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Human Factors Results for Fentanyl Iontophoretic Transdermal System (ITS) With Enhanced Controller for Postoperative Pain Management

Open AccessPublished:March 28, 2017DOI:https://doi.org/10.1016/j.jopan.2016.03.014

      Purpose

      The purpose of this analysis was to conduct summative usability evaluations, including behavioral and subjective evaluations, for the fentanyl iontophoretic transdermal system (ITS).

      Design

      Four usability studies were conducted in representative users.

      Methods

      The first three studies were conducted with (1) health care professionals (HCPs; N = 31), (2) patients who received placebo fentanyl ITS (N = 30), and (3) healthy volunteers (N = 30), and focused on the understanding and use of fentanyl ITS. The fourth study included HCPs (N = 31) and healthy volunteers (N = 30), and focused on the effectiveness of formal training regarding the use of fentanyl ITS.

      Findings

      Overall, user groups found the fentanyl ITS easy to use. There were no use errors that could potentially have safety implications. In the three early studies, there were some minor difficulties experienced; however, the introduction of a structured training reduced these difficulties.

      Conclusions

      Patients, nurses, and pharmacists were able to use fentanyl ITS with ease.

      Keywords

      FENTANYL IONTOPHORETIC Transdermal System (ITS; IONSYS, The Medicines Company, Parsippany, NJ) is a needle-free, patient-controlled analgesia (PCA) system that is indicated for the short-term management of acute postoperative pain in adult patients requiring opioid analgesia in the hospital.
      • Chelly J.E.
      • Grass J.
      • Houseman T.W.
      • Minkowitz H.
      • Pue A.
      The safety and efficacy of a fentanyl patient-controlled transdermal system for acute postoperative analgesia: A multicenter, placebo-controlled trial.
      • Grond S.
      • Hall J.
      • Spacek A.
      • Hoppenbrouwers M.
      • Richarz U.
      • Bonnet F.
      Iontophoretic transdermal system using fentanyl compared with patient-controlled intravenous analgesia using morphine for postoperative pain management.
      • Hartrick C.T.
      • Bourne M.H.
      • Gargiulo K.
      • Damaraju C.V.
      • Vallow S.
      • Hewitt D.J.
      Fentanyl iontophoretic transdermal system for acute-pain management after orthopedic surgery: A comparative study with morphine intravenous patient-controlled analgesia.
      • Minkowitz H.S.
      • Rathmell J.P.
      • Vallow S.
      • Gargiulo K.
      • Damaraju C.V.
      • Hewitt D.J.
      Efficacy and safety of the fentanyl iontophoretic transdermal system (ITS) and intravenous patient-controlled analgesia (IV PCA) with morphine for pain management following abdominal or pelvic surgery.
      • Viscusi E.R.
      • Reynolds L.
      • Chung F.
      • Atkinson L.E.
      • Khanna S.
      Patient-controlled transdermal fentanyl hydrochloride vs intravenous morphine pump for postoperative pain: A randomized controlled trial.
      • Viscusi E.R.
      • Reynolds L.
      • Tait S.
      • Melson T.
      • Atkinson L.E.
      An iontophoretic fentanyl patient-activated analgesic delivery system for postoperative pain: A double-blind, placebo-controlled trial.
      Iontophoresis (electrotransport or electrically-assisted transport) technology uses a virtually imperceptible low-intensity electric current to ionize and repel positively charged fentanyl molecules from the system anode through the skin's stratum corneum into the subcutaneous space and diffuse into the circulatory system. This method of drug delivery can provide PCA in a simple and noninvasive manner. Fentanyl ITS provides a 40 mcg dose of fentanyl per activation, delivered continuously over a 10-minute period. Dose administration is started by the patient pressing and releasing a recessed button on the top of the system twice within 3 seconds. A maximum of six 40 mcg doses can be administered per hour with each system operating for up to 24 hours or until 80 doses have been administered whichever occurs first, on which the system becomes inoperable. The system deactivates and provides an audio alert if an error condition occurs.
      The current version of fentanyl ITS is designated as the Separated System with Enhanced Controller, and separates the hydrogels in the bottom housing unit called the drug unit from the electronic circuit of the top housing unit called the controller unit during manufacture and storage (Figure 1A). The health care professional (HCP) assembles the system by snapping the drug unit and controller unit together immediately before application to the patient (Figure 1B).
      Figure thumbnail gr1
      Figure 1Illustration of the fentanyl ITS controller and drug unit. (A) Controller and drug unit before assembly. (B) Assembled fentanyl ITS system. (C) Fentanyl ITS user interface. This figure is available in color online at www.jopan.org.
      Reprinted with permission from The Medicines Company (Parsippany, NJ).
      Fentanyl ITS is intended for use for adult patients for whom an opioid agonist is indicated for the short-term management of acute postoperative pain during hospitalization. HCPs dispense and administer the system to the patient. Thus, there are three specific groups who are involved with fentanyl ITS in the hospital: (1) Nurses who work in hospitals with various areas of experience (eg, medical-surgical unit postanesthesia care unit), (2) Pharmacists who work in hospital pharmacies and are involved in dispensing medications, and (3) Adult patients who require postoperative opioid pain management therapy. Nurses have the most oversight with the fentanyl ITS user interface. They remove the system from the packaging, assemble it, apply it to the patient after preparing the skin site for application, and train patients on how to use the system. Nurses monitor patients throughout the duration of therapy, including the number of doses delivered and responding to system-generated alerts and any complaints by the patient. On completion of therapy, the nurse removes fentanyl ITS from the patient and separates the drug compartment from the rest of the system for safe disposal. Pharmacists are not expected to routinely assemble, disassemble, or monitor the system, but nurses may call them to provide support during these tasks. Patients actuate a dose when needed and report audible beeping or complaints to the nursing staff. Fentanyl ITS is intended for use in a hospital setting only and is removed from the patient before discharge. Hospitals must be certified in the IONSYS Risk Evaluation and Mitigation Strategy program to order, dispense, and administer IONSYS. Nurses and pharmacists will receive training in the field (eg, an “in-service”) before using the system per the Risk Evaluation and Mitigation Strategy. Nurses and pharmacists will have access to the Instructions for Use and Disposal (IFUD) and the full prescribing information during use of the system. Patients will be trained to use the system by the nurse who applies it. The nurse will instruct the patient on how to deliver a dose, how often to deliver a dose, and what to do in the event of a system alert (ie, notify the nursing staff).
      The US Food and Drug Administration (FDA) recognizes the importance of optimizing medical device design through applying human factors engineering and usability engineering during the development process.
      US Department of Health and Human Services
      Draft Guidance for Industry and Food and Drug Administration: Applying Human Factors and Usability Engineering to Optimize Medical Device Design.
      A draft guidance was issued on June 22, 2011 for the pharmaceutical and device industry outlining the steps needed in device development, which includes both formative (used for device refinement) and summative (used for device validation) studies.
      US Department of Health and Human Services
      Draft Guidance for Industry and Food and Drug Administration: Applying Human Factors and Usability Engineering to Optimize Medical Device Design.
      Three formative studies were completed with fentanyl ITS for the purpose of system refinement and product development. Improvements were made to the device based on the results of these three studies and a graphic “Quick Guide” or “IFUD” document was created.
      The purpose of the four summative studies described below was to demonstrate that the fentanyl ITS design met the user needs, and potential users were able to use the system without any errors or close-calls that could affect safety of the users. The fourth study also evaluated training that would be representative of HCP in-service training and patient training. The results of these studies are of particular interest to perianesthesia nurses as they are the group that most initiates and teaches patients about how to use PCA.

      Materials and Methods

      Fentanyl ITS consists of two parts, a drug unit and a controller that supplies the dosing current (Figure 1). The two parts are packaged separately and assembled before use. The three studies used either an “active” fentanyl ITS system or a “placebo” fentanyl ITS system. The active ingredient in fentanyl ITS is fentanyl (10.8 mg fentanyl hydrochloride equivalent to 9.7 mg fentanyl). Fentanyl ITS provides a 40 mcg dose of fentanyl per activation, delivered over a 10-minute period with an electrical current of 170 μA. Dose administration is initiated by the patient pressing and releasing a recessed button on the top of the system twice within 3 seconds. A maximum of six 40 mcg doses can be administered per hour. The system operates for 24 hours or until 80 doses have been used, at which point the system is automatically deactivated and becomes inoperable. The system provides audio alerts when error conditions occur. For the “placebo” fentanyl ITS, the system is exactly the same with the exception that the active ingredient is not present. The fentanyl ITS user interface is detailed in Figure 1C.
      These summative studies were performed based on the draft guidance document that was issued on June 22, 2011 for the pharmaceutical and device industry. Sample sizes of 10 to 15 are aligned with the FDA expectations and are considered appropriate for observational studies such as these.

      Study 1: HCP Study

      Before participation in the study, all HCPs provided informed consent for their involvement in a simulated use, nonclinical study.

      Objective

      The objective of the HCP study was to conduct summative testing for fentanyl ITS with the nurse and pharmacist groups. This study was intended to demonstrate that fentanyl ITS can be used by representative users under simulated use conditions (ie, no drug in the system) without producing failures that could result in harm to patients or injury to other system users.

      Study Design, Assessments, and Training

      The simulated-use validation test was conducted with 31 HCPs: 15 nurses (12 women and three men) and 16 pharmacists (13 women and three men) in a patient room in a large hospital in Houston, TX. The nurses were currently working in a hospital and had various areas of expertise (eg, medical-surgical unit, postanesthesia care unit). The pharmacists were also currently working in a hospital pharmacy. One of the participants was color-blind.
      The study evaluated the essential daily user tasks for fentanyl ITS specific to HCP interaction with the system. Tasks were evaluated by having participants use the system independently in as realistic a manner as possible, without guidance, coaching, praise, or critique from the study facilitator. Both behavioral (direct observation of behavior) and verbal (subjective participant assessment) data were collected. Tasks included system assembly (indicated by successful completion of the automated self-test performed by the system that confirms that the system has been assembled correctly); system application, removal, and disposal (indicted by successful adherence of the system to and removal from a simulated patient application site, and then indication of correct disposal methods); system display comprehension (indicated by understanding that the digital display shows the number of doses delivered); on-system warning statements comprehension (indicated by understanding the meaning of the warning statements); general system understanding (indicated by comprehension of general features of the system); and alert comprehension (indicated by understanding of, including how to respond correctly to, the dose initiation beep, the “15 second beeping/poor skin contact”, and the “continuous beeping/system error” alerts) (Table 1).
      Table 1HCP Tasks (Study 1)
      TaskSubtaskDescription
      1. System assemblyN/AThe participants were provided an IFUD and requested to read through the document. Approximately 10 min were allotted to this unless the participants said they were ready in a shorter duration. They were then handed a sealed tray containing the study system (a sealed placebo drug unit and a human factors controller; Figure 1). The first task was to assemble the system to get it ready for application to the patient.
      2. System applicationAfter assembly, the participants were told to apply the system to the mannequin. After application, the study facilitator asked the participant what they would have done to prepare the site if they were applying it to a real patient.
      Application sitesParticipants were required to select an appropriate application site.
      Site preparationParticipants were required to describe how to correctly prepare the site for application (ie, clean with alcohol, clip, not shave, hair).
      ApplicationParticipants were required to correctly apply the fentanyl ITS system to the application site on the simulated patient.
      3. System display comprehensionAt different times during the testing, the facilitator asked the study participants to identify what the system was doing (ie, what state the system was in)
      Ready stateThe LCD showed the number of doses delivered so far, and the LED blinked green slowly.
      Delivery stateThe LCD flashed the number of doses delivered, and the LED blinked green quickly.
      End of use stateThe LCD showed “80,” and the LED did not light up at all.
      Digital displayThe study facilitator asked the participants two questions about the meaning of the LCD during the study; these questions were spaced apart from each other.
      4. On-system warning statements comprehensionThe study facilitator asked the participants to read and interpret all the warning statements printed on the system.
      Only patient to press button
      Not for home use
      Remove before MRI
      5. Audible alert comprehensionThe study facilitator triggered multiple system alarms during the study and asked the participants to interpret them and state how he/she would respond to the alarms.
      15-second alertParticipants were required to identify that this signals poor skin contact.
      Continuous alertParticipants were required to identify that this signals a system error and remove the system from the simulated patient.
      Silencing alertParticipants were required to silence the continuous beeping alert by pressing and holding the dose button on the system.
      6. General system understandingThe study facilitator asked the participants the maximum number of doses one system could deliver and the amount of time one system could stay on a patient. The study facilitator also asked the participants what they would do if their skin accidentally contacted the drug, hydrogel.
      Maximum number of dosesParticipants were required to state the maximum number of doses that can be administered using the system (ie, 80 doses).
      Maximum length of timeParticipants were required to state the maximum length of time the system can be used for (ie, 24 hours).
      Drug contacting skinParticipants were required to state what should be done if the drug, hydrogel, touches their skin (ie, rinse their hands with water only).
      7. Removal and disposalThe final task was for the participants to remove and dispose of the system.
      Removing the systemParticipants were required to remove the fentanyl ITS system from the application site.
      Separating red bottom housing from systemParticipants were required to separate the red bottom housing from the system.
      Disposing of the systemParticipants were required to indicate proper disposal methods for the fentanyl ITS system (ie, drug unit in the biohazardous waste, sharps container, or flushed down toilet; controller in waste for batteries).
      ITS, iontophoretic transdermal system; IFUD, Instructions for Use and Disposal; MRI, magnetic resonance imaging; N/A, not applicable.
      The study consisted of one-on-one sessions during which the study facilitator first gave the participants a series of tasks (listed above) to perform and recorded their behavior, and then asked them a series of questions and recorded their responses. Because the study involved simulated use of fentanyl ITS with placebo systems, participants did not apply the system to a real patient, but engaged in the behaviors involved in that scenario (eg, applying the system to a mannequin). The session started with a simulation of the participants' first-time use of the system without training. The study facilitator provided a brief verbal introduction to the system and testing session, and then allowed the participants adequate time (approximately 5 minutes) to read the Instructions for Use document. The study facilitator then observed and recorded the participant's performance on the tasks. The behavioral trials were followed by a short interview, in which the participants provided their subjective assessments of the various tasks.
      The data collection and coding scheme for this study were intended to result in sufficient and appropriate data to facilitate identification and understanding of the root causes of use failures and encountered problems, inclusive of close calls and operational difficulties. “Close calls” are instances in which a user experiences confusion, misinterpretation, difficulty, or error that would result in mistreatment or harm, but the user “recovers” and no actual performance failure occurs.
      US Department of Health and Human Services
      Draft Guidance for Industry and Food and Drug Administration: Applying Human Factors and Usability Engineering to Optimize Medical Device Design.
      Standardized categories were used to record participant behavior on each task (Table 2).
      Table 2Standardized Data Coding Scheme (Studies 1 and 2)
      CategoryDefinitionAction
      UnassistedSuccessful completion of the task without any observed task failures, close calls, or assistance from the facilitator and/or observer.No review required
      ResolvedSuccessful completion of the task with an observed close call or apparent operational difficulty.Review required poststudy
      AssistedSuccessful completion of the task only possible with assistance from the facilitator and/or observer.
      UnresolvedUnsuccessful (incomplete and/or incorrect) completion of the task.
      N/AA score may be N/A when the list of behaviors in the test script was not exhibited or observed
      N/A, not applicable.

      Study 2: Patient Study

      Before study commencement, the protocol, informed consent form, and relevant study documents were reviewed and approved by an institutional review board. An informed consent was signed by each patient before any study-specific tests were performed. This study was conducted in accordance with US FDA and International Conference on Harmonisation Guidelines for Good Clinical Practice and with the ethical principles originating in the Declaration of Helsinki.

      Objective

      The objective of the patient study was to conduct summative testing for fentanyl ITS with representative users (ie, postoperative adult patients). This study was intended to demonstrate that fentanyl ITS can be used by postoperative patients under simulated use conditions (ie, no drug in the system) without producing use-related failures that could potentially result in harm to patients or injury to other system users.

      Study Design, Training, and Assessments (Patients)

      The simulated-use validation test was conducted with hospitalized, postoperative adult patients. These patients were prescribed an opioid pain management regimen (eg, IV PCA morphine) on the day of the study (1-day postoperatively) and were titrated per the sites normal procedures to a pain score of less than five on a 0 to 10 Likert Numeric Pain Rating Scale. These conditions are representative of the intended use situations for fentanyl ITS commercial product.
      The study evaluated the daily tasks for fentanyl ITS specific to the user's interaction with the system. Tasks were evaluated by having participants use the system independently in as realistic a manner as possible, without guidance, coaching, praise, or critique from the study facilitator. Both behavioral (direct observation of behavior) and verbal (subjective participant assessment) data were collected. Tasks included dose administration (indicated by the LED changing from slow blinking green to fast blinking green and a single beep) and comprehension of the alerts provided by the system (indicated by understanding the “15 second beeping/poor skin contact” and the “continuous beeping/system error” alerts, and the resulting necessary actions). For each session, the study facilitator provided a brief verbal introduction to the system and the testing session. Next, a nurse trained the patient (training typically lasted less than 3 minutes) and explained how the system was to be operated—training which is realistic with use of this system. The nurse then applied the system to the patient, either to the chest or upper outer arm, per a randomized pattern. Each patient then completed steps necessary to administer simulated doses using the system, whereas the study facilitator recorded the behavior. Because the study involved simulated use of fentanyl ITS with placebo systems, participants did not actually administer any medication, but engaged in the behaviors involved in doing so (eg, initiating a dose). The behavioral trials were followed by a short interview, in which the participant provided a subjective assessment of the system.
      Standardized categories were used to record participant behavior for dose administration (Table 2). Results from the “15-second alert recognition” and “continuous alert recognition,” were evaluated according to the following criteria: a score of “Call Nurse” meant that the participant correctly reported that he or she would call a nurse for assistance after hearing the alert; a score of “Administer Another Dose” meant that the participant reported that he or she would attempt to administer another dose of medication after hearing the alert, but would not immediately report it to a nurse. Attempting to administer another dose was not an incorrect action; however, in training, the patients were instructed to notify a nurse in the event of any alerts; a score of “Unsure” meant that the participant did not know what to do when he or she heard the alert and a score of “Did Not Notice” meant that the participant did not appear to perceive the alert.

      Staff Questionnaires

      Staff members involved with the study were asked a series of questions pertaining to ease of use and clarity of instructions. These questions addressed: ease of assembly of the system, clarity of the instructions to assemble the system, ease of application of the system, clarity of the instructions to apply the system, overall ease of use of the system, patient understanding of how to use the system, perceived degree of patient success in interacting with the system. Staff only responded to questions that were applicable to the interactions they had with the system.

      Study 3: Simulated Hospital Study

      Before study commencement, the protocol, informed consent form, and relevant study documents were reviewed and approved by an institutional review board. An informed consent was signed by the patient before any study-specific tests were performed. This study was conducted in accordance with US FDA and International Conference on Harmonisation Guidelines for Good Clinical Practice and with the ethical principles originating in the Declaration of Helsinki.

      Objective

      The primary objective was to observe the performance of the fentanyl ITS when used in a simulated hospital setting with healthy volunteers.

      Study Design, Training, and Assessments

      This was a single-center, randomized, open-label study. Healthy adult participants were screened within 30 days before randomization. A naloxone challenge was performed within 24 hours before the first fentanyl dosing. Participants received naltrexone hydrochloride (50 mg orally every 12 hours) before, during, and after fentanyl delivery to block the opioid effects of fentanyl. Fentanyl ITS was applied randomly to either the right or left upper outer arm of each participant. They self-administered an average of four fentanyl (40 mcg) doses each hour for a maximum of 48 doses over 12 hours. All staff members who “used” fentanyl ITS (ie, assembled and applied fentanyl ITS, or removed and disposed of fentanyl ITS) were to report any malfunction of the study system or any difficulty using fentanyl ITS.
      The critical tasks in this study included the steps necessary to successfully administer multiple doses of fentanyl using fentanyl ITS. For the patient user group, the task was dose administration. For the staff-member user group, the tasks included assembling the system, applying the system, removing and disposing of the system, and instruction comprehension.
      After the completion of fentanyl ITS treatment, two questionnaires were used to collect information on experience with fentanyl ITS. The first questionnaire was administered to each subject within 24 hours of the end of the treatment period. Difficulty regarding dose initiation and overall ease of use was assessed using a four-point scale (4—very easy, 3—somewhat easy, 2—somewhat difficult, 1—very difficult). The second questionnaire was completed by the clinical staff who applied and attended to the patient participants within 2 hours of the end of the treatment period or after the last patient contact during the treatment period (eg, due to a shift change). Ease of use and comprehension of instructions was assessed using a four-point scale (4—very easy/clear, 3—somewhat easy/clear, 2—somewhat difficult/confusing, 1—very difficult/confusing). A four-point scale (4—excellent understanding, 3—good understanding, 2—average understanding, 1—poor understanding) was used to measure how well the staff believed subjects understood how to use fentanyl ITS. A four-point scale (4—very successful, 3—somewhat successful, 2—somewhat unsuccessful, 1—very unsuccessful) was used to measure how successful the staff believed subjects were with fentanyl ITS.

      Study 4: HCP and Patient Study (With Formal Training)

      Objective

      Based on root cause analysis of task failures observed in the first three studies, additional risk mitigations—refinements to the IFUD and training of the HCPs and patients were introduced. The purpose of this validation study was to demonstrate the effectiveness of these mitigations in addressing the difficulties and task failures observed in the earlier validation studies and to demonstrate that the mitigations do not introduce any new issues.

      Study Design, Assessments, and Training

      HCP

      Each HCP participant completed training that lasted approximately 30 minutes that would be representative of in-service training that HCPs would receive before using the fentanyl ITS system. The training was provided in a group setting similar to what is expected for in-service training. The training consisted of an introduction to the system and the associated instructions. Areas of focus for the HCP training included: How to assemble the system (ie, press at both ends; confirm digital display reads “0” and light flashes green to confirm proper assembly); How to orient the digital display (ie, read “Doses Delivered” underneath the digital display); How to attach the system to a patient and monitor adhesion to skin (ie, clean unbroken skin; press and hold for 15 seconds; if necessary use medical tape to secure system to skin); How to understand and react to the system alerts (ie, beeping that stops is for poor skin adhesion—a recoverable alert; continuous beeping is for system error—not a recoverable event—must remove and replace); and How to train their patients on the proper use of the fentanyl ITS (ie, must press firmly in the center of the button twice within 3 seconds). The next phase of the study consisted of one-on-one sessions during where the facilitator observed tasks specific to the system.

      Patient

      The nurses who participated in the first part of the study provided training to patients (ie, healthy volunteers). In the event that nurse participants were not available for the extra duration required for training the patient, available pharmacist participants were asked to train the patient. The nurse trained the patient on the information outlined in the IFUD and the Guide for Patients (available at: https://www.ionsysrems.com/IonsysUI/rems/pdf/IONSYS_Instructions_for_Use_and_Disposal.pdf). A Guide for Patients was also available to the patients during training and testing. The HCP applied the system to the patient after the training. The system was applied on a disposable plastic cuff or wrapping on the patient's upper outer arm to avoid attaching the system directly onto the simulated patient's skin. The patient administered simulated doses with the system, responded to system alerts and answered follow-up questions.
      The tasks that were included were those that may be affected by the modifications made to the instructional materials and the training. The tasks included: system assembly and application (HCP only); comprehension of digital display (HCP only); comprehension of 15-section poor skin contact alert (HCPs and patients) and ability to initiate dose (patients only).

      Results

      Study 1: HCP Study

      The summary of errors (Table 3) demonstrates that both nurse and pharmacist user groups were able to use fentanyl ITS appropriately, without exhibiting any use errors or close calls that would result in potential harm to the patient or themselves.
      Table 3Participant's (HCP) Task Performance (Study 1: HCP Study)
      1. System Assembly
      Unassisted4
      Resolved24
      Assisted3
      Unresolved0
      2. System Application
      Application SitesSite Preparation
      One participant was not asked this question due to facilitator error.
      Application
      Unassisted312729
      Resolved010
      Assisted001
      Unresolved021
      3. System Display Comprehension
      Ready StateDelivery StateEnd-of-Use StateDigital Display
      Unassisted31272730
      Resolved0420
      Assisted0000
      Unresolved0021
      4: On-System Warning Statements Comprehension
      Only Patient to Press ButtonNot for Home UseRemove Before MRI
      Unassisted313130
      Resolved000
      Assisted000
      Unresolved001
      5. Audible Alert Comprehension
      15-Second AlertContinuous AlertSilencing Alert
      Unassisted212617
      Resolved549
      Assisted000
      Unresolved515
      6. General System Understanding
      Maximum Number of DosesMaximum Length of TimeDrug Contacting Skin
      Unassisted283115
      Resolved203
      Assisted000
      Unresolved1013
      7. Removal and Disposal
      Removing the SystemSeparating Red Bottom Housing From SystemDisposing of the System
      Unassisted282626
      Resolved354
      Assisted000
      Unresolved001
      HCP, health care professional; MRI, magnetic resonance imaging.
      One participant was not asked this question due to facilitator error.

      System Assembly

      Three HCPs required assistance with the assembly, all of them recognized that the unit was not working.

      System Application

      One HCP required assistance to properly apply the system and one was unable to properly apply the system; however, the error was likely an artifact of the testing because the arm of the mannequin was not flexible the way a human's skin is, and therefore, this issue is unlikely to occur in a real patient.

      System Display Comprehension

      Twenty-seven of the HCPs understood when the system was in the delivery state and end-of-use state without any difficulty.

      On-System Warning Statements

      All HCPs understood the “only patient to press button,” “not for home use,” and “remove before MRI” warnings printed on the system.

      Audible Alert Comprehension

      Most of the HCPs interpreted the 15-second and continuous beeping alerts correctly and were able to successfully silence the system alert. Although, as shown in Table 3, a few of the HCPs did not understand some of the alerts, the worst outcome that would result from this is delay of therapy.

      General System Understanding

      Most HCPs correctly indicated that a single system could deliver a maximum of 80 doses, and all the HCPs correctly indicated that a single system could remain on a patient for a maximum of 24 hours. Just over 50% of HCPs understood that they would rinse their hands with only water in the event that their skin came in contact with the drug hydrogel. Approximately, 40% HCPs incorrectly stated that they would use soap and water to wash their hands if their skin came in contact with the drug hydrogel. Again, these minor misunderstandings are unlikely to result in harm to either that patient or the HCP.

      Removal and Disposal

      Most HCPs were able to separate the red bottom housing from the system. All HCPs were able to correctly indicate how they would dispose of the system—drug unit.

      Study 2: Patient Study

      There were 30 patients enrolled in this study. The summary of errors (Table 4) demonstrates that the patient user group was able to use fentanyl ITS safety and effectively, without exhibiting any use errors or close calls that would result in potential harm to themselves.
      Table 4Patient Participant's Task Performance (Study 2: Patient Study)
      1. Dose Administration
      First DoseSecond Dose
      Unassisted2226
      Resolved31
      Assisted53
      Unresolved00
      2. Comprehension of Alerts Provided by the System
      15-Second Alert ComprehensionContinuous Alert Comprehension
      Call nurse2230
      Administer another dose40
      Unsure10
      Did not notice30

      Patient Tasks

      Dose Administration

      Most patients were able to administer the first dose and second dose without any assistance.

      Comprehension of Alerts Provided by the System

      As with the HCPs, most patients understood both the 15-second alert and continuous alerts on the system.

      Staff Questionnaire

      At the conclusion of the study, the nurses who participated in the study completed a questionnaire pertaining to fentanyl ITS (Table 5). Overall, the nurses rated the system as easy to use for themselves and the patient and believed it to be easily understood by the patient (Table 5).
      Table 5Nurse Questionnaire (Study 2) and Patient and Staff Responses (Study 3)
      QuestionRating ScaleMean Score
      Nurse questionnaire (Study 2)
       Rank the ease of assembly of the system1 (very difficult) to 4 (very easy)4
       Rank the instructions to assemble the system1 (very confusing) to 4 (very clear)4
       Rank the ease of application of the system1 (very difficult) to 4 (very easy)4
       Rank the instructions to apply the system to the patient1 (very confusing) to 4 (very clear)4
       Rank how well you believe the patient understood how to use the system1 (poor) to 4 (excellent)3.86
       Rank you successfully you believe the patient interacted with the system1 (unsuccessful) to 4 (successful)3.97
       Rank the overall ease of use of the system1 (very difficult) to 4 (very easy)4
      Patient and staff responses (study 3)
       Patient
      Rank how difficult it was to initiate doses1 (very difficult) to 4 (very easy)3.9
      Rank the overall ease-of-use of the system1 (very difficult) to 4 (very easy)3.9
       Staff
      Rank the ease of assembly of the system1 (very difficult) to 4 (very easy)4.0
      Rank the instructions to assemble the system1 (very confusing) to 4 (very clear)4.0
      Rank the ease of application of the system1 (very difficult) to 4 (very easy)4.0
      Rank the instructions to apply the system to the patient1 (very confusing) to 4 (very clear)4.0
      Rank the difficulty removing and disposing of the system1 (very difficult) to 4 (very easy)3.0
      Rank the clarity of the removal and disposal instructions1 (very confusing) to 4 (very clear)4.0
      Rank the overall ease of use of the system1 (very difficult) to 4 (very easy)4.0

      Study 3: Simulated Hospital Study

      Thirty eligible participants received one 12-hour treatment with active fentanyl ITS. All participants completed all 48 doses with fentanyl ITS. Ten participants were women and 20 were men. They were predominately white (83%). The mean age was 36.3 years (range: 20 to 55 years), and the mean BMI was 25 kg/m2. Two staff nurses assembled, applied, removed, and disposed of fentanyl ITS in this study.

      Patient Questionnaire

      A few participants required the staff nurses to give them system-use instructions more than once, and one participant appeared to have difficulty pressing the button quickly enough to initiate a dose, but was able to resolve the issue. The investigator did not observe any alerts (beeping) or any patients who were unable to initiate a dose. Out of the 30 patients, 26 reported that they were able to initiate doses successfully and the other four said that they were not sure if they had successfully initiated the dose, although they had in fact performed so.
      Overall, the participants found the system very easy to initiate doses and rated the overall system ease of use as very easy (Table 5).

      Staff Questionnaire

      Eighteen staff nurses participated in the study. Two staff nurses assembled, applied, removed, and disposed of the fentanyl ITS placebo, whereas the remaining 16 staff nurses notified participants to initiate their doses at the appropriate time intervals, and checked to ensure that the doses had been successfully initiated. Overall, the nurses rated the system as very easy to use with very clear instructions (Table 5). No staff members reported making any mistakes while interacting with the system.

      Study 4: HCP and Patient Study With Training

      The additional mitigations eliminated or significantly reduced the previously observed use errors and difficulties (Table 6). In the HCP group (N = 31), all successfully assembled the system, all successfully trained patients (as evidenced by the patients being able to properly use the system after training), all demonstrated proper understanding that the system was only meant for hospital use and needed to be removed before discharge; all wore gloves while handling the system, all successfully applied the system to the patient or mannequin, all correctly said that the digital display shows how many doses have been delivered, all correctly understood all warnings printed on the product, and all correctly indicated that all 80 doses had been delivered; therefore, they should dispose of it. Fourteen of 15 nurses and all 16 pharmacists correctly interpreted the 15-second alert as a poor skin contact alert and stated that they would attempt to reattach the system and/or tape it onto the patient's skin.
      Table 6Effectiveness of New Risk Mitigation Features Implemented (Study 4)
      Difficulty/Error Observed in First Three StudiesRisk Mitigation ImplementedResults From Study 4
      3/31 HCPs had difficulty assembling the system because they did not push on both ends
      • 1.
        HCP training
      • 2.
        Added instruction and improved graphics in the IFU to press on both ends of the system
      0/31 HCPs had a use error in assembling the system. All 31 HCPs pressed at both ends to assemble the system properly
      2/31 HCPs misread the screen display because they read it upside down
      • 1.
        HCP training
      • 2.
        Added instruction in the IFU for proper orientation of screen display
      0/31 HCPs had any use errors in reading and comprehending the display

      All 31 HCPs read the screen in proper orientation and demonstrated comprehension of display
      5/31 HCPs did not understand the 15-second alert for poor skin contact
      • 1.
        HCP training
      • 2.
        Improved graphics in IFU to emphasize that the poor skin contact alert would last 15 seconds
      1/31 HCPs mistook the 15-second beeping alert to be a continuous beeping alert, although he understood the two types of alerts
      1/30 patients were unable to initiate a dose
      • 1.
        HCPs trained patient on proper use of system
      • 2.
        Improved instructions in Guide for Patients
      0/15 patients made any errors initiating doses.

      All 15 patients were able to dose themselves.
      HCP, health care professional; IFU, Instructions for Use.
      In the patient group (N = 30), all were able to initiate both the first and second doses and all correctly identified the system was alerting and stated that they would call for a nurse for assistance. One patient demonstrated proper understanding of all aspects of product use, but incorrectly stated that because the system is prescribed for 24 hours, use could continue up to the prescribed 24-hour use period even after leaving the hospital.
      There were no significant residual risks from the system that required further modifications to the system design, user interface, or the instructions provided in the Instructions for Use document.

      Discussion

      In the HCP and patient trial, the user groups were able to use fentanyl ITS appropriately, without exhibiting any use errors or close calls that would result in potential harm to the patients or themselves. Therefore, there is no significant residual risk from the system that requires further modifications to the system design, user interface, or the IFUD. In the first three studies, although there were a few errors and misunderstandings, these studies represented initial use of the system. The final fourth study, which incorporated formalized training, demonstrated that fentanyl ITS could be used by nurses, pharmacists, and patients without encountering use errors or difficulties. Overall, the participants indicated that fentanyl ITS was very easy to use and easy to initiate doses.
      In the simulated hospital study, the staff nurses who assembled, applied, removed, and disposed of the systems said that they found assembling fentanyl ITS and applying it on the patients to be very easy, and the associated instructions to be very clear. They said that removing and disposing of the system was somewhat easy and that the associated instructions were very clear. Overall, the staff members indicated that the system was easy to use. On average, the staff members responded that the patients had good-to-excellent understanding of the system and were very successful using it.
      A commonly used treatment option for postoperative pain management is intravenous PCA pumps. The main known use problems with the PCA pumps include: inappropriate patient selection, programming errors, selection of the wrong medication or concentration, compounding errors, setup time delay, patient mobility inhibition, and IV line complications, which include occlusion, infiltration, and infection.
      Medication safety: PCA pump programming errors continue to cause fatal overinfusions.
      • Hicks R.W.
      • Sikirica V.
      • Nelson W.
      • Schein J.R.
      • Cousins D.D.
      Medication errors involving patient-controlled analgesia.
      • Hankin C.S.
      • Schein J.
      • Clark J.A.
      • Panchal S.
      Adverse events involving intravenous patient-controlled analgesia.
      • Palmer P.P.
      • Royal M.A.
      • Miller R.D.
      Novel delivery systems for postoperative analgesia.
      • Schein J.R.
      • Hicks R.W.
      • Nelson W.W.
      • Sikirica V.
      • Doyle D.J.
      Patient-controlled analgesia-related medication errors in the postoperative period: causes and prevention.
      Based on the known use problems with IV PCAs, the following design features were implemented with fentanyl ITS: (1) fentanyl ITS is not programmable—all units and doses are exactly the same, thus eliminating programming errors and expediting the setup process, (2) fentanyl ITS is prefilled with fentanyl to eliminate any medication mix-up or compounding errors, (3) the size of fentanyl ITS does not restrict patient mobility (ie, no IV line or pumps are required), and (4) fentanyl ITS does not require IV access. Patient selection criteria for appropriateness of therapy must be evaluated based on criteria similar to that of IV PCA.
      In addition to having an easy-to-use system, such as fentanyl ITS, time efficiency and convenience need to be evaluated. Time efficiency and convenience of fentanyl ITS and morphine IV PCAs were compared in a pooled analysis of two studies
      • Lindley P.
      • Pestano C.R.
      • Gargiulo K.
      Comparison of postoperative pain management using two patient-controlled analgesia methods: nursing perspective.
      that used the validated nurse ease-of-care questionnaire.
      • Harding G.
      • Vallow S.
      • Leidy N.K.
      • et al.
      Ease of care with patient controlled analgesia systems: questionnaire development and validation.
      In this analysis, the results of the nurse ease-of-care questionnaire suggested the fentanyl ITS was significantly more time-efficient and convenient to use when compared with morphine IV PCAs.
      • Lindley P.
      • Pestano C.R.
      • Gargiulo K.
      Comparison of postoperative pain management using two patient-controlled analgesia methods: nursing perspective.
      In addition, in this pooled analysis, nurses were significantly more satisfied with fentanyl ITS compared with morphine IV PCAs.
      The findings suggest that this system would provide a safe and effective alternative to standard IV PCA systems in many patients. The demonstrated lack of dosing errors with the use of this system suggests a significant improvement in safety as this is a major source of morbidity and mortality from the use of traditional IV PCAs that can be programmed with multiple drugs and settings. The lack of need for a separate pump, tubing, and IV access will allow for better patient mobility and comfort through the use of this system.
      A significant problem with the complexity of currently available intravenous PCA systems is the amount of time devoted by the nurse to setting up the system and additional time needed to maintain and verify it once therapy has already been established. The simplicity of setup and use of fentanyl ITS from a nursing perspective should allow for more time to be made available to address the nonpharmacologic needs and interventions for patients that can have a profound effect on both perception of discomfort and overall satisfaction with care. In addition, the ability to have this system readily available in a variety of clinical settings will prevent unnecessary analgesic gaps that often accompany initiation of standard PCA systems owing to lack of either equipment, medications, or both.
      • Panchal S.J.
      • Damaraju C.V.
      • Nelson W.W.
      • Hewitt D.J.
      • Schein J.R.
      System-related events and analgesic gaps during postoperative pain management with the fentanyl iontophoretic transdermal system and morphine intravenous patient-controlled analgesia.
      For prescribers, the fixed dosing regimen and ability of this system to record number of doses administered, should streamline and standardize the process of opioid conversion to oral medications for discharge. Although this is possible with traditional PCA, the variety of medications and dosing schedules often prevents simple conversion. This system potentially allows for more algorithmic conversion that could be more easily implemented by nonspecialist prescribers.

      Conclusion

      The four validation studies confirm that fentanyl ITS can be used for its intended uses (ie, postoperative pain management) by the intended users (nurses, pharmacists, and hospitalized postoperative patients) in the intended use environment (ie, hospital setting), without any errors or close calls that could affect safety of the users. Overall, patients, nurses, and pharmacists were able to use fentanyl ITS with ease. These are important findings for perianesthesia nurses as they are on the front-lines of postoperative pain management. They have an incredibly important role in both initiating PCA as well as teaching patients about their PCA. Having a system that is easy to use by both the nurse and the patient should translate into more time for the nurse to spend on other patient-focused activities vs time spent on programming PCA.

      Acknowledgments

      Study funding was provided by The Medicines Company (Parsippany, NJ). The analyses and writing of this manuscript were supported financially by The Medicines Company. Design Science Consulting was retained by The Medicines Company to perform the studies.

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      Biography

      Diane Santangelo, ANP-C, Stony Brook Medicine, New York, NY
      Christopher R. Page, MD, Stony Brook Medicine, New York, NY
      Hassan Danesi, MD, The Medicines Company, Parsippany, NJ
      James B. Jones, MD, The Medicines Company, Parsippany, NJ
      Nitin Joshi, PhD, The Medicines Company, Parsippany, NJ
      Steve B. Wilcox, PhD, Design Science Consulting, Inc., Philadelphia, PA
      Peter Sneeringer, MS, Design Science Consulting, Inc., Philadelphia, PA
      J. Bradley Phipps, PhD, The Medicines Company, Parsippany, NJ