Background and Requirements for Medication Monitors for TB Treatment
WHO's stop TB strategy stresses the use of supervised treatment which may need to include directly observed therapy (DOT). The supervision of treatment can be carried out by a treatment supporter, who is acceptable to the patient and trained and supervised by health services. (WHO/HTM/STB/2006.37) . The WHO website states ”Supervised treatment may have to include direct observation of therapy (DOT)”
While certainly appropriate and more reasonable than previous recommendations of DOT for everyone, this recommendation could result in treatment failure if the patient was not on DOT and the person responsible for supervising the patient failed to recognize that the patient was not taking the medication as prescribed.
Medication monitors, devices that determine when patients remove medication from a container, could improve results with this recommendation by providing the patients' adherence records to the patient and treatment supporters. This should help motivate the patient and greatly increase the effectiveness of the treatment supporters by allowing them to 1) give more intensive counseling to the less adherent patients and their families, 2) provide DOT when necessary, 3) extend the duration of therapy based on the monitor adherence record, and 4) use the time saved not giving DOT to everyone to return defaulters to treatment.
Engineers in several parts of the world have created medication monitors, However, since all of these devices have limitations the following is presented to help decision makers choose the most appropriate device, and help engineers develop optimal equipment.
The Global Drug Facility (GDF) of WHO distributes Fixed Dose Combinations (FDCs) of several different drugs in one pill. The ratio of the individual drugs within the combination is chosen so the dose can be appropriate for individuals of varying weights by providing the patient with the appropriate number of pills (2, 3, 4, or 5) to be taken at each dosing time based on his or her weight . Hopefully, the medication from the Global Drug Facility (GDF) will become the standard for what is distributed worldwide.
Except when toxicity forces the clinician to use a non standard regimen, a four drug fixed dose combination consisting of isoniazid (INH), Rifampin (RMP), pyrazinamide (PZA), and ethambutol (EMB) is usually given in the initial phase of therapy, and a two-drug combination of INH and RMP in the continuation phase of therapy.
One of the medications, EMB, is hygroscopic. Therefore, the medication for all drug combinations containing EMB should be dispensed with moisture proof protection. If the dispenser that is chosen does not use the GDF's moisture proof packaging, there would need to be another means to exclude moisture if ethambutol by itself or in a fixed dose combination is being given.
The packaged medication currently being distributed by the GDF can be used with the Clip Monitor for WHO's packaged medication, Stack Monitor, and Cover Opening Monitor.
The strip package monitor will dispense the GDF medications, but the device would be quite large and a different form or packaging will be required. Perhaps a more serious drawback of this design is that, despite the indication provided by the LED, each time the patient removes medication it is possible for him to remove either more or fewer pills than had been prescribed. This can in some cases lead to irregular dosing. It can also present the caregiver with a difficult challenge when interpreting the compliance record. The modular strip package monitor overcomes this latter problem but is somewhat more expensive.
If a dispenser is chosen that does not use the GDF's moisture proof packaging, other means to exclude moisture are described for hygroscopic medication in the section Alternate Means of Providing Moisture Protection, and Cap Opening Monitor with Buzzer to Motivate Patient to Close and Tighten Cap to Prevent Moisture from Reaching the Medication. These may not be as effective.
Medication Monitors without Packaging
If the medication being dispensed is not hygroscopic, factory packaging would not be required and a device with compartments that could be filled in the clinic could be used. Examples are 1) multi compartment monitor, 2) trace sheet monitor, or 3) a carousel configured device, like that which is shown on the section, devices developed by other groups. While all original treatment regimens currently employ ethambutol in the initial phase of treatment this may change as new drugs for TB are introduced. For instance four drug regimens containing moxifloxacin instead of ethambutol are now being considered. If this occurs, one of these latter three devices without packaging may become the preferable device.
Most devices can be separated into two classifications.
A) Cover or Cap-Opening Monitors
These devices determine when the cover or cap of a container is opened, but do not detect how much, if any, medication is removed when the device is opened. If the patient opens the device to see how many pills remain (curiosity openings) or a child opens the container to play with it, an inaccurate record of pill removal is created. If the device includes a light-emitting diode (LED) or beeper to remind the patient to take medication, these helpful features are inactivated with each spurious cover opening. If the adherence record shows that the cover has not been opened for a period of time, the patient can claim that he/she removed excess doses (pocket doses) prior to going on a trip that were ingested while away on the trip. If the patient makes such a claim, the caregiver would not know if the patient was telling the truth. On the other hand, cover-opening monitors are the least complicated and least expensive, with an estimated cost of US$10 each in production quantities (D Ellis, personal communication).
B) Dose-Removal Monitors
These devices overcome all spurious indications of medication removal when a child or adult opens the cover or cap but does not remove medication. If while traveling, a patient does not remove medication from the monitor because he/she did not take the device with him/her, but removed medication prior to going away (pocket doses), this fact will be recorded. This allows the caregiver to make a better judgment about probable adherence when record shows a period of days when no medication was removed and excess medication was removed prior to the days of non-removal. Unfortunately, dose removal monitors will be somewhat more costly, in a range between $13.00 and $18.00 in production quantities (D. Ellis, personal communication). As the device can be reused, the cost per patient would be less. This expense needs to be weighed against the cost of delivering DOT to all patients and the much greater costs of retreating failure MDR-TB patients if DOT is not given.
In sum The Cover and Cap Opening Monitors are less complicated and less expensive to construct. However, they provide less accurate data on adherence than Dose Removal Monitors. Consequently they are more likely to lead to poorer treatment surveillance and treatment failure. Therefore, if at all possible Dose Removal Monitors should be used.
Requirements for Optimal Medication Monitors for TB Medications
1) In many clinics throughout the world intermittent (2 times/week and 3 times/week) treatment regimens for TB are used. These were developed to make directly observed therapy less of a burden for the patient, clinics, and caregivers. While results at the end of treatment showed them to be effective, evidence is now emerging that intermittent regimens in service programs provide inferior long term results. Therefore, daily regimens should be employed when medication monitors are used because:
A. Patient is more likely to remember to take medication once a day rather than every other day.
B. Daily regimens will avoid adding the scheduled interruptions of intermittent therapy to the interruptions caused by the patients who fail to take medication faithfully, thus reducing the total number of interruptions.
C. While a meta-analysis of randomized controlled trials found little difference between daily and intermittent regimens (1) report from routine service programs in which patients often miss doses revealed more relapses in patients taking intermittent treatment. (2) (3)
D. Two studies show intermittent regimens lead to more drug resistance if patient is HIV positive (4)(5).
1) Menzies D, et al. PLOS medicine 2009 Sept 15
2) Chang K C et al Am J Respir Crit Care Med. 2004; 170: 1124-1130.
3) Vernon A A. Am J Respir Crit Care Med. 2004; 170: 1040-1042.
4) Burman W, Am J Respir Crit Care Med. 2006; 173: 350-356.
5) CDC- MMWR Weekly Reports. 2002; 51: 214-215.
2) Medication Monitors should dispense fixed dose combinations (FDCs) of drugs to:
A. Have fewer different items in the supply lines from the factory to the clinic in order to reduce logistics problems and reduce the chance that one or more required medications are not in the clinics, an occurrence that is called stock outs.
B. Reduce the chance that drug resistance will develop when stock outs of individual drugs occur or when the patient fails to take one or more doses of medication by ensuring that the patients take all of the prescribed drugs or none at all.
C. Decrease the size of the device.
3) The device or the packaging should provide protection against ambient moisture for any regimen that includes ethambutol, which is hygroscopic. The optimal way to achieve this is to use the packaged fixed dose combination of drugs distributed by WHO’s Global Drug Facility. Packaging at the clinic level is possible if electrically powered sealing equipment in available, but factory packaging is much more likely to be successful. Adequate moisture protection may be achieved with desiccants together with a device that has a moisture resistant cover, and buzzer to remind the patient to close the cover. A buzzer is also described in section entitled Alternate means of providing moisture protection.
4) The device and packaging should allow for adjustment of dosage for patients of different weights without multiple dosages of the same drug or drug combination in the supply lines from the factories to the clinics.
5) The device should be capable of dispensing a 2-week supply of medication in initial phase of therapy and a 4-week supply of medication in the continuation phase. This makes for a reasonable sized device. While it doesn’t provide a 4-week supply for all phases of therapy, most patients need more contact with the clinic or caregiver (every two weeks) in the initial phase. If it is absolutely necessary to give the patient a four-week supply of medication in the initial phase, the patient could be given two monitors.
6) The device should be constructed so the patients can see how much medication remains in order to make it easier for the patient to return to the caregiver for refills on time. Alternatively, but less effectively, a light emitting diode (LED) display could be used to tell the patient that the remaining supply of drugs is low or exhausted.
7) The device should minimize the likelihood that children or adults will play with it and open the cover without removing medication.
8) The device should detect the occurrence of medication removed in advance of the day when it should be ingested.
9) The device should be as small as possible to make it portable.
10) The device should be difficult for an uninformed person who might want to steal the battery to open, but easy for an informed caregiver to open for reloading the device and replacing the battery when needed. It is desirable to avoid using a lock and key, since the caregiver might lose the key, but this may not be possible.
11) The batteries should have a long life.
The devices that currently come closest to achieving these objectives are the Clip Monitor for WHO’s Packaged Medication and the Stack Monitor.
12) There must be an effective means to retrieve the adherence record. This can be done in multiple ways but probably the best way is described in the section s Retrieval of the Adherence Record with Audible Tones in the Clinic or Transmitted to the Clinic by Mobile Phones and Retrieval of Adherence record in Patient’s home using red/green/yellow LED.
13) There needs to be a means to instruct and remind the patient to take medication. This could be achieved as described in the section Using a Red LED and possibly a Buzzer to Alert and Instruct the Patient to Take Medication.