- Email: [email protected]
Innovation or regulation: IDEAL opportunity for consensus
Comment
bank in China. Furthermore, the regulations apply to eight other nearby cities. Second, measures were taken to encourage people to participate in charitable donation. A body-donor monument, the first one in China, was finished in 2005 and every donor’s name can be engraved on the monument. In 2006, a memorial hall dedicated to body donors, one of the only two in China, was completed to exhibit typical mementoes (eg, clothes, watch, pen used by the donor, biographies, memoirs written by the donors, and photographs of donors).6 Family members can receive souvenirs made of the donor’s hair or nails or a photograph from the Red Cross. Additionally, funeral expenses are met. The Bureau of Wuhan Post marked the tenth bodydonation memorial day by publishing postcards about body donation on March 25 this year. All of these factors are intended to encourage citizens to register for donation. Third, measures were taken to facilitate registration. Wuhan City has nine register offices, including two eye banks in two hospitals and three departments of anatomy in three medical colleges. All offices use a standard registration form. The donation service is provided by staff and volunteers. But some obstacles remain that might constrain expansion of the programme. First is the lack of a law on brain death. It is beyond Wuhan City’s ability to enact such a law. Instead, the National People’s Congress should pass national laws on brain death and organ donation as soon as possible. Second is the lack of a
country-wide registration and allocation system. Third is the shortage of financial support. A characteristic of body donation in China is that the Red Cross plays a dominant part in the process. China has already launched a body and organ donation system, but it has a long way to go. When the Ministry of Health is applying itself in health reform, will the Red Cross Society of China surprise us by developing a Chinese mode of donor recruitment and registration? Will the Red Cross Society of China learn from the Red Cross in Wuhan? We will have to wait and see. Xumin Shang, *Mingchang Zhang Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China (XS, MZ); and Hubei Provincial Red Cross, Wuhan, China (XS) [email protected] We thank Zheng Jun, General Secretary of Hubei Provincial Red Cross, for advice about our Comment. We declare that we have no conflicts of interest. 1 2 3
4
5
6
Red Cross Society of China. Documentation of work convention in 2010. Beijing: Red Cross Society of China, 2010 (in Chinese). Zhang MC. Strategies to resolve the problem of lack of keratoplasty materials in China. Zhonghua Yan Ke Za Zhi 2007; 43: 289–92 (in Chinese). Anon. 10 provinces and cities launched organ donation pilot project and promote the country. May 2, 2010. http://www.chinadaily.com.cn/ dfpd/2010-05/02/content_9801854_4.htm. (accessed May 4, 2010) (in Chinese). Standing Committee of Wuhan City People’s Congress. Wuhan City body donation regulations. Aug 5, 2003. http://law.baidu.com/pages/chinala winfo/1682/45/83aa5a4f7396d5d57da30e2208e3c4e5_0.html (accessed May 2, 2010) (in Chinese). Standing Committee of Wuhan City People’s Congress. Wuhan City body donation regulations (revised). Changjiang Daily (Wuhan) Jan 31, 2010. http://cjmp.cnhan.com/cjrb/html/2010-01/31/content_2655270.htm (accessed May 2, 2010) (in Chinese). Wuhan City Red Cross. Introduction of body donation of Wuhan City. 2007. http://www.wuhanrc.gov.cn/contribute/introduction.asp (accessed May 2, 2010) (in Chinese).
Innovation or regulation: IDEAL opportunity for consensus See Editorial page 1025
1034
In the past 30 years, enormous advances in interventional medical devices have affected health care, just as pharmacological innovation did the generation before. Gastric bands, coronary stents, intrauterine devices, and prosthetic joint replacements have greatly improved quality of life for millions. But nothing comes without a cost. Cunlin Wang and colleagues1 noted some of the risks in a study of the paediatric section of the US National Electronic Injury Surveillance System All Injury Program database. More than 144 000 adverse events were recorded over 2 years, and during this time nearly 1% of all unintentional injuries to children were caused
by implantable or interventional medical devices. These unwanted effects were often unforeseen, bringing into question the processes that develop, evaluate, and regulate such devices. A vigorous, ongoing process of innovation is central to continuing improvement of medical care. Although developments in surgical and interventional therapy have been impressive, there is increasing recognition that this development process substantially differs from that for drugs.2 This difference has caused difficulty in applying the phase 1–4 evaluation frameworks, which were developed for drugs, to interventional treatments. An www.thelancet.com Vol 376 September 25, 2010
attempt has been made to delineate the natural history of innovation in interventional therapies, and to develop an evaluation framework that reflects its specific needs.2–4 Although some interventional procedures have been comprehensively evaluated in large, randomised trials (eg, coronary artery stents),5 there are many other procedures for which innovation and evaluation processes stagnate at a stage of frustrated development. Strong, conflicting opinions based on poor-quality evidence, prevent consensus or further progress towards definitive trials. The need for a series of development phases between proof of concept and randomised comparison with best current treatment underlie this unsatisfactory situation. Crucial elements of the innovation environment, including the medical publishing industry, funders of research and development, professional bodies, and regulatory authorities,4 currently fail to recognise and accommodate this need and thereby perpetuate the continued production of poor-quality evidence. Regulation works differently for drugs, devices, and procedures, and although there are wide international variations, regulatory bodies generally find it difficult to devise processes that encourage technical innovations (including an early development phase, which involves frequent, minor changes to technique or design), while ensuring that patients are protected from unnecessary harm. Because of the mismatch between the realities of innovation and the requirements of regulation, honest reporting of the minor changes made in early-phase studies can lead to inappropriately burdensome reporting requirements. In turn, these requirements might inhibit innovation when the costs and delays involved mean that innovations become commercially unattractive. At the other end of the development process, general sale of devices is permitted in most jurisdictions on the basis of proof of safety, rather than of efficacy or effectiveness— the accepted standard for drug treatments. A fresh look at systems for regulating the development of interventional medical procedures and technology would require recognition that current systems are not fit for purpose, and a commitment by regulators and commercial bodies to seek consensus on more appropriate systems. The IDEAL (Idea, Development, Exploration, Assessment, Long-term Study)4 recommendations called for modifications to systems for regulating early, incremental changes in technique and device development, and for a change to the standard against which these innovations www.thelancet.com Vol 376 September 25, 2010
Science Photo Library
Comment
should be measured before being approved for general use, from demonstration of safety, to evidence of efficacy. The guidelines also suggested an open online registration system for early-phase studies and protocols, which could alleviate concerns about allowing light-touch and rapid regulation, by ensuring transparency and accountability. These constructive proposals should be seriously debated by those with the power to make the proposed changes. If the IDEAL proposals are wrong, they can be modified; if they are recognised as a potential way forward, regulatory bodies and industry should be prepared to make appropriate policy changes. Opportunities should be taken (when they can be identified) to use suitable devices and procedures as examples for pilot studies of variants on the proposed evaluation and regulation processes. Regulators and industry must seize the opportunity to bring about beneficial changes in evaluation and regulation frameworks, by adopting a cooperative, positive, and practical approach to identifying and testing solutions, rather than further refining descriptions of the problem. It is entirely appropriate that further work is now being pursued to test the IDEAL proposals, and to ensure that they result in real practical changes to the current unsatisfactory state of clinical evidence for surgery and interventional medicine. *Peter McCulloch, Frank Schuller Nuffield Department of Surgical Science, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK (PM); and Institute for Science and Society, Trinity College, Oxford, UK (FS) [email protected]
1035
Comment
PM declares that he has no conflicts of interest. FS served on the board of Stemedica International, from April, 2009, to Dec 1, 2009. 1
2
Wang C, Hefflin B, Cope JU, et al. Emergency department visits for medical device-associated adverse events among children. Pediatrics 2010; 126: 247–59. Barkun JS, Aronson JK, Feldman LS, Maddern GJ, Strasberg SM, for the Balliol Collaboration. Evaluation and stages of surgical innovations. Lancet 2009; 374: 1089–96.
3 4
5
Ergina PL, Cook JA, Blazeby JM, et al, for the Balliol Collaboration. Challenges in evaluating surgical innovation. Lancet 2009; 374: 1097–104. McCulloch P, Altman DG, Campbell WB, et al, for the Balliol Collaboration. No surgical innovation without evaluation: the IDEAL recommendations. Lancet 2009; 374: 1105–12. Hill RA, Boland A, Dickson R, et al. Drug-eluting stents: a systematic review and economic evaluation. Health Technol Assess 2007; 11: iii, xi–221.
Focal therapy meets prostate cancer
Science Photo Library
Prostate cancer remains the most common, noncutaneous human cancer with about 186 000 new cases diagnosed in 2008 in the USA1 and 214 cases per 1000 men in Europe, outnumbering lung and colorectal cancer.2 With current trends of testing for prostatespecific antigen (PSA) and the lowered PSA threshold for biopsy in some countries of the developed world, more and more men will be diagnosed with prostate cancer. Controversy about the unproven benefit of PSA screening, as well as the known side-effects, highlight the concerns about overdetection and overtreatment.3,4 The present choice of treatment for men with localised prostate cancer lies between active surveillance and radical therapy. The rationale of active surveillance for low-risk prostate cancer (PSA<10 ng/mL, Gleason grade 6 or less, and clinical stage T1c–T2a) is sound. However, the inherent risk of active surveillance is undertreatment. About a quarter to a third of patients who are thought to be ideal candidates for a no-treatment approach are later recommended to have therapy once additional information is obtained.5,6 The no-treatment approach also carries a psychological burden of allowing a known cancer to grow, and it might have consequences on the patient, his family, and his job performance, with an adverse effect on an individual’s quality of life. Prostate cancer is dogmatically regarded as a heterogeneous and multifocal disease, and is therefore usually treated with a radical whole-gland approach. Radical prostatectomy is an effective therapy for patients with clinically localised prostate cancer. Despite improvements in surgical techniques, such as the introduction of roboticassisted laparoscopic prostatectomy which allows a detailed dissection with a water-tight vesical-urethral anastomosis and a nerve sparing procedure, urinary incontinence and erectile dysfunction are not uncommon after radical prostatectomy.7,8 External beam radiotherapy and brachytherapy are effective and non-invasive but 1036
they might carry long-term risks too, such as troublesome bowel, sexual, and urinary dysfunction. In the past, the use of breast-sparing surgery, such as lumpectomy, to treat breast cancer revolutionised local control of the disease. Experience with lumpectomy shows that quality of life can successfully be integrated into the equation of cancer treatment, without major loss of treatment efficacy. Physicians and the public have started to be interested in the notion of prostate-sparing focal therapy for prostate cancer. It was the topic of the 3rd International Symposium on Focal Therapy and Imaging of Prostate and Kidney Cancer that was held in Washington DC, USA, in February, 2010. Focal therapy for prostate cancer is defined as therapy that selectively ablates known disease while preserving existing functions, with the overall aim of minimising lifetime morbidity without compromising life expectancy. Faculty at the symposium agreed that the two main crucial points for focal therapy were ideal selection of patients and presence of focal cancer. Although multifocality represents a theoretical contraindication to focal therapy, data about the predominant, or index lesion, provide insightful information, and faculty agreed that reliability and precision in tumour localisation is essential for cancer control and to minimise morbidity. Precise localisation can be obtained by template-guided transperineal biopsies and multiparametric imaging techniques, such as dynamic contrast-enhanced diffusion-weighted MRI or magnetic resonance spectroscopy. The symposium did not reach consensus on the ideal therapeutic strategies for focal therapy and different ablative energies were suggested, such as cryotherapy, high-intensity focused ultrasound, vascular-targeted photodynamic therapy, brachytherapy, radiotherapy, or tomotherapy. The crucial point about choice of ideal follow-up was addressed but no consensus was reached about the definition of biochemical-free survival after focal therapies for prostate cancer. www.thelancet.com Vol 376 September 25, 2010
bank in China. Furthermore, the regulations apply to eight other nearby cities. Second, measures were taken to encourage people to participate in charitable donation. A body-donor monument, the first one in China, was finished in 2005 and every donor’s name can be engraved on the monument. In 2006, a memorial hall dedicated to body donors, one of the only two in China, was completed to exhibit typical mementoes (eg, clothes, watch, pen used by the donor, biographies, memoirs written by the donors, and photographs of donors).6 Family members can receive souvenirs made of the donor’s hair or nails or a photograph from the Red Cross. Additionally, funeral expenses are met. The Bureau of Wuhan Post marked the tenth bodydonation memorial day by publishing postcards about body donation on March 25 this year. All of these factors are intended to encourage citizens to register for donation. Third, measures were taken to facilitate registration. Wuhan City has nine register offices, including two eye banks in two hospitals and three departments of anatomy in three medical colleges. All offices use a standard registration form. The donation service is provided by staff and volunteers. But some obstacles remain that might constrain expansion of the programme. First is the lack of a law on brain death. It is beyond Wuhan City’s ability to enact such a law. Instead, the National People’s Congress should pass national laws on brain death and organ donation as soon as possible. Second is the lack of a
country-wide registration and allocation system. Third is the shortage of financial support. A characteristic of body donation in China is that the Red Cross plays a dominant part in the process. China has already launched a body and organ donation system, but it has a long way to go. When the Ministry of Health is applying itself in health reform, will the Red Cross Society of China surprise us by developing a Chinese mode of donor recruitment and registration? Will the Red Cross Society of China learn from the Red Cross in Wuhan? We will have to wait and see. Xumin Shang, *Mingchang Zhang Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China (XS, MZ); and Hubei Provincial Red Cross, Wuhan, China (XS) [email protected] We thank Zheng Jun, General Secretary of Hubei Provincial Red Cross, for advice about our Comment. We declare that we have no conflicts of interest. 1 2 3
4
5
6
Red Cross Society of China. Documentation of work convention in 2010. Beijing: Red Cross Society of China, 2010 (in Chinese). Zhang MC. Strategies to resolve the problem of lack of keratoplasty materials in China. Zhonghua Yan Ke Za Zhi 2007; 43: 289–92 (in Chinese). Anon. 10 provinces and cities launched organ donation pilot project and promote the country. May 2, 2010. http://www.chinadaily.com.cn/ dfpd/2010-05/02/content_9801854_4.htm. (accessed May 4, 2010) (in Chinese). Standing Committee of Wuhan City People’s Congress. Wuhan City body donation regulations. Aug 5, 2003. http://law.baidu.com/pages/chinala winfo/1682/45/83aa5a4f7396d5d57da30e2208e3c4e5_0.html (accessed May 2, 2010) (in Chinese). Standing Committee of Wuhan City People’s Congress. Wuhan City body donation regulations (revised). Changjiang Daily (Wuhan) Jan 31, 2010. http://cjmp.cnhan.com/cjrb/html/2010-01/31/content_2655270.htm (accessed May 2, 2010) (in Chinese). Wuhan City Red Cross. Introduction of body donation of Wuhan City. 2007. http://www.wuhanrc.gov.cn/contribute/introduction.asp (accessed May 2, 2010) (in Chinese).
Innovation or regulation: IDEAL opportunity for consensus See Editorial page 1025
1034
In the past 30 years, enormous advances in interventional medical devices have affected health care, just as pharmacological innovation did the generation before. Gastric bands, coronary stents, intrauterine devices, and prosthetic joint replacements have greatly improved quality of life for millions. But nothing comes without a cost. Cunlin Wang and colleagues1 noted some of the risks in a study of the paediatric section of the US National Electronic Injury Surveillance System All Injury Program database. More than 144 000 adverse events were recorded over 2 years, and during this time nearly 1% of all unintentional injuries to children were caused
by implantable or interventional medical devices. These unwanted effects were often unforeseen, bringing into question the processes that develop, evaluate, and regulate such devices. A vigorous, ongoing process of innovation is central to continuing improvement of medical care. Although developments in surgical and interventional therapy have been impressive, there is increasing recognition that this development process substantially differs from that for drugs.2 This difference has caused difficulty in applying the phase 1–4 evaluation frameworks, which were developed for drugs, to interventional treatments. An www.thelancet.com Vol 376 September 25, 2010
attempt has been made to delineate the natural history of innovation in interventional therapies, and to develop an evaluation framework that reflects its specific needs.2–4 Although some interventional procedures have been comprehensively evaluated in large, randomised trials (eg, coronary artery stents),5 there are many other procedures for which innovation and evaluation processes stagnate at a stage of frustrated development. Strong, conflicting opinions based on poor-quality evidence, prevent consensus or further progress towards definitive trials. The need for a series of development phases between proof of concept and randomised comparison with best current treatment underlie this unsatisfactory situation. Crucial elements of the innovation environment, including the medical publishing industry, funders of research and development, professional bodies, and regulatory authorities,4 currently fail to recognise and accommodate this need and thereby perpetuate the continued production of poor-quality evidence. Regulation works differently for drugs, devices, and procedures, and although there are wide international variations, regulatory bodies generally find it difficult to devise processes that encourage technical innovations (including an early development phase, which involves frequent, minor changes to technique or design), while ensuring that patients are protected from unnecessary harm. Because of the mismatch between the realities of innovation and the requirements of regulation, honest reporting of the minor changes made in early-phase studies can lead to inappropriately burdensome reporting requirements. In turn, these requirements might inhibit innovation when the costs and delays involved mean that innovations become commercially unattractive. At the other end of the development process, general sale of devices is permitted in most jurisdictions on the basis of proof of safety, rather than of efficacy or effectiveness— the accepted standard for drug treatments. A fresh look at systems for regulating the development of interventional medical procedures and technology would require recognition that current systems are not fit for purpose, and a commitment by regulators and commercial bodies to seek consensus on more appropriate systems. The IDEAL (Idea, Development, Exploration, Assessment, Long-term Study)4 recommendations called for modifications to systems for regulating early, incremental changes in technique and device development, and for a change to the standard against which these innovations www.thelancet.com Vol 376 September 25, 2010
Science Photo Library
Comment
should be measured before being approved for general use, from demonstration of safety, to evidence of efficacy. The guidelines also suggested an open online registration system for early-phase studies and protocols, which could alleviate concerns about allowing light-touch and rapid regulation, by ensuring transparency and accountability. These constructive proposals should be seriously debated by those with the power to make the proposed changes. If the IDEAL proposals are wrong, they can be modified; if they are recognised as a potential way forward, regulatory bodies and industry should be prepared to make appropriate policy changes. Opportunities should be taken (when they can be identified) to use suitable devices and procedures as examples for pilot studies of variants on the proposed evaluation and regulation processes. Regulators and industry must seize the opportunity to bring about beneficial changes in evaluation and regulation frameworks, by adopting a cooperative, positive, and practical approach to identifying and testing solutions, rather than further refining descriptions of the problem. It is entirely appropriate that further work is now being pursued to test the IDEAL proposals, and to ensure that they result in real practical changes to the current unsatisfactory state of clinical evidence for surgery and interventional medicine. *Peter McCulloch, Frank Schuller Nuffield Department of Surgical Science, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK (PM); and Institute for Science and Society, Trinity College, Oxford, UK (FS) [email protected]
1035
Comment
PM declares that he has no conflicts of interest. FS served on the board of Stemedica International, from April, 2009, to Dec 1, 2009. 1
2
Wang C, Hefflin B, Cope JU, et al. Emergency department visits for medical device-associated adverse events among children. Pediatrics 2010; 126: 247–59. Barkun JS, Aronson JK, Feldman LS, Maddern GJ, Strasberg SM, for the Balliol Collaboration. Evaluation and stages of surgical innovations. Lancet 2009; 374: 1089–96.
3 4
5
Ergina PL, Cook JA, Blazeby JM, et al, for the Balliol Collaboration. Challenges in evaluating surgical innovation. Lancet 2009; 374: 1097–104. McCulloch P, Altman DG, Campbell WB, et al, for the Balliol Collaboration. No surgical innovation without evaluation: the IDEAL recommendations. Lancet 2009; 374: 1105–12. Hill RA, Boland A, Dickson R, et al. Drug-eluting stents: a systematic review and economic evaluation. Health Technol Assess 2007; 11: iii, xi–221.
Focal therapy meets prostate cancer
Science Photo Library
Prostate cancer remains the most common, noncutaneous human cancer with about 186 000 new cases diagnosed in 2008 in the USA1 and 214 cases per 1000 men in Europe, outnumbering lung and colorectal cancer.2 With current trends of testing for prostatespecific antigen (PSA) and the lowered PSA threshold for biopsy in some countries of the developed world, more and more men will be diagnosed with prostate cancer. Controversy about the unproven benefit of PSA screening, as well as the known side-effects, highlight the concerns about overdetection and overtreatment.3,4 The present choice of treatment for men with localised prostate cancer lies between active surveillance and radical therapy. The rationale of active surveillance for low-risk prostate cancer (PSA<10 ng/mL, Gleason grade 6 or less, and clinical stage T1c–T2a) is sound. However, the inherent risk of active surveillance is undertreatment. About a quarter to a third of patients who are thought to be ideal candidates for a no-treatment approach are later recommended to have therapy once additional information is obtained.5,6 The no-treatment approach also carries a psychological burden of allowing a known cancer to grow, and it might have consequences on the patient, his family, and his job performance, with an adverse effect on an individual’s quality of life. Prostate cancer is dogmatically regarded as a heterogeneous and multifocal disease, and is therefore usually treated with a radical whole-gland approach. Radical prostatectomy is an effective therapy for patients with clinically localised prostate cancer. Despite improvements in surgical techniques, such as the introduction of roboticassisted laparoscopic prostatectomy which allows a detailed dissection with a water-tight vesical-urethral anastomosis and a nerve sparing procedure, urinary incontinence and erectile dysfunction are not uncommon after radical prostatectomy.7,8 External beam radiotherapy and brachytherapy are effective and non-invasive but 1036
they might carry long-term risks too, such as troublesome bowel, sexual, and urinary dysfunction. In the past, the use of breast-sparing surgery, such as lumpectomy, to treat breast cancer revolutionised local control of the disease. Experience with lumpectomy shows that quality of life can successfully be integrated into the equation of cancer treatment, without major loss of treatment efficacy. Physicians and the public have started to be interested in the notion of prostate-sparing focal therapy for prostate cancer. It was the topic of the 3rd International Symposium on Focal Therapy and Imaging of Prostate and Kidney Cancer that was held in Washington DC, USA, in February, 2010. Focal therapy for prostate cancer is defined as therapy that selectively ablates known disease while preserving existing functions, with the overall aim of minimising lifetime morbidity without compromising life expectancy. Faculty at the symposium agreed that the two main crucial points for focal therapy were ideal selection of patients and presence of focal cancer. Although multifocality represents a theoretical contraindication to focal therapy, data about the predominant, or index lesion, provide insightful information, and faculty agreed that reliability and precision in tumour localisation is essential for cancer control and to minimise morbidity. Precise localisation can be obtained by template-guided transperineal biopsies and multiparametric imaging techniques, such as dynamic contrast-enhanced diffusion-weighted MRI or magnetic resonance spectroscopy. The symposium did not reach consensus on the ideal therapeutic strategies for focal therapy and different ablative energies were suggested, such as cryotherapy, high-intensity focused ultrasound, vascular-targeted photodynamic therapy, brachytherapy, radiotherapy, or tomotherapy. The crucial point about choice of ideal follow-up was addressed but no consensus was reached about the definition of biochemical-free survival after focal therapies for prostate cancer. www.thelancet.com Vol 376 September 25, 2010