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The potential use of markers in drug development
The Potential Use of Markers in Drug Development Kenneth F. Tempero Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey
ABSTRACT: There are at least three recurring questions crucial to the drug and drug formulation development processes that could be addressed by marker methodology: (1) Is the assessment of an effective dose or dose regimen correct? (2) Is an inadequate response or nonresponse secondary to pharmacology or to inadequate compliance? (3) Can.various formulations provide significantly better therapy for certain populations? Characteristics of an ideal marker system would include:
1. Simple and reliable to measure. 2. Able to yield reliable evaluation of routine adherence in single or multiple dose situations. 3. Biologically inert. 4. Samples for measurement can be obtained unobtrusively. 5. Samples are painless to obtain (for patient and clinic staff). 6. Absorption and kinetic characteristics approximate those of the therapeutic candidate. 7. Able to be presented in multiple formulations. Current methodology for addressing these questions is far short of ideal. Therefore, if marker methodology that lacks the limitation of present technology could be developed, it potentially would find wide use during the drug development process.
POTENTIAL ROLE IN THERAPEUTIC ASSESSMENT
A marker or family of markers could be very useful during the drug development process. At least three questions that occur during the testing of a n y n e w chemical entity for therapeutic utility could be addressed better by marker technology than by currently available methodology: 1. What dose or dose regimen is associated with the effect observed? 2. Is nonresponse or inadequate response due to pharmacologic or adherence failure? 3. Do various formulations influence adherence in target patient populations?
Address reprint requests to: Kenneth F. Tempero, M.D., Ph.D., Executive Director, Clinical Research International, Merck Sharp and Dohme Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065. Controlled Clinical Trials 5:53,5-539 (1984) © Elsevier Science Publishing Co., Inc. 1984 52 Vanderbilt Ave., New York, New York 10017
535 0197-2456/84/$03.00
536
Kenneth F. Tempero How much drug (or what regimen) a patient actually uses during a therapeutic trial w h e n efficacy or side effects are evaluated is, in the absence of contrary evidence, generally assumed to be 100% of that prescribed. Evidence indicates that this is an unrealistic assumption, but at present we lack a better one [1,2]. This assumption potentially leads to two undesirable results. Therapeutically, a recommendation may be made for more milligrams per dose or per day than are necessary. In the assessment of adverse experience, the investigator may believe that an adverse experience is associated with a higher dose than that actually in use. The second question addresses the phenomenon of nonresponse or inadequate therapeutic responses. Assuming the marker is independent of the therapeutic agent and not dissociated from the therapeutic agent by any unique bioavailability phenomena, a marker could help an investigator determine whether a lack of expected response was related to pharmacologic or adherence future. Whenever tablet or capsule intake in excess of six to eight per day is required, patient adherence has been observed to deteriorate despite good intentions on the part of the patient. This range of six to eight tablets per day is easily reached during studies utilizing "double d u m m y " technique: thus the question is of practical import. The various techniques shown in Table 1 would be improved by adequate marker technology in evaluating either of the first two questions. The third question concerns whether special formulations increase convenience sufficiently to be therapeutically significant for special patient populations. Examples of interest would include liquid formulations for children or the aged and sachets, suppositories, or injections for certain cultural groups.
CHARACTERISTICS OF AN IDEAL MARKER
Since questions exist that could be better addressed via marker technology, we should define the ideal marker's characteristics as applicable in the drug development process. Seven key characteristics are: 1. Simple and reliable to measure. 2. Able to yield reliable evaluation of routine adherence in single or multiple dose situations. Table I
Techniques for Assessing Patient Adherence Technique References Sackett et al. [3] Patient education programs Spiegel [4] Interview by staff Stamler et al. [5] Blackwell [6] Gordis et al. [7] Sackett et al. [3] Convenience factors Stamler et al. [5] Liberman [8] Records kept by patient Stewart and Cluff [9] Medication measurement Prescription refills Physiologic parameters
Use of Markers in Drug Development
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3. 4. 5. 6.
Biologically inert. Samples for measurement can be obtained unobtrusively. Samples are painless to obtain (for patient and clinic staff). Absorption and kinetic characteristics approximate those of therapeutic candidate. 7. Able to be presented in multiple formulations. The marker must be technically simple yet reliably measurable. The investigator would ideally be able to obtain a specimen without intruding into and thus influencing study design and adherence artificially. Sample procurement should be physically convenient for the patient and should require a minimum of staff time devoted to procurement, preservation, and shipment or analysis. One really wants to determine the routine or chronic adherence to a therapeutic regimen. Therefore, the ideal marker or evaluation method would allow the investigator or monitor to determine whether the patient is routinely or chronically complying with or adhering to a therapeutic regimen. A marker enabling this would also probably determine whether the patient is at steady state. Ideally, the marker will exhibit absorption and kinetic characteristics similar to those of the therapeutic agents being observed in the trial. The marker should either be free of side effects or only associated with therapeutic or side effects that will not be erroneously attributed to test agents. It should have no interaction (kinetic or therapeutic) with the agents being tested. Lastly, the ideal marker could be presented in association with multiple formulations.
THE STATE OF PRESENT ART
It is increasingly common to see an evaluation of compliance or therapeutic adherence in the report of clinical trials. The methods most frequently suggested by trial designers and utilized by investigators or study sponsors are pill counts, with or without random overages, or assays of plasma or urine. These methods, while of definite value when properly used, fall short of ideal. Pill counts require that the patient remember to bring the container back to the clinic. Additionally, accurate pill counts require careful recording of periods of use from the container, as intervals between visits tend to vary. The use of randomly varied overage is an attractive concept, but all pill count assessments are extremely time intensive. Random overage requires extra, specific record keeping at the time of packaging and calculation of compliance per container for each vial following "turn in." Expense considerations for materials are usually minor compared to those of time consumption, whether it be time expended by the investigator's staff or a central coordinating staff. The pill count method of compliance or adherence assessment must by its very nature be obvious and known to the patient. This leads to a second consideration. The patient may try to appear a better "compiler" than he or she is in reality by discarding untaken tablets or capsules. Obviously, the method of pill count and its variances can give us no d u e to this. The method
538
Kenneth F. Tempero cannot tell us whether study materials were used (let alone used as directed) or simply discarded. The second method of fairly general use, sample assay, can overcome the concern of whether the study material was consumed. But it also has a number of limitations. First and foremost is the requirement for an assay. The process of development of a new chemical entity for use as a therapeutic agent is often accompanied, in its early stages, by either nonexistent assay methodology or by laborious slow methods that lack sensitivity. Qualitative methodology, while usually faster than quantitative methodology, may be of limited value for compounds of long half-life which can be detected appreciably below concentrations associated with the targeted pharmacologic response. Quantitative assays, especially single samples, require accurate assessment of time since last dosing to be intelligible for any purpose appreciably more sophisticated than qualitative analysis. Both qualitative and quantitative assay methods require effort and collaboration beyond the "therapeutics" of the study by both the patient and the investigative staff. Many patients dislike venipuncture, especially repeated venipuncture, and either forget to bring a urine sample or cannot void in the clinic. We still basically get only a "snapshot" of compliance and can determine very little, if anything, about chronic or routine adherence. Additional methods, including those in Table 1, suffer similar problems associated with indirectness, time involvement, and expense.
SUMMARY
There is definite need for improved compliance or regimen adherence assessment methodology for use during the drug development process. If ideal marker methodology could be developed, it would be useful in the assessment of new therapies in all phases of drug assessment. However, it may be unrealistic to hope marker methodology can be easily and widely available for very many, let alone all, drugs.
REFERENCES
1. Ayd FJ" Rational pharmacotherapy: once a day drug dosage. Dis Nerv 34"371-78, 1973 2. Boyd JR Covington, JR, Stanazek WF, Coussons RT" Drug defaulting: Part 1: Determinants of compliance. Am J Hosp Pharm 31:362-67, 1974 3. Sackett DL, Haynes RB, Gibson ES, Taylor DW, Hackett BC, Roberts RS, Johnson AL: Randomized clinical trial of strategies for improving medication compliance in primary hypertension. Lancet 1:1205, 1975 4. Spiegel AD: Programmed instructional materials for patient education. J Med Educ 42-958, 1967 5. Stamler R, Gosch FC, Stamler J, Ticho S, Civinelli J, Restivo B, Pritchard D, Fine D: Adherence and blood pressure response to hypertension treatment. Lancet 2:1227, 1975 6. Blackwell B" Drug therapy; patient compliance. N Engl J Med 289:249, 1973
Use of Markers in Drug Development
539
7. Gordis L, Markowitz N, Lilienfeld AM: The inaccuracy of using interviews to estimate patient reliability in taking medications at home. Med Care 7:49, 1969 8. Liberman P: A guide to help patients keep track of their drugs. Am J Hosp Pharm 29:507, 1972 9. Stewart RB, Cluff LE: A review of medication errors and compliance in ambulant patients. Clin Pharmacol Ther 13:463, 1972
ABSTRACT: There are at least three recurring questions crucial to the drug and drug formulation development processes that could be addressed by marker methodology: (1) Is the assessment of an effective dose or dose regimen correct? (2) Is an inadequate response or nonresponse secondary to pharmacology or to inadequate compliance? (3) Can.various formulations provide significantly better therapy for certain populations? Characteristics of an ideal marker system would include:
1. Simple and reliable to measure. 2. Able to yield reliable evaluation of routine adherence in single or multiple dose situations. 3. Biologically inert. 4. Samples for measurement can be obtained unobtrusively. 5. Samples are painless to obtain (for patient and clinic staff). 6. Absorption and kinetic characteristics approximate those of the therapeutic candidate. 7. Able to be presented in multiple formulations. Current methodology for addressing these questions is far short of ideal. Therefore, if marker methodology that lacks the limitation of present technology could be developed, it potentially would find wide use during the drug development process.
POTENTIAL ROLE IN THERAPEUTIC ASSESSMENT
A marker or family of markers could be very useful during the drug development process. At least three questions that occur during the testing of a n y n e w chemical entity for therapeutic utility could be addressed better by marker technology than by currently available methodology: 1. What dose or dose regimen is associated with the effect observed? 2. Is nonresponse or inadequate response due to pharmacologic or adherence failure? 3. Do various formulations influence adherence in target patient populations?
Address reprint requests to: Kenneth F. Tempero, M.D., Ph.D., Executive Director, Clinical Research International, Merck Sharp and Dohme Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065. Controlled Clinical Trials 5:53,5-539 (1984) © Elsevier Science Publishing Co., Inc. 1984 52 Vanderbilt Ave., New York, New York 10017
535 0197-2456/84/$03.00
536
Kenneth F. Tempero How much drug (or what regimen) a patient actually uses during a therapeutic trial w h e n efficacy or side effects are evaluated is, in the absence of contrary evidence, generally assumed to be 100% of that prescribed. Evidence indicates that this is an unrealistic assumption, but at present we lack a better one [1,2]. This assumption potentially leads to two undesirable results. Therapeutically, a recommendation may be made for more milligrams per dose or per day than are necessary. In the assessment of adverse experience, the investigator may believe that an adverse experience is associated with a higher dose than that actually in use. The second question addresses the phenomenon of nonresponse or inadequate therapeutic responses. Assuming the marker is independent of the therapeutic agent and not dissociated from the therapeutic agent by any unique bioavailability phenomena, a marker could help an investigator determine whether a lack of expected response was related to pharmacologic or adherence future. Whenever tablet or capsule intake in excess of six to eight per day is required, patient adherence has been observed to deteriorate despite good intentions on the part of the patient. This range of six to eight tablets per day is easily reached during studies utilizing "double d u m m y " technique: thus the question is of practical import. The various techniques shown in Table 1 would be improved by adequate marker technology in evaluating either of the first two questions. The third question concerns whether special formulations increase convenience sufficiently to be therapeutically significant for special patient populations. Examples of interest would include liquid formulations for children or the aged and sachets, suppositories, or injections for certain cultural groups.
CHARACTERISTICS OF AN IDEAL MARKER
Since questions exist that could be better addressed via marker technology, we should define the ideal marker's characteristics as applicable in the drug development process. Seven key characteristics are: 1. Simple and reliable to measure. 2. Able to yield reliable evaluation of routine adherence in single or multiple dose situations. Table I
Techniques for Assessing Patient Adherence Technique References Sackett et al. [3] Patient education programs Spiegel [4] Interview by staff Stamler et al. [5] Blackwell [6] Gordis et al. [7] Sackett et al. [3] Convenience factors Stamler et al. [5] Liberman [8] Records kept by patient Stewart and Cluff [9] Medication measurement Prescription refills Physiologic parameters
Use of Markers in Drug Development
537
3. 4. 5. 6.
Biologically inert. Samples for measurement can be obtained unobtrusively. Samples are painless to obtain (for patient and clinic staff). Absorption and kinetic characteristics approximate those of therapeutic candidate. 7. Able to be presented in multiple formulations. The marker must be technically simple yet reliably measurable. The investigator would ideally be able to obtain a specimen without intruding into and thus influencing study design and adherence artificially. Sample procurement should be physically convenient for the patient and should require a minimum of staff time devoted to procurement, preservation, and shipment or analysis. One really wants to determine the routine or chronic adherence to a therapeutic regimen. Therefore, the ideal marker or evaluation method would allow the investigator or monitor to determine whether the patient is routinely or chronically complying with or adhering to a therapeutic regimen. A marker enabling this would also probably determine whether the patient is at steady state. Ideally, the marker will exhibit absorption and kinetic characteristics similar to those of the therapeutic agents being observed in the trial. The marker should either be free of side effects or only associated with therapeutic or side effects that will not be erroneously attributed to test agents. It should have no interaction (kinetic or therapeutic) with the agents being tested. Lastly, the ideal marker could be presented in association with multiple formulations.
THE STATE OF PRESENT ART
It is increasingly common to see an evaluation of compliance or therapeutic adherence in the report of clinical trials. The methods most frequently suggested by trial designers and utilized by investigators or study sponsors are pill counts, with or without random overages, or assays of plasma or urine. These methods, while of definite value when properly used, fall short of ideal. Pill counts require that the patient remember to bring the container back to the clinic. Additionally, accurate pill counts require careful recording of periods of use from the container, as intervals between visits tend to vary. The use of randomly varied overage is an attractive concept, but all pill count assessments are extremely time intensive. Random overage requires extra, specific record keeping at the time of packaging and calculation of compliance per container for each vial following "turn in." Expense considerations for materials are usually minor compared to those of time consumption, whether it be time expended by the investigator's staff or a central coordinating staff. The pill count method of compliance or adherence assessment must by its very nature be obvious and known to the patient. This leads to a second consideration. The patient may try to appear a better "compiler" than he or she is in reality by discarding untaken tablets or capsules. Obviously, the method of pill count and its variances can give us no d u e to this. The method
538
Kenneth F. Tempero cannot tell us whether study materials were used (let alone used as directed) or simply discarded. The second method of fairly general use, sample assay, can overcome the concern of whether the study material was consumed. But it also has a number of limitations. First and foremost is the requirement for an assay. The process of development of a new chemical entity for use as a therapeutic agent is often accompanied, in its early stages, by either nonexistent assay methodology or by laborious slow methods that lack sensitivity. Qualitative methodology, while usually faster than quantitative methodology, may be of limited value for compounds of long half-life which can be detected appreciably below concentrations associated with the targeted pharmacologic response. Quantitative assays, especially single samples, require accurate assessment of time since last dosing to be intelligible for any purpose appreciably more sophisticated than qualitative analysis. Both qualitative and quantitative assay methods require effort and collaboration beyond the "therapeutics" of the study by both the patient and the investigative staff. Many patients dislike venipuncture, especially repeated venipuncture, and either forget to bring a urine sample or cannot void in the clinic. We still basically get only a "snapshot" of compliance and can determine very little, if anything, about chronic or routine adherence. Additional methods, including those in Table 1, suffer similar problems associated with indirectness, time involvement, and expense.
SUMMARY
There is definite need for improved compliance or regimen adherence assessment methodology for use during the drug development process. If ideal marker methodology could be developed, it would be useful in the assessment of new therapies in all phases of drug assessment. However, it may be unrealistic to hope marker methodology can be easily and widely available for very many, let alone all, drugs.
REFERENCES
1. Ayd FJ" Rational pharmacotherapy: once a day drug dosage. Dis Nerv 34"371-78, 1973 2. Boyd JR Covington, JR, Stanazek WF, Coussons RT" Drug defaulting: Part 1: Determinants of compliance. Am J Hosp Pharm 31:362-67, 1974 3. Sackett DL, Haynes RB, Gibson ES, Taylor DW, Hackett BC, Roberts RS, Johnson AL: Randomized clinical trial of strategies for improving medication compliance in primary hypertension. Lancet 1:1205, 1975 4. Spiegel AD: Programmed instructional materials for patient education. J Med Educ 42-958, 1967 5. Stamler R, Gosch FC, Stamler J, Ticho S, Civinelli J, Restivo B, Pritchard D, Fine D: Adherence and blood pressure response to hypertension treatment. Lancet 2:1227, 1975 6. Blackwell B" Drug therapy; patient compliance. N Engl J Med 289:249, 1973
Use of Markers in Drug Development
539
7. Gordis L, Markowitz N, Lilienfeld AM: The inaccuracy of using interviews to estimate patient reliability in taking medications at home. Med Care 7:49, 1969 8. Liberman P: A guide to help patients keep track of their drugs. Am J Hosp Pharm 29:507, 1972 9. Stewart RB, Cluff LE: A review of medication errors and compliance in ambulant patients. Clin Pharmacol Ther 13:463, 1972