Übersichtsarbeiten/Review Articles Onkologie 1990:13:85-88
Ethical Considerations in Phase I Clinical Trials H.-M. Sass
Summary and Key Words
Zusammenfassung und Schlüsselwörter
Medical ethics has developed methods of differential ethics for a more rigid integration of bioethical reasoning into biomedical research. Due to high levels of risk and uncertainty in phase I trials, established principles of medical ethics need a specific assessment in order to provide for better moral design and moral monitoring of trial pro cedures, a better translation of medical health status data into indi vidual quality of life criteria, and strong support for trust-based cooperation between physician, research team and patient. Existing bioethical questionnaires and detailed methodological research in differential ethics could be improved further.
Die medizinische Ethik hat differentialethische Methoden entwickelt, die eine strengere Integration biocthischer Überlegungen in die bio medizinische Forschung erlauben. Die weithin anerkannten medizin ethischen Prinzipien bedürfen wegen der besonders hohen Grade von Risiko und Unsicherheit in Phase-I-Forschungen einer speziellen Bewertung, um ein besseres ethisches Design und Monitoring der Studie, eine bessere Übersetzung von medizinischen Gesundheitskri terien in individuelle Lebensqualitätskriterien und eine weiterhin gute Unterstützung für ein vertrauensbasierendes Arzt-Patientenverhältnis zu sichern. Bestehende bioethische Fragcnkatalogc und spezialisierte Methodenforschung in der Differentialcthik können weiter verbessert werden.
Bioethics - Clinical research - Chemotherapy - Human experimen tation - Medical ethics - Phase I trials - Quality o f life
Bioethik - Klinische Forschung - Chemotherapie - Versuche am Menschen - Medizinische Ethik - Phase-I-Studien - Lebensqualität
Introduction
facts, which determine the ethical situation of a given case, as scientific and technical evaluation [17], Differential ethics fol lows the same methodological reasoning of risk analysis and assessment as differential diagnosis does. Good medical prac tice integrates the interpretation of the “blood status” and the interpretation of the “value status” of the individual patient. More precisely, two sets of principles have to be balanced: the no harm principle and the benefit principle on the one hand and the autonomy principle on behalf of the patient with the responsibility principle on behalf of the physician on the other 117]. Good moral management requires a comfortably high degree of moral benefit over moral cost. Side effects, degrees of medical harm, of uncomfortableness and unpleasantness, of emotional distress and loss of libido are not only harm in medical terms but translate into moral harm to the individual patient. The acceptability of harm has to be balanced with either real and demonstrated benefits in terms of quality of life. Similar moral calculations have to be done when weighing the respect for human dignity and personal choice of the patient versus the physician's responsibility to treat and to improve treatment. This scenario has been described as an unwritten covenant between the patient and the physician, a covenant based on the patient’s need, the physicians expertise and knowledge, and on mutual trust and communication [19]. The terms of the covenant have been called beneficence in trust. In medical research higher levels of uncertainty and potential harm, together with a potential conflict of interest between patient care and medical progress require a re-arrangement and re-formulation of the traditional set of bioethical princi ples [16]. Clinical research by definition has to live with higher than normal degrees of uncertainty, unpredictability of risk,
In medical research, as in all medical activities, ethics and expertise belong together. The close integration of ethics and expertise was part of the Hippocratic tradition in medicine. It seems, however, that the development of technical and scien tific expertise in medicine has enjoyed more progress, public attention, peer recognition, methodological differentiation, and therapeutic efficacy than the refinement and differentia tion of ethical expertise. But given the strong Hippocratic tradition in clinical research, the issue is not whether bioethics should be a part of biomedicine, but rather how it should be made a most productive and efficient part in clinical assess ment and decision making. Sometimes the bioethical review of medical research has been perceived as an unprofessional intrusion from the outside, often unpleasant, even unwanted, but legally required. And, indeed, review procedures by Ethics Committees or IRB’s quite often represent an outside process of critique rather than a solid integration of moral design and monitoring into the processes of designing and monitoring clinical studies [18]. This paper argues that the traditional ethical review process of the protocol design, often armchair style, prior to the realization of the study, should be accompanied by a more professional integration o f moral design and monitoring into the design and monitoring o f clini cal research. The bioethicist should play as important a role in clinical research as die biosiaiician. Special Conditions of Medical Ethics in Phase I Studies In general, the moral evaluation of a given medical situation requires similar rigid analytical skills in diagnosing the moral
Downloaded by: Leiden University Medisch Centrum 132.229.13.63 - 10/19/2018 5:59:45 PM
Kennedy Institute of Ethics, Georgetown University, Washington DC, and Institute of Philosophy. Ruhr Universität, Bochum, FRG
harm, or efficacy. This is particularly true in potentially very harmful trials in phase I clinical oncology. While the underesti mation of technical failure is a technical as well as moral risk, the underestimation of moral risk in not taking the individual patient's concepts of risk and risk tolerance and of quality of life definitions represents an additional moral and therapeuti cal risk. Underestimation of moral uncertainty is an additional moral risk; therefore, prudent moral risk management recog nizes the need for risk reduction, as total risk elimination is not possible. Researching cytostatics and other proven cell killers adds high levels of certainty of harm to the research project, which also is a treatment project. Also, the quality of life issues which might be addressed differently by individual patients during various stages of the trial add an additional layer of uncertainty, both in technical and in moral terms. The potential of harm is associated with uncertainty in medi cine and in phase I studies in general, but in particular with contemporary phase I oncological research. As strategies for eradicating human cell tissue are tested, harm has to be measured not only in toxological or medicotechnical terms but in quality of life parameters as well. Harm in biomedical and bioethical terms includes degrees of discomfort, pain, somatic and emotional stress, nausea, vomiting, mouth soreness, alopecia, temporary or permanent loss or decrease of func tions. These differentiated forms of harm have to be balanced against expected forms of benefit such as improvements in somatic or emotional status, reduction of pain, symptoms, side effects, misery, suffering, prolongation of life or change in quality of life parameters as defined by the patient; sometimes no treatment or palliative treatment only, even death, can be regarded as beneficial when compared to harm in the form of torturous, endless and meaningless continuation of agony and pain. Efficacy of treatment as well as harm should therefore be defined in trusted interaction between proband/patient and physician/researcher. Efficiency in research results has to be differentiated from efficacy in medicotechnical terms and from the benefit in terms defined by the individual patient. This gives informed consent, a general requirement in medicine, a distinct role in human experimentation. But phase I studies have to live with ambiguous and indistinct information due to the researcher's own lack of precise and distinct knowledge. Also, desperate patients tend to consent easily and often for reasons other than calculable therapeutic benefits. The “uncertainty” as well as the “risk” principle should be made an integral part of the communicative process with the patient over the period of the study, not just prior to its start. Linear analog self-assessment forms [14] seem to improve the com municative process, especially in studies which include painful and stressful side effects. Traditional concepts of informed consent should be replaced by the concept of trust-based cooperation [19]. Cooperation methods based on trust and risk-information sharing might allow the acceptance of higher levels of risk and uncertainty but would also reward higher benefits in technical terms. As even peer review ethics committees for phase I trials might have to operate under even greater uncertainties than other committees due to a lack of specific expertise, the participa tion of lay persons, professionally experienced or trained in risk assessment, in issues of quality of life, and communication
Sass: Ethical Considerations in Phase I Clinical Trials
in areas other than clinical research, could prove to be particu larly helpful [17], As crucial moral issues occur during the process of the clinical study, which cannot be addressed beforehand by review committees, a well-trained and experi enced bioethicists on the team [17,18] would provide expertise in the ethical field the same way a biostatistician does in the issues of biostatistics. Review committees and continuous ethical monitoring of the research procedures would be well based in the covenant concept, which is person-centered, not disease-centered or research-centered. Therefore, the special rules of phase I ethics have to emphasize educated communi cation over consent. The principle of professional beneficence in trust gives priority to the patient’s well-being over the progress of research; there has to be an educated understand ing on behalf of the patient regarding alternative forms of treatment, including minimal or palliative treatment only. Also, consequences of different forms of treatment for well feeling and for life expectancy have to be discussed in order to provide the best possible outcome for the patient in an often already quite desperate situation under the covenant principle of beneficence in trust, leading to education in trust, com munication in trust and decision-making in trust.
Ethical Guidelines and Checklists Guiding Phase I Research The Helsinki-Tokyo-Venedig Declaration has become a most influential blueprint for international, national, and profes sional codes in governmental regulating and professional self regulating human experimentation. Mayor principles include: balance of risk-benefit assessments, informed consent of the patients, involvement of ethics committees/institutional review boards. The Helsinki moral risk reduction strategy by commit tee is in conflict with the older German "Reichsrichtlinien" which stressed the personal responsibility of the senior physi cian of a research facility over review board responsibility. The major deficiency of the Helsinki formula is that it requires only an outside review prior to the project, no monitoring during the project or the integration of moral and technical parame ters throughout the study. Most technical codes such as the EORTC Guidelines for Phase I Trials with Single Agents in Adults [6] follow the Helsinki set-up, setting standards for the protection of subjects and in establishing reliability and preci sion of trials. These technical reports, however, could be further improved by introducing more detailed features regarding bioethical criteria and moral codes. Existing checklists differ in regard to methods of evaluation and patient involvement. Medical performance tests such as the 10 criteria of the Karnofsky performance status scales [11] measure mobility and health status; it would be morally unac ceptable and medically unprofessional to translate these per formance criteria directly into criteria of well-being, wellfeeling, and individual quality of life [20]. More instrumental in translating clinical data into quality-of-life criteria would be detailed health and well-being indices such as Spitzer’s Quality of Life Index (QIL) [20], the Nottingham Health Profile [10], or methods involving the patients more directly, such as the LASA (Linear Analogue Self-Assessment) questionnaires [14]. There are major and yet not precisely enough addressed methodological problems in the ethics of clinical research. For
Downloaded by: Leiden University Medisch Centrum 132.229.13.63 - 10/19/2018 5:59:45 PM
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Sass: Ethical Considerations in Phase I Clinical Trials
Moral Risk Reduction Strategies in Phase I Studies As medical and moral risk cannot be totally eliminated in phase I research, risk reduction strategies could be employed in areas such as the improvement of preclinical research, patient selection and dosage escalation, and for gaining more flexibility in research design.
Table 1. Ten questions in clinical research following the Bochum questionnaire 1. 2. 3. 4. 5. 6. 7.
Is the trial design optimal from a medical-ethical perspective? Is this particular trial necessary? Did the patient give his or her informed consent? Was the information incomplete or incompletely understood? Could there be reasons that consent was not fully voluntary? What principles of justice/fairness were used in selecting patients? Does the patient know about his/her right to terminate participa tion at any time? Is such termination technically possible? 8. Will there be an ongoing communication with the patient during the trial? Who is personally responsible for continued communica tion with the patient? 9. Define conflicts between the interest of research, the presumed interest of the patient and interest of the patient as expressed by himself/herself! 10. How do you handle these conflicts of interest? Discuss these conflicts with the patient!
Table 2. Four questions in phase I oncological trials 1. Is your definition of efficiency as expressed in terms of remission or no change in conflict with the patient's definitions of quality of life? 2. Which health index profiles or checklists did you use in communi cating with the patient? Do you have your own standardized "Points to consider list', especially designed for this particular trial? 3. Is the patient aware of a possibly scanty prognosis for full recovery? What does the patient expect from the trial? What does the researcher expect? 4. Has the patient been offered the best available palliative care? Has he/she been made aware that the best palliative care will continue even if he/she withdraws from participating in the trial?
Further refinement o f preclinical studies such as animal studies, cell and tissue studies, computer simulation, and historic con trol group studies, human cancer cell and tissue research, fetal tissue research, whole animal research, formulation and bulk synthesis refinements, and toxicology and efficacy trial and simulation refinements might case risk levels in clinical research. Some of these preclinical studies, such as animal research and fetal tissue research, are under public scrutiny. But the professionals involved in clinical ethics have a strong argument in publicly discussing the moral benefits of preclini cal research for patient treatment and for reducing risk and uncertainty in clinical research. Progress in sophisticated com puter simulation and increased availability of clinical research data of historical control groups, as well as new biostatistics software suggests the experimental introduction of integrated ad-hoc non-patient investigations, parallel to dosage escala tion and interpretation of result. Correlating parallel studies on technical as well as ethical aspects of the ongoing project might benefit the technical result, and it will definitely benefit the bioethical set-up and outcome. Patient selection for optimal research design is mandatory for technical efficiency and risk reduction. Ethically comfortable patient selection will have to include non-technical criteria in patient selection criteria such as the patient’s preparedness and capability of being a partner in a highly risky enterprise, the reasons for their participation, and their understandings of quality of life issues. Optimal information and consent pro cedures prior to the trial and at all stages of the trial are preconditional for including patient-based quality of life criteria into clinical judgement and cooperative decision making. Some other improvements in reducing risk are related to the set-up of the original research design. According to the litera ture, the moral benefits of intra-person dosage escalation seem to outweigh those of inter-person trials. Also, prospective testing and pilot studies prior to phase I research and, in general, a more flexible interaction between pilot studies, phase I. phase II, and IND (investigational new drugs) pro cedures, marking the beginning of a new era of creative research design and a more flexible administrative and regulat ory oversight, might reduce the high moral risks associated with phase I trials and with protracted development due to regulatory inflexibility. This might replace the emphasis on compliance with regulative requirements by patient-centered research imperatives. Further research has to be carried out in order to establish differential and efficient criteria and methods in clinical ethics as rigid as those in other areas of clinical research [2,18] and to integrate ethical expertise and technical expertise.
References 1 Sass HM (ed): Bochumer Arbeitsbogen zur medizinethischen Praxis. Medizin und Ethik. Stuttgart, Reclam, 1987, pp 371-375. Engl, transl.: Sass HM, Spicker SF. Viefhues H: Bochum Working Paper on the Practise of Medical Ethics, Medizinethischc Materia lien No. 2a (Jan. 1989). 2 Bullinger M. Pöppel E: Lebensqualität in der Medizin: Schlagwort oder Forschungsansatz. Deutsches Ärzteblatt 1988:85:679- 680.
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the time being, it would be helpful to have an ethical checklist of "Points to Consider” specifically made as part of the trial design and refined during the trial. A good example for a general checklist which avoids the epistemological and logical fallacies of misinterpreting clinical data into "the best interest of the patient” is a list of 10 questions on human experimentation (table 1) following the Bochum Working Paper on Medical Ethical Practice [1]. Review boards or bioethicists, as consultants or members of the team, could be employed in drafting more detailed and specific questionnaires for specific trials, procedures, side effects, testing of specific substances, etc. (table 2). This would be a step closer towards a professional integration of moral design and moral monitoring into the more technical aspects of design and monitoring. The more differentiated the checklists are, the more valuable instruments they will be in improving moral design and moral monitoring and in including the patient as a partner in making hard decisions.
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14 Priestman TJ, Baum M: Evaluation of quality of life in patients receiving treatment for advanced breast cancer. Lancet 1976; 1:899-901. 15 Ramsey P: The Patient as Person. New Haven, Yale University Press. 1974. 16 Sass HM: Comparative models and goals for the regulation of human research, in Engelhardt HT. Spicker SF (eds): Human Experimentation. Dordrecht. Reidel, 1988, pp 47-89. 17 Sass HM: Bioethik in den USA. Heidelberg, Springer, 1988. 18 Sass HM: Ethics of drug research and drug development, in Wolff HP, et al (eds): Drug Research and Drug Development in the 21st Century. Heidelberg. Springer, 1989, pp 239-259. 19 Sass HM: Professional organizations and professional ethics, in Pellegrino ED (cd): Ethics and the Professions. Washington DC, Georgetown University Press, 1990 (in press). 20 Spitzer WD. et al: Measuring the quality of life of cancer patients. Chronic Desease 1981:34:585-597. 21 Stewart AL, et al: Functional status and well-being of patients with chronic conditions. JAMA 1989;262:907-913.
Request for Reprints to: Prof. Dr. H. M. Sass Zentrum für Medizinische Ethik Institut für Philosophie, GA 3 Ruhr Universität Postfach 102148 D-4630 Bochum (FRG)
Schwierige Differentialdiagnosen Neue Therapiekonzepte
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3 Cogliano-Shutta NA: Pediatric phase 1 clinical trials: Ethical issues and nursing considerations. Oncology Nursing Forum 1986: 13:29-32. 4 Clark A. Fallowsfield LJ: Quality of life measurements in patients with malignant disease: A review. Royal Soc Med 1986; 79:165-169. 5 Durry G, Dion S: The ethical approach to phase 1 clinical trials in oncology. Drugs Exptl Clin Res 1986:12:21-22. 6 EORTC, New Drug Development Subcomittee: EORTC guide lines for phase 1 trials with single agents in adults. Eur J Cancer and Clin Oncol 1985:21:1005-1007. 7 Geddcs DM: Quality of life. Clinics in Oncology 1985:4:161-176. 8 Guatt GH, et al: Measuring quality of life in clinical trials. A taxonomy and review. Can Med Ass J 1989:140:1441-1448. 9 Hofstede G: The cultural relativity of the quality of life concept. Academy of Management Review 1984:9:389-398. 10 Hunt M: McKenna SP: The Nottingham Health Profile: Subjective health status and medical consultations. Soc Sci Med 1981: 15a:221-229. 11 Karnofsky D, Burchenal JH: Clinical evaluation of chemotherapeutic agents in cancer, in McLeod CM (ed): Evalua tion of Chemotherapy. New York, Columbia University, Press, 1949. pp 190-205. 12 Markman M: The ethical dilemma of phase 1 clinical trials. Cancer Journal for Clinicians 1986:36:367-369. 13 Mathe G, Reitzenstein P: Ethics and errors of clinical trials and the role and place of different types of trial. Drugs Exptl Clin Res 1986:12:1-9.
Ethical Considerations in Phase I Clinical Trials H.-M. Sass
Summary and Key Words
Zusammenfassung und Schlüsselwörter
Medical ethics has developed methods of differential ethics for a more rigid integration of bioethical reasoning into biomedical research. Due to high levels of risk and uncertainty in phase I trials, established principles of medical ethics need a specific assessment in order to provide for better moral design and moral monitoring of trial pro cedures, a better translation of medical health status data into indi vidual quality of life criteria, and strong support for trust-based cooperation between physician, research team and patient. Existing bioethical questionnaires and detailed methodological research in differential ethics could be improved further.
Die medizinische Ethik hat differentialethische Methoden entwickelt, die eine strengere Integration biocthischer Überlegungen in die bio medizinische Forschung erlauben. Die weithin anerkannten medizin ethischen Prinzipien bedürfen wegen der besonders hohen Grade von Risiko und Unsicherheit in Phase-I-Forschungen einer speziellen Bewertung, um ein besseres ethisches Design und Monitoring der Studie, eine bessere Übersetzung von medizinischen Gesundheitskri terien in individuelle Lebensqualitätskriterien und eine weiterhin gute Unterstützung für ein vertrauensbasierendes Arzt-Patientenverhältnis zu sichern. Bestehende bioethische Fragcnkatalogc und spezialisierte Methodenforschung in der Differentialcthik können weiter verbessert werden.
Bioethics - Clinical research - Chemotherapy - Human experimen tation - Medical ethics - Phase I trials - Quality o f life
Bioethik - Klinische Forschung - Chemotherapie - Versuche am Menschen - Medizinische Ethik - Phase-I-Studien - Lebensqualität
Introduction
facts, which determine the ethical situation of a given case, as scientific and technical evaluation [17], Differential ethics fol lows the same methodological reasoning of risk analysis and assessment as differential diagnosis does. Good medical prac tice integrates the interpretation of the “blood status” and the interpretation of the “value status” of the individual patient. More precisely, two sets of principles have to be balanced: the no harm principle and the benefit principle on the one hand and the autonomy principle on behalf of the patient with the responsibility principle on behalf of the physician on the other 117]. Good moral management requires a comfortably high degree of moral benefit over moral cost. Side effects, degrees of medical harm, of uncomfortableness and unpleasantness, of emotional distress and loss of libido are not only harm in medical terms but translate into moral harm to the individual patient. The acceptability of harm has to be balanced with either real and demonstrated benefits in terms of quality of life. Similar moral calculations have to be done when weighing the respect for human dignity and personal choice of the patient versus the physician's responsibility to treat and to improve treatment. This scenario has been described as an unwritten covenant between the patient and the physician, a covenant based on the patient’s need, the physicians expertise and knowledge, and on mutual trust and communication [19]. The terms of the covenant have been called beneficence in trust. In medical research higher levels of uncertainty and potential harm, together with a potential conflict of interest between patient care and medical progress require a re-arrangement and re-formulation of the traditional set of bioethical princi ples [16]. Clinical research by definition has to live with higher than normal degrees of uncertainty, unpredictability of risk,
In medical research, as in all medical activities, ethics and expertise belong together. The close integration of ethics and expertise was part of the Hippocratic tradition in medicine. It seems, however, that the development of technical and scien tific expertise in medicine has enjoyed more progress, public attention, peer recognition, methodological differentiation, and therapeutic efficacy than the refinement and differentia tion of ethical expertise. But given the strong Hippocratic tradition in clinical research, the issue is not whether bioethics should be a part of biomedicine, but rather how it should be made a most productive and efficient part in clinical assess ment and decision making. Sometimes the bioethical review of medical research has been perceived as an unprofessional intrusion from the outside, often unpleasant, even unwanted, but legally required. And, indeed, review procedures by Ethics Committees or IRB’s quite often represent an outside process of critique rather than a solid integration of moral design and monitoring into the processes of designing and monitoring clinical studies [18]. This paper argues that the traditional ethical review process of the protocol design, often armchair style, prior to the realization of the study, should be accompanied by a more professional integration o f moral design and monitoring into the design and monitoring o f clini cal research. The bioethicist should play as important a role in clinical research as die biosiaiician. Special Conditions of Medical Ethics in Phase I Studies In general, the moral evaluation of a given medical situation requires similar rigid analytical skills in diagnosing the moral
Downloaded by: Leiden University Medisch Centrum 132.229.13.63 - 10/19/2018 5:59:45 PM
Kennedy Institute of Ethics, Georgetown University, Washington DC, and Institute of Philosophy. Ruhr Universität, Bochum, FRG
harm, or efficacy. This is particularly true in potentially very harmful trials in phase I clinical oncology. While the underesti mation of technical failure is a technical as well as moral risk, the underestimation of moral risk in not taking the individual patient's concepts of risk and risk tolerance and of quality of life definitions represents an additional moral and therapeuti cal risk. Underestimation of moral uncertainty is an additional moral risk; therefore, prudent moral risk management recog nizes the need for risk reduction, as total risk elimination is not possible. Researching cytostatics and other proven cell killers adds high levels of certainty of harm to the research project, which also is a treatment project. Also, the quality of life issues which might be addressed differently by individual patients during various stages of the trial add an additional layer of uncertainty, both in technical and in moral terms. The potential of harm is associated with uncertainty in medi cine and in phase I studies in general, but in particular with contemporary phase I oncological research. As strategies for eradicating human cell tissue are tested, harm has to be measured not only in toxological or medicotechnical terms but in quality of life parameters as well. Harm in biomedical and bioethical terms includes degrees of discomfort, pain, somatic and emotional stress, nausea, vomiting, mouth soreness, alopecia, temporary or permanent loss or decrease of func tions. These differentiated forms of harm have to be balanced against expected forms of benefit such as improvements in somatic or emotional status, reduction of pain, symptoms, side effects, misery, suffering, prolongation of life or change in quality of life parameters as defined by the patient; sometimes no treatment or palliative treatment only, even death, can be regarded as beneficial when compared to harm in the form of torturous, endless and meaningless continuation of agony and pain. Efficacy of treatment as well as harm should therefore be defined in trusted interaction between proband/patient and physician/researcher. Efficiency in research results has to be differentiated from efficacy in medicotechnical terms and from the benefit in terms defined by the individual patient. This gives informed consent, a general requirement in medicine, a distinct role in human experimentation. But phase I studies have to live with ambiguous and indistinct information due to the researcher's own lack of precise and distinct knowledge. Also, desperate patients tend to consent easily and often for reasons other than calculable therapeutic benefits. The “uncertainty” as well as the “risk” principle should be made an integral part of the communicative process with the patient over the period of the study, not just prior to its start. Linear analog self-assessment forms [14] seem to improve the com municative process, especially in studies which include painful and stressful side effects. Traditional concepts of informed consent should be replaced by the concept of trust-based cooperation [19]. Cooperation methods based on trust and risk-information sharing might allow the acceptance of higher levels of risk and uncertainty but would also reward higher benefits in technical terms. As even peer review ethics committees for phase I trials might have to operate under even greater uncertainties than other committees due to a lack of specific expertise, the participa tion of lay persons, professionally experienced or trained in risk assessment, in issues of quality of life, and communication
Sass: Ethical Considerations in Phase I Clinical Trials
in areas other than clinical research, could prove to be particu larly helpful [17], As crucial moral issues occur during the process of the clinical study, which cannot be addressed beforehand by review committees, a well-trained and experi enced bioethicists on the team [17,18] would provide expertise in the ethical field the same way a biostatistician does in the issues of biostatistics. Review committees and continuous ethical monitoring of the research procedures would be well based in the covenant concept, which is person-centered, not disease-centered or research-centered. Therefore, the special rules of phase I ethics have to emphasize educated communi cation over consent. The principle of professional beneficence in trust gives priority to the patient’s well-being over the progress of research; there has to be an educated understand ing on behalf of the patient regarding alternative forms of treatment, including minimal or palliative treatment only. Also, consequences of different forms of treatment for well feeling and for life expectancy have to be discussed in order to provide the best possible outcome for the patient in an often already quite desperate situation under the covenant principle of beneficence in trust, leading to education in trust, com munication in trust and decision-making in trust.
Ethical Guidelines and Checklists Guiding Phase I Research The Helsinki-Tokyo-Venedig Declaration has become a most influential blueprint for international, national, and profes sional codes in governmental regulating and professional self regulating human experimentation. Mayor principles include: balance of risk-benefit assessments, informed consent of the patients, involvement of ethics committees/institutional review boards. The Helsinki moral risk reduction strategy by commit tee is in conflict with the older German "Reichsrichtlinien" which stressed the personal responsibility of the senior physi cian of a research facility over review board responsibility. The major deficiency of the Helsinki formula is that it requires only an outside review prior to the project, no monitoring during the project or the integration of moral and technical parame ters throughout the study. Most technical codes such as the EORTC Guidelines for Phase I Trials with Single Agents in Adults [6] follow the Helsinki set-up, setting standards for the protection of subjects and in establishing reliability and preci sion of trials. These technical reports, however, could be further improved by introducing more detailed features regarding bioethical criteria and moral codes. Existing checklists differ in regard to methods of evaluation and patient involvement. Medical performance tests such as the 10 criteria of the Karnofsky performance status scales [11] measure mobility and health status; it would be morally unac ceptable and medically unprofessional to translate these per formance criteria directly into criteria of well-being, wellfeeling, and individual quality of life [20]. More instrumental in translating clinical data into quality-of-life criteria would be detailed health and well-being indices such as Spitzer’s Quality of Life Index (QIL) [20], the Nottingham Health Profile [10], or methods involving the patients more directly, such as the LASA (Linear Analogue Self-Assessment) questionnaires [14]. There are major and yet not precisely enough addressed methodological problems in the ethics of clinical research. For
Downloaded by: Leiden University Medisch Centrum 132.229.13.63 - 10/19/2018 5:59:45 PM
86
87
Sass: Ethical Considerations in Phase I Clinical Trials
Moral Risk Reduction Strategies in Phase I Studies As medical and moral risk cannot be totally eliminated in phase I research, risk reduction strategies could be employed in areas such as the improvement of preclinical research, patient selection and dosage escalation, and for gaining more flexibility in research design.
Table 1. Ten questions in clinical research following the Bochum questionnaire 1. 2. 3. 4. 5. 6. 7.
Is the trial design optimal from a medical-ethical perspective? Is this particular trial necessary? Did the patient give his or her informed consent? Was the information incomplete or incompletely understood? Could there be reasons that consent was not fully voluntary? What principles of justice/fairness were used in selecting patients? Does the patient know about his/her right to terminate participa tion at any time? Is such termination technically possible? 8. Will there be an ongoing communication with the patient during the trial? Who is personally responsible for continued communica tion with the patient? 9. Define conflicts between the interest of research, the presumed interest of the patient and interest of the patient as expressed by himself/herself! 10. How do you handle these conflicts of interest? Discuss these conflicts with the patient!
Table 2. Four questions in phase I oncological trials 1. Is your definition of efficiency as expressed in terms of remission or no change in conflict with the patient's definitions of quality of life? 2. Which health index profiles or checklists did you use in communi cating with the patient? Do you have your own standardized "Points to consider list', especially designed for this particular trial? 3. Is the patient aware of a possibly scanty prognosis for full recovery? What does the patient expect from the trial? What does the researcher expect? 4. Has the patient been offered the best available palliative care? Has he/she been made aware that the best palliative care will continue even if he/she withdraws from participating in the trial?
Further refinement o f preclinical studies such as animal studies, cell and tissue studies, computer simulation, and historic con trol group studies, human cancer cell and tissue research, fetal tissue research, whole animal research, formulation and bulk synthesis refinements, and toxicology and efficacy trial and simulation refinements might case risk levels in clinical research. Some of these preclinical studies, such as animal research and fetal tissue research, are under public scrutiny. But the professionals involved in clinical ethics have a strong argument in publicly discussing the moral benefits of preclini cal research for patient treatment and for reducing risk and uncertainty in clinical research. Progress in sophisticated com puter simulation and increased availability of clinical research data of historical control groups, as well as new biostatistics software suggests the experimental introduction of integrated ad-hoc non-patient investigations, parallel to dosage escala tion and interpretation of result. Correlating parallel studies on technical as well as ethical aspects of the ongoing project might benefit the technical result, and it will definitely benefit the bioethical set-up and outcome. Patient selection for optimal research design is mandatory for technical efficiency and risk reduction. Ethically comfortable patient selection will have to include non-technical criteria in patient selection criteria such as the patient’s preparedness and capability of being a partner in a highly risky enterprise, the reasons for their participation, and their understandings of quality of life issues. Optimal information and consent pro cedures prior to the trial and at all stages of the trial are preconditional for including patient-based quality of life criteria into clinical judgement and cooperative decision making. Some other improvements in reducing risk are related to the set-up of the original research design. According to the litera ture, the moral benefits of intra-person dosage escalation seem to outweigh those of inter-person trials. Also, prospective testing and pilot studies prior to phase I research and, in general, a more flexible interaction between pilot studies, phase I. phase II, and IND (investigational new drugs) pro cedures, marking the beginning of a new era of creative research design and a more flexible administrative and regulat ory oversight, might reduce the high moral risks associated with phase I trials and with protracted development due to regulatory inflexibility. This might replace the emphasis on compliance with regulative requirements by patient-centered research imperatives. Further research has to be carried out in order to establish differential and efficient criteria and methods in clinical ethics as rigid as those in other areas of clinical research [2,18] and to integrate ethical expertise and technical expertise.
References 1 Sass HM (ed): Bochumer Arbeitsbogen zur medizinethischen Praxis. Medizin und Ethik. Stuttgart, Reclam, 1987, pp 371-375. Engl, transl.: Sass HM, Spicker SF. Viefhues H: Bochum Working Paper on the Practise of Medical Ethics, Medizinethischc Materia lien No. 2a (Jan. 1989). 2 Bullinger M. Pöppel E: Lebensqualität in der Medizin: Schlagwort oder Forschungsansatz. Deutsches Ärzteblatt 1988:85:679- 680.
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the time being, it would be helpful to have an ethical checklist of "Points to Consider” specifically made as part of the trial design and refined during the trial. A good example for a general checklist which avoids the epistemological and logical fallacies of misinterpreting clinical data into "the best interest of the patient” is a list of 10 questions on human experimentation (table 1) following the Bochum Working Paper on Medical Ethical Practice [1]. Review boards or bioethicists, as consultants or members of the team, could be employed in drafting more detailed and specific questionnaires for specific trials, procedures, side effects, testing of specific substances, etc. (table 2). This would be a step closer towards a professional integration of moral design and moral monitoring into the more technical aspects of design and monitoring. The more differentiated the checklists are, the more valuable instruments they will be in improving moral design and moral monitoring and in including the patient as a partner in making hard decisions.
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Sass: Ethical Considerations in Phase I Clinical Trials
14 Priestman TJ, Baum M: Evaluation of quality of life in patients receiving treatment for advanced breast cancer. Lancet 1976; 1:899-901. 15 Ramsey P: The Patient as Person. New Haven, Yale University Press. 1974. 16 Sass HM: Comparative models and goals for the regulation of human research, in Engelhardt HT. Spicker SF (eds): Human Experimentation. Dordrecht. Reidel, 1988, pp 47-89. 17 Sass HM: Bioethik in den USA. Heidelberg, Springer, 1988. 18 Sass HM: Ethics of drug research and drug development, in Wolff HP, et al (eds): Drug Research and Drug Development in the 21st Century. Heidelberg. Springer, 1989, pp 239-259. 19 Sass HM: Professional organizations and professional ethics, in Pellegrino ED (cd): Ethics and the Professions. Washington DC, Georgetown University Press, 1990 (in press). 20 Spitzer WD. et al: Measuring the quality of life of cancer patients. Chronic Desease 1981:34:585-597. 21 Stewart AL, et al: Functional status and well-being of patients with chronic conditions. JAMA 1989;262:907-913.
Request for Reprints to: Prof. Dr. H. M. Sass Zentrum für Medizinische Ethik Institut für Philosophie, GA 3 Ruhr Universität Postfach 102148 D-4630 Bochum (FRG)
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3 Cogliano-Shutta NA: Pediatric phase 1 clinical trials: Ethical issues and nursing considerations. Oncology Nursing Forum 1986: 13:29-32. 4 Clark A. Fallowsfield LJ: Quality of life measurements in patients with malignant disease: A review. Royal Soc Med 1986; 79:165-169. 5 Durry G, Dion S: The ethical approach to phase 1 clinical trials in oncology. Drugs Exptl Clin Res 1986:12:21-22. 6 EORTC, New Drug Development Subcomittee: EORTC guide lines for phase 1 trials with single agents in adults. Eur J Cancer and Clin Oncol 1985:21:1005-1007. 7 Geddcs DM: Quality of life. Clinics in Oncology 1985:4:161-176. 8 Guatt GH, et al: Measuring quality of life in clinical trials. A taxonomy and review. Can Med Ass J 1989:140:1441-1448. 9 Hofstede G: The cultural relativity of the quality of life concept. Academy of Management Review 1984:9:389-398. 10 Hunt M: McKenna SP: The Nottingham Health Profile: Subjective health status and medical consultations. Soc Sci Med 1981: 15a:221-229. 11 Karnofsky D, Burchenal JH: Clinical evaluation of chemotherapeutic agents in cancer, in McLeod CM (ed): Evalua tion of Chemotherapy. New York, Columbia University, Press, 1949. pp 190-205. 12 Markman M: The ethical dilemma of phase 1 clinical trials. Cancer Journal for Clinicians 1986:36:367-369. 13 Mathe G, Reitzenstein P: Ethics and errors of clinical trials and the role and place of different types of trial. Drugs Exptl Clin Res 1986:12:1-9.
