THE CLINICAL TRIALS DIRECTIVE

47.  The Government acknowledged[27] traditionally "wide-spread" resistance on ethical grounds to conducting clinical trials in children, but stated that this had to be balanced by the ethical issues related to giving medicines to a population in which they had not been tested. This reflected the view in the Commission's original Explanatory Memorandum[28].

48.  Professor Chantler (pp1-2, Q 5) also acknowledged the ethical arguments against carrying out studies in children. But he pointed out that in the UK no research in children could take place without permission from a properly-constituted ethical committee. Under the proposed Regulation, paediatric investigations in children would have to be agreed by the Paediatric Committee.

49.  In many cases, he said the preparations would be researched in children who would be likely to benefit from their use. His personal view was that the Directive was sound so far as ethical issues were concerned. Most of his senior medical colleagues agreed (Q 5, Q 7).

50.  The Minister told us that the Proposal "effectively" took account of ethical concerns[29]. When we asked what this meant,[30] the Minister said that the Regulation would be based on the Clinical Trials Directive which required all clinical trials to be designed, conducted and reported in accordance with good clinical practice. This ensured that the rights, safety and well-being of participants were protected, that the results of any trials were credible, and that all medicines used in trials complied with good manufacturing practice.[31] The Directive had been implemented in the UK since 1 May 2000 and was inspected by the MHRA to ensure that the required standards were met.

51.  The Directive also set out the requirements for obtaining agreement from an ethics committee for every trial conducted in Member States. The proposed Regulation had specific cross-references to the Directive making it clear that the control and monitoring of studies in children, and the development of medicinal products for them, must comply with the Directive.

52.  The Directive also had specific requirements that:

• the ethics committee considering the trial must either have relevant paediatric expertise or take advice from persons involved in the relevant field of paediatric care;
• persons with parental responsibility or legal representatives must give informed consent to any trial involving a minor and may withdraw the minor from the trial at any time;
• the explicit wish of the minor to refuse participation in, or to be withdrawn from, a clinical trial at any time must be considered; and,
• there must be no incentives or financial inducements, other than compensation, for those taking part in the trial.

53.  Staff with experience with young persons must inform the minor involved of the risks and benefits of the trial. According to the minor's capacity to understand, they must also consider his or her explicit wish to participate or to be withdrawn from the trial at any time.

54.  The Directive also provides that:

• the clinical trial must relate directly to an illness from which the minor concerned suffers or that (sic) can only be carried out on minors;
• the trial must aim to provide some direct benefit for the group of patients involved; and,
• the interests of the patient must always prevail over those of science and society.

55.  Moreover, the clinical trial must be designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and the developmental stage of the child concerned.

56.  The Minister strongly agreed with us that the health and welfare of children must be the overriding priority in conducting paediatric trials. She assured us that unnecessary trials would not be accepted by an ethics committee. All Member States shared the British Government's view that the legislative provisions in the Regulation should be tightly drawn in this respect.

57.  She pointed out that the Paediatric Committee, which included EU health professionals from the relevant paediatric disciplines, was required to waive the requirement to conduct trials where evidence showed that the product concerned was likely to be ineffective or unsafe in part or all of the paediatric population. Waivers could also be granted where the disease or condition for which the product was intended occurred only in adult populations (for example, Alzheimer's disease). Where an appropriate product already existed, the Paediatric Committee might also decide no significant therapeutic benefit would be gained from undertaking clinical trials.

58.  If the Paediatric Committee decided that clinical trials or studies on specific products should not take place, no financial or other incentive would be given for paediatric development work to be carried out on that product.

59.  The Minister also reminded us about the deferrals procedure. This is designed to enable the Paediatric Committee to authorise products for use in adults where studies in children might take longer than studies in adults, and thus delay the introduction of the product for adults. Deferrals could also be granted where initial experience of use of the product in adults was recommended before it was studied in children.

60.  The Paediatric Committee would also be required to consider carefully the timing of any trials in children, in accordance with agreed international guidelines.

61.  Because the Regulation[32] drew on experience gained in the USA, the Regulation would require studies undertaken under the US regime to be submitted to the European Regulatory Authorities to avoid unnecessary participation of children in further trials in Europe.

62.  Both the waiver and the deferral aspects of the Proposal had the full support of Member States. No modifications had been suggested during EU discussions. But the Minister pointed out that the details of how the procedure would operate would be set out in implementing texts (guidelines) to be drawn up by the Commission in consultation with Member States. These would take account of the relevant scientific and other criteria.

63.  None of the responses to our own consultation or those to the MHRA consultation questioned the suitability of the Clinical Trials Directive as the basis for the Regulation.

64.  We conclude that the Clinical Trials Directive is an appropriate basis for this Regulation.

CONSENT

65.  We drew Professor Chantler's attention to the Minister's statement that the Clinical Trials Directive requires that a person with parental responsibility or a legal representative must give informed consent to any trial involving a minor, whereas the explicit wish of a minor to refuse participation or to be withdrawn from clinical trials "must be considered".

66.  Professor Chantler took the view that children should always be consulted. It was surprising how even very young children could understand what was in question, so long as imaginative ways of communicating with them were found. It was unacceptable to do something to any child that did not involve the child's consent. The Medical Research Council had published guidance on medical research involving children and the Department of Health had also recently published relevant advice[33]. He understood that the European Clinical Trials Committee were drafting new guidance on the ethics of studying children for the Clinical Trials Directive (Q 10, Q 11).

67.  Asked about circumstances where a child's lack of consent might need to be overridden, Professor Chantler said it was essential for the parents to be properly briefed and to give consent. If the parents agreed to a medical intervention and the child, although deemed able to give informed consent, did not, the issue would have to be referred to the Courts. He accepted that in medical intervention the essential criterion was that any action should be for the benefit of the child concerned. This did not necessarily apply to clinical trials. But where research was of no possible benefit to the child, the normal ethical requirement was to do something that was absolutely minimally invasive. He understood that the guidelines on ethical aspects of clinical trials in children which were being developed under the Clinical Trials Directive would cover such situations (QQ 13-14).

68.  We asked the Minister about this. She did not see any inconsistency in the provision. The informed consent of a parent or person with parental responsibility was an essential pre-condition of any trials. But a distinction had to be drawn between a properly-informed decision by a child and one that might be no more than a "whim" on the day concerned. That was why the Government felt children should not have an automatic veto over participation in trials (Q 51).

69.  The Minister assured us that the guidelines to be drawn up in the context of the Clinical Trials Directive would be very clear. The Government wanted to create an environment within which clinical trials would be conducted, for all the reasons that had been given, but in a very strong and robust ethical framework the details of which should become clear in the guidelines. Some decisions would probably have to be taken on a case-by-case basis
(QQ 53-56).

70.  Dr Dunne of the MHRA added that the Commission's draft guidance on the ethics of conducting clinical trials with children was expected to be released for consultation by April 2006 so that it would be in place by the time that the Regulation was adopted (QQ 54).

71.  The Minister hoped that the guidelines would also avoid the possibility that deference to children's rights might undermine the randomness essential for successful trials (Q 55).

72.  We are very troubled by this issue and not convinced from the evidence we have had that it has so far been given the necessary serious consideration. In the time available we have not been able to probe this further. But, as we see it, the ethical considerations which are likely to arise when conducting trials in children are not necessarily the same as those which arise in normal medical practice and we are not sure that the Clinical Trials Directive will cover them adequately. We accept that, where necessary, individual cases must be referred to the Courts. But we are not sure to what extent the existing law may be clear enough. The definition of informed consent and the distinction between consent and acquiescence must be interpreted clearly in relation to circumstances that are likely to arise during clinical trials.

73.  We recommend that, in drawing up the guidelines underpinning the Clinical Trials Directive, the Government should ensure that particular attention is paid to the rights and capacity of children to give informed consent to trials. The guidelines must cover adequately and clearly the vulnerability of children, the possibility of conflict between the consent of parents and children involved in trials, the definition of informed consent and the distinction between consent and acquiescence in circumstances which are likely to arise during trials involving children, as well as the extent to which any trials concerned might benefit the child in question.

AGES OF CHILDREN

74.  Bearing in mind what we had been told by Professor Chantler about the differing reactions of children to medicines, depending on age and other factors (Q 23, pp1-2), we asked the Government and whether pharmaceutical companies would be required to carry out tests on different age groups.

75.  Dr Dunne of the MHRA explained that a full programme of testing for each stage in the age range from newly-born to 18 year olds might not be necessary (QQ 40-42). Some products might well not be appropriate, for example, for the newly-born. Test information from one group might be extrapolated to other groups.

76.  Dr Dunne recognised that the newly-born were particularly vulnerable. She confirmed that some 90% of medicines given to the newly-born had not been tested for use on them. When a product was authorised for use in the paediatric population a lower age limit for safe use was usually specified. It would be quite exceptional for a blanket statement to be made authorising use in children without having a clear lower limit. This would also be made clear in the dosing information (QQ 44-47).

77.  The Minister confirmed that these aspects would be covered in the guidelines (Q 48). Dr Dunne added that the Regulation would make clear that appropriate age groups within the paediatric population should be studied. But the detail of how trials should be conducted could not be adequately covered in the Regulation. It would have to be covered by the guidelines which would be constantly revised to take account of technical advances (Q 50).

78.  We recommend that very careful consideration should also be given in the guidelines to the possible differences in the effects of medicines on children of different ages, and especially the vulnerability of the newly-born, as well other ways in which the reaction of minors may be markedly different from those of adults.

OTHER ASPECTS OF THE GUIDELINES

79.  It was clear to us from these exchanges that very careful attention will need to be paid in all other respects to getting the guidelines right, making sure they are properly understood by all the professionals concerned and kept up-to-date. We therefore asked the Minister for her officials to give us appropriate on-the-record briefing on progress in developing those guidelines after the Directive has been agreed in due course. She agreed to do so[34].

80.  In this context we were interested to see a copy of the Royal College of Paediatrics and Child Health guidelines for the ethical conduct of medical research involving children.[35] That document shows that considerable serious thought has already been given by the medical profession in this country to the ethical issues that have exercised us in this Inquiry. In our view, it will be most important to ensure that similarly serious and detailed professional consideration is given to the elaboration and updating of the guidelines related to the Regulation in a form that will be understood and implemented throughout the European Union.

81.  The draft Regulation itself offers no more than a framework for decisions based on the Clinical Trials Directive. In an understandable desire to secure that framework, we are not convinced that the Government has given a sufficient lead during the UK Presidency in focusing attention at Council level on critical ethical aspects in preparation for drawing up the all-important guidelines by which the Clinical Trials Directive will be interpreted.

82.  We conclude that, in many other respects, the ethical validity and effectiveness of the Regulation will depend as critically on the guidelines to be developed as on the text of the Directive itself. While detailed discussion of such aspects is appropriate for legal, medical and pharmaceutical experts, who must be adequately consulted, we recommend that the underlying issues of public policy should be given wider attention and political oversight. We therefore welcome the Minister's agreement that the relevant officials should give us on-the-record briefing on the progress made in developing those guidelines at an appropriate time after the Directive has been agreed by the Council.

83.  We recommend that once the guidelines are drawn up the Government should ensure that they are fully understood by the medical and pharmaceutical professions and explained to the general public.

84.  We further recommend that the Government should ensure that the guidelines are kept fully up-to-date in line with changes in medical and scientific knowledge and practice.

28   13880/04 COM (2004) 599 final  Back

29   pp 31-32 Back

30   pp 32-34 Back

31   pp 35-56 Back

32   The Government have subsequently sent us a background note on paediatric legislation in the USA
(pp 23-24). This also covers Australia and Canada where no legislative action has been taken so far, although in both countries responsible bodies have called for appropriate legislation. Back

33   Seeking Consent: working with children, published November 2001, reference 25752 Back

34   pp 57-60  Back

35   Guidelines for the ethical conduct of medical research involving children as modified and updated in 1999 by the Ethics Advisory Committee of the Royal College of Paediatrics and Child Health (reprinted as Appendix 3) Back