Editorial III

Lessons from Stafford

J.R. Sneyd

In the early 1990s, Professor David Southall supervised paediatric research studies at North Staffordshire Hospital. Following complaints and allegations by the parents of the participating children, a review was set-up and its findings have been published.1 The process of the review and the fairness of its report have been criticized2 3 and defended.3 This editorial addresses the findings of the review and their implications for clinical research in anaesthesia.

The research

The CNEP study
A novel system for ventilation of neonates was evaluated in a randomized controlled trial against standard intensive therapy. The CNEP Ventilator applied a continuous negative extrathoracic pressure as an alternative to tracheal intubation. A report of the study, published in 1996, concluded that CNEP reduced the requirement for tracheal intubation and decreased the duration of oxygen therapy required. However, it was associated with increased mortality, cranial ultrasound abnormalities and pneumothoraces (although these increases were not statistically significant).4

The hypoxia study
This investigation simulated the effects of air travel by administering 15% oxygen to 34 healthy infants of whom 13 were the siblings of children who had died from sudden infant death syndrome.5 The children were exposed to the hypoxic gas mixture for 6.3 (2.9) h. Four children developed ‘prolonged and severe’ episodes of desaturation. It is not possible to tell from the original paper exactly how low the oxygen saturations went. The average nadir of the saturations in each child was averaged and the lowest of these averages was 67%; presumably, individual episodes involved even more severe desaturation. The authors concluded that ‘additional research is urgently needed into the effects on infants of prolonged airline flights or holidays at high altitude’.

Academic criticism of the hypoxia study
The paper was accompanied by an editorial6 and a commentary criticising the study7 and explanatory comments from the Chairman of the Ethical Committee.8 There was subsequently extensive correspondence about the study, which was criticized on ethical and scientific grounds. Air travel confers a benefit against which parents can balance the risk of hypoxaemia but the research carried no potential benefit. There is no plausible mechanism to link airway hypoxia and Sudden Infant Death Syndrome. The methods used in the study were flawed and the data underanalysed and over-interpreted. Flying involves exposure to a low atmospheric pressure; the study used a normobaric hypoxic mixture.

Other issues
The review also took evidence about other research studies and the use of covert video surveillance to diagnose cases of Munchausen Syndrome by proxy.

Evidence given to the inquiry

Allegations from parents
Several parents made allegations concerning an inadequate or incomplete consent process. Specifically, they had no recollection of giving consent to randomization. CNEP was described to them as ‘a kinder, gentler treatment whose alternative was pushing tubes down the baby’. Parents said they understood that they were consenting to a treatment but were not aware that they were consenting for entry into a research trial. Additional serious allegations included the suggestion that signatures on some consent forms may have been forged. But the review also heard evidence from another well conducted research study (of extracorporeal membrane oxygenation, ECMO9) that parents who have given well-documented consent may subsequently not recall having done so.

Evidence about research supervision
Evidence given to the review suggested that new guidelines for clinical research should be produced and supported by legislation. The duties of the Local Research Ethical Committee, LREC, should be extended to include monitoring of researchers including the receipt of regular formal reports with a formal process for accountability. An independent local medical inspectorate should be created. Arrangements should be made to follow-up research subjects after the conclusion of a study, to ensure that there are no unforeseen long-term problems. A proposal was made for a comprehensive review of research within the National Health Service.

Other proposals included log-books for individual researchers, a culture of routine self-audit amongst research teams and the use of independent third parties to obtain consent to research, particularly where this involves vulnerable groups of patients or a specially stressful situation where over-reliance on medical staff might be expected from anxious patients or relatives.

Guiding principles for those obtaining consent

The Nuremberg code
Written in 1947 in the aftermath of the war crimes tribunal, this sets the standard for obtaining consent from participants in research.10 Key points are summarized in Table 1.


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Table 1 Principles of the Nuremberg Code.10 Key principles in obtaining informed consent for research
 
The Helsinki declaration
This was adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964 and has been updated and extended at subsequent meetings.11 It extends and clarifies the Nuremberg code and interprets it in the context of biomedical research. Current proposals to update the Code are controversial.12 Of relevance to anaesthesia is the debate about using placebos in clinical trials with one ‘camp’ arguing that efficacy can only be demonstrated with reference to a placebo and the other claiming that the only ethical control group is the current best therapy. The importance of this in the conduct of antiemetic studies has been extensively debated.13 14

Good clinical practice
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry to discuss scientific and technical aspects of product registration.15 The objective of such harmonization is a more economical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines whilst maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health.

Good Clinical Practice (GCP) is a set of guidelines published by ICH in 1996 which establish standards for the conduct of clinical trials.16 These standards are in universal use by the pharmaceutical industry and have been adopted by major research funders such as the Medical Research Council. There is pressure for all ‘own account’ research to be conducted to GCP standards and whilst this is a worthy objective, those who call for this may be unaware of the resource implications for monitoring, audit and archiving.

Equipoise
Well-constructed research projects test an identifiable hypothesis. In theory, the researcher should be in a state of true equipoise, for example believing the probabilities of the hypothesis being true or false to be equal. In practice, this is virtually never true and it is frequently the case that researchers believe fervently in a particular scheme of treatment. Thus equipoise is a useful intellectual construct but is seldom encountered in practice; indeed, the ethical basis of equipoise itself has recently been questioned.17 Given that researchers will always be enthusiastic about their own projects, an alternative may lie in the use of neutral third parties to explain research projects and obtain consent without the potentially biased enthusiasm of a committed researcher. Clearly, such third parties would require training and resources and any such requirement would likely inhibit a high proportion of low-cost studies and inflate the cost of others.

Current practice for obtaining consent to anaesthesia research

Consent for anaesthesia studies
Most patients scheduled for elective in-patient surgery are admitted to hospital the day before operation or, increasingly, on the same day. The interval between admission and surgery is a busy time with clerical procedures, physical examination and investigations to be completed. Current research practice includes the approaching of patients around the time of a pre-operative anaesthesia visit. Is this appropriate? What are the implications of change?

In 1998 we reported a survey of over 200 patients who had previously taken part in clinical trials run in our department.18 Most patients (97%) were aware that participation was voluntary and that their care would not be affected by the decision to participate (98%) and that they could change their mind (83%). Only 25% would have liked longer to think about the trial and some patients made comments to the effect that knowing about the trial before admission would have caused them unnecessary worry. Overall, our data suggested that our patients had generally understood what they were consenting to with 95% describing the information supplied as an accurate description of what actually happened to them. We concluded that current practice of approaching patients shortly before surgery for participation in clinical trials of anaesthesia works well for most patients and there was little reason to make drastic changes. Indeed, to do so would grossly impair the conduct of such studies as surgical schedules are frequently changed at short notice and anaesthetists seldom have access to patients before their arrival at the hospital. Clearly, it would be wholly inappropriate to extrapolate from this data about patients undergoing elective surgical procedures to alternative environments including the labour ward and the intensive care unit.

Consent in obstetrics
Complex issues are raised when a woman is in labour. Whilst she is capable of consenting to or refusing interventions including epidural analgesia or Caesarean section, it is generally considered inappropriate to raise the question of participation in a research project for the first time during labour. It has therefore become customary to offer information about obstetric research projects to patients before they commence the labour. This may involve distribution of information at antenatal clinics or by other means. Whilst such dissemination is entirely practicable, it may have unanticipated consequences. When we offered information about a study of intrathecal diamorphine for obstetric analgesia to all women attending a hospital antenatal clinic, the result was large numbers of parturients asking to participate in the study at times when the investigators were not available with subsequent disappointment to patients who were keen to participate.19

Consent in intensive care
Most patients receiving intensive care are mentally impaired by drugs, by illness or both. Thus, this group is seldom legally competent to give informed consent for participation in a research study. Critical illness is usually unanticipated and advance consent to research is therefore impossible. How then can we obtain consent for research in intensive care? Different strategies exist which represent the interaction of national laws, investigator opinion and local ethical committees. Relatives of adult patients cannot give consent to a course of treatment; however, they may be consulted and give approval, for example assent. Courts can give consent but it is usual in the UK for participation in research to be allowed if it has been approved by the ethical committee. The assent of the patient’s relatives is not legally necessary but it is customary in most, but not all, research active intensive care units to consult with relatives before patients are enrolled.

Research supervision
It is already the responsibility of senior researchers to monitor the activities of their teams and the risk taken by those who fail to do so is well known.20

Recommendations of the inquiry

The review recommended that formal guidance on research governance be developed with agreed guidance clarifying issues of consent for participation in clinical trials. A further recommendation proposed the establishment of a surveillance system for unexpected outcomes for non-drug treatments. Whilst these recommendations have no immediate effect on clinical researchers, when pursued, they may establish further formal and elaborate procedures, which must be followed by clinical researchers. The community of clinical researchers in anaesthesia must understand the direction of these changes and, where appropriate, ensure that their implications for our studies are anticipated.

How might this affect research in anaesthesia?

Consent
Consent was the key issue in the Stafford enquiry and we should reflect on how we obtain this in our own clinical trials. Anaesthetists have limited access to patients before surgery and obtaining consent has to be opportunistic. Nevertheless we must ensure that all research subjects have adequate time to discuss participation in a study before they give consent. Does this preclude consent on the day surgery unit or at the pre-operative visit on the night before surgery? Well-organized surgical specialties may bring their patients in for ‘pre-clerking’ several days before surgery. Others construct their operating lists at the last minute making it difficult to identify and obtain informed consent from surgical patients. The imposition of mandatory ‘cooling off’ periods has the potential to impair some clinical research. The timing and process of consent must be debated between researchers and their ethical committees with individual studies considered on a case-by-case basis. Researchers should be prepared to explain and defend their procedures.

What should we include on the consent form? In recent years patient information sheets and consent forms have been improved and in some regions standardized. When devising the wording of these documents we might usefully reflect on how it would read post-hoc at an inquiry! Properly worded explanations may be as useful as a patient advocate.

Who should take consent? Before we dismiss the researcher from this role we need to be clear that any proposed alternative is an improvement. Are third parties any better? Can a ‘patient advocate’ genuinely adopt a neutral role? Perhaps we should wait for this hypothesis to be rigorously evaluated in a trial of its own. At worst, a watered down and cheaply implemented version could leave us with ill informed SHO’s or research nurses taking consent on behalf of their consultants or registrars.

Supervision
The responsibilities of researchers have been emphasized20 21 and the role of the ethical committee explained.22 At a time of intense public scrutiny of the medical profession we must be accountable for our research but who is to do the supervising? Ethics committees already monitor research but with their present resources they cannot police it. If they are to check and audit the research process they will require additional resources. What rules would determine the relationship between committee and researcher? Research ethics committees are not statutory bodies and establishment of a formal regulatory role would require legislation. These issues will need consultation before change is introduced or we may end up with unworkable law and unresourced supervisory bodies. Serving on an ethics committee is already hard work and ill-considered changes may make clinicians reluctant to participate.

Anaesthetists are well positioned to lead the debate in their own institutions. Ethical committees need advice from clinicians who understand pharmacology and who appreciate the context in which clinical research takes place. If we simply await the outcome of others deliberations we may find our research activities are crippled.

J. R. Sneyd

Department of Anaesthesia

Derriford Hospital

Plymouth

PL6 8DH

UK

References

1 NHS Executive West Midlands Regional Office. Report Of A Review Of The Research Framework In North Staffordshire Hospital NHS Trust; 2000 http://www.doh.gov.uk/wmro/northstaffs.htm

2 Smith R. Inquiring into inquiries. BMJ 2000; 321: 715–6[Free Full Text]

3 Hey E, Chalmers I, Griffiths R, Stacey TE, Struthers J. Investigating allegations of research misconduct: the vital need for due process Commentary: Response from members of the Griffiths inquiry. BMJ 2000; 321: 752–8[Free Full Text]

4 Samuels MP, Raine J, Wright T, et al. Continuous negative extrathoracic pressure in neonatal respiratory failure. Pediatrics 1996; 98: 1154–60[Abstract]

5 Parkins KJ, Poets CF, O’Brien LM, Stebbens VA, Southall DP. Effect of exposure to 15% oxygen on breathing patterns and oxygen saturation in infants: interventional study. BMJ 1998; 316: 887–91[Abstract/Free Full Text]

6 Milner AD. Effects of 15% oxygen on breathing patterns and oxygenation in infants [editorial]. BMJ 1998; 316: 873–4[Free Full Text]

7 Savulescu J. Commentary: safety of participants in non-therapeutic research must be ensured. BMJ 1998; 316: 891–2; discussion 3–4[ISI][Medline]

8 Hughes V. Commentary: ethical approval of study was warranted. BMJ 1998; 316: 892–3[ISI][Medline]

9 UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group [see comments]. Lancet 1996; 348: 75–82[ISI][Medline]

10 Anonymous. The Nuremberg Code (1947). BMJ 1996; 313: 1448[Free Full Text]

11 Anonymous. World Medical Association declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects [see comments]. JAMA 1997; 277: 925–6[ISI][Medline]

12 Rothman KJ, Michels KB, Baum M. For and against: Declaration of Helsinki should be strengthened. BMJ 2000; 321: 442–5[Free Full Text]

13 Goodman NW. Trials of postoperative antiemetics need three arms. BMJ 1999; 318: 942[Free Full Text]

14 Tramer MR, Reynolds DJM, Moore RA, McQuay HJ. When placebo controlled trials are essential and equivalence trials are inadequate. BMJ 1998; 317: 875–80[Free Full Text]

15 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. http://www.ifpma.org/ich1.html

16 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline for Good Clinical Practice. http://www.ifpma.org/pdfifpma/e6.pdf

17 Weijer C, Shapiro SH, Glass KC, Enkin MW. For and against: Clinical equipoise and not the uncertainty principle is the moral underpinning of the randomised controlled trial. BMJ 2000; 321: 756–8[Free Full Text]

18 Montgomery JE, Sneyd JR. Consent to clinical trials in anaesthesia. Anaesthesia 1998; 53: 227–30[ISI][Medline]

19 Sneyd JR, Meyer-Witting M. Intrathecal diamorphine (heroin) for obstetric analgesia. Int J Obs Anesth 1992; 1: 149–52

20 Sneyd JR. Ethics and research in anaesthesia [editorial]. Anaesthesia 1998; 53: 422–3[ISI][Medline]

21 Anonymous. Good Medical Practice. London: General Medical Council, 1995

22 Gilbertson AA. Ethical review of research [editorial]. Br J Anaesth 1999; 82: 6–7[Free Full Text]





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