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Microelectronic adherence monitors for metered-dose inhalers: Who monitors the monitors?☆☆☆★

1999; Elsevier BV; Volume: 104; Issue: 1 Linguagem: Inglês

10.1016/s0091-6749(99)70108-9

1097-6825

Donald P. Tashkin,

Allergic Rhinitis and Sensitization

Metered-dose inhalers (MDIs) are the most widely prescribed agents for the treatment of asthma. According to current consensus guidelines, 1National Asthma Education and Prevention Program Expert Panel Report 2. Guidelines for the diagnosis and management of asthma. Department of Health and Human Services, National Heart, Lung and Blood Institute, 1997Google Scholar optimal pharmacotherapy for control of persistent asthma generally requires regular daily use of inhaled corticosteroids in appropriately prescribed doses, usually administered twice daily, together with a short-acting inhaled bronchodilator for quick relief of symptoms as needed. For moderate-to-severe asthma, adjunctive therapy with a long-acting inhaled β-agonist is often prescribed also for maintenance use twice daily. Unfortunately, despite the pivotal role of inhaled medication in asthma management, adherence to prescribed use of inhalers for asthma is generally poor, resulting in underuse of regularly scheduled inhaled medication and frequent overuse of short-acting inhaled β-agonists. 2Mawhinney H Spector SL Kinsman RA Siegel SC Rachelefsky GS Katz RM et al.Compliance in clinical trials of two nonbronchodilator, antiasthma medications.Ann Allergy. 1991; 66: 294-299PubMed Google Scholar, 3Mawhinney H Spector SL Heitjan D Kinsman RA Kirks JF Pines I. As-needed use in asthma usage patterns and patient characteristics.J Asthma. 1993; 30: 61-71Crossref PubMed Scopus (38) Google Scholar Poor adherence to prescribed use of inhalers for asthma is believed to contribute substantially to treatment failure, 4Milgrom H Bender B Ackerson L Bowry P Smith B Rand C. Noncompliance and treatment failure in children with asthma.J Allergy Clin Immunol. 1996; 98: 1051-1057Abstract Full Text Full Text PDF PubMed Scopus (565) Google Scholar and thus it likely contributes to asthma morbidity and mortality and represents a major challenge to health care providers. A number of studies have used microelectronic devices for monitoring MDI use, notably the Nebulizer Chronolog (Forefront Technologies, Inc, Lakewood, Colo), which contains a mechanical microswitch and microprocessor within the case housing the MDI canister to electronically record and store the date and time of each actuation. Each of these studies has shown that patient self-reporting markedly overestimates adherence to regularly scheduled inhaled controller medication, 2Mawhinney H Spector SL Kinsman RA Siegel SC Rachelefsky GS Katz RM et al.Compliance in clinical trials of two nonbronchodilator, antiasthma medications.Ann Allergy. 1991; 66: 294-299PubMed Google Scholar, 4Milgrom H Bender B Ackerson L Bowry P Smith B Rand C. Noncompliance and treatment failure in children with asthma.J Allergy Clin Immunol. 1996; 98: 1051-1057Abstract Full Text Full Text PDF PubMed Scopus (565) Google Scholar, 5Spector SL Kinsman R Mawhinney H Siegel SC Rachelefsky GS Katz RM et al.Compliance of patients with asthma with an experimental aerosolized medication: implications for controlled clinical trials.J Allergy Clin Immunol. 1986; 77: 65-70Abstract Full Text PDF PubMed Scopus (156) Google Scholar, 6Gong Jr, H Simmons MS Clark VA Tashkin DP. Metered-dose inhaler usage in asthma. Comparison of nebulizer chronolog and daily diary recordings.J Allergy Clin Immunol. 1988; 82: 5-10Abstract Full Text PDF PubMed Scopus (54) Google Scholar, 7Coutts JAP Gibson NA Paton JY. Measuring compliance with inhaled medication.Arch Dis Child. 1992; 67: 332-333Crossref PubMed Scopus (245) Google Scholar, 8Rand CS Wise RA Nides M Simmons MS Bleecker ER Kusch JW et al.Inhaler adherence in a clinical trial: comparison of self-report and canister weighing to the nebulizer chronolog.Am Rev Respir Dis. 1992; 146: 1559-1564Crossref PubMed Scopus (290) Google Scholar, 9Tashkin DP Rand C Nides M Simmons M Wise R Coulson AH et al.A nebulizer chronolog to monitor compliance with inhaler use.Am J Med. 1991; 91: 335-365PubMed Google Scholar thus compromising the physicians’s ability to ascertain true adherence in the absence of objective monitoring. Moreover, unlike electronic monitors, canister weights are not informative with regard to the daily pattern of inhaler use and fail to detect the “dumping” phenomenon, in which canisters are deceptively discharged shortly before an office visit to give the spurious appearance of good adherence in a clinical trial. 8Rand CS Wise RA Nides M Simmons MS Bleecker ER Kusch JW et al.Inhaler adherence in a clinical trial: comparison of self-report and canister weighing to the nebulizer chronolog.Am Rev Respir Dis. 1992; 146: 1559-1564Crossref PubMed Scopus (290) Google Scholar These findings have important implications not only for physicians providing care to patients with asthma but also for the interpretation of clinical trial outcomes. The Nebulizer Chronolog has also been shown to be capable of enhancing inhaler adherence when feedback of the monitoring results was provided to study participants by a health professional, 10Nides MA Tashkin DP Simmons MS Wise RA Li VC Rand CS. Improving inhaler adherence in a clinical trial through the use of the nebulizer chronolog.Chest. 1993; 104: 501-507Crossref PubMed Scopus (126) Google Scholar thus providing the opportunity for improved clinical care. 11Cramer JA. Feedback on medication dosing enhances patient compliance.Chest. 1993; 104: 333-334Crossref PubMed Scopus (10) Google Scholar The usefulness of microelectronic devices for objectively monitoring adherence in either clinical practice or a clinical trial, however, is critically dependent on the accuracy and reliability of these devices. In previously reported field experience with the Nebulizer Chronolog, 53% of the devices malfunctioned for reasons other than subject misuse at one or more times during a 7 ½ -month study, resulting in data loss on 14% of the total number of monitored days. 6Gong Jr, H Simmons MS Clark VA Tashkin DP. Metered-dose inhaler usage in asthma. Comparison of nebulizer chronolog and daily diary recordings.J Allergy Clin Immunol. 1988; 82: 5-10Abstract Full Text PDF PubMed Scopus (54) Google Scholar In a more recent 2-year adherence study, over 10% of the devices could not be read because of battery failure or technical difficulties in data registration and retrieval. 12Simmons M Nides M Rand C Wise R Gong Jr, H Tashkin DP. Trends in compliance with bronchodilator inhaler use between follow-up visits in a clinical trial.Chest. 1996; 109: 963-968Crossref PubMed Scopus (72) Google Scholar The Nebulizer Chronolog has been replaced by later models, including the MDI Chronolog model MC-311 (Medtrac Technologies, Lakewood, Colo), which uses a thermistor, rather than a mechanical microswitch, to detect the temperature change resulting from each actuation of the pressurized MDI. However, experience with the latter device when used to monitor adherence to inhaled corticosteroids in an actual clinical setting has raised serious questions concerning the reliability of the device. On subsequent bench testing at the clinical site, with the manufacturer’s cooperation, a number of technical problems were identified, including a fragile thermistor sensor, excessive battery voltage drain, faulty interface cable connections for downloading data, and clogging of mouthpieces, causing both data loss and the erroneous appearance of missed doses. 13Brueckner JW Marshik P Sherman J Hendeles L. Reliability of the Medtrac MDI chronolog.J Allergy Clin Immunol. 1997; 100: 488-491Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Disconcertingly, these deficiencies apparently had escaped detection, or if detected, had not been remedied as part of the manufacturer’s own quality control procedures during product development or subsequent commercial production after Food and Drug Administration (FDA) device clearance. An independent study by Wamboldt et al 14Wamboldt FS Bender BG O’Connor SL Gavin LA Wamboldt MZ Milgrom H et al.Reliability of the model MC-311 MDI Chronolog.J Allergy Clin Immunol. 1999; (•••): 104Google Scholar that appears in this issue of The Journal has also documented serious defects in the model MC-311 MDI Chronolog during controlled laboratory testing, with only 42% to 67% of the 24 bench-tested devices demonstrating “acceptable” reliability and all of the “acceptable” chronologs underestimating actual MDI activation. The authors identified the primary problem to be a delicate thermistor that was vulnerable to damage during washing of the mouthpiece, resulting in bursts of erroneous activation recordings that secondarily led to battery failure. Because these failures occurred under rigorously controlled laboratory conditions in which the devices were handled in strict accordance with the manufacturer’s recommendations, the authors suggest that the failure rates would be considerably higher in field studies involving patients. When the thermistor-actuated MDI Chronolog was used to monitor adherence in 2 clinical trials, the Chronolog underestimated overall adherence (independently assessed by canister weights) by greater than 20% in over 50% of visits. 15Weeks K Rand C Wise R. Reliability of the thermistor-actuated metered dose inhaler (MDI) chronolog.Am J Respir Crit Care Med. 1997; 155 ([abstract]): A259Google Scholar Moreover, even when carefully quality-control tested before and after use by each patient in another clinical trial, the same device exhibited a 28.4% rate of malfunction. 16Bender B Ackerson L Milgrom H Rand C. Metered dose inhaler chronologs—monitoring the monitors.Am J Respir Crit Care Med. 1997; 155 ([abstract]): A259Google Scholar As a result of these deficiencies, which were detected by clinical investigators (with the full cooperation of the manufacturer) after FDA device clearance and commercialization of the MC-311 MDI Chronolog, the manufacturer has discontinued production of this thermistor-based electronic monitor and is developing a new generation of microelectronic monitors for both MDI and dry powder inhaler use using different technology. What are the implications of these findings for clinicians and investigators who have an interest in using microelectronic devices for monitoring inhaler adherence in patient care or clinical research settings, as well as for the manufacturers of these devices? First, clinicians and investigators cannot assume that the in-house quality-control process used by manufacturers both during development and after commercial release of these monitoring devices in conformity with regulatory requirements of the FDA is adequate to detect major deficiencies in either hardware or software that, if not remedied, are likely to lead to device failure or malfunction. The possible consequences of such defects are data loss or, more seriously, inaccurate and potentially misleading data that could lead to false assumptions concerning adherence. Consequently, these devices need to undergo additional rigorous bench testing before patient use either by the clinician or by another independent laboratory to verify the manufacturer’s assurance of accuracy and reliability. Professional societies that have an interest in inhaler adherence should consider convening a panel of experts to develop recommendations for quality control standards for microelectronic monitoring devices, analogous to the equipment performance standards for spirometry recommended by the American Thoracic Society. 17American Thoracic Society Standardization of spirometry. 1994 Update.Am J Respir Crit Care Med. 1995; 152: 1107-1136Crossref PubMed Scopus (6278) Google Scholar Once suitable standards for quality assurance are formulated, an independent central laboratory, preferably at an academic institution, could be established for performance testing of FDA-cleared electronic monitoring devices to assess whether the recommended standards are fulfilled. For a suitable fee, manufacturers of these devices could submit their product to the central laboratory for validity and reliability testing, the results of which, if favorable, would foster consumer confidence in their device and reduce the need for bench testing by individual physicians and researchers. A second implication of these findings is that demonstrated reliability during stringent bench testing does not guarantee that the device will function satisfactorily during normal clinical use, as clearly demonstrated by Brueckner et al. 13Brueckner JW Marshik P Sherman J Hendeles L. Reliability of the Medtrac MDI chronolog.J Allergy Clin Immunol. 1997; 100: 488-491Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Consequently, clinicians need to be alert to the possibility of device failure in the field, to promptly replace malfunctioning units, and to return these to the manufacturer for identification of the cause of the malfunction. It would be prudent for investigators who rely on these devices for controlled clinical trials to perform visual inspection and battery testing periodically as an additional quality-control precaution. Significant problems detected during clinical or research applications of these devices should be reported to both the manufacturer and the FDA. A high rate of device malfunction during clinical use should result in an FDA audit of the manufacturer and could lead to device recall. Microelectronic monitoring devices are a potentially important clinical and investigative tool for adherence assessment and behavioral research and may also have therapeutic utility by enhancing adherence. Establishing a workable and efficient mechanism for manufacturer-independent quality assurance of these devices is a challenge that, if successfully met, could lead to more reliable and dependable adherence monitoring devices with benefits to both patients and clinical investigators.