Authored by Rashmi K Gurnani

Vikrant Patnaik

"THE USE OF MOBILE SOLUTIONS IN CARDIOVASCULAR TRIALS - DATA

CAPTURE AND TRIAL ADHERENCE"

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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 a-

“WOW! 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, CRO’s, 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 world’s 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 patient’s 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 patient’s 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 patient’s 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. 30–31.

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 Bio-

pharma 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.