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190 Clinical trials in developing countries — ethical dilemmas
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Friday, 2 February 2001
ferent. The exceptionally high incidence of cancers of the mouth/oropharynx, cervix in India, esophagus and liver in China, provide abundant materials for studying these specific cancers. Attractive prospects of studies range widely from epidemiological search for causative environmental factors, genetic analyses, to clinical research for cost-effective investigation methods and therapeutic intervention. Facing the huge caseload with scarce resources, exploration for effective clinical care is specially challenging, as the proposed management must be practical and affordable. Besides orthodox western medicine, developing countries also offer unique chances for understanding various alternative medicines and testing their value. All these possibilities open up enormous opportunities, and the different perspectives revealed will surely enhance our ability to fight against cancers: 190
Clinical trials in developing countries - ethical dilemmas R.P. Abratt ; . . . . ;' . • Groote Schuur Hospital, Dept~ of Radiation Oncology, Cape Town, South Africa Purpose: The relevance of contempq(a~ eth;ical principles to the special problems of clinical trials in developing countries are reviewed. Methods: Three interacting ethical principles underpin clinical trials. These are respect for patient autonomy, beneficence and social justice. The Helsinki declaration of 1964 is currently under review by the World Medical Association as It has been argued that the above ethical principles are not appropriate for developing countries (moral relativist or pluralist view). It is proposed, inter alia, that .local standards of care, which may bypass effective forms of treatment, be accepted in control arms of studies, and that there be a loosening of standards for informed consent. Results: At least certain ethical principles and obligations are universal. The practice based on these principles may vary depending on cultural and ethical expectations. The notion of relativism in standards of care would, in the trial setting, mean that a standard of care has been abandoned and would institutionalize global inequalities in health care. Clinical trials in developing countries also need to be seen in the context of growth and development. Clinical trial methodology and terminology inform evaluation of disease and review of treatment outcome. Outcome of clinical trials plays an important role in practical management. Conclusions: There has been a change in the environment with various groups arguing that the diseases to which they are susceptible be included in clinical studies. Diseases specific to developing countries should be studied in clinical trials. Developing countries should be able to contribute to and benefit from worldwide studies. Clinical trials play an educative role in all countries and will contribute to growth in developing countries. Clinical trials remain accountable to ethical principles but should be conducted in a culturally sensitive manner 191
Quality assurance in clinical trials: a necessary evil for all of us ? P. Poortmans Dr Bernard Verbeeten Institute, Tilburg, The Netherlands The clinical results of any cancer treatment largely depend on the quality of the given treatment. This is even more so in the framework of a clinical trial because the final conclusions of the trial might lead to a modification of current standard treatment strategies. The set up of a clinical trial will have to take into account the infrastructural possibilities of the health care system for whose patients the trial is intended to be. Especially in the circumstance of infrastructural limitations, care has to be taken to ensure an optimal balance between the efficacy of the treatment and the investment in personnel, equipment and money. Trials designed to investigate this precious balance of efficiency are of utmost importance in order to stimulate the optimal use of the available infrastructure. The optimal level of Quality Assurance (QA) within or outside a clinical trial, is highly dependent on this infrastructure. "Efficient" QA will improve the overall quality of treatment for most patients at an acceptable cost. It might, in this Viewl be considered to investigate'institutional irifrast~'ucture of all radiotherapy departments, irrespective of a given clinical trial, to detect and correct variations in the delivered dose due to uncertainties in the treatment prescription and preparation, and in the calibration of the treatment machines. This will improve the treatment of all patients, whether they participate in a clinical trial or not. On the Other hand, "cumbersome" QA will hinder daily routine and might even discourage participation in clinical trials. The level of QA needed for a given trial highly depends on the general QA measures available and on the set up of the trial itself. A tailored QA pro-
Symposia
gram in the framework of a clinical trial can detect potential systematic treatment deviations and improve inter-inistitutional consistency. This will limit the chance for a false positive or a false negative result of the trial, thereby optimizing the use of the available infrastructure.
ENDOVASCULAR
BRACHYTHERAPY
192
Biological basis for endovascular therapy Abstract not received 193
Comparison of systems V.L.M.A. Coen P.C. Levendag Daniel den Hoed Cancer Center, Department of Radiotherapy, Rotterdam, The Netherlands Various approaches to deliver intravascular radiation have been proposed: catheter based techniques with removable gamma or beta radiation emitting sources and permanent implant of radioactive stents. Different types of removable sources are currently available, as either sealed line sources, consisting of seeds or a wire, or liquid or gas filled balloons. The BetaCath System (Novoste) is a manual, hydraulic delivery system, with three Sr-90 source train lengths available; 30 mm, 40 mm and 60 mm. The source train consists of resp. 12, 16 and 24 cylindrical sources of 2.5 mm length each and an inactive, radiopaque gold marker at each side. The delivery catheter is a 5 F non-centered, monorail catheter with triple lumen. The Galileo system (Guidant) is a fully automated afterloader with a solid P-32 source. The wire is 27 mm long and encapsulated in a 0.018 inch nitinol hypotube. The delivery catheter is a 3.9 F monorail catheter with spiral baIIoon, inflated with saline, centering the source in the vessel lumen and allowing perfusion. The Intravascular Radiation Therapy System (Cordis) is a manual delivery device with an Ir-192 source. The source consists of 6, 10, 14, 18 or 22 seeds, each 3 mm long and sealed in stainless steel capsules, embedded in a nylon ribbon with a 1 mm gap between the capsules. The total length of the source varies between 23 mm and 87 mm. The delivery catheter is a 3.7 F monorail, non-centering catheter. The CURE and Radiant systems deliver radiation using a balloon delivery catheter, filled with a liquid radioisotope solution of Re-188. The Radiocath device is similar, but the isotope is Re-186. The RDX radiation delivery system (Radiance) incorporates the P-32 isotope in the balloon material of a PTCA-type catheter. Radioisotope stents (IsoStent) are stainless steel stents with P-32 embedded beneath the surface of the stent. They are 15 mm long, mounted on a currently approved stent delivery system (balloon) with integral sheath and covered with a protective plastic lucent shield. The implementation techniaue is identical to non-radioactive stents. A wide range of different activities and loading patterns is available. 194
Potential applications of coronary vascular brachytherapy M. Horrigan Austin & Repatriation Mad. Centre, Heidelberg, Australia A growing body of evidence from carefully conducted clinical trials has demonstrated the value of intracoronary radiation in the attenuation of cellular proliferation, which occurs in the coronary artery restenosis process. Positive results from y-radiation trials indicate that coronary vascular brachytherapy may be the first potent therapy for in-stent restenosis. The safety and efficacy of y-radiation has been maintained at 3-year follow up and 13trials are proving equally effective. Whether brachytherapy has a wider application for treatment of de-novo lesions after angioplasty or stenting is yet to be fully established. It has been proven that irradiation has a positive effect in the absence of stenting, by inhibiting fibrointimal proliferation, and by preventing constrictive negative remodelling at the lesion site. Potential benefits are most likely to be demonstrated in patients with a high risk of recurrence. This cohort includes patients with diabetes, long lesions, saphenous vein graft stenoses and small vessel (<2.75 mm) lesions. Sub group analysis is required and ongoing. Issues relating to the future success of coronary vascular brachytherapy include late stent thrombosis, the edge effect and the efficacy of new technologies Such as coated stents. Coronary vascular brachytherapy is still far from being a panacea, but it continues to gather momentum in the interventional cardiologist's fight against coronary artery disease.
Friday, 2 February 2001
ferent. The exceptionally high incidence of cancers of the mouth/oropharynx, cervix in India, esophagus and liver in China, provide abundant materials for studying these specific cancers. Attractive prospects of studies range widely from epidemiological search for causative environmental factors, genetic analyses, to clinical research for cost-effective investigation methods and therapeutic intervention. Facing the huge caseload with scarce resources, exploration for effective clinical care is specially challenging, as the proposed management must be practical and affordable. Besides orthodox western medicine, developing countries also offer unique chances for understanding various alternative medicines and testing their value. All these possibilities open up enormous opportunities, and the different perspectives revealed will surely enhance our ability to fight against cancers: 190
Clinical trials in developing countries - ethical dilemmas R.P. Abratt ; . . . . ;' . • Groote Schuur Hospital, Dept~ of Radiation Oncology, Cape Town, South Africa Purpose: The relevance of contempq(a~ eth;ical principles to the special problems of clinical trials in developing countries are reviewed. Methods: Three interacting ethical principles underpin clinical trials. These are respect for patient autonomy, beneficence and social justice. The Helsinki declaration of 1964 is currently under review by the World Medical Association as It has been argued that the above ethical principles are not appropriate for developing countries (moral relativist or pluralist view). It is proposed, inter alia, that .local standards of care, which may bypass effective forms of treatment, be accepted in control arms of studies, and that there be a loosening of standards for informed consent. Results: At least certain ethical principles and obligations are universal. The practice based on these principles may vary depending on cultural and ethical expectations. The notion of relativism in standards of care would, in the trial setting, mean that a standard of care has been abandoned and would institutionalize global inequalities in health care. Clinical trials in developing countries also need to be seen in the context of growth and development. Clinical trial methodology and terminology inform evaluation of disease and review of treatment outcome. Outcome of clinical trials plays an important role in practical management. Conclusions: There has been a change in the environment with various groups arguing that the diseases to which they are susceptible be included in clinical studies. Diseases specific to developing countries should be studied in clinical trials. Developing countries should be able to contribute to and benefit from worldwide studies. Clinical trials play an educative role in all countries and will contribute to growth in developing countries. Clinical trials remain accountable to ethical principles but should be conducted in a culturally sensitive manner 191
Quality assurance in clinical trials: a necessary evil for all of us ? P. Poortmans Dr Bernard Verbeeten Institute, Tilburg, The Netherlands The clinical results of any cancer treatment largely depend on the quality of the given treatment. This is even more so in the framework of a clinical trial because the final conclusions of the trial might lead to a modification of current standard treatment strategies. The set up of a clinical trial will have to take into account the infrastructural possibilities of the health care system for whose patients the trial is intended to be. Especially in the circumstance of infrastructural limitations, care has to be taken to ensure an optimal balance between the efficacy of the treatment and the investment in personnel, equipment and money. Trials designed to investigate this precious balance of efficiency are of utmost importance in order to stimulate the optimal use of the available infrastructure. The optimal level of Quality Assurance (QA) within or outside a clinical trial, is highly dependent on this infrastructure. "Efficient" QA will improve the overall quality of treatment for most patients at an acceptable cost. It might, in this Viewl be considered to investigate'institutional irifrast~'ucture of all radiotherapy departments, irrespective of a given clinical trial, to detect and correct variations in the delivered dose due to uncertainties in the treatment prescription and preparation, and in the calibration of the treatment machines. This will improve the treatment of all patients, whether they participate in a clinical trial or not. On the Other hand, "cumbersome" QA will hinder daily routine and might even discourage participation in clinical trials. The level of QA needed for a given trial highly depends on the general QA measures available and on the set up of the trial itself. A tailored QA pro-
Symposia
gram in the framework of a clinical trial can detect potential systematic treatment deviations and improve inter-inistitutional consistency. This will limit the chance for a false positive or a false negative result of the trial, thereby optimizing the use of the available infrastructure.
ENDOVASCULAR
BRACHYTHERAPY
192
Biological basis for endovascular therapy Abstract not received 193
Comparison of systems V.L.M.A. Coen P.C. Levendag Daniel den Hoed Cancer Center, Department of Radiotherapy, Rotterdam, The Netherlands Various approaches to deliver intravascular radiation have been proposed: catheter based techniques with removable gamma or beta radiation emitting sources and permanent implant of radioactive stents. Different types of removable sources are currently available, as either sealed line sources, consisting of seeds or a wire, or liquid or gas filled balloons. The BetaCath System (Novoste) is a manual, hydraulic delivery system, with three Sr-90 source train lengths available; 30 mm, 40 mm and 60 mm. The source train consists of resp. 12, 16 and 24 cylindrical sources of 2.5 mm length each and an inactive, radiopaque gold marker at each side. The delivery catheter is a 5 F non-centered, monorail catheter with triple lumen. The Galileo system (Guidant) is a fully automated afterloader with a solid P-32 source. The wire is 27 mm long and encapsulated in a 0.018 inch nitinol hypotube. The delivery catheter is a 3.9 F monorail catheter with spiral baIIoon, inflated with saline, centering the source in the vessel lumen and allowing perfusion. The Intravascular Radiation Therapy System (Cordis) is a manual delivery device with an Ir-192 source. The source consists of 6, 10, 14, 18 or 22 seeds, each 3 mm long and sealed in stainless steel capsules, embedded in a nylon ribbon with a 1 mm gap between the capsules. The total length of the source varies between 23 mm and 87 mm. The delivery catheter is a 3.7 F monorail, non-centering catheter. The CURE and Radiant systems deliver radiation using a balloon delivery catheter, filled with a liquid radioisotope solution of Re-188. The Radiocath device is similar, but the isotope is Re-186. The RDX radiation delivery system (Radiance) incorporates the P-32 isotope in the balloon material of a PTCA-type catheter. Radioisotope stents (IsoStent) are stainless steel stents with P-32 embedded beneath the surface of the stent. They are 15 mm long, mounted on a currently approved stent delivery system (balloon) with integral sheath and covered with a protective plastic lucent shield. The implementation techniaue is identical to non-radioactive stents. A wide range of different activities and loading patterns is available. 194
Potential applications of coronary vascular brachytherapy M. Horrigan Austin & Repatriation Mad. Centre, Heidelberg, Australia A growing body of evidence from carefully conducted clinical trials has demonstrated the value of intracoronary radiation in the attenuation of cellular proliferation, which occurs in the coronary artery restenosis process. Positive results from y-radiation trials indicate that coronary vascular brachytherapy may be the first potent therapy for in-stent restenosis. The safety and efficacy of y-radiation has been maintained at 3-year follow up and 13trials are proving equally effective. Whether brachytherapy has a wider application for treatment of de-novo lesions after angioplasty or stenting is yet to be fully established. It has been proven that irradiation has a positive effect in the absence of stenting, by inhibiting fibrointimal proliferation, and by preventing constrictive negative remodelling at the lesion site. Potential benefits are most likely to be demonstrated in patients with a high risk of recurrence. This cohort includes patients with diabetes, long lesions, saphenous vein graft stenoses and small vessel (<2.75 mm) lesions. Sub group analysis is required and ongoing. Issues relating to the future success of coronary vascular brachytherapy include late stent thrombosis, the edge effect and the efficacy of new technologies Such as coated stents. Coronary vascular brachytherapy is still far from being a panacea, but it continues to gather momentum in the interventional cardiologist's fight against coronary artery disease.