One of the most important elements of a prescription drug's ability to provide the anticipated therapeutic benefit is time. Increasingly, drugs are being formulated with greater specificity and for a "stepped-care" approach, whereby medications are prescribed in escalating strengths or chemical combinations, depending upon a patient's resistance to initial treatments. In this environment, the patient's compliance with the recommended dosing regimen (i.e., their ability to consistently take the prescribed dosage at the proper time) is essential for the patient's safety, as well as for maximum drug effectiveness. Within the clinical-trial setting, compliance is equally critical, as the efficacy of new drugs is reliant upon accurate data.
Unfortunately, study after study report systematic noncompliance, especially among those patients taking multiple medications. According to information compiled by Zug, Switzerland-based AARDEX(R) Ltd. (www.aardex.ch), a supplier of compliance packaging for the pharmaceutical market, only one-sixth of patients execute a drug regimen with strict punctuality. At the lowest rung of the compliance ladder, approximately 17 percent of patients "take few or no doses, while maintaining the appearance of satisfactory, if not perfect, compliance."
Thomas Grinnan, vp, business development for MeadWestvaco Healthcare Packaging (www.meadwestvaco.com/healthcare.nsf) says that poor regimen compliance has resulted in an estimated $100 billion in yearly expenses to the U.S. healthcare system. "Additionally, pharmaceutical companies in the U.S. lose an estimated $30 billion in potential revenues due to noncompliance each year," he relates. "What is more, noncompliance figures for Europe and Japan combined are believed to be as large as those for the U.S."
Just as alarming, information from The Healthcare Compliance Packaging Council (www.unitdose.org) indicates that noncompliance can be blamed for the deaths of more than 125,000 Americans annually. Furthermore, the information reports that 10 percent of all hospital admissions are the result of pharmaceutical noncompliance, and 23 percent of all nursing home admissions are due to people's inability to take their medications as prescribed.
According to Grinnan, there are several reasons for noncompliance. Fifty percent of the time, patients do not know why they have been given a medication; only 30 to 50 percent of those patients who fill the prescription take it correctly because they are not fully convinced that it is necessary; and many patients fail to refill, with 28 percent of patients aged 45+ admitting that they have discontinued a prescription prematurely.
For at least a decade, packaging suppliers have teamed with pharmaceutical drug companies to bring to market packages that encourage and simplify adherence to drug regimens. Until recently, however, feedback on compliance has relied primarily on the patient's recollections, especially in clinical trials where they are asked to record their drug usage in a diary. "There's a lot of evidence that indicates that the diary winds up being a historical document," Grinnan says. "If people are seeing their doctor every two weeks or on a monthly basis, then the diary is being filled out every two weeks or every month, which is kind of sad, but is quite, quite common. So literally, people just can't remember."
Other ways that compliance is documented in clinical trials is through drug reconciliation, where clinicians count the drugs left in the actual package and try to reconcile that number with the diary, and by taking blood, which, while it may indicate the amount of an active ingredient in a patient's system, will not show the regularity with which the patient has been taking the drug.
Over the last several years, as smart packaging technologies have become more accessible, a number of companies have developed new solutions that incorporate electronics to address noncompliance. In addition to providing the patient with visual or audio cues to encourage greater compliance, these packages also enable more accurate data collection for use in clinical trials, as well as by physicians to help counsel patients on improved compliance.
"Noncompliance is not a psychological defect," notes Grinnan. "It's a matter of training, understanding, knowledge and education in order to influence behavior. Electronic compliance packaging provides a way to measure that information, but we've also found it to be a very good intervention. If you show a patient the data, they see it, and they want to do better."
With these solutions, our customers go from being 'pill producers' to becoming healthcare providers.
While the electronic packaging solutions presently on the market for compliance may differ in format—mainly bottles and blister-packs—they all incorporate three essential components: an electronic chip to gather and store information; a reader to transfer that information to a PC; and software to compile the data.
The MEMS cap from AARDEX
The company with perhaps the most experience in electronic-compliance monitoring solutions mentioned in this article, AARDEX Ltd. was formed in 1995 when the European division of U.S.-based Aprex® was acquired by key staff. In 1999, the company acquired Aprex, which was responsible for the company's development of electronic monitoring solutions in the 1980s.
Explains Dr. Jean-Michel Metry, chairman and CEO of AARDEX, "In 1986 and 1987, two objective methods for compliance were developed: electronic monitoring and low-dose, slow-turnover chemical markers incorporated into dosage forms. While neither method is without limitations, both have enabled major advances in the understanding of patient's compliance with dosage regimens and thus, the spectrum of drug exposure in ambulatory care.
"Both methods also show that the predominant errors are those of omission, i.e. delays or lapses of scheduled doses. The marker methods prove dose ingestion during the three to seven days prior to blood sampling, but do not reveal the timing of doses. The electronic monitoring methods, i.e., time- and date-stamping micro-circuitry incorporated into drug packages, provide a continuous record of the timing of presumptive doses throughout periods of many months, but do not prove dose ingestion."
AARDEX' electronic monitoring solution, the Medication Event Monitoring System (or MEMS(R)) bottle cap was introduced in 1987. Available in standard diameters of 38, 42 and 45 mm for use with pharmaceutical bottles with a threaded neck finish of 38/400, 42/400 and 45/400 respectively, the MEMS cap incorporates a microelectronic circuit that registers and stores data on when the closure is opened, and when it is closed.
The MEMS 6 TrackCap, manufactured by Swiss molder Indtec S.A., features a battery life of 36 months from initialization, which takes place before the package is shipped. Says Metry, "In the past, initialization was done at the time of production, limiting the functional lifetime of the monitors." All event information gathered by the system is stored in a nonvolatile, EEPROM (electrically erasable programmable read-only memory), so that even if the battery fails, all stored data are preserved for reading and analysis for at least 10 years. The monitor features a memory capacity of 3,968 events, minus 150 events per year (e.g., 3,818 events after 12 months, 3,668 events after 24 months, etc.).
Another version of MEMS 6, the MEMS 6 SmartCap (A), offers the same functionality as the TrackCap, but has a battery life of 18 months and includes an LCD that indicates the number of times the package has been opened since the beginning of the day. Twelve bars in a circle around the central number indicate the number of hours that have passed since the last opening.
To transfer the time-stamped medication events stored in the MEMS 6 cap, users place the system on the MEMS 6 Communicator, a reader that connects directly to a Windows-based PC, for downloading to the company's PowerView(R) software. PowerView stores the data in a database, calculates the results and displays or prints reports of these results. According to AARDEX, the software provides several views of a dosing history to help the user rapidly pinpoint crucial dosing errors. Event information can also be downloaded directly to a secure website.
Another service offered by AARDEX is SMS (short message service) support, whereby patients are reminded to take their medications via SMS messages sent to their mobile phones.
Among the pharmaceutical companies cited by AARDEX as having used the MEMS cap are Abbott, Pfizer, Sanofi-Aventis and Bristol-Myers Squibb.
BOM's Helping Hand, IDAS II
Bang & Olufsen Medicom a/s (www.medicom.bang-olufsen.com), a wholly owned subsidiary of Bang & Olufsen a/s based in Struer, Denmark, was established in 1989 to develop compliance devices and services for use in clinical trials and as an integrated part of marketed drug concepts, relates Christian Husegaard, head of sales and marketing for BOM. Its solutions include The Helping Hand(TM) electronic blister-card and dispenser (B) and the IDAS II (Intelligent Drug Administration System) compliance monitor for clinical trials.
The Helping Hand, also known as the IDAS I, was launched in January 2004 and is designed to remind patients to take their medication, helping them to achieve a high level of compliance through the use of the very simple, intuitive and well-known format of a blister-card. Tablets are housed in a nonmedical, easy-to-access dispenser that uses an electronic chip and a mechanical switch to manage algorithms such as reminders, registration, feedback, resetting, power-down, shut-down, etc. The solution uses visual (LED) and acoustic reminders, and shows the patient's dose-intake pattern for the previous week, or two weeks, via a patented traffic-light color-code system.
Custom-designed for each pharmaceutical client's needs, The Helping Hand will soon be used in solutions for hypertension, osteoporosis, anticoagulation, transplantation, depression and other medications, according to signed agreements with BOM. While presently being employed only in Europe, the package could also be introduced in the U.S. and Japan, upon request, says Husegaard.
The IDAS II was developed in 2002 and 2003 for clinical trials and for delicate medical treatments that demand a very high compliance rate, where the recording of each tablet intake is required, along with the ability to export data for statistical analysis. The device works with blister-strips printed with lines of conductive ink. The lines are placed over the thin foil that covers the wells containing the tablet or capsule, while the blister-strip is held in a monitor equipped with contact points for the conductive lines. A microprocessor sends an electric current through the conductive lines at regular intervals. When the patient takes a tablet/capsule from the pack, the foil and conductive line are broken. This is registered in the microprocessor as an event.
This information is stored in the monitor's memory until it is loaded onto a PC or a server via a USB cable. Uploaded data, which is compatible with AARDEX' PowerView software, is presented in a graphic format with relevant tables for use by prescribing physicians and investigators. The device is also being further developed and prepared for wireless data transfer.
Like The Helping Hand, the IDAS II also has acoustic and visual indicators to remind the patient to take their medication, while its LCD screen shows the time since last dose, actual time and a battery indicator.
BOM says that the IDAS II has also been used for the company's internal purposes, in order to obtain more knowledge about compliance and persistence for use in developing technical solutions such as The Helping Hand, for high-volume, commercial applications. Relates Husegaard, "A recent study on patients with hypertension demonstrated an average compliance of 94 percent over a four-month period using our devices.
"With these solutions, our customers go from being 'pill producers' to becoming healthcare providers. A good drug with a good delivery system that empowers patients to be compliant creates a full solution."
The Med-ic ECM and eCAP from IMC
Established by Dr. Allan Wilson and business partner Michael Peterson just three years ago, Ottawa, ON-based Information Mediary Corp. (www.informationmediary.com) has created packaging solutions that use custom-designed Class 3 EPC (electronic product code) RFID (radio-frequency identification) tags, RFID readers and printed electronics to monitor patient compliance. Its flagship products are the Med-ic(R) ECM (electronic compliance monitor) device (C), which couples electronics with a standard blister-pack, and the eCAP(TM) (D), which IMC says is "the world's first and only RFID smart cap."
"RFID is a hot topic in pharmaceuticals and logistics," explains Peterson. "Although Med-ic merely utilizes RFID to transfer data and keep track of packages, it is an excellent way to combine both compliance monitoring and track-and-trace applications into one simple solution."
Med-ic was first previewed in March 2002 at the Interphex tradeshow. At the following year's event, IMC made a commercial announcement on the product, and since then, Peterson tells PD, various parties have been conducting validations, tests and trials for the future integration of Med-ic into their projects.
The Med-ic ECM device works much like BOM's IDAS II. The blister-pack uses proprietary patterns of conductive ink attached to an RFID tag to monitor and store information on the removal of a tablet or capsule from the pack. Unlike the BOM system, however, Med-ic uses a standard, wallet-style paperboard blister-card with the smart label applied to the pack, and is engineered for large-scale, industrial production.
Med-ic ECM package technology consists of a generic tag and a printed smart label that is custom-designed for each package configuration. As of July 2004, IMC has brought all packaging design and production activities in-house, where it manufactures the self-adhesive smart labels for application by the pharmaceutical customer to their blister-pack.
We are able to keep the Med-ic cost low while maintaining the ability to mass-produce the complex, electronic components by using our own proprietary, water-based, flexographic conductive ink [now commercially available as XINK Instacure(TM) from IMC subsidiary XINK Labs (www.xink.biz)]," explains Peterson. He adds that Med-ic's ECM tag can be connected to any layout of dosing regimen, without having to reprogram or retool the electronics, via a simple two-point connection, regardless of the number of tablets per package.
The transfer of event information from the package to a custom software interface is accomplished via the Med-ic CertiScan(TM) 13.56-Mhz RFID reader, developed by IMC and distributed by its subsidiary Intelligent Devices, Inc. (www.ecmdevices.com). Peterson explains that IMC designed CertiScan as a standard RFID read/write system with a twist: It actually verifies and corrects any recorded timestamps downloaded from any ECM.
A special download protocol speeds data transmission from the ECM-equipped device to the desktop, allowing, for example, 40 events from a Med-ic blister-pack to be downloaded in less than one-tenth of a second. Proprietary GUI (Graphical User Interface) software provides the user with an intuitive display and an overview of the patient's compliance history.
Optional features that could be incorporated into the Med-ic ECM blister-pack if requested include the capability to record temperature and humidity, as well as an alert/reminder function, Peterson relates. He adds that some areas where the company sees the blister-pack as being especially useful include brand-launch kits, opiate dispensing and monitoring systems, HIV treatments, niche applications such as organ antirejection therapies, semi-supervised tuberculosis treatments, marketing materials and promotions, post-marketing studies, and hospitals and chronic-care facilities.
Introduced in the spring of 2004, IMC's eCAP bottle cap records each opening of a standard, 33-mm, child-resistant (CR) pharmacy vial or a 38-mm medication bottle and includes a programmable reminder feature. Compatible with the same reader and software solution used with Med-ic ECM, the eCAP consists of an RFID tag embedded into a RemindCap(R) bottle cap from Remind Cap Ltd. (www.remindcap.com), with the cap, plastic liners and bottles supplied by Owens-Illinois Prescription Products (www.us.o-i.com).
The eCAP is currently being used in commercial applications by the University of Texas SW and by Weill Medical College at Cornell University. According to Peterson, the Med-ic ECM blister-pack is being tested by several university study groups and has been included in the protocol of various clinical studies. In addition, IMC has also signed a partnership agreement with contract research organization ABR Pharma of France. Together, Peterson says, the companies plan to make an announcement in the near future regarding a "sizable, three-year study, representing one of the first large-scale commercial rollouts of Med-ic electronic-adherence blisters—indeed the largest electronic-adherence-monitored study ever conducted."
Brought to market in the spring of 2004 for clinical-trial applications, the Cerepak(TM) (E) smart blister-pack from MeadWestvaco Healthcare Packaging uses technology similar to competitive electronic blister-packs, but goes a step further, incorporating the ability to capture patient QOL (quality of life) information via a reusable, electronic questionnaire. "That's very unusual," says Grinnan. "Typically, you can only gather that information during a doctor's visit. To be able to capture that data in real-time is very attractive to the clinical industry."
MeadWestvaco's Cerepak is the result of an agreement with Swedish technology development company Cypak AB (www.cypak.com), which engineered the concept of Intelligent Pharmaceutical Packaging (IPP), combined with MeadWestvaco's standard pharmaceutical heat-seal blister-cards, such as its CR Dosepak(R) compliance packaging. MeadWestvaco forged a licensing agreement with Cypak in early 2004 that gives the company exclusive rights to produce and market IPP technology in the Americas, as well as a nonexclusive right in the rest of the world.
The Cerepak solution includes four components: the data capture device, or the package; the reader; the software; and the analytical tools to create reports. Of these, Cypak's technology resides in the electronic module, or chip, that is embedded in the blister-pack, the way in which conductive inks are used in the package, and the interface that enables information to be uploaded from the package to a PC.
The Cerepak blister-pack is produced at MeadWestvaco's facility in Mebane, NC, where the heat-seal card is printed with a conductive trace, or ink pattern, and the electronic chip is adhered to the card. "The pattern in which the ink is printed would fall under the term 'know- how,'" says Grinnan. "There are very precise specifications for the width and the density of the ink and the way in which the card is sealed so that the ink does not scuff or dissipate and affect the connectivity of the package. The ink itself is not the key to the puzzle. It's more about designing and printing the trace, and then being able to seal the chip to the card afterward."
The Cerepak's electronic chip provides firmware and memory to store the data collected from its 32 inputs, where lines of ink are connected to the chip. Each input represents one blister cavity—or a place where a pill or a dose resides—or one answer in the package's QOL questionnaire. The chip also has a speaker and can be designed to activate an LED light to provide patient reminders. Options are also available to monitor temperature at predetermined times and to measure shock and vibration—"It's all a matter of cost and desire," Grinnan says.
Unique to Cerepak, the blister-card's QOL questionnaire is programmed by the firmware within the chip and consists of buttons embossed on the card that, when depressed, register in the chip as a change in the resistance of the conductive ink printed underneath. The way the questionnaire function works is totally dependent on the customer's preferences. For example, the area can be deactivated, except at certain times, based on when a pill is removed. "The primary methodology that we have come up with is to activate the pad immediately after the patient removes a pill," says Grinnan. "What you are measuring is how that patient feels right at that moment, which probably measures more the effect of the previous pill they took, rather than the one they just took thirty seconds ago, or a minute ago."
Questions may deal with things such as possible side effects, the patient's level of pain, etc., with each answer representing one input. MeadWestvaco says that while the chip currently validated for use with Cerepak offers 32 inputs, the company hopes to offer chips in the future that can provide up to 100 inputs.
As with other electronic compliance systems, Cerepak uses a mousepad-like reader that connects to a Windows-based PC via a USB port. The contactless reader, made in Europe under contract by Cypak, uploads information to AARDEX' PanelView software or to its password-protected website, the former of which Grinnan says is preferred for clinical trial work, and the latter, for academic purposes.
And lastly, the Cerepak solution provides the customer with analytical tools in the form of a complete analysis of the compiled data by AARDEX. "Many times with this technology, it's the data that is important, not the package," says Grinnan. "If the data is not used effectively, the industry will not adopt the technology, no matter how sexy or interesting it might be. The data needs to be compelling. It needs to help make trials less-expensive and more effective and to make drug development much more medically sound."
Although MeadWestvaco is under nondisclosure agreements with all of its Cerepak customers, Grinnan confirms that trials of the package have occurred in both the U.S. and Europe. "The package provides a tremendous amount of data that simply was not available before," he remarks. "There's been a lot more interest in reducing liability with the package than we originally foresaw. I think pharmaceutical companies see it as a way of being smarter in the way they are designing drugs."
Though it has been marketed first and foremost for the clinical-trial industry, the Cerepak blister-pack can also be used as an effective tool for some commercial applications, as well. These include chronic disease states and health conditions with asymptomatic indications, like high blood pressure or diabetes. Grinnan says that the Cerepak should be in commercial application by mid-2006.
More information is available:
AARDEX® Ltd., 41 41 768 01 01. www.aardex.ch
Bang & Olufsen Medicom a/s, 45 96 84 58 00. www.medicom.bang-olufsen.com
Cypak AB, 46 8 545 008 35. www.cypak.com
The Healthcare Compliance Packaging Council, 703/538-4030. www.unitdose.org
Indtec S.A., 41 27 329 08 34.
Information Mediary Corp., 613/745-8400. www.informationmediary.com
Intelligent Devices, Inc., 613/745-8400. www.ecmdevices.com
MeadWestvaco Healthcare Packaging, 800/864-2685. www.meadwestvaco.com/healthcare.nsf
Owens-Illinois Prescription Products, Inc., 800/321-3391. www.us.o-i.com
Remind Cap Ltd., 419/247-8529. www.remindcap.com
XINK Laboratories Ltd., 613/745-8400. www.xink.biz