Figure 4: Opened Cover Opening Monitor showing the use of protruding tabs to open the cover.
When the cover is closed, as in Figure 3, it depresses a button which opens a switch mounted on the monitor's circuit board. When the patient opens the cover, as shown in Figure 4, the button is released and the switch closes. This causes the monitor's microcontroller to direct the LED to flash red or green depending on whether the box had been previously opened that day. If the box had not been opened earlier in the day, the microcontroller would record the box-opening event as representing medication removal. (If the box is opened again during the day, it is assumed that the patient was not removing additional medication since the LED would be instructing the patient not to take additional medication.)
Since it might be difficult for the caregiver to use the button which senses opening of the cover as the button with which the microcontroller is directed to display the adherence record, a second query button may be provided, as shown in Figures 3 and 4. This query button would also activate a switch on the monitor's circuit board. It would be accessible without opening the cover through a query button access hole in the cover as shown in Figure 3. The patient could also use this query button to query the monitor as to whether medication had been taken, without opening the container. This might reduce extraneous openings by patients who wanted to know if they had taken medication but did not intend to take medication immediately if they had not already taken it.
Cover Opening Monitors with Spring Loaded Cover and Alternative Opening Tabs;
The protruding tabs shown in Figures 3 and 4 might invite children or an adult to "play" with the device by grasping the tabs, opening the device, and creating a false record of medication removal. The device in Figure 3a and 4a should reduce this occurrence, by substituting a downward directed vertical opening wall for the upward protruding vertical opening tab. The patient would open this device by placing his fingers into the pocket behind the vertical opening wall and bring the two tabs together with his thumb on the horizontal opening tab. Otherwise the device would function the same as shown in Figures 3 and 4.
I. Cover and Cap Opening Monitors
The simplest form of a medication monitor detects when the cover of a container of medication is opened. The patient is instructed to open the container to remove the prescribed doses of medication and to close the cover after the medication has been removed. A record of when the container is opened or not opened then provides reasonable evidence of when the medication was taken.
As of April 2007 Cap Opening Monitors are commercially available, and are designed to have their data retrieved by an electronic data collection system, either a computer or a PDA. The data collection system may be periodically connected directly to the monitor, or data may be transferred to a remote data collection system through a telephone or other data link.
Cover and Cap Opening Monitors could be made much more applicable to developing countries if they didn’t require an electronic data collection system or data link to retrieve the compliance record. This could be achieved simply by including an inexpensive “built in” LED that could:
1) Instruct the patient when to take medication,
2) Display an indication of how faithful the patient was in opening the container each day, which would aid caregivers and treatment supporters in deciding on the appropriate degree of supervision for the patient.
3) Display the number of months since the patient started therapy,
4) Display the sputum status or other clinical data
5) Display an indication of the extent to which the patient takes medication near the same time each day, which may prove to be a useful predictor of subsequent adherence,
6) Display the charge remaining in the monitor’s battery.
To implement these functions, the monitor would include an electronic unit which would generally incorporate a microcontroller with associated electronic memory and clock, a red/green LED, batteries, a switch to sense when the container was opened, and a button which could be used by the caregiver to retrieve information. In some designs, this button could also activate the switch, which senses container opening, as described below for the Cover Opening Monitor without a spring to close the cover.
When both the red and green LEDs are illuminated a yellow light is emitted. For convenience, the red/green LED, which can produce red, green or yellow illumination, will be referred to simply as the LED.
Data transfer from the Cover and Cap Opening Monitor to a computer or PDA should also be possible when a red/green LED is available. A pair of external sensors, one sensitive to the light from the red LED and one sensitive to the light from the green LED could be used to create an optical coupling through which data could be transferred.
It should be possible to manufacture Cover and Cap Opening Monitors in large volumes for $5.00 each, or less. Since each monitor could be reused by a number of successive patients unless it was lost or broken the cost per patient should be less.
Treatment adherence related information, which could be collected by a Cover and Cap Opening Monitor, includes:
1) For each day, whether the container was opened, or not.
2) For each day, whether the container was left open rather than being closed.
3) For each day that the container was opened, at what time was it opened.
With a simple Cover and Cap Opening Monitor, however, it would not be possible to determine whether medication was removed when the container was opened, how much medication was removed, or whether medication was returned to the container. Like all medication monitors it would not prove that the medication was ingested.
Use of Display by the Patient
The red/green LED could be used to remind the patient to take medication. This would be effective as long as the device was kept in a location that it could be readily seen. There are multiple ways the LED could be used since the LED can flash red, green, or yellow. It can also flash continuously or intermittently. One suggestion would be to have it flash sequentially, red, yellow, and green when the time comes to remind the patient to take medication and remain off after the patient takes medication and at all other times.
Alternatively, a beeper or buzzer could be used to remind the patient. While this has the advantage that it could be heard if the device was kept in a location where it could not be seen, it has the disadvantage that it might annoy a family member who would open the device or remove medication to turn off the beeper when the patient was not home. This would create record of removal of medication that the patient probably did not take. This problem could be minimized by programming the beeper to beep late in the evening on those days that the patient had failed to take medication, because the patient is likely to be home by late in the evening
If the patient decides to take medication without first being reminded, he or she could use the LED to answer the question, "Did I or did I not take medication today?” This could be done by opening the cover or cap on the Cover and Cap Opening Monitor or by pushing a query button. Both actions would activate a query switch. Pushing the query button would be preferable because it would not create the record that the cover had been opened.
Either of these actions would initiate illumination(s) of the LED to instruct the patient. If the patient was supposed to take the medication it would probably be best to use the same set of intermittent illuminations that were used to alert the patient. If the patient had already taken medication and was not supposed to take it, a constant red illumination could be used.
In addition, several seconds after the patient opened the cover it would probably be best to have the LED flash and continue to flash yellow until the cover was closed to remind the patient to close the cover. If the patient does not close the cover a buzzer could be activated to further notify the patient to close the cover. Alternatively, the cover could be attached with a spring-loaded hinge, which would automatically close the cover as shown in Figures 3 through 5.
Since there are multiple ways the display could be used, determination of optimal combination of illuminations may need to be established with field studies.
A potential minor problem arises if the patient opens the cover to visualize how much medication remains in the container (curiosity openings) and does not remove medication. The monitor would then create a false record of medication removal. If later in the day the patient opened the cap or cover again to take medication, the red LED would instruct him not to take it. If this resulted in the patient not taking medication only occasionally it would not be serious. To minimize the occurrence of such curiosity openings the container should be made of transparent material so the patient would be able to see how much medication remains without opening the container.
Use of Display by the Caregiver
When the caregiver wants to retrieve the adherence record and determine the charge remaining in the batteries, he or she would use the query button to introduce a code like one of the codes in the Morse code. The LED would then flash green if the batteries were fully charged, yellow if partially discharged, or red if the batteries needed replacement. Then, the caregiver would initiate a process of information retrieval, by pressing the query button again.
There are numerous ways in which adherence information collected by the Cover and Cap Opening Monitor could be presented to the caregiver with the LED. Two useful presentations would be:
1) The percentage of adherence (the percentage of days the cover was opened)
2) The detailed adherence record, which will only be needed occasionally.
Obtaining the percentage of adherence
To obtain the percentage of adherence since the last refill, the caregiver could push the query button again and the LED would flash
1 Green flash for > 90% adherence since last refill
1 Red flash for 80-89% adherence
2 Red flashes for 70-79% adherence
3 Red flashes for 60-69% adherence
An increasing number of red flashes for greater degrees of poor adherence if this much detail is needed.
If the patient had not closed the cover for one or more days this would be counted as non-adherence and the caregiver would be notified that the cover had not been closed with a number of yellow flashes corresponding to the number of days the cover had not been closed.
With this display the caregiver could quickly learn the overall adherence of the patient since the last refill. At this point the caregiver or supporter would most likely want talk to the patient and family responding with praise, or mild reprimands, depending on the degree of adherence that was found. The caregiver could then retrieve the adherence record for the preceding interval between refills with a second push of the button. This process could be repeated until the entire adherence record from the start of therapy had been retrieved. After the entire adherence record had been viewed, the next push of the button would yield no illumination of the LED. Following this, an additional push of the button would elicit a display of the number of months since the start of therapy with one green flash for each month. If the patient had been given medication once a month, this information would be redundant and not needed. If the patient had been given medication at more frequent intervals this function could be helpful.
Obtaining a detailed adherence record (Needed only rarely)
If the patient has a poor or fair percentage of adherence, the caregiver might want to examine the record in detail, especially if the patient claims he took medicine out in advance e.g. to have medicine while away on a trip without taking the device with him. If he took out medicine in advance it would show up as days when medication was not taken because the cover would not be opened for the days he was on the trip.
The detailed adherence record could be displayed for each interval between refills with two quick pushes of the button. The record would be presented as a series of flashes of the LED in which each flash represents one day. If the patient opened the monitor on a particular day, the LED would flash green for that day. If the patient failed to open the container on a particular day, the LED would flash red for that day. If the container had been left open all day, the LED would flash yellow. Using this sequence of flashes the caregiver could roughly determine if the adherence record was consistent with the days when the patient claimed he took medicine in advance and counsel the patient appropriately. If there were a number of yellow flashes, the caregiver would want to reinforce the instruction to close the container each time medication was removed.
There are other special situations where the caregiver might want to review the detailed adherence record. For instance, the patient might take 100% of his 28 doses of medication. but not return until four weeks later (56 days since the device was refilled). The patient might have a record which showed he took 100% of his medication because he took 14 doses and returned in 14 days and sold the remaining 14 doses on the black market. A long (5 second) red illuminations of the LED could alert the caregiver that the detailed record needs to be examined in these situations.
While obtaining this detailed compliance record would be more time consuming than observing the percentage of medication removed, this detailed information would probably be needed only occasionally.
Determining Time of Day Consistency
There is preliminary evidence that those patients who consistently take medication near the same point in time each day are more likely to complete treatment than patients who take medication at different points in time even though both groups take medication each day. (Menzies, et. al. Int J Tuberc Lung Dis. 2005; 9: 1343- 1348).
If confirmed with additional studies, this information about time of day consistency would be useful in choosing the appropriate degree of supervision for the patient. The degree of consistency could be captured with this device, and displayed with the LED. To do so criteria would need to be chosen for good, intermediate, and poor time of day consistency and the microcontroller programmed to place the patient in one of these three groups.
To retrieve the time of day consistency information, the caregiver would use the same button, but introduce a different code; and the microcontroller would direct the LED to flash green if the patient fell into the consistent category, red if he was inconsistent, and yellow if he had intermediate consistency.
Additional Data that Could be Gathered and Displayed
Sometimes all written records on the patient are lost and the caregiver does not have basic clinical information on the patient. For, instance, is the patient sputum positive or negative? This data could also be displayed with the LED. If the caregiver introduced another different code the LED could flash red if sputum positive, green if sputum negative, and yellow if the sputum status was unknown.
Use of Programmable and Non Programmable Microcontroller
During the initial trial phase, investigators will probably want to determine how best to display the compliance record so it can be readily accessed and understood by the caregiver. Fortunately, the device could be made with a programmable microcontroller that makes this possible. Once the optimal presentation has been determined and the decision is made to mass-produce the device for millions of patients a non-programmable microcontroller would probably be preferable since it costs about $1.00 less.
Description of Cover Opening Monitors:
Possible cover opening monitors include an unlimited range of design variations. The four monitors described here are boxes approximately 5.60"x 6.10"x 1.75" inches (14.2 x 15.5 x 4.5 centimeters), about the size of a thick small to medium book. These are designed to accommodate a two week supply of strips each containing up to 5 pills of the four-drug combination tablet of isoniazid (INH), rifampin, (RMP), pyrazinamide (PZA), and ethambutol (EMB) used in the initial phase of therapy, or a four week supply of smaller strips also containing up to 5 pills of the INH and RMP combination tablet used in the continuation phase of treatment. (Both of these preparations are supplied by WHO's Global Drug Facility.)
Cover Opening Monitor Without Spring Loaded Cover
This device is the least expensive, least subject to mechanical breakdown, and easiest for the staff to learn to use. It will probably prove to be the most practical device if the potential problem of patients failing to close and latch the cover is found to be less significant than erroneous recordings resulting from people playing with a spring loaded cover described in Figures 3 through 5 plus the added cost and inconvenience of the spring closure.
Figure 2. Cover Opening Monitor for the Isoniazid and Rifampin Tablet.
Figure 2. shows the same monitor as Figure1 with a four-week supply of the INH and RMP combination tablet.
To motivate the patient to close the cover the LED could start flashing yellow 15 seconds after the cover was opened, and or a buzzer could initiate a buzzing sound 30 seconds later if the cover was not closed.
Figure 3. Cover Opening Monitor with spring loaded cover, for dispensing Global Drug Facility packaged TB medication.
The monitor shown in Figure 3 incorporates a hinged cover with a spring to hold the cover closed. With this design, the spring acts against two protruding tabs, one on the box and one on the cover. These tabs are designed so that they can be grasped with one hand in order to open the box, as shown in Figure 4. While the cover is thus held open by one hand, the other hand can remove a dose of medication.
Figure 3a: Cover Opening Monitor with spring loaded cover and alternative opening tabs.
Figure 4a: Opened Cover Opening Monitor showing the use of Alternative Opening Tabs to open the cover.
Cover Opening Monitors with Spring Loaded Cover without Opening Tabs;
The spring loaded device shown in Figure 5 depicts a second way of avoiding the use of protruding tabs by incorporating an extension on one side of the cover which can be used to hold the cover open. This extension is roughly parallel to the side of the box and incorporates a flanged groove. There is a corresponding flanged groove in the side of the box. To open the box, the patient would hold the box with the left hand, lift the cover with the right thumb, and slide the thumb along the extension until it reaches the flanged grooves. When the thumb is in the grooves it will hold the cover open. At this point the patient can grasp the box with the rest of the right hand and free up the left hand to remove a dose of medication.
Figure 5: Cover Opening Monitor with a spring loaded cover which can be held open by the patient's thumb.
With this design, it is even more difficult to use the button which senses the cover opening for the purpose of retrieving the compliance record. So, the second query button which is accessible without opening the cover probably becomes essential with this design.
Use of a hinged cover with a spring to close the cover, as shown in Figures 3, 3a, 4, 4a and 5, offers reasonable assurance that the patient will not leave the cover open. This would largely avoid the problem of recording and interpreting days when the cover was left open and could offer better protection to the medication than a box which could be left open. However, the spring loaded cover adds some cost to the monitor and is somewhat of an inconvenience to both the patient and the person responsible for filling the container. Furthermore, the device shown in Figure 5 may be an inconvenience to the patient. In addition, the spring loaded cover might invite the patient or members of the patient's family to play with the monitor creating erroneous recordings, especially with the device shown in Figures 3 and 4. For these reasons the device shown in Figure 1 is probably preferable.
If it is necessary to use the device for medications that are placed in packages in the clinic, the type of package shown in Figure 7 could be used. However, packages filled in the clinic may not provide adequate protection against moisture for those medications where moisture protection is needed.
Figure 7: Package for multiple different pills to be filled in the clinic.
Description of Cap Opening Monitor:
Two companies produce medication monitors that determine when a cap is removed from a bottle of medication. These monitors require a computer or PDA to retrieve the compliance record.
Aprex Inc. www.aardex.ch/aardex/index.htm
Information Mediary Inc. www.informationmediary.com
One company markets an advanced Cap Opening Monitor, which sends a cell phone signal to a server each time the bottle is opened:
Simpill Inc. www.simpill.com
The server keeps the adherence record and can automatically notify the patient, the caregiver, and or the supervising office every time the patient fails to take medication. It may prove to be useful in the developed countries, but because of the added cost of the cell phone capability, it is difficult to justify in poor developing countries.
As noted above, Cover and Cap Opening Monitors with built in displays would be more applicable in developing countries. Figure 8 shows a conceptual design for a Cap Opening Monitor incorporating a LED for presenting compliance data in the same manner as for the Cover Opening Monitor.
Figure 1. Cover Opening Monitor for Four-Drug Combination Tablet.
Figure 1 shows a cover opening monitor having a simple, integral, hinge without spring closure, which contains a two-week supply of the four-drug combination tablet.
Figure 8: Cap Opening Monitor with built-in display
The Cap Opening Monitor has advantages relative to the Cover Opening Monitor since it is slightly less expensive and less bulky, which makes it easier to take on a trip.
However, since it dispenses loose pills rather than strips of packaged medication there is a greater likelihood for the patient to take an incorrect dose. Also, since the medication is not packaged, it provides less adequate moisture protection for hygroscopic medications. On the other hand this type of device might be suitable for the continuation phase of therapy, since Rifamate* (The Fixed Dose Combination of Isoniazid and Rifampin) is usually dispensed in bottles in the United States.
Cap Opening Monitor with Buzzer to Motivate Patient to Close and Tighten Cap to Prevent Moisture from Reaching the Medication
Ethambutol is hygroscopic. This means the fixed dose combination of isoniazid, rifampin, pyrazinamide, and ethambutol is also hygroscopic. There is evidence which suggests that when this combination of drugs gets moist, the effectiveness of the preparation is reduced. Therefore, the amount of ambient moisture reaching the medication should be reduced to the greatest extent possible. This is usually done by placing a desiccant in the bottle of medication.
However, if the patient leaves the cap open after removing a dose the desiccant can become saturated with moisture rendering it ineffective. Therefore, additional measures may needed to make sure the cap is closed and fully tightened after each dose is removed.
Other reasons for making sure the cap is closed is to reduce the chance that the medications will be spilled or some other substance will get into the bottle.
One way of encouraging the patient to close the cap would be to build a buzzer into the cap that would start buzzing a short interval after the cap was removed (15 seconds) and continue to buzz until the cap was closed. This should remind the patient to close the cap. If the patient failed to do this, the continued buzzing noise would most likely prove to be a sufficient annoyance that some one in the family would be motivated to close the cap.
It may be necessary to go one step further and create a means that motivates the patient to tighten the cap after it has been closed.
A mechanism to achieve this objective is shown in Figures 9, 10,11,12
Figure 9 shows a bottle cap shell with a ring around the cap with a small ring for attaching a strap or chain to connect the cap to the bottle while the cap is removed. It also shows a query button for the patient and caregiver.
Figure 9: Closure warning bottle cap which can be attached to bottle
Figure 10 shows how the cap incorporates a seal plate with an elastomer seal, which seals against the rim of the bottle. The seal plate is able to move within the cap shell, as will be described later.
Figure 11: Cut away view of closure warning bottle cap showing means for sensing required sealing force.
Figure 11 shows that the seal plate has a central projection, which contacts a switch lever to actuate a switch. Around this projection is a spring. As the cap is screwed onto the bottle, the seal plate moves up in the cap shell compressing the spring between the seal plate and a spring support plate. The spring force is the force pressing the seal against the lip of the bottle. When the spring compression is sufficient, the projection has moved far enough to open the switch, signaling that the bottle is sealed. There is a thrust washer between the end of the spring and the seal plate which allows the seal plate to rotate relative to the cap shell without "winding up" the spring.
When the cap is unscrewed, the projection moves away from the switch lever closing the switch and signaling that the bottle has been opened. If the cap remains unscrewed for some period of time (perhaps 15 seconds) a buzzer sounds reminding the patient to screw the cap onto the bottle.
The closing of the switch signals a microcontroller to record when the cover is opened and medication presumably removed. Time information is derived from a real time clock (not shown).
Figure 11 also shows that the top of the warning cap has a screw cap that can be removed to change the batteries. As indicated in Figure 11, the query button extends the through the top of the cover. If the query button was constructed with enough travel, it could be pushed down below the inner surface of the top cover allowing the cover to be unscrewed. Otherwise it would function as a lock when it was not pushed down to a sufficient extent. This would normally prevent the patient from unscrewing this cover.
Figure 12 shows the circuit board with the microcontroller, buzzer, batteries, query button, and LED. The query button along with the microcontroller and LED can be used by the patient for instructions when to take medication and by the caregiver to retrieve the adherence record as described in the section, 'Use of Display by the Patient' and 'Use of Display by the Caregiver'.
Figure 10: Cut away view of closure warning bottle cap showing seal.
Figure 12: Cut away view of closure warning bottle cap showing multiple elements
Summary
Despite the minor limitations of the Cover and Cap Opening monitors compared with Dose Removal Monitors that determine when each dose is removed, they provide a much better means of determining compliance than current approaches: pill counts, appointments kept, urine tests, staff judgments, etc. This plus the fact they are less complicated and less expensive makes them very attractive.
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I. Cover and Cap Opening Monitors
II. Dose Removal Monitors
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