IoPPN/SLaM R&D Protocol Guidance v16
A research protocol is a detailed set of instructions that outline the procedures for conducting a research study and collecting data. It should contain detailed information about the study design and methodology. The protocol is also a manual for the research team to ensure they adhere to the methods outlined. Generally, your protocol should include sufficient detail so that someone unfamiliar with the study would be able to use it to conduct the study in your absence, should they need to do so.
A research protocol is a mandatory document for submission to the research ethics committee.
It is important that your study design is classified correctly, and it is particularly important to identify whether or not your study is a clinical trial. Clinical trials are managed in particular ways as mandated by the Department of Health: - clinical trials now must be registered on a public trials database and NHS trusts are monitored on their recruitment performance to clinical trials.
Please see Section A for guidance on classifying your study
Please see Section B for clinical trial protocol guidance and standards
Protocol templates
Researchers within King’s Health Partners are asked to use a good quality protocol template appropriate for their study type. There are a range of protocol templates available as follows:
Clinical Trial of an Investigational Medicinal Product (CTIMP)
If you are conducting a Clinical Trial of an Investigational Medicinal Product (CTIMP) please use the KHP CTO protocol template. This is downloadable on the KHP CTO website along with their SOP on writing a GCP compliant protocol: http://www.khpcto.co.uk/SOP/gcpProtocolSOP.html
Other clinical trial (non-CTIMP)
If you are conducting a non-CTIMP clinical trial (for example a therapy randomised controlled trial) please use the King’s College London CTU clinical trial protocol template available from the IoPPN/SLaM R&D office or from the King’s Clinical Trials Unit directly
Basic science study
If you are conducting a basic science study, please use the GCP non-CTIMP protocol template available from the IoPPN/SLaM R&D office
Other research
For other research where a clinical trial or basic science protocol template is not be appropriate, please see below for details of good practice protocols which might be helpful.
https://drupal02.floridahospital.org/researchadmin/content/protocol-development-0
http://www.rch.org.au/emplibrary/cebu/Guidelines_for_writing_a_protocol.pdf
Additional guidance: for non-clinical research study designs, such as observational studies, the STROBE guidance is a useful resource: http://www.strobe-statement.org/
PRISMA statement deals with systematic reviews and meta-analysis: http://www.prisma-statement.org/
For research studies being submitted for NHS research ethics / HRA approval, please also see the following guidance on the HRA website:
‘Before you apply for approval’ http://www.hra.nhs.uk/research-community/before-you-apply/protocol/
‘HRA assessment criteria and standards’ covers what the HRA expect to be included in the protocol, IRAS form and consent documents: http://www.hra.nhs.uk/resources/hra-approval-applicant-guidance/hra-assessment-criteria-and-standards/
All Study Types: It would greatly benefit your protocol if you could include details of quality assurance of the conduct of your study using Good Clinical Practice standards and the SPIRIT statement. Although these standards relate primarily to clinical trials, where appropriate they should be used as a reference for basic science and other study types.
Details of Good Clinical / Research Practice can be found here:
- MRC guidelines https://www.mrc.ac.uk/research/policies-and-guidance-for-researchers/good-research-practice/
- KHP CTO: GCP training: http://www.khpcto.co.uk/SOP/trainingSOP.html
- MHRA (CTIMPs only) http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodClinicalPractice/
The SPIRIT statement is at the end of this guidance document
Please also see the World Health Organisation recommended format for a research protocol: http://www.who.int/rpc/research_ethics/format_rp/en/
The following points which should be included in your protocol where applicable:
· The source of study funding on the protocol, and whether anything is being provided (for example if a company is providing the study drug at no cost). For externally funded studies please include details of the funder(s). Where studies have not been awarded external funding please contact the R&D office for an R&D costings form and return this to us with your protocol.
· Where a protocol has not been scientifically reviewed by an external funder, the R&D office will organize an independent peer review. This will be done in parallel with risk assessment review. Please provide the R&D office with the names and contact details of three potential reviewers who have expertise in the area but are independent of the study. We will organise the peer review and forward the comments to you.
· Where participants will be recruited from (for example whether from the NHS, advertisement, existing registries).
· Where the consent and screening visit and subsequent study visits (post consent) will take place.
· For studies involving a drug, whether consent is taken by a medic, if not how the consent process will be properly delegated.
· For studies involving a drug, where the drug/placebo is sourced, and which pharmacy is storing and dispensing.
· An outline of risks and burdens (and a description of side effects of the study drug if applicable, including contraindications).
· Safety reporting as per NRES guidelines (http://www.hra.nhs.uk/resources/during-and-after-your-study/progress-and-safety-reporting/ or contact the R&D office for a copy of current NRES guidelines). Any safety reporting to NRES must also be copied to the sponsor via the SLaM/IoPPN R&D office.
· If you are randomizing, include the process of randomization and blinding, procedures and conditions for unblinding. (please see the Emergency out of hours code break Flow Diagram document)
· If you are taking tissue samples, include details of storage and analysis of all tissue samples (including urine, saliva, hair samples) - where they are stored and analysed and for how long, whether they are stored under an organizational Human Tissue Authority licence, who will have access to the samples in the future (including any other organisations/commercial companies).
· Details of data management – how data will be managed appropriate to the study type, including data handling and coding for computer analysis, monitoring and verification and assuring the quality of the data. Include a description of the statistical methods to be used for the data analysis, reasons for selection of the sample size and power of the study.
· For clinical trials - details of the Data and Ethics Monitoring Committee (DMEC) and Trial Steering Committee (TSC) arrangements, or the reasons if these are not being set up. For all other study types such as basic science please include an explanation of appropriate oversight arrangements.
· It would also be helpful if you could include details of quality assurance of the conduct of the study using Good Clinical Practice standards and SPIRIT statement. Although these standards relate primarily to clinical trials, where appropriate they should be used as a reference for basic science and other study types. Details of GCP and SPIRIT are on the R&D office protocol guidance.
Appendix A Classification of studies
1. Classification of clinical trials
A. Is the study potentially a Clinical trial of an investigational medicinal product (CTIMP)
If your study involves administering or analysing a drug or other substance it is essential that we determine whether or not it is a CTIMP. As a rule of thumb, this will apply if you are administering any drug or substance, or if the protocol includes anything that looks as if you are trying to find out more information about a study drug, whether or not you are administering this yourself (this includes a drug that is being used already in routine clinical care).
The MHRA provide an algorithm to assist investigators and sponsors determine whether a study is a clinical medicinal trial. Often a research study can be classified straightforwardly into CTIMP or non CTIMP. There are a small number of studies however where it this is not clear and in these cases the algorithm can be of limited use. Whether a study is a CTIMP or not is not always related to whether a drug is administered as a part of the research. The MHRA have in the past classified studies as CTIMPs where the drug involved has been administered to patients as part of their clinical care rather than being administered by the research team for the purposes of the trial. In other studies where a drug is administered by the research team but is being used as a probe in a scanning study for example, such studies have been classified as non-CTIMPs.
Where there is uncertainty about how to classify a study the R&D office consults with the KHP Clinical Trials Office, and will take their view as to whether there is a need to refer the protocol to the MHRA for a decision. It is important that we do this, as if we make the decision ourselves to classify a study as a non-CTIMP and were then to be inspected by the MHRA, it is possible that inspectors would take a different view.
Where a referral to the KHP CTO and/or MHRA is required, this can take up to 3-4 weeks. Investigators are advised to contact R&D at the earliest stage if their study might potentially be classified as a CTIMP.
B. Classification of clinical trials other than trials of medicines or devices (in line with the Health Research Authority)
The Department of Health definition of a clinical trial is as follows: A set of medical research procedures conducted on human participants to allow safety and adverse effects of interventions, their efficacy, or their effectiveness to be established often by comparison with alternative or placebo/sham interventions. Interventions may be drugs, diagnostics, prophylactics, surgery, devices, non-invasive therapies, screening or other healthcare procedures or technologies.
Clinical trials are managed in a specific way and so it is important that they are correctly classified at the outset. The HRA require clinical trials to be registered on a public trials database and for trials being conducted in the NHS their recruitment is measured against Department of Health benchmarks. This applies to trials of medicines and devices as well as other clinical trials which this section covers.
Both the HRA and the Department of Health classify clinical trials as those selecting one of the first four options on the IRAS project filter section 2:
· Clinical trial of an investigational medicinal product
· Clinical investigation or other study of a medical device
· Combined trial of an investigational medicinal product and an investigational medical device
· Other clinical trial to study a novel intervention or randomised clinical trial to compare interventions in clinical practice
This guidance covers the fourth option (Other clinical trial). The IRAS project filter guidance states that this option should be selected for clinical research not involving investigational medicinal products or medical devices. For example, this option would be appropriate for research involving:
¾ Surgery; Radiotherapy; Imaging investigations; Mental health investigations or therapies; Physiological investigations; Trials of products not defined as medicines or medical devices (e.g. nutritional); Complementary or alternative therapies
This option should be selected where a study is studying a novel intervention or randomised clinical trial to compare interventions in clinical practice and has an impact on patient clinical care. Where a study has clinical elements and doesn’t have an impact on clinical care, the next option on the IRAS project filter will be more appropriate:
· Basic science study involving procedures with human participants
This option may involve patients or healthy volunteers as participants, but the study does not affect any clinical care that the participant may be receiving. It is appropriate for scientific investigations involving procedures with participants that are additional to any clinical care, but not studying a novel clinical intervention or involving randomisation between treatment groups or any other change in existing clinical care. For example, it would be suitable for studies involving:
¾ Imaging investigations (MRI, ultrasound etc); Physical examinations; Physical tests; computer tests; Filming or photography; Sample-taking.
There are some cases where a study will have an impact on clinical care but is not studying a novel clinical intervention. In these cases it might be more appropriate to select the following IRAS project filter option:
· Other study:
This option is selected only if the research does not appear to fit any other category but might be relevant where a study does impact on clinical care but where it is not studying a novel intervention or randomised clinical trial to compare interventions in clinical practice.
Where a study impacts on patient clinical care and/or involves randomization and the investigator has classified it as a non-clinical trial, the R&D office will need to record the reasons for this, and will ask you to provide details of the rationale. Where the IRAS project filter option ‘other clinical trial’ has been selected and a decision is made to not register the study on a clinical trials database, the sponsor/CI is required to write to the HRA providing the reason for non-registration. If this is not done the study will be deemed by the HRA to be in breach of its ethics approval. Full details are on the HRA website: http://www.hra.nhs.uk/about-the-hra/our-plans-and-projects/transparency/
Appendix B Clinical trial protocol development and standards
The following guidance and standards apply to clinical trials and you are advised to refer to these when developing your clinical trial protocol.
SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) is an international initiative that aims to improve the quality of clinical trial protocols by defining an evidence-based set of items to address in a protocol. For details including the SPIRIT checklist of protocol items please see: http://www.spirit-statement.org/ and http://www.bmj.com/content/346/bmj.e7586 for an explanation and elaboration of the SPIRIT guidelines.
Please see the SPIRIT checklist below.
CONSORT (Consolidated Standards of Reporting Trials) are a set of initiatives developed by the CONSORT Group to alleviate the problems arising from inadequate reporting of randomised controlled trials. Details of the CONSORT statement, 25 item checklist for reporting trials and links to the initiatives can be found here: http://www.consort-statement.org/
There are currently nine extensions to the CONSORT statement that cover various trial designs, interventions and data (including reporting ‘harms’) which can be found here: http://www.consort-statement.org/extensions. Please also see the following article on CONSORT extensions http://annals.org/article.aspx?articleid=739590