- Email: [email protected]
Effect of clinical routine on patients' outcome
CORRESPONDENCE
This has been brought home to me on many occasions over the past 30 years, most recently in discussions with staff at the UK’s Wellcome Trust and the Royal Institution, and with the media experts that the Medical Research Council uses to train its staff. Until organisations such as these— and a government that professes a commitment to informed choice for patients—take this issue more seriously, people like your correspondent will remain unnecessarily confused when confronted with incompatible claims about the effects of medical treatments. Iain Chalmers James Lind Library, James Lind Initiative, Summertown Pavilion, Middle Way, Oxford OX2 7LG, UK (e-mail: [email protected]) 1
2
Huntingford CA. Confusion over benefits of hormone replacement therapy. Lancet 2004; 363: 332. McPherson K. Where are we now with hormone replacement therapy? BMJ 2004; 328: 357–58.
Effect of clinical routine on patients’ outcome Sir—The remarkable article by Jeffrey M Peppercorn and colleagues (Jan 24, p 263)1 addresses a very politically loaded question. Better outcomes for patients enrolled in clinical trials have been used as an argument for improving the infrastructure of non-research hospitals to the standard of research hospitals or units. Research hospitals have been pioneering equipment quality control long before it came into practice elsewhere, and such measures are a prerequisite for transfer of research protocols into clinical practice. Radiotherapy departments that fail to deliver a carefully monitored radiation beam, for instance, would be unable to duplicate the (good) results of new techniques.2 A current example of the effect of infrastructure on treatment results is the use of positron emission tomography (PET) scans in lung cancer staging, which has been shown to allow for better selection of patients for lung surgery.3 These better results will never be duplicated in centres deprived of PET facilities. Therefore, patients enrolled in trials with a staging PET scan will do better than those treated without. Research protocols are usually undertaken by dedicated staff members (research nurses, data managers, etc). Patients enrolled in clinical trials have better access to medical professionals, allowing for appropriate interventions
whenever necessary, and without undue delay. What really differs between treatment given according to a trial protocol and in a non-research setting is the organisation and the way timing is respected (eg, time between surgery and chemotherapy, between surgery and radiotherapy, and radiotherapy without undue delay or interruptions). All these points are as important for the treatment outcome as the protocol itself. Process control is crucial, yet often deficient— eg, it has been shown in the Netherlands that in a cohort of women receiving adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) for breast cancer (1988–1992), only 68% received a relative dose intensity of 85% or more. The outlook for breast cancer patients in this population was similar to that of patients enrolled in randomised trials of adjuvant CMF. The only treatment-related variable of value for prognosis was dose intensity.4 Last but not least, international guidelines, such as indication for adjuvant chemotherapy in premenopausal, node-positive women with breast cancer, can take years to be implemented in practice, as noted by Palazzi and colleagues.5 Although this is not, strictly speaking, correlated to being included in a trial or not, a delay in the implementation of new therapeutics is detrimental to patients eligible for a proven treatment. If such patients were included in a trial, they would at least benefit from an optimum standard therapy, not because the trial itself is superior, but because the clinical routine in a non-research setting is deficient. Pierre G M Scalliet Cliniques Universitaires Saint Luc, Université Catholique de Louvain, 10 Avenue Hippocrate, B-1200 Brussels, Belgium (e-mail: [email protected]) 1
2
3
4
Peppercorn JM, Weeks JE, Cook EF, Joffe S. Comparison of outcomes in cancer patients treated within and outside clinical trials: conceptual framework and structured review. Lancet 2004; 363: 263–70. Bentzen SM, Bernier J, Davis JB, et al. Clinical impact of dosimetry quality assurance programmes assessed by radiobiological modelling of data from the thermoluminescent dosimetry study of the European Organization for Research and Treatment of Cancer. Eur J Cancer 2000; 36: 615–20. Vansteenkiste JF, Stroobants SG, Dupont PJ, et al. Prognostic importance of the standardized uptake value on (18) Ffluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: an analysis of 125 cases. J Clin Oncol 1999; 17: 3201–06. Ottevanger PB, De Mulder PH, Grol RP, et al. Effects of quality of treatment on prognosis in primary breast cancer patients treated in daily practice. Anticancer Res 2002; 22: 459–65.
5
Palazzi M, De Tomasi D, D’Affronto C, et al. Are international guidelines for the prescription of adjuvant treatment for early breast cancer followed in clinical practice? Results of a population-based study on 1547 patients. Tumori 2002; 88: 503–06.
Merck Sharp and Dohme versus Laporte Sir—Your News article (Jan 24, p 298)1 about Joan-Ramón Laporte’s allegations against Merck Sharp and Dohme (MSD), and his refusal of our requests to respond in Butlletí Groc, concerns us. After the publication of your article, the court decided not to grant MSD’s rectification request. However, the court did not find that MSD engaged in the conduct alleged in the Butlletí Groc. Laporte’s statements were based almost entirely on a non-peer-reviewed Commentary published in 2002.2 Several inaccuracies are present in the Commentary regarding the design, conduct, and reporting of the VIGOR trial.3 The principal investigator, the heads of the data and safety monitoring board, the cardiovascular event adjudication committee, and MSD addressed these errors in a letter to the editor. Unfortunately, the letter was not published. MSD is fully committed to the highest standards of scientific integrity, ethics, and protection of patient’s wellbeing in our research. We have a tradition of partnership with leaders in the academic research community, as shown by the CONSENSUS, 4S, FIT, ELITE II, RENAAL, OPTIMAAL, and LIFE trials, among others. The VIGOR trial reflects these high standards of scientific rigour, and we reject all allegations to the contrary. The trial was sponsored by MSD, with a steering committee—responsible for the scientific conduct of the trial—and a data and safety monitoring board, drawn from the academic research community. It is unacceptable that MSD and the scientists who collaborated on the VIGOR trial should have their conduct challenged in Butlletí Groc with no opportunity to respond to Laporte’s claims. MSD’s commitment to open scientific debate is shown by our rapid disclosure of the results of the VIGOR trial, which have been thoroughly studied by the medical, regulatory, and scientific communities over the past 3 years. Peter Honig Worldwide Regulatory Affairs and Product Safety, MSD, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486, USA (e-mail: [email protected])
THE LANCET • Vol 363 • March 27, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
1079
This has been brought home to me on many occasions over the past 30 years, most recently in discussions with staff at the UK’s Wellcome Trust and the Royal Institution, and with the media experts that the Medical Research Council uses to train its staff. Until organisations such as these— and a government that professes a commitment to informed choice for patients—take this issue more seriously, people like your correspondent will remain unnecessarily confused when confronted with incompatible claims about the effects of medical treatments. Iain Chalmers James Lind Library, James Lind Initiative, Summertown Pavilion, Middle Way, Oxford OX2 7LG, UK (e-mail: [email protected]) 1
2
Huntingford CA. Confusion over benefits of hormone replacement therapy. Lancet 2004; 363: 332. McPherson K. Where are we now with hormone replacement therapy? BMJ 2004; 328: 357–58.
Effect of clinical routine on patients’ outcome Sir—The remarkable article by Jeffrey M Peppercorn and colleagues (Jan 24, p 263)1 addresses a very politically loaded question. Better outcomes for patients enrolled in clinical trials have been used as an argument for improving the infrastructure of non-research hospitals to the standard of research hospitals or units. Research hospitals have been pioneering equipment quality control long before it came into practice elsewhere, and such measures are a prerequisite for transfer of research protocols into clinical practice. Radiotherapy departments that fail to deliver a carefully monitored radiation beam, for instance, would be unable to duplicate the (good) results of new techniques.2 A current example of the effect of infrastructure on treatment results is the use of positron emission tomography (PET) scans in lung cancer staging, which has been shown to allow for better selection of patients for lung surgery.3 These better results will never be duplicated in centres deprived of PET facilities. Therefore, patients enrolled in trials with a staging PET scan will do better than those treated without. Research protocols are usually undertaken by dedicated staff members (research nurses, data managers, etc). Patients enrolled in clinical trials have better access to medical professionals, allowing for appropriate interventions
whenever necessary, and without undue delay. What really differs between treatment given according to a trial protocol and in a non-research setting is the organisation and the way timing is respected (eg, time between surgery and chemotherapy, between surgery and radiotherapy, and radiotherapy without undue delay or interruptions). All these points are as important for the treatment outcome as the protocol itself. Process control is crucial, yet often deficient— eg, it has been shown in the Netherlands that in a cohort of women receiving adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) for breast cancer (1988–1992), only 68% received a relative dose intensity of 85% or more. The outlook for breast cancer patients in this population was similar to that of patients enrolled in randomised trials of adjuvant CMF. The only treatment-related variable of value for prognosis was dose intensity.4 Last but not least, international guidelines, such as indication for adjuvant chemotherapy in premenopausal, node-positive women with breast cancer, can take years to be implemented in practice, as noted by Palazzi and colleagues.5 Although this is not, strictly speaking, correlated to being included in a trial or not, a delay in the implementation of new therapeutics is detrimental to patients eligible for a proven treatment. If such patients were included in a trial, they would at least benefit from an optimum standard therapy, not because the trial itself is superior, but because the clinical routine in a non-research setting is deficient. Pierre G M Scalliet Cliniques Universitaires Saint Luc, Université Catholique de Louvain, 10 Avenue Hippocrate, B-1200 Brussels, Belgium (e-mail: [email protected]) 1
2
3
4
Peppercorn JM, Weeks JE, Cook EF, Joffe S. Comparison of outcomes in cancer patients treated within and outside clinical trials: conceptual framework and structured review. Lancet 2004; 363: 263–70. Bentzen SM, Bernier J, Davis JB, et al. Clinical impact of dosimetry quality assurance programmes assessed by radiobiological modelling of data from the thermoluminescent dosimetry study of the European Organization for Research and Treatment of Cancer. Eur J Cancer 2000; 36: 615–20. Vansteenkiste JF, Stroobants SG, Dupont PJ, et al. Prognostic importance of the standardized uptake value on (18) Ffluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: an analysis of 125 cases. J Clin Oncol 1999; 17: 3201–06. Ottevanger PB, De Mulder PH, Grol RP, et al. Effects of quality of treatment on prognosis in primary breast cancer patients treated in daily practice. Anticancer Res 2002; 22: 459–65.
5
Palazzi M, De Tomasi D, D’Affronto C, et al. Are international guidelines for the prescription of adjuvant treatment for early breast cancer followed in clinical practice? Results of a population-based study on 1547 patients. Tumori 2002; 88: 503–06.
Merck Sharp and Dohme versus Laporte Sir—Your News article (Jan 24, p 298)1 about Joan-Ramón Laporte’s allegations against Merck Sharp and Dohme (MSD), and his refusal of our requests to respond in Butlletí Groc, concerns us. After the publication of your article, the court decided not to grant MSD’s rectification request. However, the court did not find that MSD engaged in the conduct alleged in the Butlletí Groc. Laporte’s statements were based almost entirely on a non-peer-reviewed Commentary published in 2002.2 Several inaccuracies are present in the Commentary regarding the design, conduct, and reporting of the VIGOR trial.3 The principal investigator, the heads of the data and safety monitoring board, the cardiovascular event adjudication committee, and MSD addressed these errors in a letter to the editor. Unfortunately, the letter was not published. MSD is fully committed to the highest standards of scientific integrity, ethics, and protection of patient’s wellbeing in our research. We have a tradition of partnership with leaders in the academic research community, as shown by the CONSENSUS, 4S, FIT, ELITE II, RENAAL, OPTIMAAL, and LIFE trials, among others. The VIGOR trial reflects these high standards of scientific rigour, and we reject all allegations to the contrary. The trial was sponsored by MSD, with a steering committee—responsible for the scientific conduct of the trial—and a data and safety monitoring board, drawn from the academic research community. It is unacceptable that MSD and the scientists who collaborated on the VIGOR trial should have their conduct challenged in Butlletí Groc with no opportunity to respond to Laporte’s claims. MSD’s commitment to open scientific debate is shown by our rapid disclosure of the results of the VIGOR trial, which have been thoroughly studied by the medical, regulatory, and scientific communities over the past 3 years. Peter Honig Worldwide Regulatory Affairs and Product Safety, MSD, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486, USA (e-mail: [email protected])
THE LANCET • Vol 363 • March 27, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
1079