The Patient's Journey to Adherence. An Exploration of Factors, Studies, Education and Drug Delivery Devices

Transcription

1 The Patient's Journey to Adherence An Exploration of Factors, Studies, Education and Drug Delivery Devices

2 The Patient's Journey to Adherence New and emerging treatment options and drug delivery devices such as autoinjectors, prefilled syringes and pulmonary treatment devices for chronic conditions have required patients to selfadminister medication as part of their treatment regimen. Every year, more patients are introduced to injection and pulmonary treatment devices and although self-management offers patients convenience and time, adherence rates are still less than 50 percent after six months of treatment. 1 The impact of nonadherence on the pharmaceutical industry is lower drug consumption, lower sales, lower expectations of drug efficacy and lower brand equity. 1 Adherence is a multidimensional concept, and along with self-administration of drug delivery devices there are a variety of cognitive, emotional and environmental factors that can cause inconsistencies in treatment. This document will explore factors of patient nonadherence, onboarding, common device usage errors, user studies and recommendations for improving adherence.

3 Patient nonadherence Onboarding Common device usage errors User studies Improving adherence

4 Factors of Nonadherence Five dimensions of nonadherence: 2 Patient-Related Socioeconomic Health Care Team / Health System Condition-Related Treatment-Related L 14% of patients don t think their medication is needed 4 Patient Nonadherence 2

5 The following section provides a brief overview of the five dimensions. Patient-Related Factors of Nonadherence 2 Forgetfulness Stress, anxiety, anger Physical challenges Knowledge about disease Perceived risk/susceptibility to disease Understanding need for medication Expectations or attitudes toward treatment Perceived benefit of treatment Confidence in ability to follow treatment regimen Motivation Fear of dependence Feeling stigmatized by the disease 46% of patient s don t understand prescription dosing instructions % of patients stopped taking medication before the supply ran out 3 25% of respondents had taken less than the recommended dose 3 31% of patients admit to not filling a prescription 3 20% of patients are concerned about side-effects 4 17% of patients stated their prescribed medicine costs were too high 4 49% of patients admit to forgetting a prescribed medicine 3 10% of patients are unable to get the prescription filled, picked up or delivered 4 3 Patient Nonadherence

6 Socioeconomic-Related Factors of Nonadherence 2 Medication cost Demographics (age, race and gender) Low health care literacy Lack of family or social support network Burdensome schedule Lack of health care insurance Limited access to health care facilities Inability or difficulty accessing pharmacy Cultural and lay beliefs about illness and treatment Health Care Team/System-Related Factors of Nonadherence 2 Poor provider/patient relationship (time spent, communication style, follow ups and monitoring) Poor provider communication (skills contributing to lack of patient knowledge or understanding of the treatment regimen) Lack of knowledge on adherence challenges and of effective interventions for improving it Inadequate reimbursements Poor medication distribution systems Limited capacity of the system to educate patients and provide follow-up Patient information materials written at higher literacy level High drug costs, co-payments, or both Poor access or missed appointments Lack of continuity of care I have been on the drug more than 15 years with three different providers. You have to almost beg for training. market research participant 5 Patient Nonadherence

7 Patient Medication Adherence COPD / Asthma Diabetes Depression Osteoporosis Hypertension Hyperlipidemia Cancer Multiple Sclerosis 33% 51% 62% Medication Possession Ratio (MPR) 5 are the most common measures of medication adherence using refill records. They are usually reported as percentages of the time when a patient has medication available. Condition-Related Factors of Nonadherence 2 Severity of symptoms from chronic conditions Lack of apparent symptoms Rate of progression and severity of disease Depression Treatment-Related Factors of Nonadherence 2 Complexity of medication regimen (number of daily doses; number of concurrent medications) Treatment requires mastery of certain techniques (injections, inhalers) Duration of therapy Frequent changes in medication regimen Lack of immediate benefit of therapy Medications with social stigma attached to use Actual or perceived unpleasant side effects Treatment interferes with lifestyle or requires behavioral changes Patient Nonadherence 8

8 Patient Onboarding and Drug Delivery Devices The first 30 days after diagnosis is the time when a patient is first introduced and trained on their injection or pulmonary treatment device. After receiving in-office training, patient's return home and are expected to adhere to a prescribed treatment by self-injection or inhaler. Many times, patient's have difficulties recalling the exact process that a trained health care professional conducted at the hospital or doctor s office. Memory recall is important for adherence. The more information delivered by the health care provider, the lower the probability to correctly recall the information. Typically, only half of the correct information is retained. Other variables include physical factors, such as mobility, age and dexterity impairments associated with specific therapeutic categories, which make it challenging to use the device. Emotional factors, such as fear and anxiety associated with self-injecting, can lead to avoidance behaviors impacting treatment. A combination of these factors can result in user errors, injuries and adverse events. The cause of these factors can often be tied to ineffective training and a lack of awareness of administration techniques, procedures and sequences. Drug delivery device instructions for use (IFU) have multiple steps that must be correctly followed. Any variance from the structured protocols has the potential to adversely affect the effectiveness of the drug and could lead to intervention and changes in the patient s treatment plan L to 80% of medical information provided by a health care provider is forgotten immediately. 7 9 Onboarding

9 Patient Onboarding Timeline RECEIVE DISEASE MGMT. / TRAINING MATERIALS RECEIVE DISEASE MGMT. / TRAINING MATERIALS PRIMARY CARE PHYSICIAN NURSE TRAINING FIRST INJECTION: AT HOME NEXT OFFICE VISIT 90 DAYS SPECIALIST PHARMACY 30 DAYS 60 DAYS RECEIVE DISEASE MGMT. / TRAINING MATERIALS RECEIVE DISEASE MGMT. / TRAINING MATERIALS ADDITIONAL TRAINING / EDUCATION VIA WEB

10 The Training Process from Pharmaceutical Company to Patient Message Erosion Bio Pharma Company Sales Rep HCP Patient day(s) of training Approx. 30 mins of training Approx. 30 mins of training 19% communication of patients have a higher risk of nonadherence due to poor physician/patient 8 A study on patient adherence conducted by the New England Journal of Medicine found patients feel their physicians don t spend enough time explaining the drug requirements and the importance of completing the full dose Onboarding

11 Study of Correct Usage of Drug Delivery Devices According to a study conducted by the University of Texas Medical Branch in Galveston (UTMB), most patients use their autoinjectors incorrectly. Patients were asked to demonstrate the steps needed to correctly self-administer their autoinjectors, with more than half missing three or more steps. Mistakes made by patients included failing to hold the device in place for the required amount of time, not pressing the device hard enough to trigger the release of the drug and not choosing a suitable injection site. 10 Despite the redesign of the autoinjector for easier use, most patients continued to make at least one mistake with the device. Most patients made multiple mistakes and would not have benefited from self-administration of the potentially lifesaving treatment if the need arose Dr. Rana Binds, MD, Assistant Professor, Internal Medicine, Division of Allergy and Immunology, UTMB. The UTMB study also focused on correct usage of inhalers resulting in an outcome of 93 percent of patients using their inhalers incorrectly. Again more than half the patients missed three or more steps with the most prevalent being a failure to exhale fully before using the inhaler Lof 93% patients use their inhaler incorrectly 10 Common Device Usage Errors 16

12 Prescription Refill Rates 9 Age Adherence 9 Common Errors with MDI and Epinephrine Autoinjector Drug Delivery Devices 10 Year 1 Year 2 Year 3 36% 23% 17% 24.2% % % % 70+ Race / Ethnicity Adherence % black american Gender Adherence % 31.0% female male 29.5% asian 33.2% caucasian 15.6% hispanic 21.7% other 21.7% native american MDI 93% of MDI users demonstrated imperfect technique 63% missed 3 or more steps Most common error: 66% of users failed to fully exhale prior to using their MDI MDI Device Technique 1. Remove caps from MDI and spacer and then connect = 18% performed step incorrectly 2. Hold MDI and spacer together and then shake = 38% performed step incorrectly 3. Exhale to functional residual capacity or residual volume = 66% performed step incorrectly 4. Tilt head back or keep level = 21% performed step incorrectly 5. Insert mouthpiece between lips = 15% performed step incorrectly 6. Actuate canister once = 25% performed step incorrectly 7. Inhale slowly and deeply = 25% performed step incorrectly 8. Should hear a hissing sound not a whistle = 52% performed step incorrectly 9. Hold breath 5-10 seconds = 25% performed step incorrectly 10. Wait seconds = 38% performed step incorrectly 11. Shake again before a second actuation = 42% performed step incorrectly Autoinjector Epinephrine 84% of users demonstrated imperfect technique 56% missed 3 or more steps Most common error: 76% of users failed to hold unit in place for at least 10 seconds after triggering Autoinjector Device Technique 1. Remove safety cap = 38% performed incorrectly 2. Hold device in palm = 60% performed incorrectly 3. Using a swinging motion, place the orange tip on the outer thigh = 43% performed incorrectly 4. Push in hard until the trainer function is heard = 55% performed incorrectly 5. Hold in place for 10 seconds = 76% performed incorrectly Common Device Usage Errors 18

13 18% 84% of attending pediatricians were of patients use familiar with and their autoinjector able to demonstrate incorrectly 10 use of an epinephrine autoinjector correctly 76% of participating pediatricians failed to review device use with patients 68% of participants demonstrated use of an epinephrine autoinjector incorrectly 36% of pediatric residents were able to demonstrate use of an epinephrine autoinjector correctly Other studies reinforce lack of correct drug delivery device administration technique Care takers, patients and physicians lack knowledge of correct autoinjector technique. Assessment of self-administered epinephrine among food-allergic children and pediatricians families were enrolled which included food-allergic children and teenagers who were prescribed a self-injectable epinephrine, primarily by pediatricians and allergists. Patients were prescribed EpiPen (n = 93), EpiE-Z Pen (n = 11), and Ana-Kit (n = 3). Twenty-nine attending pediatricians were enrolled (mean fourteen years in practice; mean four epinephrine prescriptions/year). Familiarity with the devices was as follows: EpiPen (86%), EpiE-Z Pen (17%) and Ana-Kit (7%). Seventeen pediatric residents were enrolled. 65% were familiar with the EpiPen and only one resident was familiar with Ana-Kit. The study found that physicians, teenagers and parents of food-allergic children cannot correctly administer a self-injectable epinephrine. The study also found physicians lacked familiarity with the devices and highlighted the need to improve patient and physician education. Common Device Usage Errors 20

14 Patients lack knowledge of correct asthma drug delivery device technique 12 Physicians fail to provide assessment or demonstration. A study published in the American Academy of Pediatrics investigated the extent that children, ages 8 through 16 with mild, moderate, or severe persistent asthma used metered dose inhalers, turbuhalers, diskuses, and peak flow meters correctly. The study also focused on five pediatric practices to find out how often health care providers assess and demonstrate use of metered dose inhalers, turbuinhalers, diskuses, and peak flow meters during pediatric asthma visits. All of the medical visits were audio-recorded. Children were interviewed after their medical visits, and their device technique was observed and rated by the research assistants. Data was collected and analyzed for 296 patients, which resulted in the following findings: The study found that a majority of the health care providers did not demonstrate or assess child use of metered dose inhalers, turbuhalers, diskuses, or peak flow meters during pediatric asthma visits. I wasn't aware of all the training. I kinda feel upset the doctor never mentioned anything like this. market research participant 21 Common Device Usage Errors % 84% 78% 76% of participants failed to perform all the MDI IFU steps correctly of participants failed to perform all the turbuhaler IFU steps correctly of participants failed to perform all the diskus IFU steps correctly of participants failed to perform all the peak flow meter steps correctly

15 Device Trainer User Studies Multisensory Learning 13 Multisensory learning incorporates cross-modal cues of visual, auditory and somatic senses as part of the learning process. Studies regarding individual processing of multiple sources of information have shown improvements including precision, accuracy, processing speed and memory retention as compared to unisensory learning. Do - Have Actual Experience Act 80% Think Auditory + Visual + Somatic Auditory + Visual Visual Auditory Visual Discuss & Explain Hear, See, & Touch Hear & See See Hear Read 90% 70% 50% 30% 20% 10% Active Passive L 74% of patients reported they should have used a training device 23 User Studies

16 Device Trainer Errors Average Errors (Out of 15 Steps) 26% 16% 12% 6% 4 errors 2.5 errors 1.9 errors 0.9 errors Instructions for Use (IFU) Only 84% prefer error correcting device training Mechanical Trainer & IFU 86% 15% Talking Trainer & IFU Device Preference across all groups confidence INCREASED decrease in ANXIETY Error Correcting Trainer & IFU Multisensory Device Training Background In July 2014, an independent market research company, sponsored by Noble, conducted a user study to evaluate training stimuli with regard to self-injected therapies. Outputs included qualitative measures related to patient preference, satisfaction and performance. Methodology The study consisted of four homogeneous groups used to evaluate the effectiveness of an independent variable: training. This process followed a structured protocol to prevent adverse effects due to errors or biases. Participants were divided into four test groups including: Group 1: Instructions for Use (document only) Group 2: Instructions for Use and talking trainer Group 3: Instructions for Use and mechanical trainer Group 4: Instructions for Use and error correcting trainer Findings All self-reported and performance measures were evaluated in relation to participants learning preference, confidence, anxiety and number of errors within each group. Findings revealed patients using training devices had a reduction in errors as well as a decrease anxiety and increase in confidence. Findings also revealed as the level of device training interaction (mechanical, talking and error correcting) with participants increased the number of errors decreased. User Studies 26

17 56% 61% Respiratory Device Training Background In March 2014, an independent user study was conducted by Noble to evaluate education stimuli for self-administered inhalable therapies. Outputs included qualitative and quantitative measures related to patient performance, and cognitive capabilities including satisfaction and anxiety. Methodology The study was designed to evaluate the preference of an independent variable: training. This process followed a structured protocol to prevent adverse effects due to errors or biases. Participants completed the study of a 12-step inhalation process. Preinterview, during-interview and post-interview surveys were administered to evaluate the preference of training methods on confidence, anxiety and inhalation outcomes. Findings Upon completing the fieldwork portion of the study, all self-reported and observational measures were evaluated in relation to training preferences and the prevention of errors. While the interviews were qualitative in nature, surveys and other tools provided access to a variety of metrics related to training and onboarding support. Below charts are a summary of these findings and how they related to the objectives of the user study. Conclusion Based on a review of secondary literature, errors are significant adherence barriers for patients using pulmonary delivery devices. The findings of this user study suggest that training devices could be effective tools to increase patient confidence and decrease anxiety, two variables that are closely associated with adherence and patient outcomes. Though the findings were robust and insightful, follow-up research is recommended to further evaluate the effects of device training on actual patient errors and long-term outcomes % of patients use their auto injection device incorrectly 90% of patients rated the value of a trainer 7 or higher of patients have never used a trainer 73% of participants prefer device trainers that incorporate multisensory technology of patients do not completely read the instructions 76% of participants prefer error detection technologies 18% of participants reported a decrease in anxiety after evaluating device trainers 41% of participants reported increased confidence using a smart training device 27 User Studies

18 Link Between Device Training and Patient Compliance Background According to a recent study by the University of Texas Medical Branch at Galveston, 84% of patients use their auto injection device incorrectly. Based on literature review and other activities, this study further explores the relationship between device training and patient compliance. Objective: Investigate if compliance differs between patients who trained with a training device versus those who did not train with a training device. To accomplish this objective, patients were placed into the following groups: Group 1: Patients who did train with a device trainer Group 2: Patients who did not train with a device trainer Methodology This research consisted of a 31-question online survey to patients who regularly selfadminister a prescription injection medication. Patients were asked detailed questions related to the training and onboarding of their injectable prescription drug. Findings Patients prefer multisensory learning. As age increases, the value of device training increases. Patients who use a trainer are less likely to discontinue treatment. Patients who use a trainer are more compliant. Patients who are recommended to use a trainer by their HCP and use as recommended or more, are more compliant. Conclusion Based on the statistical analysis of the data, with a 90% confidence level, training devices improve compliance. With 99% confidence, patients who use a trainer as recommended by their HCP improved compliance. Therefore, not only is it of value to have the training device, it is also important to use it in a manner consistent with how the physician recommends. With more than half of patients having not used a trainer, the opportunity for increased compliance is high. 29 User Studies It s almost like you have a nurse right there... Mimi

19 Recommendations for Improving Adherence As stated previously there are multiple dimensions affecting nonadherence. The following section will explore ways to improve adherence based upon common factors of the five dimensions. Reminders A common reason patients don t take their medications as prescribed is forgetfulness. There have been a number of studies conducted focusing on reminder methods to aid patients with treatment regimen compliance. An examination of multiple, controlled, trial studies analyzed the use of opt-in reminders in the form of text messages, automated phone calls and audiovisual reminder devices. The findings revealed patients with reminders have a higher tendency to adhere to medication compared to patients without reminders. The study published in Dove Medical Press found a significant adherence increase in groups receiving reminder intervention compared to control groups: 66% higher incidence of adherence with reminders vs. 55% without reminders L 48% of patients have an increase of adherence when receiving written and oral education. 20 Improving Adherence 32

20 Another study conducted by Huang et al. found participants who received text message reminders showed a decrease in delayed and missing doses compared to the controlled group which did not receive text message reminders. 15 To aid with patient adherence, some providers, retail pharmacies, and pharmaceutical and third-party companies are investigating and implementing multiple reminder methods including texts, automated phone calls, s and smartphone applications along with reminder devices, such as smart pill bottles and pill organizers. 6,16 Better Physician/Patient Communication The relationship between physician and patient has been shown to be a factor in increasing adherence with both the quality and quantity of visits being important. 17 Some of the methods that have been shown to increase adherence include COPE principles 17, SIMPLE 18 and Find out more. 19 All of these methods include patient education as a component. Patient Education Patients who are provided with written and oral education regarding their diagnosis, management, treatment and medications have been shown to have higher adherence rates. 20 Education and Brand Preference A study conducted by HealthPrize asked physicians if a particular medication as compared to competitors in the same class, offered a medication adherence service for patients, how would it influence their view of that medication? 21 Patient Education with Drug Delivery Device Trainers Drug delivery device training tools have been developed to support patients in learning how to properly use their drug delivery devices. These devices are customized to the needs of specific patient populations and delivery platforms to accurately mimic device characteristics and build adherent behaviors in patients. Currently, marketed training devices use mechanical reset and multisensory technologies (visual, auditory, and tactile) to complement health care provider training and create consistent training experiences for patients. 33 Improving Adherence You re getting the information as you do it. You don t forget certain instructions like I do. Joyce 90% 79% 12% decrease in missed doses for participants receiving text message reminders decrease in delayed doses for participants receiving text message reminders higher adherence rate with reminders

21 Common errors that can be addressed through device training include: Injection into an unapproved site Failure to remove device cap before actuating the device Insertion angle of needle or positioning of the device on the injection site Improper sequence to prepare or unlock safety mechanisms Recapping the device and damaging the needle or accidentally actuating the device Premature or out-of-sequence actuation of the device Improper hold time to receive a full dose The training device takes the anxiety away. Blair These devices help to establish a baseline for training and ensure that a consistent experience is received each time a patient self-injects. After in-office training, patients should repeat and practice at home to reinforce memory recall and establish muscle memory, which can help prevent errors and build confidence. The key is to provide this training device prior to the patient's first injection, so that the learning curve occurs in a simulated training environment that provides corrective feedback vs. trial and error with the actual drug delivery device. The error-correcting trainer is just one example of improved training technology that includes the addition of electronics, smart sensors, audio, LED, and tactile simulations. This technology makes patients aware of their errors in real time, increases message recall through repetition, and utilizes multisensory technology that engages the five senses, which helps solidify learning. For example, Noble's Smart Injection Practice Pad is equipped with technology that detects and corrects errors via the pad and not the pen. Integrating proprietary electronic technologies into the pad instead of the pen helps reduce cost, miniaturization of electronic components and adds ease to manufacturability. Improving Adherence 36

22 37% of physicians said they of would be more likely to meet with a pharma rep if the pharmaceutical company offered a medication adherence program 48% 61% 72% physicians believe in education as an influence to improve adherence 21 of patients were adherent to their treatment when doctors probed for nonadherence causes, discussed personal beliefs and provided disease education 19 of physicians said they might be more likely to or would view it in a more positive light for a product that had a medication adherence program Noble understands every client s needs are unique. Customized Educational and Training Solutions Noble believes improved patient education is key, and to that end, offers customized solutions for pharmaceutical companies in an effort to help patients use their inhalers and injectable devices correctly. Noble assists in the design of simulated devices for training purposes, which can use multiple modalities such as voice-guided training and error correction, platform technology that can be built into training devices or packaging, and ancillary support tools, which monitor patient behavior and notify them if an error is made. As technology continues to develop at a rapid pace, medical manufacturers, too, must evolve to incorporate technological advances that will help improve the patient experience. Improved training technologies like error correction and wireless features allow brands to engage patients and provide personalized training content based on individual patient needs and performance. As new brands continue to launch and augment markets, they will continue looking for strategies to differentiate themselves from competitors. In the modern era of patientcentric care, those able to provide a superior product and educational experience to patients will be competitively positioned to benefit from the loyalty established with patients and health care providers. About Noble After all, we re still human. And we do make errors. I do em all the time! Rita Noble, the leader in onboarding and device training, is a patient-centered product development and manufacturing company. Noble works closely with the world s leading pharmaceutical and biotechnology companies to develop educational and training solutions. Solutions are designed to provide positive patient onboarding experiences, reduce errors and improve patient outcomes. Cross-disciplinary designers and engineers provide fully customized solutions from the first concept sketch through production in both regulated and non-regulated environments. Improving Adherence 38

23 Customizable Audio Tactile Feedback Sensors Syncing Error Correction LED Erganomics Patient Onboarding There are many variables contributing to patient adherence and therapy acceptance during onboarding including anxiety, confidence, memory and understanding the correct administration technique. These patient factors can detrimentally influence attitudes and perception toward medications and drug delivery devices, resulting in training gaps and treatment barriers. Device Training These devices have been designed to mimic actual commercial drug delivery devices, providing a low-cost, reusable solution for safe and effective onboarding. Injection Product features AI and PFS trainers: Off-the-shelf platforms and customized solutions, including proprietary technologies Technologies range from resettable mechanical to smart features, such as sensors, audio and error-correcting Trainers designed to mimic actual device characteristics: - Shape and design - Needle puncture and insertion forces - Needle tip - Breakout, glide forces and viscosities - Controlled plunger speed - Shroud lock-out Respiratory Product Features MDI and DPI trainers: Off-the-shelf platforms and customized solutions, including proprietary technologies Technologies range from resettable mechanical to smart features, such as sensors, audio and error-correcting Trainers designed to mimic actual device characteristics - Shape and design - Inhalation forces - Lock-out Training Support Products Designed to create a complete training program and solution. Angle aid tools Clip-on assistive tools Administration assistive tools Training packaging Training IFU 39 Improving Adherence Improving Adherence 40

24 Device training happens here. Development and Production Noble s proven repeatable process takes client opportunities from concept to distribution. Our team works meticulously to define and answer product challenges, ultimately producing superior designs optimized for manufacturability and high-volume production. Our in-house design lab provides Noble with the ability to produce prototypes and conduct extensive engineering and benchmark testing, with quality assurance involved at every level through project realization. Noble s dedication to delivering quality products extends beyond our corporate headquarters. Our ISO 9001 and certified global manufacturing partners use a systematic approach to perform in-line functionality testing, in-process inspection, analysis and line improvements with other production testing including 100 percent verification testing of critical product features and functionality before delivery. Choose Noble As the number of patients being required to self-administer medication via drug delivery devices continues to grow, training and education will remain a critical success determinant of a patient s ability to safely and effectively use these devices and adhere to therapy. Novel training technologies such as mechanical and smart, error-correcting autoinjectors, prefilled syringes and pulmonary delivery devices, angle aid tools, auditory packaging and other multisensory solutions help empower patients to lead healthier lives. In the modern era of patient-centric care, products that are able to provide superior onboarding and patient experiences will be well positioned and benefit from reduced patient errors, while improving patient satisfaction and outcomes. Noble s focus is to drive innovation in onboarding and device training, bringing value to our clients. 41 Improving Adherence Through faith and teamwork, be an industry leader in innovation, resulting in value growth, allowing all stakeholders and our community to prosper.

25 References: 1. Capgemini Consulting. (2011, May). Patient adherence: The next frontier in patient care. Retrieved from pt.capgemini.com/resource-fileaccess/resource/pdf/patient_adherence The_Next_Frontier_in_Patient_Care.pdf 2. World Health Organization. (2003). Adherence to long-term therapies - evidence in action. Retrieved from who.int/medicinedocs/pdf/s4883e/ s4883e.pdf 3. National Community Pharmacists Association. (2006, December 15). Take as directed: A prescription not followed. Retrieved from org/pdf/adherence/patientadherence-pr1206.pdf 4. Boston Consultant Group. (2003, December). The hidden epidemic: Finding a cure for unfilled prescriptions and missed doses. 5. PMC. (2013, April 11). Patient Characteristics Associated with Medication Adherence. Retrieved from PMC / 6. CVSHealth. (2014). Insights: Adherence CVS Health. Retrieved from cvs-health-research-institute/insightsadherence 7. Kessels, R. P. (2003, May). Patients Memory for Medical Information. Retrieved from pmc/articles/pmc539473/ 8. Haskard Zolnierek, K. B., & DiMatteo, M. R. (2009, August). Physician Communication and Patient Adherence to Treat- ment: A Meta-analysis. Retrieved from 9. Banefield, Jennifer, Murphy, Kevin R. (2015, February). Adherence in Asthma and COPD. Retrieved from on_copd_issue11/focus_on_copd_issue11_adherence_in_asthma_and_copd.html 10. Bonds, R., Asawa, A., & Ghazi, A. (2014, November 18). Misuse of medical devices: a persistent problem in self-man- agement of asthma and allergic disease. Retrieved from Sicherer, S., Forman, J., & Noone, S. (2000, February). Use assessment of self-administered epinephrine among food-allergic children and pediatricians. - PubMed - NCBI. Retrieved from pubmed/ Sleath, B., Ayala, G. X., Gillette, C., Williams, D., Davis, S., Tudor, G.,... Yeatts, K. (2011, April). Provider Demonstra- tion and Assessment of Child Device Technique During Pediatric Asthma Visits. Retrieved from gov/pmc/articles/pmc / 13. Shams, L., Wozny, D. R., Kim, R., & Seitz, A. (2011, October 18). Influences of Multisensory Experience on Subsequent Unisensory Processing. Retrieved from Fenerty, S. D., West, C., Davis, S. A., Kaplan, S. G., & Feldman, S. R. (2012, February 10). The Effect of Reminder Sys- tems on Patients Adherence to Treatment. Retrieved from Huang, H., Li, Y., Hsieh, Y., Kuo, F., Tsai, W., Chai, S., Lin, B., Kung, P., & Chuang, C. (2013, November 16). Effects of and Satisfaction with Short Message Service Reminders for Patient Medication Adherence: a Randomized Controlled Study. - PubMed - NCBI. Retrieved from pubmed/ Enriquez, J. (2014, October 13). Medication Adherence Technologies Take Center Stage - nuviun content library. Retrieved from content/medication-adherence-technologies-take-center-stage 17. Lakatos, P. L. (2009, September 14). Prevalence, predictors, and clinical consequences of medical adherence in IBD: How to improve it? Retrieved from American College of Preventive Medicine. (n.d.). Medication Adherence Time Tool - American College of Preventive Medicine. Retrieved from Lowes, R. (1998, March 5). Patient-Centered Care for Better Patient Adherence - Family Practice Management. Re- trieved from fpm/1998/0300/p46.html 20. Practicing Clinicians Exchange. (2011). Strategies for Increasing Adherence. Retrieved from nicians.com/crohns4/crohns5.html 21. Health Prize. (2015). The physician s view of medication nonadherence. Retrieved from tico.com/docs/2015/02/20/encuesta_ adherencia.pdf 22. Martin, L., Williams, S., Haskard, K., & DiMatteo, M. (2005, September). The challenge of patient adherence. Retrieved from pmc/articles/pmc / 23. Jha, S. (2014, November 17). Patient Non-adherence: Perceived Challenge or Next Big Opportunity - Business Today. Retrieved from intoday.in/story/pharmaceutical-companies-digital-health-start-up-drug-com- panies/1/ html

26 2016 Noble International, Inc. All rights reserved. Products shown do no contain medication or a needle and are intended for training purposes only. Multiple Patents Pending.