5.2 CTIMPS - Arrangements for compliance with the Clinical Trials Regulations assessed

Introduction

The Medicines for Human Use (Clinical Trials) Regulations 2004, as amended, regulate the conduct of clinical trials of investigational medicinal products (CTIMPs) in the UK. The regulations include a number of provisions important to the protection of public health including

• good clinical practice – The requirement to conduct all CTIMPs in accordance with the principles of good clinical practice (GCP) helps ensure that all CTIMPs conducted in the UK are to the appropriate high standard and the risks to participants are minimised
• good manufacturing practice – The requirement to manufacture all investigational medicinal products (IMPs) to good manufacturing practice (GMP) standards ensures participants do not receive poor quality or badly prepared medicines
• inspections – Inspections by the Medicines and Healthcare products Regulatory Agency (MHRA) to check the study follows the principles of GCP and GMP improves the overall quality of CTIMPs conducted in the UK and identifies areas of non-compliance
• protection for incapacitated adults – There are provisions for the additional protection of adults unable to give informed consent, who should be able to participate in a CTIMP and maybe benefit from an improved condition
• protection for minors – There are provisions for additional protection of minors (i.e. persons under the age of 16) who may take part in a CTIMP
• pharmacovigilance arrangements – Investigators and Sponsors together must record safety information and report, to the MHRA, serious unexpected adverse reactions they think the IMP causes

When considering granting a Clinical Trial Authorisation (CTA), the MHRA assess the information and data relating to both the handling and safety of the IMP. The MHRA does not review the participant information sheet or review the arrangements for the monitoring or pharmacovigilance of the CTIMP (although they check for safety reporting provisions).When considering giving a favourable opinion, the NHS Research Ethics Committee (REC) reviews the participant information sheet and the overall arrangements for monitoring safety during the study.Under the regulations the Sponsor has specific responsibilities in relation to the initiation, management and financing (or arranging the financing) of a CTIMP. Study wide reviewers should ensure that the sponsor is clear how it will meet its responsibilities. The Sponsor may delegate tasks within these responsibilities to third parties or to the research site.

Conduct of the CTIMP at participating NHS/HSC organisations

The study protocol should clearly describe the conduct of the study at participating NHS/HSC organisations. It may be that the study will be conducted differently at different types of participating NHS/HSC organisations, in which case the arrangements of the conduct of the research at each of these ‘site types’ should be clearly explained. The study agreement should accurately reflect the study design as described in the protocol (and other relevant documents). If the study agreement describes something differently or in addition to the protocol, then clarification should be sought by Study Wide Reviewers from the sponsor.The Medicines for Human Use (Clinical Trials) Regulations prohibit children under the age of 16 from giving consent to take part in a CTIMP. Young people who are16 or over are presumed to be capable of giving consent on their own behalf to participate in Clinical Trials of Investigational Medicinal Products (CTIMPs). The study should clearly describe what arrangements will be in place for obtaining consent from participants assented as children upon attaining majority, should they do so whilst still participating in the research.

Management of the CTIMP at participating NHS/HSC organisations

It should be clear to participating NHS/HSC organisations how the study will be managed. This should include details regarding how the study will be monitored, processes for source data verification (including verification of the consent process and participant’s consent to take part in the CTIMP), the arrangements for the handling of the IMP and its storage, preparation and dispensing and processes for storage and archiving of trial materials such as documents and samples in a secure manner. Where these arrangements will be different at some NHS/HSC participating organisations as opposed to others this should be clearly stated.The sponsor should confirm that, in the case of Phase 1 dose escalation studies, 100% source document verification will be used to support the dose escalation decisions. In the event that alternative arrangements are proposed the sponsor should provide a justification of this.

Delegation of activities

The sponsor should clearly state whether any activities described in the protocol will be delegated, either to the participating NHS/HSC organisations or to a third party. These might include central laboratory testing, out-of-hours medical cover for safety issues and/or the specific use of sponsor provided equipment to carry out procedures.

Witnessed consent

There is no requirement under The Medicines for Human Use (Clinical Trials) Regulations 2004 for informed consent to be routinely witnessed as the decision whether an individual has been appropriately informed, and is therefore capable of giving informed consent is one that only the individual in question can make. However, the Regulations do make provision for ‘if the person is unable to sign or to mark a document so as to indicate his consent, is given orally in the presence of at least one witness and recorded in writing’. There is no requirement that this witness be impartial, and it may therefore, for example, be a member of the research team (though it should be a different individual to the one actually taking informed consent from the study participant). Witnessed consent can be seen as an important means of increasing inclusivity in clinical trials by enabling those unable to write, but otherwise fully capable of deciding to participate, to take part.

Protection for incapacitated adults

The recruitment of Adults [20] that lack capacity to consent for themselves is governed by the requirements of the Medicines for Human Use (Clinical Trials) Regulations 2004. This is applicable UK wide and supersedes the relevant nation specific legislation applicable in non-CTIMPs.Phase 1 healthy volunteers trials must not include adults unable to consent for themselves, as one of the requirements of Part 5 of Schedule 1 to the Regulations is that there are grounds for expecting that administering the investigational medicinal product will produce a benefit to the subject outweighing the risks or produce no risk at all. (This is considered incompatible with the definition of a Phase 1 trial under the Regulations.)

REC Favourable Opinion

REC favourable opinion should be sought from a REC recognised by UKECA to review CTIMPs of the relevant type. The REC does not also need to be flagged to review studies involving adults lacking capacity/adults with incapacity but is required by Regulation 15(7) of the Clinical Trials Regulations to obtain advice before giving its opinion on any trial involving adults unable to consent for themselves.Where the trial is to be conducted at one or more sites in Scotland, and the Chief Investigator is professionally based in Scotland (Scotland A REC), it should be allocated to ‘the Ethics Committee’ constituted by Scottish Ministers under the Adults with Incapacity (Scotland) Act 2000 (Scotland A REC).Only a single ethical opinion is required to cover the whole of the UK (including where this review is undertaken by Scotland A REC).

Appointment of Legal Representatives

A legal representative can be asked to give consent on behalf of an adult who lacks the capacity to do so themselves. The sponsor should explain how they will appoint and provide information to legal representatives. The process for identification of legal representatives should be clearly explained by the sponsor who should ensure that this complies with the requirements of the common law duty of confidentiality. The legal representative must be:

• told that they are being asked to give consent on behalf of the incapacitated adult,
• told that they are free to decide whether they wish to make this decision or not, and
• told that they are being asked to consider what the adult would want, and to set aside their own personal views when making this decision
• given sufficient information, in an understandable form, about the trial to ensure that they can make an informed decision

Those who are able to act as a legal representative in Clinical Trials of Investigational Medicinal Products (CTIMPs), in England, Wales and Northern Ireland are:

1. personal legal representative i.e. a person not connected with the conduct of the trial who is suitable to act as the legal representative by virtue of their relationship with the adult and is available and willing to do so
2. if a personal legal representative is not available then a Professional legal representative i.e. a doctor responsible for the medical treatment of the adult if they are independent of the study, or a person nominated by the healthcare provider may be utilised

Those who are able to act as a legal representative in Clinical Trials of Investigational Medicinal Products (CTIMPs), in Scotland are:

1. personal legal representative i.e. Adult's Welfare Guardian or Welfare Attorney, or if not appointed: The adult's nearest relative [21]
2. if neither are reasonably contactable the researchers may approach a Professional legal representative i.e. a doctor responsible for the medical treatment of the adult if they are independent of the study, or a person nominated by the healthcare provider

Provision of Information to participants who lack capacity

Even if they are unable to consent for themselves participants should be provided with information about the study, its risks, and benefits, according to their capacity of understanding. If, at any time the participant expresses a view, in any way (which may not necessarily be verbally) that they do not wish to take part in the research, this view must be acted upon.

Emergency Research

In the UK the law allows adults not able to consent for themselves to be recruited into Clinical Trials of Investigational Medicinal Products (CTIMPs) without prior consent in emergency situations if (in addition to the other requirements of the Medicines for Human Use (Clinical Trials) Regulations:

1. treatment needs to be given urgently, and
2. it is also necessary to take urgent action to administer the drug (IMP) for the purposes of the trial, and
3. it is not reasonably practicable to obtain consent from a legal representative, and
4. the procedure is approved by an NHS Research Ethics Committee, and
5. consent is sought from a legal representative as soon as possible

Should an individual recruited in such a manner die before consent can be sought from a legal representative the sponsor should consider its position in relation to the Common Law duty of Confidentiality. If the research, in an emergency setting, can be considered as only one option (among several) by which care can be provided then the processing of identifiable patient data for the purpose of delivering that care is covered by the legal basis of necessity. The sponsor should consider whether, further processing for research purposes, for example completion of CRF’s requires the processing of personal identifiable data, or whether such processing can be conducted using data which is only identifiable to the care team (and otherwise anonymised such that the Common Law duty of Confidentiality no longer applies). Where this is not possible the sponsor should explain what alternative legal basis will be relied upon.

Arrangements for compliance with the further requirements of the Medicines for Human Use (Clinical Trials) Regulations 2004 in relation to adults that lack capacity to consent for themselves

The sponsor should

1. state what clinical condition the participants in the trial will have, explain how the proposed trial relates directly to this condition and explain why the trial could not be carried out as effectively if confined to adults capable of giving consent
2. detail the grounds for expecting that administering the medicinal product to be tested in the trial will produce a benefit to the subject outweighing the risks or produce no risk at all
3. detail the risk threshold and explain how the degree of distress will be defined and constantly monitored
4. refrain from offering any incentives or financial inducement to the participant or their legal representative, except provision for compensation in the event of injury or loss

Protection for minors

The Medicines for Human Use (Clinical Trials) Regulations prohibit children under the age of 16 from giving consent to take part in a CTIMP. The sponsor should be clear what arrangements will be put in place to seek appropriate consent to include individuals under the age of 16 in the trial, where appropriate. Where individuals will reach the age of 16 during the trial the sponsor should explain what arrangements are in place to take consent from these individuals at this time and provide appropriate documentation for this purpose.

Study-wide considerations

• has the sponsor explained how the study will be conducted and managed at different participating NHS/HSC organisations, taking into account differences between the activities undertaken at these organisations and the different ‘site types’ participating in the research?
• has the sponsor explained how the study will be monitored, including whether this will be remote or in person, including details regarding source document verification (which should be 100% in Phase 1 escalation studies), the arrangements for the handling of the IMP and its storage, preparation and dispensing and processes for storage and archiving of trial materials such as documents and samples in a secure manner
• has the appropriate study agreement been selected based on the design of the study and does the proposed agreement accurately reflect the study arrangements? If the study agreement describes something differently or in addition to the protocol, then clarification should be provided by the sponsor
• where the study proposes to recruit children has the sponsor put appropriate arrangements in place to take consent from the appropriate legal parties (such as parent or legal representative). Where children will reach 16 during the course of the research what arrangements has the sponsor made to obtain consent (if they will still be involved in the study)
• has the sponsor stated whether any activities will be delegated and are these reflected in the proposed contract arrangements (where applicable)?
• has the sponsor made appropriate arrangements for witnessed consent (where applicable)? If they have the sponsor should provide an explanation regarding why this is considered necessary and detail the relevant practical arrangements, including how the impartial witness will be identified (including if this will have any resource implications for participating NHS/HSC organisations) and how will it be known that the potential participant gives their informed consent for the purposes of audit and monitoring purposes
• in relation to Adults that lack capacity to consent for themselves:
  • has the sponsor made provision for appropriate ethical review (including where review by Scotland A REC is required)? Has the sponsor provided relevant information to facilitate this review, including:
    • whether the trial be carried out equally effectively if confined to adults capable of giving consent?
    • whether the trial relates directly to the clinical condition of the participants
    • what benefit is provision of the IMP is expected to have for the study participants and does the trial involve any foreseeable risk or burden for these participants, or interfere in any way with their freedom of action or privacy?
  • does the process for the identification of legal representatives comply with the common law duty of confidentiality?
  • has the sponsor made appropriate arrangements for the provision of information to legal representatives and has appropriate documentation been provided for this purpose?
  • has the sponsor explained what information will be provided to participants, according to their capacity of understanding? Where the sponsor does not propose to provide any such information an appropriate justification should be provided
  • where the sponsor proposes to recruit in an emergency setting has the sponsor
    • explained why this is necessary
    • made appropriate arrangements to seek consent from Legal Representatives, or the study participant themselves, as soon as possible
    • explained how data will be processed in accordance with the common law duty of confidentiality, particularly in circumstances where the participant dies before consent from a Legal Representative can be obtained
    • obtained favourable opinion for the proposed procedures from a recognised REC
  • has the sponsor made arrangements to offer any incentives or financial inducement to the participant or their legal representative? If so, except in the case of provision for compensation in the event of injury or loss. study wide reviewers should challenge this as such payments are prohibited by the Regulations
  • does the protocol (or other relevant document) have appropriate processes in place for who will make the decision on whether participants have capacity to consent for themselves

Pharmacy Assurance

Although not required for regulatory purposes HRA Pharmacy assurance is in place to provide a central technical pharmacy review. This is a process to support identified NHS/HSC sites’ pharmacy departments to assess whether they can participate in the research by providing information to sites to support their assessment of Capacity and Capability/NHS/HSC permission therefore supporting study set up.The review is completed by the lead nation. In Scotland and Northern Ireland, the review is completed as part of national SW processes, though in England and Wales it is optional. The aim in England, Northern Ireland and Wales is for the review to start prior to the IRAS submission and for it to be completed by the point of the HRA/HCRW Initial Assessment letter being sent to the applicant, though sometimes the review can still be ongoing after this point. In Scotland the coordinated pharmacy review process is started after the IRAS submission is made.Reviewers in all nations should record in their UK SW review whether the study is in receipt of a nationally coordinated Pharmacy Assurance or whether it is still going through the process. Pharmacy Assurance does not need to be in place before the SW review is complete.It is important for SW reviewers to ascertain whether the study is being or has been processed through Pharmacy Assurance so that confirmation of this can be included in the relevant correspondence. In England and Wales this confirmation should be provided to the REC in the Initial Assessment for REC form, as well as to participating NHS organisations in the HRA/HCRW Initial Assessment and Approval letters.A Pharmacy Assurance flag will be visible in HARP if the study has been or is going through Pharmacy Assurance, and the confirmation of Pharmacy Assurance email will also be uploaded to the study documents. SW reviewers should be aware that it may take up to a day after import of the application into HARP for the Pharmacy Assurance flag and confirmation email to be made available as this is done manually.Any queries regarding the Pharmacy Assurance can be addressed to the lead nation:Scotland - gram.nrspcc@nhs.scotNorthern Ireland - pharmacytechnicalassurance@hscni.netEngland or Wales - pharmacy.assurance@hra.nhs.ukAs Pharmacy Assurance is optional in England and Wales, no action needs to be taken if the applicant has not submitted through this route.