"THE USE OF MOBILE SOLUTIONS IN CARDIOVASCULAR TRIALS - DATA CAPTURE AND TRIAL ADHERENCE"

Authored by Rashmi K Gurnani Vikrant Patnaik

Clinical trials pave the way for safe and effective medical products i.e.; drugs, devices, and biologics to enter into the market. We are in an era where people are aware and conscious about the kind of medication they consume with regulatory authorities becoming very stringent in the drug approval process. It has been observed that there have been trials which have given rise to drugs which were in widespread use and have later been found to be detrimental raising concerns that extend much beyond just the cost implication. Hence the use of any technology that can improve capturing of patient data pertaining to the desired drug effects vis-a vis the real effect in subjects can prove to save time, money and also ensure the safety of subjects in a clinical trial.

CARDIOVASCULAR DISEASE PREVALENCE: Cardiovascular diseases are caused by disorders of the heart and blood vessels, and includes coronary heart disease (heart attacks), cerebrovascular disease (stroke), raised blood pressure (hypertension), peripheral artery disease, rheumatic heart disease, congenital heart disease and heart failure.(1) Cardiovascular diseases are the prime cause of death worldwide. A World Health Organization report suggests that by 2030, almost 23.6 million people will die from cardiovascular diseases, mainly heart disease and stroke. (2)

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RISK FACTORS FOR CARDIOVASCULAR DISEASES:

21st Century - has certainly brought in a world full of changes in our daily lives. With more comforts, high tech gadgets and machines to cater to our smallest needs, cheese filled hamburgers and pizzas! All of these bringing aWOW! What a life. What most of us sitting in air conditioned offices feel is the ease in carrying out a particular activity as against how it was done a couple of decades back. It feels awesome no doubt, but what we are forgetting is the warm welcome that we give to lifestyle diseases due our modified lifestyle. While genetic factors do play a part in causing cardiovascular diseases, 80 to 90% of people dying from coronary heart disease have one or more major risk factors that are influenced by lifestyle. Behavioral risk factors such as unhealthy diet, physical inactivity and tobacco use are the most important causes of heart diseases and strokes. The intermediate risk factors thus are high blood pressure, raised blood glucose, raised blood lipids and obesity. The other factors could be the ones such as ageing, poverty, stress etc. Hypertension as a risk factor: Hypertension is one of the most important preventable causes of premature deaths worldwide. Hypertension contributes to around half of all cardiovascular diseases. High blood pressure is a phenomenon that affects both young and old in several countries. It has been estimated that 50 to 60% of the adults worldwide would be in better health if they reduced their blood pressure by increasing physical activity, maintaining ideal body weight and eating more fruits and vegetables.
(3)

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High cholesterol as a risk factor: High cholesterol causes one third of all cardiovascular diseases worldwide.
(3)

Adequate exercise and diet control can effectively bring

down cholesterol levels. Tobacco as a risk factor: Although cigarette smoking is primarily responsible for causing lung cancer, by far more smokers suffer from cardiovascular diseases, particularly heart attack and stroke. Quitting smoking effectively reduces cardiovascular risk to close to that of a person who has never smoked. Obesity as a risk factor: Obesity plays a major role in causing cardiovascular diseases. Obesity ranges are determined by calculation of Body Mass Index (BMI). Since BMI is directly proportional to body weight of an individual, it is essential that an obese person makes efforts to keep his weight under control. This can be achieved by regular exercise and proper diet. Diabetes as a risk factor: Diabetes is another essential risk factor that causes cardiovascular diseases. Diabetes is more prevalent in developed countries, but modernization and lifestyle changes are likely to result in a future epidemic of diabetes in developing countries. Lifestyle changes in childhood, in particular unhealthy diets and low exercise levels, are leading to an increasing prevalence of type 2 diabetes in children. Socioeconomic status as a risk factor: A WHO report states that Low- and middle-income countries are disproportionally affected: 82% of CVD deaths take place in low- and middle-income countries and occur almost equally in men and women
[4]

. Studies in developed countries suggest that low income is

associated with higher incidence of coronary heart disease and with

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higher mortality after a heart attack. The prevalence of risk factors for heart disease such as high blood pressure, smoking and diabetes is also higher in the low socioeconomic status groups as compared to the higher.

THE CARDIOVASCULAR TRIALS ARENA: The cardiovascular therapeutic area has been the largest or second-largest in conduct of clinical trials for the past decade, making up 15.5% of all clinical trials
[5]

. Correspondingly, the cardiovascular therapeutic area

commands the largest market for prescription drugs nearly one fourth of branded prescription drug sales as the dominant indication for branded medicines sold commercially during the past few years. The total worldwide cardiovascular market is expected to show revenues of $91.2 billion in 2008, an increase of 6.9% compared with 2003
[6]

Globally, the population of people over 65 years of age is increasing by 750,000 each month. The older population is expected to triple in many developing countries within the next 30 years
[7]

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IMPORTANCE OF PATIENT REPORTED OUTCOMES IN CARDIOVASCULAR TRIALS: Patient reported outcomes play a vital role in of cardiovascular trials as the medical intervention is aimed at to improving the health related quality of life of the patient or to prevent premature deaths which are important aspects when concerning a heart patient. These patient reported outcomes become particularly important when the intervention aims at improving symptoms or the functional status of the patient. In cases of cardiovascular clinical trials, the primary aim is to improve observation and capturing of patient symptoms, functional status or quality of life of the patients, hence patient reported outcome measures become crucial. A study has shown that cardiovascular trials that mention quality of life have increased more than three fold since 1997. By 2009, about 14% of trials mentioned quality of life. (8)

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THE CARDIOVASCULAR TRIALS SCENARIO: It has been observed that due to the various risk factors which cause cardiovascular diseases, these diseases are now prevalent in both young and the elderly. Hence, a large number of trials are being conducted in this therapeutic area. With such high numbers of trials being conducted, there are several factors which the sponsors and investigators have to consider while conducting the trial. 1. Patient adherence to treatment: Cardiovascular diseases may be both acute and chronic. In both these cases, the patients adherence to the treatment medication as per the protocol is very essential as missing even a single dose of the medication in cardiovascular disease treatment such as for angina may lead to disastrous results for the patient enrolled in the trial. Additionally the patient may represent a geriatric group wherein due to poor memory the patient may not consume his/her medication at the prescribed time or may forget their visit schedule. Also sometimes the protocol is so complex that it becomes difficult for the patient to remember about his/her next visit to the investigator thus making them non- adherent to the protocol. 2. Patient compliance to protocol: The cardiovascular trials conducted these days are mostly efficacy based trials. These trials include both the young and the elderly. Although such trials include varied age groups, since the population of the elderly (65 and above) is growing, and there are several trials that focus on improving health related quality of life of the elderly. In such a scenario wherein the patient population consists of the elderly, it becomes very important for the investigators and sponsors to ensure

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that the patients comply with the protocol and participate in getting on board better trial results. 3. Loss to follow up: There are several reasons due to which there may be patient dropouts or loss to follow up during clinical trials. Some of the reasons may be as follows: Inability of the patient to come to the clinic which may further be due to transportation problems- fatigue which is most commonly observed in cardiovascular disease patients Plain ignorance in not following the study protocol The patient may have migrated to a far off region due to which there may be loss to follow up Demise of the patient.

4. Patient monitoring: In cardiovascular diseases, it is not only the treatment adherence which is important, the monitoring of various other factors which influence the patients well being need to be monitored. The patient has to also avoid the risk factors which may cause a cardiovascular disease other than what he may be suffering from. In addition the patient may have to avoid risk factors which may deteriorate his present condition. Hence it becomes important for the investigator to keep a check that the patient is following the specified exercise and physical activity regimen, following the right diet, refrain from smoking, maintain the right body weight etc.

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5. Measuring vitals: For any patient participating in a cardiovascular trial, it is paramount to keep track of his/her vitals such as blood pressure levels which is an indication of whether the patient suffers from hypertension and weight conditions, to check if the patient is progressing towards maintaining a normal BMI. Apart from this, in cardiovascular trials, the measurement of cholesterol levels is very important. A sponsor, investigator and the trial staff has to ensure that the patient vitals are recorded on regular intervals based on the protocol.

Research on treatment and treatment adherence for people suffering from cardiovascular diseases has been going on for many years and several measures have been adopted towards improving patient care at different levels. Treatment regimen is of utmost importance for the treatment of cardiovascular diseases. Until recent times technology only empowered physicians to monitor patients and their treatment regimen but today, we certainly can improve the same by allowing the patients to be performing a part of the doctors job and proactively manage their medication intake, be compliant to the treatment regimen, follow strict site visit schedules etc. Mobile technology in such cases proves to be a boon to the clinical research industry and appears to be a one stop solution to sponsors, CROs, trial staff and most importantly the trial patients.

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THE INFORMATION TECHNOLOGY ADVANTAGE A clinical trial is largely dependent on the data provided by the subjects enrolled into the trial, who consume the drug under question. A drug for it to be launched in the market after extensive research takes anywhere around 15 to 20 years. Also millions of dollars are spent each year by Sponsors on clinical trials. With such a lot of effort, time and money going into trials, the success of the trial becomes very essential. This success can largely be achieved by the right data reported within the right frame of time by the patient. Till date most trials have this data (PRO) captured by using the paper based system wherein all the questionnaires are administered by means of paper. With the modernization of the world and tremendous development of technology, time has come where all the players of the clinical research industry should use the features of information technology for improved results. The ePRO (Electronic patient reported outcomes) and mPRO(Mobile Based Patient Reported Outcomes) provide an edge over the traditional paper based system allowing: Rapid data capture, Avoidance of data entry errors, Ability to trigger alerts/notifications for specific responses of concern Elimination of double data entry processes Real-time tracking of survey and compliance Reduction in missing information as compared to with paper administration Increase in patients willingness to report sensitive information Secure data storage in a compliant environment

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Easy access and storage of data which omits the problem of data archival which is a huge problem with data storage as the regulations require the data to be stored for a minimum of 15 years after the start of the trial and 3-5 years after the drug has obtained marketing approval.

INTERNET vs. MOBILE The internet certainly has played a very important role in giving a new dimension to the way things were and how they are today, however, with the advent and prevalence of mobile phones, there is a new dimension that can be explored and benefited from. Today we can achieve higher compliance ratios, better treatment follow up and intervention in cardiovascular trials using mobile technology. Global statistics show that there are more than 4 billion mobile phone users across the globe which constitutes of 2/3 rd of the worlds population, which is three times that of the internet users. HOW MOBILE SOLUTIONS CAN BE ADVANTAGEOUS IN CARDIOVASCULAR TRIALS: In cardiovascular trials it is very important to make sure that the patient follows the protocol and it is also important to track the patients progress after medication intake. Since there are various reasons for loss to follow up of a patient in any clinical trial, the sponsors should adopt means which can better monitor the patient. In such cases mobile solutions serve as an affordable, easy and reliable solution. The most important aspect of cardiovascular trials is to make sure that the patients enrolled in the trial consume medication on time, eat food at the prescribed times as per the protocol, follow the prescribed diet, follow a strict exercise regimen, visit the clinic for biochemistry assessments on time, provide required data to the investigator for their own betterment and
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successful completion of the trial. All these aspects can be taken care of with ease, using a mobile solution. PaDiSys NEXT GENERATION PATIENT DATA CAPTURING AND TRIAL ADHERENCE MANGEMENT SYSTEM Patient Diary System (PaDiSys) allows patients enrolled in clinical trials to use smart phone devices to report their clinical outcomes electronically. PaDiSys is a mobile technology platform built from a ground up approach, complying with international regulatory and compliance guidelines such as CFR 21 Part 11, FDA, EMEA etc. The PaDiSys System has two major configurations, namely; 1. PaDiSys mPRO Mobile Based Patient Reported Outcome Capturing Solution 2. PaDiSys mTA Mobile Based Patient Trial Adherence Solution

The aforementioned mobile solutions can be used across therapeutic areas; however, can find high utility in cardiovascular trials and treatments.
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ENHANCING EFFICIENCY OF PATIENT REPORTED OUTCOMES IN CARDIOVASCULAR TRIALS USING PaDiSys: PaDiSys mPRO incorporates a feature of capturing patient data at source- as per the clinical trial protocol or the treatment regimen. The mPRO configuration allows the patient to fill up assessments/questionnaires to monitor patients health status as per the requirement of study protocol or the treatment being administered to the patient. With such a solution the patient or in critical cases the patients caregiver fills up questionnaires that appear on a mobile phone device at the convenience of their homes/sites/care centers, without having to go to the site to submit the same. Understanding the need to capture and collect valid information, the system allows the information and data transfer to happen over secure and compliant environment- REAL TIME. Real time data capture makes the task at the investigator/cardiologists end much simpler and quicker with them able to take further actions and for making amendments to the treatment faster. The system allows investigators to manage multiple patient groups and send specific group related information or customized individual alerts and instructional messages. In cardiovascular trials a huge emphasis is laid on improvement of health related quality of life, symptoms and functional status of patients enrolled in the trial. Any drug/medical device/surgical procedure which improve the quality of life of patients by even a minor percentage is of great value to sponsors and investigators in cardiovascular trials keeping in mind the high number of deaths happening every year due to cardiovascular diseases. To determine the levels of stress, depression and the quality of life of the subjects in the trial, several questionnaires are to be filled up by the patients. The same holds true for measuring the quality of life of subjects in
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a cardiovascular trial for which Quality Of Life (QOL) questionnaires need to be filled by the subjects. To fill up these questionnaires, the patient will have to visit the clinic several times. This stress to the patient can be avoided by allowing patients to complete such assessments via the mobile phone using the PaDiSys mPRO solution. All the responses provided by the patient reside on a secure database and also the data is captured real time. Hence the information provided by the patient can be viewed by the investigator immediately. Immediate visibility to information can help the investigator know if the drug is effective on a patient and incase the investigator decides based on his experience that the drug may cause side effects to the patient or if the drug is already causing some side effect to the patient, the medication can be immediately discontinued without waiting for the patients next visit to the clinic and hence stopping the situation from worsening. Any side effects experienced by the subject can be immediately reported to the investigator using the PaDiSys mPRO. In case of severe visible side effects, a picture can be immediately taken by the patient and sent to the trial staff. With the usage of such a system, there are reduced chances of inaccurate data capture from patients. - Cardiovascular diseases are caused by a group of risk factors. The protocol of such trials may be a little more complex as it may consist of consumption of concomitant medications such as anti-hypertensives or insulin administration in case of diabetic patients along with the drug under study. Also the protocol consists of instructions about the kind of diet to be taken at various time schedules, exercise regimens etc. It becomes difficult for the patients, research coordinators and the investigators to remember the schedule of every assessment, visit, drug intake etc. To make things easier, the PaDiSys mPRO is provided with a patient calendar where the patient can view his medication, assessment and site visit schedules in advance. This is a boon also to the investigators and the coordinators as they need not
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remind the patient of their visits and also it ensures patients adherence to the protocol. - Patient follow up in cardiovascular trials is extremely valuable to gather safety and efficacy end point information which is essential to the study as well as the life of the trial subject. It is observed in clinical trials that several patients are lost to follow up or dropout, which can prove to be very expensive. In addition it also extends the trial duration which again proves to be costing the sponsors hugely. The loss to follow up may be due to inability of the patient to visit the clinic often. This problem is taken care of by PaDiSys mPRO as the patient can fill his vital information using a simple cellular smart phone while he/she is at home. Another reason of loss to follow up or patient dropout is the migration of patients to far off regions, in the case of which the patient is not able to visit the clinic. This aspect of follow up also is easily taken care of by PaDiSys mPRO as these products are portable, light and handy.

- Cardiovascular diseases may be caused by a number of factors such as stress, depression, obesity, and hypertension etc. sometimes cardiovascular diseases such as strokes may make the patient bed ridden. In such cases apart from the medication, palliative care also becomes very important. At every point in the trial it becomes imperative to check the levels of stress, depression, anxiety and various other parameters essential and important in cardiovascular trials.

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FEATURES OF THE PADISYS mTA THAT CAN BE USED IN CVD TRIALS: PaDiSys mTA, is a subdued version of the PaDiSys mPRO solution, essentially focused towards improving trial/treatment compliance in trials which not necessarily, need patient data capture. In this system, text messages or mobile alerts are generated for the trial patients regarding the consumption of medication, their next visit to the doctor, and the dates of biochemistry evaluation in which case blood draws are required. Such reminder systems are extremely useful in cases of cardiovascular trials as reminders for exercises, food intake, abstaining from tobacco etc can be sent to patients own mobile phone which ensures that the patient stays away or at least controls the risk factors which may worsen the patients clinical condition. PADISYS IN CARDIOVASCULAR MEDICAL DEVICES AND SURGICAL TRIALS: Cardiovascular disease conditions can be greatly improved by using medical devices such as stents, pacemakers, implantable cardioverter-defibrillator (ICD) etc. There are many trials which are being conducted in the development of new and more effective medical devices which can prove to be much more beneficial than the existing medical devices for the heart. Such developments include devices such as drug eluting stents, devices using microchips etc; which require extensive trials with quality data as they are implanted within the human body. In the same way there are various surgeries which are done to relieve a patient from cardiovascular disease which result from blockage of small blood vessels that supply blood to the heart (coronary heart disease). There have been innovations in this field too. Since there are innovations, clinical

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trials in this field are necessary prior to surgeries being done on normal patient population. An example of such an innovation is the robotic surgery. The end points of such trials are more subjective in nature. Thus, after the medical device trial or surgical trial for the cardiovascular system is conducted, it is important that the patient is followed up over time efficiently and the levels of distress, pain and anxiety of the patient is checked periodically. Also in surgical trials, it is evident that concomitant medications need to be taken by the patient and some cases may also require exercises. In case of medical device implantation and surgeries patients are bed ridden and may not be able to visit the clinical/hospital to fill up the required assessments. In such cases, questionnaires may be administered over the mobile phone which enables to assess the patient condition immediately. By this any deterioration in patient condition can be immediately known and addressed. Also reminders of medication intake, food intake, exercise alerts can be sent which in better patient outcome. This proves beneficial to patients (in terms of improved health), investigators (in terms of improved monitoring), and sponsors (in terms of better chances of trial success).

COST EFFECTIVENESS The pharmaceutical industry spends approximately 26.4 billion dollars annually for research and development (4.1 billion dollars in cardiovascular products)
(8)

. This implies that around 15.5% of the investment is in

cardiovascular research and development. With such huge investments in cardiovascular trials, it is essential to ensure that there are no losses encountered in the conduct of trials and maintain patients safety and well being as well. Every aspect of cardiovascular trials beginning from the selection of the site, compensation to trial subjects to final regulatory
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submissions takes investment, time and resources. If any inaccurate data is recorded during the trial, it ultimately results in further losses to the sponsor as the required safety and efficacy end points which are essential to the study will not be obtained. Every patient lost to follow up is a loss to the study. Also it results in a delay in the completion of the study. In clinical trials, each day lost, is thousands of dollars lost in added expenses and loss of opportunities. The PaDiSys mPRO and PaDiSys mTA are low cost solutions that ensure patient compliance to protocol, treatment adherence, regular and timely visit to the clinic/investigator and most importantly accurate data capture that can bring down the costs of loss to day, by a significant amount. It is estimated that in the long run the trial/treatment cost for a cardiovascular study or treatment would be reduced by a very large extent using mobile technology. All this in turn result in timely submissions to the regulatory authorities and above all appropriate trial results which can prove to be useful to cardiovascular disease patients worldwide. CONCLUSION: As clinical trials continue to evolve, investigators and sponsors will be challenged to find the optimum balance between trial data quality and scientific and medical integrity that can best evaluate new interventions at lowest costs possible. This can be efficiently achieved by using mobile solutions. It is important that the industry experts both in the Life Sciences and healthcare spheres understand this requirement and take action to implement such available technology services for treating patients suffering from chronic and terminal illnesses. Cardiologists and sponsors across the globe must take the initiative of using cost effective methods to monitor their patients and provide better point of care.

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REFERENCES: 1. http://www.who.int/topics/cardiovascular_diseases/en/ 2. http://www.who.int/mediacentre/factsheets/fs317/en/ 3. "The Atlas of Heart Disease and Stroke" by WHO in collaboration with US Centers for Disease Control and Prevention (CDC) http://www.who.int/cardiovascular_diseases/resources/atlas/en/ 4. Key Facts- Cadriovascular Diseases WHO Media centre http://www.who.int/mediacentre/factsheets/fs317/en/index.html 5. Hovde M. Getting to the heart of the cardiovascular indication. GCPj. 2003. pp. 3031. 6. Cardiovascular Markets Global Markets & Developments. Theta Reports.p.202.http://www.marketresearch.com/product/display.asp?p roductid=974912&SID=13585805-288440936-301862885&xs=r April 7, 2004, Pub ID: VB974912. 7. The World Health Report Life in the 21st century: a vision for all. Geneva: WHO. 1998 8. Outcome selection and role of patient reported outcomes in contemporary cardiovascular trials: systematic review Kazem Rahimi, specialist registrar and senior clinical researcher, Aneil Malhotra, specialist registrar in cardiology, Adrian P Banning, consultant cardiologist, Crispin Jenkinson, professor of health services research 9. Reducing the costs of phase III cardiovascular clinical trials- Eisenstein EL, Lemons PW 2nd, Tardiff BE, Schulman KA, Jolly MK, Califf RM.

About the Authors: Rashmi K Gurnani: Assistant Business Analyst, Global Marketing and Comm. Vikrant Patnaik: Sr. Manager Global Marketing and Comm.

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About the Company: NowPos M-Solutions is a Mobile Technology Development and Services Organization specializing in Life Sciences and Healthcare. In the past years the organization has gained significant expertise in the mobile and web domain with several mobile based products. NowPos is primarily focusing on developing end to end mobile solutions for capturing Patient Related Outcomes in the Clinical Trials Domain of the Biopharma and Life Sciences Industry. Working in a completely secure environment and adhering to international compliance guidelines and following the GAMP 4/5 development methodology, NowPos as an organization believes in bringing a paradigm shift in the way things were being done earlier. As an initiative to cater to the fast growing mobile applications and technologies, the NowPos Technology Services Group offers custom mobile application development on upcoming mobile technologies. The Technology Services Group also offers consulting services for development on iPhone, Android and Symbian applications.

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