Mrc guidelines good clinical practice clinical trials

Whilst they should have TSC experience, they do not necessarily need to be a clinician. In either case, the process of choosing the Chair should be clear and detailed in the invitation to join the TSC. Additional trial team members and Sponsor or Funder representatives may attend the TSC to provide information only, but they are not considered members of the TSC; therefore, when a vote is required to reach a decision, these members should not be included in voting see also question 8: How should decisions be reached within the TSC?

No difference should exist between the aims of the non-independent and independent TSC members. Their relationship should be viewed as collaborative, with each member having respect for what the others contribute. Independent members offer experience, expertise, and a fresh look at the trial. On the other hand, non-independent members have an important role in the provision of in-depth knowledge of the day-to-day running of the trial.

Nevertheless, the TSC should only be considered quorate for decision-making when the number of independent members outweighs the number of voting non-independent members. However, these recommendations do not take into account the specialities that should be represented or the appropriate composition and number of members present for decision-making. To ensure that independence is maintained, the TSC independent members should not be from the same institution as the Sponsor, co-Sponsor, co-applicant, or the clinical trials unit involved in the management of the trial.

When there is potential for a perception of influence, the members should clarify that it does not prohibit them from making impartial decisions. Some UK Funders will not accept an independent TSC member if they are from the same institution as one of the investigators or recruiting sites. This criterion is potentially too restrictive, and expert panel members reported incidences where this definition was difficult to enforce and agreed that this should be a desirable criterion rather than mandatory.

Instead, they proposed that those responsible for appointing TSC members, often the Funders, should be reassured of the absence of any working relationship that would influence the decision-making of the independent TSC member. A consideration of both the appropriateness and independence of proposed independent members is required and for UK publically funded trials, this role is often taken on by the Funder and may be a condition of funding. Concerns were expressed that if a Funder has the right to both appoint and dismiss members, then the independence of the members from the Funder is compromised.

The expert panel recommended that the Sponsor, given their overall responsibility for the trial [ 9 , 10 ], should also be ultimately responsible for appointing and dismissing TSC members, an approach taken for DMC members within the ICH GCP [ 11 ].

However, it is important for all stakeholders to be confident in the expertise and independence of the proposed members. The expert panel recommended reaching agreement between stakeholders with provision of clear reasons should a stakeholder wish to reject or dismiss members. If concerns are raised about the conduct or participation of an independent member, then these concerns should be discussed in the Trial Management Group. The Chief Investigator, as Chair of the TMG, should then lead on discussions with the TSC member to give the opportunity to acknowledge difficulties and act accordingly.

If the concerns are maintained, then the decision to dismiss ultimately lies with the Sponsor. In an ideal scenario, where statistical resources are not limited, the panel agreed that the statisticians involved in the preparation of a DMC report that contains unblinded or comparative data should not be a voting member of the TSC. The key issue discussed was whether the statistician felt that their knowledge of the data in the DMC report would compromise their contributions and decision-making.

Many of the expert panel felt that this would not be the case, provided that the statistician was experienced and confident to refuse to answer questions that could lead to inferences about effectiveness or safety between treatment arms. The panel noted that the knowledge of the unblinded statistician reflected a specific data cut and, therefore, a point in time that may no longer reflect the current situation in the trial.

The discussion did not result in a firm answer but rather that the pros and cons of each circumstance should be considered; however, the panel agreed that the statistician producing the DMC report could attend the TSC meetings as an observer.

All members of the TSC should have a commitment to the trial and skills that will help them act within their role as a TSC member, including being actively involved in trials themselves. Training to ensure the future capacity of experienced members is essential.

Prior to acting as an independent member, the member should exhibit previous trials experience and acting as a non-independent member or an as observer for part of a wider trial team should be required. Members acting in an independent capacity for the first time may benefit from an independent mentor who would not attend the TSC meetings but would be bound by confidentiality and be willing to discuss issues with the appointed member. Further discussion took place specifically about the experience of the independent TSC Chairperson.

The TSC is usually established after notification of a funding award, with the first meeting of the TSC taking place between gaining ethical approval and the start of recruitment. Like the DMC, the main role of a TSC prior to trial recruitment is to agree on the way in which they will operate and to review the trial protocol. As indicated in DAMOCLES, due to the timing of this meeting, this first meeting usually involves protocol acceptance rather than proposing protocol changes. Attention should be given to the timing of the next TSC meeting following protocol acceptance; ideally, this meeting will be planned based on time elapsed rather than on patient numbers recruited.

This approach to the timing of the meeting ensures that issues with trial opening, site opening, or recruitment can be addressed. The TSC should also consider themselves to be on standby throughout the trial should important issues arise, particularly if there is a planned DMC meeting. All agreed that review and approval of the trial protocol was essential and that the terms of reference should include a statement to acknowledge that members have read and agreed on trial conduct in accordance with a specified version of the trial protocol.

Formal sign off of the protocol by the TSC, on the other hand, is not required. The expert panel debated the roles of the TSC and the DMC because the potential existed for the line between these different roles to be blurred with resulting duplication of effort. Specific reference was given to the checks of randomisation and review of baseline data split by treatment group; in this instance, the panel agreed that whilst the TSC would need to be assured that such checks had taken place, the actual completion of the checks was normally the responsibility of the DMC.

All accepted that the TSC should not view post-baseline data split by treatment group, but an exception could be made for baseline data, provided that the justification was clear and that this was agreed on in advance by both the DMC and the TSC. The panel also recommended that the TSC members are given the opportunity to comment on the proposed content of the routine DMC reports, prepared at agreed-upon stages of the trial by the trial statistician and provided to the DMC, so that the TSC members can be assured that the DMC is provided with all necessary information to check areas of concern.

During the trial, the TSC should be provided with a report that is based on the information included in the open section of the DMC report. Care should be taken to avoid unblinding of any party TSC or TMG by inclusion of data based on the timing of visits or safety profiles. The content was agreed on with some minor additions, and a suggested template is provided in Table 2. A summary of core documents that the TSC should have opportunity to comment on, together with reference documents that should be made available to the TSC, are given in Table 3.

Question 5b and 5c were not discussed in detail by the expert panel. With respect to external evidence, the panel agreed that it is the responsibility of the Chief Investigator CI and the trial team to provide information on new external evidence. There were limited examples of TSCs that cover multiple trials, and therefore, a case-by-case approach to the materials available should be taken in these circumstances, while using the suggested report content and documentation Tables 2 and 3 as a starting point for discussions.

Discussion on question 6 was limited, and the expert panel noted that it was difficult to identify examples. The panel agreed that blinding of the TSC must be maintained, and that the TSC should not request the DMC to provide opinion on matters that could be influenced by their knowledge of comparative analyses. Examples of such matters include changes to primary outcome [ 12 , 13 ], amendments to statistical analysis plans, and planned sample size.

The expert group noted that where there is no DMC, the TSC members should consider the justification and agree whether this is appropriate. Members of the TSC should only agree to membership if they are comfortable with the oversight structure in place for the trial.

This emergency DMC should include independent members, who will review the un-blinded data and make a recommendation to the TSC, however the timeframe will need to be considered.

Wherever possible, the TSC should aim to reach consensus with all members non-independent and independent on the preferred plan of action for addressing an issue. Voting may be necessary when consensus cannot be reached, but the voting rights of members should be made clear, and as already described, the number of independent members voting should outweigh the number of non-independent members.

See question 2b. The TSC can have a role in contextualising complex ethical issues and identifying an appropriate course of action. The TSC also has a role in identifying early issues that might represent ethical concerns, such as deviation from the trial protocol, unexpected events that compromise patient safety, rights or wellbeing, and the potential impact of new external information.

The panel recommends that when such issues are identified, they should be fed back to the trial team and a course of action agreed on in a case-by-case basis. For example, there may be some instances where further discussion takes place with the TSC, and a course of action is agreed on; alternatively, issues may need to be discussed with the trial Sponsor.

If considered necessary by the TSC or the trial Sponsor, then issues may also be discussed further with the Ethics Committee that provided approval for the trial. An example was given where a trial participant had received an incorrect dose of the trial treatment, which constituted a breach of protocol.

Ethical concerns were raised about whether or not to inform the patient. In this instance, the TSC were able to identify taking into account the views of the PPI contributor that the dose received by the participant was not above a standard daily dose, and that the potential worry that the patient might undergo, if informed, far outweighed any potential harms.

As a result, agreement was reached by the TSC and the trial team that the patient did not need to be informed. Here the expert panel reflected that in a situation when the DMC recommends stopping the trial for efficacy or safety, the TSC should ask the DMC whether their decision was unanimous and request that the independent TSC members be unblinded.

Should the trial continue, the unblinded TSC members do not need to be replaced, but details of who has been unblinded should be included in the meeting minutes. As noted previously, the TSC should be on standby at the time of a DMC meeting, so that if an issue arises, a meeting can be scheduled at short notice. All agreed that the process should include an escalation clause to describe how a difference of opinion on, for example, changes to the protocol or trial continuation should be managed.

Options could include referral to the Sponsor, Funder or co-opted experts. The process should be clarified and agreed on by all members within the terms of reference. The TSC should consider patient safety and data integrity and be mindful of the relationships between the trial site and investigators when making recommendations of how to progress.

Although the Funder may withdraw funding from a trial, this does not necessarily mean that the trial should stop, as the decision to stop the trial ultimately lies with the Sponsor. In the event that funding is withdrawn, the TSC should consider whether they agree with trial closure, and if not, may offer advice and guidance to the trial team on continuation and alternative sources of funding.

The expert panel noted that the response to this question would depend on the specific request and the stage of the trial. As a result, specific guidance could not be generated, but instead, the panel suggested a general process whereby requests from Funders or external bodies for information should be sent to the Chair of the TSC. However, the TSC should have the opportunity to comment on trial publications, and certainly, at a minimum, on the main trial report.

The TSC membership, name and affiliation, should be included in the acknowledgements section of publications with the permission of the members. The importance of ensuring timely reporting was echoed in the expert panel discussions who felt that the TSC had an ethical obligation to ensure that trial results were published.

Examples were given where the TSC had helped to push publication by the trial team and also an example where the trial data was taken on by the DMC and subsequently reported with the Chair of the DMC as first author. All agreed these approaches were acceptable if, without them, the trial would remain unpublished. The feasibility of an oversight committee taking on the responsibility of publishing the results of the trial, if the team fail to do so, needs further consideration.

The TSC has a role in reviewing requests for data sharing, particularly when requests, in line with the trial data sharing agreement, compete with the ongoing or planned work of the TMG. The TSC may not have a role in all requests for data sharing, only those that require careful consideration due to implications for ongoing data collection and planned analyses.

The expert panel remarked that the life span of the TSC should be taken into account when planning for future data requests. These are often submitted sometime after the trial has ended.

A decision should be made as to whether the TSC would reconvene for such decisions or would be happy to pass this onto a central committee considering such requests across a portfolio of clinical trials, for example, within a clinical trials unit.

Expert panel discussion identified further areas of uncertainty in the role and operation of the TSC. These are discussed below. In particular, they addressed whether the TSC is considered to maintain independence and continue to act as the TSC for the trial. Try out PMC Labs and tell us what you think. Learn More. Good Clinical Practice GCP is an international ethical and scientific quality standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials.

It also serves to protect the rights, integrity and confidentiality of trial subjects. It is very important to understand the background of the formation of the ICH-GCP guidelines as this, in itself, explains the reasons and the need for doing so. In this paper, we address the historical background and the events that led up to the formation of these guidelines.

Today, the ICH-GCP guidelines are used in clinical trials throughout the globe with the main aim of protecting and preserving human rights. GCP provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are respected and protected [ 1 ]. It was finalised in and became effective in , but was not enforced by law at that time. It is very important to understand the background of the formation of the ICH-GCP guidelines as this, in itself, explains the reasons and the need for doing so Table 1.

In the United States, the first landmark in the regulation of drugs was the Food and Drugs Act of This was a result of harmful and lethal drugs that could be bought across the counter just like any other consumer product. In , the Federal Food, Drug and Cosmetic Act was enacted by the Food and Drug Administration FDA and for the first time, manufacturers were required to test drugs for safety and present the evidence of safety testing to the FDA prior to marketing [ 3 ].

In , the Nuremberg Code was created as a result of the unethical and horrific experiments carried out during World War II at Nazi war camps by German physicians, who were subsequently tried and charged at the Nuremberg Military Tribunal.

This code states the need for a scientific basis in research on human subjects and voluntary consent and protection of participants [ 4 , 5 ]. The Universal Declaration of Human Rights December 10th was also adopted and proclaimed by the United Nations after the atrocities of World War II and it further reiterated the human factor involved in medical experiments.

The focus of this declaration is the protection of the rights of human subjects and this is clear in its introduction [ 6 ]:. It is the duty of the physician to promote and safeguard the health of the people. In the world was once again shocked by the severe foetal limb deformities linked to the use of maternal thalidomide.

In fact this drug reaction was only discovered after 10, infants were born in over 20 countries worldwide. In response to this, the Kefauver-Harris Amendments were passed which required the FDA to evaluate all new drugs for safety and efficacy [ 3 ].

The principles of this report are as follows:. Respect for Persons : This principle acknowledges the dignity and freedom of every person.

It requires obtaining informed consent from research subjects or their legally authorised representatives. Beneficence : This principle requires that researchers maximise benefits and minimise harms associated with research. Research-related risks must be reasonable in light of the expected benefits. Justice : This principle requires equitable selection and recruitment and fair treatment of research subjects.

This document was released to help developing countries apply the principles of the Declaration of Helsinki and the Nuremberg Code [ 3 ]. Worldwide, many organisations and committees issued various documents and guidelines on the same issue, and a decision was taken to consolidate all these guidelines into one universal guideline to be used globally. This guideline was approved on 17 July and implemented for clinical trials from 17 January The participants of these guidelines were representatives of authorities and pharmaceutical companies from the EU, Japan and the United States as well as those of Australia, Canada, the Nordic countries and WHO [ 8 ].

The ICH-GCP is a harmonised standard that protects the rights, safety and welfare of human subjects, minimises human exposure to investigational products, improves quality of data, speeds up marketing of new drugs and decreases the cost to sponsors and to the public. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected and consistent with the principles of the Declaration of Helsinki, and that the clinical trial data is credible [ 8 ].

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Accept additional cookies Reject additional cookies View cookies. Hide this message. Home Good practice, inspections and enforcement. Guidance Good clinical practice for clinical trials. Print this page. Related content Good clinical practice inspection metrics Annual review of good clinical practice referrals Good clinical practice: guidance and inspections Clinical trials: how NHS trusts and health boards can maintain compliant electronic health record systems MHRA phase I accreditation scheme Detailed guidance Good manufacturing practice and good distribution practice Collection Good clinical practice: guidance and inspections.

Explore the topic Good practice, inspections and enforcement. Is this page useful? Maybe Yes this page is useful No this page is not useful. Thank you for your feedback. Report a problem with this page. What were you doing? What went wrong? Email address. Dr Connell responded to the Infringement notice to confirm that he has relinquished his license to practice medicine in the UK and has no intentions of practicing medicine again in the UK.

Dr Connell has confirmed that if he does take part in clinical trials in the UK in the future, he will comply with the conditions of the infringement notice.

Dr Connell also confirmed that he did not retain any data or documents from the trials in question, therefore the MHRA also wish to highlight that without any retained data it is not possible to verify the conclusions published from this clinical trial.

Mrs Zirka Yousaf responded to the Infringement Notice to confirm she has implemented an SOP and checklist to ensure future work is adequately documented, will ensure future work commitments are feasible and will not outsource or subcontract work to another contractor. Mrs Zirka Yousaf has confirmed that she will comply with the conditions of the infringement notice.

MHRA has verified that there is no impact on patient safety. Therefore, sponsors have a requirement to ensure oversight of all staff working on their trials, including contractors and those that may be home based. Suitably robust contracts and adequate oversight mechanisms could identify and therefore reduce the likelihood of the non-compliances observed in this infringement notice. Dr Kerrane responded to the Infringement notice to confirm that he has undertaken further training associated with GCP , information governance and financial probity.

Dr Kerrane has confirmed that he has not taken part in clinical trial activities since and has no intentions of undertaking trial work in the future. The MHRA would like to remind investigators of the requirement to comply with the approved trial protocol to ensure the safety of trial participants and the integrity of the data collected; and trial sponsors of the need for effective monitoring.