, we
`cannot recommend the approval of the proposed drug/device delivery system without the
`completion of a comprehensive usability and human factors study as described to the applicant in
`the March 25, 2009 letter. In addition, as noted in the previous consult, it is our position that a
`phannokinetic analysis is warranted to measure the level of drug being inhaled by the patient per
`each nine-breath administration cycle.
`
`However, if CDBR determines that the clinical risk associated with potential overdose or
`underdose of inhaled treprostinil from the device is minor compared to the relative benefit
`associated with the availability of the product to the intended population, then the usability may
`be conducted as a post-market requirement.
`
`The applicant’s proposed labeling is incomplete, and should be revised.
`
`Because the Optineb-IR has not been cleared as a general-purpose nebulizer in the United States,
`and is proposed in the current submission solely for the delivery of inhaled treprostinil, we
`recommend that the Instructions for Use should be tailored specifically to the use of the proposed
`device to deliver treprostinil. A comprehensive IFU should include assembly instructions for the
`device, clear instructions to the patient in using the proposed device to delivery treprostinil, and '
`relevant cleaning and maintenance information.
`
`The name of the device is not under the regulatory jurisdiction of the Office of Device Evaluation.
`If you seek further guidance on this matter, please contact the Office of Combination products.
`
`

`

`B. Device Description
`
`The Optineb®-IR Nebulizer is a device intended for single patient use in the administration of inhaled
`treprostinil. The nebulizer operates ultrasonically by energizing a piezoelectric transducer at 2.4 MHz.
`This action collirnates distilled water stored in the water reservoir, thus energizing liquid medicine stored
`in the medicine cup and creating an aerosolized cloud of medication to be delivered to the patient. The
`dome and baffle components of the nebulizer are designed to control the size of the particles that are
`emitted from the device. The nebulizer’s software responds by providing visual and audible signals to the
`patient synchronizing the patient’s breathing with the nebulization process. The Optineb-IR performs this
`operation for three consecutive cycles, and dispenses the prescribed dosage at a specified particle size.
`
`1 electronic control
`~-»—-——\
`The,Optineb®-IR consists of a low voltage, .
`unit, plastic nebulizer components which are reusable for up to —~ days, daily disposable medicine cups,
`and daily disposable inhalation and exhalation filter media.
`
`The Optineb®-IR may be powered by one of three methods:
`
`I” VAC power supply, or
`0 A TUV Recognized component (IEC60601-l & EN60601-1-2)
`o
`A rechargeable battery pack that my be used in conjunction with the aforementioned power supply, or b(4)
`o A 12VDC automobile (cigarette lighter) adapter.
`
`Treprostinil (lSAU81, UT—l 5) is a stable tricyclic benzindene analogue of the naturally occurring
`prostacyclin, PGI2 (epoprostenol), a member of the eicanosoid family of autocoids; these compounds
`occur widely in tissues and have important pharmacological properties with potent activity, especially on
`the cardiovascular system'and smooth muscle. Tyvaso® (treprostinil sodium) Inhalation Solution, 0.6
`mg/mL, has been developed as a treatment for pulmonary arterial hypertension (PAH), an orphan disease
`with a global prevalence of approximately 50,000-100,000 patients.
`‘
`
`The recommended dose of Tyvaso is up to nine breaths (54 micrograms) per administration and up to 4
`administrations per day; i.e., up to 36 breaths per day, with a maximum dose of twelve breaths (72
`micrograms) per administration. The maximum theoretical aerosol concentration of nebulized treprostinil
`in Tyvaso is ,
`___J
`\, although the actual aerosol concentration is
`considerably lower.
`
`“(4)
`
`The Optineb-IR device is not a general-purpose nebulizer, and is intended exclusively for use with
`treprostinil inhaled solution. The applicant has not submitted a separate 510(k) Premarket Notification for
`the device, and all device-related information is included in the context of TND 70,362 and NDA 22-387.
`As such, the device is not currently cleared for any intended use in the United States, and the current
`submission is solely attempting to validate its use with Tyvaso Inhalation Solution.
`
`C. Biocompatibilig Review
`
`Potential device-related effects were evaluated in a program of biocompatibility studies with extracts of
`the nebulizer materials that come in contact with the drug.
`
`The testing program was determined by reference to ISO 10993-1.
`
`There are three different materials of construction in the ventilatory pathway, as shown below.
`
`

`

`Device Components in the Ventilatory Pathway
`
`
`Device Part
`Medicine Cu
`
`Sealin; O-Rin_
`Remainin Parts
`
`Material of Construction
`
`
`
`a.) for testing. The studies and study references
`The study materials were provided .
`are listed in the summary below. Updated biocompatibility documentation, including test reports for
`studies that were previously listed as “ongoing,” was provided for review on April 29, 2009.
`The required testing was determined in accordance with ISO 10993—1 for Tissue/Bone/Dentin
`communicating, chronic exposure devices. This testing includes cytotoxicity, intracutaneous reactivity,
`sensitization, genotoxicity, and implantation on all device parts in the ventilatory pathway.
`
`{“4}
`
`Since the mouthpiece comes into direct contact with the patient, this part requires sub-chronic toxicity and
`intracutaneous reactivity (irritation) testing as well.
`
`The results of the testing are discussed below.
`
`Cytotoxicig;
`
`The MEM Elution test was designed to determine the cytotoxicity of extractable substances. An extract of
`the sample was added to cell monolayers and incubated. The cell monolayers were examined and scored
`based on the degree of cellular destruction. The samples are scored against a set of controls on a scale of
`0-4. The sample meets USP requirements if all results are Grade 2 or less.
`‘
`
`All the tested components met the requirement.
`
`Intracutaneous Reactivity glrritation)
`
`The Intracutaneous Reactivity test was designed to. determine if any chemicals that may leach or be
`extracted fiom the test article were capable of causing local irritation in the dermal tissues of rabbits. The
`device components were extracted per protocol against saline solution and cottonseed oil. The resulting
`extracts were then used for testing. All of the device components in both extracts met the ISO 10993-1
`requirements and were determined to be non-reactive.
`
`Sensitization
`
`This test is designed to evaluate the allergenic potential or sensitizing capacity of a test article. Extracts of
`the test material are tested as potential contact allergens in guinea pigs. All of the device component
`materials specified in the table above met the ISO 10993-1 requirements for sensitization.
`
`

`

`Implantation
`
`The purpose ofthis study is to evaluate the local effects of a test article in direct contact with living
`skeletal muscle tissue. Implantation studies were performed by the manufacturer of the . \_
`component, f Similar testing has also been completed for the medicine cup
`and sealing ring
`,. ._.__, components of the proposed device.
`
`33(4)
`
`All tests have demonstrated that the materials that the materials are biocompatible as per ISO 10993-1.
`
`This test is designed to evaluate potential genetic effects of the test articles. Ames mutagenicity testing
`was performed by the manufacturer of the
`component, «.3 r. The. \ material met
`the ISO 10993-1 requirements for this test.
`
`Genotoxicity testing has also been completed for the medicine cup _ w and sealing ring 75
`components ofthe proposed device. Mouse lymphoma testing and chromosomal aberration testing were
`also completed for the proposed device, and have demonstrated that the patient-contacting materials of the
`proposed device are not genotoxic.
`
`M4)
`
`Sub-Chronic Toxicity
`
`The purpose of this study is to evaluate the systemic toxicity of leachable compounds from the test article.
`
`This test is intended for medical devices with a contact duration categorized as permanent (greater than 30
`days). This testing is required only for the mouthpiece,
`and has been completed.
`
`The test report demonstrates that leachable components from the test article were within measurable limits.
`
`M4)
`
`Review Comments:
`
`All protocols and acceptance criteria provided by the applicant are adequate in reference to ISO 10993-1,
`and completed test reports have been provided demonstrating the biocompatibility of the proposed device.
`
`. Human Factors Review
`
`Human Factors Device Consult Reviewer: Ron Kaye (ODEflMGID/GHDB)
`
`In the initial review of the submission, several user-related concerns were identified by the Agency and
`were communicated to the applicant in a letter dated March 3, 2009. In this letter, the Agency
`communicated a concern to the applicant that the current design of the device and the materials supporting
`its use (e.g. user manual) could possibly induce or allow use-errors that may compromise the user’s ability
`to deliver medication properly and could thereby pose significant risks.
`
`Please see Appendix 1 below for the full test of the human factors-related deficiency sent to the applicant
`on March 3, 2009.
`
`Among the major concerns identified by the Agency was whether users can properly dose themselves with
`a total of nine breaths using the currently designed breath counter mechanism. This counter counts only up
`to three and the patient must restart the device two additional times to receive the required nine breaths.
`
`

`

`Additional risks include the following:
`
`0
`
`Possible risk associated with delivery of less than the prescribed dose given the apparently challenging
`requirement for the user to take nine deep breaths within the specified time limit of ninety seconds.
`0 Whether the inhalation or exhalation into the mouthpiece triggers a change in the count displayed by
`the breath-counter mechanism, whether this trigger is time-related, and whether the user needs to be
`aware of how this process operates to ensure proper use and delivered dosage.
`The ability of users to correctly assemble your device under conditions consistent with home-use to
`include proper physical connection of device components and loading of appropriate levels of
`medication into the cup.
`
`0
`
`On April 17, 2009, the applicant submitted a preliminary Human Factors Study for review.
`
`The Human Factors Usability Test report is evaluated here with respect to the comments provided to the
`applicant following review of the Drafi Usability Test Protocol on March 3, 2009 (see Appendix 1).
`
`1. Essential Components of User Interaction
`
`The simulated use performed in the Usability Test was modified to include breathing through the device
`and included placing the mouth on the mouthpiece. The components of interaction between the user and
`the device were developed into a “Use Error Checklist” presented as Appendix D. Although the checklist
`items are extensive and appear to be comprehensive, they are not prioritized and results with respect to the
`clinical impact of errors found using these checklist items is not presented in the test report. The Agency
`needs to understand the relative risk of user performance and use errors on the health and well being of the
`device user to adequately evaluate the safety of the use of your device. See recommendation (below).
`
`2. Training
`
`The training process included the use of Competency Test to screen participants. Given that the
`population of users evaluated excluded those who did not pass the Competency Test and that passing this
`test is considered essential for safe and effective use of the device, the requirement of passing the test prior
`to being allowed to use the device should be highlighted in the IFU including the Package Insert.
`If this is
`not clearly stated, then the entire test results are biased and non-representative of actual intended users.
`Discussion of testing results, in addition to previous and subsequent comments, should include a
`discussion of the realism of a 2—hour training course for intended users and assurance to the Agency of
`how this will occur and why it is of realistic to expect that general users will receive the same level of
`training used in this study. See recommendation (below).
`
`3. Screening Participants
`
`The method used for screening participants involved in the Usability Study was modified from the drafi
`protocol such that it is acceptable.
`
`4. Testing Procedure
`
`The method used for Testing Procedure involved in the Usability Study was modified from the draft
`protocol such that it is acceptable.
`
`5-7. Data Reduction, Analysis, and Reporting,
`Measures of User Performance and Acceptable Performance Criteria (Pass/Fail Criteria),
`and Modifications to Device Design
`
`

`

`The reporting findings include the frequencies of each error recorded and a reference Task number during
`which the error occurred. There were 76 use errors reported with a fiequency of occurrence ranging from
`10 occurrences to 1. The errors were associated with 12 of the 13 tasks evaluated.
`
`Further interpretation ofthe findings with respect to the priority of the findings in terms of risk to the
`intended population ofusers, actions and plans associated with identified risks as necessary was deferred
`to UTC who developed a separate document linking use errors to risk analysis. Review under this
`heading corresponds includes that document: “Human Factors Use-Related Risk Assessment.”
`Acceptable/unacceptable performance is not identified in either the test report or the use-risk assessment
`document. The latter document assigns risk levels to each use error found according to probability of
`occurrence and severity of outcome. Overall, the testing and analysis is incomplete in a number of ways:
`
`3.
`
`1. Subjective assessment of device interaction that focuses on high-priority aspects of device use is
`considered an important aspect of Usability or Human Factors evaluation. No subjective assessment
`data was collected in the study and was not included in the evaluation of the use-safety of the device.
`2. That the use error involving a user who took 27 breaths instead of 9 in the study, as well as 6 other
`cases involving more or less breaths than specified in the task instructions represents an “acceptable”
`risk level is questionable and appears that its assessment is questionable (see next).
`If a use error could result in significant harm, assessment of a probability of “low” given the relatively
`small number of uses involved in this study is difficult to justify. It is likely that a confusion of
`definition exists between the concept of “acceptably low” and “relatively low”.
`'
`4. The issue of over- and under closing is not well captured in the risk assessment document in which risk
`is assigned according to individual breaths and cycles. Overall breath count being high or low
`(misdosing) does not appear. This has caused such errors to be considered in other sub-tasks that do
`not bear directly on over— and under-dose for the entire treatment and the clarity of this seemingly
`important and central issue is obscured due to the methodology used in assessing its risk.
`
`Review Comments:
`
`This study is insufficient and does not adequately address any of the specific device-related concerns
`previously communicated to the applicant. We recommend that the usability analysis and human factors
`study be completed in accordance with the recommendations given to the applicant on March 3, 2009.
`
`Given the concerns cited above, the risks associated with the use ofthe device cannot be mitigated solely
`with modifications to the training protocol or labeling (Level 2) or with the potential for design changes.
`These measures leave the question of the effectiveness ofthe proposed modifications unanswered.
`Accordingly, these risk definitions are not acceptable for device use since it cannot be accurately
`determined whether or not they will be effective. Use safety is not considered to be validated from a
`device review perspective unless the study is expanded to cover mitigation strategies in order to
`demonstrate that they are effective. For the Agency to adequately understand the risks associated with the
`use errors identified and their associated mitigation measures requires that we review results of an
`evaluation that includes this information. Therefore the applicant should provide the results of an
`additional study that address these and the other concerns contained in this review of your usability test.
`
`As of this review, the applicant has not performed an acceptable Usability Analysis incorporating the
`evaluation and prioritization of user-related risk. Following this evaluation, it has been recommended that
`the applicant perform a Human Factors Study demonstrating the safe simulated-use of the Optineb-IR
`device in an environment that approximates the intended home-care setting. As stated in the March 3,
`2009 letter (See Appendix 1), the purpose of this study is to evaluate the severity of the risks anticipated in
`the initial Usability Analysis, and to identify user—related risks that may have been unanticipated by the
`applicant. In the end stages of the study, the applicant should propose adequate mitigation measures for
`the identified user-related risks, and may be expected to modify and revalidate the proposed device as
`necessary to alleviate safety-related concerns regarding its use.
`'
`
`

`

`E. Labeling Review
`
`A summary of the labeling information for the Tyvaso Inhalation Solution was provided for review in
`NDA 22—387. The information is provided in the form of a User’s Manual, in which the device is
`described in detail, including complete descriptions of all components and optional accessories.
`
`Comprehensive instructions are given regarding how to assemble the nebulizer, how to connect the
`nebulizer to the power supply, how to fill the medication, and how to operate the nebulizer. Cleaning
`instructions are provided for the nebulizer chamber lid, continuous filling equipment, nebulization
`chamber and the mouthpiece of the device. For each part, cleaning, disinfection, and machine washing
`instructions are provided. Troubleshooting information for various faults is included in the manual,
`including potential causes and mitigations. Problems covered include insufficient nebulization, failures in
`the power indicator on the face of the device, and overflow of medication from the medication cup.
`
`Electrical emissions and immunity information are also provided, and will be discussed in further detail.
`
`Revised copies of the Instructions for Use and Patient Pac