A deep dive into global digital healthcare trends exposes the pros and cons of using technology in decidedly human applications. After a thorough explanation of market drivers, the authors focus on primary and secondary packaging that can enhance distribution safety, improve compliance and perhaps offer an alternative for drug manufacturing.
By Pascale Gauthier and Jean-Michel Cardot
We live in a digital era. For at least 10 years, people have integrated the internet into their daily lives. This development of a simplified digital universe that is no longer exclusive to information technology (IT) engineers allows people to integrate the computer into their daily life, giving them access to knowledge in all fields. Social media and this simplified access (mainly due to the smartphone) have convinced all generations to “stay connected,” and speaking to their children and grandchildren is reason enough for the elderly to learn to use the technology.
But in the last decade and with the ageing of baby boomers, digital use has grown exponentially, especially in healthcare. A lot of free or low-cost software applications have been developed. They’ve allowed a shift from the more simple “communication and email between generations” to the more dedicated “technical solution for the medical device to monitor treatment”—or simply to provide education on the disease.
But digital systems can also be integrated directly into the product or onto pharmaceutical and medical packages as new delivery systems for treatment.
General definitions on digital health universe
So what do we mean by digital healthcare? Several notions are possible:
eHealth is defined bythe World Health Organization (WHO) as the transfer of health resource/care by electronic means for delivering health information; improving public health service; educating and training health workers; and using electronic-business practices in health systems management.
mHealth is eHealth accessible by smartphone or tablet, allowing the delivery of healthcare services via mobile devices, including all patient-level data, as well as healthcare information to practitioners, researchers and patients.
Mobile applications (apps) correspond to the software applications that are tailored to a mobile platform and executed on a server.
TeleHealth and eTeleHealth involve the consistent and accurate remote monitoring and management of health conditions, including vital signs monitoring. This exchange of information helps avoid hospital admissions, supports early discharge and, at the very least, can be used to train and support people to provide self-care.
Telemedicine uses telecommunications and electronic information technologies to provide clinical healthcare at a distance to improve access to medical services and communication between patient and medical staff.
Bio-sensing wearables refer to analytical devices that convert a biological response into an electrical signal. All the changes in physiology can be monitored to provide continuous physiological information [1,2,3,4].
Digital health, rules and guidance
The Food and Drug Administration (FDA) has proposed guidance for medical device data systems, medical image storage devices and medical image communications. FDA recognizes that the progression to digital health offers the potential for more efficient patient care and has issued a classification of Medical Device Data System (MDDS) from Class III (high risk) to Class I (low risk), without specific registration and listing premarket review requirements for MDDS .
To facilitate innovation, the FDA has reduced regulatory requirements since 2011. For example, distributors (that is, companies that do not manufacture) of mobile medical apps are not responsible, meaning they are not subject to regulation, unlike manufacturers.
FDA intends to apply its regulatory oversight to only those mobile apps that are medical devices and whose functionality could pose a risk to a patient’s safety if the mobile app were not to function as intended. Most apps do not fit into a category that FDA intends to regulate . The European Commission (EMA) adopted a regulation on medical devices and a second one on in-vitro diagnostic medical devices. All software with a medical purpose could be a medical device and are defined in the medical device directive [6,7]. For the protection of all personal data, the European General Data Protection Regulation (GDPR) has been implemented.
eHealth and chronic diseases
eHealth can provide simple and secure follow-up for patients in their everyday life for a lot of diseases. Virtual teams of healthcare professionals can be created and are being created. More and more programs are being developed for telemedicine in European countries and the USA that allow daily monitoring for patients who need supervision of their condition.
These electronic surveys seem particularly adapted to chronic diseases, such as cardiovascular issues, chronic heart disease or diabetes . Controlling blood pressure with adapted measurement can be done by nurses or directly by the patient with a convenient accessory that directly transmits to a doctor or centralized health survey. This way, daily supervision can be easily implemented and is useful for lack of regular medicine due to geographical problems or budget cuts that give priority to emergency problems.
An interesting approach is to integrate telemedicine as constant supervision in connection with adequate supply, in case of emergency. Telemedicine requires proper implementation and full coordination of all links in the chain of care, but the outlook is huge: Around 300,000 patients are followed by eMedicine in the areas of heart failure, chronic obstructive pulmonary disease (COPD), high blood pressure, diabetes and mental illness.
Huge growth is expected in the coming years, with approximately 600% in five years for the U.S., and an estimate of 1.8 million patients treated worldwide through 2017 [1,2,8]. An economic study has found that remote monitoring technologies could save about $200 billion over the next 25 years in the United States. Teleconsultation is a new system under development in all the countries and can be fully implemented with reimbursement of some teleconsultation, that is studied in France.
However, even constant electronic surveillance can never replace regular human contact between patient and doctor, which is essential.New technologies are a nice touch—if everything is correctly set up in a well-established infrastructure that doctors and patients can understand and appreciate how it benefits their organizations and their well-being, respectively. This technology must only stay, though, if it’s an additional help.
And this new approach to medicine should not lead to a new kind of doctor, one that is without contact with real patients who are only connected to machines delivering biological data. Thinking that the doctor is not necessary and can be replaced by a click on Google is a risk.
Another important issue is that the ease of using the equipment may lead patients to being “too connected” to the health supervising technology. Too much attention to extensive health supervision can create hypochondriacs or increase a patient’s existing worries.
Medical apps, an exponential market
The number of mHealth applications published on the two main platforms (iOS and Android) represents an exponential number, with 325,000 apps published (more than doubled in 2.5 years) and 3.7 million downloaded in 2017. As shown by the report GSMA “State of the Nation,” digital health represents a huge market for mobile networks operators (MNO), with revenue that is set to increase almost threefold from 2015 to 2020 .
The largest markets for digital health services will be U.S./Canada (53%), Asia Pacific (24%) and Europe (18%). For 2020, the addressable opportunity for MNOs in the health sector is 7.4 billion.
Digital is also a way to save money: $400 billion has been saved in 2017 from the annual healthcare bill in developed countries as a result of mobile healthcare solutions.
Publishers of mHealth apps have selected two main targets: chronically ill patients (31%) and people who are interested in health and fitness (28%). Additionally, physicians are targeted by 14% of app developers.
A lot of apps already exist but many of them need improving, as emphasized by a worldwide survey of 1,130 patients and healthcare professionals regarding their needs in health apps. Patients/caregivers/professionals want apps to help understand medical conditions and treatment (61%), manage the planning (55%) and communicate with medical staff (45%) .
The main problem is that, with so many apps, making a choice and then assessing the value of the app is difficult.
In the survey, the top five barriers are:
1. Lack of trust in health apps (who develops or funds them?) (38%).
2. Confusion over huge number of apps to choose from (37%).
3. Uncertainty about which apps to use (32%).
4. Preference for face-to-face with doctor/nurse (31%).
5. Lack of knowledge of relevant health apps (30%).
The survey identifies key needs in five therapy areas:
• For cancer—People need an app that helps manage screening requirements and test results.
• For diabetes—Patients want an intuitive app for calculating insulin, as well as feedback on proper maintenance for improved health.
• For disability—Patients require an app to support pain management.
• For mental health—People need an app to help manage a personal mental crisis.
• For wellness—People look for an app that gives feedback on how treatment/care/lifestyle can impact health/wellbeing.
Regarding the apps themselves, how can patients, caregivers, clinicians and developers work together to develop high-quality apps? Suggestions include: involve patients; address unmet needs; set up a one-stop advice shop for developers; share best practices; gain “air time” for quality apps; find a successful business model; demonstrate clinical rigor; bring apps to the mainstream; and enable informed choices .
Apps allow monitoring almost everything and each year, for health topics from A to Z, people can find the apps ranking and best choice for their disease. But apps can also be useful to recognize pills or monitor treatments. Devoted apps for people who suffer from severe diseases, such as Alzheimer’s, can be found (see Figure 1).
Figure 1: Examples of various health-related apps [11,12].
Definitely, smartphones or accessories associated to apps can provide a variety of features.For example, in the cardiology field, a good cardiac monitoring device can be easily integrated as a safety complement during a sporting activity, such as running. Easy to use and understand, these applications can help people enjoy a reasonable sporting activity and adapt their efforts to improve their own health-and-wellness possibilities.
For the first time, an iPhone ECG can turn a mobile phone into a portable electrocardiogram (ECG) (see Figure 2, left). And the first medical smartphone “LifewatchV” (see Figure 2, right), introduced in 2012, looks like a classic smartphone but integrates different sensors to measure ECG and to detect an abnormal heart rate in 30 seconds. The device can also tell people their state of stress and their body fat via the electrical conductivity of their skin.
Another sensor indicates the level of oxygen in the blood (saturation); a playback of glucose is proposed by inserting top strips with a drop of blood for analysis; and an infrared sensor placed on the back of the smartphone can measure your temperature when you place it on your forehead. This helpful “all-in-one health” measurement tool can also call a doctor if needed because it is a mobile phone (see Figure 2, right).
Figure 2: Smartphones as a health partner [13,14].
Through apps, smartphones allow people to monitor their heart rate or their blood pressure but also their diabetes, weight and food intake. They help people take care of their babies or teach their children how to brush their teeth. Each day new apps emerge, without limit on imagination, for daily monitoring that fits in perfectly with our nomadic life (see Figure 3).
Some unusual apps are being developed to detect retina cancer using photos and your smartphone. That’s a good idea for early detection of this rare disease, but a bad thing if it generates excessive fears. In 2016, Roche developed a smartphone-based monitoring system for measuring the fluctuation of symptoms of people suffering from Parkinson disease. And in 2018, a research paper has indicated that smartphone-sensor technologies provide reliable, valid, clinically meaningful and highly sensitive phenotypic data in Parkinson's disease [15,16].
Introduced in 2014, the new and tiny SciO scanner can detect the molecular signature of food. It sends the details to your smartphone through its Bluetooth connection. SciO’s database translates that signature into nutritional content, becoming the first pocket molecular sensor. And a French start-up company has developed the clever DietSensor nutrition coaching app, named a CES 2016 Best of Innovation Awards, that helps diabetics in their daily life [17,18].
Figure 3: Smartphone for various monitoring [19,20,21,22,23].
Digital and drug packaging
Now that we better understand the market drivers, let’s look at primary packs for drugs and devices, along withnew systems and components that better address patient specificities .
For solid oral forms, we have numerous pack formats for contraceptive drugs , where drug compliance is the fundamental way to prevent undesired pregnancy. Slim blister packs for on-the-go, diary-printed blisters, stickers to remind you when to take pills (see Figure 4, left)—a lot has been done either with packs or with formulations (placebo pills avoid any treatment interruption, for example).
For contraceptives, the first intelligent tablet dispenser, called the Clyk, has been co-developed by Bayer Medical GmbH and Balda Medical GmbH . It won the Columbus award in 2012 for intuitiveness and ease of use (see Figure 4, center). This system provides monitoring, as well as offers real-time information on contraception use. It can be easily combined with a mobile phone application to send you reminders via “SMS” (Smart Message System, also known as text messages) of when to take the pill—a high-tech solution especially useful for teenagers.
Figure 4: Examples of blisters packs [24,25,26,27].
All these ideas can be used for numerous chronic treatments to improve compliance and reduce oversights. Pillboxes connected to smartphones are arriving and can be helpful specifically for the elderly who may have difficulties managing multiple medications (often more than three pills per day). New security features emit a warning signal and contact the patient’s family by GMS networks, which is useful in cases of compliance troubles or to prevent drug misuse (see Figure 4, bottom center). There are even digital systems that can be included in packs for monitoring treatments (see Figure 4, right).
Here is another example: Digital systems can be successfully used for drugs in pulmonary administration, where people with chronic diseases such as asthma or COPD need devices with the best design for easy integration—without stigma—in everyday life. Design is essential for all the drug forms and, since the mid-2000s, has been associated with improved functionality and product performance.
In February 2016, the Food and Drug Administration (FDA) issued a guidance document for applying human factors and usability engineering to medical devices . The goal was to support manufacturers in improving device design to minimize potential use errors and prevent any resulting harm. Numerous devices for non-pressurized systems—with an active drug in dry powder, pre-dosed in caps or containers—offer a simple use with only three short steps: “open/breath in/close.”
For drugs that are efficient in low dosages, counters and digital screens are essential to avoid taking the active drug too many times, either by accident or on purpose. An electronic reminder can be added to lock the system and help prevent overdosing (see Figure 5, left) . They also have been proposed for nasal spray (e-advancia)  and ophthalmic administration (system e-novelia) , to both help patients use the devices and monitor treatments (see Figure 5).
For injectable drugs—one of the most regulated pharmaceutical sectors—a lot of devices allow simple and safe use by nurses, caregivers or patients themselves . At first mainly developed for insulin and diabetic therapeutics, many systemsare now available for other chronic diseases that required regular injections (see Figure 5, center).
For example, hormonal treatment (somatropin)  in auto-injectors with an electronic display allow a clear calculation of the right dosage, making it easy for patients to just follow instructions on the screen (see Figure 5, right). Digital can be integrated into various packaging platforms for the safe and reproducible reconstitution/injection of products. A new range of connected pens or additional connected sensors are converting previously “dumb” injection devices into powerful internet-connected systems that vastly improve drug administration.
Figure 5: Examples of devices integrating digital in various administration fields. [29,30,31,32,33,34,35,36]
For secondary packaging, new products are enabling a huge evolution into digital. Pictograms have improved drug recognition (regardless of the patient’s age and eyesight), but a new challenge appears: The need to authenticate and prove the safety of genuine products.
Various holograms and two-dimensional codes (see Figure 6, left) have been used in the past. Now smart tags are here, connecting users via a smartphone to an internet site that explains the drug and its use. Radio-frequency identification (RFID) tags help fight counterfeiting, improve safe use and preserve a drug. Now near-field communication (NFC) technology can create “smart” packaging that enables a high level of communication between consumers and brands with only three elements: an NFC tag, a smartphone (with NFC technology) and an application. This smart packaging provides nearly unlimited information—accessed via the cloud—for authentication, education, temperature safety markers for vaccines and anything else.
Following this trend of smart labels, flexible electronics and the emerging technology of sensors and electronics circuits made directly onto a thin and pliable plastic film have been developed for packaging . They are used to form low-cost electronic blisters (see Figure 6, right) with various uses, such as monitoring adherence. When the patient pushes a tablet through the blister pack, it breaks conductive lines. An integrated electronic chip records the time and date; and transfers the data via a suitably equipped smartphone to their doctor. Initial medical trials of these blisters showed promising results, but performance must be improved to be more simple to use and to offer a reliable tool for assessing treatment adherence [38,39].
Figure 6: Examples of smart blisters [24,37,38,39].
Digital and drug monitoring / distributing systems
New technologies are not only associated with drug packaging but can also provide proper direct delivery of an active drug. The first digital medicine has been proposed for serious mental illness, where treatment compliance must be perfect. Proteus, an ingestible sensor, is associated in a single tablet—aripiprazole pill (Abilify)—to digitally record ingestion and, with patient consent, share information with their healthcare professionals and caregivers. The FDA first approved this system as a new drug application (NDA) in September 2015, then declined it in April 2016, asking for more tests, and finally approved it again in November 2017 [40,41,42].
In the area of wearables devices, “electronic tattoos” (see Figure 7, left)—awarded at netexpo in 2013—are small flexible, lightweight and stretchable patches, easily tolerated on the skin for several days. They represent “all-in-one” non-invasive technology for monitoring vital signs, and transmitting medical data . The E-skin thermometer reached the market in 2015 to determine skin temperature, and can be customized as little friends for children (see Figure 7, top center) .
In cosmetics, to prevent excessive exposure to ultraviolet light from the sun, My UV-patch, presented at CES 2016, was the first flexible patch for measuring UV exposure (see Figure 7, bottom center) . The color of the patch changes depending on exposure time, preventing the risk related to excessive exposure to the sun. The system has been miniaturized into a nail patch in 2018 and at CES 2019, the first patch for measuring skin pH has been presented—one step further for connected wearable tools [46,47] that can help prevent skin problems.
Following these trends, researchers in South Korea  have developed an electronic “smart” bandage that can detect tremors, store data and deliver drugs through the skin in a small piece thinner than a single sheet of paper. And a first prototype skin patch that can sense the glucose level, as well as deliver a drug when needed, has been developed . Freeing diabetics from frequent finger-pricks and drug injections is also the goal of research from Google and Novartis into smart contact lens (see Figure 7, top right) that can measure glucose level in tears, which could be a possible revolution for those patients .
Figure 7: Electronic tattoos with various purposes [44,45,49,50].
We also might see a digital revolution in the manufacturing process. The well-respected publication International Journal of Pharmaceutics devoted its May 2015 issue to inkjet and 3D printing used for making drugs . Various papers explore many possible applications and consider printing both solutions and solids.
For example, anti-cancer drugs can be printed onto microneedles, and flexography printing can make medicated oral wafers, as well as various film coaters. Moving on to solid or semi-solid forms, researchers are looking at 3D printing to make modified and controlled-release tablets, such as multi-compartment tablets and tablets with specific geometries not achievable with powder compaction.
As an industrial process, 3D-printing has reached a new step with the FDA approval of Spritam (levetiracetam, an antiepileptic drug from Aprecia Pharmaceuticals). The Zip Dose technology uses a three-dimensional printing platform to formulate a drug where the drug itself dissolves at a quicker rate than during the traditional manufacturing process . Printed drugs may enable personalized medicine by printing a dose of one’s own medicine.
This overview on the digital world underlines that new emerging systems are becoming a reality and can greatly improve how to treat and understand diseases. Definitely, we are just at the starting point of a full revolution toward diagnostic, medicines and compliance tools, personalized for patients’ own specificities and pathologies. The challenge could be choosing which of them are the most helpful.
All these new technologies and digital products should be seen as opportunities for better monitoring and understanding of treatments, as well as for new drug delivery and manufacturing methods. However, this greater connectivity must not overwhelm the patient but should allow him or her to have a better comprehension of both disease and treatment.
More than a trend, digital represents an evolution that everyone needs to accept and integrate as the great tool it is for helping patients’ everyday life.
Co-author Dr. Pascale Gauthier is a pharmacist with a Ph.D. and is in charge of marketing and design courses at Clermont Auvergne University, serving on the UMR MEDIS 454, Faculty of Pharmacy Clermont-Ferrand in France. Reach her by email at firstname.lastname@example.org.
Co-author Jean-Michel Cardot is a pharmacist with a Ph.D., and is a professor at Clermont Auvergne University, serving on the UMR MEDIS 454, Faculty of Pharmacy Clermont-Ferrand in France.
References and Notes:
1 - PricewaterhouseCoopers, “Touching lives through mobile health assessment of the global market opportunity”
3 - Gauthier, P., “Gaming how it can advance drug delivery, digital health and a better world?” Drug Delivery Congress Europe, DDP, Berlin, Sept. 16-17, 2015.
4 - World Health Organization, “mHealth: New horizons for health through mobile technology”
7 - White & Case LLC, “Mobile health apps: Are they a regulated medical device”
10 - PatientView Ltd., “What do patients and carers need in health apps – but are not getting?”
11 - MobiHealthNews, “Samsung releases Backup Memory app for Alzheimer’s patients”
12 - mHealth Spot, “Researchers at UCLA testing apps to fight addiction”
18 - www.dietsensor.com/
19 - Medgadget LLC, “LifeWatch V: Android-based Healthcare Smartphone Packed with Medical Sensors”
24 - Gauthier, P., “Much more than packs! Overview of innovative packaging that changes life of drugs forms.” Pharmapack Europe 2015, Paris, UBM Canon, Paris, Feb. 11-12, 2015.
25 - Gauthier, P., Cardot, J.M., “Teenagers as a Moving Target: How Can Teenagers Be Encouraged to Accept Treatment?” Journal of Personalized Medicine, 2012, 2, 277-286.
26 - The HCPC alliance Columbus award 2012: Clyk the intelligent tablet dispenser from Bayer Healthcare
29 - Gauthier, P., “Spray and foam: Overview of products and use.” Aerosol Europe, 2013, 21, 6, 12-17.
32 - Gauthier, P., “Design adaptation to injectable forms depending users and drugs specificities.” 2nd Annual Prefilled syringes and novel injectors devices, Informa Drug Delivery Summit, Berlin, Sept. 17-18, 2013.
33 - Landmark Dose Indicator from Aptar Pharma
34 - BioCorp press release, “The Datapen awarded at Pharmapack Europe”
35 - BioCorp press release, “BioCorp receives CE mark approval for its smart cap EasyLog”
36 - Press release: Pharmapack Europe award for medical device Intuity Lyo
37 - Van den Brand, P., “Flexible pharma.” Pharmaceutical Manufacturing and Packing Sourcer (PMPS), May 2013, p.60-62.
38 - PharmTech.com, www.pharmtech.com/smart-labels-enhance-drug-packaging
40 - Proteus Digital Health press release, “U.S. FDA Accepts First Digital Medicine New Drug Application for Otsuka and Proteus Digital Health”
41 - Mobi Health News, “FDA declines to approve Proteus-Otsuka sensor-equipped pill, asks for more tests”
42 - Mobi Health News, “Otsuka, Proteus finally win FDA approval for sensor-equipped Abilify”
44 - http://vivalnk.com/
45 - Digital Trends, “Hands on: L’Oreal My UV patch”
49 - MIT Technology Review, “Controlling diabetes with a skin patch”
52 - Forbes, “FDA approves 3D printed drug available in the US”
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