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Behavioral aspects of the use of medical markers in clinical trials
Behavioral Aspects of the Use of Medical Markers in Clinical Trials Michael L. Russell Baylor College of Medicine and the Methodist Hospital, Houston, Texas
ABSTRACT: Nonadherence by trial participants to the study drug regimen threatens the satisfactory conduct of the best designed clinical trial. Reduced adherence confounds the interpretation of the study's results and may leave the study's primary question unanswered. Recent reports from multicenter clinical trials have reported adherence rates of 60%-90%. This presentation examines the use of a drug marker in counseling to improve participant adherence to a medication regimen. Potential benefits and problems are identified, and several recommendations are offered. Increasingly, behavioral counseling has been used by clinic staff members to improve the medication adherence of trial participants. Behavioral counseling is a databased counseling process emphasizing patient collaboration with the clinician in identifying, diagnosing, and intervening in medication adherence problems. A valid, accurate drug marker would have direct application in both identifying and intervening on a medication adherence problem. However, a marker would not contribute substantially to the clinician's ability to diagnose accurately the nature of the medication adherence problem. A major concern is the manner in which the clinician introduces the drug marker into the counseling process. The use of data from a drug marker can have a strong positive or negative effect on the medication adherence problem. It also can significantly influence the continuing relationship between the clinician and the participant. Examples are presented. It is strongly recommended that the clinician identify the specific goals for the marker's use prior to the introduction of data from a medical marker into the participant counseling process. Further, the manner in which the marker is introduced into the interview with the participant must be considered carefully. It is recommended that special training be required of clinical staff for the use of data from drug markers for both monitoring and counseling for medication adherence.
N O N A D H E R E N C E IN CLINICAL TRIALS
Nonadherence by trial participants to a study drug regimen or protocol threatens the satisfactory conduct of the best designed clinical trial. R e d u c e d a d h e r e n c e c o n f o u n d s the interpretation of the study's results a n d m a y leave the study's p r i m a r y question u n a n s w e r e d [1]. Reports from multicenter clinical trials, including the Aspirin Myocardial Infarction S t u d y [2], the C o r o n a r y Primary P r e v e n t i o n Trial [3,4], and the N o r w e g i a n Timolol Trial [5] have indicated participant a d h e r e n c e rates ranging from 60% to 90%. Address reprint requests to: Michael L. Russell, Ph.D., The Methodist Hospital, 6535 Fannin Street, Houston, Texas 77030
ControlledClinicalTrials5:526--534(1984) © ElsevierSciencePublishingCo., Inc., 1984 52 VanderbiltAve., NewYork, New York10017
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0197-2456/84/$3.00
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Recent reports, however, have indicated that participant adherence to the study protocol and the medication regimen can be dramatically improved through highly focused medication adherence counseling provided by trial clinic staff [6,7]. Although many study participants adhere to the study medication regimen with minimal or no difficulty, significant numbers of participants do require aid. Counseling these participants is a time-consuming process that needs to be accomplished as efficiently as possible. The following discussion directs attention to the benefits, limitations, and potential problems related to the use of data from an accurate, reliable drug marker in medication adherence counseling. COUNSELING FOR MEDICATION ADHERENCE
From the perspective of a clinician responsible for helping trial participants adhere to a study drug regimen, how useful are the data from a drug marker? To understand the potential usefulness of these data, a review of the process of adherence counseling is necessary, with an indication of the type of data needed at each step. Increasingly, the model for adherence counseling that has been adopted by clinicians in clinical trials can be described as a behavioral counseling model [8,9]. Behavioral counseling is a data-based counseling process emphasizing patient collaboration with the clinician to identify, diagnose, and intervene on presenting problems [10-12]. Behavorial counseling to resolve medication adherence problems can be described as an eight-step process (Table 1). Step 1 is the clear identification of the presence of a medication adherence problem (e.g., the participant's adherence remained steady, but low, for most of the days since he or she was last seen in the clinic, but increased dramatically for the days immediately preceeding the clinic visit). Step 2 is a quantification of the problem. Usually, the clinician obtains data regarding the frequency of the problem (e.g., the participant's adherence was 75% for most days, but reached 100% during the last 3 days prior to the visit). Step 3 is the clinician's formulation of a behavioral diagnosis of the presenting problem and selection of a specific adherence goal. The clinician must identify how Usefulness of Data from Self-Reports, Self-Observations, and Drug Markers for Conducting Medication Adherence Counseling Useful as data source? Steps in SelfSelfDrug behavioral counseling report observation marker 1. Identify the problem Yes Yes Yes 2. Examine quantitative data Yes Yes Yes 3. Formulate a behavioral diagnosis Yes Yes No 4. Set goal and develop strategy Yes No No 5. Initiate the strategy Yes No No 6. Examine quantitative data Yes Yes Yes 7. Reformulate behavioral diagnosis Yes Yes No 8. Modify strategy Yes Yes No Table 1
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the medication adherence problem interacts with the participant's social and physical environment. Through discussions with the participant, an appropriate adherence goal is determined. In step 4, the clinician selects or develops a strategy to resolve the problem. Usually, the strategy is designed to alter either the participant's environment or the consequences for adherence and nonadherence to the medication regimen. In step 5, the strategy is implemented, and its effects are carefully monitored in step 6. For the strategy to be considered successful, quantitative changes must be observed in the medication adherence rate. As step 7 indicates, if quantitative changes are not observed, the clinician must reformulate the behavioral diagnosis. If a reformulation is necessary, a new or modified strategy is selected or developed and initiated. This process continues, using quantitative changes in medication adherence to determine w h e n the presenting problem has been solved. As can be seen from Table 1, information from participant self-reports (i.e., recall) can be used in all eight steps. If needed, more accurate data can be collected by the participant from self-observations (e.g., daily records or diaries). These data are usually more reliable than self-reports because the participant collects them as they occur. Systematic self-observations are useful in collecting data needed for five of the eight steps. For some participants, however, self-observation data are either difficult to obtain or of questionable validity [13]. Data obtained from a drug marker would be particularly helpful in three steps in medication adherence counseling: step 1, to detect a medication adherence problem; step 2, to quantify it; and step 6, to monitor the effects of a strategy designed to improve adherence to the medication regimen. The early acquisition of information from a drug marker indicating the presence and degree of nonadherence would be extremely valuable to the clinician. Medication adherence counseling could then begin early. Early detection of a problem minimizes the deterioration of the participant's adherence to the regimen and, therefore, maximizes the participant's adherence level throughout the trial. Also, early intervention would require less counseling time and effort than would be required if the regimen were to be reinitiated from low levels of adherence or complete nonadherence. Data from a drug marker also would be useful to identify the quantitative changes that have occurred in a participant's medication adherence after the introduction of a strategy. A precise measurement of adherence is as important to the counseling of participants as is the measurement of blood pressure in the treatment of hypertension. The blood pressure level reflects the current status of the patient's hypertension and indicates the patient's response to treatment. Data from a drug marker would indicate the effectiveness of the new strategy in improving patient adherence to the drug regimen. Detecting and monitoring adherence to a medication regimen are only part of the clinician's task, however. The goal of counseling is to resolve the medication adherence problem. The clinician's most difficult task in medication adherence counseling is to determine a correct behavioral diagnosis. A behavioral diagnosis is the clinician's formulation of the participant's activities, beliefs, and thoughts in relation to his or her social and physical environment that are functioning as barriers to regimen adherence or are supportive of nonadherence. The clinician also determines which variables could support the participant's adherence and discourage nonadherence. To
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determine a behavioral diagnosis, the clinician systematically reviews the circumstances surrounding each incidence of participant nonadherence to the study drug regimen. Unfortunately, data from a drug marker cannot offer this information.
DRUG MARKERS AS FEEDBACK
Accurate drug markers might appear to be inherently useful to the clinician since they give the participant information about his or her performance. H o w useful are the data from a drug marker as feedback to the participant? The purpose of feedback in a system is to enable adjustmments to be made to achieve desired operating characteristics. To be effective as feedback, data from a drug marker should have the following characteristics: 1. The data must describe a problem of concern to the participant. 2. The data must provide unique information; that is, they must provide quantitative or qualitative information that would otherwise not be available. 3. The data must be of use to the individual; that is, they must lead to corrective actions. 4. The data must be in a meaningful form. 5. The data must be timely. Feedback is useful only if the problem is of concern to the participant. Although this seems obvious, the clinician must be careful not to assume that, since the problem is of concern to the clinician or to the trial, the participant will share the concern. Before initiating the use of data from a drug marker to evaluate the participant's adherence to the medication regimen, the clinician must be convinced that the participant's goal for medication adherence corresponds with the clinician's goal. The clarification of goals, that is, the determination of the participant's "motivation," is crucial before beginning any counseling program. For a feedback mechanism to be worthwhile, it must offer data not otherwise available; that is, the feedback must offer quantitative or qualitative information that is sufficiently superior to other available information to justify the efforts involved in its acquisition. In general, feedback is most effective when the participant has not been aware of his or her current performance. In terms of medication adherence, data from a drug marker would be most effective for those who do not have a clear view of their past or current level of medication adherence and for w h o m other available methods (e.g., selfrecording) are not feasible. Presentation of data from a drug marker that accurately reflect a participant's adherence to a medication regimen is useful only if the participant can use the data to take actions in the future that have the potential for changing his or her behavior. The participant must understand the relationship between the data being presented and the behavior involved. The participant also must understand what activities might be appropriate to modify the situation, if needed. The clinician is responsible for ensuring that the participant fully comprehends the use of the data from a drug marker for making adjustments.
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Of major concern, and often overlooked by clinicians, is the need to present data in a form that is meaningful to the participant. For feedback to be useful, it must be interpretable at the operational level to be used to make corrective adjustments. For example, medication adherence data that are in the form of summary statistics reflecting the participant's average performance over a month (e.g., a mean adherence of 75%) may be useful for categorizing the participant in relation to other participants (i.e., distinguishing the moderate adherer from the good adherer), but they are not useful to help the participant improve adherence to a medication regimen. The most useful data from a drug marker would be data that reflected whether or not each dose was taken. Finally, the usefulness of data from a drug marker would be determined by its timeliness. The most effective use of feedback occurs w h e n the data are immediately available to the participant. Corrective actions can thus be taken and the performance improved. The longer the time lag between the participant's nonadherence and the presentation of feedback and the more intermittent the data presentation, the less value the data have for taking corrective actions. This is probably the stiffest challenge confronting those desiring to develop a drug marker applicable to the medication adherence counseling process. The drug marker must provide timely data. It appears, therefore, that data from a drug marker would contribute to improved medication adherence counseling by functioning as feedback if the data were available in the appropriate format and at the appropriate time. However, the data must be integrated appropriately into the counseling process and handled in an appropriate manner by the clinician. PARTICIPANT'S ACTIVE INVOLVEMENT The introduction of data from a drug marker into the counseling process raises concerns about its impact on the continuing relationship between the participant and the clinician. Effective behavior change depends upon the participant's full cooperation and involvement in the counseling process. Unlike the medical treatment of a patient's disease where the physician can obtain all necessary information and come to a medical diagnosis independent of the patient's knowledge or beliefs, in medication adherence counseling the clinician must collaborate with the participant to resolve the medication adherence problem. This cooperation is necessary because the participant has information and knowledge that is only partially available to the clinician, even through detailed questioning. Because the clinician does not have access to the relationships between the participant and his or her social and physical environment, the participant's observations must be used. The participant always will know more about his or her environment than will the clinician. Therefore, medication adherence counseling stresses the importance of a sustained active collaboration between the clinician and the participant. The participant's active involvement in the counseling process has significant implications for the clinician's use of information from a drug marker. The way the clinician introduces a drug marker can strongly affect the relationship. If data from the marker are introduced unexpectedly, or if collected without the participant's knowledge and presented to the participant, the
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participant can become offended and angry. Moreover, deceptive, covert monitoring raises the ethical issue of violation of informed consent procedures [14]. The participant should know that these data are being collected and why. With the participant fully informed and anticipating the data, the clinician can discuss with the participant how the medication regimen might be improved or modified without placing blame on the participant. The use of these data becomes a positive, contributing aspect of the counseling process. If the participant is approached as an individual with a unique life-style, then the resolution of the participant's difficulties with a standardized medication regimen becomes a problem to resolve and not an exercise in the attribution of blame. SKILLS TRAINING FOR STAFF
Data from a drug marker are unlike other medical data collected during a trial. Medical data collected from the participant during a trial reflect biochemical, physical, or physiological changes over which the participant has no control. Because the participant has no control, he or she neither has the self-perception nor is perceived by the physician as having direct responsibility for whether or not the disease or illness responds to the medical treatment. Similarly, the participant has no direct responsibility for any fluctuation of his or her blood chemistries. In contrast, data from a drug marker reflect the participant's performance of a specific action over which he o r she has direct control. Therefore, the participant is viewed as having direct responsibility for the level of medication adherence. As a result, the data collected using a drug marker are considered a direct evaluation of the participant's actions. The participant quickly recognizes this responsibility. Because the participant is viewed as being directly responsible for the level of medication adherence, the data from a drug marker must be handled differently from other medical data collected during the trial. The clinic staff must possess skills in the appropriate use of data from a drug marker in the conduct of medication adherence counseling. Examples of some of the skills a staff member should possess are presented in Table 2. The first three skills are fundamental and necessary for medication adherence counseling [8]. An example of an interviewing skill is: The clinician uses open-ended questions appropriately. An example of a problem identification and analysis skill is: The clinician obtains specific characteristics of the adherence problem, including its frequency, duration, intensity, and onset. An example of a counseling skill is: The clinician solicits the participant's suggestions regarding a strategy for resolving the adherence problem. Additional skills would be included to ensure that the clinician can understand and interpret these data appropriately. Other skills would include the ability to manage the interview process effectively when the data from the drug marker are discussed. These areas would need to be carefully reviewed, and a listing of specific abilities would need to be identified. Special training would be required for clinic staff to acquire proficiency in the clinical use of these skills. The results of evaluations of clinical trial staff
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1. 2. 3. 4. 5. 6.
Examples of Clinical Skills Required of Staff Members for the Appropriate Use of Data from a Drug Marker Ability to interview effectively. Ability to conduct a problem identification and analysis. Ability to counsel effectively. Ability to describe accurately the purpose of the drug marker. Ability to resolve discrepancies between data from a drug marker and data from other, participant-collected measures of medication adherence. Ability to properly analyze and interpret longitudinal data from a drug marker.
use of this fundamental set of interviewing and counseling skills for medication adherence indicate that these skills are not necessarily acquired through experience in counseling trial participants [15]. Instruction in these abilities is necessary and could be incorporated readily within local or trialwide training programs in medication adherence counseling. The structure, methods, and content of effective training programs in medication adherence counseling have been described fully elsewhere [16-18].
SUMMARY
In summary, from the viewpoint of the clinician charged with the responsibility of maintaining and improving trial participants' adherence to a study medication regimen, what are the potential benefits to be derived from a drug marker? In this presentation, three major benefits have been identified. A drug marker would improve the clinician's ability (1) to identify the presence of a medication adherence problem, (2) to quantify its status, and (3) to monitor the effects of a strategy designed to improve the participant's medication adherence rate. The advantages of accurate, reliable data to accomplish these objectives would offer a significant tool to the clinician. However, it also was discussed that although a drug marker would provide valuable data, the data would not be sufficient to conduct successful medication adherence counseling. The clinician needs data not available from a drug marker that indicate the interrelationships of the medication adherence problem, the participant's daily activities, the participant's social environment, and the participant's thoughts and feelings about the drug regimen. These data are needed to develop an accurate behavioral diagnosis and to select or develop a successful adherence strategy. The data from a drug marker would contribute little to this process. Finally, because the data from a drug marker reflect an action or lack of action by the participant over which the participant has direct responsibility, the data must be handled carefully during the counseling session. The manner in which the clinician introduces and discusses these data can have strong positive or negative effects on the counseling process and the continuing relationship between the clinician and the participant. The covert use of these data would raise serious ethical problems for the clinician. The clinician must thoroughly understand the objectives and the method for the use of data from a drug marker.
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RECOMMENDATIONS Two recommendations are offered regarding the usefulness of a drug marker to the clinician c o n d u c t i n g medication a d h e r e n c e counseling with trial participants. First, data from a d r u g m a r k e r w o u l d make a substantial contribution to medication a d h e r e n c e counseling. The further d e v e l o p m e n t of d r u g markers should be encouraged. Second, it is strongly r e c o m m e n d e d that special training be required of clinical staff for the appropriate, ethical use of data from d r u g markers for monitoring a n d counseling to improve medication adherence. Training in the use of the d r u g m a r k e r could be readily integrated into established p r o g r a m s for instructing trial staff in the f u n d a m e n t a l skills for medication a d h e r e n c e counseling.
REFERENCES 1. Feinstein, AR: Biostatistical problems in compliance bias. Clin Pharmacol Ther 16:846-857, 1974 2. Mattson ME: Compliance patterns in AMIS. (Abstract.) Controlled Clin Trials 3(2):137, 1982 3. Burke J, Stoy D, McKeown M, LaRosa J: Comparison of good and poor adherers. (Abstract.) Controlled Clin Trials 3(2):137, 1982 4. Doherty WJ, Schrott HG, Metcalf L, Iasiello-Vailas L: Effect of spouse support and health beliefs on patient adherence. (Abstract.) Controlled Clin Trials 3(2):137, 1982 5. The Norwegian Multicenter Study Group: Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocaradial infarction. N Engl J Med 304(14):801-807, 1981 6. Probstfield JL, Russell ML, Henske JC, Reardon R, Insull W Jr: A successful program for returning drop-outs to a clinical trial. (Abstract.) Controlled Clin Trials 1(2):168, 1980 7. Sugars C, Borhani NO: Multiple intervention: A key to behavior change. (Abstract.) Controlled Clin Trials 3(2):147, 1982 8. Russell ML, Insull W Jr: Evaluation and training of medication adherence counselors in a clinical trial: Application of a skill inventory to video-recorded interviews. Controlled Clin Trials 2:133-148, 1981 9. Zifferblatt SM: Increasing patient compliance through the applied analysis of behavior. Prevent Med 4:173-182, 1975 10. Krumboltz JD, Thoresen CE: Behavioral Counseling: Cases and Techniques. New York: Holt, Rinehart, and Winston, 1969 11. Krumboltz JD, Thoresen CE: Counseling Methods. New York: Holt, Rinehart, and Winston, 1976. 12. Thoresen CE, Hosford RE: Behavioral approaches to counseling. Behavior Modification in Counseling: The Seventy-Second Yearbook of the National Society for the Study of Education, Thoresen CE, Ed. Chicago: University of Chicago Press, 1973 13. Nelson RO: Assessment and therapeutic functions of self-monitoring. Progress in Behavior Modification. Hersen M, Eisler R, Miller P, Eds. New York: Academic Press, 1977 14. Levine RJ: Ethical considerations in the development and application of compliance strategies for the treatment of hypertension. Patient Compliance to Prescribed Antihypertensive Medication Regimens: A Report to the National Heart Lung and
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15.
16. 17. 18.
Blood Institute. Haynes RB, Mattson ME, Engebretson TO, Eds. Washington, D.C.: U.S. Government Printing Office, 1980 Russell ML, Insull W Jr, Probstfield JL: Identification of varied training needs of a clinical trial staff by objective documentation of their interviewing and counseling skills. (Abstract.) Controlled Clin Trials 2(1):84, 1981 Russell ML, Insull W Jr: A video-recording system for evaluating the clinical interview: a simple, inexpensive method. Med Prog Technol 6:141-145, 1979 Russell ML, Ghee KL, Probstfield JL, Insuli W Jr: Developing simulated patients for training and evaluating trial staff in adherence counseling. (Abstract.) Controlled Clin Trials 3(2):155, 1982 Dunbar JB, Peterson F, Schrott H, Schucker B, Smith T, Russell ML, Wetzel R: Design of a national counseling skills program for clinical staff. (Abstract.) Controlled Clin Trials 2(1):86, 1981
ABSTRACT: Nonadherence by trial participants to the study drug regimen threatens the satisfactory conduct of the best designed clinical trial. Reduced adherence confounds the interpretation of the study's results and may leave the study's primary question unanswered. Recent reports from multicenter clinical trials have reported adherence rates of 60%-90%. This presentation examines the use of a drug marker in counseling to improve participant adherence to a medication regimen. Potential benefits and problems are identified, and several recommendations are offered. Increasingly, behavioral counseling has been used by clinic staff members to improve the medication adherence of trial participants. Behavioral counseling is a databased counseling process emphasizing patient collaboration with the clinician in identifying, diagnosing, and intervening in medication adherence problems. A valid, accurate drug marker would have direct application in both identifying and intervening on a medication adherence problem. However, a marker would not contribute substantially to the clinician's ability to diagnose accurately the nature of the medication adherence problem. A major concern is the manner in which the clinician introduces the drug marker into the counseling process. The use of data from a drug marker can have a strong positive or negative effect on the medication adherence problem. It also can significantly influence the continuing relationship between the clinician and the participant. Examples are presented. It is strongly recommended that the clinician identify the specific goals for the marker's use prior to the introduction of data from a medical marker into the participant counseling process. Further, the manner in which the marker is introduced into the interview with the participant must be considered carefully. It is recommended that special training be required of clinical staff for the use of data from drug markers for both monitoring and counseling for medication adherence.
N O N A D H E R E N C E IN CLINICAL TRIALS
Nonadherence by trial participants to a study drug regimen or protocol threatens the satisfactory conduct of the best designed clinical trial. R e d u c e d a d h e r e n c e c o n f o u n d s the interpretation of the study's results a n d m a y leave the study's p r i m a r y question u n a n s w e r e d [1]. Reports from multicenter clinical trials, including the Aspirin Myocardial Infarction S t u d y [2], the C o r o n a r y Primary P r e v e n t i o n Trial [3,4], and the N o r w e g i a n Timolol Trial [5] have indicated participant a d h e r e n c e rates ranging from 60% to 90%. Address reprint requests to: Michael L. Russell, Ph.D., The Methodist Hospital, 6535 Fannin Street, Houston, Texas 77030
ControlledClinicalTrials5:526--534(1984) © ElsevierSciencePublishingCo., Inc., 1984 52 VanderbiltAve., NewYork, New York10017
526
0197-2456/84/$3.00
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Recent reports, however, have indicated that participant adherence to the study protocol and the medication regimen can be dramatically improved through highly focused medication adherence counseling provided by trial clinic staff [6,7]. Although many study participants adhere to the study medication regimen with minimal or no difficulty, significant numbers of participants do require aid. Counseling these participants is a time-consuming process that needs to be accomplished as efficiently as possible. The following discussion directs attention to the benefits, limitations, and potential problems related to the use of data from an accurate, reliable drug marker in medication adherence counseling. COUNSELING FOR MEDICATION ADHERENCE
From the perspective of a clinician responsible for helping trial participants adhere to a study drug regimen, how useful are the data from a drug marker? To understand the potential usefulness of these data, a review of the process of adherence counseling is necessary, with an indication of the type of data needed at each step. Increasingly, the model for adherence counseling that has been adopted by clinicians in clinical trials can be described as a behavioral counseling model [8,9]. Behavioral counseling is a data-based counseling process emphasizing patient collaboration with the clinician to identify, diagnose, and intervene on presenting problems [10-12]. Behavorial counseling to resolve medication adherence problems can be described as an eight-step process (Table 1). Step 1 is the clear identification of the presence of a medication adherence problem (e.g., the participant's adherence remained steady, but low, for most of the days since he or she was last seen in the clinic, but increased dramatically for the days immediately preceeding the clinic visit). Step 2 is a quantification of the problem. Usually, the clinician obtains data regarding the frequency of the problem (e.g., the participant's adherence was 75% for most days, but reached 100% during the last 3 days prior to the visit). Step 3 is the clinician's formulation of a behavioral diagnosis of the presenting problem and selection of a specific adherence goal. The clinician must identify how Usefulness of Data from Self-Reports, Self-Observations, and Drug Markers for Conducting Medication Adherence Counseling Useful as data source? Steps in SelfSelfDrug behavioral counseling report observation marker 1. Identify the problem Yes Yes Yes 2. Examine quantitative data Yes Yes Yes 3. Formulate a behavioral diagnosis Yes Yes No 4. Set goal and develop strategy Yes No No 5. Initiate the strategy Yes No No 6. Examine quantitative data Yes Yes Yes 7. Reformulate behavioral diagnosis Yes Yes No 8. Modify strategy Yes Yes No Table 1
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the medication adherence problem interacts with the participant's social and physical environment. Through discussions with the participant, an appropriate adherence goal is determined. In step 4, the clinician selects or develops a strategy to resolve the problem. Usually, the strategy is designed to alter either the participant's environment or the consequences for adherence and nonadherence to the medication regimen. In step 5, the strategy is implemented, and its effects are carefully monitored in step 6. For the strategy to be considered successful, quantitative changes must be observed in the medication adherence rate. As step 7 indicates, if quantitative changes are not observed, the clinician must reformulate the behavioral diagnosis. If a reformulation is necessary, a new or modified strategy is selected or developed and initiated. This process continues, using quantitative changes in medication adherence to determine w h e n the presenting problem has been solved. As can be seen from Table 1, information from participant self-reports (i.e., recall) can be used in all eight steps. If needed, more accurate data can be collected by the participant from self-observations (e.g., daily records or diaries). These data are usually more reliable than self-reports because the participant collects them as they occur. Systematic self-observations are useful in collecting data needed for five of the eight steps. For some participants, however, self-observation data are either difficult to obtain or of questionable validity [13]. Data obtained from a drug marker would be particularly helpful in three steps in medication adherence counseling: step 1, to detect a medication adherence problem; step 2, to quantify it; and step 6, to monitor the effects of a strategy designed to improve adherence to the medication regimen. The early acquisition of information from a drug marker indicating the presence and degree of nonadherence would be extremely valuable to the clinician. Medication adherence counseling could then begin early. Early detection of a problem minimizes the deterioration of the participant's adherence to the regimen and, therefore, maximizes the participant's adherence level throughout the trial. Also, early intervention would require less counseling time and effort than would be required if the regimen were to be reinitiated from low levels of adherence or complete nonadherence. Data from a drug marker also would be useful to identify the quantitative changes that have occurred in a participant's medication adherence after the introduction of a strategy. A precise measurement of adherence is as important to the counseling of participants as is the measurement of blood pressure in the treatment of hypertension. The blood pressure level reflects the current status of the patient's hypertension and indicates the patient's response to treatment. Data from a drug marker would indicate the effectiveness of the new strategy in improving patient adherence to the drug regimen. Detecting and monitoring adherence to a medication regimen are only part of the clinician's task, however. The goal of counseling is to resolve the medication adherence problem. The clinician's most difficult task in medication adherence counseling is to determine a correct behavioral diagnosis. A behavioral diagnosis is the clinician's formulation of the participant's activities, beliefs, and thoughts in relation to his or her social and physical environment that are functioning as barriers to regimen adherence or are supportive of nonadherence. The clinician also determines which variables could support the participant's adherence and discourage nonadherence. To
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determine a behavioral diagnosis, the clinician systematically reviews the circumstances surrounding each incidence of participant nonadherence to the study drug regimen. Unfortunately, data from a drug marker cannot offer this information.
DRUG MARKERS AS FEEDBACK
Accurate drug markers might appear to be inherently useful to the clinician since they give the participant information about his or her performance. H o w useful are the data from a drug marker as feedback to the participant? The purpose of feedback in a system is to enable adjustmments to be made to achieve desired operating characteristics. To be effective as feedback, data from a drug marker should have the following characteristics: 1. The data must describe a problem of concern to the participant. 2. The data must provide unique information; that is, they must provide quantitative or qualitative information that would otherwise not be available. 3. The data must be of use to the individual; that is, they must lead to corrective actions. 4. The data must be in a meaningful form. 5. The data must be timely. Feedback is useful only if the problem is of concern to the participant. Although this seems obvious, the clinician must be careful not to assume that, since the problem is of concern to the clinician or to the trial, the participant will share the concern. Before initiating the use of data from a drug marker to evaluate the participant's adherence to the medication regimen, the clinician must be convinced that the participant's goal for medication adherence corresponds with the clinician's goal. The clarification of goals, that is, the determination of the participant's "motivation," is crucial before beginning any counseling program. For a feedback mechanism to be worthwhile, it must offer data not otherwise available; that is, the feedback must offer quantitative or qualitative information that is sufficiently superior to other available information to justify the efforts involved in its acquisition. In general, feedback is most effective when the participant has not been aware of his or her current performance. In terms of medication adherence, data from a drug marker would be most effective for those who do not have a clear view of their past or current level of medication adherence and for w h o m other available methods (e.g., selfrecording) are not feasible. Presentation of data from a drug marker that accurately reflect a participant's adherence to a medication regimen is useful only if the participant can use the data to take actions in the future that have the potential for changing his or her behavior. The participant must understand the relationship between the data being presented and the behavior involved. The participant also must understand what activities might be appropriate to modify the situation, if needed. The clinician is responsible for ensuring that the participant fully comprehends the use of the data from a drug marker for making adjustments.
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Of major concern, and often overlooked by clinicians, is the need to present data in a form that is meaningful to the participant. For feedback to be useful, it must be interpretable at the operational level to be used to make corrective adjustments. For example, medication adherence data that are in the form of summary statistics reflecting the participant's average performance over a month (e.g., a mean adherence of 75%) may be useful for categorizing the participant in relation to other participants (i.e., distinguishing the moderate adherer from the good adherer), but they are not useful to help the participant improve adherence to a medication regimen. The most useful data from a drug marker would be data that reflected whether or not each dose was taken. Finally, the usefulness of data from a drug marker would be determined by its timeliness. The most effective use of feedback occurs w h e n the data are immediately available to the participant. Corrective actions can thus be taken and the performance improved. The longer the time lag between the participant's nonadherence and the presentation of feedback and the more intermittent the data presentation, the less value the data have for taking corrective actions. This is probably the stiffest challenge confronting those desiring to develop a drug marker applicable to the medication adherence counseling process. The drug marker must provide timely data. It appears, therefore, that data from a drug marker would contribute to improved medication adherence counseling by functioning as feedback if the data were available in the appropriate format and at the appropriate time. However, the data must be integrated appropriately into the counseling process and handled in an appropriate manner by the clinician. PARTICIPANT'S ACTIVE INVOLVEMENT The introduction of data from a drug marker into the counseling process raises concerns about its impact on the continuing relationship between the participant and the clinician. Effective behavior change depends upon the participant's full cooperation and involvement in the counseling process. Unlike the medical treatment of a patient's disease where the physician can obtain all necessary information and come to a medical diagnosis independent of the patient's knowledge or beliefs, in medication adherence counseling the clinician must collaborate with the participant to resolve the medication adherence problem. This cooperation is necessary because the participant has information and knowledge that is only partially available to the clinician, even through detailed questioning. Because the clinician does not have access to the relationships between the participant and his or her social and physical environment, the participant's observations must be used. The participant always will know more about his or her environment than will the clinician. Therefore, medication adherence counseling stresses the importance of a sustained active collaboration between the clinician and the participant. The participant's active involvement in the counseling process has significant implications for the clinician's use of information from a drug marker. The way the clinician introduces a drug marker can strongly affect the relationship. If data from the marker are introduced unexpectedly, or if collected without the participant's knowledge and presented to the participant, the
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participant can become offended and angry. Moreover, deceptive, covert monitoring raises the ethical issue of violation of informed consent procedures [14]. The participant should know that these data are being collected and why. With the participant fully informed and anticipating the data, the clinician can discuss with the participant how the medication regimen might be improved or modified without placing blame on the participant. The use of these data becomes a positive, contributing aspect of the counseling process. If the participant is approached as an individual with a unique life-style, then the resolution of the participant's difficulties with a standardized medication regimen becomes a problem to resolve and not an exercise in the attribution of blame. SKILLS TRAINING FOR STAFF
Data from a drug marker are unlike other medical data collected during a trial. Medical data collected from the participant during a trial reflect biochemical, physical, or physiological changes over which the participant has no control. Because the participant has no control, he or she neither has the self-perception nor is perceived by the physician as having direct responsibility for whether or not the disease or illness responds to the medical treatment. Similarly, the participant has no direct responsibility for any fluctuation of his or her blood chemistries. In contrast, data from a drug marker reflect the participant's performance of a specific action over which he o r she has direct control. Therefore, the participant is viewed as having direct responsibility for the level of medication adherence. As a result, the data collected using a drug marker are considered a direct evaluation of the participant's actions. The participant quickly recognizes this responsibility. Because the participant is viewed as being directly responsible for the level of medication adherence, the data from a drug marker must be handled differently from other medical data collected during the trial. The clinic staff must possess skills in the appropriate use of data from a drug marker in the conduct of medication adherence counseling. Examples of some of the skills a staff member should possess are presented in Table 2. The first three skills are fundamental and necessary for medication adherence counseling [8]. An example of an interviewing skill is: The clinician uses open-ended questions appropriately. An example of a problem identification and analysis skill is: The clinician obtains specific characteristics of the adherence problem, including its frequency, duration, intensity, and onset. An example of a counseling skill is: The clinician solicits the participant's suggestions regarding a strategy for resolving the adherence problem. Additional skills would be included to ensure that the clinician can understand and interpret these data appropriately. Other skills would include the ability to manage the interview process effectively when the data from the drug marker are discussed. These areas would need to be carefully reviewed, and a listing of specific abilities would need to be identified. Special training would be required for clinic staff to acquire proficiency in the clinical use of these skills. The results of evaluations of clinical trial staff
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1. 2. 3. 4. 5. 6.
Examples of Clinical Skills Required of Staff Members for the Appropriate Use of Data from a Drug Marker Ability to interview effectively. Ability to conduct a problem identification and analysis. Ability to counsel effectively. Ability to describe accurately the purpose of the drug marker. Ability to resolve discrepancies between data from a drug marker and data from other, participant-collected measures of medication adherence. Ability to properly analyze and interpret longitudinal data from a drug marker.
use of this fundamental set of interviewing and counseling skills for medication adherence indicate that these skills are not necessarily acquired through experience in counseling trial participants [15]. Instruction in these abilities is necessary and could be incorporated readily within local or trialwide training programs in medication adherence counseling. The structure, methods, and content of effective training programs in medication adherence counseling have been described fully elsewhere [16-18].
SUMMARY
In summary, from the viewpoint of the clinician charged with the responsibility of maintaining and improving trial participants' adherence to a study medication regimen, what are the potential benefits to be derived from a drug marker? In this presentation, three major benefits have been identified. A drug marker would improve the clinician's ability (1) to identify the presence of a medication adherence problem, (2) to quantify its status, and (3) to monitor the effects of a strategy designed to improve the participant's medication adherence rate. The advantages of accurate, reliable data to accomplish these objectives would offer a significant tool to the clinician. However, it also was discussed that although a drug marker would provide valuable data, the data would not be sufficient to conduct successful medication adherence counseling. The clinician needs data not available from a drug marker that indicate the interrelationships of the medication adherence problem, the participant's daily activities, the participant's social environment, and the participant's thoughts and feelings about the drug regimen. These data are needed to develop an accurate behavioral diagnosis and to select or develop a successful adherence strategy. The data from a drug marker would contribute little to this process. Finally, because the data from a drug marker reflect an action or lack of action by the participant over which the participant has direct responsibility, the data must be handled carefully during the counseling session. The manner in which the clinician introduces and discusses these data can have strong positive or negative effects on the counseling process and the continuing relationship between the clinician and the participant. The covert use of these data would raise serious ethical problems for the clinician. The clinician must thoroughly understand the objectives and the method for the use of data from a drug marker.
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RECOMMENDATIONS Two recommendations are offered regarding the usefulness of a drug marker to the clinician c o n d u c t i n g medication a d h e r e n c e counseling with trial participants. First, data from a d r u g m a r k e r w o u l d make a substantial contribution to medication a d h e r e n c e counseling. The further d e v e l o p m e n t of d r u g markers should be encouraged. Second, it is strongly r e c o m m e n d e d that special training be required of clinical staff for the appropriate, ethical use of data from d r u g markers for monitoring a n d counseling to improve medication adherence. Training in the use of the d r u g m a r k e r could be readily integrated into established p r o g r a m s for instructing trial staff in the f u n d a m e n t a l skills for medication a d h e r e n c e counseling.
REFERENCES 1. Feinstein, AR: Biostatistical problems in compliance bias. Clin Pharmacol Ther 16:846-857, 1974 2. Mattson ME: Compliance patterns in AMIS. (Abstract.) Controlled Clin Trials 3(2):137, 1982 3. Burke J, Stoy D, McKeown M, LaRosa J: Comparison of good and poor adherers. (Abstract.) Controlled Clin Trials 3(2):137, 1982 4. Doherty WJ, Schrott HG, Metcalf L, Iasiello-Vailas L: Effect of spouse support and health beliefs on patient adherence. (Abstract.) Controlled Clin Trials 3(2):137, 1982 5. The Norwegian Multicenter Study Group: Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocaradial infarction. N Engl J Med 304(14):801-807, 1981 6. Probstfield JL, Russell ML, Henske JC, Reardon R, Insull W Jr: A successful program for returning drop-outs to a clinical trial. (Abstract.) Controlled Clin Trials 1(2):168, 1980 7. Sugars C, Borhani NO: Multiple intervention: A key to behavior change. (Abstract.) Controlled Clin Trials 3(2):147, 1982 8. Russell ML, Insull W Jr: Evaluation and training of medication adherence counselors in a clinical trial: Application of a skill inventory to video-recorded interviews. Controlled Clin Trials 2:133-148, 1981 9. Zifferblatt SM: Increasing patient compliance through the applied analysis of behavior. Prevent Med 4:173-182, 1975 10. Krumboltz JD, Thoresen CE: Behavioral Counseling: Cases and Techniques. New York: Holt, Rinehart, and Winston, 1969 11. Krumboltz JD, Thoresen CE: Counseling Methods. New York: Holt, Rinehart, and Winston, 1976. 12. Thoresen CE, Hosford RE: Behavioral approaches to counseling. Behavior Modification in Counseling: The Seventy-Second Yearbook of the National Society for the Study of Education, Thoresen CE, Ed. Chicago: University of Chicago Press, 1973 13. Nelson RO: Assessment and therapeutic functions of self-monitoring. Progress in Behavior Modification. Hersen M, Eisler R, Miller P, Eds. New York: Academic Press, 1977 14. Levine RJ: Ethical considerations in the development and application of compliance strategies for the treatment of hypertension. Patient Compliance to Prescribed Antihypertensive Medication Regimens: A Report to the National Heart Lung and
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16. 17. 18.
Blood Institute. Haynes RB, Mattson ME, Engebretson TO, Eds. Washington, D.C.: U.S. Government Printing Office, 1980 Russell ML, Insull W Jr, Probstfield JL: Identification of varied training needs of a clinical trial staff by objective documentation of their interviewing and counseling skills. (Abstract.) Controlled Clin Trials 2(1):84, 1981 Russell ML, Insull W Jr: A video-recording system for evaluating the clinical interview: a simple, inexpensive method. Med Prog Technol 6:141-145, 1979 Russell ML, Ghee KL, Probstfield JL, Insuli W Jr: Developing simulated patients for training and evaluating trial staff in adherence counseling. (Abstract.) Controlled Clin Trials 3(2):155, 1982 Dunbar JB, Peterson F, Schrott H, Schucker B, Smith T, Russell ML, Wetzel R: Design of a national counseling skills program for clinical staff. (Abstract.) Controlled Clin Trials 2(1):86, 1981