CONSENTING CHILDREN for Clinical Trials Helen.hill@rlc.nhs.uk CHIP Trial 10 th December 2007

1. CONSENTING CHILDREN for Clinical Trials Helen.hill@rlc.nhs.uk CHIP Trial 10th December 2007

2. Legal Issues

3. Consent and Clinical Trials Medicines for Human Use (Clinical Trials) Regulations 2004 Schedule 1 part 1 paracraph (3) 1 A person gives informed consent to take part in a clinical trial only if his decision is given freely after that person is informed of the nature, significance, implications and risks of the trial; European Union Clinical Trials Directive 2001/20/EC Written consent must be given by parents or those with legal responsibility for the child, but children should also give their assent (the voluntary permission given by one who is old enough to understand and know if they want to take part or not) DOH Seeking Consent working with children 2001 consent to be valid: Capacity - Capable of taking that particular decision (competent) Voluntary - not under pressure duress of anyone Informed - enough information to make the decision

4. Medicines for Human Use (Clinical Trials Regulations) 2004 Informed consent in clinical trialsS.I.2004:1031 as amended by S.I.2006:1928 and S.I.2006:2984. • Good Clinical Practice legal requirement part 4 eg 20 elements Minors Clinical Trials – Minor person under age 16 years ‘special protection’ • Not included if the same results can be obtained using persons capable of giving consent. • Normally included only when IMP direct benefit to the patient, outweighing the risks. BUT • Need for clinical trials involving children to improve the treatment available to them. • Medicinal products which are likely to be of significant value for children are fully studied. • Carried out under conditions affording the best possible protection for the subjects

5. Continued…. Conditions and Principles - • ‘6’ information according to capacity to understand from staff with experience with minors • ‘8’ No incentives of financial inducements. • ’13’. Informed consent by parent/ legal representative shall represent the minor’s presumed will. • ’16’ The interests of the patient always prevail over those of science and society.

6. Parental Responsibility Children’s Act 1989 - Part 1 Responsibilities for Children • Married Parents • Unmarried mother • Unmarried father if acquired by agreement order in accordance with the provisions of this Act. • Residence order (part 1 8,& 12 the father or another person) • Local Authority if the child is in care ( Part 1 section 31 & 33) Adoption and Children Act 2002 • Unmarried father if registered on birth certificate (effective from Dec 2003 – but not if born before 2003) N.B new born may not yet have a birth certificate

7. Hierarchy of informed consent for a minorMedicines for Human Use Clinical Trial Regulation (2004) • Parent or person with parental responsibility - should always be approached if available. • Personal legal representative – emergency situations only person not connected with the conduct of the trial who is: • (a) suitable to act as the legal representative by virtue of their relationship with the minor, and • (b) available and willing to do so. • May be approached if no person with parental responsibility can be contacted prior to the proposed inclusion of the minor, by reason of the emergency nature of the treatment provided as part of the trial. • Professional legal representative • A person not connected with the conduct of the trial who is: • (a) the doctor primarily responsible for the medical treatment of the minor, or may be approached if no person suitable to act as a personal legal representative is available. • (b) a person nominated by the relevant health care provider (e.g. an acute NHS Trust or Health Board).

8. Capacity and Children • Assessing Capacity - Mental Capacity Act 2005 (2006) 4 aspects: • Understand the information relevant to a decision • Retain that information • Use or weigh the information as part of the process of making a decision ‘typically interpreted as “orientated in reality”. • Be able to communicate the decision • Good practice to involve their families in decision making. • A person with parental responsibility can take that decision for them until aged 18 yrs • Best Interest - Clinician can provide treatment and care • Age under 16years are not presumed to be legally competent unless they have sufficient understanding and intelligence to enable him or her to understand fully • No specific lower age it depends on the seriousness and complexity of the treatment being proposed. • Consented for a trial then must be reconsented at 18years

9. Child’s Capacity ‘competence’ ‘a minor can provide valid consent provided they are competent ie of sufficient intelligence and understanding to understand what is proposed (House of Lords) Consent to TreatmentGillick v west Norfolk and Wisbech AHA 1985 Refusal of Treatment if Gillick Competent • Refused treatment for anorexia • Lord Donaldson drew an analogy between consent and a flak jacket to protect medics from civil or criminal action.. ‘a competent minor can provide this protection but so too can the patients parents or the courts’ and treatment was authorised in best interests. • The result of this case means that a competent minor cannot always refuse treatment where consent has been provided from an alternative legally valid source. • BUT No test case for clinical trials • Clinical Trials Consent if the child refuses is difficult to argue ‘best interest’

10. Practicalities

11. ICH GCP (4.8.5) ‘The Investigator or a person designated by the investigator should fully inform the subject and the written informed consent form should be signed and dated by the person who conducted the informed consent discussion’

12. Involves research Purpose of the trial Treatment and the probability of random assignment Trial procedures Subjects responsibility Experimental aspects of the trial Risks or Inconveniences – including the nursing infant Expected benefits – especially when no intended clinical benefit to the subject Alternative treatments available Compensations available for trial related activity 20 Elements of informed consent ICH 4.8.10

13. Prorated payment (just adults) • Expenses • Voluntary participation in the trial may withdraw at any time • Must agree to direct access to medical records • Trial records will be kept confidential • Will be informed of any new information in a timely manner • Contact person • Reasons for termination of participation • Expected duration of participation • Approximate number of subjects involved in the trial

14. Information - oral and written Information Sheet parent + age <5 / 6-12/ 13- 15 years NRES use information sheet to guide your ‘informed consent’ • Ample time – deemed to be 24 hours but • - situation dependent (emergency) • No –coercion also not obliged • Check their understanding • Signed and dated by subject (or witnessed) • Consent form filed: study site file patient copy medical records Plus trial co-ordinating centre if requested (recently agreed) • Continuous Process – during intervention and follow up - pre admission and post admission

15. ‘Researchers …should see the giving of informed consent as a process, not as an event; regular updates and reinforcement increase parental understanding and facilitate continuous participation.. The informed consent process is not merely reading and signing a form, but it a continuous dialogue which takes place over time'. Yeung 2007

16. Improving the Quality of consent to RCT by using Continuous ConsentAllmark and Mason 2006 • Toby Trial – neonatal asphyxia treated with full body cooling 34oC • Continuous consent – information given at 3 different stages • Consented within 6 hours of birth • Mothers ‘validity’ affected by opoids /traumatic birth /very sick infant • Findings: • 48% no knowledge of side effects before signing • 13% did not recall receiving an information sheet before signing • Validity 73% mothers 8% fathers problems at signing • Reduced to 24% mothers and 15% fathers at later stage • Recommends informed consent as a process

17. Nurses Consenting

18. ‘Confident Competent and Delegated’ and ‘willing’ Confident & Competent • Audit trail for training in consent, GCP and protocol > • UKCRN course on 16th January 2007 or on line • Specified qualifications in protocol +/- i.e. ENB 415 • Assessed by Principal Investigator • Aware of the risks and responsibilities Delegated • Delegation Log or specific Trust Documentation > • Ethics Form SSA states persons consenting • CV on Site Master File ELIGIBILITY ‘The medical care given to and medical decisions made of behalf of subjects shall always be the responsibility of an appropriately qualified doctor‘ MHU(CT)Regulatio 2004 MHRA expect a medic to make the eligibility decision and to record it!!

20. Nurses Consenting • Royal College of Nursing Indemnify Nurses for clinical trials but not the trial not phase 1 First into man studies - ? unlicensed or off label see Informed Consent in Health and Social Care Research 2006 • NMC legal advisors – Professional Code of Conduct - accountability ‘ delegated to suitably qualified person’ (Declaration of Helsinki) • Medicines forHumanUseRegulatoryAgency Regulation (2004:1031) adequate training re protocol and GCP delegated formally by investigator *physician answers medical questions the nurse cannot answer procedure approved by ethics *subjects capacity – if in doubt then a physician must consent

21. UKCRN • Training- in the protocol and consent with Audit Trail GCP/Consent law & process / clinical skills Investigational Medicinal Product SOP’s Nature, significance implications risks & benefits Treatment choices Serious adverse events Process of taking informed consent (focus on legislation pertinent to vulnerable ‘paediatric populations’ Knowledge and experience to allow the participant to make a fully informed choice about participating in the trial Documented training in relevant laws Regulations and GCP (data protection and confidentiality)

22. Consenting for IMP’s12 Key Points on Consent the law in England DOH ‘you may seek consent on behalf of a colleague if you are capable of performing the procedure in question or if you have been specifically trained to seek consent for that procedure’. This resolves the concern that a nurse may not take consent in relation to a clinical trial for a drug that she may not prescribe.

23. Ensure: • Trial protocol & SOP – adhere to what they say • Trust Consent Policy – preferably state ‘Clinical Trials IMP’s’ - specific delegation form • Trust R & D Governance Approval (protocol) • Research Ethics Committee Approval (consenters listed on SSA) • Delegation log PI ensure written evidence of education and training (CV’s +) • Person taking consent must sign the consent form (RCN)

24. Document the process……………….Continuous Negative Extra-thoracic Pressure Professor Southall Carl and Debbie Henshall, of Clayton in Staffordshire, recently won an Appeal Court hearing which said the GMC should review its decision to reject their complaints that doctors did not give properly informed consent to medics for their girls to take part. ‘None of the investigations has supported parents' claims they were misled and consent forms forged’

25. CHIP TRIAL

26. CHIP – effective consent Capacity - Post admission parents distressed /traumatised Ample time - pre admission clinics Parental Responsibility to consent & Child’s competence to assent Informed – Risks balanced against benefits > parents Adult study Van den Berghe Trial 2001 Benefits of patients in studies + additional monitoring MCRN – Paediatric Regulations EU need for studies - Adoption process Unlicensed and off label Use information sheet as a guide (consider parents initialling) Make a checklist for each patient and sign yourself Translators or Interpreters Voluntary – empowers parents to have control to withdraw at anytime / choice Data Protection – if not a member of the clinical team consider Caldicott - patient information from Consultant

27. Allmark & Mason 2007 ‘Our main concern was whether it would have side effects, that was our main concern; any side effects and we wouldn’t have given our consent.’ (Father: 11) For other parents, the situation may have seemed so severe that side effects were of little importance to them: ‘We fully understood what he wanted to do in terms of treatment … we fully understood the side effects if there was going to be any, or the risks involved, but obviously whatever anyone tells you all you listen to is that your child is damaged’ (Mother: 2)

28. Promote the Trial within the team • Research Team and Clinical Team recruit up to day 5 -eligibility V – Ventilated I - Inotropes T – Twelve hours minimum on PICU A - Arterial Line L 5 Less than 5 days since admission • Retrieval Team /Transport • Document clearly what you /they have said (follow info sheet) • If legal action a nurse will be scrutinised more than a Principal Investigator • Document the person has refused to avoid ‘over asking’

29. A patient refusing to give their consent to a trial is not a sign that you have failed but it may indicate that you were conscientious enough to ensure that they are properly informed to make a free decision. • Large numbers of patients refusing may indicate a problem with the study. (BMJ 1995;311:734-737 16 September)

30. Articles • DOHwww.doh.gov.uk/consent • Seeking consent working with children 2001 • Good Practice in consent implementation guide consent to examination or treatment 2001 RCN Informed Consent in health and social care research 2006 NRES www.nres.npsa.nhs.uk Yeung V Paediatric Drug Handling (2007) Pharmaceutical Press 1st edition p 86-119 P Allmark and S Mason Improving the quality of consent to RCT by using continuos consent and clinical training in the consent process J Med Ethics 2006 32: 439 -443