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TABLE OF CONTENTS

INTRODUC TION

ME THODOLOGY

FINDINGS & RESULTS

DISCUSSION

REFERENCES

Treatment groups

Procedure

Training stimuli

Other study materials

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Patients were highly engaged with training devices 9

Training devices improved patient performance

Patients prefer hands-on training with training devices at home

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3LONGITUDINAL STUDY © Noble. All Rights Reserved. INTRODUCTION

INTRODUCTIONIn the United States, one in two adults live with a chronic disease, and one in four adults are diagnosed with two or more chronic conditions (e.g., asthma, heart disease, cancer, autoimmune disease, etc.). With advancements in science and technology, many of these conditions are treated with biopharmaceuticals that patients must properly self-inject due to the unique clinical profiles and structures of these medications. As the patient population and demand for these treatments continue to grow, so will the number of patients onboarding to drug delivery devices that require self-injection. This growing trend further necessitates the need for effective training and onboarding as more patients find themselves self-managing their treatments outside of clinics.

Within the drug delivery industry, the first few months of a patient’s treatment is commonly referred to as the onboarding stage. During the onboarding process, healthcare providers (HCPs) introduce patients to their therapies and drug delivery devices and are intended to train patients on proper self-injection prior to sending them home with their devices and other related materials.

However, the quality and quantity of training patients received varies greatly. A 2018 survey of HCPs found that 49% of patients prescribed self-injection devices did not receive in-office training, with similar training rates for other delivery device modalities (Lang & Nalan, 2018). Recent studies have also found that only 61% of patients read the Instructions for Use (IFU) and other forms of print collateral that are commonly used for patient training, education and risk management. As a consequence of these and other training gaps, research has found that 84% of patients make errors when using autoinjectors, many of which can be mitigated through proper training and onboarding (Potera, 2015).

The learning and forgetting curve theories shown to the left are commonly used to describe how individuals learn, retain and recall information. However, there is a limited amount of published literature assessing and applying these theories to self-administered drug delivery devices. To address this gap in research, Noble partnered with a third-party human factors engineering organization, Insight Product Development, to field a longitudinal cohort study to bridge this gap and apply these models to patient onboarding and drug delivery device use. The following objectives of this study were developed to help organizations formulate effective onboarding solutions that maximize patient performance and outcomes with drug delivery devices.

49%of patientsprescribed self-injection devicesdid not receivein-office training

84%of patients makeerrors when usingautoinjectors

The learning curve proposes that an initially difficult task becomes easier with practice, leading to the mastery of the skill. Retention and recall continue to increase through repetition and experience. The forgetting curve posits that, without practice and repetition, retention and recall degrade over time. Internalizing information is dependent on a combination of intrinsic and extrinsic factors, such as a subject’s age at the onset of disease and their learning environment. Low retention causes such errors as: injecting at the wrong angle, removing the device prematurely from the injection site, non-adherence to treatment, etc.

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The primary goal of this research was to comparatively evaluate the effects of three training conditions – as they relate to the performance, engagement and preferences of injection-naïve people experiencing a self-administered injection for the first time − following a 14-day decay period.

Specific objectives included:

• Assessing the effects of different training materials on self-injection performance • Understanding how patients engage and interact with training materials • Evaluating the effects of different training materials in relation to patient confidence, anxiety, preparedness, preference and potential compliance.

METHODOLOGY

Over the years, Noble has conducted multiple cross-sectional studies to understand patient onboarding needs and how training could be used to increase confidence and decrease anxiety. Using these research outputs as a foundation, this study sought to understand how patients interact with training collateral during the first 14 days of their treatment by applying a longitudinal cohort methodology. The study was composed of three cohorts who received different training stimuli for use during the decay period. To create the most realistic onboarding experience for participants, the study employed a deception paradigm in which test participants were told they would have to self-inject using an actual autoinjector in the second session. This technique was used to condition the participants into believing they would be self-injecting to make participate interaction and performance as close to a real onboarding experience as possible. With this paradigm, the study protocol was reviewed and approved by Advarra, a third-party institutional review board (IRB).

Treatment GroupsParticipants in this study were meant to serve as a representative sample of self-injecting populations. The sample size for this study included 27 bio-naïve subjects lacking prior experience with self-injection devices or formal training as an HCP. The study was fully recruited with no drop-outs throughout its duration. Participants were recruited by a third-party agency using predefined screening criteria. Participants were matched on age, gender and education level across the cohorts so there were similar characteristics across the three groups. Upon arrival at the testing center for their first session, participants were re-introduced to the study protocol, randomly assigned a participant ID and then designated to one of three cohorts.

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5LONGITUDINAL STUDY © Noble. All Rights Reserved. METHODOLOGY

COHORT A (N=9)

AGE

GENDER

HANDEDNESS

HIGHES T LEVELOF EDUCATION

COHORT B (N=9) COHORT C (N=9) T O TAL (N=2 7 )

Cohort A: Cohort A served as the control group for this study and was only provided with the Medication IFU to take home and use during the decay period. To understand the effect of having access to a training device in-office only, participants were given the training device to practice with during Session 1, but the training device was not taken home.

This group is not intended to represent the minimum amount of training a patient may receive, but to set a baseline for evaluating the effects of having training materials at home.

Cohort B:This group was given the same Session 1 conditions as Cohort A (the IFU and in-office training), but they were instructed to take both the training device and IFU home. This group was designed to assess the effect of having access to and practicing with a training device at home after the initial session. These participants were told to keep track of how many times they used these materials and practice as much or as little as they wanted.

Cohort C: Participants in this enhanced training group were given the IFU, a training device and an interactive training video to work with during Session 1 as well as to take home. The video was provided for participants to use in conjunction with their training device, allowing them to walk through the physical motions of the injection experience and see if they were doing anything wrong to help solidify their technique.

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Procedure

As mentioned, a two-part, simulated-use study employing a deception paradigm was used. Participants were led to believe during the recruitment period that they would be performing an actual injection on themselves at the return session. Two one-on-one interviews were conducted with each participant at a third-party usability research facility. A 14-day decay period was built in after the first session to mimic a common injection frequency. During this period, participants logged their experiences using an online diary before returning for the second in-person session.

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Session 1:Simulated in- office training (45 minutes)

14 daysDecay Period: Self-injection

assessment(60 minutes)

Session 2:

SESSION 1: Simulated in-office training (45 min.)Session 1 was developed to replicate an optimal in-office learning experience between patients and their HCPs. This interaction focused on introducing participants to the drug delivery device and training them how to properly use it. The following activities were completed in Session 1:

• Participant Enrollment – Review of study protocol and informed consent.

• Background Interview – Introduction to participants and background.

• Treatment & Device Introduction – Simulated HCP training of participants following predetermined workflow.

• Self-Training – Use of instructions and a mechanical training device by participants.

• Simulated-Use Evaluation – Practice injection performed by participants under supervision of the moderator. Feedback was given to participants during this process and mistakes were corrected.

• Dismissal – Participants were issued their training stimuli to take home and use during the decay period. Participants were told to use these materials as if they were onboarding to a real treatment.

DECAY PERIOD: 14 daysThe purpose of the 14-day decay period was to mimic the first time participants would take their medication after the initial training session, where they should have received training and/or performed their injection with their HCP. After 14 days, patients for many on-market medications would need to self-inject without assistance from their HCP. This method allowed participants to experience onboarding firsthand as they would in real-world scenarios.

“Taking the trainer home was so helpful. I was much more comfortable having it.”

(Cohort B4, Age 67)

7LONGITUDINAL STUDY © Noble. All Rights Reserved. METHODOLOGY

SESSION 2: Self-injection assessment (60 min.)Session 2 was conducted after the 14-day decay period and focused on evaluating participants’ ability to use the actual device and their recall of the instructional materials they were provided. Participants were informed in this session that they would be injecting into a pad and not into themselves. Session 2 activities are outlined below.

• Simulated-Use Evaluation – Participants conducted a simulated injection using a real autoinjector and injection pad. Participant performance was monitored and tabulated by human factors engineers following a task flow protocol.

• Participant Experience Questions – Open-ended questions relating to patients’ memory and use of their stimuli during the decay period.

• Qualitative Feedback – Additional feedback collected following a predefined discussion guide.

TRAINING STIMULI

Medication Instructions for Use A simulated Medication IFU was created to provide context for study participants. Adapted from currently marketed autoinjector IFUs in order to closely align with what pharmaceutical manufacturers would develop and provide in each product package, this version contained 12 steps and included warnings (important information), storage information, pre-injection preparation information, a step-by-step walkthrough of the injection and post-injection disposal instructions. The Medication IFU also provided a labeled diagram of the autoinjector and illustrations for each section. In this study, all participants were given access to the Medication IFU in the training session and took it home to simulate what a patient might receive after getting a new prescription.

Training DeviceThe training apparatus used in this study was a mechanical training device designed to simulate the self-injection process. The Training Device mimicked the operation of its corresponding platform autoinjector regarding actuation forces, operation steps and feedback mechanisms. The fundamental differences between the Training Device and its commercial analog are that the Training Device did not contain a needle or solution and was resettable for repeated practice. The Training Device was presented to participants in the Training Device Package, which also contained a Training Device IFU. All participants were given the opportunity to use and practice with the Training Device during Session 1. Only participants in Cohorts B and C took home a Training Device per their assigned training stimuli.

“I would like the trainer device. If I had it, I wouldhave remembered taking the cap off. For those who are anxious, it stops the anxiety. You have it, you are used to the noise, to the click, etc.”

(Cohort A1, Age 40)

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Training Device IFUThe Training Device IFU included in the Training Device Package included instructions and diagrams of each of the following steps: prepare for injection training, pull off reset cap, press the safety cover onto skin, press and release the injection button, monitor injection progress and completion. The Training Device IFU also include a labeled diagram of the Training Device and reset instructions. The Training Device IFU differed from the Medication IFU and focused only on aspects relevant to the Training Device, such as how to reset the Training Device. It was also a shorter and simplified IFU and did not include all the warnings found in the Medication IFU. Only participants in Cohorts B and C took home a Training Device IFU per their assigned training stimuli.

Interactive Training VideoAn instructional video was developed to walk participants through the injection experience and was intended to be used in conjunction with a Training Device to create an active learning experience. The purpose of this video was to provide a more interactive training tool, with more emphasis on visual cues to understand how this level of training affected the participants. During the video, each step was explained verbally and demonstrated by a person completing the action. Visuals and instructions that appear in the Training Device IFU were also highlighted in the video with live demonstrations following each step. The instructional video focused exclusively on the use of the Training Device and emphasized the critical steps of the injection experience. All participants had the opportunity to watch the Interactive Training Video while practicing with the Training Device during Session 1. For this study, only Cohort C received the Interactive Training Video as part of their training materials.

OTHER STUDY MATERIALS

Real AutoinjectorFor the second session, participants were provided a single-use, prefilled, button-actuated autoinjector for use in their simulated injection. These devices were production-level samples and used to make the injection experience as realistic as possible. Participants injected these samples into injection pads during their simulated injection.

SIMULATED INJECTION SUPPLIESAdditional supplies that were used during participants’ Session 2 simulated injection include:

• Alcohol swabs• Injection pad• Sharps container

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“The training materials were great. The trainer device was helpful, you can actually practice and get to be hands-on.”

(Cohort A8, Age 65)

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FINDINGS & RESULTS

Training devices improved patient performanceIn Session 2, performance on self-administering the injection differed starkly between training groups. The cohorts with Training Device access performed better and successfully completed all the critical steps during their simulated injections (see data on left). Overall, participants who received training devices were happy with the materials they received.

In Session 2, participants’ performance was evaluated based on their ability to successfully self-inject using an injection pad tied to their preferred site. Participants were asked to complete this evaluation under the observation of a human factors engineer. The tasks most critical to a successful self-injection include:

• Removing the Cap – Before using the device, the user removes the cap.

• Placing the Autoinjector at 90-Degree Angle – Placing the device on the selected injection site to depress the needle shield.

• Depressing the Needle Shield – Depressing the needle shield unlocks the device, allowing for the injection button to be pressed.

• Pushing and Releasing Injection Button – Pushing and immediately releasing button to start the injection. An initial audible “click” signifies the injection has begun.

• Holding the Autoinjector in Place – Holding the autoinjector in place after pressing the injection button for the recommended time frame. A second audible “click” occurs, signaling the injection is complete.

COHORT A MEDICATION IFU Only had access to Medication IFU during the 14-day decay period.

COHORT B TRAINING DEVICE • 33% practiced 10 or more times.• 56% practiced 5-9 times.• 100% practiced at least 3 times.

COHORT C TRAINING DEVICE & INTERACTIVE VIDEO• 33% practiced 10 or more times.• 83% practiced 5-9 times.• 100% practiced at least 3 times.

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COHORT A MEDICATION IFU

56%made mistakes on crit ical steps

COHORT B TRAINING DEVICE

100%successf ul completionof crit ical steps

COHORT C TRAINING DEVICE & INTERACTIVE VIDEO

100%successf ul completionof crit ical steps

Patients were highly engaged with training devicesIn recent years, research has found that patients who are more involved in their health care experience achieve better outcomes and incur lower costs. In concept, patient engagement seeks to integrate patients’ knowledge, skills, ability and willingness to manage their own health with strategies aimed at improving their care and outcomes. In this study, participants were sent home with training materials to practice as if they were real patients and prepare for their injection during the second session. To track participant engagement, diaries were used during the 14-day decay period to record patient feelings about their upcoming injection. Throughout the study, it was found that training devices significantly increased patient engagement during the decay period.

Patients prefer hands-on training with training devices at homePatient education and training directly affects self-injection performance, as seen in the previous section. The three treatment groups were designed to understand how different training materials and conditions, particularly the availability of the Training Device and Interactive Training Video during the 14-day decay period, affect outcomes for patients prescribed an injection device. After the post-injection debriefing, participants were asked which of the three training methods they would have preferred to receive.

Overall, 92% of participants would prefer to receive a training device to take home and practice with prior to conducting their self-injection. Participants who did not have a training device at home had to rely on the experience of using the Training Device in Session 1 and on rote memory from reading the instructions, resulting in more critical errors. With the Training Devices to take home, participants from Cohorts B and C were able to practice and, as a result, build motor memory and improve their performance. These participants were more confident about how to manipulate the device and the order in which they needed to perform tasks.

When asked to describe the most important aspects of effective training devices, participants felt that ideal training devices should work exactly like the real device, with exception to real needles and medication(s). A training device close in design and function to its analogue allows users to operate the training device as if conducting an actual self-injection.

Specific features participants cited include:• Timing – Timing of visual and auditory feedback of the injection progress should mirror the actual autoinjector as closely as possible.

• Auditory Feedback – Consistent auditory cues to gain information on the state of the device.

• Physical Structure – The shape and size should be similar (or the same as) the actual device, as well as any buttons or other features contained on the actual device.

• Forces – The forces required to remove the cap, depress the needle shield and press the injection button should be as close as possible to the actual device. If the forces between the training device and the real device differ, users may think they are performing an action incorrectly (e.g., if the force to remove the cap is greater in the actual injection device, users may think they are doing something incorrect by removing it).

As mentioned earlier, Cohort C received the Interactive Training Video as part of their training materials to take home. Participants in both Cohorts B and C completed all the critical steps successfully. The results demonstrate that while the Training Device helped participants better prepare for the self-injection, the Interactive Training Video can serve as supplementary

10LONGITUDINAL STUDY © Noble. All Rights Reserved. FINDINGS & RESULTS

92%of participants wouldprefer to receive a training device to take home and practice with prior to conductingtheir self-injection

“Practicing helped me mentally prepare for the injection.”

(Cohort C7, Age 18)

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material in the onboarding process. The Interactive Training Video was helpful, and the participants preferred the hands-on experience of using a training device.

Overall, giving a patient a training device to practice with at home that is close in design and function to the commercial device facilitates the development of a mental framework and motor memory conducive to a successful self-injection.

DISCUSSIONTo ensure that patients successfully self-administer their medication(s), both the patients and their HCPs should develop a strategy leading to improved therapeutic outcomes. An informed patient is essential for developing a framework focused on treating his/her illness and preventing behaviors detrimental to treatment. The findings from this study demonstrate that the cohorts who took the Training Device and other training materials home to review and practice with performed better in the self-injection assessment. For an effective patient engagement framework, HCPs must also be informed of the existence of training materials. In a survey involving HCPs, it was found that 49% of HCPs did not train patients how to properly use a self-injection device and 43% of HCPs reported not receiving any device training themselves in their office (Lang & Nalan, 2018). To facilitate successful self-injections, training devices should be designed as close to the actual device as possible in both the function and usage environment. Overall, the findings from this study show the implementation of a training device and its usage in the home environment helps the user perform successful self-injections, further validating its potential benefit in the onboarding process. Based on our findings, additional research is recommended on patients training over a longer decay period to better understand how onboarding influences patient behavior and outcomes.

LONGITUDINAL STUDY FINDINGS & RESULTS © Noble. All Rights Reserved. DISCUSSION

49%of HCPs did nottrain patients howto properly use a self-injection device

43%of HCPs reported notreceiving any devicetraining themselvesin their of f ice

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REFERENCES & RESOURCES

1. Lang, V.A. Nalan, D. (2018). Combination Product Patient Training: How are Patients Trained and Who Conducts the Training? The American Society of Mechanical Engineers. Frontiers in Biomedical Devices, 2018 Design of Medical Devices conference (): V001T09A003. Retrieved from http://proceedings.asmedigitalcollection.asme.org/proceeding.aspx?articleid=2685407

2. Potera, Carol. (2015). Misuse of Autoinjectors and Inhalers. American Journal of Nursing, 115 (3), pp.17. Retrieved from https://journals.lww.com/ajnonline/Fulltext/2015/03000/Misuse_of_Autoinjectors and_Inhalers.12.aspx

3. Boissy, Adrienne. (2017, May 17). Patient Engagement versus Patient Experience. Retrieved from https://catalyst.nejm.org/patient-engagement-vs-patient-experience/

4. James, J. (2013, Feb 14). Patient Engagement. HealthAffairs. Retrieved from https://www.healthaffairs.org/do/10.1377/hpb20130214.898775/full/

5. Murre, J.M.J. Dros, J. (2015, July 6). Replication and Analysis of Ebbinghaus’ Forgetting Curve. PLoS One 10(7): e0120644. Retrieved from https://journals.plos.org/plosone/article?id=10.1371/journal pone.0120644#sec001

6. Oostrum, S.H. Gijsen, R. Stirbu, I. Korevaar, J.C. Schellevis, F.G. Picavet, H.S.J. Hoeymans, N. (2016, Aug. 2). Time Trends in Prevalence of Chronic Diseases and Multimorbidity Not Only due to Aging: Data from General Practices and Health Surveys. PLoS One, 11(8): e0160264. Retrieved from https://www.ncbi.nlm nih.gov/pmc/articles/PMC4970764/

7. Simmons, L.A. Wolever, R.Q. Bechard, E.M. Snyderman, R. (2013, Dec. 5). Patient Engagement as a risk factor in Personalized Health Care: A Systematic Review of the Literature on Chronic Diseases. Genome Medicine 6: 16. Retrieved from https://genomemedicine.biomedcentral.com/articles/10.1186/gm533

8. National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP). (2018, Aug. 6). About Chronic Diseases. Retrieved from https://www.cdc.gov/chronicdisease/about/index.htm

9. Partnership to Fight Chronic Disease. (N.D.). The Growing Crisis of Chronic Disease in the United States. Retrieved from https://www.fightchronicdisease.org/sites/default/files/docs GrowingCrisisofChronicDiseaseintheUSfactsheet_81009.pdf

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