Ethics review and clinical trials

CORRESPONDENCE

Ethics review and clinical trials Sir—The Lancet does not seem to regard ethics approval as necessary for a prospective trial involving random allocation of patients to different operative conditions for laparoscopic cholecystectomy. G B Hanna and colleagues’ investigation (Jan 24, p 248)1 involved comparison of conventional two-dimensional videoendoscopic imaging with a threedimensional imaging display. The study looked at the influence of each imaging system on the performance of laparoscopic cholecystectomy. The rationale for the study was the absence of objective data showing benefit of three-dimensional imaging systems on clinical practice. Primary study endpoints were execution times and errors made: presumably the investigators believed that operative time and surgical errors might differ with the technique. Nevertheless, Hanna and colleagues state that “ethics approval was not influenced by the study allocation”. This short-sighted assumption ignores the alternative hypothesis that patient allocation might alter clinical outcome and runs against the principles of ethics review We believe that research ethics committees have an essential role in not only promoting the principles of the Declaration of Helsinki (1964), but also ensuring the scientific rigour and validity of the proposed research.2,3 Several concerns raised by this study might have been addressed by an ethics review. First, no mention is made about information presented to study participants. Since patients entering the trial risked randomisation to a procedure done by a trainee using unfamiliar equipment, which might impede proprioceptive and visual perception, it seems surprising that “all (960) patients gave full consent. Second, sample size calculation is not included. Third, analysis of operative errors (one of two primary study endpoints) is incomplete. Little mention is made of the distribution of errors between treatment groups. Complications such as diaphragmatic perforation might provide evidence that three-dimensional imaging systems are harmful to clinical practice. Fourth, it is inappropriate to use trainees to evaluate new surgical techniques in a clinical trial. Last, in view of the limitations and difficulties of current three-dimensional imaging systems, formal training in their use before starting the study might have made the comparison between the two systems more valid. Hanna and colleagues should be

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applauded for their systematic study of a surgical technique. Too often new interventions and procedures are implemented without the rigours of peer review of performance practice.4 But to assume that such studies are immune from ethics review places patients, clinical research, and public perception of medical practice at risk. *Hilary Madder, Paul Myles, Roderick McRae The Alfred, PO Box 315, Prahran, Victoria, 3181, Australia 1

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Hanna GB, Shimi S, Cuschieri A. Randomised study of influence of twodimensional versus three-dimensional imaging on performance of laparoscopic cholecystectomy. Lancet 1998; 351: 248–51. Department of Health. Ethics committee review of multicentre research. London: Department of Health, 1997 (HSG[97]23). Eichler H-G. Hazards of misguided ethics committees. Lancet 1995; 346: 1115–16. Horton R. Surgical research of comic opera: questions, but few answers. Lancet 1996; 347: 984–85.

Author’s reply Sir—Hilary Madder and colleagues criticise our study mainly on the grounds that we did not seek ethical approval. Although I totally agree that ethical approval is essential for randomised studies in which the treatment that patients receive is determined at random, I disagree that this was the case in our study. Our patients all received the same treatment—ie, laparoscopic cholecystectomy done in accordance with the Dundee technique1 by a specialist registrar assisted by one of two consultant surgeons. The randomisation concerned the image display system, either two-dimensional (2D) or three-dimensional (3D). Both systems are in widespread established practice in Europe and North America (and I suspect in Australia). Some surgeons believe that 3D gives a better depth perception, others do not. In laboratorybased randomised studies involving consultants and specialised registrars, we noted and reported no difference between the two systems in terms of task efficiency, task quality, and execution times.2 If Madder and colleagues’ objection is upheld, then surgeons would have to obtain ethical approval for use of different camera systems, monitors, telescopes, electrosurgical units, and the plethora of ancillary technology used in endoscopic surgery. In UK teaching hospitals, most elective laparoscopic cholecystectomies are done by surgical specialist registrars assisted by consultant surgeons. The patients knows this and the practice is, of course, the cornerstone of

apprenticeship surgical training. Moreover, the reported prospective external audit on the training initiative lists set up by the Scottish royal colleges has shown conclusively that postoperative outcome of patients undergoing laparoscopic operations by surgical specialist registrars assisted by consultant tutors is, if anything, better than that reported in publications.3 With respect to calculation of sample size, Madder and colleagues are aware that this is based on expected differences. There are no reported clinical data on 2D versus 3D. Laboratory randomised studies by our group showed no difference between the two imaging systems.2 As indicated in the report, the ergonomic errors were evenly distributed between the two arms, and only one error results in a material intraoperative complication, when the assisting consultant took over. There were no postoperative complications. The statement by Madder and colleagues that “it is inappropriate to use surgical trainees to evaluate new surgical techniques in a clinical trial” is valid but does not apply to our study since all patients had the same routine well-established operation. The inference from their statement is that all surgical randomised studies should only be carried out by consultant staff. This is surely a highly restrictive policy but, I agree, needs debate. My own view is that the magnitude of the intervention and associated risks should determine the grade of the participating surgeons. All the four specialist registrars were at the end of their higher surgical training (within 1 year of certification). All had training and exposure with both 2D and 3D imaging systems in the Surgical Skills Unit before involvement in the study. The decision not to seek ethical approval was mine since I was and firmly remain convinced that the random allocation did not change the treatment the patients received, the participants were familiar with both imaging systems, and the standard management of these patients was not altered by the conduct of the study. Nonetheless, high-technology assessment in endoscopic surgery needs clarification—should we have ethical approval always or ethical approval when technology alters treatment? Alfred Cuschieri Department of Surgery, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK 1

Crosthwaite G, Chung T, Dunkley P, Shimi S, Cuschieri A. Comparison of direct vision and electronic two-and threedimensional display systems on surgical task efficiency in endoscopic surgery. Br J Surg

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1995; 82: 849–51. Nathanson LK, Shimi S, Cuschieri A. Laparoscopic cholecystectomy: the Dundee technique. Br J Surg 1991; 78: 155–59. Cuschieri A, Wilson RG, Sunderland G, et al. Training initiative list scheme (TILS) for minimal access therapy: the MATTUS experience. J R Coll Surg Edin 1997; 42: 295–302.

Sir—Your editorial (Jan 24, p 225) advocating pragmatism in research ethics is of concern, particularly in view of The Lancet’s willingness to lower its ethical standards for studies carried out in tyrannies.1,2 The proposed pragmatism of “compatible with the realities of health care in the country where the study is to be conducted” would sanction the work of Josef Mengele.3 Responsibility for ethical standards cannot be completely devolved to local ethical committees because many factors other than ethical matters might influence their decisions. Questions need to be raised about why a particular population was chosen, who will benefit, and who has financed the research and why. The reason that trials of antiviral agents for the treatment of HIV are liable to be unethical in African countries is that the local population is unlikely to benefit from the results of the trial because of the cost of the drug. It is unethical to conduct research on a population when the results of that research will not be of use to that population. The non-availability of standard therapy in a particular healthcare system is not sufficient grounds to make placebo control still ethical. Those who want to pursue placebo-controlled trials of one agent may have had a hand in influencing the health authorities not to make standard treatment available, as might have happened in the UK with respect to ␤-interferon for multiple sclerosis. International journals are a major bastion against unethical practice. The test is whether a journal such as The Lancet would refuse to publish a wellconducted and scientifically important study because it was unethical. A pragmatic approach suggests it would publish, giving the green light to unscrupulous investigators to travel the world looking for opportunities to conduct ethically dubious research. Simon J Ellis North Staffordshire Royal Infirmary, Keele University, Princes Road, Hartshill, Stoke-onTrent, Staffordshire, ST4 7LN, UK 1

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CAST collaborative group. CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischaemic stroke. Lancet 1997; 349: 1641–49. Ellis SJ. Interpretation of IST and CAST stroke trials. Lancet 1997; 350: 443. Gilbert M. The holocaust: the Jewish tragedy. London: Fontana Press, 1987; 687–89.

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Sir—Vigorous debate has taken place on the ethics of conducting clinical trials in the developing world.1–3 However, one fundamental issue has not been directly addressed: that the study population should benefit from the trial in which they have taken part. The HIV-1 trials clearly address the needs of developing countries, but most of their study populations will not benefit from the trials, simply because the cheaper zidovudine regimens are beyond their limited means and will probably remain so for some time to come. The clinical trials have become separated from the implementation of their findings, probably because the populations’ actual health needs and resources were not taken into account during the trial design. We believe that trialists should take responsibility for not only testing an intervention’s efficacy, but also for ensuring its local adoption once the trial is over. This approach requires collaboration between trialists, national ministries of health, and drug manufacturers. Indeed, many such collaborations already exist. The UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases is co-developing drugs for tropical diseases with the pharmaceutical industry. This collaboration should make it possible for effective drugs to be approved rapidly and made available at concessionary prices for public-sector use in affected countries.4 On occasions, pharmaceutical companies have unilaterally donated large quantities of drugs to support worldwide WHO eradication campaigns. The first was Merck Sharp & Dohme’s donation of ivermectin for onchocerciasis; a more recent example is SmithKline Beecham’s offer of albendazole for WHO’s Filariasis Control Programme. Agreements have also been set up between national drug regulatory authorities (DRA) and individual drug companies. In Sri Lanka, the manufacturer of the antibiotic, vancomycin, provides the drug at a reduced price to the local distributor in return for a guarantee that the drug will not be re-exported and sold at a profit in another country. This arrangement was set up because the local DRA was concerned that a drug considered essential in specific situations was basically unaffordable. A different form of collaboration has been developed between WHO, UNICEF, and vaccine manufacturers. In this arrangement, countries are able to buy the vaccines at prices that reflect their ability to pay. In return for

charging poor countries lower prices, the manufacturers gain a large market which could not otherwise afford the vaccines. The developed world has much to gain from clinical trials in the developing world,5 but we must not forget that the primary responsibility of any trial is to directly benefit the population in which it is being conducted. *Michael Eddleston, Krisantha Weerasuriya, Piero Olliaro *Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK; Department of Pharmacology, University of Colombo, Colombo, Sri Lanka; and UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland (e-mail: [email protected]) 1

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Halsey NA, Sommer A, Henderson DA, Black RE. Ethics and international research. Research standards are the same throughout the world; medical care is not. BMJ 1997; 315: 965–66. Aaby P, et al; DeCock K, et al; Semba RD; Cooper PA; Vaughan W. Ethics of HIV trials. Lancet 1997; 350: 1546–47. Mann JM. Leadership is a global issue. Lancet 1997; 350 (suppl III): 23. Olliaro P. Will the fight against tropical diseases benefit from orphan drug status? Trop Med Int Health 1997; 2: 113–15. Mittra I. Clinical cancer trials in developing countries. Lancet 1997; 349: 290.

Hyphenosis Sir—The Lancet is suffering from a nasty case of hyphenosis. I made a tentative diagnosis when I came across “public-health professionals” (p 591) and “practice-GPs” (p 593) in two adjacent papers (Feb 21). Supportive evidence was not hard to find; “medical-school education” (p 535), “upper-airway sphincter” (p 539), and “solid-organ transplants” (p 540). The diagnosis was clinched by the discovery of the rare “internal-mammary-artery grafts” (p 570). I was surprised that “league table” (p 555) had escaped and puzzled to see that “strip tests” and “strip-test results” (p 564) had and had not. I recognise that the hyphen can be used flexibly to join words both semantically and syntactically, but imagine that most of your readers are able to make these connections for themselves. I write, I should add, as an editor with an international reputation for the over-use of the semi-colon. Roger Jones UMDS, Department of General Practice, Division of Primary Health Care, London SE11 6SP, UK

THE LANCET • Vol 351 • April 4, 1998