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Volume 2 - Issue 2

✓ PATIENT COMPLIANCE Strategies to enhance Adherence and Health Outcomes


Medication Adherence In People of Culturally and Linguistically Diverse Backgrounds The Moral Imperative of Improving Patient Adherence to Pharmacotherapy for Cardiodiabesity Part 2: A Focus on Cardiovascular Disease Perceptions and attitudes of people with Disabilities and Older Adults about Child-resistant Drug Packaging Trends in Electronic Compliance Monitoring






Patient Story Helping Patients Take Their Medication: Lessons from Helping Patients Quit Smoking Smokers are not patients or, at least, that’s the view that most people have of smokers. Like most “self-inflicted” health risks, the stigma attached to smoking and smokers is pervasive. Michael Wong, founder of the advocacy group and Physician-Patient Alliance for Health & Safety, explains how not treating smokers as patients and seeing smoking as a disease can lead us to not apply valuable lessons from quit smoking programmes.

Strategies to enhance Adherence and Health Outcomes

DIRECTORS Martin Wright PUBLISHER Mark A. Barker MANAGING EDITOR Mark A. Barker EDITORIAL MANAGER Jaypreet Dhillon EDITORIAL ASSISTANTS Nick Love, Kevin Cross, Lanny McEnzie DESIGN DIRECTOR Ricky Elizabeth RESEARCH & CIRCULATION MANAGER Dorothy Brooks BUSINESS DEVELOPMENT Kristine Saunders ADMINISTRATOR Petya Stefanova FRONT COVER © iStockphoto PUBLISHED BY Pharma Publications Unit J413, The Biscuit Factory Tower Bridge business complex 100 clements road, London SE16 4DG Tel: +44 (0)20 7237 2036 Fax: +0014802475316 Email: Journal For Patient Compliance – Strategies to enhance Adherence and Health Outcomes. ISSN 2045-9823 is published quarterly by PHARMAPUBS.

Watch Pages 10 Patient-reported Outcomes Data and Motivational Factors Clinical trial participants join clinical trials for various reasons, and in order to keep subjects engaged these factors should be well understood and addressed in research practice. Kai Langel, who provides a consultative role to CRF Health, explains how study protocol may require a certain level of compliance with the study medication regiment when assisting electronic data collection, especially ePRO. 12 How can Pharma Better Address the Problem of Medicines Non-adherence? Over the last few years pharma has been investing significant resource into improving adherence to medicines among patients. Aunia Grogan, Commercial Director of Atlantis Healthcare, focuses on current industry trends and discusses the challenges facing pharma to make progress in addressing the medicines non-adherence epidemic. 14 Patients and Healthcare Professionals (HCP’s) Must Work Together to Drive Proper Adherence to Prescribed Medicines. Improving adherence is a matter of communication and collaboration. Some physicians still believe that adherence is a patient issue, and many have grown frustrated over their lack of success in improving adherence. Colin Wheeler, Managing Partner at M2WorldWide Limited, discusses the 64 million Euro question of why patients do not understand how to take their medicines as prescribed on a consistent basis. Regulatory & Marketplace

The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright.

16 Adherence Improvement Efforts are Popping Up All Over. With spring on the horizon, renewal, growth and change in the issue of medication non-adherence is also apparent. Medication non-adherence is historically under-recognised and often thought to be an intractable public health problem, whilst extracting significant personal health and national economic costs. Ray Bullman, Executive Vice President at NCPIE, explains why and how there are adherence improvements.

2012 PHARMA PUBLICATIONS Volume 2 issue 2

Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 1

Contents 18 Medication Adherence in People of Culturally and Linguistically Diverse Backgrounds. Medication adherence is the extent to which a person takes medication as prescribed by a health professional. Internationally, medication adherence continues to be a major problem leading to extensive morbidity and mortality. Professor Elizabeth Manias from Melbourne School of Health Sciences at The University of Melbourne describes why for people of culturally and linguistically diverse backgrounds, medication adherence has been found to be of particular concern. 22 Home Healthcare - Helping to Improve Patient Adherence. Inadequate adherence to both prescribed medication and health improvement behaviours is a problem with important implications for all clinicians, public health strategists and policy-makers. Dr Mehmood Syed, Medical Director at Bupa Home Healthcare, explains how market access and valuebased pricing become increasingly significant issues for pharmaceutical companies to contend with, and improving adherence to particular therapies is also becoming more important to the forward-thinking pharmaceutical companies. Behaviour Programmes 24 Compliance Begins in the Mind; So Does Hypnosis For many people, hypnosis has been shown to be an effective method for changing behaviour, even under adverse circumstances, like the extreme discomfort of smoking cessation or the severe pain of childbirth. How much more potent might this time-tested technique be when the focus is on a clear-cut medical plan, and the motivation is one’s own health and wellbeing. Richard A. Blumenthal, originator of the Rational Suggestion Therapy counselling technique, explains how, with clear goals and a willing person, the skilled hypnosis professional can place the patient on the path to full compliance and long-term adherence for optimal treatment results. 28 Listening to the Patient: Using PatientReported Outcomes to Optimise Adherence and Inform Healthcare Decisions The World Health Organization (WHO) has stated that, across diseases, patients’ non-adherence to prescribed treatment protocols is the single most modifiable factor compromising treatment outcomes. As ever-increasing healthcare expenditure reaches unprecedented levels, promoting patient adherence to treatments is one of the primary challenges for healthcare professionals, researchers and policy-makers today. Adam Gater, Senior Research Manager at Adelphi Values, explains how patient-reported outcomes represent a valuable tool by which to understand patients’ perspectives of their treatments and to optimise adherence.

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32 Quantification of Adherence Initiatives Results It is proven that most chronic drugs work well in a clinical trial environment. However, with compliance rates of 50%, they do not necessarily have the same effect in “everyday” environments. Companies discover that potential benefits of resolving poor compliance issues are very appealing; such as the impact it could have on sales for pharmaceuticals and pharmacies. However, the risk highlighted above is due to poor adherence rates averaging around 50%; there is sufficient concern that drugs do not work half of the time. Cassie Schutte, Chief Executive Officer at Health Window, explains why the risk highlighted above by the former US Surgeon General is due to poor adherence rates, and that drugs do not work half of the time. Clinical Trials 36 The Moral Imperative of Improving Patient Adherence to Pharmacotherapy for Cardiodiabesity, Part 2: A Focus on Cardiovascular Disease This is the second paper in a series addressing the moral imperative of improving patient adherence to pharmacotherapy for cardiodiabesity. Adrienne Richards, Medical Director, and J. Rick Turner, Senior Director at Quintiles, focus on cardiovascular disease and how it effectively captures three chronic and interrelated diseases of enormous relevance to global public health. Therapeutic 42 Patient Empowerment – An Innovative Approach in Rare Diseases Approximately four million people in Germany are affected by rare diseases. Out of the 30,000 known illnesses, about 7000-8000 are among the rare diseases. All fields of medicine are affected by rare diseases. Deformity syndromes, psychiatric illnesses, metabolic disorders and storage diseases are examples. The rarity of an illness presents challenges to research and patient care which the medical care system can only partially meet. Birgit Bering, Health Care Service Manager at Lysosomal Storage Disorders, explores how a study by the Federal Ministry of Health analyses current care for patients with rare diseases. The objective of the investigation was to show the situation of affected persons in defining improvement measures. Modern Technology 46 Trends in Electronic Compliance Monitoring The idea that patients tend to be poorly compliant with prescribed medication and other therapies has been around for hundreds of years. Despite this, the phenomenon has been and still is poorly understood. Allan Wilson, Managing Director at Information Mediary Corporation, discusses how patient compliance relates to information theory, which views all interventions as exercises in optimising a signal to noise ratio.

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Contents Drug Delivery, Drug Packaging, Labelling & Dispensing 50 Patient Compliance – an Essential Consideration in Auto-Injector Design Patient compliance with medication is generally lower than many would expect. Different statistics have been reported over the last few decades, including that 75% of all patients fail to comply with prescribed medication in some form and up to 50% of patients with chronic conditions fail to comply. Barbara Lead, product development director at Anaxsys Ltd, provides an overview of how auto-injectors have been used for many years to make self-administration of subcutaneous and intramuscular drugs as easy as possible for the patient. 54 Perceptions and Attitudes of People with Disabilities and Older Adults about Child-resistant Drug Packaging Drug packages protect and deliver prescription and over-thecounter drugs, as well as communicate necessary warnings and directions so that the pharmaceuticals contained within can be used correctly. Laura Bix at Michigan State University explains the perceptions and attitudes of two groups regarding childresistant drug packaging. The analysis of these focus groups’ transcripts revealed two major themes within this article.

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60 Changing a Problem into a Solution – Technological Alchemy from Protomed It is the central question of economics – how to match infinite demands with finite resources. And, for the NHS, tackling the age-old problem of compliance is at the heart of finding an answer to it at a time when the demands are going up and resources are going down. The problem of compliance has been around ever since doctors first started prescribing potions to cure ailments. Norman Niven, CEO of Protomed, discusses why solving compliance is now a critical issue for NHS suppliers, rather than just a desirable goal. Think Tank 63 Who Is Responsible for Adherence? The issue about who should take responsibility for adherence is one that is being debated at all levels. Poor medicine adherence carries a huge cost, both in terms of patient safety and quality of life. It also represents a serious problem for health systems, leading to inferior health outcomes, and unnecessary treatments and hospitalisations. Providing adherence support for medicines has never been more important than in these times of austerity. Healthcare systems are now evaluating drugs on real-world outcomes rather than on clinical trials. An adherence strategy not only differentiates a brand, but it also emphasises your commitment to stakeholder support and improves health outcomes. Carole North, co-founder of 90TEN Healthcare, raises the question of “Where does this responsibility ultimately lie?”

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Foreword According to the father of medicine, Hippocrates, “The physician must not only be prepared to do what is right himself, but also to make the patient … cooperate”. Although Hippocrates’ paternalistic tone might affront modern physicians and patients, the challenge of promoting patient adherence to effective treatments still confounds providers 23 centuries later. Adherence has become an increasingly central aspect of patient care because of the burgeoning array of effective treatments for many chronic diseases. In the face of remarkable medical advances, it is especially distressing that evaluation of patient adherence (also called compliance or pill-taking) remains an imperfect science at best. Low adherence to prescribed medical regimens is a ubiquitous problem. Typical adherence rates are about 50% for medications and are much lower for lifestyle prescriptions and other more behaviourally demanding regimens. In addition, many patients with medical problems do not seek care, or drop out of care prematurely. Although accurate measures of low adherence are lacking for many regimens, simple measures, such as directly asking patients and watching for appointment nonattendance and treatment non-response, will detect most problems. For short-term regimens (≤2 weeks), adherence to medications is readily achieved by giving clear instructions. On the other hand, improving adherence to long-term regimens requires combinations of information about the regimen, counselling about the importance of adherence and how to organise medication-taking, reminders about appointments and adherence, rewards and recognition for the patient’s efforts to follow the regimen, and enlisting social support from family and friends. Successful interventions for longterm regimens are all labour-intensive but ultimately can be cost-effective. I read a paper recently entitled: Physician-patient interaction: what do elders want? by JN Vieder, MA Krafchick, AC Kovach and KE Galluzzi. The purpose of this study was to identify communication styles and physician characteristics that correlate with improved patient adherence and satisfaction during geriatric healthcare interactions. A multiphase study design, incorporating the use of focus groups, socialisation hours, educational seminars, and survey questionnaires, was used to discover the most effective methods for improving communication between physicians and their geriatric patients. Elders favoured direct, interactive verbal communication over alternative communication styles such as role-playing activities or the use of visual aids. Chi-square analyses showed that men desired more time with medical providers than women, who instead expressed a preference for more thorough explanations of disease processes. Further, men--and African American men in particular--sought medical advice from trusted friends more frequently than did women, who often preferred to solicit medical advice from family members. The most significant barriers affecting physician-patient interaction were created by patients’ inflated expectations for consultation time and by physicians’ ineffective presentation styles. This study also reveals that physicians’ characteristics and patients’ gender and race also impacted the success of medical encounters. This paper points out some interesting facts on how we should tailor our healthcare system, and patient communication. In this issue, we have some excellent topics which will help us to achieve a better degree of adherence for most chronic conditions. Michael Wong of Physician-Patient Alliance for Health & Safety discusses the lessons learned from helping patients quit smoking. Kai Langel of CRF Health discusses patient-reported outcomes data and the motivational factors. Professor Elizabeth Manias from Melbourne School of Health Sciences at The University of Melbourne explains medication adherence in people of culturally and linguistically diverse backgrounds. We have featured a unique article by Richard A. Blumenthal, originator of the Rational Suggestion Therapy counselling technique on how and if hypnosis can be utilised to achieve a better level of compliance in patients. Well, food for thought really. I am sure many of you will be preparing to be at the 9th Annual Patient Summit 2012, 29th-30th May 2012, London. As the official supporting publication to the event, I will like to congratulate the team at EyeForPharma for organising an excellent array of speakers, and topics. I am sure we will learn a lot from the event. I hope to see all of you there.

Editorial Advisory Board Andree Bates, Managing Director, Eularis Anna Dirksen, Senior Manager, PSI Behavior Change Chris Penfold, Vice Chairman - East Midlands Packaging Society, Consultant, Freelance Packaging Specialist Carole North, Managing Director, 90 TEN Healthcare Dyan Bryson, Managing Partner/VP Patient Strategy & Outcomes for Inspired Health Strategies Elisabeth Moench, President & CEO of Medici Global Helen Lawn, Managing Director, Helen Lawn & Associates a healthcare PR and communications agency Isabelle Moulon, Head of Medical Information Sector, European Medicines Agency Jay H. Bolling, President and CEO, Roska Healthcare Advertising Joseph Bedford, Director of Marketing Almac Clinical Technologies Laura Bix, Assoc. Prof. School of Packaging Michigan State University Louis A. Morris, Ph.D., is President of Louis A. Morris and Associates, Inc Mark Duman, Managing Director , MD Healthcare Consultants Michael Wong is Managing Director at hcCatalyst Peter van Iperen, Experienced Pharmaceutical Professional Phill Marley, Packaging Account Manager, Global Quality Operations AstraZeneca Ronald E. Weishaar, Executive Director, Observational Research, PharmaNet Development Group Saurabh Jain, Director of Patient Value Services and CME Solutions at Indegene. Steve Kemp, Business Development Director at Brecon Pharmaceuticals and Chairman of HCPC Europe Tassilo Korab, Co-founder of HCPC Europe (Healthcare Packaging Council) Vassilis Triantopoulos, CEO of BIOAXIS Healthcare Walter Berghahn, Executive Director, The Healthcare Compliance Packaging Council

I hope you enjoy reading this issue. Mark A. Barker 6 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

Volume 2 - Issue 2

Patient Story

Helping Patients Take Their Medication: Lessons from Helping Patients Quit Smoking Smokers are not patients -- or, at least, that’s the view that most people have of smokers. Like most “self-inflicted” health risks, like drinking too much alcohol and sharing needles, the stigma attached to smoking and smokers is pervasive.1 Unfortunately, not treating smokers as “patients” and seeing smoking as a “disease” can lead us to fail to apply valuable lessons from quit smoking programmes to helping patients take their medication. The interesting thing about smoking cessation is that we as a society often treat this as a social problem. For example, to get dad to quit, we solicit the help of his family (wife, kids) and friends. We suggest aids that may help, like exercise and diet. We recommend that he see his doctor and try nicotine replacement therapy. Surrounding the patient with the necessary support that he needs to quit (and not what we want) is critical. With that in mind, I, together with the Vietnamese American Cancer Foundation (VACF) and GlaxoSmithKline (GSK) developed a programme directed towards the Vietnamese American community targeting “Little Saigon” in Orange County, California. Little Saigon has the largest number of Vietnamese outside of Vietnam. Unfortunately, this community was facing a number of enormous challenges. It had one of the US market’s highest smoking rates (36 per cent)2 and had therefore been deeply impacted by the scars of this addiction – death, disease and their consequences on family wellbeing and livelihood. Moreover, entrenched cultural and social acceptance of smoking made it an even more difficult task, with smoking for example still occurring in restaurants and offices with social impunity. We purposely engaged the entire community in the programme (doctors, a community patient advocate, and a pharmaceutical company). Local doctors were asked to actively speak with their smoking patients about the need to quit. As Dr Loc D. Bui (a Little Saigon doctor) urged his colleagues at the start of the campaign, “As physicians, we know the danger of smoking. I would like to see all the physicians in our community talk to their patients about smoking and strongly encourage them to quit.” The pharmaceutical GSK, although a manufacturer of nicotine replacement products, was content to fund these activities without active product promotion. For example, in a survey of local physicians, doctors’ attitudes and beliefs about nicotine replacement therapies involving gums, patches and lozenges were explored along with “cold turkey”, herbal supplements, diet, exercise, or anything else they might recommend to their patients. These patients were made aware of the cadre of healthcare experts, quit lines, and volunteers at the VACF that stood ready to assist them. “People don’t realize that it is not 8 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

just their health, it is the health and welfare of their whole family that the smoker puts at risk,” said Leonard Tran (then Executive Director of VACF). “Men who develop smokingrelated diseases often leave their families without means for support. By quitting smoking, men can give themselves their best chance of being able to be there for their families in the long term.” The community responded to VACF’s message. A young widow, for example, spoke on community radio to tell her heart-wrenching story of not getting her husband to quit soon enough. Sadly, he had then recently died, leaving his wife and kids to deal with bills and payments, and continuing to live their lives without him. The results? Activity on the quit lines and at VACF increased dramatically. As one doctor observed, epitomising the programme results, “Since the programme started, I have had 4-5 patients per month quit smoking which is 4-5 times more than I usually have.” However, what the programme had really done is motivational counselling at its best -- doctors intervened as Volume 2 - Issue 2

Patient Story

Median medication adherence was 49% in the telephone group and 41% in the control group. In short, as the osteoporosis researchers concluded, “In this randomized controlled trial, we did not find a statistically significant improvement in adherence to an osteoporosis medication regimen using a telephonic motivational interviewing intervention.” Unfortunately, the results of studies like these may result in programmes like these never starting. As Dr Jon Ebbert (Professor of Medicine at Mayo Clinic) emailed me: Tragically, this may mean that stakeholders may not pay attention to what may be a very promising and innovative strategy to improve medication adherence. Behavioral strategies have been used very successfully in getting patients to quit smoking and can be a great tool in getting patients to take their physician-prescribed medication. So, the next time you start to think about an adherence programme, take a page from smoking cessation -- make sure it listens to patients and responds to their individual needs in improving medication adherence. This patient-centric approach should be a part of each and every strategic decision. Why? Because the old marketing adage that the customer is always right applies even to the healthcare industry. Don’t discount such things as complaints of side effects, lifestyle inconveniences, and forgetfulness -listening and responding may be the difference between an adherent patient and a non-adherent patient.

the medical authority, the community provided stories and emotional support, and the local cancer foundation (VACF) gave individualised and group counselling and advice. More importantly, we applied techniques that we knew would work. We were not encumbered with the need and desire to wait for clinical trial data, or to have confirmed and documented returns on investments from other smoking cessation programmes before starting the Little Saigon programme. Waiting for this data before acting is truly regrettable. Recently, for example, the Archives of Internal Medicine reported on the results of a study to examine whether a telephone-based counselling programme rooted in motivational interviewing would improve adherence to osteoporosis medication. For this study, more than 1000 Medicare patients who had been newly prescribed osteoporosis medication were divided into a control group who were mailed educational materials and an intervention group who received telephone-based counselling.

References 1. Stuber J et al., “Smoking and the emergence of a stigmatized social status” Social Science and Medicine (May 2008) http:// stuber_smoking%20and%20stigma_2008.pdf (accessed April 8, 2012). 2. A Provider’s Handbook on Culturally Competent Care, Smoking Among Asian Americans: A National Tobacco Survey Michael Wong is the founder of the advocacy group, Physician-Patient Alliance for Health & Safety (www. Michael has been behind many healthcare initiatives, including encouraging people to quit smoking, get tested and treated for hepatitis, and take their medications as prescribed by their physicians. Michael and PPAHS are currently developing a safety checklist targeting PCA (patient-controlled analgesia) pumps. Email: Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 9

Watch Pages

Patient-reported Outcomes Data and Motivational Factors Clinical trial participants join clinical trials for various reasons, and in order to keep subjects engaged, these factors should be well understood and addressed in research practice. In a recent study1, the following were the top reasons for subjects to join a clinical study: 1) Altruism 2) Personal relevance 3) Anticipated learning about science, research or health topics It seems that subjects are truly interested in the objectives of the study and want to feel they are part of the research, rather than an isolated entity with little or no visibility to the overall study objectives or progress. Electronic data collection, especially ePRO, provides new methods and tools to keep study subjects motivated. For example, subjects can be provided with explanations of the impact of their actions (or non-actions) to the overall research. The study protocol may require a certain level of compliance with the study medication regimen, and if the subject is close to not meeting this level, the eDiary can provide the following message: “The mechanism of this investigational product requires constant level of medication in your blood for it to be effective. You missed the correct time of two daily doses this week, which makes it very difficult to analyse your results. Please take all of your daily doses between 6-10 AM from now on.” Subjects should [may?] also be given feedback for good performance: “You have completed the initial treatment period with 99% compliance for data entry and 100% compliance for your study drug intake. This places you in the top 10% of all study participants. On behalf of the whole research team, we thank you for your efforts!” Another important consideration is what happens during the study visits. Sometimes the visits are few and far between, and ePRO provides the research staff at the site with an excellent opportunity to make sure the subjects stay engaged until the end of the study. One method that can be used is to discuss the subject’s performance and results over the previous study period. If electronic data collection is used, the results are likely to be available to the site staff in real time, and they can review visual reports together with the subject and discuss their condition, medication or data-entry compliance. While automated tracking systems and messages can be effective, they cannot replace human interactions and feedback – especially when these discussions are specifically focused on the subject’s personal results and supported by their own data. These examples tie the feedback to the research objectives, and can go a long way toward keeping the subjects motivated throughout the study. This is important 10 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

to the subjects; they named the top factors associated with positive experiences as: 1) Close relationships with the research staff 2) Study involved learning and was interesting 3) Free health monitoring and treatment The opposite is also true. Disorganised and unprofessional staff, as well as negative interactions with them, ranked very high on the list of factors associated with negative experiences. It is understandably sometimes difficult to see things from the study participant’s perspective when designing the research protocol, tools for collecting data, or other studyrelated procedures. At the same time, conducting clinical research is expensive, and demotivated and non-compliant subjects can seriously impact the schedule, quality and budget expectations of the whole study. Study sponsors are highly recommended to have the right tools in place for their trials, as well as to include input from study sites and even patients in the form of focus groups or usability tests. References; Rhonda G. Kost , M.D. 1 , Laura M. Lee , R.N., B.S.N.3, Jennifer Yessis , Ph.D.2 , Barry S. Coller , M.D. 1 , and David K. Henderson , M.D.3, and The Research Participant Perception Survey Focus Group Subcommittee4 Kai Langel has worked with CRF Health since the company’s inception in 2000 and is one of the pioneers in the ePRO industry. During this time, Kai has been involved in all aspects of ePRO operations from system design to deployment and support. Kai spent 5 years in the United States where he was responsible for building CRF Health’s technical delivery team. He is currently based in Europe in a consultative role providing advice and guidance to both customers and CRF Health’s internal teams on technical, operational and regulatory issues. Kai is a true global ePRO expert, having worked both in the United States, Europe and more recently in Japan and Asia. Email: Volume 2 - Issue 2

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How can Pharma Better Address the Problem of Medicines Non-adherence? Over the last few years pharma has been investing significant resource into improving adherence to medicines among patients. This development has largely been driven by the industry undergoing fundamental changes as it hits the patent cliff and pipelines dry up. These changes have consequently forced reappraisals of business models and considerations of other revenue streams that haven’t been taken seriously before. Why we should Invest in Adherence Enormous pressure is being placed on pharma to deliver evidence of value versus other (often cheaper) alternatives. It is increasingly difficult to command a premium for a therapy based solely on clinical efficacy. There is also growing demand for ‘real world’ data demonstrating superior outcomes for patients, which brings the challenges of non-adherence into sharp focus. A strong case for adherence support has arisen now that health systems are more aware of the financial impact of non-adherence. Health systems are becoming increasingly sophisticated in their use of data and health economics to track and allocate resource, and non-adherence is now recognised as extremely costly to both systems and to patient wellbeing. For example, in the United Kingdom, the NHS is expected to deliver efficiency challenges of £120 billion. Investing in adherence reduces wastage in medical spending while also ensuring treatments provide optimal value for patients. Barriers to Adherence There are three significant hurdles to overcome to achieve better adherence, and these hurdles are consistent regardless of location. • Enrolment to patient support programmes is a huge barrier. How do we access the patients who will benefit most and encourage them to join programmes? Access to patients is an issue across the US and Europe. Getting the right patients onto support programmes requires close collaboration with healthcare professionals (HCPs) who have a one-on-one relationship with patients. Ensuring these clinicians are motivated to get a patient enrolled is crucial. But as we know, HCPs are busy people, and if they don’t see the value and benefits of getting their patient onto a support programme, they will prioritise other issues during consultations. • Suspicion is another barrier. Given that most patient support programmes are sponsored by pharma, rightly or wrongly, there is a high level of suspicion from HCPs around the motives of pharma. 12 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

Pharma need to respond to this issue head on: do they hope to benefit commercially from encouraging adherence? Yes, absolutely. But that doesn’t mean that adherence isn’t good for patients and health systems. That is the point that often gets missed; pharma benefiting shouldn’t necessarily mean that other people lose out - in fact, the most sustained solutions are where you can define a win, win, win: for patients, health systems and pharma. Volume 2 - Issue 2

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order to achieve this, solutions must be based on evidence and be completely transparent about the capabilities of the programme. In my experience, the single most important success factor here is ensuring you have a senior champion who will endorse a programme and encourage and/or mandate people in their organisation to get involved. Future Developments in the Adherence Space Technological innovations offer new opportunities to tackle non-adherence issues all the time – especially for nonintentional non-adherence. But I believe that changes in how we use technology will be of equal or greater importance. How we interact with the world around us is evolving, by the hour it seems, and this offers huge opportunities. We have only really scratched the surface on using social networks to support patients. And the potential to create programmes for patients across all of their medications, then connecting this to their health records (thus outcomes) is a very real possibility in the near term. I feel this is the single biggest opportunity - more genuinely personalised programmes integrating disease management (medication, diet and exercise) for an individual patient across all their conditions, and between patients and their HCPs. Social media is another dynamic channel to connect patients with support, but there are tremendous challenges around data privacy and liability, and unfortunately once people become aware of that, there is a tendency to back away from those solutions as a result. Longer term, social media offers the potential to deliver integrated personal support for patients, their families, and where appropriate, better links to their HCPs.

• Resistance to new approaches is a self-imposed barrier to better adherence; there is reluctance to try new things in pharma. This isn’t unique to adherence - any innovative approach or technology generally comes up against this issue. And it is a very real barrier for ‘big pharma’. The implication is that we need to take out some of the risk of trying new approaches. With a focus on adherence, in

Aunia Grogan is the chief executive officer of Atlantis Healthcare. In her previous role as the Global Head of Adherence at Novartis Pharma Ag, Aunia led a team responsible for designing and implementing innovative patient adherence programmes. Under her leadership Novartis built a Patient Adherence Centre of Excellence, working closely with global medical and marketing colleagues and local teams to: create insights platforms for programme development; identify innovative technology solutions to promote adherence; develop innovative programmes to positively influence patient adherence behaviour; and design and execute pilots to test approaches and assess impact. Email:

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Watch Pages

Patients and HCPs Must Work Together to Drive Proper Adherence to Prescribed Medicines Why don’t patients understand how to take their medicines as prescribed on a consistent basis? This is the 64 million Euro question. Many would say it is because patients and carers do not understand the effects of poor compliance and/or adherence. Others would say it is because healthcare practitioners (HCPs) (prescribers, nurses and pharmacists) do not provide patients with enough information on how to effectively manage their medicines. And the remainder in this space would say that the burden is on both patients and HCPs. It is those few who are SPOT ON. I recall hearing about some early primary research on Viagra that showed that 50% of men asking their HCPs if Viagra is right for them were turned away without a prescription or diagnosis. They were often given a variety of reasons: it is all in your head, let’s talk about it at your next visit, you don’t need it, and so on and so forth. And for the lucky millions of men that did get a prescription, 50% of them actually did not refill their second prescription - again for a variety of reasons: they didn’t wait long enough after taking the pill, they had a meal with red meat that evening, they had expectations that were not realistic, and the list goes on. The main message here is that both the HCP and patient must have all of the information they need to present for therapy and then sustain proper adherence levels. Before we go any further, I think it is important to understand the reasons for non-adherence. When asked why they don’t take their medication, many patients will say “I forget”. If it was that simple, reminders alone would solve the problem. But there is more to non-adherence than that. In fact, there are at least six underlying reasons why patients are not adherent: 1) Side-effects or poor tolerance of the medication 2) Self-image (taking medication makes me feel sick or old) 3) Complexity of the treatment regimen 4) Belief the medication is not needed after symptoms disappear 5) Unrealistic expectations for the product, which lead to the perception that the product is not effective 6) Cost (more of a challenge in the US, I believe) Regardless of the reason, improving adherence is a matter of communication and collaboration. Some physicians still believe that adherence is a patient issue, and many have grown frustrated over their lack of success in improving adherence. Simply telling a patient that they may feel drowsy or that they need to change their diet does little good. Patients want direction and support in treating a medical condition “Don’t tell me the medication may make me drowsy - tell me what I might be able to do about it,” is a common remark heard in focus groups. Relationship marketing (opt-in marketing or direct-topatient marketing) can fill this need, helping to sustain compliant behaviour and even getting people on therapy sooner. 14 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

Addressing the underlying reasons behind non-adherence and overcoming the many condition-related barriers throughout the patient journey are key to success in this dialogue. One of the cornerstones of success is for HCPs to truly understand the patient journey and ask the right questions at the right time. Here is an actual case study about the benefit of enhanced communications in driving behaviour change among hypertension patients. Physicians in the US had long been frustrated with their inability to get hypertension patients to comply with the medication and lifestyle changes needed to get their condition under control. One pharmaceutical company saw this frustration as an opportunity to create a collaboration between HCPs and patients that would lead to a successful outcome for both. The key elements of the programme were as follows: * Materials enabling HCPs to introduce patients to the programme at the time of the prescription * A series of communications that combined disease education with information to help patients make changes in their lifestyle * Patient communications addressed many of the underlying reasons for non-adherence as well as condition-specific barriers * Programme materials also included a blood pressure tracker, doctor discussion guide and other content designed to improve communication between HCPs and patients The results of the programme demonstrate the value of this collaboration between manufacturer, HCP and patient. More than half of the company’s target physicians were aware of the programme at its peak, and there were clear shifts in preference for the company’s hypertension products. More importantly, there were significant lifts in adherence, as measured by days of therapy, for all of the products in the hypertension portfolio. The lesson here is that communication and collaboration are essential to success. Pharmaceutical companies are beginning to evolve towards a service and support approach, partnering with providers to help patients manage their disease. It’s an old-fashioned solution that remains effective today. Colin Wheeler is the Managing Partner of M2WorldWide Limited, based in M2WorldWide’s European headquarters in London. Colin has worked extensively in the pharma and healthcare industry throughout the past 25 years. M2WorldWide are leaders in global marketing and communications providing profitable solutions for clients worldwide. Recently M2WorldWide and Harte-Hanks Europe announced a strategic partnership providing closed loop marketing solutions for companies operating in the health and life science industry. Email: Volume 2 - Issue 2

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Adherence Improvement Efforts are Popping Up All Over Spring came early this year to the mid-Atlantic region. In mid-March, the temperature reached over 80 degrees. With spring comes renewal, growth, and change – including for the issue of medication non-adherence. Medication non-adherence, an historically under-recognised, and often thought to be intractable public health problem, extracts significant personal health and national economic costs. How and why are adherence improvements now taking root? It’s not by happenstance or the coming of warmer weather earlier than usual due to global warming. It’s because the spadework done over recent decades to prepare the soil (as it were) is now paying off. Toiling in the Fields The seeds for such growth were planted almost two decades ago, when medication non-adherence (then dubbed “noncompliance”) popped up on, and then quickly receded from, the public health radar. In the mid-1990s, the National Council on Patient Information and Education (NCPIE), a patient safety coalition formed in 1982, convened an invitational meeting of diverse stakeholders representing medicine, pharmacy, nursing, public health, government, and health communication. These experts examined medication non-adherence and its consequences, and then developed stakeholder-specific recommendations for action to promote better medicine adherence. This 1994 meeting, “Advancing Prescription Medicine Compliance: New Paradigms, New Practices”, resulted in the development and broad dissemination of multiple adherence-focused work products by NCPIE and invited authors, subsequently published in the Journal of Pharmacoepidemiology (Vol. 3, Number 2, 1995). Déjà vu All Over Again: Adherence Re-examined In October 2007, NCPIE released its second report on medication adherence, “Enhancing Prescription Medicine Adherence: A National Action Plan” -- a renewed nationwide call to action for improving medication adherence through patient information and education, health professional intervention, expanded research, and supportive government policies. Included in the report was a suggested 10-step plan of action for diverse stakeholders’ consideration. See: medicine_adherence.pdf

largely unaddressed public health challenge. A recent study of over 195,000 e-prescriptions found that more than one in four new prescriptions were never filled by patients. This percentage was especially high for new medications treating chronic conditions. For example, 31.4% of new prescriptions for common diabetes medications went uncollected. The Foundation’s research initiative is addressing two primary objectives: a.Measure PMN: Develop a metric that can be efficiently implemented across a wide range of pharmacies for benchmarking PMN rates. b.D  evelop and test PMN intervention(s): Utilise the PMN metric to determine the effectiveness of one or more pharmacy-based interventions to improve primary medication adherence rates.  he Foundation has selected two sets of research T collaboratives to implement these PMN measures in a realworld setting to assess the practicality and utility of these measures for benchmarking of PMN rates, and to assess the effectiveness of PMN interventions. The selected research teams will be led by Harvard University and the University of Mississippi, and are both on track to launch the PMN intervention in 2012. In May 2011, the National Consumers League (NCL), a longtime NCPIE board member launched the Script Your Future national medication adherence public awareness campaign. In so doing, they effectively advanced one of NCPIE’s 10 recommendations for action to enhance prescription, per its 2007 Action Plan report. NCPIE serves on the Script Your Future campaign operating committee, responsible for overseeing this collaborative project that engages multiple public and private stakeholders. See:

Many Hands on the Tiller -- Collaboration is Key

In August 2011, the National Alliance of State Pharmacy Associations (NASPA) – Alliance for Patient Medication Safety (APMS) funded six Adherence Discovery Project proposals from state pharmacy associations seeking to identify ways in which pharmacists can assist patients to improve adherence. The goal of this research effort was to select projects intended to produce measurable, scalable, replicable and sustainable programmes in community pharmacy to improve adherence or methods to identify non-adherent patients.

In January 2011, the National Association of Chain Drug Stores (NACDS) Foundation released a request for proposals (RFP) soliciting submissions from research teams to analyse and improve Primary Medication Non-Adherence (PMN) -- a

Of the six projects, one researched a new adherence toolkit for use by the pharmacist and patient, two used a telephone model, and three used either a health coaching or modified health coaching system. For the final report and details

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about each project, see: NASPAAdherenceDiscoveryProjectProcess.pdf In September 2011, NEHI, a not-for-profit, independent health policy institute unveiled The Medication Adherence Roadmap: A Path Forward, laying out multiple over-arching routes for addressing medication adherence improvement by addressing broad megatrends and high-level opportunities as key to adherence advancement. NCPIE served as a member of the NEHI Conference Advisory Committee and participated in development of the Adherence Roadmap. See: patient_medication_adherence

In February 2012, NCL, the National Association of Chain Drug Stores (NACDS) Foundation, and the American Association of Colleges of Pharmacy (AACP), organisations represented on NCPIE’s Board of Directors, awarded five pharmacy schools, selected from 81 participating colleges and schools of pharmacy, Script Your Future Medication Adherence Challenge Awards to recognise pharmacy students’ public education efforts to help patients understand the importance of taking medications as directed. See: media/Documents/SYFAwardsFINAL.pdf

In November 2011, the National Institutes of Health (NIH) Adherence Network published a call for research project grant applications that propose practical interventions to improve adherence to medication. This funding opportunity supports research to test interventions with the potential to significantly improve medication adherence in patients with chronic health conditions in settings where primary healthcare is delivered - including dental and eye care settings. Research testing complementary and alternative medicine approaches to improving medication adherence will also be supported by this call for research projects. Studies should use the most rigorous design and methodology possible given the populations and settings in which the study is taking place, and include a health outcome or biomarker that is expected to be affected by changes in the targeted adherence behaviour. See: pa-files/PA-12-022.html

In 2012, NCPIE will convene an invitational, broad-based stakeholder project advisory team (PAT) to provide input into the formulation of a multi-year Adherence Action Agenda (NCPIE A3 Project). Watch for details.

In January 2012, the National Association of Chain Drug Stores (NACDS) Foundation announced a research opportunity to study the health impact of pharmacistprovided medication management in care teams to explore strategies to improve medication use in accountable care organisations and patient-centred medical homes. The NACDS Foundation intends to fund, over a two year period, approximately two grants to non-profit research organisations or academic institutions. Selected research projects are anticipated to begin this fall (2012) and last approximately two years in duration to capture long-term he lth outcomes and the impact of medication management services. See: Request for Proposal.

In the Hopper: The NCPIE Adherence Action Agenda

Keeping a Weather Eye The above reflections are evidence of the dedication of NCPIE and other key stakeholders to promoting medication adherence, safe and appropriate medicine use, and better health outcomes. Almost thirty years after NCPIE’s founding, medication adherence and enhanced medicine communication is poised to benefit patients, clinicians, consumers and care-givers alike. Here’s looking toward a bountiful harvest. Mr. Ray joined the National Council on Patient Information and Education (NCPIE) in 1985. He has served as Executive Vice President since January 1995. NCPIE, organised in 1982, is a non-profit coalition of diverse member organisations working together to stimulate and improve communication of information on safe and appropriate use of medicine to consumers and health care professionals. ( Email:

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Medication Adherence in People of Culturally and Linguistically Diverse Backgrounds Introduction Medication adherence is the extent to which a person takes medication as prescribed by a health professional. Internationally, medication adherence continues to be a major problem, leading to extensive morbidity and mortality. Currently, people are adherent to about 50% of their medications, although rates may vary depending on whether an acute or chronic condition is involved. Rates of adherence also tend to be lower in developing compared with developed countries1. In people of culturally and linguistically diverse (CALD) backgrounds, medication adherence has been found to be of particular concern. Comparative studies consistently show that people of CALD backgrounds have lower adherence rates than those of non-CALD backgrounds. For example, in a retrospective cohort study (N= 56,561) involving people with hypertension and dementia, those individuals of a Hispanic or African American background had significantly lower medication adherence rates (66% and 64% respectively) compared with white people (69%) for the use of angiotensin converting enzyme inhibitors2. In a prospective study examining physician-patient communication and antidepressant adherence over a 100-day period following a physician visit, Sleath et al.3 found people of a Hispanic background had a mean adherence rate of 59%, while those of a nonHispanic background had a mean adherence rate of 75%. As the proportion of people of CALD backgrounds continues to increase in developed countries, it is very likely that problems associated with medication adherence will also escalate. It is timely, therefore, to reflect on the barriers associated with promoting medication adherence in people of CALD backgrounds, the strategies for improvement, and research that has been undertaken to address this problem in innovative ways. Barriers Associated with Promoting Medication Adherence in People of CALD Backgrounds Several barriers exist for people of CALD backgrounds. There are barriers relating to equity of access to healthcare services, a lack of health literacy, time constraints, a lack of access to appropriate interpreters, and trust and communication styles. A number of characteristics associated with people of CALD backgrounds can contribute to the barrier involving equity of access to healthcare services. Language problems, combined with the added burden of religious and other cultural beliefs, poverty, poor education, immobility associated with chronic conditions such as osteoporosis or osteoarthritis, can affect people experiencing difficulties in seeking out and using healthcare services. According to the National Healthcare Disparities Report4,5, healthcare disparities associated with race and ethnicity continue to be disproportionately associated with problems relating to healthcare access. Examples of 18 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

services that tend to be under-utilised by people of CALD backgrounds include counselling for the self-management of chronic conditions, and consultation with allied health professionals such as dieticians and podiatrists4,5. Another barrier to medication adherence in people of CALD backgrounds is health literacy. Health literacy relates to individuals’ ability to obtain, process, and understand health information. Low levels of health literacy have been shown to lead to less healthy behaviours, higher rates of hospitalisation, difficulties in verbally communicating with health professionals and poorer health status6. More specifically, an individual with a low level of health literacy is less likely to understand written information about medications, is less likely to be able to communicate effectively with health professionals about medications, and is less likely to follow prescription instructions. This situation contributes to poor medication adherence7,8. The time required to give and receive information about managing treatment regimens is another barrier to medication adherence. When people of CALD backgrounds are confronted with changes in their health status, it is possible that health professionals may need additional time to review their current regimens and educate them about modifications to their healthcare management. Lack of time is frequently mentioned as a barrier for the provision of safe and effective healthcare9. People of CALD backgrounds are often disproportionately affected by time constraints because of their communication difficulties, leading to an inability to take medications appropriately10. Poor adherence to medications is significantly more prevalent among non-English-speaking people compared with those of English-speaking backgrounds11. If there is a lack of availability of professional interpreters, communication through the use of English-speaking family members or friends may occur. This situation can lead to possible miscommunication of medication instructions, manifesting as inappropriate medication use. In addition, older people who are accustomed to an established hierarchical age-based power structure may feel helpless if their English-speaking offspring assume this position of power. It has been shown that errors made by ad hoc interpreters were significantly more likely to cause errors than those made by professional interpreters12. Trust and communication styles associated with the patient-doctor relationship can act as another barrier. Past research has demonstrated links between communication styles with health professionals and medication adherence13. People of CALD backgrounds have been found to be less verbally expressive and less assertive in their interactions with doctors compared with those of non-CALD backgrounds. For some cultures, people’s communication styles may mean it is difficult for them to establish trust and rapport with health Volume 2 - Issue 2

Regulatory & Market Place professionals, which manifests as ineffective information exchange and poor medication adherence. People who have changed their medication regimen themselves may not openly discuss this situation with their doctor, especially if trust has not been established in the relationship. To avoid being perceived as disrespectful, people of CALD backgrounds may be reluctant to offer information about these changes, for fear of being judged or reprimanded14. Furthermore, some people of CALD backgrounds may be reluctant to communicate and demonstrate a passive approach because they have unquestionable trust in doctors. As a result, people may assume that they do not need to actively participate in self-managing their chronic conditions because they trust that their doctor is the only one who can make decisions on their behalf. Strategies for Improvement A number of strategies have been employed in an attempt to improve medication adherence in people of CALD backgrounds. In a recent systematic review examining interventional studies aimed at addressing medication adherence in people of a CALD background15, strategies comprised multifaceted programmes, such as testing the role of education in combination with psychosocial or behavioural initiatives. Strategies also involved the provision of providerdirected programmes, such as the implementation and evaluation of medication reviews. Ways in which information was delivered included pictorial instructions, handouts, DVDs, medication timer devices, telephone reminders, home visits, and group and individual education sessions. Interventions were delivered either on one occasion or were given over several sessions. The length of interventions tended to vary according to whether individuals being treated had a chronic or acute condition. In the interventions, bilingual resources were used in three main ways to address specific needs of people from CALD backgrounds: through a bilingual assistant; the delivery of written forms of communication in intervention groups; and the delivery of data collection tools. Out of 46 studies examined in the systematic review, 20 showed statistical improvements in medication adherence15. In considering the characteristics of interventions employed in past studies, a number of issues are apparent that provides insight into why previous attempts in improving adherence have not been effective15. These issues relate to the continued emphasis on education and bilingual instructors, the focus of interventions from the health professionals’ perspective rather than from the perspective of people from a CALD background, and homogenisation of results relating to participant groups. An examination of these issues can help to clarify how medication adherence may be improved. Past work has consistently demonstrated that education alone does not lead to improvements in medication adherence15. In addition, the sole use of bilingual instructors and translated resources in educational interventions are also not sufficient for enhancing medication adherence. Such approaches have failed to take into account the psychosocial, political and economic factors that affect people’s health and their access to healthcare. In view of the focus placed in many developed societies on the individual’s responsibility towards healthcare and the marginal positions occupied by some 20 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

people of CALD backgrounds, it can lead to ‘victim blaming’ for poor medication adherence outcomes16. People can be impugned for not following an educational approach in an appropriate way, or for not using instructions or reminders in the way they were intended. Such reprimands can be employed rather than examining people’s social and economic circumstances, and their experiences of marginalisation in dealing with health professional relationships. Another issue relates to the homogenisation of participant groups when considering how the intervention is put together in the first place15. During the development phase of some interventions, if the focus is on particular customs and practices of a specific CALD group, it may not be representative of the complex human behaviours and social realities of all participants of the group. This possibility exists because in examining the ways in which interventions are developed, there is little evidence of how they may have evolved from people of various CALD backgrounds. People can differ in terms of many aspects, including their values, beliefs, morals, ways of communication, self-esteem, health literacy, lifestyle activities, social support systems, language, religion, psychosocial characteristics and socioeconomic status15. Lack of information about people’s contribution to intervention development negates the importance and critical value of their involvement. It is apparent that interventions are largely developed by health professionals who may not have clear insights into the complex barriers confronting these participants, despite the fact that health professionals may actually belong to a particular CALD group. The assumption that all people would follow a particular set of traditions can lead to a cookbook checklist approach16 to healthcare, without consideration given to diversity and individualised needs. A related issue is the homogenisation of results associated with medication adherence. For example, in examining the results of intervention studies, outcomes related to medication adherence have tended to involve combined data on people of CALD and non-CALD backgrounds, or combined data on people of different CALD backgrounds15. This homogenisation of results leads to lack of understanding about how a particular intervention may improve medication adherence in relation to cultural diversity associated with people of a specific group. Most importantly, this situation creates lack of insight into how interventions could be modified to improve medication adherence. Research that has Attempted to Address this Problem in Innovative Ways Examples exist of interventional studies that have examined the healthcare concerns of people of CALD backgrounds in innovative ways, with the aim of improving medication adherence. Unfortunately, the presence of such studies is rare and their potential benefits have not been adequately tested. Clearly, more work is needed in developing and testing such interventions to determine their value in medication adherence. Boutin-Foster et al.17 used interviews with 60 black people with hypertension to develop a culturally tailored, educational workbook. Themes obtained from the interviews were used to provide valuable information from the Volume 2 - Issue 2

Regulatory & Market Place individuals’ perspective about taking control and managing hypertension, and on providing knowledge and health behaviour techniques. Since the workbook was developed specifically from the individuals for whom it was meant to benefit, it was perceived to offer a practical and effective means of educating patients about blood pressure control and medication adherence. Haafkens et al.18 described a cluster-randomised controlled trial, which involved testing three culturallyappropriate hypertension education sessions, culturallyspecific educational materials and targeted lifestyle support compared to usual care, in terms of improving medication adherence. In developing culturally-specific educational materials for the intervention, the researchers elicited people’s perceptions of hypertension treatment. Discussions with people of CALD backgrounds identified potential communication barriers and ways in which to create rapport through regular contact. People of CALD backgrounds were encouraged to deal with the complex challenges associated with achieving treatment goals within the broader context of their life. Conclusion Strategies such as bilingual instructors to deliver an intervention, translated resource materials, and educational strategies are themselves insufficient in tackling the complex adherence needs of CALD people. A more productive approach is for clinicians, researchers and policy-makers to gather information from people of CALD backgrounds that can be then incorporated in interventions. Extensive diversity exists within and between people of CALD backgrounds and this diversity needs to be identified, appreciated and valued. References 1. World Health Organization. Adherence to Long-Term Therapies: Evidence for Action. Geneva, World Health Organization (2003). 2. P  oon, I., Lal, L. S., Ford, M. E. & Braun, U. K. Racial/ethnic disparities in medication use among veterans with hypertension and dementia: a national cohort study. The Ann. of Pharmacother. 43, 185-193 (2009). 3. Sleath, B., Ruben, R. H. & Huston, R. A. Hispanic ethnicity, physician-patient communication and antidepressant adherence. Compr. Psychiatry. 44, 198-204 (2003). 4. Agency for Healthcare Research and Quality. National healthcare disparities report. Rockville, MD, US Department of Health and Human Services (2008). 5. Agency for Healthcare Research and Quality. National healthcare disparities report. Rockville, MD, US Department of Health and Human Services (2010). 6. Weiss, B. D. Health literacy and patient safety: Help patients understand. Chicago, IL, American Medical Association Foundation and American Medical Association (2007). 7. D  evraj, R. & Gupchup, G. V. Identifying aspects of pharmacists’ attitudes and barriers toward health literacy: A factor analytic study. The Ann. of Pharmacother. 45, 771779 (2011). 8. Y  oumans, S. L. & Schillinger, D. Functional health literacy and medication use: The pharmacist’s role. The Ann. of Pharmacother. 37, 1726-1729 (2003).

9. Manias, E., Claydon-Platt, K., McColl, G. J., Bucknall, T. K. & Brand, C. A. Managing complex medication regimens: Perspectives of consumers with osteoarthritis and health professionals. The Ann. of Pharmacother. 41, 764-771 (2007). 10. Walker, C., Weeks, A., McAvoy, B. & Demetriou, E. Exploring the role of self-management programmes in caring for people from culturally and linguistically diverse backgrounds in Melbourne, Australia. Health Expectations. 8, 315-323 (2005). 11. Westberg, S. M. & Sorensen, T. D. Pharmacy-related health disparities experiences by non-English-speaking patients: impact of pharmaceutical care. Journal of the American Pharmacists Association. 45, 48-54 (2005). 12. Gany, F., Kapelusznik, L., Prakash, K., Gonzalez, J., Orta, L. Y., Tseng, C.-H. & Changrani, J. The impact of medical interpretation method on time and errors. J. Gen. Intern. Med. 22, 319-323 (2007). 13. Schouten, B. C. & Meeuwesen, L. Cultural differences in medical communication: a review of the literature. Patient Educ. Couns. 64, 21-34 (2006). 14. Chin, M. H., Walters, A. E., Cook, S. C. & Huang, E. S. Interventions to reduce racial and ethnic disparities in health care. Med. Care Res. Rev. 64, 7S-28S (2007). 15. Manias, E. & Williams, A. Medication adherence in people of culturally and linguistically diverse (CALD) backgrounds: A systematic review and meta-analysis. The Ann. of Pharmacother. 44, 964-982 (2010). 16. Williamson, M. & Harrison, L. Providing culturally appropriate care: A literature review. Int. J. Nurs. Stud. 47, 761-769 (2010). 17. Boutin-Foster, C., Ravenell, J. E., Greenfield, V. W., Medmim, B. & Ogedegbe, G. Applying qualitative methods in developing a culturally tailored workbook for black patients with hypertension. Patient Educ. Couns. 77, 144-147 (2009). 18. Haafkens, J. A., Beune, E., van Charante, E. P. M. & Agyemang, C. O. A cluster-randomized controlled trial evaluating the effect of culturally-appropriate hypertension education among Afro-Surinamese and Ghanaian patients in Dutch general practice: study protocol. BMC Health Serv. Res. 9, (2009). Professor Elizabeth Manias works in the Melbourne School of Health Sciences at The University of Melbourne, Australia, and is a registered nurse and pharmacist. Her areas of interest include medication adherence, patient safety, consumer participation, and medication communication. More specifically, Professor Manias is interested in social, structural and environmental aspects of how health outcomes are affected. Her work considers different individuals’ perspectives and the complexities of dynamic environments in which medication adherence takes place. Email:

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Home Healthcare – Helping to Improve Patient Adherence Inadequate adherence to both prescribed medication and health improvement behaviours is a problem with important implications for all clinicians, public health strategists and policy-makers. As market access and value-based pricing become increasingly significant issues for pharmaceutical companies to contend with, improving adherence to particular therapies is also becoming more important to forward-thinking pharmaceutical companies. Inadequate adherence is a global problem. It has been estimated that only 50% of medication is taken as prescribed in the developed world, with dramatically lower levels of adherence in the developing world.1 Health literacy and socioeconomic factors are of course major influences of adherence across all economies, with the poorest in any region also suffering disproportionately from the additional combination of poorer lifestyle choices, greater incidence of disease, lesser access to high quality healthcare and, unsurprisingly, poorer health outcomes as a result. Whilst policy-makers, public health organisations and health economists may strive to address many of these influences on health outcomes, poor adherence to prescribed treatments remains a stubborn but critical problem if any medical treatment or public health intervention is to work. If outcomes are to be achieved more effectively, clinicians, policy-makers and pharma companies must therefore give consideration to effective evidence-based, behaviour change interventions, either as a standard component of a health system or as a discrete service tied to a particular therapy. It is in this space that increasing numbers of organisations, and most notably home healthcare companies, are able to play a growing and significant role. Home Healthcare Home healthcare in the UK is an industry which has grown in importance since its inception in 1975. Although originally focussed on community dispensing and drug delivery, the drive in recent years to move more activity out of hospital has led several home healthcare organisations to evolve their services. Home healthcare now incorporates a far broader spectrum of services, including: aseptic compounding of drugs; drug delivery; nursing care for patients with long-term health needs; early discharge services to reduce hospital length of stay; admissions avoidance through community long-term conditions management; and adherence support programmes for particular interventions. Adherence Support Programmes The nature of the services provided by home healthcare companies and the prolonged close relationship that develops between staff and patients enables provider organisations to exercise a high degree of influence over both adherence and lifestyle improvement. Patients quickly forge 22 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

trusting relationships with nurses and call centre staff and frequently interact with the same staff members, wherever possible. The frequency of contact varies from monthly or fortnightly to daily in some cases, and may continue for several years. Home healthcare providers therefore have greater proximity to patients than that provided by most standard NHS health services or private health insurers, and far greater than that allowed for pharmaceutical companies. This proximity is ideally suited to both the promotion of patient adherence and the collection of real-world data for Phase IV observational studies that pharma companies may seek to conduct. Adherence support programmes provided by home healthcare companies may take several forms. At one end of the spectrum are simple reactive telephone support services for patients with particular queries about their medication. At the other end of the spectrum, sophisticated interventions are deployed which draw upon health psychology frameworks and models of behaviour change theory. When provided to support a particular therapy, these sophisticated support programmes may incorporate the other services provided by the home healthcare providers, and therefore include home delivery of the prescribed medication, home nursing and nurse-led training on drug administration, where required. A key feature of the adherence support offered by leading providers is telephonic health coaching. In addition to helping patients overcome barriers to good adherence, the transfer of knowledge to enable patients to better understand their illness and the medication they have been prescribed is an additional aim of the service provided. An approach that has been used successfully begins with an assessment of an individual’s immediate healthcare needs, their readiness and motivation to change their behaviour, and an evidence-based assessment of their immediate risk of non-adherence to the prescribed treatment. Dependent upon this assessment, the consequent interventions are altered to suit the needs of the particular patient. Interventions can include the provision of specific health information, SMS messaging and reminders, home nursing visits and regular coaching calls. Providing a service that is truly patient-centric is vital. Health coaching should be available 24 hours a day so that the health coaches can contact patients at a time that is suited to their needs. Outbound calls need to assess individual health status and health goals as well as overall motivation to alter behaviour. The Transtheoretical Model of behaviour change 2 can then be used to determine the patient’s position in relation to adopting a given behaviour change (see box 1) and once equipped with this understanding, coaches are then able to motivate the patient to progress through the next stage of the model. A ‘whole person’ approach should be taken which uses the Volume 2 - Issue 2

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patient’s condition as the starting point for the interaction, but also seeks to understand their comorbidities, their social situation, their ‘locus of control’ and personal attitude towards both healthcare and health in general. Health information provided by the coaches needs to be backed by an evidence-based database which is updated continuously to provide the latest information on side-effects of medication and interactions between medication, and updates on both long-term conditions management and preference-sensitive conditions. In addition to supporting patients, it is imperative that services also ease the work of clinicians. In my experience, a way to achieve this is to use a web-enabled IT system to log all interactions occurring between any home healthcare staff, health coaches and patients. Clinicians and patients are then able to log into their own versions of the system to see what interactions have occurred and can send information to coaches either through a webpage, a mobile app or a standard SMS message. Conclusion The overall holistic approach to adherence support provided by Bupa Home Healthcare is not typical of home healthcare companies, but demonstrates how innovative providers are able to influence a core problem which limits the achievement of health outcomes. The approach has proven powerful in modifying adherence issues and ultimately improving persistence on treatment in a range of long-term conditions, including multiple sclerosis and most recently, hepatitis C. As shifts in demographics and disease management will soon result in a greater proportion of people than ever before living well into their eighth and ninth decades of life, improving adherence will become increasingly critical for health systems. The demands of both value-based pricing and economic austerity in the developed world will also drive pharmaceutical companies to offer broad adherence support services. These services offer the opportunity to augment therapies and improve both differentiation from rival drugs of similar efficacy as well as the outcomes attributable to them. Box 1: Six stages of the Transtheoretical Model of behaviour change2: 1. Precontemplation 2. Contemplation 3. Preparation 4. Action 5. Maintenance 6. Termination

Dr Mehmood Syed will be speaking about the adherence programme that was devised for Hepatitis C patients at the eyeforpharma Patient Summit 2012 in London on 29th May. References 1. W  HO Report. Adherence to long term therapies. Evidence for action. Report 2003. en/d/Js4883e/ 2. Prochaska JO, Velicer WF. The Transtheoretical Model of Health Behavior Change. American Journal of Health Promotion: 1997; 12(1): 38-48. Mehmood Syed is a practising GP and joined the team in November 2010, having previously worked in a senior medical management position with the NHS Hammersmith & Fulham. He is a Member of the Royal College of General Practitioners, an MBA alumnus of Imperial College and coauthor of a textbook of differential diagnosis in primary care. At Bupa Home Healthcare, Mehmood is leading on clinical governance and quality improvement and provides clinical oversight to marketing and business development activities Email: Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 23

Behaviour Programmes

Compliance Begins in the Mind; So Does Hypnosis For many people, hypnosis has been shown to be an effective method for changing behaviour, even under adverse circumstances, like the extreme discomfort of smoking cessation or the severe pain of childbirth. How much more potent might this time-tested technique be when the focus is on a clear-cut medical plan, and the motivation is one’s own health and wellbeing, perhaps even a matter of living or dying? With clear goals and a willing person, the skilled hypnosis professional can place the patient on the path to full compliance and long-term adherence for optimal treatment results. Some years ago, a dear friend, the head of the nephrology department at a busy suburban New York hospital, lamented to me that one of the greatest challenges he faced in his medical practice was not the lack of proven treatments, or a shortage of equipment, but the frustrating failure on the part of many patients to follow the treatment protocols so carefully laid out for them by their physicians. In his case it might take the form of a no-show for dialysis, skipping follow-up visits, forgetting to take medicine, etc. Needless to say, such neglect invites huge risk to the patients’ recovery, not to mention the high monetary cost of playing medical catch-up. When illness becomes more serious and more urgent, it’s like that expensive, complex treatment may be necessary. In many respects, the conversation was a familiar one to me, because I have spent a good deal of my life helping people to identify and overcome their personal obstacles to achieving specific goals. Here, the goal was better defined than most. Here, the reason for wanting success was more obvious than most. If ever there was a perfect match between psychological technique and situational need, it is the marriage of hypnosis and patient compliance. What is hypnosis, really? You know from your everyday experience that the mind exists in various states. Sometimes you are in a completely awake state and very aware of all that is happening around you. Sometimes you are deeply asleep and completely oblivious to your surroundings, until you are jostled out of your slumber. Other times, you may be caught in a twilight sort of place, awake yet lost in a daydream. Hypnosis, which literally means induced sleep, is also a mental state, characterised by an intense inward concentration where the person is far more involved in an inner reality than any awareness of the outer world. Brain scans of people under hypnosis tell us that some parts of the brain remain fully awake, while other parts are put at rest. What is so useful about the hypnosis state of mind is that this mixture of awake and at rest enhances the quality of suggestibility. We are always, to some extent, suggestible, that is, open to incorporating ideas from others into the way that we think. However, the great gatekeeper to the degree of suggestibility is our critical thinking. Do we trust 24 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

the information coming to us to be truthful and helpful? For example, the awake mind is more suggestible to the ideas presented by a trusted person than to those of a stranger. Still, even in this instance, critical thinking prevents complete and utter suggestibility. The critical thinking wall of doubt protects us from foolish gullibility. The state of hypnosis, on the other hand, seems to suppress or bypass critical thinking and disbelief, which promotes suggestibility far beyond what is ordinarily experienced. Such enhancement of suggestibility is the immense practical value of hypnosis, because during the time that the mind is thus open to suggestion, there exists an excellent chance to place new, beneficial ideas directly into the thought process of the person, strengthening or even changing what was hitherto an unreachable part of the mind. In a 1984 article for the journal Medical Hypnoanalysis, I developed a method for including hypnosis into a cognitive behavioural treatment strategy called Rational Suggestion Therapy (RST). RST holds that, during the course of therapy, people may come upon ideas they wish could be included in the way that they think, thereby inclining them toward the thinking that is necessary to reach their therapeutic goals for behaviour and emotion. The method actually calls for those desired ideas to intentionally be searched for, in a rational, purposeful way, rather than accidentally coming upon them. The desired ideas become therapeutic suggestions during a subsequent hypnosis session. They are then tested in vivo for their effectiveness in helping to achieve the person’s stated goals. Together, the therapist and the person fine-tune the hypnosis suggestions during the therapeutic process. There is every reason to believe that an RST procedure similar to this could be as useful for addressing the issues of patient compliance. Indeed, the suggestion portion of the hypnosis may prove considerably easier to identify, if the compliance stakeholders are willing to participate cooperatively. Those stakeholders would be the patient, the physician, and the hypnotherapist. Before defining what the stakeholders’ various roles in the compliance RST would look like, it might be helpful to understand the need for a custom hypnosis, as opposed to a generic hypnosis, and just what is entailed in the development of a custom hypnosis. The words spoken by the hypnotherapist during the hypnosis session are called the script. The hypnosis script is comprised of two main parts, with other parts that are designed to increase the effectiveness of the main parts. Those main parts are the hypnotic induction and the hypnosis suggestions. Hypnotic induction usually requires the intense concentration of the patient’s attention. Techniques such as staring at a candle flame, focusing on a blinking light or a spot on the wall, or following a spiralling shape, are examples of visual aids that have been used in the past to concentrate the attention while the script is Volume 2 - Issue 2

Company profile

“Drugs don’t work in people that don’t take them”

Charles Everett Koop, Former US Surgeon General

In 2003 the World Health Organization published “Adherence to Long Term Therapies: Evidence for Action”. The report cleverly summarizes their findings on a page called “Take home findings”. The first finding is:“Poor adherence to treatment of chronic diseases is a worldwide problem of striking magnitude. Adherence to long-term therapy for chronic illnesses in developed countries averages 50%.” If drugs don’t work in people that don’t take them, and with adherence of 50%... does your product work in the real world? The ability to quantify to doctors that your product has “inherent compliance”, that can be ‘scripted’ with the product, which delivers high rates of adherence and the ability to offer doctors results for their patients, is a major product differentiator. Health Window uses the powerful Differenza Disease Management Software to care for patients whilst making disease and adherence outcomes measurable. The ability to influence is often born of relationships. Health Window speaks to patients. Within a relationship we can use technology. But first we care, then we consult. The ability to deliver on large scale. Health Window has a global call centre footprint through strategic partnerships with the world’s largest call centre company. Health Window uses the Differenza Disease Management software which is web-based, and available throughout the globe. The ability to sell your adherence benefits falls within the scope of the sales function, expanding adherence initiatives from the usual marketing-only approach. Health Window provides powerful sales force tools with which to make a persuasive argument that your product works in the real world… The ability to do away with assumptions is important to ensure investment is channelled where it matters. If the users who download health apps, “Google” for their disease online, and enrol themselves, are taking the initiative for their disease treatment, shouldn’t investment be channelled to the patients that don’t take the initiative, don’t download health apps, and are not adherent? Without quantifying whether these technologies improve from baseline adherence,

Clinical Trials


investment might inadvertently be channelled to “preach to the converted” – to the patients who help themselves online, whilst the non-adherent patient in denial remains untouched, not enrolled, and non-adherent, and their diseases not controlled. Do obese patients forget that they should eat properly and exercise? If not, why is pharma investing in “reminders” when “forgetting” is an unproven assumption? The ability to understand our patients’ belief systems, psychological profiles, unique fears and concerns is vital to offering patients solutions to their individual obstacles to adherence. The ability to do it sensibly – by verifying improvements in adherence and quantifying real, direct ROI, without assumptions, makes the business case for Health Window programmes a logical consideration. Health Window has over 60,000 patients active on several adherence programmes, ranging from pharmacy- to doctorenrolled programmes. Within these relationships we are able to influence towards resolving adherence obstacles, and can quantify behavioural change, improvement in disease outcomes, and even benefits in downstream cost reduction. The end result to pharma: We can help you offer your prescribers - Real-world efficacy - Quantified in terms of adherence and disease outcomes improvements - Worldwide footprint to deliver services - Powerful software and reporting that matters The end result to funders or medical aids: We can help you - Draw the link between improved adherence and reduced downstream cost (e.g. hospitalisation) - Adherence to managed care schedules. - Improving treatment cost-efficacy by ensuring adherence to formularies - Powerful software and reporting that matters. Visit – view our ONLINE VIDEOS or download YOUR BRAND’s compliance data. Visit – to view how the sales force can use your programme’s results to detail doctors on real-world results (and baseline against competitor’s results – if any). Visit to see the power of the software solutions we employ. Visit – to see which other companies worldwide have partnered with Health Window to offer global footprint with the central software and reporting services that ensures worldwide implementation, local customisation, and comparative reporting. Tel: +2712 8449000 Fax: +2712 8043742 Email: Address: Rentmeester Park, 74 Watermeyer Str, Val de Grace, Pretoria, 0184

Behaviour Programmes recited. However, the induction method preferred by many modern hypnotherapists relies mostly on tapping into the imagination of the person. The best way of accomplishing this is for the induction to exploit the rich inner sensory registry of the person’s imagination, which simply means that all of the outward senses human beings use to gather information about their environs are also represented in inward, imaginary constructs. When designing the induction narrative portion of the hypnosis, the therapist should make an attempt to include as many of the senses as possible: what is seen, what is heard, what is felt on the skin, the temperature, the smells - all of these add immeasurably to the patient’s perceived plausibility of the imaginary experience. Please realise that plausibility does not in any way indicate that the scenario must make logical sense to everyone. It only must contain meaning for one person the person being hypnotised. I mention this to illustrate how including the personal preferences of the patient can make for a much more enjoyable, hence deeper and more productive hypnosis experience. Here is an example of what could go wrong if the person’s preferences are ignored. A popular induction scenario is a relaxing walk along a sunny beach. Most people find this quite pleasant and comfortable. Yet it fails to consider people who may be very fair-skinned and burn easily in the bright sunshine. Such a walk might actually present a painful, distressing situation which could sabotage the induction at the very start, or at least present a considerable hurdle with which the patient must contend for any semblance of success. After all, since the goal of the induction scenario is for the person to become intensely focused on an inner reality and distant from the surrounding environment, it is improbable that the patient would be fascinated by a reminder of discomfort. You can see how strong a case is made here for the use of a custom hypnosis induction. If asked some easily answered questions in order to ascertain the patient’s personal preferences for building her or his ideal induction scenario, the likelihood for a positive experience will be that much greater, as well as increasing the patient’s propensity for wanting, even looking forward to listening to the hypnosis more often, thereby increasing the chances for compliance. Just as it is important for the induction to be tailored to the preferences of the patient, it is equally important, if not more so, for the next part, the suggestion section of the hypnosis, to be precisely what the patient needs and desires. Once the state of hypnosis has been induced through imagination, the mind is ready to receive and accept the compliance suggestions, planting them into the cognitive processes of the patient. While it is possible for the therapist to recite a set of generic ideas regarding general cooperation with one’s doctors and other health professionals and allude to following their instructions, there is undoubtedly far more value in the specifics about the requirements of a particular patient’s participation in their medically-related activities. What is compliance after all, but a series of rational decisions to behave in a specified manner, based on medical information and instruction. Specificity is key to an effective compliance hypnosis. Proper construction of the suggestions raises yet another truth about hypnosis from RST. Hypnosis is a form of 26 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

communication between the therapist and the patient. Ideas are being presented to the patient’s mind through the spoken word. Using the language conveying the desired meaning is paramount. Word and phrase choices must resonate with the person, especially uncommonly used words that possess medical meanings. What may be everyday language to the physician, may be completely unintelligible to the patient, perhaps meaning something entirely different in conversational language. Evidently, care should be taken when crafting the entire hypnosis to use words clearly understood, even to the point of using words originating with the patient whenever possible. There is another vital need that is fulfilled through the use of custom hypnosis for patient compliance. In discussing the suggestions, there lies a real opportunity for the patient to reveal their personal obstacles to compliance, which may not have even come to mind before. I once wrote an Volume 2 - Issue 2

Behaviour Programmes large pill might be needed. Ideally, all of this points to the inclusion of the three compliance stakeholders – patient, physician and hypnotherapist – each with a role to play in the crafting of suggestions. The therapist would act as facilitator, meeting first with the physician and then with the patient. From the physician, the therapist obtains a clear understanding of what total compliance would look like for that patient, taking detailed notes to be shared with the patient. Then meeting with the patient, the therapist discusses the compliance plan. Since doctors will usually want to speak to their patients directly or through other medical personnel early on, the patient will likely have heard some or all of this already. Still, the great value of discussion between patient and therapist has already been addressed above. If there is a problem with the treatment plan, the therapist may want to consult with the physician again. Once the plan is settled and suggestions have been put into words by the therapist and patient working together, the induction is likewise worded according to the patient’s preferences. The therapist will then record the hypnosis and load it onto a portable playback device. Use of a recording is far more desirable than a live recitation because the hypnosis is now a training tool to be used at least daily for as long as necessary. The custom hypnosis should be available to the patient at all times. Hypnosis is not only for training the patient in compliance, however. Often, a large part of the physician’s advice pertains to changes in lifestyle, such as a special diet or exercise or other ongoing changes that require constant reinforcement and support for the long term, maybe for life. Hypnosis can also provide that type of service, repeating the stakeholders’ procedure with the lifestyle changes as suggestions. As in RST, we do not assume that all is finished when the hypnosis is delivered to the patient. Follow-up is imperative in order to fine-tune the suggestions and/or induction based on the results as reported by patient and physician. A well-crafted custom hypnosis can be a lifelong tool for healthy living.

article for The International Journal of Psychosomatics, in which I coined the term “autoprediction”. It included the case study of a bulimic. Using her imagination, the person was easily able to predict for me how she would feel and behave in future situations related to her condition. Using that information, we could, together, craft a plan of action. Autoprediction applied to patients imagining their future adherence to medical advice, as well as their degree of compliance with prescribed therapeutic activities, may not only point the way to hypnosis suggestions, but reveal the need for additional or modified treatment options, before they become problematic. For example, a patient may be called upon to take a large pill once a day. In predicting what may happen, the patient tells of trouble swallowing a large pill. Is there an alternative? A liquid, or several smaller pills, or breaking the large pill, or a weekly injection? If there is no alternative, an hypnosis suggestion about taking a

References 1. Blumenthal, R.A. Rational Suggestion Therapy: a subconscious approach to RET. Medical Hypnoanalysis 1984; 6, 57-60. 2. Blumenthal, R.A. Autoprediction in Rational Suggestion Therapy. International Journal of Psychosomatics 1984; 31(4): 17-20. Richard A. Blumenthal holds a Master of Science Degree in Counseling from Long Island University. He is a New York State Licensed Mental Health Counselor and the author of numerous professional works in the fields of hypnosis and counselling. Mr Blumenthal is the originator of the Rational Suggestion Therapy counselling technique. He was awarded a United States Patent for the invention of hypnosis software, which may be found at Email: Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 27

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Listening to the Patient: Using Patient-Reported Outcomes to Optimise Adherence and Inform Healthcare Decisions The World Health Organization (WHO) has stated that, across diseases, patients’ non-adherence to prescribed treatment protocols is the single most modifiable factor compromising treatment outcomes1. As ever-increasing healthcare expenditure reaches unprecedented levels, promoting patient adherence to treatments is one of the primary challenges for healthcare professionals, researchers and policy-makers today. However, while those developing, evaluating and prescribing treatments value adherence as a means to promote treatment efficacy, the patients actually taking those treatments may place greater value on other treatment-related factors (e.g. convenience, sideeffects etc). Patient-reported outcome (PRO) measures therefore represent valuable tools by which to understand patients’ perspectives of their treatments and to optimise adherence. Using PROs to Measure Rates of Non-adherence Estimates across empirical studies suggest that as many as 25% of patients are non-adherent to therapy2. Quantifying the true problem of non-adherence, however, is challenging as no method of adherence is without limitations or exempt from bias. Direct measures of adherence (e.g. direct observation of medication-taking behaviour or measurement of drug, metabolite or biologic markers in blood/urine) are, in most cases, costly and impractical means of assessing adherence. For the most part, therefore, researchers and healthcare providers tend to be reliant upon a range of ‘indirect’ measures as means to assess patients’ adherence to treatment regimens. These indirect measures imply that medication has been used by a patient and can be further categorised into ‘objective’ (e.g. pill counts; electronic monitoring systems; review of prescription records / claims) or ‘subjective’ outcomes (e.g. clinician-reported outcomes and PROs) assessments. Indirect measures are susceptible to a number of biases: • All indirect measures by their very nature are subject to the ‘Hawthorne effect’ (i.e. consideration that patient’s knowledge of assessment of adherence may influence adherence behaviour)3; • While objective assessments imply that the medication has been used by the patient, there is no guarantee that the medication has indeed been taken and, if it has been taken, whether it was taken in accordance with the prescribed regimen (e.g. adequate dosing, timing, administration procedures); • Clinician-reported levels of adherence tend to differ from patients’ actual levels of adherence, in most cases underestimating the problem of non-adherence4; • PRO measures provide an excellent opportunity to investigate patients’ own evaluation of their medication28 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

taking behaviour, but are subject to social desirability bias (i.e. people’s tendency to respond in a manner that will be viewed favourably by others)5. In light of such limitations and the absence of a universally accepted ‘gold-standard’ measure of adherence, a multimethod approach, including combinations of objective and subjective assessments, is considered to be the optimal strategy for adherence measurement1. By providing unique insight into the patient’s own personal perspective of treatment behaviour, PRO assessments are key components of such strategies. Using PROs to Understand Non-adherence and to Promote Adherence to Treatment Regimens Traditional approaches to understanding adherence to medical interventions have adopted a ‘reductionist’ and/or ‘epidemiological ‘ perspective, in which it is assumed that patients are passive recipients of medical interventions, and that non-adherence can be understood in terms of “atrisk” groups defined according to generalisable patient and disease characteristics. There is growing recognition, however, that these approaches provide an incomplete understanding of adherence. For example, there is a documented lack of consistent evidence regarding the predictive validity of demographic variables2,6 and, as such, these variables can be considered only ‘weak’ or ‘distal’ predictors of adherence7. Adherence is best understood from a psychosocial perspective whereby, consistent with well-established social cognition models that seek to explain patients’ participation in health behaviours (e.g. Health Belief Model; Theory of Planned Behaviour; Social Cognitive Theory)8-10, an individual’s own personal knowledge and beliefs about their illness, motivation and confidence (self-efficacy) in managing their treatment, satisfaction with treatment, and their expectations regarding the outcome of treatment and consequences of poor adherence, are all factors that can influence a patient’s adherence to therapy. Such factors are (by their very nature) patient-centric and PROs can, therefore, play a critical role not only in measuring adherence as part of a battery of assessments, but also as a means of understanding reasons that may contribute to non-adherence. This is a key consideration for clinical drug development, where measures can be used to support the effectiveness of treatments. In addition such information is a key consideration for management in clinical practice, where information can assist in identifying patients who may potentially be at risk of non-adherence, so that issues can be addressed before the clinical consequences of non-adherence occur. In addition to understanding the problem of nonadherence, use of PROs in clinical practice may also go some Volume 2 - Issue 2

Behaviour Programmes way towards alleviating the problem of non-adherence. Evidence suggests, for example, that adherence to treatment regimens is highest when patients have perceived involvement in their own treatment decisions11. As a result, the delivery of patient-centred care is the cornerstone of numerous healthcare initiatives and reforms: see the “Equity and Excellence: Liberating the NHS” UK White Paper (2010), for example, a key excerpt from which indicates that “We want the principle of “shared decision-making” to become the norm: no decision about me without me”12. Use of patientreported outcomes as a tool in patient/doctor interactions therefore provides a formalised and efficient way by which to involve and engage patients in the decision-making process at both an individual and wider service level. Practical Example of the Use of PROs to Optimise Adherence: Deferasirox for the Treatment of Iron Overload Given the aforementioned points, researchers and healthcare decision-makers are becoming increasingly more interested in ways in which to utilise PRO data, extending beyond indicators of treatment efficacy (e.g, improvement in patient symptoms, engagement in activities of daily living) to other peripheral benefits of treatment (including treatment satisfaction and adherence). A prime example of the value of PRO data in informing life-changing healthcare decisions can be seen in European reimbursement decisions regarding deferasirox (Exjade®) for the treatment of iron overload. Iron overload (the accumulation of excess iron in the body) is a potentially fatal complication in patients with transfusion-dependent disorders (e.g. ß-Thalassemia). Prior to the approval of deferasirox, deferoxamine (DFO), delivered via continuous subcutaneous infusion over 8 to 12 hours for 5-7 times a week, was the standard of care for the treatment of iron overload. The time-consuming nature of DFO regimens and side-effects associated with this form of ICT13,14 have been shown to have a detrimental impact on numerous facets of patients’ Health-related Quality of Life (HRQoL), limiting patients’ satisfaction with therapy and ultimately threatening rates of adherence15. As a once-daily oral therapy, deferasirox was designed to improve treatment satisfaction and adherence among users. To test this hypothesis, a disease-specific PRO measure of treatment satisfaction, adherence and persistence was developed for inclusion in clinical studies: the Satisfaction with Iron Chelation Therapy questionnaire (SICT)16,17. One early study, which involved a prospective evaluation of deferasirox compared with DFO, demonstrated that the proportion of patients treated with deferasirox and who were very satisfied or satisfied with treatment was significantly higher than those treated with DFO at the end of a 52-week treatment period (85.1% vs 38.7%; p < 0.001)18. At the same time point, the majority of those treated with deferasirox reported that treatment was very convenient or convenient compared with those treated with DFO (92.7% vs 11.3%, respectively; p < 0.001). Finally, the proportion of patients indicating a willingness to continue study therapy at the end of the study was significantly greater in those receiving deferasirox than in those receiving DFO (85.8% vs 13.8%; 30 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

p < 0.001).Further evidence in patients previously receiving DFO indicated that the proportion of patients who reported always following their ICT regimen as directed by a healthcare professional (a proxy of adherence) increased from 36.0% to 69.2% following treatment with deferasirox. Likewise, the proportion of patients who reported never thinking about stopping ICT (a proxy for persistence) increased from 44% to 80% over the same period19. While such evidence is not referenced in initial regulatory approval decisions from the US Food and Drugs Administration (FDA) or European Medicines Agency (EMA), guidance from reimbursement agencies in the UK (including the Scottish Medicines Council and All Wales Medical Strategy Group) and France (Haute Autorité de Sante Transparency Committee) all made reference to data which was supportive of improvements in convenience, satisfaction and adherence and HRQoL – highlighting the value of PRO data regarding patients’ evaluation of treatment in informing healthcare decisions beyond product labelling claims20. Key Considerations for Maximising the Value of Information Collected via PROs Whether PRO instruments are to be used in clinical studies designed to investigate patient evaluation of therapy (e.g. treatment satisfaction, adherence or persistence) or are to be used in clinical practice to facilitate discussions with patients, there exist well-established standards for the development of PROs21. Firstly, given that the purpose of these PROs is to reflect the experiences of patients receiving therapy, Volume 2 - Issue 2

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instruments must be developed and validated with input from patients to confirm that these instruments measure concepts that are important to patients, and measure them in a way that is easily understood by patients22. PRO instruments must also be used firmly with ‘the end in mind’ and constructed in such a way that this makes sense to the measurement of the targeted concept for that specific population. Important considerations in this regard may be the response options used (e.g. Likert scales, numerical response scales), the recall period referred to (instruments that require patients to recall over long periods of time may introduce responder bias) and instrument administration (where and when will patient complete the measure) and scoring procedures (what it is that we will ultimately derive from the measure of interest). Finally, in looking to facilitate the patient-provider relationship, there needs to be a clear and identifiable relationship between information collected from patients and resulting treatment decisions. In conclusion, the need for a patient-centred approach to understanding and reducing rates of non-adherence to medical interventions is well documented. PRO assessments are valuable tools that can be used to obtain insight into adherence-related issues from the patient’s own personal perspective, which is key to informing life-changing healthcare decisions for patients and the development of individuallytailored solutions for promoting adherence. References 1. Sabate E. Adherence to Long-Term Therapies: Evidence for Action. World Health Organisation; 2003.

2. DiMatteo MR. Variations in Patients’ Adherence to Medical Recommendations: A Quantitative Review of 50 Years of Research. Medical Care 2004;42(3). 3. Roethlisberger FJ, Dickson WJ. Management of the Worker. Cambridge, MA: Harvard University Press; 1939. 4. Miller L, Liu H, Hays R, Golin C, Beck C, Asch S, et al. How well do clinicians estimate patients’ adherence to combination antiretroviral therapy? Journal of General Internal Medicine 2002 Jan 1;17(1):1-11. 5. Edwards AL. The relationship between the judged desirability of a trait and the probability that the trait will be endorsed. Journal of Applied Psychology 1953;37:90-3. 6. Jin J, Sklar GE, Min SO, V, Chuen LS. Factors affecting therapeutic compliance: A review from the patient’s perspective. Ther Clin Risk Manag 2008 Feb;4(1):269-86. 7. McHorney CA. The Adherence Estimator: a brief, proximal screener for patient propensity to adhere to prescription medications for chronic disease. Curr Med Res Opin 2008 Dec 10;25(1):215-38. 8. Becker MH, Maiman LA, Kirscht JP, Haefner DP, Drachman RH. The Health Belief Model and prediction of dietary compliance: a field experiment. J Health Soc Behav 1977 Dec;18(4):348-66. 9. Ajzen I. The theory of planned behaviour. Organizational Behavior and Human Decision Processes 1991;50:179-211. 10. Bandura A. Social foundations of thought and action: a social cognitive theory. Engelwood Cliffs, NJ: Prentice-Hall; 1986. 11. Loblaw DA, Bezjak A, Bunston T. Development and Testing of a VisitSpecific Patient Satisfaction Questionnaire: The Princess Margaret Hospital Satisfaction With Doctor Questionnaire. Journal of Clinical Oncology 1999 Jun 1;17(6):1931. 12. Department of Health. Equity and Excellence: Liverating the NHS. 2010. 13. Giardina PJ, Grady RW. Chelation therapy in beta-thalassemia: an optimistic update. Semin Hematol 2001 Oct;38(4):360-6. 14. Rebulla P. Transfusion reactions in thalassemia. A survey from the Cooleycare programme. The Cooleycare Cooperative Group. Haematologica 1990 Sep;75 Suppl 5:122-7.:122-7. 15. Abetz L, Baladi JF, Jones P, Rofail D. The impact of iron overload and its treatment on quality of life: results from a literature review. Health Qual Life Outcomes 2006 Sep 28;4:73.:73. 16. Rofail D, Abetz L, Viala M, Gait C, Baladi JF, Payne K. Satisfaction and adherence in patients with iron overload receiving iron chelation therapy as assessed by a newly developed patient instrument. Value Health 2009 Jan;12(1):109-17. 17. Rofail D, Viala M, Gater A, Abetz-Webb L, Baladi JF, Cappellini M. An instrument assessing satisfaction with iron chelation therapy: Psychometric testing from an open-label clinical trial. Advances in Therapy 2010 Aug 1;27(8):533-46. 18. Cappellini MD, Bejaoui M, Agaoglu L, Porter J, Coates T, Jeng M, et al. Prospective evaluation of patient-reported outcomes during treatment with deferasirox or deferoxamine for iron overload in patients with betathalassemia. Clinical Therapeutics 2007 May;29(5):909-17. 19. Porter JB, Athanasiou-Metaxa M, Bowden DK, Troncy J, Habr D, Domokos G, et al. Improved Patient Satisfaction, Adherence and Health-Related Quality of Life with Deferasirox (Exjade®) in ß-Thalassemia Patients Previously Receiving Other Iron Chelation Therapies . Blood (ASH Annual Meeting Abstracts) 2009;(114):2486. 20. Doward L, Gnanasakthy A, Baker M. Patient reported outcomes: looking beyond the label claim. Health and Quality of Life Outcomes 2010;8(1):89. 21. FDA. Guidance for Industry. Patient Reported Outcomes Measures:Use in Medical Product Developmentto Support Labeling Claims. 2009. 22. Lasch K, Marquis P, Vigneux M, Abetz L, Arnould B, Bayliss M, et al. PRO development: rigorous qualitative research as the crucial foundation. Quality of Life Research 2010 Oct 1;19(8):1087-96.

Adam Gater Senior Research Manager, Adelphi Values Patient-Reported Outcomes (PRO) practice. With a strong background in health psychology, Adam provides strategic advice to healthcare businesses on the selection, development and validation of PRO measures as a means of demonstrating the value of medical products and services. Email:

Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 31

Behaviour Programmes

Quantification of Adherence Initiatives Results “Drugs don’t work in people that don’t take them” – C. Everett Koop, Former US Surgeon General It is proven that most chronic drugs work well in a clinical trial environment. However, with compliance rates of 50%, they do not necessarily have the same effect in “everyday” environments. Companies discover that potential benefits of resolving poor compliance issues are very appealing, such as the impact it could have on sales for pharmaceuticals and pharmacies. However, the risk highlighted above by the former US Surgeon General is that, due to poor adherence rates averaging around 50%, there is sufficient concern that drugs do not work half of the time – the times when they’re not taken! Right below is a fundamental checklist for “Planning a Quantified Adherence Solution”, but allow me to diverge just for a moment. Imagine the following scenario: Doctor Smith prescribes a 10mg product for a chronic disease. Our patient immediately fills the script at a pharmacy. Six months later our patient returns to the doctor, who discovers (after taking some biometric readings) that his disease control levels are appalling. Consequently, the doctor increases the dosage to 20mg. The patient revisits his pharmacist, who, to his dismay, refuses to dispense. Resentfully, the patient complains to the doctor, who then angrily phones the pharmacist to confront him directly: “How dare you?” The pharmacist calmly replies: “Doctor, I am not sceptical about your diagnosis or the product you prescribed, but the dosage was not the problem. I can see on my dispensing system that the patient has been filling scripts extremely irregularly. He was self-medicating, according to what he believed was symptoms. The problem here is compliance, not dosage. It would be unethical for me to allow an overdose...” Quantification of the various benefits of adherence programmes, as well as quantifying the possible risks in neglecting the adherence problem, is crucial in ensuring progress in the body of knowledge relating to improving the wellbeing of our patients. Browse over these numbers below and gauge how important it is to quantify some of these statistics from within your patient adherence programmes. Quantifying Market Penetration Adherence programs have managed to penetrate very small sections of the chronic markets across the globe. Adherence improvements that can be quantified are great, and indicate a workable solution. However it is necessary to measure, to which extent those adherence gains are extrapolated to a wider audience. Influencing just one or 32 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

two percent of a market with improved adherence, does not really improve on the negative global phenomenon of poor adherence. Nor does it seize the potential opportunities. Therefore pharmaceuticals - and their adherence partner companies - could be well served by adherence solution “penetration barometer” that both parties follow closely to monitor and manage toward improved market penetration and influence. In South Africa there are 50 000 “managed patients” that fill twice as many scripts (on average) within a year, as compared to family and friends that receive no patient support. At a monthly cost of less than €2.00 per patient. Dispenses to these patients have doubled (typically through improved persistence or ‘drug loyalty’, rather than frequency of script fills) since they were enrolled on a support programmes. Even though these numbers are quantified from pharmacy dispense data, this great result impacts only a fraction of the chronic market. Influence on the total market is a factor of the adherence gains achieved multiplied with the number of patients that had these adherence improvements. Market penetration, cost efficiency and improved adherence (visible in sales) are three key foundational measurements of success for patient adherence programs. Quantifying Influence Within patient relationships, it is possible to strongly influence patient behaviour towards improved disease outcomes in an ethical manner. Diabetes Type 2 patients on insulin report average HbA1c levels of 11% when they join our support programme. Within three to four months patients report a reduction in HbA1c levels to 7.6%. Being able to effortlessly produce these types of reports, and to validate them, is a very important measure of programme effectiveness. Evidently, it gives pharmaceutical companies something to sell: Our product works in the “real world”. And logically, it is possible to carry out studies to validate it further in order to obtain certified results that can be published. Such results are in stark contrast to the average adherence rates of chronic products that fail to be “packaged” with an adherence programme. Now, we are able to influence patients towards improved adherence, as well as influence doctors regarding “real world efficacy”. Improved disease outcome results are significant, but only 4000 diabetes patients in South Africa are currently on operative diabetes support programmes. Another group is on support programmes where results aren’t actually clear. Hence, these patients are left to support themselves, and as WHO data shows – they don’t: “pharmacy records to show that patients with type 2 diabetes averaged about 130 days per year of continuous drug therapy, and that at the end of 1 year, only 15% of the patients who Volume 2 - Issue 2

Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 35

Behaviour Programmes had been prescribed a single oral medication were still taking it regularly.” (Edited by Eduardo Sabaté, Adherence to Long Term Therapies: Evidence for Action. 2003. Published by the World Health Organization.) Patient Profiles: “Disease management” in the chronic disease areas requires adherence as soup requires water. It is an essential ingredient. Good products with poor adherence rates do not produce positive disease outcomes. Therefore, once focused on quantifying disease management results, the next logical step is to empower doctors with adherence and disease outcomes information for their practices, as part of their disease management information. Quantifying results-per-practice allows doctors to be informed of – and therefore influence - patient behaviour regarding adherence. Doctors have always been able to script a product. Now they are able to ‘script’ adherence by ensuring that the patient is on a quality adherence programme that returns adherence data to the doctor. Doctors tend to be uninterested in enrolling patients on programmes just to never receive feedback from them again. Deploying software that can automatically update doctors on their patients’ adherence after they enrolled and consented strengthens the information available to the doctor to deliver quality disease management. Patients confirm to doctors the interactions they’ve had with disease educators, and doctors who receive quantified results for patients they care about can sense the value of the “Good Product with Good Adherence” submission. Even this is possible by quantifying how many patients are enrolled in adherence programmes by specific doctors. By doing this we are able to quantify the extent to which doctors believe that a patient adherence programme has value, and their “rate of enrolment.” The patient’s health profile in his or her file is no longer made up of diseases, symptoms and biometric readings. In addition, doctors now have a new, vital reading – their patient’s adherence. An authentic question for doctors might be whether it is ethical to script a product with an inherently low expectation of compliance, when a product that comes packaged with good compliance monitoring and management is available? Targeting and Segmentation: In our own experience it is possible to distinguish two groups of patients – those who incline towards non-adherence, and others who are likely to be adherent to the best of their ability. The latter invest the time to understand their disease and work together with their doctor for optimal results. Patients who DON’T take the initiative of dealing with their disease are the patients we should be devoting time to! Those that browse websites, read up about their disease(s), and download applications are the ones we expect to be compliant, since they’re taking the initiative. Yet, many adherence initiatives rather blindly invest in popular technologies. Has anyone quantified whether different patient populations are being correctly targeted based on their individual adherence rates? Are we perhaps investing 34 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

90% of funding into developing applications, portals, adherence programmes and media for the 50% that would have been adherent regardless, because they help themselves online? Would they have simply adhered by digesting some of the heaps of already available medical information on the internet? (And perhaps without any additional investment from pharmaceuticals?) This is a question which still begs an answer from the research community. Without the ability to either segment populations, or target the patients that really need adherence support, and without quantifying behaviour changes due to technology we deploy, we might inevitably be ‘preaching to the converted’. We might simply be offering more technology to patients who are already assisting themselves online or electronically. This does not mean we’re sceptical about technology, just increasingly dedicated to focus it where it matters. Return on Investment: Adherence initiatives require a service provider to reach patients and influence behaviour at a reasonable cost. Two Key Performance Indicators we use to calculate ROI are: - Cost-per-patient, and - Additional-sales-per-patient The inability to measure these two parameters is a reminder of the days where marketing was simply advertising with flyers, on TV, or an advertisement in a magazine. The shotgun approach to marketing was the best we had at the time, but we could not count how many extra boxes were sold because of the advertisement. We knew the cost, but often not the return. Adherence programmes that have a well-known cost, but unknown returns (in terms of additional sales) are sooner or later likely to be questioned for their lack of proven ROI. Cost can be drastically influenced by ensuring operational efficiency at the adherence service provider’s offices – another important aspect which should be quantified and used operationally for process improvement. Downstream Costs In our company’s history we have had remarkable feedback from country heads (CEOs) of multinational pharma companies. During one meeting and after five minutes of presentation, a gentleman got up, walked out and stated “This is a no-brainer. Please get it going.” The words were directed at his marketing director after he saw compliance gains quantified in real sales data. This power to convince stakeholders with quantified results is within reach of pharma companies. Pharmaceuticals can further use their adherence programmes with good, quantified results, to engage funders regarding reimbursement issues. If pharma proves via its adherence programmes that their drugs work on a large scale in ‘everyday’ environments, and can track reduction in e.g. cardiac events because of controlled hypertension, or reduced hospital days for diabetics because hypo- and hyperglaecemias are prevented, products might make more sense of a funder’s formulary. Generic manufacturers that have very low-cost products, and are yet to find a cost-effective adherence solution to penetrate the “real world” non-compliant markets in which they operate, are at peril. Generic companies have Volume 2 - Issue 2

Behaviour Programmes opportunities to undercut prices, but probably don’t receive the financial capacity in the cost of a packet of tablets, to also fund compliance management for the patient taking it. There is sufficient data available to prove that lower cost have a strongly positive effect in improving adherence. In fact, in an article published 15 November 2011 by Fox News Latino, findings of a study led by Dr Niteesh Choudry of Brigham and Woman’s were published under the heading: “Give patients free medicine and many still won’t take it, study says.”

to electronically communicate this information to medical aids or insurance companies, doctors and doctor-networks, or pharmacies, allows pharmaceutical companies to differentiate themselves by delivering everyday-environment results, and drugs that work because … ‘people take them’.

A good adherence programme should be able to quantify baseline adherence rates, as well as improved adherence rates. Various means exist

Planning a Healthy Quantified Adherence Programme Planning a good adherence programme that doctors can participate in actively, as described above, requires very specific tools, software and process management. Below we provide a rough checklist we propose for assessing the quantification needs for adherence programmes: 1. Does your programme have quantifiable baseline compliance on your products? (You can visit www. to download free compliance and persistence data for thousands of brands.) 2. Can you accurately quantify improved compliance? 3. Can you track improvement in disease outcomes? 4. Can your pharmaceutical sales force detail doctors about how your product has impact in the everyday environment because of clinically-efficient adherence rates? 5. Can you prove to medical aids / funders that your compliance solution reduces hospitalisation costs? 6. Can your sales team give doctors feedback on how your programme improved compliance and disease outcomes per practice? 7. Can you expand your programme internationally, yet retain the power to quantify results across borders even with customised local programmes? Summary We are familiar with the axiom: “You can’t manage what you can’t measure”. Measuring market penetration, improved compliance against baseline, disease outcomes, and hospitalisation days, allows you to engage with stakeholders on a completely new level of value than what was previously possible. Doctors, funders, pharmacies and sales forces become part of your adherence team. The ability

to do this with transactional or patient-reported information. This example was generated ‘by the click of a button’, from pharmacy dispense data, and show that supported (blue) patients filled substantially more scripts than unsupported (red) patients. Specific support services may strongly influence these results.

Cassie Schutte started working with Hoechst Marion Roussell (HMR) in 1998 in their IT department. He supported several business critical systems including decision support systems, sales management, financial, and telecoms systems. Following HMR’s merge with Rhone Polenck Rhorer (RPR) to become Aventis, and the subsequent merge between Aventis and Sanofi-Synthelabo, he quickly developed into the Head of IT for the South African operation by 2003. In 2006 he joined the small startup firm Health Window with 7 employees as investor and marketing manager. In 2007 he took on the role of CEO and started building a market leading organization, currently with 64 staff, and clients including the largest pharmacy groups in South Africa, and multi-national pharmaceutical companies including Astra-Zeneca, Boehringer Ingelheim, Eli-Lilly, Novartis, Pfizer, Sanofi and several others. Email:

Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 35

Clinical Trials The Moral Imperative of Improving Patient Adherence to Pharmacotherapy for Cardiodiabesity, Part 2: A Focus on Cardiovascular Disease Introduction This is the second paper in a series addressing the moral imperative of improving patient adherence to pharmacotherapy for cardiodiabesity. The first paper, published in the previous issue of this journal1, focused on type 2 diabetes mellitus, and this paper focuses on cardiovascular disease (CVD). As noted in the earlier paper, while the term cardiodiabesity2,3 has not currently gained the same traction as some other relatively recent additions to the biomedical lexicon, it effectively captures three chronic and interrelated diseases of enormous relevance to global public health: obesity, diabetes, and CVD. Given their inter-relatedness and the high occurrence of comorbidities, ultimate prevention and treatment considerations must adopt an integrated perspective, which will be discussed in a later paper in this series. Nonetheless, as a first step, addressing the diseases individually can be instructive. Following discussions pertinent to CVD medication adherence specifically, some pragmatic suggestions from the previous paper that generalise to this domain are recapped. It should be noted that, since both authors work in the United States, statistics presented are from US-based associations. The points made, however, readily translate to other countries. Cardiovascular Disease The term CVD covers many diseases including hypertension, coronary heart disease, heart failure, and stroke. The American Heart Association’s “Heart Disease and Stroke Statistics: 2010 Update”4 presented data from 2006 to estimate the likely occurrence of CVD in 2010. On the basis of 2006 mortality rate data, nearly 2300 individuals die of CVD each day, which represents an average of one death every 38 seconds. Coronary heart disease caused approximately one out of every six deaths in 2006. It was estimated that, in 2010, 785,000 individuals would have a new coronary attack, and 470,000 would have a recurrent attack. It is estimated that an additional 195,000 silent first myocardial infarctions occur each year. Such figures led to the statement that “every 25 seconds, an American will have a coronary event, and approximately every minute, someone will die of one.” With regard to stroke, each year approximately 795,000 people experience a new or recurrent stroke. Approximately 610,000 of these are first attacks, and 185,000 are recurrent attacks. Mortality data from 2006 indicate that stroke accounted for approximately one out of every 18 deaths in the United States. On average, every 40 seconds, someone has a stroke. Finally, approximately 11% of all death certificates in 2006 mentioned heart failure. Projecting likely increases in CVD is even more concerning. Currently, as the leading cause of death, CVD is responsible for 17% of US health expenditure. However, “these costs are expected to rise substantially” in the next two decades.5 By 2030, 40.5% of the population is projected to have some 36 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

form of CVD. Using methodology to project future costs of care for CVD that avoided ‘double counting’ of costs for patients with multiple cardiovascular conditions, the authors projected that between 2010 and 2030 the total direct real medical costs (calculated in 2008 US$) would triple from $273 billion to $818 billion. Real indirect costs due to lost productivity for all CVD were estimated to increase from $172 billion to $276 billion, an increase of 61%.5 Non-adherence to Pharmacotherapy for Cardiovascular Disease Howran6 defined the term adherence as one used to describe “the extent to which an individual’s behavior coincides with health-related instructions or recommendations given by a healthcare provider in the context of a specific disease or disorder.” He also emphasised that adherence is as fundamental a component of effective healthcare as the treatment regimen itself. The available and growing evidence on non-adherence supports this statement and highlights the association of non-adherence with adverse outcomes and healthcare expenditure. Two rapidly growing drivers for the escalating incidence and prevalence of heart disease are obesity and an aging population. In turn, these are closely aligned with factors driving non-adherence, including a growing number of people taking medication for chronic conditions: nonadherence for chronic conditions is noted to be higher than for acute conditions.7 The risk for non-adherence begins with the transition period from hospital discharge to the outpatient setting and continues to increase over time. In the setting of secondary prevention after hospitalisation for acute coronary syndrome, patients self-reported the use of cardioprotective medication over six to twelve months as low. Whereas 71 % of patients reported persistent aspirin use, less than half of these same patients reported persistent use of beta-blockers (46%), lipidlowering agents (44%), and all three medications (21%).8 When these data were further analysed to include the effect on clinical outcomes, the groups with the highest risk of poor outcomes were the ones with the least consistency of use of evidence-based therapies: The elderly and patients with diabetes and evidence of heart failure were amongst those groups. Barriers to Adherence Hypertension is another risk factor for other cardiovascular diseases and comorbidity in the triad of obesity, diabetes, and cardiovascular disease. It is a unique risk factor because, despite the devastating end-organ complications of the disease (e.g., myocardial infarction, stroke, and end-stage renal disease), in the majority of patients it is not associated with obvious symptoms. In addition, patients often associate the use of antihypertensive medications with side-effects and no noticeable symptom relief. Examining the patterns Volume 2 - Issue 2

Clinical Trials of adherence to an antihypertensive regimen highlights the common barriers for medication adherence and those unique to cardiovascular medications. Major predictors of non-adherence to medication in general encompass factors under the patient’s control, those that involve the patient-provider interaction, and those directly related to the healthcare system. These predictors include treatment of asymptomatic disease, side-effects of medications, lack of belief in the benefit of treatment, lack of patient insight into the disease, cost of medication, inadequate follow-up or discharge planning, complexity of treatment, and a poor provider-patient relationship. With specific regard to antihypertensive therapy, a unique factor is that self-monitoring of blood pressure has been shown to enhance adherence.9 Decreasing the number of doses of medication has also been shown to be of greater importance in encouraging adherence than decreasing the total number of medications.10 In a subset of particularly challenging patients for both general practitioners and the cardiologists, i.e., those with refractory hypertension, a study using micro-electronic monitors resulted in more than 30% having controlled blood pressure as a result of monitoring, and the identification of another 20% of patients that had lapsed adherence.11 Interventions to Improve Medication Adherence In an environment where escalating costs and decreasing resources are at the forefront of almost every healthcare discussion, complying with treatment guidelines and developing strategies to address known risk factors is increasingly important. Improving patient adherence to medication regimens is a means of greatly facilitating decreasing costs, and it needs to be addressed at the three different levels already noted: the patient level to give patients self-empowerment, the patient-provider interaction level, and the level of healthcare systems. One system that is used by the authors’ company to engage patients is an online service, MediGuard,12 that provides a forum to empower patients with knowledge about their medications, conditions, and other risk factors such as age and sex. It currently has over 2,500,000 members. Also, using this service, knowledge about patients can be collected and analysed to identify differences in adherence amongst patient populations and, in turn, enable healthcare providers to offer a customised plan to improve outcomes of interventions that address non-adherence.13 It has been noted that omissions of doses and delays in the timing of doses make up the majority of errors in medication-taking behaviour. Directly related to this finding is that adherence is inversely proportional to the frequency at which a medication is administered.7 Recommending that providers prescribe less complex regimens is one application of this knowledge. A recent paper by Goodyear-Smith and colleagues14 investigating the patient-provider relationship included discussions of patients’ preferences for communicating benefit of cardiovascular medication. The overall indication was that more than 60% of participants preferred a doctor’s opinion about a medication instead of an explanation of risk. When risk is presented, more than half preferred a pictorial representation of treatment benefit. If numbers are used, 38 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

two-thirds of the participants preferred relative risk over other ways of presenting the same data.14 These findings highlight the need for improved communication between providers and their patients, and the development of tools that adequately emphasise risks and outcomes of diseases. Providers also need to be aware of the health literacy of their patients and direct their communication accordingly. Ratzan and Parker15 defined health literacy as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.” In 1998 the National Academy on an Aging Society released estimates of the cost of limited health literacy to the US healthcare system as between $50 and $73 billion per year.16 A specific indicator in the cardiovascular population that highlights its importance here is that nearly half of the elderly population score in the lowest skill level of literacy.15 Healthcare systems also need to be cognisant of their role in either perpetuating or addressing this costly problem. The American Heart Association has partnered with the American Diabetes Association and the American Cancer Society to establish a programme for outpatient practices entitled The Guideline Advantage.17 It is offered at no cost to healthcare providers to provide them with updated information about best practices and emerging scientific knowledge. In parallel, there is online patient education to assist patients in taking an active role in the management of their health. There are patient and consumer education brochures to help prevent and manage disease. Another wide-reaching programme is the Script Your Future initiative that was introduced in May 2011 by US Surgeon General Dr Regina M. Benjamin in conjunction with the National Consumers League when launching the Medication Adherence Awareness Campaign.18 It is focused on addressing the estimated $290 billion cost of poor adherence to medications with resources to help patients and healthcare professionals in three disease areas, including CVD, diabetes and respiratory disease. The success of this initiative will be evaluated using a baseline survey to measure consumers’ awareness of medication adherence as a health issue, and then again at the end of the three-year campaign. This initiative was discussed in more detail in the first paper in this series.1 The Future of Cardiovascular Agents Two targeted areas of development for CVD medications are directly related to age being the most significant risk factor for CVD, as well as the increased survival from myocardial infarction that has contributed to the expanding population of atrial fibrillation and heart-failure patients. The emergence of three new oral anticoagulants (OACs) onto the market comes with high expectations to address the pitfalls of warfarin use in atrial fibrillation, and particularly its narrow therapeutic range and food-drug interactions that require frequent monitoring. The need for alternative agents was highlighted in a recent article by Budnitz and colleagues19 that lists warfarin as the number one drug responsible for adverse drug events in older Americans. These three new agents have been found to be as effective as warfarin in decreasing thromboembolic stroke risk from nonvalvular Volume 2 - Issue 2

Clinical Trials atrial fibrillation, while also addressing warfarin’s unique challenges. While the focus of this series of papers is on patient nonadherence, two recent reports address the degree to which patients are prescribed OACs by physicians in accordance with practice guidelines. These guidelines recommend OACs for atrial fibrillation patients at moderate/high risk of stroke.20,21 Antiplatelet or no therapy is recommended for those at low/ moderate risk. Ogilvie et al.20 conducted a PubMed literature search (years 1994-2010) to identify ‘real-world’ studies of clinical event rates for atrial fibrillation patients receiving OAC therapy, antiplatelets, or no therapy. Event rates were extracted for each treatment and setting. Patients receiving antiplatelet/no therapy had higher rates of ischaemic stroke than OAC-treated patients. Bleeding rates were similar between the groups. Wilke et al.21 analysed claims-based data for more than 180,000 atrial fibrillation patients from two large mandatory German medical insurance funds for the year 2008. The authors noted that “On between 40.5 and 48.7% of the observed patient-days, there was no antithrombotic protection by OAC, other anticoagulants, or aspirin.” The risk of OAC under-use varied by patient group. Older female patients with a high number of comorbidities had a higher risk of OAC under-use, while patients who had already experienced a thromboembolic event had a lower risk of OAC under-use. Taken together, the papers concluded that OAC under-use is widespread, it is associated with severe clinical consequences, and increasing utilisation of anticoagulants in clinical practice could improve patient outcomes.20,21 Heart Failure There is a paucity of new agents for heart failure and a growing need to find new therapeutic agents that improve short-term outcomes to address the frequent rehospitalisations that accompany this condition. The latter is being addressed by exploring new clinical trial designs to improve the number and accuracy of enrolment of the appropriate patients. In the current setting, telemonitoring devices and heart-failure clinics have been at least partially successful, but acute decompensated heart failure remains the most common reason for unscheduled hospitalisations in patients over 65 years of age.22 Statins Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, more commonly known as statins, are widely available, inexpensive, and a potent therapy for treating elevated cholesterol.23 Data from many sources provide compelling evidence for the use of statins for primary and secondary prevention.23-25. Lewis25 observed that “If correctly dosed in appropriate patients, currently approved statins are generally safe and provide significant cardiovascular benefits in diverse populations, including women, the elderly, and patients with diabetes.” Approved agents include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, and rosuvastatin. As with other classes of drugs, non-adherence to statins is a considerable problem, and one addressed by many authors. Schedlbauer et al.26 observed that increased patientcentredness, placing emphasis on patients’ perspective and

shared decision-making, might be useful when searching for tools to encourage patients to take lipid-lowering medication. The general theme of educating patients on the nature of their disease and the need for taking medications as prescribed also occurs in other publications in the literature.27 Mann et al.28 discussed various sociodemographic, medical, and healthcare utilisation characteristics associated with statin non-adherence. Age had a U-shaped association with adherence, with the youngest and oldest subjects having lower adherence than middle-aged subjects. Women and patients with lower incomes were more likely to be non-adherent than were men and those with higher incomes. A history of CVD and a diagnosis of hypertension or diabetes were associated with better adherence. Mauskop and Borden29 observed that influences on patient adherence include patient factors (demographics, socioeconomic status, comorbidities, and sideeffects), physician factors (the physician’s own adherence to applying guideline recommendations, office visits, and their interactions with patients), and healthcare factors (including cost and access to care), and there are often interactions between these categories. There are clearly many avenues to be pursued to address these influences. Residual Risk The term residual risk is used to describe the remaining cardiovascular risk in patients aggressively treated with statins for primary and secondary prevention. One class of agents that has received significant attention is the cholesteryl ester transfer protein (CETP) inhibitors. These are therapeutics targeted at raising high-density lipoprotein cholesterol (HDLc) levels. The inverse relationship between HDLc (the “good cholesterol”) and CVD risk suggested that increasing HDLc could potentially reduce the disease risk.30 CETP inhibitor development began with torcetrapib, which was demonstrated to inhibit the development of atherosclerosis in non-clinical studies (a rabbit model), and, in early-phase clinical studies, to increase HDLc by 60% to 100% while at the same time lowering low-density lipoprotein cholesterol (LDLc, the “bad cholesterol”) by up to 20%.31 This evidence suggested a cardioprotective effect of torcetrapib. The Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial tested the proposition that torcetrapib would reduce the risk of clinical cardiovascular events. However, torcetrapib was associated with an increased risk of major cardiovascular events, and also increased mortality (from both cardiovascular and non-cardiovascular causes). The drug’s sponsor terminated ILLUMINATE prematurely at the recommendation of the trial’s independent steering committee, based on advice from the Independent Data and Safety Monitoring Board.32 Thus, paradoxically, two highly regarded biomarkers for reduced cardiovascular risk, increased HDLc and decreased LDLc, were associated with an increased risk of clinical cardiovascular events (although it was a theoretical possibility that the putative relationships were incorrect.)33 An off-target response to torcetrapib was increased blood pressure. Twelve months into ILLUMINATE, systolic blood pressure had increased from baseline by a mean of 5.4 mmHg in the torcetrapib group. However, various aspects of blood pressure increases and the baseline values from which the Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 39

Clinical Trials increases were seen made clear statements of blood pressure effects difficult.32 Subsequent animal and clinical studies have shown that “the increase in cardiovascular mortality reported with torcetrapib was molecule specific and independent of its CETP inhibition effect.”30 Two other CETP inhibitors, dalcetrapib and anacetrapib, were well tolerated in Phase I and II clinical trials and, unlike torcetrapib, did not affect blood pressure and aldosterone levels. Since none of the drugs in class has yet been marketed it is not possible to comment on adherence to them. Additional citations concerning the development of CETP inhibitors are provided.34-37 Concluding Comments Influences impacting adherence to cardiovascular drugs reflect many of those reviewed in the first paper in this series, which addressed non-adherence to antidiabetic drugs for type 2 diabetes mellitus.1 Individual characteristics are also present. As noted earlier, the use of home blood pressure monitoring is specific to increasing adherence to antihypertensive agents, and similar specificity was noted in the first paper with regard to administering insulin in a pre-filled pen compared with a vial/syringe.38 There is convincing evidence in the literature that medical visit communication is associated with patient outcomes, and that appropriate communication enhances adherence.39 Accordingly, Turner and Strumph1 noted that physicians must become very well trained in the behavioural and educational/ communication sciences. This will enable them to help their patients to become as knowledgeable as possible about their disease and the full ramifications of non-adherence to prescribed medication regimens. Patients must be given detailed information and counselling on strategies aimed at facilitating adherence. Another factor is the activity of biopharmaceutical companies in addressing non-adherence. The cost of bringing cardiovascular agents to market is a strong incentive for them to maintain a vested and growing interest in adherence to regimens including their medications. The commitment of other players in the healthcare arena to provider and patient education, and acknowledgement of the role that medication adherence has with regard to the implementation of evidence-based medicine to address risk factors and improve outcomes, will also be extremely important. It is a moral imperative to improve patient adherence to pharmacotherapy for cardiodiabesity. References 1. The moral imperative of improving patient adherence to pharmacotherapy for cardiodiabesity. Part I: A focus on type 2 diabetes mellitus. Journal for Patient Compliance. 2012;2(1):32-36. 2. w (Accessed March 20, 2012) 3. w Newsletters/200810.pdf (Accessed March 20, 2012) 4. Lloyd-Jones D, Robert J. Adams RJ, Brown TM, et al. Executive Summary: Heart Disease and Stroke Statistics—2010 Update. Circulation. 2010;121:948-954. 5. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting 40 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

the future of cardiovascular disease in the United States: A policy statement from the American Heart Association. Circulation. 2011;123:933-944. 6. Howren MB, 2012, Patient Adherence. In Gellman M, Turner JR (Eds), Encyclopedia of Behavioral Medicine. New York, Springer, in press 7. Osterberg L and Blaschke T. Adherence to medication. New England Journal of Medicine, 2005;254:487-497. 8. Newby LK, LaPointe NMA, Chen AY, Kramer JM, Hammill BG, DeLong ER, Muhbaier LH, Califf RM. Long-term adherence to evidence-based secondary prevention therapies in coronary artery disease. Circulation, 2006;113:203-212. 9. Feldman R, Bacher M, Campbell N, Drover A, Chockalingam A. Adherence to pharmacologic management of hypertension. Canadian Journal of Public Health, 1998;89:116-118. 10. Eisen SA, Miller DK, Woodward RS, Spitznagel E, Przybeck TR. The effect of prescribed daily dose frequency on patient medication compliance. Archives of Internal Medicine, 1990;150:1881-1884. 11. Burnier M., Schneider MP, Chiolero A, Stubi CL, Brunner HR. Electronic compliance monitoring in resistant hypertension: the basis for rational therapeutic decisions. Journal of Hypertension, 2001;19:335-341. 12. (Accessed March 22, 2012) 13. Cascade E, Cousins F, Connor U, Sandy R. Variance in medication adherence by patient behavioral segment: A multi-country study in hypertension. Accepted for presentation at ISPOR 2012, Washington DC. 14. Goodyear-Smith F, Kenealy T, Wells S, Arroll B, Horsburgh M. Patients’ preferences for ways to communicate benefits of cardiovascular medication. Annals of Family Medicine, 2011;9:121-127. 15. National Library of Medicine. Current bibliographies in medicine 2000-1. Health Literacy. archive//20061214/pubs/cbm/hliteracy.html. (Accessed March 20, 2012) 16. Friedland RB. Understanding health literacy: new estimates of the costs of inadequate health literacy. Washington DC: National Academy on an Aging Society; 1998. 17. (Accessed March 20, Volume 2 - Issue 2

Clinical Trials

2012) 18. (Accessed March 20, 2012) 19. B  udnitz D, Lovegrove M, Shehab N, Richards C. Emergency hospitalizations for adverse drug events in older Americans. New England Journal of Medicine, 2011;365:2002-2012. 20. O  gilvie IM, Welner SA, Cowell W, Lip GY. Ischaemic stroke and bleeding rates in ‘real-world’ atrial fibrillation patients. Thrombosis and Haemostasis. 2011;106(1):34-44. 21. W  ilke T, Groth A, Mueller S, et al. Oral anticoagulation use by patients with atrial fibrillation in Germany. Adherence to guidelines, causes of anticoagulation under-use and its clinical outcomes, based on claims-data of 183,448 patients. Thrombosis and Haemostasis. March 8 2012 [Epub ahead of print] 22. A  dams KF, Lindenfeld J, Arnold JMO, et al. Executive summary: HFSA 2006 comprehensive heart failure practice guideline. Journal of Cardiac Failure, 2006;12:10-38. 23. M  inder CM, Blaha MJ, Horne A, et al. Evidence-based use of statins for primary prevention of cardiovascular disease. American Journal of Medicine. 2012 Mar 1. [Epub ahead of print] 24. T  onelli M, Lloyd A, Clement F, et al. Alberta Kidney Disease Network. Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis. Canadian Medical Association Journal. 2011;183(16):E1189-1202. 25. Lewis SJ. Lipid-lowering therapy: who can benefit? Vascular Health and Risk Management. 2011;7:525-534. 26. Schedlbauer  A, Davies P, Fahey T. Interventions to improve adherence to lipid lowering medication. Cochrane Database of Systematic Reviews (Online). 2010;(3):CD004371. 27. G  ialamas A, Aylward P, Vanlint S, Stocks NP. Cholesterol lowering medication - patients’ knowledge, attitudes and experiences. Australian Family Physician. 2011;40(7):519522. 28. M  ann DM, Woodward M, Muntner P, Falzon L, Kronish I. Predictors of nonadherence to statins: a systematic review and meta-analysis. Annals of Pharmacotherapy. 2010;44(9):1410-1421. 29. M  auskop A, Borden WB. Predictors of statin adherence. Current Cardiology Reports. 2011;13(6):553-558.

30. Ghosh RK, Ghosh SM. Current Status of CETP Inhibitors in the Treatment of Hyperlipidemia: An update. Current Clinical Pharmacology. March 20, 2012 [Epub ahead of print] 31. Rader DJ. Editorial. Illuminating HDL — Is it still a viable therapeutic target? New England Journal of Medicine. 2007;357:2180-2183. 32. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. New England Journal of Medicine. 2007;357:2109-2122. 33. Cohen O, Smith B, Stocum M, Verst C. Commentary: Building value through biomarkers: The “Smarter Development” imperative. Drug information Journal, in press. 34. Robinson JG. Dalcetrapib: A review of Phase II data. Expert Opinion on Investigational Drugs, 2010;19:795-805. 35. Hooper AJ, Burnett JR. Anacetrapib, a cholesteryl ester transfer protein inhibitor. Expert Opinion on Investigational Drugs. 2012;21:103-109. 36. Sirtori CR, 2011, Investigational CETP antagonists for hyperlipidemia and atherosclerosis prevention. Expert Opinion on Investigational Drugs. 2011;20:1543-1554. 37. Boettcher MF, Heinig R, Schmeck C, et al. Single-Dose Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of BAY 60-5521, a Potent Inhibitor of Cholesteryl Ester Transfer Protein. British Journal of Clinical Pharmacology. 2012;73(2):210-8. 38. Buysman E, Conner C, Aagren M, Bouchard J, Liu F. Adherence and persistence to a regimen of basal insulin in a pre-filled pen compared to vial/syringe in insulin-naive patients with type 2 diabetes. Current Medical Research and Opinion. 2011;27(9):1709-1717. 39. Roter D, Hall JA, 2012, Doctor-patient communication: Why and how communication contributes to the quality of medical care. In Gellman MD, Turner JR (Eds), Encyclopedia of Behavioral Medicine, New York: Springer, in press. Adrienne L. Richards, MD, is Associate Medical Director, Cardiovascular and Metabolic Therapeutic Delivery Unit, Quintiles. Prior to joining Quintiles in 2010, she practised as a non-invasive cardiologist for almost a decade. She is a fellow of the Stanley J. Sarnoff Endowment for Cardiovascular Science and was honored for her Sarnoff research year with The Dr. Harold Lambert Biomedical Research Prize. Email: J. Rick Turner, PhD, is Senior Director, Integrated & Translational Cardiovascular Safety, Quintiles. He is a clinical triallist, Editor-in-Chief of the Drug Information Journal, a Senior Fellow at the Center for Medicine in the Public Interest, and a Fellow of the Society for Behavioral Medicine. He is an author of more than 100 peer-reviewed papers and articles in professional journals, and has published 14 books. Email: The authors are members of Quintiles’ Cardiovascular and Metabolic Therapeutic Area Writing Committee. Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 41


Patient Empowerment – An Innovative Approach in Rare Diseases Approximately four million people in Germany are affected by rare diseases. Out of the 30,000 known illnesses, about 7000– 8000 are classified as rare diseases. All fields of medicine are affected by rare diseases. Deformity syndromes, psychiatric illnesses, metabolic disorders and storage diseases are examples.

Task group 3 specifically works on important themes for individual patients affected by lysosomal metabolic disorders. Among others, members are determining what a centre for rare diseases should ideally look like – that is, what prerequisites and facilities (personnel, know-how, equipment) it would need.

The rarity of an illness presents challenges to research and patient care, which the medical care system can only partially meet. To obtain lasting improvements, the EU Commission recommends that the EU member countries create national action plans for rare diseases by no later than 2013. Various measures were also taken in Germany; among them the founding of the National Action League for People with Rare Diseases (Nationales Aktionsbündnis für Menschen mit seltenen Erkrankungen = NAMSE). However, more than political commitment is needed – pharmaceutical companies and payers can also be an important part of the care network.

The goal is to define various levels of centres and networks, leading to recom-mendations for working methods as well as tasks and criteria for certification/quality management in this organisation.

Patient Care Needs Improvements The founding of NAMSE was based on a study by the Federal Ministry of Health which analysed current care for patients with rare diseases. It was implemented by the research group for health economics at the Leibniz University of Hanover. The objective of the investigation was to show the situation of affected persons to define improvement measures. The results show that quite a few things need improvements: so far, there are no confirmed diagnostic procedures and knowledge for many illnesses. Also, there is often no drug treatment available. Current payment systems for medical treatment also do not sufficiently consider how complicated and differentiated therapy may be in individual cases. There is often little information; patients tend to be unaware of their few options. These results clarify that it is not just the therapy for rare diseases which requires further improvements – availability of information and research support also needs to get better. Diagnosis times must also be shortened to secure future care for these patients – even beyond drug therapy. NAMSE NAMSE was founded in Germany on 08 May 2010 to implement these require-ments. The most important task of the action league is to improve the health situation of patients with rare diseases. Four different NAMSE task groups were formed to distribute tasks effectively. TG 1: Information management TG 2: Paths to early diagnosis of rare diseases TG 3: Treatment, centres, networks TG 4: Research 42 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

To obtain broad consensus, many relevant stakeholders in German healthcare are represented in the NAMSE task groups: representatives from 25 associations and organisations such as healthcare funds, doctors, ministries and patient representatives. Last but not least, the German Association of Researchbased Pharmaceutical Companies is also among them. Genzyme, a company in the Sanofi Group, is also included here. This biotechnology company concentrates on research and treatment for rare diseases, particularly lysosomal storage diseases and multiple sclerosis. Genzyme is an example of a company which not only provides medications, but participates in further improvements to healthcare structures. Action Goals of NAMSE: - Improve knowledge of the epidemiology of rare diseases - Support the spread of information about rare diseases - Shorten the diagnosis time - Improve outpatient and drug therapy options - Support research projects Changes to legal conditions are a first step. But it takes time for affected persons to actually feel the changes. Patients, however, usually need immediate help. Operative support can often be realised faster to provide speedy assistance, e.g. in specialised centres. Cooperation is Needed Care for patients with rare diseases such as lysosomal storage diseases often places particularly high demands on knowhow and structures. Comprehensive, holistic patient care is needed. But doctors often do not have the time in everyday practice work and especially in these complex illnesses to deal comprehensively with patient concerns beyond drug therapy and medical problems. This gap must be closed. There are specialised centres for this purpose which have the required comprehensive knowledge: experts regularly engage in national and international exchanges, and form networks, ensuring a flow of scientific information. Multidisciplinary teams of treating personnel cooperate in diagnostics, disease monitoring and therapy and document the results – some in large disease-specific registries. Volume 2 - Issue 2

Therapeutic But the basis for comprehensive care of patients with rare diseases lies in cooperation between the centre, the treating physician and the patient. Patients and treating physicians should use centre expertise to guarantee constant optimal care. To monitor disease progression and react quickly to changes, patients should come in to centres for regular check-ups. Close contact between the treating physician and the experts is also desirable for comprehensive care for these diseases. The example below shows what such a project can look like. In view of short-term support requirements, the Expert Centre for Rare Metabolic Disorders at the Charité Berlin initiated a coaching programme which is specifically oriented to the needs of patients with Gaucher and Fabry Disease. Health Coaching – a Pilot Project The conditions for which the Expert Centre for Rare Metabolic Disorders provides ideal prerequisites which are important in a patient care programme: the specialised centre is interdisciplinary – experts from various fields work together closely. The bundled knowledge, especially about Gaucher Disease and Fabry Disease, makes it possible to give patients comprehensive holistic care and recognise needs early. In this way the coaching programme was optimally developed to meet the wishes and needs of patients with these rare diseases. It is difficult for doctors to meet all of their patients’ needs – even those which go beyond medical care. This project, in which patients are supported by specifically trained health coaches, can help them find ideas for optimally managing their illness. Earlier discussions with patients showed that there is a special need for support in the areas of physical exercise, nutrition, disease coping, and social affairs questions in the healthcare system. The goal of the programme is to allow patients to better manage the special challenges of their illness and handle common everyday problems. The project strengthens self-competence (patient empowerment) and adherence, improving long-term quality of life. The coaching programme for Gaucher and Fabry patients was initiated by the Expert Centre for Rare Metabolic Disorders, and is supported by the company Genzyme started as a pilot project in the Berlin region in 2012. Practical Implementation The programme was developed and implemented with the support of the service provider Pharmexx, which brought specifically trained health coaches to the project. These experienced patient care-givers each have four appointments with the participant; coaches visit them at home or another location desired by the participants to support them in handling their disease. Patients who received information about the coaching programme from their treating physician were able to register themselves for the project through Pharmexx. Before the project started, an informational meeting was held for physicians and patients at the Charité Berlin. Every participant had an individual choice of four different themes: managing the disease, physical exercise, nutrition and social affairs questions in the healthcare system (see figure). Since coaching is oriented to the patient’s 44 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

personal needs and questions, no fixed theme schedule was provided, and participants were given the option to select focal themes themselves.

Finally, the Charité evaluated acceptance among doctors and patients to recommend whether the project should continue and how to develop it further. In particular, questions asked during the project are helping to address patient needs more closely in the future. The feedback which the Charité received showed that patients have responded positively to the pilot project and were satisfied with the additional care offerings.

Figure: Pilot project set-up; KAM = Key Account Manager, CSA = Customer Sales Associate (Sales Force)

Genzyme supported the initiative of the Charité Berlin within its LysoSolutions® project, so that participation in the coaching programme was offered to patients free of charge. With its many years of experience in the field of lysosomal storage disorders, the biotechnology company recognised the high value of continuous information flow and the need for special service offers. It therefore offers complex options for supporting both patients and doctors under the umbrella of the LysoSolutions® service. With this continuous Volume 2 - Issue 2


commitment, the company, for instance, actively supports an exchange of experiences between experts and patients, allowing it to provide extensive support which is tailored to actual needs. Expert Centre for Rare Metabolic Disorders The Expert Centre for Rare Metabolic Disorders organises interdisciplinary diagnosis, treatment and scientific research into rare metabolic disorders in adults. The goal of the Expert Centre is to provide comprehensive diagnostics and therapy for patients with rare metabolic disorders. Continuous holistic care with specialised, experienced service providers is enabled through interdisciplinary networking at the Charité Berlin. The scientific environment makes it possible to collect knowledge to continue improving diagnostics and therapy for rare diseases. Gaucher Disease and Fabry Disease – two examples of rare diseases Lysosomal storage disorders are rare genetic disorders due to a lack of specific enzymes which are responsible for the degradation of various substrates in a healthy metabolism. In patients with lysosomal storage disorders, these enzymes are formed insufficiently or not at all. Certain metabolic products are then no longer degraded and continue to be stored in the lysosomes. This leads to cell damage and dysfunction, and later, failure of various organ systems.

Gaucher Disease is an autosomal recessive hereditary disorder, which is caused by the defect of the lysosomal enzyme beta-glucocerebrosidase. As a result, ß-glucocerebrosidase activity is insufficient to prevent accumulation of glucocerebroside in the cells. With increasing accumulation, glucocerebroside-engorged macrophages, termed “Gaucher cells”, most commonly collect in the spleen, liver and bone marrow organs, causing progressive multisystem organ damage. The protruding abdomen which is caused by organ enlargement is a typical sign of Gaucher Disease.

Fabry Disease is caused by a defect in the gene for the lysosomal enzyme alpha-galactosidase A, which is located on the X chromosome. Due to reduced or absent activity of alpha-galactosidase A, lipid substances (glycosphingolipids) are no longer split and collect in tissues throughout the entire body. This process (glycosphingolipid accumulation) causes life-threatening clinical symptoms in the kid-neys, heart and brain. The first symptoms of Fabry’s Disease are generally in childhood, with pain, fever, hypohidrosis, fatigue and movement intolerance. However Fabry Disease is often undiagnosed until adulthood, when organ system damage has already taken place. Causal Therapy Biotechnologically produced enzymes for intravenous enzyme replacement therapy are available as causal therapy for both lysosomal storage disorders. Diagnosis and intravenous enzyme replacement therapy generally take place at the Expert Centre. With stable progression, enzyme replacement therapy, which is administered at 14-day intervals, can be continued under the control of a general practitioner (GP) or dialysis physician. References Birgit Bering has worked with several international research companies in the pharmaceutical industry in various indications and for various products in the marketing field since 1986. Ms. Bering has worked with Genzyme, first in the marketing field, since 2002, followed by work as Health Care Service Manager for Lysosomal Storage Disorders since October 2010. Her responsibility focuses on developing integrated communication concepts and developing new services in the field of lysosomal storage disorders. E-mail:

Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 45

Modern Technology

Trends in Electronic Compliance Monitoring The idea that patients tend to be poorly compliant with prescribed medication (and other therapies) has been around for hundreds of years, but despite this, the phenomenon has been (and still is) poorly understood. The problem has been the lack of methodologies for studying this form of patient behaviour. It is only in the last two decades that progress has been made, and even that has been slow. Fortunately, help is on the horizon. The starting point for discussing patient compliance relates to information theory, which views all interventions as exercises in optimising a signal to noise ratio (S/N). The signal is the desired result of the intervention; the noise all the other variables that tend to obscure the signal. Does the result of the intervention stand out from the background? The goal is to maximise the S/N so the observer has confidence that what is being prescribed is actually benefitting the patient. This has obvious implications in the area of clinical trials of new pharmaceuticals, where the demonstration of efficacy and safety culminates in regulatory approval, something that translates directly to revenues. The signal, here, is the degree to which the drug does what it is designed to do – relieve the signs and symptoms associated with a disorder or disease. Does the T-cell count improve? Do the hallucinations disappear? Is the pain reduced? The signal, then, is usually clear-cut, at least for a clinical trial. The problem is the noise. There are myriad sources of noise that conspire to obscure the signal. Things like the age, sex, body mass, comorbid illness, alcohol use, other medications, individual difference in drug metabolism, activity level, etc. are but a few of such sources of noise. Since more noise translates into less confidence in the treatment, strategies are available to reduce noise. The classic drug trial (in its simplest form – there are many more sophisticated variations) involves collecting a group of patients with the disorder of interest, dividing them into two groups, and giving one group the drug and the other group a placebo. The S/Ns for the two groups are evaluated. Many statistical tests to assess this are literally signal-to-noise ratios. For example, the analysis of variance calculates an F-ratio, which is literally an S/N. The larger the F the more confidence that the drug is doing what it is supposed to do. In drug trials, confidence translates directly into regulatory approval and revenues. Collecting large groups of patients and running drug trials takes time and money. One way to improve this is to reduce the noise in a study, thus optimising the S/N. The ideal study would involve two groups of clones whose behaviours, physical characteristics and biochemistries were identical. The noise would reduce to near zero and the signal would stand out. Were such a study possible, few subjects would be needed to inspire confidence in the drug. Although this ideal scenario is impossible (at least currently), investigators do try to make the groups as homogeneous as possible, by such strategies as using only males or only females, excluding patients with 46 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

other illnesses or who are taking drugs that might interfere with the study, excluding substance abusers, using subjects from a narrow age range, etc. These all help bring the study close to the ideal and help optimise the S/N. However, one major source of noise is the differences between subjects in their compliance. Non-compliance has been documented extensively over the last 30 years to the point where it has become the elephant in the bedroom of clinical trials. Historically this was due to the lack of means of addressing it. Medication diaries, patient self-reporting and pill counting paid lip service to the issue, but are known to be ineffective. Fortunately, this is no longer the case, and the pharmaceutical industry is being dragged, somewhat reluctantly, to the altar of electronic compliance monitoring. Aardex pioneered the field with its MEMS™ vial cap to monitor patient compliance, and IMC developed its eCAP™. This format has been used extensively as it can be deployed in small-scale trials and pilots with little effort, and can also incorporate reminders to the patient to take their medication. The limitation of equating cap openings with pill-taking is that there are many scenarios where false events can occur. With the advent of blister packaging (itself touted as complianceimproving) the monitoring and recording of individual pill events took a large stride forward. Currently, electronically monitored blister-packaged medication is the state of the art, combining unit-dose monitoring with value-added features such as reminders and real-time patient input. Compliance Monitoring in Classical Clinical Trials The last five years have seen an increase in the use of vial cap monitors for small, locally-developed pilot projects and trials. The reason is that such studies do not have the funds to support blister packaging, but they can incorporate a compliance-monitoring cap through their local pharmacies. There is also increased interest in the use of time-to-take reminders as part of the cap. While the effectiveness of reminders has not been demonstrated empirically, the concept makes sense. On the down side, there is likely a modest risk associated with the use of reminders. Although the chance of a reminder cap’s electronics failing in a manner to give faulty next-dose instructions to the patient, and the patient following the instructions and having a clinically significant negative outcome, is vanishingly small, it cannot be dismissed entirely. With electronically enabled blister packaging, there has been a dramatic increase in interest on the part of large pharmaceutical companies in the last three years, with the momentum continuing to build. The idea of “what do we do with compliance data if it shows that subjects were poorly compliant” seems to have been put to rest and there is wider recognition that “cleaner” data (ie: less noise) is good all around. Part of this shift comes from pharmaceutical companies gaining confidence that compliance-monitoring Volume 2 - Issue 2

Journal For Patient Compliance Strategies to enhance Health Outcomes 37

Modern Technology systems are robust, reliable and here to stay; part from regulatory pressure to control for compliance; and possibly part from medico-legal concerns. The widespread adoption of ITT (intent to treat) designs makes getting a handle on non-compliance noise even more valuable from a return-oninvestment perspective. Vendors rarely hear “Who has used this?” any more. A number of large clinical trials are currently using electronic compliance monitor-equipped blister packages, and more are in the planning stages. Compliance Monitoring in Trials Using Subjects as Their Own Controls There is also an increasing trend in clinical trials research toward addressing the noise problem by using individual subjects as their own controls. This is an extension of the idea of the ideal study being comprised of clones. In the simplest case, an N-of-1 trial controls for the noise variables by comparing an individual subject’s response to the trial drug to the same subject’s response to a placebo. In theory, variables such as metabolism, biochemistry, activity level, etc. should be the same in both situations. With a low level of noise the signal will stand out. Of course this is a simplification. For example, there could be carry-over from one treatment condition to the next, or there might be order effects, either of which would bias the results. Most such trials have more elaborate designs, such as having each patient switch from condition to condition multiple times, as in an ABBA or ABAB sequence. The more elaborate the design, the more changes over time and washout introduce noise. There are numerous drivers for N-of-1 trials. With increased understanding of the genetics of disease, it is possible to target drug treatment to genetically controlled disorders. Fortunately, many such disorders are rare in the population, but this makes it difficult to enlist adequate numbers for classical clinical trials. In addition, many new drugs are extremely expensive to produce, making such trials excessively costly. Even for diseases that are relatively common and where the drugs are not dramatically costly, there is still the bottom line - return on investment. With estimates for the cost of bringing a drug to market around US$1bn, any potential efficiencies in the system merit scrutiny. Thus the advent of N-of-1 trials. These have the potential to reduce the sample sizes necessary to demonstrate effectiveness, since they start out with low noise, making it easier to attain high S/Ns (which equate to confidence and regulatory approval). Smaller samples reduce the cost of carrying out the trial, reduce the time to bring a drug to market, and thus increase the ensuing period of patent protection. So this might seem like a win-win situation. However, that is not necessarily the case. Although the individual patient’s compliance behaviour could be assumed to be the same from treatment condition to condition, that is not necessarily the case. What if the patient breaks up with her boyfriend in mid-trial or catches the ‘flu? Her compliance might change across treatment conditions. And here’s the problem. The benefit of using subjects as their own controls goes out the window. And things get worse. Because of the reduced sample size of the N-of-1 study and the degree of reliance on homogeneity of background noise within the subject, the contribution of the non-compliance generated 48 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

noise to the S/N is disproportionately high compared to its effect in classical trials. This works against obtaining an unbiased test of the drug’s effectiveness. In summary, patient compliance is even more important to N-of-1 studies than to classical trial designs. In N-of-1 studies electronic compliance monitoring becomes essential in the interest of reaping the benefits inherent in the design. In addition, the cost of such monitoring is less of an issue due to the smaller samples involved. Compliance Monitoring in Clinical Pharmacy The idea of an S/N is just as relevant to clinical care as it is to research. When a physician prescribes an antibiotic, he or she is interested to know if it works. Noise may obscure the signal. When the patient says at follow-up that the earache is persisting, there are many possible explanations. Perhaps this is the wrong antibiotic for the organism, maybe the patient metabolises the medication abnormally, or perhaps he did not take it as prescribed. Of course, patients rarely confess to the latter, so the physician assumes the medication is at fault and prescribes something else. Clinical decision-making is always based on assessment of the S/N. There are two general areas of clinical pharmacy that are set to reap the benefits of electronic compliance monitoring. Volume 2 - Issue 2

Modern Technology between pain and anxiety. Pain creates anxiety; opiates relieve pain and reduce anxiety. Toward the end of the interdose interval, twinges of discomfort remind the patient that they have pain, and the mechanism they have to reduce the pain is to take the next dose. Patients thus shorten the interdose interval, gradually requiring more and more medication. Coupled with the development of physiological tolerance, this is a perfect storm for the development of addiction. By the time the prescribing physician or pharmacist becomes aware there is a problem, it is often too late. The patient has already developed an addiction. Equipping opiate analgesics with compliance monitors would enable the clinician to detect potentially problematic patterns of non-compliance early in the process, when the patient is still amenable to education and direction. NFC (Near Field Communication) Readers Reading the data from RFID-enabled compliance monitors has always been problematic, as expensive, dedicated readers have had to be deployed, running up the cost of monitoring compliance. Now, with the proliferation of NFC-enabled cell phones, electronic compliance monitors can be read from devices already in the field. Further, using cell phones to read compliance monitors opens up the possibility of uploading compliance data in real time. This has several potential advantages, not the least of which is allowing clinicians to intervene immediately in a patientâ&#x20AC;&#x2122;s maladaptive medicationtaking. Such targeted education is more likely to result in behavioural change than education supplied at weekly or monthly follow-up visits.

The first is where the patient population is at high risk of noncompliance, such as geriatrics or those with mental illnesses, including substance use disorders. In such groups, confusion, complex polypharmacy and impaired cognition combine to create poor compliance with prescribed medications. For example, a physician prescribes a neuroleptic medication for a patient who reports auditory command hallucinations. At follow-up he or she asks if the voices have stopped and the patient indicates they have not. The physician assumes the medication is ineffective and switches to another. The patient is unlikely to disclose that she is smoking cannabis on the weekends and not taking her medication because she does not like the feeling when she takes both. Even if the physician probes about non-compliance it is unlikely the patient will admit to it. A second area is where some aspect of the medication itself predisposes to poor compliance. Opiate analgesics, medications that characteristically have unpleasant sideeffects, and extremely expensive medications are all examples. Opiate analgesics are one of the most widely prescribed categories of drugs (IMS, 2011). Unfortunately, they are also the most widely abused. Many patients who start on these drugs for legitimate medical indications become addicted. The reason is the intimate relationship

Longer-Term Outlook With the advent of increasingly expensive medications, electronic compliance is certain to form part of the electronic continuum of care. Electronically enabled systems are being developed that range from simple telephone reminders to real-time audio-visual links incorporating calls to the patient to monitor her progress clinically, automated measurement of vital signs, biochemistry, hematology, drug plasma levels and other parameters, and feedback of these data to control administration of therapeutics such as insulin, psychotropics and antibiotics. Electronic compliance monitoring of oral medications plays an important role in these systems of the future. References 1. Full Professor of Psychiatry, University of Ottawa Dr. Wilson As a Professor of Psychiatry and Head, Section of Addiction Medicine, University of Ottawa, and Director, Substance Use and Concurrent Disorders Program, Royal Ottawa Hospital, Dr. Wilson has worked in the health-care field for both private and public sectors. His research interests lie in clinical pharmacology, biotechnology, and large data systems. Internationally known as a researcher in the field of chemical dependency, and is the author of over 100 academic publications. Email: Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 49

Drug Delivery, Drug Packaging, Labelling & Dispensing

Patient Compliance – an Essential Consideration in Auto-Injector Design Patient compliance with medication is generally lower than many would expect. Different statistics have been reported over the last few decades, including that 75% of all patients fail to comply with prescribed medication in some form, and up to 50% of patients with chronic conditions fail to comply. The American Heart Association has reported that “the cost of non-compliance in terms of human life and money is shocking.”1 In the UK, NICE has published a guideline on medical adherence in which advice is given to healthcare professionals on how to influence good patient compliance.2 Professor M. Partridge, Professor of Respiratory Medicine at Imperial College London, quoted the following compliance statistics at an evening symposium at the European Respiratory Society meeting in 2000, and similar statistics have been reported more recently:3 Compliance with Treatment Eye drops for glaucoma Insulin for diabetes Antihypertensives Cyclosporin following transplants Chronic obstructive pulmonary disease Asthma

40% 48% 53% 50% 15% 46%

NICE have stated that “it is thought that between a third and a half of all medication prescribed for long term conditions are not taken as recommended. The costs are both economic and personal.” In its guideline on Medical Adherence, NICE advises healthcare professionals to pay particular attention to communication and education for patients with long term conditions in order to promote compliance with prescribed medication.3 The costs of patient non-compliance in the USA have been quoted as causing an estimated 340 deaths per day with associated financial costs of care lying in the range $100– 300 billion per year. Key drivers of these costs include three times as many patient doctor visits at a cost of $2000 per patient per year, and an increase of between 33% and 69% in medication-related hospital admissions at an estimated cost of around $100 billion per year.4 The reasons for poor compliance are many and complex, and each patient is different. A combination of physical, emotional, cultural and cognitive factors will be involved. Drug side-effects can be a reason for non-compliance while the perception of “not having an effect” or a lack of perceived efficacy can also be a contributory factor. For example, asthmatics often do not take their steroids when they are asymptomatic because they don’t perceive the need, which can then lead to deterioration as the underlying inflammatory process continues and symptoms return. So is non-compliance a patient problem, or is it an issue that should be tackled by the medical profession and the pharmaceutical industry? 50 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

For chronic conditions, a patient’s specific needs will vary over time. Asthma and diabetes are conditions that can start in childhood and remain throughout the patient’s life. In the case of children, the parent will either administer the medication or supervise the child doing so, depending upon age and ability, and therefore non-compliance is not normally an issue. However, as adolescence approaches, the child is expected to take responsibility for his or her treatment, and it is during this transition period, where parental supervision recedes, that compliance becomes an issue. In particular, the administration of drugs requiring delivery devices such as injections and inhalers can cause distress for the child and the parent. The behaviour of the parent during these early stages of treatment will have a lasting influence. The actions of over-protective parents can lead to rebellion and denial in the child, and hence to poor compliance in adolescence. A supportive approach taken by parents which encourages the child to take responsibility and ownership of the condition and their medication regimen is more likely to lead to good compliance in adolescence and adulthood. When faced with a diagnosis of a chronic condition, patients will have many concerns and often be in denial that they are actually sick. It is essential that the physician giving the initial diagnosis takes time to listen to the patient and evaluate their initial response. At this time the patient is given a lot of information and, for conditions such as diabetes and asthma, the patient will commonly be given medication that requires a drug delivery device. For example, diabetes patients will often be prescribed an auto-injector, and inhalers will usually be prescribed for patients with asthma. Addressing the concerns of the patient is essential to their acceptance of the diagnosis. Understanding concerns like possible side-effects, ability to continue with their current lifestyle and potential impact on their working life is very important. Advice on how to manage chronic conditions, including lifestyle changes and trigger avoidance, as well as discussing how to incorporate medication into their daily routines, can help the patient to take greater responsibility for the management of their condition. Psychologists tell us that we understand on average 25% of new information, and remember only 15%. Therefore, information leaflets, references to patient advisory websites and sources of additional information are essential tools in supporting the patient at this time, and will have an effect on compliance. Involving the patient in the choice of drug delivery device, such as an auto-injector or inhaler for example, along with careful training and evaluation of user technique, is vital to promote compliance. Although the factors affecting compliance are complex, they can be broken down into drug-related and non-drugrelated factors.

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Drug Delivery, Drug Packaging, Labelling & Dispensing Drug-Related


Acceptability of dosage form


Side-effect profile

Age and sex

Dosage regimen


Multiple drugs

Cognitive factors

Acceptability of drug delivery device

Physical factors

Ability to use drug delivery device

Cultural factors


Doctor-patient communication


The drug-related factors that affect patient compliance can be addressed in some part by the pharmaceutical industry. It is well known that tablet size and shape can influence acceptability, for example. Many patients cannot swallow large capsules or tablets, and some tablet shapes are easier to swallow. It is also well understood that side-effect profile can be influenced by formulation; coated tablets can eliminate bad taste and gastric side-effects, for example, and slowrelease formulations can reduce certain side-effects. Many years ago I was involved in the introduction of a new eye drop formulation that eliminated stinging on application. Sales increased by more than 30% and patients reported that they found it much more acceptable than the previous one. Drug combination products are also becoming more common, as companies attempt to improve patient compliance for multiple drugs commonly taken together but prescribed separately. Combinations of a steroid (preventer) and a long-acting beta agonist (reliever) have been very successful in improving patient compliance with asthma medication. Chest physicians have reported a significant fall in patient referrals from general practitioners since their introduction over the last decade. Such combinations have also been approved by the FDA, which traditionally has not favoured fixed dose drug combinations, on the basis that the established good compliance with the reliever could be leveraged to improve compliance with a preventer. Biopharmaceuticals are rapidly becoming the drugs of the future. Biological drugs for the treatment of rheumatoid arthritis, irritable bowel syndrome, cancer, multiple sclerosis, asthma, osteoporosis, fertility, and human growth hormone feature in the pipelines of many pharma companies. Many of these drugs pose new challenges with respect to formulation and route of administration. Oral administration is usually not possible, and parenteral delivery, typically by subcutaneous or intramuscular injection, is often the only option. Injection volumes can be large (up to 10ml) and formulations can also be viscous or fragile which means that traditional parenteral delivery options are not suitable. An additional consideration is the difficulty that many patients have with injections, whether given by a healthcare worker or self-administered, presenting additional challenges in the selection of a delivery device. Self-administration is desirable from both the patient’s perspective and the healthcare provider’s perspective, as more control is given to the patient while the reduced requirement for visits to a hospital or clinic minimises the impact on the patient’s lifestyle and reduces overall healthcare costs. Auto-injectors have been used for many years to make self-administration of subcutaneous and intramuscular drugs as easy as possible for the patient. Auto-injectors suitable for 52 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

use with the new generation of biological drugs must be able to address a range of criteria, including being: • suitable for a wide range of drug volumes • suitable for a range of drug viscosities • acceptable to the patient • intuitive to use • safe to use • suitable for the specific needs of the patient Current auto-injectors fail to meet a number of these criteria, and it is apparent that different designs will be required for different drugs and different patient needs; one size will not fit all. Failure by pharmaceutical companies to select suitable designs of auto-injector that have been tailored to the specific needs of their target patient population could result in low levels of patient compliance, leading to increased patient morbidity, increased healthcare costs, and reduced revenues to industry.

Many patients have a fear of needles, and this fear factor has to be overcome in a number of ways. Good communication from the patient’s doctor about their condition and the benefits provided by the prescribed medication is essential. Auto-injector design can reduce this fear factor by shielding the needle, but if the device design does not take all of the needs of the patient into account, addressing specific requirements such as concealing the needle and keeping the device as small as possible will not necessarily make the device acceptable to the patient. Since patients’ needs change over time, many factors need to be taken into account when designing the patient interface. Young children will accept what their doctor prescribes and their parent helps and encourages them to use. Teenagers, however, are often more concerned about what their peers may say, and may prefer designs that look ‘cool’ and are not obviously medication, in order to avoid embarrassment. Elderly patients may be less concerned about the aesthetics of the device, but reduced dexterity or visual acuity requires devices that are easy to use and which overcome any physical limitations. The more intuitive a drug delivery device is to use, the easier it will be for the patient. An understanding of how different patient groups use auto-injectors can contribute Volume 2 - Issue 2

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to more intuitive and acceptable designs. Fear of needles is very common, so design considerations should include features to shield the needle prior to injection and retract it automatically after use. Needle-stick injuries are not uncommon, with injuries to both patients and healthcare workers being reported. Injuries to patients arise with the current generation of auto-injectors from confusing visual signals which result in the device being actuated in the wrong position. For a patient who already has a fear of needles, such an injury could affect their readiness to comply with their medication, with further consequences. Devices that are intuitive to use result in fewer dosing errors and lead to higher levels of patient acceptability. Devices which are not require detailed and often complex user instructions to ensure safe and effective use. However, many patients either do not follow the instructions properly or lose them. Effective training is essential, but user technique can deteriorate over time, requiring retraining. Well-designed devices are intuitive to use with reduced complexity, making training easier and user instructions simper. The less a patient has to remember, the greater the chances are that the device will be used correctly. Simple is best. Feedback mechanisms can also improve patient acceptability. A device which provides feedback that the full dose has been delivered can improve the patient’s confidence in its use. New biological drugs that are prescribed with higher dose volumes and/or viscosities will require longer injection times, therefore appropriate feedback mechanisms that inform the patient that the full dose has been taken will become very important features. The successful autoinjectors of the future will have patient interfaces that are designed for the needs of specific patient groups and the nature of the drug being dispensed. Understanding the needs of specific patient groups will require a different way of working for pharmaceutical companies. Device engineers are usually removed from the patient and criteria such as design for manufacture and cost of manufacture are considered to be most important, often leading to reluctance in making revolutionary changes in device design. As the industry moves to more patient-centred treatments, it is essential that device designers understand the needs of the patient and that sufficient focus is given to

the following factors during product development: • appropriate segmentation of patient populations • s pecification of acceptable user interfaces for each population segment • incorporation of feedback mechanisms • training implications • simplification of user instructions Meeting these criteria will require a significant change from the pharmaceutical industry with regard to how it approaches device design and development. In the past the resources dedicated to drug delivery device design have been relatively small, and there has been a tendency to modify what is available rather than taking a completely new approach. This needs to change in the future if the new generation of biological drugs are to achieve maximum market penetration. New approaches to auto-injector design should be carefully considered with particular emphasis on market segmentation by patient needs. Greater consideration should also be given to patient acceptability of the device and how it can affect uptake and compliance. References 1. American Heart Association. The Hidden Health Threat. July 19, 1999 2. NICE Guidance 56. Medical Adherence 3. Professor Martyn Partridge presentation at Orion Pharma Symposium ERS 2000 4. Costs of Patient Non Compliance. Dr Allan Showalter. www. Barbara Lead is a product development specialist with over 30 years’ experience in the pharmaceutical and medical device industry. She has considerable experience working with drug-device combinations in a number of therapy areas, and in product development and marketing. She has held senior positions in a number of pharmaceutical companies, and is currently a director of Anaxsys Ltd and nonexecutive director for Oval Medical Technologies. Email: Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 53

Drug Delivery, Drug Packaging, Labelling & Dispensing

Perceptions and Attitudes of People with Disabilities and Older Adults about Child-resistant Drug Packaging Abstract The objective of this research was to explore the perceptions and attitudes of two groups (older adults and people with disabilities) regarding child-resistant (CR) drug packaging. Six participants with disabilities and eight older adults participated in two separate focus groups. Analysis of focus group transcripts revealed two major themes. Firstly, tested designs did not clearly communicate. This failure related to both procedures for opening and information about the safe and effective use of the products. This was a problem of package affordance as well as unclear/confusing directions. The problem was further compounded for users who were blind or visually impaired. Secondly, requisite physical actions were challenging along many dimensions. Sometimes packages required too much force, while in other cases the size of the package or its features were too small. Introduction Drug packages protect and deliver prescription and overthe-counter (OTC) drugs, as well as communicate necessary warnings and directions so that the pharmaceuticals contained within can be used correctly. Packages that consider the patient’s abilities, needs and goals have the potential to positively impact therapeutic outcomes. Patient behaviour is extremely complex. One simple reason why patients do not comply with therapeutic treatments is that they encounter obstacles associated with the package. 1 For instance, patients who have difficulty opening packages, or cannot read dosage instructions and important warnings on package labels, show reduced rates of compliance. 1-7 Ineffective packaging and labelling can result in a number of possible types of medication error, including: wrong drug, wrong dose, wrong time of administration, dose omission, wrong patient, extra dose, and wrong route of administration.8 At the same time that manufacturers must aid access for adult populations, they must keep small children from accessing drug products. The United States Consumer Product Safety Commission (US CPSC) administers the Poison Prevention Packaging Act of 1970 (PPPA) in order to protect children from the inadvertent ingestion of dangerous household products, including pharmaceuticals, by mandating child-resistant (CR) packaging systems. In the time since the PPPA was enacted, there have been significant reductions in the deaths attributed to accidental ingestion of household substances by children. Yet, the American Association of Poison Control Centers still reports almost a million annual calls following the unintentional exposure of children less than five to medicines and household chemicals. In the US alone, there are an average of 50 deaths of children per year related to this cause. 9 54 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

The US CPSC lists misuse of child-resistant containers in the home (leaving the cap off, or transferring the medication to a non-child-resistant package) and the availability of both prescription and OTC drugs in non-child-resistant (nonCR) packages as some of the reasons why poisonings still occur. 9 To compound the problem, today’s toys and computers have improved kids’ fine motor skills and made it easier for them to interpret symbols, like the common line-up-thearrow method on many existing bottle caps. 10 As a result, children are becoming increasingly skillful at younger and younger ages, making it more difficult to prevent access to medications. 10-12 This makes researching effective designs that allow marginalised populations access, yet maintain child-resistance, an increasingly critical area for investigation. As the population ages and becomes more infirm, the issue becomes even more critical. The elderly are at greater risk for non-compliance than the general population,5,1316 and older consumers and people with disabilities have a higher per capita rate of consumption of both OTC and prescription drugs. 15,17-19 Over the past four decades studies have been published on the issue of CR packaging. 20-39 Several have shown that elderly people 23,25,29,32,36,37,40 and people with disabilities 24,27,33,34 encounter a number of difficulties associated with the use of drug packages. Despite this work, many of the current commercial CR formats use operational principles that have been available since the late 60s. For instance, in 1971 Lane et al.30 studied Palm-’N’-Turn®, a system similar to current push-down-and-turn vials, and found that users were significantly less compliant with this system compared to a non-CR. 41 Despite the number of intervening years, and the negative finding, the push-down-and turn remains one of the most popular CR formats in the US.42 Radical rethinking of the design of drug containers has the potential to provide more suitable packaging which, in turn, may improve adherence to medical regimens. We conducted a study to develop guidelines for designing more inclusive CR packaging. 42 The first part of this research consisted of user characterisation (older adults, people with disabilities, and young children) and packaging testing.43 The second part, reported herein, was comprised of two focus groups consisting of people not eligible for CPSC testing (70+ and people with disabilities), and had the following objectives: • To get a sense of how people with disabilities and older adults use CR drug packages. • To gain an understanding of each group’s needs related to drug packages. Materials and Methods Two qualitative focus groups were conducted to discuss Volume 2 - Issue 2

Drug Delivery, Drug Packaging, Labelling & Dispensing issues related to CR packaging. One focus group consisted of older adults aged 70+, and another consisted of people with varied cognitive, physical, and perceptual disabilities. Participants and Recruitment Participants were recruited from the greater Lansing area (Michigan, USA) through two organisations, the Capital Area Center for Independent Living (CACIL) (Lansing, Michigan) and the Abbott Parkside Senior Apartments (East Lansing, Michigan) in accordance with procedures approved under IRB #05-454. Six participants with disabilities and eight older adults participated. Focus Groups Guide A focus group guide was used to facilitate discussion of CR packaging. The meetings started with a general introduction of all participants and warm-up questions. The guide included key and probe questions and was divided into topics such as purchase, openability, general use, labelling, and compliance, and concluded with recommendations for industry (see Table 1).

Focus Groups Results Participant Characteristics Six adults with varied disabilities, and at least partial use of one hand, comprised one of the focus groups (m = 54 years, sd = 16), and consisted of six females. People in this group reported to take, on average, 10 medications daily (sd = 7, min = 4, max = 24) (Table 3).

Procedure The focus groups were conducted by a moderator at two different locations: CACIL offices and Abbott Parkside Senior Apartments. Sessions were video-recorded with a digital camcorder connected to a high-fidelity omnidirectional microphone to capture the conversation and facilitate the transcription process. Each focus group lasted for approximately one hour and 20 minutes. Packages Eight CR packages were distributed in an activity-based task during the discussion of openability (Table 1 and Fig. 4 -11). Each package was identified by a letter (Table 2). Five 10-dram 1-Clic速 packages and five 13-dram ScrewLoc 速 packages were used by focus groups during a second activity during the labelling discussion (Table 1). Each package had a standard US prescription label in black and white that was 81mm wide and 52mm tall (Fig. 2). Additionally, two prescription warning labels (Fig. 1), 40mm wide and 10mm tall, were also affixed. The stickers were actual warnings used by a local pharmacy, and were identified by a number for ease of discussion. Focus Groups Analysis Post-hoc reviews of the digital recordings were conducted to study how participants manipulated the packages during the discussion. Audio was transcribed and analysed for recurring themes.

Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 55

Drug Delivery, Drug Packaging, Labelling & Dispensing equal to zero and one are considered negative ratings, 2 is neutral, and 3 and 4 are positive ratings. Figure 3 summarises average ratings and standard deviation for both working groups. See Table 2 for mechanisms of opening. Generally speaking, participants criticised features of all tested designs, and participants with disabilities rated packages lower than the older adults group. However, no evidence of significance existed, with one exception. An independent-samples t test comparing the average ratings of each package suggested a significant difference between the means of the two focus groups for package E, the push and turn closure (t(12) = 3.172 , p < 0.05). For the push and turns, the mean rating of the people with disabilities group was significantly lower (m = 1.2, sd = 1.1) than the mean rating of the older adults group (m = 3.1, sd = 1.1).

The second group consisted of eight adults with at least partial use of one hand (m = 83 years, sd = 6, min = 71, max = 90); one was male and seven were female. People in this group reported to take, on average, seven medications daily (sd = 4, min = 1, max = 12) (Table 4). Purchase and CR Packaging Point of purchase and types of packaging for prescription drugs emerged as themes when discussing the topic of purchase. Participants indicated that cost and convenience were also key factors for the decision of where to purchase. Most people purchased their medication in supermarkets (i.e., Kroger, Meijer, Wal-Mart) or pharmacies (i.e., Apothecary Shop). Three participants also used mail order. Supermarkets were preferred because of convenience (some of them deliver), and cost. For participants with disabilities, free delivery was highly valued. In general, CR packaging was negatively perceived. When asked about the meaning of CR, one of them joked that it means that “children can get into it but adults cannot”, and all others nodded in agreement. A participant said “old people should not get child-proof containers.” Other comments included, “Once I get the package open, I never close it again”, “If I forget to tell them that I want the nonchild-resistant cap, I have a horrible time to get them off.” Neither group was unanimously aware that they could request non-CR packaging. A participant pointed out that mail-order pharmacies are not permitted to send non-CR packages by mail. When asked about their preferences there was no clear agreement on which package they liked best. However, it was clear that participants did not like blister packaging with multi laminated backing (CR blistersPackage H). Openability The participants were given eight different CR packages (marked A through H - see Figures 4 - 11) and asked to rate them on a five-point scale (with zero being hardest to open and four the easiest). For the purpose of this analysis, ratings 56 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

Both groups rated package H, the peel push blister system, extremely negatively. For the people with disabilities group, Package A (line-up arrows and push off cap) received the highest rating (m = 2.0, sd = 1.1); for the older adults group, package E (push down while turning cap) obtained the highest average rating (m = 3.1, sd = 1.1). A brief analysis of each package follows: • Package A (line-up arrows and push off cap, Figs. 3 and 4): five participants out of 14 rated it with positive ratings. Five participants rated it neutrally (two). A blind participant suggested that aligning the arrows was arduous. Another person mentioned that aligning the arrows was difficult because they are hard to see. One participant pointed out that a significant amount of strength is needed to pop up the cap, and her thumb is not that strong.

• Package B (push down while turning cap, Figs. 3 and 5): seven participants rated it positively, five participants remained neutral. The ones that disliked it mentioned the difficulties in pushing down, that the package was too small, and that pills tended to spill out while opening it.

• Package C (squeeze sides below cap, Figs. 3 and 6): 11 participants rated it negatively. They mentioned that instructions were very hard to read because its letters were just embossed, with no color contrast. Other participants mentioned that they could not pinch hard enough to gain Volume 2 - Issue 2

Drug Delivery, Drug Packaging, Labelling & Dispensing

access. A visually impaired participant could not get it open.

• Package D (squeeze tabs and turn cap, Figs. 3 and 7): six participants gave it negative ratings, four participants rated it positively, and four remained neutral. The main criticism was that the package was too small. A participant with limited fingertip sensation found it very hard to open. A visually impaired participant could not tell how to open it. When another participant explained the design, the person with visual impairments was able to do so.

• Package E (push down while turning cap, Figs.3 and 8): in the older adults group, seven out of eight participants responded positively. They mentioned the fact that it is larger than most other packages as the rationale (ease of grasping). One participant reported it was difficult to open any package that is push-and-turn. In the group of people with disabilities, four participants rated E negatively and two gave it positive ratings. The criticism from this group focused on the amount of force required. • Package F (squeeze sides while turning cap, Fig. 9): this

package received six positive ratings, three neutral, and five negative ratings. Participants indicated trouble reading directions (also embossed letters, lack of contrast). As a result, many found it difficult to locate the proper area to squeeze. • Package G (push tab while lifting lid, Figs. 3 and 10): eleven participants rated this design negatively, three persons positively. Many could not open it, indicating the instructions were not clear. People who understood the opening feature thought it was easy to use. • Package H (remove corner, peel back paper, and push through foil, Figs. 3 and 11): ease of opening ratings were universally poor for package H. None of the study participants could open the CR blister without scissors. All participants rated this system with a zero.

General Use Most participants (12 out of 14) reported transferring portions of their medications to weekly or daily pill organisers, and storing original packages in closets or cabinets, or on kitchen countertops or the tops of appliance (e.g. refrigerators or microwaves).

Participants found pill organisers to be very useful reminders for compliance. Two participants did not like organisers because they couldn’t identify medication; these participants indicated they did not use them. The older adults unanimously reported carrying their medications in something other than the original packaging. Within the group of people with disabilities, the two participants who did not use organisers reported placing all vials within a plastic bag which was then loaded into a purse.

Labelling Participants could only read part of the labels; they needed a magnifying glass for the smaller print. Label elements people considered important were: the name of the drug, the phone number of the pharmacy, the doctor’s name, the number of refills remaining, and the number of pills to take. Some participants thought the information on the labels was not helpful and they rely on the doctor’s instructions (when to take the medication, how many pills, etc.). Participants preferred large symbols and large print. Symbols and coloured warnings were perceived positively. However, many reported the symbols presented to them were hard to interpret (See Figure 1). Black letters on yellow or white background were the preferred contrasts. Other background colors were indicated to be more challenging. Black text on pink background and black on blue were considered as poor contrasts. A visually impaired participant reported placing Braille labels on pharmacy vials. Small vials which will not accommodate her labels are placed into larger vials that she requests from the pharmacy, which will. Compliance All participants reported always following directions indicated by the labelling. They recognised that they have forgotten to take their medications at some point, but indicated these to generally be random occurrences. Participants agreed that if they do not see the pill organiser, it is likely that they will forget to take the medication. Associating the medication intake with a meal makes it easier to remember.

Journal For Patient Compliance Strategies to enhance Health Outcomes 57

Drug Delivery, Drug Packaging, Labelling & Dispensing Conclusion At the end of the meetings, participants were asked the following question: “Imagine that you could talk with a drug packaging manufacturer; what would you say to him/her?” • “ Cheaper medication for everybody who needs them.” • “Manufacturers should talk to a group like us and perhaps some other specialty groups to get some input. I don’t know who designed some of these. I don’t think there is any interaction there, between the consumer and the manufacturer.” • “The emphasis has been on child-proof for some containers, but for older people with arthritis they pose a problem.” • “ I think they should make it all as the flip-top.” • “ I like to put those ones upside-down [pointing to a 1-Clic® package] but my pharmacy doesn’t have those… then I can switch to a pharmacy where I can get those caps but I don’t get free delivery… and I can’t go and pick them up so I have to turn around my priorities. My delivery is more important to me but it would be really neat if there were some options… my assumption is that the reason there is no options is because the cost is probably a little bit more, so the pharmacy is going to give you the cheapest thing they can get.” Suggested Improvements Participants suggested improvements frequently. Improvements that participants would like to see on CR packages can be classified into three general themes: • Issues related to the clarity of the directions on a package aimed to explain how the package works. In many cases, these directions lacked contrast or used confusing wording. Suggestions included increasing colour contrast, increase font size, and use of simple wording. • Issues related to labelling communication. An ideal label would have larger, clear diagrams/symbols, large print, high colour contrast, and information in columns, because long lines in a round vial were reported as harder to read. • Issues related to physical effort, dexterity, and motor skills. Participants would like easier to open packages. Many suggested that the ideal is the simple flip-top cap or a screw cap. A further suggestion was to avoid small containers, because they pose higher demands on dexterity and physical effort. Bigger containers were thought to be easier to open and smaller ones are difficult. Conclusions After listening to the participants of the two focus groups, it is clear than CR packages for medications are problematic for these users, and are especially challenging for people with disabilities. The interaction between these users and these packages resulted in two critical themes, both of which impact medication compliance. Firstly, tested designs did not clearly communicate. This failure related to both procedures for opening and information about the products themselves. This was a problem of package affordance as well as unclear/confusing directions. The problem is further compounded for users who were blind or visually impaired. Secondly, requisite physical actions were challenging along many dimensions. Sometimes packages required too 58 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

much force; in other cases the size of the package or its features was too small. Innovative CR package designs are needed to address the needs of these users - a segment of users that, given the actual trend, is likely to increase in size. References 1. S chneider K. Prevention of Accidental Poisoning Through Package and Label Design. The Journal of Consumer Research. September 1977;4(2):67-74. 2. Tennesen M. Before you play doctor. Health. January/ February 2, 1998:98-100, 102-103. 3. S ansgiry S, Cady P. The effect of label content and placement on consumers’ understanding of OTC product label information. Journal of Pharmaceutical Marketing Management. 1995;9(3):55-67. 4. Wogalter M, Magurno A, Scott K, Dietrich D. Facilitating information acquisition for over-the-counter drugs using supplemental labels. Paper presented at: The Human Factors and Ergonomics Society, 40th Annual Meeting; September 2-6, 1996; Philadelphia, Pennsylvania, USA. 5. B raus P. Did you take your medicine? American Demographics. January 1993:14-15. 6. D iscenza R, Fergurson J. The instrumental role of product information: A study of warning labels for non-prescription drugs. Health Marketing Quarterly. 1992;10(1/2):155168. 7. L umpkin J, Strutton D, Lim C, Lowrey S. A shopping orientation based prescription for the treatment of OTC medication misuse among elderly. Health Marketing Quarterly. 1990;8(1/2):95-110. 8. V idt DGM. How physicians can prevent medication errors: practical strategies. Cleveland Clinic Journal of Medicine. 1997;64(7):355-359. 9. U .S. Consumer Products Safety Commission. Poison prevention packaging: A text for pharmacists and physicians. Washington, DC1999. 10. Krum AJ. Parenting. Vol 14. Aug 2000:25. 11. M acQuarrie M. Toys 2000: Kids put this year’s best to the test. Today’s Parent. 2000;17(10):54. 12. M cCarthy MJ. Wall Street Journal. Feb 3, 2000;B: 1. 13. Fulmer T, Kim TS, Montgomery K, Lyder C. What the literature tells us about the complexity of medication compliance in the elderly. Generations. Winter 20002001:43-48. 14. Caranasos G, Stewart R, Cluff L. Drug-induced illness leading to hospitalization. Journal of American Medical Association. 1974;228(6):713-717. 15. B eers M. Age-related changes as a risk factor for medication-related problems. Generations. Winter 20002001:22-48. 16. H olt G, Hall E. The self-care movement. Handbook of nonprescription drugs. 1990:1-9. 17. Food and Drug Administration. Proposed Rule on Labeling of OTC Drug Products. Federal Register. Vol Washington, DC1997:9024-9062. 18. Woolley S. The Quest for Youth. Forbes. 1999;163(9):146151. 19. Conn VS. Self-Management of Over-The-Counter Medications by Older Adults. Public Health Nursing. Volume 2 - Issue 2

Drug Delivery, Drug Packaging, Labelling & Dispensing 1992;9(1):29-36. 20. Rees JA, Forbes J, Ross AJ. Difficulties in the use of medicine packaging. Int J Pharm Pract. 1992;1:160163. 21. A tkin P, Finnegan T, Ogle S, Shenfield G. Functional ability of patients to manage medication packaging: a survey of geriatrics inpatients. Age and Ageing. 1994;23(2):113116. 22. S herman FT. Tamper-resistant packaging: is it elderresistant, too? J. Am. Geriatr. Soc. 1985;33(2):136-141. 23. Keram S, Williams ME. Quantifying the ease or difficulty older persons experience in opening medication containers. J. Am. Geriatr. Soc. 1988;36(3):198-201. 24. L isberg R, Higham C, Jayson M. Problems for rheumatic patients in opening dispensed drug containers. Br J Rheumatol. 1983;22(3):188-189. 25. D onaghy A, Wright D. Standardising risk assessment to reduce unintentional non-compliance in aged patients predischarge. Int J Pharm Pract. 2003;11(3):Supplement. 26. C hambers T. Child-resistant containers for drugs. Archives of Disease in Childhood. 1981;56:739-740. 27. L e Gallez P, Bird HA, Wright V, Bennet AP. Comparison of 12 different containers for dispensing anti-inflammatory drugs. British Medical Journal. 1984;288. 28. M cIntire MS, Angle CR, Sathees K, Lee PS. Safety packaging: What does the public think? American Journal of Public Health. 1977;67(2):169-171. 29. F leming BB, Pulliam CC, Perfetto EM, Hanlon JT, Bowling JM. Medication use by home health patients. Journal of Geriatric Drug Therapy. 1993;73:33-46. 30. L ane MF, Barbarite RV, Bergner L. Child-resistant medicine containers: experience in the home. American Journal of Public Health. 1971;61(9):1861-1868. 31. M yers CE. Patient experiences with a child-resistant prescription container. American Journal of Hospital Pharmacy. 1977;34:255-258. 32. S herman FT, Warach JD, Libow L, L.S. Child-resistant containers for the elderly? J. Am. Med. Assoc. 1979;241(10):1001-1002. 33. M ason D, Brooks P, Mavrikakis M. Study of opening medicine bottles in patients with rheumatoid arthritis. Journal of Clinical Pharmacy. 1976;34:255-256. 34. L ambert JR, Hopkins R, Wright V, Cardoe N. Childresistant containers: an apprasaisal in arthritic patients. Rheumatology. 1978;17:89-90. 35. K andheria M, Clausing M. The safety cap and the senior citizen. Veterinary and Human Toxicology. 1979;4:239240. 36. M eyer M, Schuna A. Assessment of geriatric patients’ functional ability to take medication. Geriatrics and Gerontology. 1989;23:171-175. 37. R ahman NJ, Thomas J, Rice MS. The relationship between hand strength and the forces used to access containers by well elderly. Am. J. Occup. Ther. 2002;56(1):78-85. 38. K resel JJ, Lovejoy FH, Jr., Boyle WE, Jr, Easom JM. Comparison of large and small child-resistant containers. J Toxicol Clin Toxicol. 1982;19(4):377-384. 39. Walburn JN, Benson BE, Burga M. Pharmacists’ poison prevention advice to the elderly. Clinical Toxicology. 1991;29(2):265-271.

40. K  andheria M, Clausing M. The safety cap and the senior citizen. Veterinary and Human Toxicology. 1980;4:239240. 41. O ’Connell PJ. Personal communication: Child-resistant packaging 2006:Vice President, Sales & Marketing, Owens-Illinois Prescription Products. 42. d e la Fuente J. The use of a universal design methodology for developing child resistant drug packaging. East Lansing: School of Packaging, Michigan State University; 2006. 43. d e la Fuente J, Bix L. User-pack interaction: insights for designing inclusive child-resistant packaging. In: Langdon P, Clarkson PJ, Robinson P, eds. Designing Inclusive Interactions. London, United Kingdom Springer; 2010:89-100. Dr. Laura Bix is an associate professor at the School of Packaging at Michigan State University and an adjunct associate at Clemson University. She was appointed, and currently serves as the US delegate to ISO TC122 WG 9, a group which is developing a standard for measuring the accessibility of packages. Bix served as the Vice-Chair of Committee D10.32, the Committee on Consumer, Pharmaceutical and Medical Packaging, from 2004-2007, and as a member of Committee F-02, the flexible barrier material committee, since 2002. In 2008 she was named one of the 100 most notable people in the medical device industry by Medical Devices and Diagnostics Industry. Email: Javier de la Fuente is the founder and CEO of Factor IDD, a design consulting company specializing in packaging and product design. He is pursuing a doctorate at the Michigan State University School of Packaging. His current research focuses on usability issues of flexible packaging. He earned his Master of Science degree from the same school and holds a five-year degree in Industrial Design from the University of Buenos Aires, Argentina. Email:

Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes 59

Drug Delivery, Drug Packaging, Labelling & Dispensing

Changing a Problem into a Solution – Technological Alchemy from Protomed It is the central question of economics – how to match infinite demands with finite resources. And, for the NHS, tackling the age-old problem of compliance is at the heart of finding an answer to it at a time when the demands are going up and resources are going down. The problem of compliance has been around ever since doctors first started prescribing potions to cure ailments. It might have been more understandable then – some of those concoctions had dangerous side-effects as well as tasting foul, or were hard to persist with – but since medical science has been based on knowledge and evidence, getting patients to follow doctors’ orders has been a good idea for both the patient and the system treating him or her. So why is solving compliance now a critical issue, rather than just a desirable goal? The answer lies in three key factors which have come together to create a perfect storm for organisations supplying the NHS: people, money and management. Firstly, the people factor is driving demand for NHS healthcare up and there is simply not enough in the budget to meet the increasing demand. There are three reasons driving this: Demography By 2030, the number of over-85s is expected to have quadrupled to four million, and the number of over-65s the system will have to take care of will have doubled. The demand for the care of patients with long-term conditions is expected to increase by 250 per cent by 2050 as a result. But as we start to live longer, healthier lives, the NHS will not, as it is currently arranged, be able to keep up with the needs of that growing ageing population. Technology The second driver in the people factor is medical technology. It is developing at an incredible pace and as new innovations become available, the public naturally feel they should be available on the NHS, no matter how expensive they are. Why? Because of the third driver behind increasing demand - public expectations. Public Expectations These days the public is much better informed about medicine than ever before thanks to the media and the internet. Many more patients arrive at the GP’s surgery or at the local pharmacy every day having already used Google and popular medical websites to self-diagnose their condition. So when they come through the door, they are more demanding than they were in years past. So overall demand, too, has increased, and will continue to do so, in line with this growing and well-informed population. The next factor on the radar of the NHS suppliers comes 60 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

back to that central economic question – limited financial resources. Or in this case, a worse scenario – shrinking resources. Given the global economic situation and the Coalition Government’s clear focus on reducing the national debt, it is no surprise that even the long-protected NHS budget is shrinking, and with it, its capacity to keep up with demand. The last time its finances were this tight was in 1981, and the then Secretary of State, Norman Fowler, was depicted on Spitting Image as Jack The Ripper - slashing unsuspecting hospitals in “Murder Most Fowler”. Over the years since, we have become accustomed to the health budget increasing in line with inflation at the very least. At best, there has always been a financial cushion available to improve things and fix problems. But now we are into new territory. Four billion pounds in running costs have already been taken out of the NHS in the last three years. But that is just the tip of the iceberg. There are a further £20 billion of cuts to management costs still to come in the pipeline. It is a chilling figure, but one which we Volume 2 - Issue 2

Drug Delivery, Drug Packaging, Labelling & Dispensing must use to help us focus on what we can do to make the most of what money there will be. NHS spending is crucial to all of us, so it is in the interests of all to adapt and help this new health service deliver more for less. The final element in this unprecedented situation is that the Health Bill has moved from the Commons to the Lords, so there is no turning back. But no matter what happens with it, reform, and the move towards a national commissioning

board, will go ahead. Which means that as suppliers and partners to the NHS, it is going to be a case of survival of the fittest. Or in practice, the most effective. The crux of the reforms is that the NHS is going to change the model of how it pays providers. Why? Because, as the national QIPP lead, Peter Rowe, said: “A business model based on waiting for patients to present worsening symptoms is simply not sustainable”. Under Payment by Results (PbR) it will pay providers based on the patient outcomes they achieve rather than outputs. So, for example, hospitals will no longer be paid just for treating patients – they will only be paid if the patient is not readmitted for the same complaint within 30 days. So it is fair to say that it is all about outcomes and maximising them from here on in. One of the key principles of marketing is very relevant - “You cannot manage what you cannot measure”. For the NHS, and for those working in the health and care industries, measuring the benefits that medication and pharmacy

services deliver will dictate whether we flourish or flounder in the years ahead. We will all be challenged to show our value and become indispensable partners to the new commissioning groups. And that is why improving compliance will become crucial to squaring this circle. The problem of patients not adhering to medicine regimes is a hugely costly one for the NHS – not only does it compromise health outcomes for patients, but it also puts the public purse under severe strain. Between one-third and one-half of all medicines are not taken as recommended – a shocking figure resulting in up to hundreds of millions of pounds spent on preventable hospital admissions. And that is the most expensive place to treat anyone. At a recent GP Commissioning Conference, Practice Manager Jose Tarnowski explained that a day’s admission to an acute hospital costs the same as a whole year’s care by a GP practice. It is therefore unsurprising that Sir David Nicholson, the Chief Executive of the NHS, stated at the same conference that for ‘the new NHS’ the emphasis will be on caring for patients in their own homes wherever possible. That has been a desirable goal for a long time, but now it will be crucial to managing the shrinking NHS budget with the increasing demands set to be made of it. This is why ensuring compliance can become the keystone to making ‘the new NHS’ work – by helping patients stay at home and saving the NHS the huge extra cost of hospital care – as well as ensuring providers are paid. There is a real opportunity for compliance to move from an expensive problem to the key to the solution of the NHS budget puzzle. But only if technologies like those spearheaded by Protomed are adopted quickly and widely enough. A case in point is Britain’s estimated 614,000 dementia sufferers, for whom complying with doctors’ orders is a greater challenge than for most of us. While in-home care is understandably a priority for NHS reforms for financial reasons, taking dementia sufferers away from a hospital or caring environment – where medication can be administered and monitored – dramatically increases the risk and cost of non-adherence. So what challenges do they face in complying with medicine regimes at home, and how can we overcome them cost-effectively? Memory loss is the biggest obstacle to compliance for patients with dementia. The fact that many dementia sufferers take a range of medicines to treat multiple conditions only exacerbates the situation. Prescribers can encourage greater adherence by reducing the number of medicines taken and the number of doses required each day. This involves reviewing the need for a medicine or using combination products containing two or more medicines in one tablet. Historically, these have been frowned upon because they are generally more expensive, however prescribing complex regimes which dementia patients will not stick to does not make sense. Similarly, an article in The Pharmaceutical Journal last February [2011] argued that switching patients from a branded medicine familiar to the patient, to a pharmacologically identical but cheaper generic may make Journal For Patient Compliance Strategies to enhance Health Outcomes 61

Drug Delivery, Drug Packaging, Labelling & Dispensing financial sense in the short-term, but often results in worse compliance because the patient does not have the same confidence in the ‘new’ medicine as the familiar one. This is particularly true of dementia sufferers, who can be easily confused and often rely on the shape and colour of the tablet or packaging to identify which medicines to take. It’s estimated that confusion over packaging and labelling instructions alone causes one-third of all medication errors. Currently, pharmacy contractors are incentivised to source the cheapest generic medicine or equivalent import and a clawback mechanism penalises those that do not. As a result, patients can be given different brands of medicines each time their prescription is dispensed with different packaging and different-shaped or coloured tablets. This practice carries significant dangers to confused patients and compounds the existing compliance problem for them. There is a dire need for commissioners to work with local prescribers and pharmacists to ensure consistency of supply for patients with dementia – even if it means prescribing branded medicines. It is a false economy to prescribe the cheapest generic medicine if it leads to a patient with dementia being admitted to hospital when they are not able to manage their medicines. As in-home care for dementia sufferers becomes preferable to residential homes, the role of carers and nurses in administering and policing medication regimes must be fulfilled in an alternative, more cost-effective way. That is where technologies designed specifically to aid compliance can play a vital role. Monitored dosage systems (MDS) such as Protomed’s Biodose and BeMAR incorporate visual reminders and safeguards to support patients and carers as they manage and administer medication. Pre-measured, colour-coded and even microchipped medication management systems have been found to be effective in reducing the risk and cost of non-compliance, and Biodose trials indicate a substantial increase in compliance in care homes and domiciliary care. The success of MDS in care homes and in-home care has set a precedent for similar savings as part of hospitals’ and GP surgeries’ discharge procedures. Pharmacists fund 100 per cent of the cost of monitored dosage systems in care homes and domiciliary care, in return for an increase in revenue through gaining more contracts through their use. But why are they not being paid for delivering this invaluable service? Because of historical precedence. No pay at the start means no pay on the way. Through case studies, we have already seen that improving compliance through technology can transform the operation of a care home, and residents’ welfare, and saves the NHS the high cost of a hospital readmission. For example, pharmacists supplying York House care home in Clacton reported that after care staff started using the Biodose system to administer medication, round times were reduced by 60 per cent, and there was 75 per cent less waste, meaning greater compliance, with all its benefits. There are 480,000 care home beds in the UK, so if you extrapolate this success nationally it shows there is huge potential for pharmacies to differentiate themselves, help the NHS solve its key budget challenge, and become allies with the new health consortia. And avoid paying money 62 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

back to the NHS under Payment by Results if it is extended to apply to community pharmacies and care homes as well as hospitals. For the NHS, that makes perfect sense, as their effectiveness in ensuring compliance by their customers and residents directly affects the NHS’s ability to work within its budget – because if they fail, the customer or resident becomes another very expensive in-patient. So it would make sense to extend the onus of compliance to community pharmacies and care homes too. The good news for them is innovative Protomed technologies such as Biodose, BeMAR™ and our upcoming product Biodose Telepack™. The opening of a medication pod in the Biodose TelePak™ triggers a wireless data transfer to the provider – allowing compliance patterns to be measured and monitored for danger signs, so that staying on top of their residents’ and customers’ compliance could not be simpler. Another more indirect way in which Protomed’s BeMAR™ can help the NHS live within its budget is by helping the CQC do the same. It seems that laying blame at the door of inspectors, regulators and professional bodies is becoming routine in the media these days - the CQC is just the most recent in a list of bodies to have fallen into the firing line (the GLA and Border Agency have also taken their fair share too). But the root cause of these issues is lack of resources to carry out their work. The CQC has fewer staff, vacant positions and significantly less budget, yet faces an enlarged remit - adding domiciliary care to care home monitoring, additional services to cover and more suppliers to assess. But trying to meet more demands and new objectives with fewer resources seems like asking them to do a magic trick worthy of Paul Daniels, not just demanding efficiency. The CQC is tasked with monitoring and reporting only. And it is doing just that – reporting what it sees, which are often unacceptable practices. This is not the CQC’s fault, or responsibility. But the time, and money, it takes is its central strategic issue now. Protomed’s solutions can help solve the CQC’s resources problem in care homes and in domiciliary settings, by providing inspectors with secure and forensically auditable data records on databases to inspect, rather than the current libraries of paper patient records which no inspector could, even with the best will in the world, check through in the time allotted for a visit. Addressing compliance from the ground up in this way can speed up the CQC’s processes and improve the outcomes of their findings. And, in the bigger picture of the NHS’s central challenge, it means that carers will be aided in ensuring compliance and avoiding the costly avoidable hospital admissions the system can no longer afford. Norman Niven is the founder of Protomed, specialists in medication management systems. Creator of the Biodose and BeMAR systems, Norman has 30 years’ experience in the health and caring sectors. Norman is a pharmacist and former director of BUPA Care Services. Email: Volume 2 - Issue 2

Think Tank

Who is Responsible for Adherence? The issue about who should take responsibility for adherence is one that is being debated at all levels. But where does this responsibility ultimately lie? Poor medicine adherence carries a huge cost, both in terms of patient safety and quality of life. It also represents a serious problem for health systems, leading to inferior health outcomes, and unnecessary treatments and hospitalisations. Pharma invests heavily in developing new drugs, and only a small proportion of those ultimately reach the patient. While electronic monitoring of patients’ medicines adherence is becoming standard practice in clinical trials involving chronic diseases, most patients are left to their own devices outside of the controlled environment. Providing adherence support for medicines has never been more important in these times of austerity. Healthcare systems are now evaluating drugs on real-world outcomes rather than on clinical trials. An adherence strategy not only differentiates a brand, but it also emphasises your commitment to stakeholder support and improves health outcomes. Many stakeholders believe that it is pharma’s responsibility to not only bring the drug to market, but also ensure that the patients adhere to those drugs once they have been prescribed. Physicians, however, don’t consider medicine adherence to be their responsibility and, to compound matters, are sceptical about pharma-sponsored adherence programmes. Of course pharma have an interest in supporting patients to stay on their own drugs, but if this improves health outcomes overall, then everyone wins. Policy-makers are aware of the problem but don’t have the funding to build adherence programmes for every condition. Generic adherence programmes that cover all chronic conditions don’t take into account that patients have specific issues on specific treatments for individual conditions. A diabetic patient, for example, has very different health beliefs, support requirements and information needs to someone living with HIV.

This is where the crux of the debate lies. Healthcare policymakers need to be placing greater emphasis on re-educating local physicians to understand the value of pharmasponsored adherence programmes. Medicines managers should play a role in driving this message downwards with local policy. On the industry side, pharma need to build adherence programmes that meet local needs, incorporate behavioural change tactics and, most importantly, support the physician in their management of that patient. Their adherence programmes must have value propositions that demonstrate: • W hy the programme is required to support health outcomes • That the programme was developed in consultation with physicians and patients • W hy they should recommend the programme to their patients • H ow the programme assists healthcare professionals, by: o Complementing their treatment of the patient o Reinforcing their advice o Supporting the dialogue between them and their patient o Keeping them closely informed about the progress of patients on the programme

So What is the Solution? A partnership between all stakeholders – pharma, physicians, payors and patients would be the ideal solution. Demonstrating the value of a successful adherence programme on health outcomes can be important enough to get your drug onto formulary. As an example, an adherence programme 90TEN Healthcare is currently delivering internationally has, in one market, resulted in the drug and adherence programme being added to the recommended treatment pathway in several local areas. In the US, where the direct and indirect costs of medication non-adherence amount to an estimated $100 million to $300 million each year, US Surgeon General Dr Regina Benjamin believes, “Physicians, nurses, pharmacists, and other clinicians play a critical role in addressing nonadherence.”1

Sources: 1. Mediaplanet – Patient Adherence. http://doc.mediaplanet. com/all_projects/7711.pdf –(last accessed 04.05.12)

And finally, let’s not forget the patient. Adherence programmes are there to support their treatment and improve their health outcomes. They may not know whether they could benefit from that kind of support at the start of treatment, which is where the physician plays an important role in explaining the benefits of the programme to them. After all, a survey conducted by 90TEN in 2011 revealed that most patients signed up to their adherence programme because their physician recommended it, highlighting that patients put a lot of trust in their physicians. If we are going to make any progress in reducing medicine wastage and improving health outcomes, the responsibility for adherence programmes requires a joined-up approach from all stakeholders.

Carole North is co-founder of 90TEN Healthcare and has over 10 years’ experience of delivering programmes that increase adherence to treatment by empowering patients to change their health beliefs and behaviours, support healthcare professionals to manage those patients, reduce acute hospital admissions, and provide on-demand reporting tools that demonstrate ROI. 90TEN Healthcare is currently delivering patient adherence programmes in 23 countries across a variety of therapy areas. Email: Journal For Patient Compliance Strategies to enhance Health Outcomes 63

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64 Journal For Patient Compliance Strategies to enhance Adherence and Health Outcomes

Volume 2 - Issue 2

Journal for Patient Compliance  

Journal for Patient Compliance - Strategies to enhance Adherence & Health Outcomes

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