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The Evaluable Subject
Guest editorial
The evaluable subject The clinical trial evaluating new pharmaceutical modalities has become an important part of the allergist’s repertoire. Never before has the allergist become so involved as an investigator in this billion dollar industry. This has occurred, I believe, in part due to the decline of clinical practice revenue and also because allergists view themselves as clinical scientists interested in new frontiers in asthma and allergy research. Furthermore, there has been a shift in clinical trials away from academic centers to the office setting. In this milieu, the allergist wears two hats, first and foremost as caregiver and second, as a clinical trials investigator. Although the goals of both are similar, that is, the ultimate welfare of the patient, there are situations when there appears to be confusion, if not conflict, in finding the evaluable subject. In this issue of the Annals, Cockcroft and associates confront this very situation in the asthmatic patient.1 From their perspective, it is difficult to find suitable subjects for clinical trials if the patients are adequately managed. Thus, they suggest that the usual inclusion criteria used to qualify a patient for study protocol such as frequent asthma symptoms, abnormal pulmonary function tests including an FEV1 between 50% to 80% of predicted, and 15% FEV1 reversibility after bronchodilator, which fit the category of persistent moderate asthma by the new NIH guidelines,2 cannot be frequently found in the allergist’s office. This is consistent with their view that asthma severity should be based on the quantity of inhaled corticosteroids necessary to completely control the asthma.3 They report in this issue that less than 10% of 590 asthmatic charts reviewed retrospectively fulfill the pulmonary
VOLUME 79, SEPTEMBER, 1997
function test criteria necessary to enter a study. To circumvent this difficulty, they suggest three approaches that might be employed, including withdrawing antiinflammatory medication, enrolling patients who continue to be symptomatic in spite of medication, or to enroll patients not currently receiving adequate asthma care. All three approaches, they believe, are inappropriate, being unethical in the first case and unsatisfactory in the latter two instances. Their answer to this conundrum is to devise a protocol, which they point out they have employed before,4 that evaluates the ability to withdraw anti-inflammatory therapy while maintaining good asthma control as the primary end point. The current paper, while not totally redressing the problem, raises some very fundamental questions regarding selection of the evaluable subject and the safety of clinical trial protocols as currently performed. Such questions include the following: (1) How are clinical trials conducted? (2) Why should subjects have active asthma when they enter the study and are placebo controls really necessary? (3) Why should asthmatic subjects participate in studies that may have risk? (4) What safeguards are in place to protect the subject? and (5) Are there data that show morbidity and mortality from placebo controlled studies? The study protocols in the United States begin with a screening visit where subjects are evaluated to determine whether they are suitable to participate based on asthma symptoms, pulmonary function tests, medication requirements, and laboratory tests to evaluate the subjects’ general health. They are excluded from the study if they have very severe unstable asthma and other disease entities with associ-
ated medication needs. Those passing the screening procedure enter a run-in of 2 to 4 weeks’ duration during which time a diary is kept of all signs and symptoms of asthma, rescue medication, and peak expiratory flow rates. Albuterol is allowed during this time on an as-needed basis and frequently the anti-inflammatory agent, if it is part of the patient’s management medication before the study, is continued. Evaluated during this period are subject compliance, asthma stability and activity. After completing the run-in period, the subject is randomized to receive either the study drug or placebo if certain criteria have been met. The period that follows randomization, usually 12 weeks in duration, is monitored carefully by office visits on a weekly to monthly basis. During this time, the subject is not allowed any asthma therapy except study medication and rescue albuterol for asthma unless there is a significant exacerbation. Placebo-controlled studies in patients who need therapy have recently raised ethical issues noted by several federal agencies including the National Bioethics Advisory Committee formed in 1995.5 This format, however, has been promulgated by the U S Food and Drug Administration because they find it difficult to prove efficacy without it.6 Merely comparing a new agent with known therapy without placebo may not produce useful data because the control itself may be as effective as the new drug. Asthmatic subjects are selected on the basis of active disease defined by clinical and spirometric variables so that a distinct drug effect and dose response, when required, can be determined. This may not be as clear-cut using drug withdrawal as an end point as suggested by Cockcroft et al. Sub-
173
jects are excluded for histories suggesting unstable asthma including emergency room visits, hospitalizations, or systemic steroid use during the 6 to 12 months prior to study. Cockcroft argues that this profile is difficult to find in the well managed patient seen in the allergist’s practice. Allergists, however, find these subjects in several ways, including in their own practice, since many studies utilize stable patients with rather minimal symptoms who are for the most part well controlled on anti-inflammatory therapy. It is also true that many patients fail entry criteria because they are so stable. The removal or reduction of anti-inflammatory therapy can be done, but only in patients who are well known and have been stable for long periods of time. This would be part of their usual management program to determine minimal therapy necessary to control asthma. Subjects who are not on anti-inflammatory agents are a minority in the allergists’ practice unless asthma is a minor problem and they have been referred for another reason. These subjects are usually found in the primary care environment or unaffiliated with any medical practice and are frequently recruited by advertisement. They are enrolled in studies only after it has been determined that they fit entrance criteria for asthma activity and stability. The protocol suggested by Cockcroft et al and previously reported by them4 has recently again been employed in severe steroid dependent patients. Noonan et al successfully evaluated the effectiveness of fluticasone using the endpoint of prednisone withdrawal without deterioration of asthma in steroid-dependent asthmatic patients.7 It would seem that this type of protocol works best where asthma severity is great and the risk of abrupt withdrawal of anti-inflammatory medication would be very great. All human research is based on benefit to risk ratio. In a recent paper, Bush points out that benefit may be (1) generalizable helping patients with the disease entity in general or providing a
174
better grasp of disease pathogenesis or (2) direct, benefiting the individual patient in a study protocol.5 Certainly, patients receiving placebo in such studies may not benefit directly, but do benefit in the development of better therapeutic agents for that disease entity. Even in these studies patients often can participate in extended open trials after completion of the doubleblind phase where they can directly benefit from study drugs not yet available to the general public. Other patient benefits include education; good asthma follow-up, which can continue after study completion; and financial renumeration. Although efficacy is important, safety is also a prime concern. Since benefit in these studies is usually generalizable, risk must be minimal. Safety issues include potential side effects of study drug and asthma exacerbations particularly in the placebo group. Asthma protocols attempt to minimize the risk to the patient in several ways. Subjects who have unstable asthma are excluded from entry into the study. In my experience, most asthma studies include subjects who are on the mild side of moderate with minimal symptoms; FEV1 generally in the range of 65% to 70%; and no recent emergency room visits, hospitalizations, or chronic systemic steroid usage. During the study, guidelines are established that provide a “safety net” for the subject that, if exceeded, mandate notification of the physician investigator and usually result in discontinuation from a study. Subjects are required to keep daily diaries with symptom scores, medication usage, and monitoring of peak expiratory flow rates twice each day. As an example, subjects are dropped from the study if they exceed stability limits such as two days or more of 12 puffs per day of albuterol, two nights of awakening requiring albuterol, three days of 20% decrease in peak expiratory flow rate, or 20% decrease from baseline FEV1 during study visit. In addition, subjects are generally discontinued if they require an emergency
room visit, hospitalization, or systemic steroids during the study. In some studies one to two short bursts of prednisone are allowed. How well does this system work? Data have been presented evaluating the morbidity and mortality of the placebo group in asthma studies. In a report of more than 1,500 subjects receiving inhaled corticosteroids representing six clinical trials who went through a placebo-controlled study, 442 subjects received placebo. Using “safety net” criteria, approximately 60% of these patients were discontinued due to lack of efficacy. There was one asthma exacerbation (less than 1% of the total number of placebo subjects) not requiring hospitalization and no deaths.8 In four clinical trials representing more than 1,000 inhaled-corticosteroid-naive subjects, 272 received placebo. There were four asthma exacerbations, two resulting in hospitalization (less than 2%) and no deaths.9 These data suggest that subjects who fit criteria for moderately severe asthma, provided they are given a “safety net” for physician notification and study discontinuation, can safely be evaluated in clinical trials and are exposed to a minimal risk under these conditions. The Pharmacotherapeutics Committee of the American Academy of Allergy, Asthma and Immunology has recently proposed recommendations to ensure that patient recruitment and enrollment occur with minimal risks (Melamed J, personal communication). Several suggestions warrant repeating and comment. 1. All study personnel must have appropriate background and training in asthma pathogenesis, signs and symptoms, and therapy. 2. Before initial office evaluation, patients should not be told to withdraw regular asthma medication. Hamilos et al10 also comment on the risk of withholding asthma medication and emphasize that patients must be seen before they are advised to stop medications. If potential patients are screened by telephone, particularly if not receiving
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
regular care, the wording used should be carefully presented so that they do not stop medications in order to get into the study before the office visit. It has been our policy to do a pre-screening visit to determine whether patients can safely withhold medication, including beta agonist, prior to the screening visit which requires that the patient be off beta agonist for six hours to adequately evaluate pulmonary function and reversibility. 3. Written informed consent as approved by an IRB must be obtained prior to any intervention in therapy. 4. Patients in studies that require withdrawal of regular medications should be supplied with peak flow meters and printed instructions regarding how to withdraw medications and a patient diary with specific details of specific safety criteria. The potential study subject must notify study personnel if any of these safety criteria are exceeded. Patients must have 24-hour emergency access to study personnel. 5. Although patients should be compensated for study participation, it should never be of such a magnitude to adversely affect the judg-
VOLUME 79, SEPTEMBER, 1997
ment of either the patient or study personnel. Cockcroft and associates present cogent arguments and concerns about the current selection of the evaluable subject. Even with the current U S Food and Drug Administration requirements, protocol safety guidelines, in conjunction with careful monitoring and follow-up by the physician investigator and his staff, have resulted in a good safety record and important progress in development of better therapeutic agents for a condition that in itself has some mortality and considerable morbidity. I would share in this conclusion based on my experience in performing clinical trials in the office setting for the past 15 years. STANLEY P GALANT, MD Clinical Professor of Pediatrics Director of Pediatric Allergy/Immunology University of California, Irvine Director of Pediatric Allergy Immunology Irvine, California REFERENCES 1. Cockcroft DW, Jokic R, Marciniuk DD, et al. The current dilemma with spirometric inclusion criteria for asth-
2. 3. 4.
5. 6. 7.
8.
9. 10.
matic drug trials. Ann Allergy 1997; 79:226 – 8. Guidelines for the diagnosis and management of asthma, NIH Publication #97-4051A, May, 1997. Cockcroft DW, Swystun VA. Asthma control vs asthma severity. J Allergy Clin Immunol 1996;98:1016 – 8. Kerigan AT, Pugsley SO, Cockcroft DW, et al. Substitution of inhaled beclomethasone propionate for oral prednisone in steroid dependent asthmatic patients. Canadian Med Assoc J 1997; 116:876 – 81. Bush C. When your subject is a child. Appl Clin Trials 1997;6:54 – 6. Wechsler J. Human subject research captures worldwide attention. Applied Clinical Trials 1997;6:22–7. Noonan M, Chervinsky P, Busse WW, et al. Fluticasone propionate reduces oral prednisone use while it improves asthma control and quality of life. Am J Respir Critical Care Med 1995; 152:1467–73. Kellerman D, Schaberg A, Shah T, et al. Are placebo controlled asthma clinical trials safe? An update [Abstract]. Presented to European Respiratory Society, September 1995, Barcelona. Data on file with Glaxo-Wellcome. Hamilos DL, Oppenheimer JJ, Nelson HS, et al. Suggested approaches for research protocols involving the potential for life threatening reactions. J Allergy Clin Immunol 1993;91:1101–20.
175
The evaluable subject The clinical trial evaluating new pharmaceutical modalities has become an important part of the allergist’s repertoire. Never before has the allergist become so involved as an investigator in this billion dollar industry. This has occurred, I believe, in part due to the decline of clinical practice revenue and also because allergists view themselves as clinical scientists interested in new frontiers in asthma and allergy research. Furthermore, there has been a shift in clinical trials away from academic centers to the office setting. In this milieu, the allergist wears two hats, first and foremost as caregiver and second, as a clinical trials investigator. Although the goals of both are similar, that is, the ultimate welfare of the patient, there are situations when there appears to be confusion, if not conflict, in finding the evaluable subject. In this issue of the Annals, Cockcroft and associates confront this very situation in the asthmatic patient.1 From their perspective, it is difficult to find suitable subjects for clinical trials if the patients are adequately managed. Thus, they suggest that the usual inclusion criteria used to qualify a patient for study protocol such as frequent asthma symptoms, abnormal pulmonary function tests including an FEV1 between 50% to 80% of predicted, and 15% FEV1 reversibility after bronchodilator, which fit the category of persistent moderate asthma by the new NIH guidelines,2 cannot be frequently found in the allergist’s office. This is consistent with their view that asthma severity should be based on the quantity of inhaled corticosteroids necessary to completely control the asthma.3 They report in this issue that less than 10% of 590 asthmatic charts reviewed retrospectively fulfill the pulmonary
VOLUME 79, SEPTEMBER, 1997
function test criteria necessary to enter a study. To circumvent this difficulty, they suggest three approaches that might be employed, including withdrawing antiinflammatory medication, enrolling patients who continue to be symptomatic in spite of medication, or to enroll patients not currently receiving adequate asthma care. All three approaches, they believe, are inappropriate, being unethical in the first case and unsatisfactory in the latter two instances. Their answer to this conundrum is to devise a protocol, which they point out they have employed before,4 that evaluates the ability to withdraw anti-inflammatory therapy while maintaining good asthma control as the primary end point. The current paper, while not totally redressing the problem, raises some very fundamental questions regarding selection of the evaluable subject and the safety of clinical trial protocols as currently performed. Such questions include the following: (1) How are clinical trials conducted? (2) Why should subjects have active asthma when they enter the study and are placebo controls really necessary? (3) Why should asthmatic subjects participate in studies that may have risk? (4) What safeguards are in place to protect the subject? and (5) Are there data that show morbidity and mortality from placebo controlled studies? The study protocols in the United States begin with a screening visit where subjects are evaluated to determine whether they are suitable to participate based on asthma symptoms, pulmonary function tests, medication requirements, and laboratory tests to evaluate the subjects’ general health. They are excluded from the study if they have very severe unstable asthma and other disease entities with associ-
ated medication needs. Those passing the screening procedure enter a run-in of 2 to 4 weeks’ duration during which time a diary is kept of all signs and symptoms of asthma, rescue medication, and peak expiratory flow rates. Albuterol is allowed during this time on an as-needed basis and frequently the anti-inflammatory agent, if it is part of the patient’s management medication before the study, is continued. Evaluated during this period are subject compliance, asthma stability and activity. After completing the run-in period, the subject is randomized to receive either the study drug or placebo if certain criteria have been met. The period that follows randomization, usually 12 weeks in duration, is monitored carefully by office visits on a weekly to monthly basis. During this time, the subject is not allowed any asthma therapy except study medication and rescue albuterol for asthma unless there is a significant exacerbation. Placebo-controlled studies in patients who need therapy have recently raised ethical issues noted by several federal agencies including the National Bioethics Advisory Committee formed in 1995.5 This format, however, has been promulgated by the U S Food and Drug Administration because they find it difficult to prove efficacy without it.6 Merely comparing a new agent with known therapy without placebo may not produce useful data because the control itself may be as effective as the new drug. Asthmatic subjects are selected on the basis of active disease defined by clinical and spirometric variables so that a distinct drug effect and dose response, when required, can be determined. This may not be as clear-cut using drug withdrawal as an end point as suggested by Cockcroft et al. Sub-
173
jects are excluded for histories suggesting unstable asthma including emergency room visits, hospitalizations, or systemic steroid use during the 6 to 12 months prior to study. Cockcroft argues that this profile is difficult to find in the well managed patient seen in the allergist’s practice. Allergists, however, find these subjects in several ways, including in their own practice, since many studies utilize stable patients with rather minimal symptoms who are for the most part well controlled on anti-inflammatory therapy. It is also true that many patients fail entry criteria because they are so stable. The removal or reduction of anti-inflammatory therapy can be done, but only in patients who are well known and have been stable for long periods of time. This would be part of their usual management program to determine minimal therapy necessary to control asthma. Subjects who are not on anti-inflammatory agents are a minority in the allergists’ practice unless asthma is a minor problem and they have been referred for another reason. These subjects are usually found in the primary care environment or unaffiliated with any medical practice and are frequently recruited by advertisement. They are enrolled in studies only after it has been determined that they fit entrance criteria for asthma activity and stability. The protocol suggested by Cockcroft et al and previously reported by them4 has recently again been employed in severe steroid dependent patients. Noonan et al successfully evaluated the effectiveness of fluticasone using the endpoint of prednisone withdrawal without deterioration of asthma in steroid-dependent asthmatic patients.7 It would seem that this type of protocol works best where asthma severity is great and the risk of abrupt withdrawal of anti-inflammatory medication would be very great. All human research is based on benefit to risk ratio. In a recent paper, Bush points out that benefit may be (1) generalizable helping patients with the disease entity in general or providing a
174
better grasp of disease pathogenesis or (2) direct, benefiting the individual patient in a study protocol.5 Certainly, patients receiving placebo in such studies may not benefit directly, but do benefit in the development of better therapeutic agents for that disease entity. Even in these studies patients often can participate in extended open trials after completion of the doubleblind phase where they can directly benefit from study drugs not yet available to the general public. Other patient benefits include education; good asthma follow-up, which can continue after study completion; and financial renumeration. Although efficacy is important, safety is also a prime concern. Since benefit in these studies is usually generalizable, risk must be minimal. Safety issues include potential side effects of study drug and asthma exacerbations particularly in the placebo group. Asthma protocols attempt to minimize the risk to the patient in several ways. Subjects who have unstable asthma are excluded from entry into the study. In my experience, most asthma studies include subjects who are on the mild side of moderate with minimal symptoms; FEV1 generally in the range of 65% to 70%; and no recent emergency room visits, hospitalizations, or chronic systemic steroid usage. During the study, guidelines are established that provide a “safety net” for the subject that, if exceeded, mandate notification of the physician investigator and usually result in discontinuation from a study. Subjects are required to keep daily diaries with symptom scores, medication usage, and monitoring of peak expiratory flow rates twice each day. As an example, subjects are dropped from the study if they exceed stability limits such as two days or more of 12 puffs per day of albuterol, two nights of awakening requiring albuterol, three days of 20% decrease in peak expiratory flow rate, or 20% decrease from baseline FEV1 during study visit. In addition, subjects are generally discontinued if they require an emergency
room visit, hospitalization, or systemic steroids during the study. In some studies one to two short bursts of prednisone are allowed. How well does this system work? Data have been presented evaluating the morbidity and mortality of the placebo group in asthma studies. In a report of more than 1,500 subjects receiving inhaled corticosteroids representing six clinical trials who went through a placebo-controlled study, 442 subjects received placebo. Using “safety net” criteria, approximately 60% of these patients were discontinued due to lack of efficacy. There was one asthma exacerbation (less than 1% of the total number of placebo subjects) not requiring hospitalization and no deaths.8 In four clinical trials representing more than 1,000 inhaled-corticosteroid-naive subjects, 272 received placebo. There were four asthma exacerbations, two resulting in hospitalization (less than 2%) and no deaths.9 These data suggest that subjects who fit criteria for moderately severe asthma, provided they are given a “safety net” for physician notification and study discontinuation, can safely be evaluated in clinical trials and are exposed to a minimal risk under these conditions. The Pharmacotherapeutics Committee of the American Academy of Allergy, Asthma and Immunology has recently proposed recommendations to ensure that patient recruitment and enrollment occur with minimal risks (Melamed J, personal communication). Several suggestions warrant repeating and comment. 1. All study personnel must have appropriate background and training in asthma pathogenesis, signs and symptoms, and therapy. 2. Before initial office evaluation, patients should not be told to withdraw regular asthma medication. Hamilos et al10 also comment on the risk of withholding asthma medication and emphasize that patients must be seen before they are advised to stop medications. If potential patients are screened by telephone, particularly if not receiving
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
regular care, the wording used should be carefully presented so that they do not stop medications in order to get into the study before the office visit. It has been our policy to do a pre-screening visit to determine whether patients can safely withhold medication, including beta agonist, prior to the screening visit which requires that the patient be off beta agonist for six hours to adequately evaluate pulmonary function and reversibility. 3. Written informed consent as approved by an IRB must be obtained prior to any intervention in therapy. 4. Patients in studies that require withdrawal of regular medications should be supplied with peak flow meters and printed instructions regarding how to withdraw medications and a patient diary with specific details of specific safety criteria. The potential study subject must notify study personnel if any of these safety criteria are exceeded. Patients must have 24-hour emergency access to study personnel. 5. Although patients should be compensated for study participation, it should never be of such a magnitude to adversely affect the judg-
VOLUME 79, SEPTEMBER, 1997
ment of either the patient or study personnel. Cockcroft and associates present cogent arguments and concerns about the current selection of the evaluable subject. Even with the current U S Food and Drug Administration requirements, protocol safety guidelines, in conjunction with careful monitoring and follow-up by the physician investigator and his staff, have resulted in a good safety record and important progress in development of better therapeutic agents for a condition that in itself has some mortality and considerable morbidity. I would share in this conclusion based on my experience in performing clinical trials in the office setting for the past 15 years. STANLEY P GALANT, MD Clinical Professor of Pediatrics Director of Pediatric Allergy/Immunology University of California, Irvine Director of Pediatric Allergy Immunology Irvine, California REFERENCES 1. Cockcroft DW, Jokic R, Marciniuk DD, et al. The current dilemma with spirometric inclusion criteria for asth-
2. 3. 4.
5. 6. 7.
8.
9. 10.
matic drug trials. Ann Allergy 1997; 79:226 – 8. Guidelines for the diagnosis and management of asthma, NIH Publication #97-4051A, May, 1997. Cockcroft DW, Swystun VA. Asthma control vs asthma severity. J Allergy Clin Immunol 1996;98:1016 – 8. Kerigan AT, Pugsley SO, Cockcroft DW, et al. Substitution of inhaled beclomethasone propionate for oral prednisone in steroid dependent asthmatic patients. Canadian Med Assoc J 1997; 116:876 – 81. Bush C. When your subject is a child. Appl Clin Trials 1997;6:54 – 6. Wechsler J. Human subject research captures worldwide attention. Applied Clinical Trials 1997;6:22–7. Noonan M, Chervinsky P, Busse WW, et al. Fluticasone propionate reduces oral prednisone use while it improves asthma control and quality of life. Am J Respir Critical Care Med 1995; 152:1467–73. Kellerman D, Schaberg A, Shah T, et al. Are placebo controlled asthma clinical trials safe? An update [Abstract]. Presented to European Respiratory Society, September 1995, Barcelona. Data on file with Glaxo-Wellcome. Hamilos DL, Oppenheimer JJ, Nelson HS, et al. Suggested approaches for research protocols involving the potential for life threatening reactions. J Allergy Clin Immunol 1993;91:1101–20.
175