CENTER FOR DRUG EVALUATION AND
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` RESEARCH
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` APPLICATION NUMBER:
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`208276Orig1s000
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` CLINICAL REVIEW(S)
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`M E M O R A N D U M
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`Food and Drug Administration
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`
`Center for Devices and
`Radiological Health
`Office of Device Evaluation
`White Oak Building 66
`10903 New Hampshire Avenue
`Silver Spring, MD 20993
`
`Date:
`
`From:
`
`To:
`
`March 13, 2015
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`
`Jessica D. Eisner, MD, General Hospital Devices Branch, DAGRID, ODE, CDRH
`
`
`CDR Alan Stevens, Engineer, General Hospital Devices Branch, DAGRID, ODE, CDRH
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`
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`Device Name P140032 - RIS – Remodulin Implantable System [SynchroMed implantable pump]
`I.
`Issue
`Provide a clinical review of the subject PMA submission.
` The submission states that “Medtronic considers the use of the RIS as not significantly affecting
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`the quality of the human environment. Use of the RIS is intended to be used in a manner in
` which waste will be controlled or the amount of waste expected to enter the environment may
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`reasonably be expected to be non-toxic. As such, an environmental assessment has not been
`included in this PMA application.”
` The Administrative Documents submitted as part of the submission states that “The Clinical
`Studies section of the PMA provides:
`•The DelIVery for PAH Clinical Study report, MDT2055289 DelIVery for PAH PMA Report (G100017).
`• Design differences between the DelIVery for PAH clinical study system and the RIS are provided.
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`• A complete list of centers, investigators, and IRBs is provided in MDT2055289 Appendix 6.3 of the
`DelIVery for PAH PMA Report.
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`• Death summaries are provided in MDT2055289 Appendix 6.12 of the DelIVery for PAH PMA Report.
`
`• A copy of the Clinical Investigation Plan and change history”
`Background:
`Remodulin (treprostinil) Injection (NDA approval number 021-272)8 is a sterile sodium salt
`formulated for continuous subcutaneous or intravenous (IV) administration. Remodulin is an
`existing prostanoid therapy for treating PAH patients. Treprostinil sodium, the active ingredient
`in Remodulin Injection, is designated as an Orphan Product. With IV administration, Remodulin
`is administered via an external infusion pump and surgically placed central venous catheter.
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`Remodulin is supplied in 20 mL vials in concentrations of 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL,
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`and 10.0 mg/mL and is diluted with 0.9% Sodium Chloride Injection or Sterile Water for IV
`administration.
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`Remodulin is currently FDA approved for the same patient population and route of delivery. The
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`use of Remodulin in the RIS does not change the drug’s indicated patient population, drug
`dosage, formulation or route of administration for which the drug has already received FDA
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`approval. Remodulin is marketed by United Therapeutics Corporation (UTC).
`The submission states that UTC will submit an NDA supplement to add RIS to the Remodulin
`labeling for the undiluted 2.5 mg/mL, 5.0 mg/mL, and 10.0 mg/mL concentrations.
`
`Reference ID: 4409052
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`

`

`Remodulin Label (excerpts):
`Indication: Remodulin is indicated for the treatment of pulmonary arterial hypertension (PAH)
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`(WHO Group 1) to diminish symptoms associated with exercise. Studies establishing
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`effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of
`idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary
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`shunts (23%), or PAH associated with connective tissue diseases (19%).
`Adverse Events with Subcutaneously Administered Remodulin
`Patients receiving Remodulin as a subcutaneous infusion reported a wide range of adverse
`events, many potentially related to the underlying disease (dyspnea, fatigue, chest pain, right
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`ventricular heart failure, and pallor). During clinical trials with subcutaneous infusion of
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`Remodulin, infusion site pain and reaction were the most common adverse events among those
`treated with Remodulin. Infusion site reaction was defined as any local adverse event other than
`pain or bleeding/bruising at the infusion site and included symptoms such as erythema,
`induration or rash. Infusion site reactions were sometimes severe and could lead to
`discontinuation of treatment.
`
`Other adverse events included headache, diarrhea, rash, jaw pain, edema, vasodilatation and
`nausea, and these are generally considered to be related to the pharmacologic effects of
`Remodulin, whether administered subcutaneously or intravenously. The safety of Remodulin
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`was also studied in a long-term, open-label extension study in which 860 patients were dosed for
`a mean duration of 1.6 years, with a maximum exposure of 4.6 years. Twenty-nine (29%)
`percent achieved a dose of at least 40 ng/kg/min (max: 290 ng/kg/min).
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`The safety profile during this chronic dosing study was similar to that observed in the 12-week
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`placebo controlled study except for the following suspected adverse drug reactions (occurring in
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`at least 3% of patients): anorexia, vomiting, infusion site infection, asthenia, and abdominal
`pain.
`Post-Marketing Experience
`In addition to adverse reactions reported from clinical trials, the following events have been
`identified during post-approval use of Remodulin. Because they are reported voluntarily from a
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`population of unknown size, estimates of frequency cannot be made. The following events have
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`been chosen for inclusion because of a combination of their seriousness, frequency of reporting,
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`and potential connection to Remodulin. These events are thrombophlebitis associated with
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`peripheral intravenous infusion, thrombocytopenia bone pain, pruritus and dizziness. In addition,
`generalized rashes, sometimes macular or papular in nature, and cellulitis have been
`infrequently reported.
`Overdose: Signs and symptoms of overdose with Remodulin during clinical trials are extensions
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`of its dose-limiting pharmacologic effects and include flushing, headache, hypotension, nausea,
`vomiting, and diarrhea. Most events were self-limiting and resolved with reduction or
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`
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`withholding of Remodulin.
`II.
`Documents
`P140032 and G199917
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`Reference ID: 4409052
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`

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`III. Review
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`Indications for Use:
`
`The proposed indication for use for the Remodulin Implantable System is:
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`The Remodulin® Implantable System is intended for the chronic intravenous infusion of
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`Remodulin® (treprostinil) Injection for use in the treatment of pulmonary arterial hypertension
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`(PAH) in patients that are indicated for Remodulin®.
`
`Principle of Operation: The submission explains that “Remodulin (the “drug”) enters the
`Remodulin Implantable System implantable infusion pump (the “pump”) through the reservoir
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`fill port and passes through the reservoir over pressurization valve and into the pump reservoir.
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`At normal body temperatures, propellant exerts pressure on the reservoir bellows which contains
`the drug. This pressure advances drug into the pump tubing. The battery-powered electronics and
`motor precisely delivers the programmed dose out through the catheter port and into the
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`Remodulin Implantable System intravascular catheter (the “catheter”). The peristaltic action of
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`
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`the pump moves the drug from the pump reservoir, through the pump tubing, check valve,
`catheter port, and implanted catheter, to the infusion site.”
`Device Description
`The submission states that “the Remodulin Implantable System (RIS) is a programmable,
`implantable drug delivery system for chronic intravenous infusion of Remodulin in patients with
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`Pulmonary Arterial Hypertension (PAH). The RIS, tools and accessories are described in this
`section along with the regulatory status of each component. The RIS being proposed for this
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`PMA is depicted in Figure 1-1 and includes:
`x Model 8201 Implantable Intravascular Catheter [Not used during the clinical study]
`x Model 8637 SynchroMed II Programmable Pump for RIS (CFNs 8637P20 and 8637P40)
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`x Model 8840 N’Vision Clinician Programmer and Model 8870 Application Card including
`RIS software application
`Remodulin Implantable System
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`Reference ID: 4409052
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`

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` Catheter: Reviewer comments: Of significant note, the catheter that is being proposed for
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`marketing in the RIS system (Model 8201) is not the same one that was used in animal or clinical
`studies (Model 10642). Note the excerpted portion of the Table below from the submission,
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`Model 8201 will be described first
` The PMA submission states the following: “The Model 8201 Implantable Intravascular Catheter:
`
`The Model 8201 Implantable Intravascular Catheter (Figure 1-2 below; pasted from submission)
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` consists of a 2-piece design: a catheter body segment and a pump segment. Drug will be
`dispensed from the RIS pump into the patient’s vasculature via the Medtronic Model 8201
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`
`Implantable Intravascular Catheter that is available in three lengths appropriate to the patient’s
`anatomy. Catheter lengths of 80, 100 and 120 cm include both the catheter body and pump
`segments. The catheter body segment is new and contains the catheter tip, which is placed in the
`superior vena cava. The pump segment is the FDA approved sutureless connector which
`connects the catheter body to the pump.”
`
`
`Reviewer comments: The design and use of the sutureless connectors throughout the clinical
`trial appears to have changed regularly. The submission states that the sutureless connector
`was developed by Medtronic and originally FDA approved under P860004/S81 March 22, 2006.
`The go on to explain that there were recently approved with design changes under
`P860004/S136 on December 15, 2011 [i.e. 5 months after the start of the clinical trial) and
`P860004/S167 on February 17, 2012 [i.e. almost 2 years after the start of the clinical study].
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`Reference ID: 4409052
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`(b) (4)
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`

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`The Sponsor goes on the state that the Model 8201 catheter [not used during the clinical study]
`will include the most recently approved sutureless connector design. The redesigned sutureless
`connector was submitted as a change to the clinical study Model 10642 catheter (G100017/S032,
`accepted May 8, 2013 [i.e. 6 months after the last patient enrolled in the clinical trial]).
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` The submission states that the catheter is made of radiopaque silicone with enhanced radiopacity
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`at the distal tip. The submission states that “the Model 8201 catheter is similar to other
`Medtronic intravascular and intrathecal catheters except for the one-way valve at the distal end,
`metal coil reinforced catheter body and soft distal, closed catheter tip.” Also included in the
`catheter package:
`• Market released vein pick (P/N 103548) will be included as an optional implant tool.
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`• An additional market-released sleeve will also be included in the package for strain relief as an
`optional component.
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`
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`The following Table 1-6 {below) has been pasted from the submission; it lists the components
`for the catheter Model 8201 (which was not used during the clinical study but is being proposed
`for marketing).
`
`Reference ID: 4409052
`
`(b) (4)
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`(b) (4)
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`(b)
`(4)
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`

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`The following Table describes how the Model 8201 catheter has been designed to mitigate the
`risk of certain issues. There is no comparative Table for the Model 10642 catheter that was used
`in the clinical trial.
`
`Reference ID: 4409052
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`

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`The submission states that “Model 8201 implantable intravascular catheter is new. An evaluation
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` of biocompatibility and biostability was performed to demonstrate that the components of the
`catheter are biocompatible and biostable. The biological evaluation, including exhaustive
`extractions and toxicological assessments demonstrated compliance of the materials used in the
`Model 8201 implantable intravascular catheter with ISO 10993-1. All catheter materials were
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`found to be biologically stable and safe such that the device is expected to perform as intended
`after exposure to the in vivo environment for the intended duration of the device life.”
`The Sponsor has also submitted an extensive table of “Catheter Design Verification”
`performance testing for the Model 8201 catheter; the submission claims that the Model 8201
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`catheter passed all of these tests. There is no such table or comparison for the Model 10642 that
`was used in the clinical studies. Instead the Sponsor submitted a Table (see Appendix A) which
`compares “Market Release Catheters to the Model 8201” – but does not include the Model
`10642 used in the clinical study in this chart.
`As to Model 10642, the submission explains that “The versions of the devices (Model 10642
`catheter and Model 8637 pump) used in the animal study was the same design iteration used in
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`the clinical study. These devices share the same primary design, materials and similar
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`manufacturing processes as the RIS, however the Model 8201 catheter has an updated anchor
`sleeve and offers additional lengths. The Model 8637 pump for RIS has been configured to
`communicate exclusively with the RIS software application.”
`Reviewer Comments: No engineering figures of the Model 10642 catheter used in the study
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`are presented in the current submission; nor is there a feature comparison table between
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`Model 10642 and Model 8201. In addition, none of the clinical studies were performed
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`using this catheter model. This, as it related both to patient safety and the pre-determined
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`safety endpoints that were analyzed in this study will be further discussed later in the
`submission.
`Catheter – continued – Model 10642 – used in the clinical study:
`Model 10642 Implantable Intravascular Catheter (with sutureless connector) The Model 10642
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`Implantable Intravascular Catheter is designed to be connected to the SynchroMed II Implantable
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`Infusion System. The catheter is used with the currently available Medtronic sutureless
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`connector. For purposes of this clinical study, the catheter tip is intended to be positioned in the
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`superior vena cava, and to deliver the drug systemically and continuously. Table 2 (pasted from
`the submission) indicates the features of the Model 10642 Catheter.
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`Reference ID: 4409052
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`

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`Study Design and Protocol (per the PMA submission):
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` Overview:
` • Prospective, single arm, non-randomized open label study
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`• 10 US sites, up to 70 subjects
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`• • A minimum of 22,000 subject follow-up days were necessary to evaluate the end point–
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`• Study procedures: Screening [PE, blood collection, pregnancy test, walk test, NYHA
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`classification, QoL and AEs] (see Appendix B for full schedule)
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`• Study visits:
`Scheduled: Baseline, implant, Weeks 1 & 6, Months 3, 6, 12, & then q 6 mos. until end
`Unscheduled (i.e., pump refill, dose change, AE)
`• Average time between refills is ~6-8 weeks
`• Study Duration: The expected study duration is approximately 28 months. Study subjects will
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`be followed until approval is granted from a regulatory body, or official study closure.
`Protocol:
`The purpose of the clinical trial was to evaluate the safety profile of the Model 10642
`Implantable Intravascular Catheter, a component of the PAH Implantable Vasodilator Therapy
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`(PIVoT) system. The clinical study was designed as a multi-center, prospective, single arm, non-
`randomized open label Investigational Device Exemption (IDE) clinical study. Up to 70 subjects
`at 10 centers were planned for implant and follow-up. This study is conducted in the United
`States. The study enrolled subjects who met the approved Remodulin indication, using the
`approved concentrations, and approved intravenous route of administration and who met all
`inclusion and no exclusion criteria.
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`Subjects: The study is expected to enroll up to 70 subjects to ensure at least 50 subjects are
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`successfully implanted. Reviewer comment: This goal was achieved.
`Inclusion Criteria
`x 18 years of age or older
`x able to provide written informed consent
`x able to comply with the protocol, including required follow- up visits
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`x diagnosed with Pulmonary Arterial Hypertension (World Health Organization
`(WHO) Category Group 1 [by the WHO Clinical classification system])
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`x Receiving continuous infusion of Remodulin therapy via IV using an external pump system.
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`Patient on stable Remodulin dose (no change in dose) for at least 4 weeks
`x $nticoagulation therapy can be managed to permit safe device implantation
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`x 1o history of pulmonary embolism since the initiation of subcutaneous or IV therapy for PAH
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`Exclusion Criteria
`x Pregnant, nursing, or of child bearing potential and not on a reliable form of birth control
`x Patient is enrolled, has participated within the last 30 days, or is planning to participate in a
`concurrent drug and/or device study during the course of this clinical trial.
`x Initiated on a new oral PAH therapy in the last two months
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`x Recent (within three months) or otherwise unresolved infection requiring Abx treatment
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`Reference ID: 4409052
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`

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`x Diagnosed with PAH associated with hemoglobinopathies , HIV, schistosomiasis, portal
`hypertension, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis
`x ,mplanted with electrical stimulation medical devices(s) anywhere in the body (e.g., cardiac
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`pacemakers, implantable cardioverter defibrillators (ICDs), spinal cord stimulators).
`x Chronic kidney disease (serum creatinine > 2.5 mg/dl) within 90 days prior to baseline visit;
`chronic kidney disease is defined as that lasting or expected to last more than 3 months
`x Patient is a person for whom the implantable vascular catheter length of 80 cm was excessively
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`long or too short to be properly implanted
`x Has an existing external catheter(s) that would remain in place after the pump implant
`x Implantable pump cannot be implanted 2.5 cm or less from the skin surface
`x Body size is not sufficient to accept implantable pump bulk and weight
`x Hast increased susceptibility to systemic or soft tissue infections
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`x Patient is Functional Class IV (New York Heart Association (NYHA))
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`Endpoints:
`The stated primary objective of the clinical study was to demonstrate that the Model 10642
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`Implantable Intravascular Catheter was safe when used with the Medtronic SynchroMed II
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`Implantable Infusion System to deliver Remodulin. The endpoint of this objective was catheter-
`related complications per 1000 patient days.
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`The ancillary objectives were:
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`x To characterize % change of six-minute walk test distance from baseline to 6 wks post-implant
`x To characterize changes in quality of life
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`Reference ID: 4409052
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`

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`x To characterize the incidence of adverse events
` x To characterize healthcare utilization (hospitalizations, emergency room visits, & urgent clinic
`visits)
`x To assess pump fluid delivery accuracy
`x To assess subject/caregiver involvement in system management
`x To characterize plasma treprostinil concentration change
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`
`
` Review of Data and Results in PMA submission:
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`Demographics (cut & pasted from the PMA submission)
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`The Sponsor explains that the average age of the enrolled subjects, was 50.1 ± 13.5 years.
`Women represented 80% of the total subjects enrolled in the study, which was expected since the
`prevalence of women among those diagnosed with PAH in the general U.S. population is
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` approximately 78%. One subject was enrolled and exited prior to fully completing the baseline
`visit. This subject only had demographic data collected. Therefore, data from only 63 subjects
`are included in most of the tables.
`Reviewer comment: Agreed with Sponsor’s presentation & assessment of age/gender data and
`conclusions.
`Demographics continued (Table below cut & pasted from submission)
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`
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`Reviewer comment: The Sponsor does not comment on the racial aspects of demographic
`distribution. It is noted that not many South East Asian or African Americans were included
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`Reference ID: 4409052
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`

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`in the study. In particular South East Asians and African Americans appear to be under
`represented. This could also be an issue in regards to the refill procedure as it could be more
`difficult to perform refills in darker skinned individuals; in addition, darker-skinned South
`East Asians, African Americans and Latinos have a higher tendency to produce keloid
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`scarring. Please justify how the study population reflects the racial and ethnic diversity of
`PAH patients in the US and explain who they will all be able to access and utilize the RIS
`system.
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` Reviewer comment: Please provide justification for why 7 patients were enrolled into the
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`study with pneumonia at baseline. Please also explain whether these same seven patients
`experienced excessive infections or other adverse events during the study.
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`Review comments: The baseline Cardiac History for the patietns in the study is indecipehrable
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`and not possible to place into proper context. It appears as though approximately 9 (minimum)
`– 15 (maximum) patients had rhythm disturbances upon entering the study (from the baseline
`cardiac characteristics). However, from the presentation of the data the baseline cannot be
`determined as one patient may have more than one type of arrhythmia; please characterize the
`arrhythmia data so that it indicates how many patients (N and %) had history of an
`arrhythmia upon study entry; also compare this to the number (N & %) observed during the
`study and explain how the risk of arrhythmias is minimized for implantation (since this and
`other cardiac AEs can obviate the presumed benefits of the RIS system if they prove to be fatal
`or life threatening). Analyze the cardiac rhythm-related adverse events in the study with what
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`was present at baseline and what would be generally expected in the PAH population.
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`Study Exits (not-due to Death): Four subject exits that occurred prior to implant. No subjects
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`have exited post-implant (with the exception of the five subjects who died post-implant)
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` \Study Deaths: There were five deaths that occurred doing the trial. These deaths were
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`reviewed by the Adverse Event Advisory Committee (AEAC), and all were adjudicated as not
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`related to the investigational system.
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`Reference ID: 4409052
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`(b) (6)
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`(b) (6)
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`(b) (6)
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`

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`Reviewer comment: The SAE report forms and narrative of these deaths were reviewed; the
`adjudication of the Death events appears acceptable.
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`Study Implant information (table below pasted from the submission):
`
`Reviewer comment: It is noted that only one patient received the Model 8637-20 pump (20 ml
`pump).
`.
`
`Safety:
`The submission states that “the AEAC adjudicated all adverse events in the trial.” and “that the
`AEAC consists of a minimum of three non-Sponsor employed physicians, including an AEAC
`chairperson. At least three AEAC members must adjudicate, at a minimum, all deaths, serious
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`AEs, and AEs related to any component of the system under investigation and/or Remodulin
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`Injection. All other AEs will be adjudicated by at least one physician member of the AEAC
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`composition of the DMC was complete with a total of three members.” The list of the AEAC
`meetings has been pasted below (Table 12 - from the submission).
`
`Reference ID: 4409052
`
`(b) (4)
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`

`

`Reviewer comments: It is noted that nearly one-third of all AEs in the clinical study for this
`PMA’s two-year long clinical study were adjudicated on a single day (November 26, 2012).
`
`What were the quality control or quality assurance processes in place to ensure that time
`constraints and the (non-voting) presence of the Primary Study PI did not adversely impact
`AE review and adjudication?
`
`
`Adverse events were to be classified according to related, as is described in the table below
`(Table 79 pasted from the submission).
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`Reference ID: 4409052
`
`

`

`The following (Table 78) defines catheter related events.
`
`Reference ID: 4409052
`
`
`

`

` Reviewers comments: According to various document submitted under the IDE for this
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`combination drug-device study, the Table above was created to define the catheter –related
`events which would be used to calculate the safety endpoint (see Table 78 below). However,
`throughout the IDE process and the pre-PMA submission process it has been documented that
`ALL system complications will be considered in the device evaluation process. In addition,
`risk-benefit will be assessed looking at the totality of the data – not just the pre-specified
`events. Noted again here is the fact that this study was designed around the Model 16042
`catheter (which utilized one anchor sleeve and two sutureless connector components for this
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`trial).
`
`Adverse event Evaluation:
`
` The submission states that there were 737 AEs reported during the study and all AEs were
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`
`reported throughout the study. Documented pre-existing conditions were not considered AEs
`
` unless the nature or severity of the condition had worsened.
` The Sponsor states that there were 22 pre-implant AE’s in the study. Three of the pre-implant
`
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` AE’s were device related infection from the subject’s pre-existing PICC line, two AE’s were
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` reported for hypokalemia, two for vessel site puncture pain, and all other AE’s were single
`events.
`Reviewer comments: The 22 pre-implant AEs were reviewed. All of them appear to be
`obviously unrelated to any RIS component or procedure. However, a few of these AEs beg
`questions about the conduct of the trial. Specifically, was the patient who had Klebsiella
`bacteremia allowed to proceed with receiving the implant? Also did the patient who tested
`
`positive for urine leukocyte esterase go on to test negative for this before proceeding with the
`implant procedure? These are two instances which could set a patient up for and AE or
`implant failure due to infection.
`The submission goes on to list “unavoidable” events; an event was considered unavoidable if the
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`onset and resolution occurred within the specified timeframe.
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`Reference ID: 4409052
`
`

`

`Per the submission (see Table pasted below), there were 20 unavoidable adverse events
`following the 60 implants.
`
`The Sponsor then states that “Following the 60 implants, there were 713 post-implant adverse
`events, 20 of which were unavoidable.”
`
`Reviewer comments: The definition of unavoidable events is acceptable; however, in
`presenting the actual PMA data, no timeframes are given for these events to ascertain whether
`they met the defined requirements. The AEs were also not discussed in the context of the
`
`entire implant procedure and how this impacts the risk-benefit of the Remodulin Implantable
`System.
`
`Discussion with the Agency agreed upon a set of “Catheter-related Events specific to the Model
`
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`16042 catheter” (see Table 79 which has been cut & pasted above). Subsequently, the
`submission goes on to present all of the events which they deemed to be “Catheter-related Events
`specific to the Model 16042 catheter”. These are presented below in Table 36 as “Primary
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`Endpoint Events”.
`
`Reference ID: 4409052
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`

`

`Subject ID
`
`. tE
`n mary E d
`T bl 36 P .
`n 1pom
`a e
`ven s
`t
`Days
`post-
`Preferred
`AE Desrription
`implant Ter m
`Pneumo th It was noted that the surgeon had venous access difficulty during the implant
`0
`or ax
`procedure. Following the procedure the subject got up to go to the bathroom
`and reported shortness of breath. A chest x-ray showed a large left
`pneumothorax. A chest tube was inserted.
`On!
`'the subject hyperextended her arm. The catheter slid into the
`Device
`dislocation intrnclavicular region and the subject reported pain, erythema and swelling
`at the catheter insertion site (left clavicle), left neck, and left shoulder. She
`also reported oain radiatiCg down her left arm. System modification
`perfmmed on
`.
`
`7
`
`42
`
`lthe subject complained of non-radiating stabbing pain in
`Device
`Onl
`dislocation her left abdomen above the implanted pump, which was exacerbated with
`movement or sitting up. It was noted that the left abdomen was swollen
`above the implanted pump. The subject's left upper quadrant was tender
`with palpation. Abdominal CT scan showed pump and catheter in
`subcutaneous tissue ofleft abdomen. Admitted to hospital on
`I
`I System modification done onl
`I
`
`Reference ID: 4409052
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`

`

`the subj ect‘s recliner chair broke and caused her to fall
`backwards. She did not have any assistance and pulled / strained herself
`flying to get out of her chair. 011
`(b) (6) she contacted the site and
`complained of muscle soreness and fatigue. 011
`(b) (6) the site
`contacted the subject and she reported abdominal soreness and noted that
`the area near the pump had “a little redness“. The subject refused to come
`in to be seen. On
`(b) (6) the site contacted the subject and she stated
`that the redness was worse. She noted that it “had spider web and a
`lightning streak above her pump site”. The subject was advised to come in
`for assessment. On
`(b) (mfluoroscopy was used to image pump and
`catheter. The catheter was found c01
`'
`'
`
`(b) (6) the subject reported soreness and inflammation at pump
`On
`site (lower rigfllt abdomen) that had decreased but persisted for two weeks.
`The subject‘s last refill was on
`(b) (wand the subject denied any
`fever. discharge. heat fi‘om site. or worsening of PAH symptoms.
`Fluoroscopy was utilized to image pump system integrity and the PI
`believed the system was intact. In August the subject was evaluated by
`Dermatology and Infectious Disease. On
`an (6)the subject's
`pump/catheter was explanted due to possible catheter leak and site pain.
`A new system was implanted on the left side with no complications. The
`ex lanted catheter was found to have been dama ed unctured .
`
`1021
`
`Device
`
`damage
`
`Venous
`stenosis
`
`upper extremity edema. which began in the light hand on the evening of
`(b) (6) By the morning of
`(b) (wit had extended to the upper
`arm. On the afternoon of
`(b) (6) the subject saw her PCP for a
`regularly scheduled apt. The PCP ordered venous doppler studies. which
`were completed on
`(b)(6)a11d were inteipreted as negative. On
`(b) (6) the subject called the study coordinator to report the edema was
`worsening. She also now reported some pain with the increased swelling and
`noted intermittent temperann‘e and color changes in fingers of light hand.
`The subject was brougfllt to clinic for evaluation and admitted to the hospital
`for further workup. The final diagnosis was “Stenosis at the junction of the
`light subclavian vein-SVC“.
`
`
`
`(b) (6) the subject had a difficult refill. After three attempts were
`made. some redness was noted. After two additional attempts. the redness
`appeared to spread. At that time. fluoroscopy was requested and the catheter
`appeared to be in front of pump. The site accessed the pump under fluoro &
`completed the refill.
`The subject denied any worsening PAH symptoms including SOB. dyspnea.
`headache. flushing or chest pain. Following the refill. no systemic
`symptoms were reported but the subject continued to have site pain and
`redness. On
`(b) (6) the subject's pump/catheter was explanted due to
`possible catheter leak and site pain. A new system was implanted on the lefi
`side with no complications. The explained catheter was formd to have been
`
`Subiect ]]LI(b
`
`Reference ID: 4409052
`Reference ID: 4409052
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`

`

`However, later in the adverse event section of the submission the test states that “a system-
`related adverse event” is defined as an adverse event related to one or more of the systems
`
`components: the catheter, pump, and programmer. Table 53 (cut & pasted below) lists these
`events and states there were 16 system-related (pump or catheter) adverse events occurring in the
`study. There were no events deemed related to the programmer.
`
`Table 53: Post-Implant System-related Adverse Events
`
`Number of Events (Number
`of Subjects, % of Subjects)
`
`Adverse Event
`Preferred Term
`Device dislocation1
`Implant site
`extravasation
`Device damage2
`Venous stenosis
`Abdominal pain lower
`Abdominal pain upper
`
`Dermatitis contact
`Medical device pain
`Muscle spasms
`Skin striae
`Total
`
`Events
`4 (3, 5.0%)
`3 (3, 5.0%)
`
`Complications
`3 (2, 33%)
`3 (3, 5.0%)
`
`2 (1, 1.7%)
`1 (1, 1.7%)
`1 (1, 1.7%)
`1 (1, 1.7%)
`1 (1, 1.7%)
`1 (1, 1.7%)
`1 (1, 1.7%)
`1 (1, 1.7%)
`16 (11, 18.3%)
`
`2 (1, 1.7%)
`1 (1, 1.7%)
`0 (0, 0.0%)
`0 (0, 0.0%)
`0 (0, 0.0%)
`0 (0, 0.0%)
`0 (0, 0.0%)
`0 (0, 0.0%)
`9 (6, 10.0%)
`
` Figure 16 from the submission shows the timing of the first system-related adverse e